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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK65916_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK65916_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK65916_"><span class="title" itemprop="name">Chronic Myelogenous Leukemia Treatment (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Adult Treatment Editorial Board</span>.</p><p class="small">Published online: April 2, 2015.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000062876__412">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000062876__413">This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000062876__1"><h2 id="_CDR0000062876__1_">General Information About Chronic Myelogenous Leukemia (CML)</h2><div id="CDR0000062876__224"><h3>Incidence and Mortality</h3><p id="CDR0000062876__175">Estimated new cases and deaths from CML in the United States in 2015:[<a class="bk_pop" href="#CDR0000062876_rl_1_1">1</a>]</p><ul id="CDR0000062876__176"><li class="half_rhythm"><div>New cases: 6,660.</div></li><li class="half_rhythm"><div>Deaths: 1,140.</div></li></ul><p id="CDR0000062876__234">CML is one of a group of diseases called the
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myeloproliferative disorders. Other related entities include the following: </p><ul id="CDR0000062876__233"><li class="half_rhythm"><div>Polycythemia vera.</div></li><li class="half_rhythm"><div>Myelofibrosis.</div></li><li class="half_rhythm"><div>Essential thrombocythemia.</div></li></ul><p id="CDR0000062876__235">(Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062927/">Chronic Myeloproliferative Neoplasms Treatment</a> for more information.) </p></div><div id="CDR0000062876__380"><h3>Molecular Biology and Cytogenetics of CML</h3><p id="CDR0000062876__3">CML is a clonal disorder that is usually easily diagnosed
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because the leukemic cells of more than 95% of patients have a distinctive
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cytogenetic abnormality, the Philadelphia chromosome (Ph1).[<a class="bk_pop" href="#CDR0000062876_rl_1_2">2</a>,<a class="bk_pop" href="#CDR0000062876_rl_1_3">3</a>] The Ph1
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results from a reciprocal translocation between the long arms of
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chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors.[<a class="bk_pop" href="#CDR0000062876_rl_1_4">4</a>]
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This translocation results in the transfer of the Abelson (ABL) on chromosome 9 oncogene to an
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area of chromosome 22 termed the breakpoint cluster region (<i>BCR</i>).[<a class="bk_pop" href="#CDR0000062876_rl_1_4">4</a>] This, in
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turn, results in a fused <i>BCR/ABL</i> gene and in the production of an abnormal
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tyrosine kinase protein that causes the disordered myelopoiesis found in CML.
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Furthermore, these molecular techniques can now be used to supplement
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cytogenetic studies to detect the presence of the 9;22 translocation in
|
|
patients without a visible Ph1 (Ph1-negative).
|
|
</p></div><div id="CDR0000062876__381"><h3>Prognosis and Survival</h3><p id="CDR0000062876__382">Ph1-negative CML is a poorly defined
|
|
entity that is less clearly distinguished from other myeloproliferative
|
|
syndromes. Patients with Ph1-negative CML generally have a poorer response to treatment
|
|
and shorter survival than Ph1-positive patients.[<a class="bk_pop" href="#CDR0000062876_rl_1_5">5</a>] Ph1-negative patients who have <i>BCR/ABL</i>
|
|
gene rearrangement detectable by Southern blot analysis, however, have prognoses
|
|
equivalent to Ph1-positive patients.[<a class="bk_pop" href="#CDR0000062876_rl_1_6">6</a>,<a class="bk_pop" href="#CDR0000062876_rl_1_7">7</a>]</p></div><div id="CDR0000062876__383"><h3>Diagnosis</h3><p id="CDR0000062876__78"> A small subset of patients have <i>BCR/ABL</i>
|
|
detectable only by reverse transcriptase–polymerase chain reaction (RT–PCR),
|
|
which is the most sensitive technique currently available. Patients with RT–PCR evidence of the <i>BCR/ABL</i> fusion gene appear clinically and prognostically
|
|
identical to patients with a classic Ph1; however, patients who are
|
|
<i>BCR/ABL</i>-negative by RT–PCR have a clinical course more consistent with chronic
|
|
myelomonocytic leukemia, which is a distinct clinical entity related to myelodysplastic
|
|
syndrome.[<a class="bk_pop" href="#CDR0000062876_rl_1_6">6</a>,<a class="bk_pop" href="#CDR0000062876_rl_1_8">8</a>,<a class="bk_pop" href="#CDR0000062876_rl_1_9">9</a>] Fluorescent <i>in situ</i> hybridization of the <i>BCR/ABL</i> translocation can be performed on the bone marrow aspirate or on the peripheral blood of patients with CML.[<a class="bk_pop" href="#CDR0000062876_rl_1_10">10</a>]
|
|
</p><p id="CDR0000062876__178">At the time of diagnosis of patients with CML, splenomegaly is the most common finding on physical examination.[<a class="bk_pop" href="#CDR0000062876_rl_1_10">10</a>] The spleen may be enormous, filling most of the abdomen and
|
|
presenting a significant clinical problem, or the spleen may be only minimally
|
|
enlarged. In about 10% of patients, the spleen is neither palpable nor
|
|
enlarged on splenic scan.
|
|
</p><p id="CDR0000062876__86">The median age of patients with Ph1-positive CML is 67 years.[<a class="bk_pop" href="#CDR0000062876_rl_1_11">11</a>] While the median survival used to be 4 to 6 years, with the advent of the new oral therapies, the median survival is expected to approach normal life expectancy for most patients, although it is still too soon to say this definitively.
|
|
</p></div><div id="CDR0000062876_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_1_1">American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. <a href="http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed October 30, 2015.</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_2">Kurzrock R, Kantarjian HM, Druker BJ, et al.: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138 (10): 819-30, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12755554" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12755554</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_3">Goldman JM, Melo JV: Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med 349 (15): 1451-64, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14534339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14534339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_4">Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11071626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11071626</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_5">Onida F, Ball G, Kantarjian HM, et al.: Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer 95 (8): 1673-84, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12365015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12365015</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_6">Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood 78 (1): 205-11, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/2070054" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2070054</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_7">Cortes JE, Talpaz M, Beran M, et al.: Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer 75 (2): 464-70, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7812917" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7812917</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_8">Oscier DG: Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Br J Haematol 92 (3): 582-6, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8616021" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8616021</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_9">Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11387365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11387365</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_10">Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/23090888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23090888</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_1_11">Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9738555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738555</span></a>]</div></li></ol></div></div><div id="CDR0000062876__6"><h2 id="_CDR0000062876__6_">Stage Information for CML</h2><p id="CDR0000062876__7">Bone marrow sampling is done to assess cellularity, fibrosis, and cytogenetics.
|
|
The Philadelphia chromosome (Ph1) is usually more readily apparent in marrow
|
|
metaphases than in peripheral blood metaphases; in some cases, it may be
|
|
mashed and reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescent <i>in situ</i> hybridization analyses on blood or marrow aspirates may be necessary to demonstrate the 9;22
|
|
translocation.
|
|
</p><p id="CDR0000062876__9">Histopathologic examination of bone marrow aspirate demonstrates a shift in the
|
|
myeloid series to immature forms that increase in number as patients progress
|
|
to the blastic phase of the disease. The marrow is hypercellular, and
|
|
differential counts of both marrow and blood show a spectrum of mature and
|
|
immature granulocytes similar to that found in normal marrow. Increased
|
|
numbers of eosinophils or basophils are often present, and sometimes
|
|
monocytosis is seen. Increased megakaryocytes are often found in the marrow,
|
|
and sometimes fragments of megakaryocytic nuclei are present in the blood,
|
|
especially when the platelet count is very high. The percentage of lymphocytes
|
|
is reduced in both the marrow and blood in comparison with normal subjects, and
|
|
the myeloid/erythroid ratio in the marrow is usually greatly elevated. The
|
|
leukocyte alkaline phosphatase enzyme is either absent or markedly reduced in
|
|
the neutrophils of patients with chronic myelogenous leukemia (CML).[<a class="bk_pop" href="#CDR0000062876_rl_6_1">1</a>]
|
|
</p><p id="CDR0000062876__10">Transition from the chronic phase to the accelerated phase and later the blastic
|
|
phase may occur gradually over a period of 1 year or more, or it may appear
|
|
abruptly (blast crisis). The annual rate of progression from chronic phase
|
|
to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent
|
|
years.[<a class="bk_pop" href="#CDR0000062876_rl_6_2">2</a>,<a class="bk_pop" href="#CDR0000062876_rl_6_3">3</a>] Signs and symptoms commonly indicating such a change include the following:
|
|
</p><ul id="CDR0000062876__81"><li class="half_rhythm"><div>Progressive leukocytosis.</div></li><li class="half_rhythm"><div>Thrombocytosis or thrombocytopenia.</div></li><li class="half_rhythm"><div>Anemia. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062734/#CDR0000062734__20">Fatigue</a> for more information on anemia.) </div></li><li class="half_rhythm"><div>Increasing and painful splenomegaly or hepatomegaly.</div></li><li class="half_rhythm"><div>Fever. </div></li><li class="half_rhythm"><div>Bone pain. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062738/">Pain</a> for more information.)</div></li><li class="half_rhythm"><div>Development of destructive bone lesions.</div></li><li class="half_rhythm"><div>Thrombotic or bleeding
|
|
complications. </div></li></ul><p id="CDR0000062876__82">In the accelerated phase, differentiated cells persist,
|
|
though they often show increasing morphologic abnormalities, and increasing
|
|
anemia and thrombocytopenia and marrow fibrosis are apparent.[<a class="bk_pop" href="#CDR0000062876_rl_6_1">1</a>]</p><p id="CDR0000062876__11">Studies have suggested that certain presenting features have prognostic
|
|
significance.
|
|
The following are predictive of a shorter chronic phase:
|
|
</p><ul id="CDR0000062876__83"><li class="half_rhythm"><div>Increased splenomegaly.</div></li><li class="half_rhythm"><div>Older age.</div></li><li class="half_rhythm"><div>Male gender.</div></li><li class="half_rhythm"><div>Elevated serum lactate
|
|
dehydrogenase.</div></li><li class="half_rhythm"><div>Cytogenetic abnormalities in addition to the Ph1.[<a class="bk_pop" href="#CDR0000062876_rl_6_4">4</a>]</div></li><li class="half_rhythm"><div>A
|
|
higher proportion of marrow or peripheral blood blasts.</div></li><li class="half_rhythm"><div>Basophilia.</div></li><li class="half_rhythm"><div>Eosinophilia.</div></li><li class="half_rhythm"><div>Thrombocytosis.</div></li><li class="half_rhythm"><div>Anemia.</div></li></ul><p id="CDR0000062876__84"> Predictive models using multivariate analysis have been derived.[<a class="bk_pop" href="#CDR0000062876_rl_6_2">2</a>,<a class="bk_pop" href="#CDR0000062876_rl_6_3">3</a>,<a class="bk_pop" href="#CDR0000062876_rl_6_5">5</a>-<a class="bk_pop" href="#CDR0000062876_rl_6_8">8</a>]</p><p id="CDR0000062876__87"><b><div class="milestone-start" id="CDR0000062876__12"></div>Chronic-phase CML</b></p><p id="CDR0000062876__13">Chronic-phase CML is characterized by bone marrow and cytogenetic findings as described above with
|
|
less than 10% blasts and promyelocytes in the peripheral blood and bone marrow.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000062876_rl_6_9">9</a>]
|
|
</p><p id="CDR0000062876__88"><b><div class="milestone-start" id="CDR0000062876__14"></div>Accelerated-phase CML</b></p><p id="CDR0000062876__15">Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone
|
|
marrow.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000062876_rl_6_9">9</a>]
|
|
</p><p id="CDR0000062876__89"><b><div class="milestone-start" id="CDR0000062876__16"></div>Blastic-phase CML</b></p><p id="CDR0000062876__17">Blastic-phase CML is characterized by 20% or more blasts in the peripheral blood or bone marrow.
|
|
</p><p id="CDR0000062876__18">When 20% or more blasts are present in the face of fever, malaise, and
|
|
progressive splenomegaly, the patient has entered blast crisis.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000062876_rl_6_9">9</a>]
|
|
</p><p id="CDR0000062876__90"><b><div class="milestone-start" id="CDR0000062876__79"></div>Relapsing CML</b></p><p id="CDR0000062876__80">Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:</p><ul id="CDR0000062876__101"><li class="half_rhythm"><div>Increasing myeloid or blast cells in the peripheral blood or bone marrow.</div></li><li class="half_rhythm"><div>Cytogenetic positivity when previously cytogenetic-negative.</div></li><li class="half_rhythm"><div>FISH positivity for <i>BCR/ABL</i> (breakpoint cluster region/Abelson) translocation when previously FISH-negative.</div></li></ul><p id="CDR0000062876__102">Detection of the <i>BCR/ABL</i> translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000062876_rl_6_10">10</a>]</p><div id="CDR0000062876_rl_6"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_6_1">Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/23090888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23090888</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_2">Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63 (4): 789-99, 1984. [<a href="https://pubmed.ncbi.nlm.nih.gov/6584184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6584184</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_3">Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25 (1): 49-61, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3279515" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3279515</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_4">Fabarius A, Leitner A, Hochhaus A, et al.: Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118 (26): 6760-8, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22039253" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22039253</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_5">Kantarjian HM, Smith TL, McCredie KB, et al.: Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood 66 (6): 1326-35, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/3864497" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3864497</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_6">Sacchi S, Kantarjian HM, Smith TL, et al.: Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia. J Clin Oncol 16 (3): 882-9, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9508169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9508169</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_7">Hasford J, Pfirrmann M, Hehlmann R, et al.: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90 (11): 850-8, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9625174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9625174</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_8">Kvasnicka HM, Thiele J, Schmitt-Graeff A, et al.: Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. J Clin Oncol 19 (12): 2994-3009, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11408494" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11408494</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_9">Cortes JE, Talpaz M, O'Brien S, et al.: Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 106 (6): 1306-15, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16463391" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16463391</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_6_10">Martinelli G, Iacobucci I, Rosti G, et al.: Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol 17 (3): 495-502, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16403813" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16403813</span></a>]</div></li></ol></div></div><div id="CDR0000062876__19"><h2 id="_CDR0000062876__19_">Treatment Option Overview for CML</h2><p id="CDR0000062876__232">Treatment of patients with chronic myelogenous leukemia (CML) is usually initiated when the
|
|
diagnosis is established, which is done by the presence of an elevated white
|
|
blood cell (WBC) count, splenomegaly, thrombocytosis, and identification of the <i>BCR/ABL</i> (breakpoint cluster region/Abelson) translocation.[<a class="bk_pop" href="#CDR0000062876_rl_19_1">1</a>] The optimal frontline treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves specific inhibitors of the <i>BCR/ABL</i> tyrosine kinase.</p><p id="CDR0000062876__21"> In a randomized trial comparing imatinib mesylate with interferon plus cytarabine, with 5 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in more than 80% of newly diagnosed patients; in addition, the annual rate of progression to accelerated phase or blast crisis dropped from 2% to less than 1% in the fourth year on the imatinib arm.[<a class="bk_pop" href="#CDR0000062876_rl_19_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335131/" class="def">Level of evidence: 1iiDiii</a>] However, most of these continually responding patients still showed detectable evidence of the <i>BCR/ABL</i> translocation by the most sensitive measurement of reverse transcriptase–polymerase chain reaction (RT–PCR).[<a class="bk_pop" href="#CDR0000062876_rl_19_3">3</a>-<a class="bk_pop" href="#CDR0000062876_rl_19_5">5</a>] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Although evidence-based survival advantages are unavailable because of crossover in randomized trials, the overall survival rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML.[<a class="bk_pop" href="#CDR0000062876_rl_19_6">6</a>] </p><p id="CDR0000062876__225">Tyrosine kinase inhibitors with greater potency and selectivity than imatinib for <i>BCR/ABL</i> have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients comparing nilotinib with imatinib, the rate of major molecular response at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (<i>P</i> < .0001 for both comparisons).[<a class="bk_pop" href="#CDR0000062876_rl_19_7">7</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587983/" class="def">Level of evidence: 1iiDiv</a>] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression occurred in only two patients (<1%, <i>P</i> = . 0003) and in five patients (<1.8%, <i> P</i> = .0089), respectively, on two-dose schedules of nilotinib.[<a class="bk_pop" href="#CDR0000062876_rl_19_7">7</a>] </p><p id="CDR0000062876__226">Similarly, in a randomized, prospective study of 519 patients comparing dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib (<i>P</i> < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib (<i>P</i> < .0001).[<a class="bk_pop" href="#CDR0000062876_rl_19_8">8</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587983/" class="def">Level of evidence: 1iiDiv</a>] Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) on imatinib and in six patients (2.3%) on dasatinib (not statistically different).[<a class="bk_pop" href="#CDR0000062876_rl_19_8">8</a>]</p><p id="CDR0000062876__230">Although one of these two studies showed statistically significant decreased rates of progression to accelerated or blastic phase, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm this prolonged survival with these agents. The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.[<a class="bk_pop" href="#CDR0000062876_rl_19_9">9</a>]</p><p id="CDR0000062876__159"> The only consistently successful curative treatment of CML beyond 10 years' follow-up has been allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT).[<a class="bk_pop" href="#CDR0000062876_rl_19_10">10</a>] Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the <i>BCR/ABL </i> translocation by any available test (e.g., cytogenetics, RT–PCR, or fluorescent <i>in situ</i> hybridization [FISH]). Many patients, however, are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, substantial morbidity and mortality result from allogeneic BMT or SCT; a 15% to 30% treatment-related mortality can be expected, depending on whether a donor is related and on the presence of mismatched antigens.[<a class="bk_pop" href="#CDR0000062876_rl_19_10">10</a>] </p><p id="CDR0000062876__85">Long-term data are also available for patients treated with interferon alpha.[<a class="bk_pop" href="#CDR0000062876_rl_19_11">11</a>-<a class="bk_pop" href="#CDR0000062876_rl_19_13">13</a>] Approximately 10% to 20% of these patients have a complete cytogenetic response with no evidence of <i>BCR/ABL</i> translocation by any available test, and the majority of these patients are disease free beyond 10 years.[<a class="bk_pop" href="#CDR0000062876_rl_19_10">10</a>] Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.
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</p><p id="CDR0000062876__68">Newly diagnosed patients with very high levels of circulating leukocytes (WBC >100,000/mm<sup>3</sup>) require immediate therapy with imatinib mesylate to avoid cerebrovascular events or death from leukostasis. Leukophoresis and plateletpheresis are sometimes required for an even more emergent reduction of counts.</p><div id="CDR0000062876_rl_19"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_19_1">Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/23090888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23090888</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_2">Druker BJ, Guilhot F, O'Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355 (23): 2408-17, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17151364" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17151364</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_3">Bhatia R, Holtz M, Niu N, et al.: Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101 (12): 4701-7, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12576334" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12576334</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_4">Hughes TP, Kaeda J, Branford S, et al.: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349 (15): 1423-32, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14534335" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14534335</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_5">Rosti G, Martinelli G, Bassi S, et al.: Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 103 (6): 2284-90, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14645009" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14645009</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_6">Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108 (6): 1835-40, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16709931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16709931</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_7">Kantarjian HM, Hochhaus A, Saglio G, et al.: Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12 (9): 841-51, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21856226" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21856226</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_8">Kantarjian HM, Shah NP, Cortes JE, et al.: Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119 (5): 1123-9, 2012. [<a href="/pmc/articles/PMC4916556/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4916556</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22160483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22160483</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_9">Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010. [<a href="/pmc/articles/PMC3000369/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3000369</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21108851" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21108851</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_10">Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9738555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738555</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_11">Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood 82 (10): 2975-84, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8219189" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8219189</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_12">Kantarjian HM, Smith TL, O'Brien S, et al.: Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 122 (4): 254-61, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7825760" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7825760</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_19_13">Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 92 (5): 1541-8, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9716581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9716581</span></a>]</div></li></ol></div></div><div id="CDR0000062876__26"><h2 id="_CDR0000062876__26_">Chronic-Phase CML</h2><div id="CDR0000062876__257"><h3>Treatment Options for Chronic-Phase CML</h3><ol id="CDR0000062876__258"><li class="half_rhythm"><div><a href="#CDR0000062876__259">Targeted therapy with tyrosine kinase inhibitors</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062876__271">High-dose therapy followed by allogeneic bone marrow transplant (BMT) or stem cell transplantation (SCT)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062876__283">Hydroxyurea</a>.</div></li><li class="half_rhythm"><div>Splenectomy may be required and useful in patients having hematologic
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problems and physical discomfort from a massive spleen.</div></li></ol><div id="CDR0000062876__259"><h4>Targeted therapy with tyrosine kinase inhibitors </h4><p id="CDR0000062876__261">A trial randomly assigning 1,106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented a 76% complete cytogenetic response rate with imatinib mesylate versus 14% for interferon plus cytarabine at a median follow-up of 19 months.[<a class="bk_pop" href="#CDR0000062876_rl_26_1">1</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335131/" class="def">Level of evidence: 1iiDiii</a>] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase chronic myelogenous leukemia (CML) or blast crisis compared with 91.5% of the interferon plus cytarabine group (<i>P</i> < .001). Because 90% of the combination group had switched to imatinib by 18 months (mostly because of intolerance of side effects), a survival difference may never be observed. By the 5-year median follow-up of this trial, imatinib mesylate induced complete cytogenetic response in more than 80% of the participants, with the annual rate of progression to accelerated-phase CML or blast crisis dropping from 2% in the first year to less than 1% in the fourth year.[<a class="bk_pop" href="#CDR0000062876_rl_26_2">2</a>] In addition, the overall survival (OS) rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. More than 90% of completely responding patients still show detectable evidence of the <i>BCR/ABL</i> translocation, usually by reverse transcription-polymerase chain reaction (RT–PCR) or by fluorescence <i>in situ</i> hybridization of progenitor cell cultures.[<a class="bk_pop" href="#CDR0000062876_rl_26_3">3</a>-<a class="bk_pop" href="#CDR0000062876_rl_26_5">5</a>] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Poor compliance is the predominant reason for inadequate molecular response to imatinib.[<a class="bk_pop" href="#CDR0000062876_rl_26_6">6</a>]</p><p id="CDR0000062876__262">Tyrosine kinase inhibitors with greater potency and selectivity for BCR/ABL than imatinib have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients that compared nilotinib with imatinib, the rate of major molecular response at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (<i>P</i> < .0001 for both comparisons).[<a class="bk_pop" href="#CDR0000062876_rl_26_7">7</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587983/" class="def">Level of evidence: 1iiDiv</a>] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, <i>P</i> = .0003) and in five patients (1.8%, <i>P</i> = .0089), respectively, for those patients on two-dose schedules of nilotinib.[<a class="bk_pop" href="#CDR0000062876_rl_26_7">7</a>] Nilotinib-treated patients had a lower rate of treatment-emergent BCR/ABL mutations than did imatinib-treated patients.[<a class="bk_pop" href="#CDR0000062876_rl_26_8">8</a>]</p><p id="CDR0000062876__263">Similarly, in a randomized, prospective study of 519 patients that compared dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib (<i>P</i> < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib (<i>P</i> < .0001).[<a class="bk_pop" href="#CDR0000062876_rl_26_9">9</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587983/" class="def">Level of evidence: 1iiDiv</a>] Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) on imatinib and in six patients (2.3%) on dasatinib (not statistically different).[<a class="bk_pop" href="#CDR0000062876_rl_26_9">9</a>]</p><p id="CDR0000062876__264">Although one of these two studies showed statistically significant decreased rates of progression to accelerated- or blastic-phase CML, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm prolonged survival with these agents. In randomized prospective trials (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=550175" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT00471497</a> and <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=558511" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT00481247</a>), nilotinib and dasatinib show higher rates of earlier molecular response compared with imatinib; whether this will translate to improved long-term outcomes is unclear.[<a class="bk_pop" href="#CDR0000062876_rl_26_10">10</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_11">11</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587983/" class="def">Level of evidence: 1iiDiv</a>] The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.[<a class="bk_pop" href="#CDR0000062876_rl_26_12">12</a>]</p><p id="CDR0000062876__398">A <i>BCR/ABL</i> transcript level of less than 10% in patients after 3 months of treatment with a specific tyrosine kinase inhibitor is associated with the best prognosis in terms of failure-free survival, progression-free survival (PFS), and OS.[<a class="bk_pop" href="#CDR0000062876_rl_26_10">10</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_11">11</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_13">13</a>-<a class="bk_pop" href="#CDR0000062876_rl_26_16">16</a>] However, in a retrospective analysis, even patients with a <i>BCR/ABL</i> transcript level greater than 10% after 3 months of therapy did well when the halving time was less than 76 days.[<a class="bk_pop" href="#CDR0000062876_rl_26_17">17</a>] Mandating a change of therapy based on this 10% transcript level at 3 to 6 months is problematic because 75% of patients do well even with a suboptimal response.[<a class="bk_pop" href="#CDR0000062876_rl_26_18">18</a>]</p><p id="CDR0000062876__265">Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors (such as dasatinib or nilotinib, and allogeneic SCT) are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[<a class="bk_pop" href="#CDR0000062876_rl_26_19">19</a>-<a class="bk_pop" href="#CDR0000062876_rl_26_23">23</a>] Dose escalation of imatinib can be considered for patients with suboptimal response, but clinical trials are required to establish the relative efficacy and sequencing of dose escalation versus the use of dasatinib or nilotinib.[<a class="bk_pop" href="#CDR0000062876_rl_26_20">20</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_21">21</a>] Two studies looked at dose escalation of imatinib in almost 200 previously untreated patients, most of whom were of intermediate Sokal risk; 63% to 73% achieved a major molecular response by 18 to 24 months and only three patients showed progression to advanced phase in these preliminary phase II results.[<a class="bk_pop" href="#CDR0000062876_rl_26_24">24</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_25">25</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] Until randomized studies are performed, it is unclear whether the increased response with increased dosage will translate into longer durations of response or survival advantages.[<a class="bk_pop" href="#CDR0000062876_rl_26_22">22</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_26">26</a>]</p><p id="CDR0000062876__385">A single-center, retrospective analysis of 483 patients with chronic phase CML who were treated with imatinib (400 mg or 800 mg daily), dasatinib, or nilotinib indicated that patients who have better than 35% t(9;22)+ cells at 3 months of therapy have inferior event-free, transformation-free, and OS rates compared with patients who have better early cytogenetic responses.[<a class="bk_pop" href="#CDR0000062876_rl_26_27">27</a>]</p><p id="CDR0000062876__267">Among the many unanswered questions are the following:</p><ul id="CDR0000062876__268"><li class="half_rhythm"><div>Will responses on tyrosine kinase inhibitors be durable beyond 10 years, and can we ever stop treatment with them? In a prospective, nonrandomized study, Stop Imatinib (STIM) (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=554895" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT00478985</a>), 100 patients in complete molecular remission stopped imatinib after more than 2 years of therapy; by 1 year, 61% of patients relapsed and all responded to the reintroduction of imatinib.[<a class="bk_pop" href="#CDR0000062876_rl_26_28">28</a>] Longer follow-up is required to see if some patients maintain a long-term remission after discontinuation of therapy. The same investigators have shown in the According to Stop Imatinib (A-STIM) study that molecular remission can be re-established anecdotally after restarting therapy.[<a class="bk_pop" href="#CDR0000062876_rl_26_29">29</a>]</div></li><li class="half_rhythm"><div>Should the newer tyrosine kinase inhibitors dasatinib or nilotinib replace imatinib as frontline therapy?</div></li><li class="half_rhythm"><div>Does time-to-response matter if a good response is obtained eventually?</div></li><li class="half_rhythm"><div>Does a good response in a high-risk patient overcome the adverse prognosis of the high-risk
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features?</div></li><li class="half_rhythm"><div>What is the role of allogeneic BMT or SCT for younger, eligible patients and when should it be offered?[<a class="bk_pop" href="#CDR0000062876_rl_26_30">30</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_31">31</a>]</div></li><li class="half_rhythm"><div>Should other active agents be added to therapy with tyrosine kinase inhibitors?[<a class="bk_pop" href="#CDR0000062876_rl_26_32">32</a>]</div></li></ul><p id="CDR0000062876__269">All of these issues have led to an active reappraisal of recommendations for optimal frontline therapy for chronic-phase CML.</p></div><div id="CDR0000062876__271"><h4>High-dose therapy followed by allogeneic BMT or SCT</h4><p id="CDR0000062876__272">The only consistently successful curative treatment of CML has been high-dose therapy followed by allogeneic BMT or SCT.[<a class="bk_pop" href="#CDR0000062876_rl_26_33">33</a>] Patients younger than 60 years with an identical twin or with
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HLA-identical siblings can be considered for BMT early in the chronic phase. Although the procedure is associated with
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considerable acute morbidity and mortality, 50% to 70%
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of patients transplanted in the chronic phase survive 2 to 3 years, and the
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results are better in younger patients, especially those younger than 20 years.
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The results of patients transplanted in the accelerated and blastic phases of the
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disease are progressively worse.[<a class="bk_pop" href="#CDR0000062876_rl_26_34">34</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_35">35</a>] Most transplant series suggest improved survival when the
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procedure is performed within 1 year of diagnosis.[<a class="bk_pop" href="#CDR0000062876_rl_26_36">36</a>-<a class="bk_pop" href="#CDR0000062876_rl_26_38">38</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] The data supporting early transplant, however, have never been confirmed in controlled
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trials. In a randomized, clinical trial, disease-free survival and OS were
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comparable when allogeneic transplantation followed preparative therapy with
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cyclophosphamide and total-body irradiation (TBI) or busulfan and
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cyclophosphamide without TBI. The latter regimen was associated with less
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graft-versus-host disease and fewer fevers, hospitalizations, and hospital
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days.[<a class="bk_pop" href="#CDR0000062876_rl_26_39">39</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.[<a class="bk_pop" href="#CDR0000062876_rl_26_40">40</a>
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,<a class="bk_pop" href="#CDR0000062876_rl_26_41">41</a>]</p><p id="CDR0000062876__273">About 20% of otherwise eligible CML patients lack a suitably matched sibling
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donor.[<a class="bk_pop" href="#CDR0000062876_rl_26_42">42</a>] HLA-matched unrelated donors or donors mismatched at one-HLA antigen
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can be found for about 50% of eligible participants through the National Marrow
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Donor Program.[<a class="bk_pop" href="#CDR0000062876_rl_26_42">42</a>] A retrospective review of 2,444 patients who received myeloablative allogeneic SCT showed OS at 15 years of 88% (95% confidence interval [CI], 86%–90%) for sibling-matched transplant and of 87% (95% CI, 83%–90%) for unrelated donor transplant.[<a class="bk_pop" href="#CDR0000062876_rl_26_43">43</a>] The cumulative incidences of relapse were 8% (95% CI, 7%–10%) for sibling-matched transplant and 2% (95% CI, 1%– 4%) for unrelated donor transplant.[<a class="bk_pop" href="#CDR0000062876_rl_26_43">43</a>]</p><p id="CDR0000062876__274"> Although the majority of relapses occur within 5 years
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of transplantation, relapses have occurred for as long as 15 years following BMT.[<a class="bk_pop" href="#CDR0000062876_rl_26_44">44</a>] In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable <i>BCR/ABL</i> transcript by PCR analysis.[<a class="bk_pop" href="#CDR0000062876_rl_26_45">45</a>]
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The risk of relapse appears to be less in patients transplanted early in
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disease and in patients who develop chronic graft-versus-host disease.[<a class="bk_pop" href="#CDR0000062876_rl_26_35">35</a>,<a class="bk_pop" href="#CDR0000062876_rl_26_46">46</a>]
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</p><p id="CDR0000062876__275">With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or SCT has been cast in doubt.[<a class="bk_pop" href="#CDR0000062876_rl_26_31">31</a>] Allogeneic SCT is the preferred choice for patients presenting with accelerated-phase or blast-phase disease, for patients with a <i>T3151</i> mutation (resistant to currently available tyrosine kinase inhibitors), and for patients with complete intolerance to the pharmacologic options.[<a class="bk_pop" href="#CDR0000062876_rl_26_47">47</a>] </p><p id="CDR0000062876__340">In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched, related donor underwent early allogeneic SCT while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched, unrelated-donor transplant in remission.[<a class="bk_pop" href="#CDR0000062876_rl_26_48">48</a>] With a 9-year median follow-up, survival still favored the drug treatment arm (<i>P</i> = .049), but most of the benefit was early as a result of transplant-related mortality, with the survival curves converging by 8 years.[<a class="bk_pop" href="#CDR0000062876_rl_26_48">48</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>] Among the many unanswered questions are the following:</p><ul id="CDR0000062876__276"><li class="half_rhythm"><div>Should younger eligible patients move quickly toward allogeneic SCT after induction failure by imatinib mesylate? </div></li><li class="half_rhythm"><div>Does the substantial toxicity and mortality of allogeneic transplantation render its early use obsolete? </div></li></ul><p id="CDR0000062876__277">Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.</p></div><div id="CDR0000062876__386"><h4>Tyrosine kinase inhibitor-resistant CML</h4><p id="CDR0000062876__387">For patients resistant to several tyrosine kinase inhibitors, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of BCR/ABL) has shown a hematologic response rate of 67% and a median PFS of 7 months in a small, phase II study of 46 patients.[<a class="bk_pop" href="#CDR0000062876_rl_26_49">49</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>]</p></div><div id="CDR0000062876__283"><h4>Hydroxyurea</h4><p id="CDR0000062876__284">Hydroxyurea is given daily by mouth (1–3 g per day as a single dose on
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an empty stomach). Hydroxyurea is superior to busulfan in the chronic phase of
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CML, with significantly longer median survival and significantly fewer severe
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adverse effects.[<a class="bk_pop" href="#CDR0000062876_rl_26_50">50</a>] A dose of 40 mg/kg per day is often
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used initially and frequently results in a rapid reduction of the white blood
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cell (WBC) count. When the WBC count drops below 20,000 mm<sup>3</sup>,
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the hydroxyurea is often reduced and titrated to maintain a WBC count between
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5,000 and 20,000. Hydroxyurea is
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currently used primarily to stabilize patients with hyperleukocytosis or as
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palliative therapy for patients who have not responded to other therapies.</p></div></div><div id="CDR0000062876__TrialSearch_26_sid_4"><h3>Current Clinical Trials</h3><p id="CDR0000062876__TrialSearch_26_10">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=39069&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">chronic phase chronic myelogenous leukemia</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062876__TrialSearch_26_18">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div><div id="CDR0000062876_rl_26"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_26_1">O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/15998838" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15998838</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_41">Bacher U, Klyuchnikov E, Zabelina T, et al.: The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia--a report from the German Registry covering the period from 1998 to 2004. Ann Hematol 88 (12): 1237-47, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19319532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19319532</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_42">Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9738555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738555</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_43">Goldman JM, Majhail NS, Klein JP, et al.: Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol 28 (11): 1888-95, 2010. [<a href="/pmc/articles/PMC2860369/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2860369</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20212247" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20212247</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_44">Maziarz R: Transplantation for CML: lifelong PCR monitoring? Blood 107 (10): 3820, 2006.</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_45">Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107 (10): 4171-6, 2006. [<a href="/pmc/articles/PMC1895293/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1895293</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16449534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16449534</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_46">Pichert G, Roy DC, Gonin R, et al.: Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 13 (7): 1704-13, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7602361" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7602361</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_47">O'Brien S, Berman E, Moore JO, et al.: NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia. J Natl Compr Canc Netw 9 (Suppl 2): S1-25, 2011. [<a href="/pmc/articles/PMC4234100/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4234100</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21335443" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21335443</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_48">Hehlmann R, Berger U, Pfirrmann M, et al.: Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109 (11): 4686-92, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17317858" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17317858</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_49">Cortes J, Digumarti R, Parikh PM, et al.: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 88 (5): 350-4, 2013. [<a href="/pmc/articles/PMC5558840/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5558840</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23468307" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23468307</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_26_50">Hehlmann R, Heimpel H, Hasford J, et al.: Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood 82 (2): 398-407, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8329700" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8329700</span></a>]</div></li></ol></div></div><div id="CDR0000062876__38"><h2 id="_CDR0000062876__38_">Accelerated-Phase CML</h2><div id="CDR0000062876__285"><h3>Treatment Options for Accelerated-Phase CML</h3><ol id="CDR0000062876__286"><li class="half_rhythm"><div>Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT). In 132 patients with accelerated-phase chronic myelogenous leukemia (CML), a cohort study compared imatinib as first-line therapy versus allogeneic SCT; with a median follow-up of 32 months, overall survival was improved using allogeneic SCT for the Sokal high-risk patients (100% vs. 17.7%; <i>P </i>= .008).[<a class="bk_pop" href="#CDR0000062876_rl_38_1">1</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] Sokal low- and intermediate-risk patients showed no survival differences starting with either approach. Induction of remission using a tyrosine kinase inhibitor followed by an allogeneic SCT, when feasible, is a standard approach for patients with accelerated-phase CML.[<a class="bk_pop" href="#CDR0000062876_rl_38_1">1</a>] </div></li><li class="half_rhythm"><div>Imatinib mesylate. Among 176 patients with accelerated-phase CML, the complete hematologic response was 82%, and the complete cytogenetic response was 43%; with a median follow-up of 41 months, the estimated 4-year survival was 53%.[<a class="bk_pop" href="#CDR0000062876_rl_38_2">2</a>] Other tyrosine kinase inhibitors need to be evaluated as first-line therapy in accelerated-phase CML.</div></li><li class="half_rhythm"><div> Interferon alpha.[<a class="bk_pop" href="#CDR0000062876_rl_38_3">3</a>] Although the response rate is lower for accelerated-phase disease than it is for chronic-phase disease, durable responses and
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suppression of cytogenetic clonal evolution have been reported.[<a class="bk_pop" href="#CDR0000062876_rl_38_3">3</a>,<a class="bk_pop" href="#CDR0000062876_rl_38_4">4</a>] When
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cytarabine was added to interferon alpha, in comparison to historical controls
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of interferon alone, the response rate and 3-year survival appeared to be
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improved in late-stage patients.[<a class="bk_pop" href="#CDR0000062876_rl_38_4">4</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]
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</div></li><li class="half_rhythm"><div>High-dose cytarabine.[<a class="bk_pop" href="#CDR0000062876_rl_38_5">5</a>]
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</div></li><li class="half_rhythm"><div>Hydroxyurea.
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</div></li><li class="half_rhythm"><div> Busulfan.
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</div></li><li class="half_rhythm"><div>Supportive transfusion therapy.
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</div></li></ol><p id="CDR0000062876__104">Patients with accelerated-phase CML show signs of progression without meeting the criteria for blast crisis (acute leukemia). Symptoms and findings include the following:</p><ul id="CDR0000062876__105"><li class="half_rhythm"><div>Increasing fatigue and malaise. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062734/">Fatigue</a> for more information.)</div></li><li class="half_rhythm"><div>Progressive splenomegaly.</div></li><li class="half_rhythm"><div>Increasing leukocytosis and/or thrombocytosis.</div></li><li class="half_rhythm"><div>Worsening anemia.</div></li></ul><p id="CDR0000062876__106"> Bone marrow examination shows increasing blast cell percentage (but ≤30%) and basophilia. Additional cytogenetic abnormalities occur during the accelerated phase (trisomy 8, trisomy 19, isochromosome 17Q, p53 mutations or deletions), and the combination of hematologic progression plus additional cytogenetic abnormalities predicts for lower response rates and a shorter time-to-treatment failure on imatinib mesylate.[<a class="bk_pop" href="#CDR0000062876_rl_38_6">6</a>] At 1 year after the start of imatinib, the failure rate is 68% for patients with both hematologic progression and cytogenetic abnormalities, 31% for patients with only hematologic progression, and 0% for patients with cytogenetic abnormalities only. Before the availability of imatinib, the median survival time of accelerated-phase CML patients was less than 1 year.[<a class="bk_pop" href="#CDR0000062876_rl_38_6">6</a>]</p></div><div id="CDR0000062876__TrialSearch_38_sid_5"><h3>Current Clinical Trials</h3><p id="CDR0000062876__TrialSearch_38_10">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=39070&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">accelerated phase chronic myelogenous leukemia</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062876__TrialSearch_38_18">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div><div id="CDR0000062876_rl_38"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_38_1">Jiang Q, Xu LP, Liu DH, et al.: Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 117 (11): 3032-40, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21252092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21252092</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_38_2">Kantarjian H, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience. Cancer 103 (10): 2099-108, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15830345" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15830345</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_38_3">Cortes J, Talpaz M, O'Brien S, et al.: Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol 16 (10): 3279-85, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9779702" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9779702</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_38_4">Kantarjian HM, Keating MJ, Estey EH, et al.: Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 10 (5): 772-8, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1569449" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1569449</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_38_5">Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 10 (3): 398-405, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1740679" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1740679</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_38_6">O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12176881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12176881</span></a>]</div></li></ol></div></div><div id="CDR0000062876__48"><h2 id="_CDR0000062876__48_">Blastic-Phase CML</h2><div id="CDR0000062876__287"><h3>Treatment Options for Blastic-Phase CML</h3><ol id="CDR0000062876__288"><li class="half_rhythm"><div>Imatinib mesylate, dasatinib, and nilotinib have demonstrated activity in patients with
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myeloid blast crisis and lymphoid blast crisis or Philadelphia
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chromosome–positive acute lymphoblastic leukemia.[<a class="bk_pop" href="#CDR0000062876_rl_48_1">1</a>,<a class="bk_pop" href="#CDR0000062876_rl_48_2">2</a>]
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Two trials of imatinib mesylate and one trial of dasatinib involving a total of 518 patients in blastic-phase chronic myelogenous leukemia (CML) confirm a hematologic response rate of 42% to 55% and a major cytogenetic response rate of 16% to 25%, but the estimated 2-year survival rate is under 28%.[<a class="bk_pop" href="#CDR0000062876_rl_48_2">2</a>-<a class="bk_pop" href="#CDR0000062876_rl_48_4">4</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with blastic-phase CML.[<a class="bk_pop" href="#CDR0000062876_rl_48_5">5</a>] </div></li><li class="half_rhythm"><div>Vincristine and prednisone with or without an anthracycline is another treatment option (for the
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approximately 25% of patients with terminal deoxynucleotidyl transferase-positive cells and lymphoblastic transformation).[<a class="bk_pop" href="#CDR0000062876_rl_48_6">6</a>,<a class="bk_pop" href="#CDR0000062876_rl_48_7">7</a>]
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</div></li><li class="half_rhythm"><div>Allogeneic bone marrow transplantation (BMT) represents the only potentially curative
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approach in these patients. Allogeneic BMT is more effective in
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patients induced into a second chronic phase.
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</div></li><li class="half_rhythm"><div>Hydroxyurea as palliative therapy.
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</div></li><li class="half_rhythm"><div>High-dose cytarabine.[<a class="bk_pop" href="#CDR0000062876_rl_48_8">8</a>]</div></li></ol></div><div id="CDR0000062876__TrialSearch_48_sid_6"><h3>Current Clinical Trials</h3><p id="CDR0000062876__TrialSearch_48_10">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=39071&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">blastic phase chronic myelogenous leukemia</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062876__TrialSearch_48_18">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div><div id="CDR0000062876_rl_48"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_48_1">Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11287973" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11287973</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_2">Saglio G, Hochhaus A, Goh YT, et al.: Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116 (16): 3852-61, 2010. [<a href="/pmc/articles/PMC4993589/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4993589</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20564086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20564086</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_3">Kantarjian HM, Cortes J, O'Brien S, et al.: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99 (10): 3547-53, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11986206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11986206</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_4">Sawyers CL, Hochhaus A, Feldman E, et al.: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99 (10): 3530-9, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11986204" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11986204</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_5">Fruehauf S, Topaly J, Buss EC, et al.: Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 109 (8): 1543-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17340589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17340589</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_6">Preti HA, O'Brien S, Giralt S, et al.: Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 97 (1): 60-5, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8030658" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8030658</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_7">Walters RS, Kantarjian HM, Keating MJ, et al.: Therapy of lymphoid and undifferentiated chronic myelogenous leukemia in blast crisis with continuous vincristine and adriamycin infusions plus high-dose decadron. Cancer 60 (8): 1708-12, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/3477315" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3477315</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_48_8">Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 10 (3): 398-405, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1740679" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1740679</span></a>]</div></li></ol></div></div><div id="CDR0000062876__56"><h2 id="_CDR0000062876__56_">Relapsing CML</h2><p id="CDR0000062876__161">Overt failure is defined as a loss of hematologic remission or progression to accelerated-phase or blast-crisis phase chronic myelogenous leukemia (CML) as previously defined. A consistently rising quantitative reverse–transcription polymerase chain reaction <i>BCR/ABL</i> level suggests relapsing disease. For initial use of imatinib mesylate, the designation of relative failure or suboptimal response has been proposed for lack of complete hematologic remission by 3 months, no cytogenetic response by 6 months, or no major cytogenetic response by 12 months.[<a class="bk_pop" href="#CDR0000062876_rl_56_1">1</a>,<a class="bk_pop" href="#CDR0000062876_rl_56_2">2</a>] Nilotinib and dasatinib induce such high rates of complete cytogenetic responses and major molecular responses within several months that new benchmarks are required for responsiveness.[<a class="bk_pop" href="#CDR0000062876_rl_56_3">3</a>] These investigators propose that a complete cytogenetic response by 3 months should define an optimal response.[<a class="bk_pop" href="#CDR0000062876_rl_56_4">4</a>]</p><p id="CDR0000062876__162">In case of treatment failure or suboptimal response, patients should undergo BCR/ABL kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation.[<a class="bk_pop" href="#CDR0000062876_rl_56_5">5</a>,<a class="bk_pop" href="#CDR0000062876_rl_56_6">6</a>] Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate; alternative inhibitors such as dasatinib, nilotinib, or bosutinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) have been studied in this setting.[<a class="bk_pop" href="#CDR0000062876_rl_56_7">7</a>-<a class="bk_pop" href="#CDR0000062876_rl_56_19">19</a>] In particular, the <i>T315I</i> mutation marks resistance to imatinib, dasatinib, nilotinib, and bosutinib. In a phase II study with 449 patients, 60% of the 129 patients with the <i>T315I</i> mutation had a molecular response to ponatinib, an oral tyrosine kinase inhibitor.[<a class="bk_pop" href="#CDR0000062876_rl_56_20">20</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] Ponatinib also has activity in heavily pretreated-resistant CML and in a third of the patients with accelerated-phase or blast-crisis phase CML.[<a class="bk_pop" href="#CDR0000062876_rl_56_20">20</a>]</p><p id="CDR0000062876__388">For patients resistant to several tyrosine kinase inhibitors, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of <i>BCR/ABL</i>) has shown a hematologic response rate of 67% and a median progression-free survival of 7 months in a small, phase II study of 46 patients.[<a class="bk_pop" href="#CDR0000062876_rl_56_21">21</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>]</p><p id="CDR0000062876__60">Infusions of buffy-coat leukocytes or isolated T cells obtained by pheresis
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from the bone marrow transplant donor have induced long-term remissions in more
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than 50% of patients who relapse following allogeneic transplant.[<a class="bk_pop" href="#CDR0000062876_rl_56_22">22</a>,<a class="bk_pop" href="#CDR0000062876_rl_56_23">23</a>] The efficacy
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of this treatment is thought to be the result of an immunologic graft-versus-leukemia
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effect. This treatment is most effective for patients whose relapse is
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detectable only by cytogenetics or molecular studies and is associated with
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significant graft-versus-host disease. After relapse from allogeneic SCT, some patients will
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also respond to interferon alpha.[<a class="bk_pop" href="#CDR0000062876_rl_56_24">24</a>] Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)[<a class="bk_pop" href="#CDR0000062876_rl_56_25">25</a>-<a class="bk_pop" href="#CDR0000062876_rl_56_27">27</a>]
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</p><div id="CDR0000062876__TrialSearch_56_sid_7"><h3>Current Clinical Trials</h3><p id="CDR0000062876__TrialSearch_56_10">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=38720&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">relapsing chronic myelogenous leukemia</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062876__TrialSearch_56_18">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div><div id="CDR0000062876_rl_56"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062876_rl_56_1">Baccarani M, Saglio G, Goldman J, et al.: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108 (6): 1809-20, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16709930" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16709930</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_2">Marin D, Milojkovic D, Olavarria E, et al.: European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 112 (12): 4437-44, 2008. [<a href="/pmc/articles/PMC6143157/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6143157</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18716134" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18716134</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_3">Jabbour E, Kantarjian HM, O'Brien S, et al.: Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response? J Clin Oncol 29 (32): 4260-5, 2011. [<a href="/pmc/articles/PMC3221527/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3221527</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21990394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21990394</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_4">Jain P, Kantarjian H, Nazha A, et al.: Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 121 (24): 4867-74, 2013. [<a href="/pmc/articles/PMC3743466/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3743466</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23620574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23620574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_5">Soverini S, Hochhaus A, Nicolini FE, et al.: BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118 (5): 1208-15, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21562040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21562040</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_6">Parker WT, Lawrence RM, Ho M, et al.: Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol 29 (32): 4250-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21990409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21990409</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_7">Jabbour E, Cortes J, Kantarjian HM, et al.: Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 108 (4): 1421-3, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16601247" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16601247</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_8">le Coutre PD, Giles FJ, Hochhaus A, et al.: Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 26 (6): 1189-94, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22076466" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22076466</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_9">Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18401416" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18401416</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_10">Guilhot F, Apperley J, Kim DW, et al.: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109 (10): 4143-50, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17264298" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17264298</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_11">Kantarjian HM, Giles FJ, Bhalla KN, et al.: Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117 (4): 1141-5, 2011. [<a href="/pmc/articles/PMC4916554/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4916554</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21098399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21098399</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_12">Kantarjian H, Cortes J, Kim DW, et al.: Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood 113 (25): 6322-9, 2009. [<a href="/pmc/articles/PMC4916944/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4916944</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19369231" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19369231</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_13">Jabbour E, Jones D, Kantarjian HM, et al.: Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 114 (10): 2037-43, 2009. [<a href="/pmc/articles/PMC4186638/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4186638</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19567878" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19567878</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_14">Apperley JF, Cortes JE, Kim DW, et al.: Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 27 (21): 3472-9, 2009. [<a href="/pmc/articles/PMC4979080/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4979080</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19487385" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19487385</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_15">Hughes T, Saglio G, Branford S, et al.: Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 27 (25): 4204-10, 2009. [<a href="/pmc/articles/PMC4979230/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4979230</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19652056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19652056</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_16">Kantarjian H, Pasquini R, Lévy V, et al.: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 115 (18): 4136-47, 2009. [<a href="/pmc/articles/PMC5345391/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5345391</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19536906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19536906</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_17">Saglio G, Hochhaus A, Goh YT, et al.: Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116 (16): 3852-61, 2010. [<a href="/pmc/articles/PMC4993589/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4993589</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20564086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20564086</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_18">Cortes JE, Kantarjian HM, Brümmendorf TH, et al.: Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118 (17): 4567-76, 2011. [<a href="/pmc/articles/PMC4916618/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4916618</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21865346" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21865346</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_19">Khoury HJ, Cortes JE, Kantarjian HM, et al.: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119 (15): 3403-12, 2012. [<a href="/pmc/articles/PMC4916559/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4916559</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22371878" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22371878</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_20">Cortes JE, Kim DW, Pinilla-Ibarz J, et al.: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369 (19): 1783-96, 2013. [<a href="/pmc/articles/PMC3886799/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3886799</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24180494" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24180494</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_21">Cortes J, Digumarti R, Parikh PM, et al.: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 88 (5): 350-4, 2013. [<a href="/pmc/articles/PMC5558840/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5558840</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23468307" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23468307</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_22">Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107 (10): 4171-6, 2006. [<a href="/pmc/articles/PMC1895293/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1895293</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16449534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16449534</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_23">Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10607686" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10607686</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_24">Pigneux A, Devergie A, Pochitaloff M, et al.: Recombinant alpha-interferon as treatment for chronic myelogenous leukemia in relapse after allogeneic bone marrow transplantation: a report from the Société Française de Greffe de Moelle. Bone Marrow Transplant 15 (6): 819-24, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7581075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7581075</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_25">Olavarria E, Ottmann OG, Deininger M, et al.: Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 17 (9): 1707-12, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12970768" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12970768</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_26">Kantarjian HM, O'Brien S, Cortes JE, et al.: Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 100 (5): 1590-5, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12176876" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12176876</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062876_rl_56_27">Hess G, Bunjes D, Siegert W, et al.: Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 23 (30): 7583-93, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16234522" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16234522</span></a>]</div></li></ol></div></div><div id="CDR0000062876__93"><h2 id="_CDR0000062876__93_">Changes to This Summary (04/02/2015)</h2><p id="CDR0000062876__94">The PDQ cancer information summaries are reviewed regularly and updated as
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new information becomes available. This section describes the latest
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changes made to this summary as of the date above.</p><p id="CDR0000062876__411">Editorial changes were made to this summary.</p><p id="CDR0000062876__disclaimerHP_3">This summary is written and maintained by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/adult-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Adult Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062876__AboutThis_1">About This PDQ Summary</a> and <a href="http://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000062876__AboutThis_1"><h2 id="_CDR0000062876__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062876__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062876__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000062876__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062876__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/adult-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Adult Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000062876__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062876__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000062876__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Chronic Myelogenous Leukemia Treatment are:</p><ul><li class="half_rhythm"><div>Eric J. Seifter, MD (Johns Hopkins University)</div></li><li class="half_rhythm"><div>Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)</div></li></ul><p id="CDR0000062876__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062876__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062876__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a <a href="/books/n/pdqcis/CDR0000062796/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000062876__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062876__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000062876__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062876__AboutThis_15">National Cancer Institute: PDQ® Chronic Myelogenous Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: <a href="http://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq</a>. Accessed <MM/DD/YYYY>.</p><p id="CDR0000062876__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="http://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062876__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062876__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="http://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062876__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062876__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="http://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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class="bk_col_itm"><a href="/books/NBK65916.2/">NBK65916.2</a></span> January 22, 2016</li><li><span class="bk_col_itm">NBK65916.1</span> April 2, 2015 (Displayed Version)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#CDR0000062876__1" ref="log$=inpage&link_id=inpage">General Information About Chronic Myelogenous Leukemia (CML)</a></li><li><a href="#CDR0000062876__6" ref="log$=inpage&link_id=inpage">Stage Information for CML</a></li><li><a href="#CDR0000062876__19" ref="log$=inpage&link_id=inpage">Treatment Option Overview for CML</a></li><li><a href="#CDR0000062876__26" ref="log$=inpage&link_id=inpage">Chronic-Phase CML</a></li><li><a href="#CDR0000062876__38" ref="log$=inpage&link_id=inpage">Accelerated-Phase CML</a></li><li><a href="#CDR0000062876__48" ref="log$=inpage&link_id=inpage">Blastic-Phase CML</a></li><li><a href="#CDR0000062876__56" ref="log$=inpage&link_id=inpage">Relapsing CML</a></li><li><a href="#CDR0000062876__93" ref="log$=inpage&link_id=inpage">Changes to This Summary (04/02/2015)</a></li><li><a href="#CDR0000062876__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related publications</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" 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class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389432" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Acute Myeloid Leukemia Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Acute Myeloid Leukemia Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Adult Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389470" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Chronic Lymphocytic Leukemia Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Chronic Lymphocytic Leukemia Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Adult Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/38630974" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Juvenile Myelomonocytic Leukemia Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Juvenile Myelomonocytic Leukemia Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389171" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Acute Lymphoblastic Leukemia Treatment (PDQ®): Health Professional Version.</a><span 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