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Allogeneic Stem Cell Transplantation for Philadelphia Chromosome–Positive Acute Myeloid Leukemia Vijaya Raj Bhatt, MBBSa; Mojtaba Akhtari, MDa; R. Gregory Bociek, MDa; Jennifer N. Sanmann, PhDb; Ji Yuan, MD, PhDc; Bhavana J. Dave, PhDb; Warren G. Sanger, PhDb; Anne Kessinger, MDa; and James O. Armitage, MDa Abstract Philadelphia chromosome–positive acute myeloid leukemia (Ph+-AML) has a poor response to anthracycline- and cytarabine-containing regimens, high relapse rate, and dismal prognosis. Although therapy with imatinib and allogeneic stem cell transplantation (alloSCT) is promising, relatively short follow-up limits understanding of long-term results of these therapies. This report describes the outcomes of 3 cases of Ph+-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. These patients, young and without major comorbidities, received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib and consolidation therapy with high-dose cytarabine (with or without imatinib). All patients underwent 10/10 HLA-matched peripheral blood allo-SCT (sibling donor for first and third patients and unrelated donor for the second patient; all had acute graft-versus-host disease (GVHD), and the first and third patients had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively. This report shows that the use of allo-SCT with resultant graft-versus-leukemia effect and the addition of imatinib can result in long-term remission and possible cure in some patients with Ph+-AML. (J Natl Compr Canc Netw 2014;12:963–968)

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation. This activity is accredited for 1.0 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity. All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/ node/48801; and 4) view/print certificate. Release date: July 8, 2014; Expiration date: July 8, 2015

Learning Objectives

NCCN: Continuing Education Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

From the aDepartment of Internal Medicine, Division of HematologyOncology; bHuman Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation; and cDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. Submitted September 9, 2013; accepted for publication December 6, 2013. Dr. Armitage has disclosed that he receives consulting fees from ZIOPHARM Oncology, Inc.; GlaxoSmithKline; Spectrum Pharmaceuticals; and Roche; and serves on the board of directors for TESARO Bio, Inc. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Correspondence: Vijaya Raj Bhatt, MBBS, University of Nebraska Medical Center, Department of Internal Medicine, Division of HematologyOncology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680. E-mail: [email protected]

Upon completion of this activity, participants will be able to: • Describe the rationale for the use of imatinib in the treatment of patients with Ph+-AML • Identify the evidence supporting clinicopathologic distinction between Ph+-AML and chronic blast phase CML • Discuss the role of SCT in the treatment of Ph+-AML

EDITOR Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network Ms. Green has disclosed that she has no relevant financial relationships. CE AUTHORS Deborah J. Moonan, RN, BSN, Director, Continuing Education & Grants Ms. Moonan has disclosed that she has no relevant financial relationships. Ann Gianola, MA, Manager, Continuing Education & Grants Ms. Gianola has disclosed that she has no relevant financial relationships. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations Ms. Gregory has disclosed that she has no relevant financial relationships.

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Philadelphia

chromosome–positive acute myeloid leukemia (Ph+-AML) is rare, accounting for approximately 1% of all cases of AML.1–3 Whether Ph+-AML is distinct from the blast phase of chronic myeloid leukemia (CML) was controversial until recently. A 2013 study showed that NPM1 mutations are seen exclusively in Ph+-AMLs (22%; n=9) whereas ABL1 mutations are exclusive to the blast phase of CML (20%; n=5), suggesting that Ph+-AML is distinct from blast phase CML. These mutational analyses can be helpful in clinical practice or research trials to distinguish between the entities.4 Clinical characteristics might also be helpful in making the distinction, including no history of CML or myeloproliferative disorder, no evidence of chronic or accelerated phases of CML after induction therapy, and no characteristics of CML, such as splenomegaly and basophilia. In addition, compared with the blast phase of CML, Ph+-AML is associated with very high leukocytosis, the p210 BCR-ABL protein (vs p190 BCR-ABL protein), and the coexistence of normal metaphases in addition to Ph+ metaphases.5 The presence of dwarf megakaryocytes in bone marrow4; additional cytogenetic aberrations, such as an extra copy of Ph chromosome, trisomies 8 and 19, and isochromosome 17q; and the persistence of t(9;22) after induction therapy are more common in the blast phase of CML than in Ph+-AML.5 None of these features, however, are diagnostic of blast-phase CML or Ph+-AML. The presence of the Ph chromosome in acute lymphoblastic leukemia is a poor prognostic factor leading to the recommendation of allogeneic stem cell transplantation (allo-SCT) whenever possible,6 but its prognostic significance and the optimal treatment of Ph+-AML are not clear. With the current treatment options, the outcome is dismal (with a median overall survival of 9 months in one study).1 Although several therapy options are promising, including imatinib and allo-SCT, relatively short follow-up limits understanding of long-term results of these therapies.7 This report describes the outcomes of 3 cases of Ph+-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. Despite the lack of consensus on accurate case definition, the lack of prior history of CML or myeloproliferative disorder, and the absence of the evidence of chronic or accelerated phases of CML after induction therapy seem to be the most important diagnostic criteria for Ph+-AML and were

used for case definition in this and other reports.1 All patients reported had palpable spleens and absolute basophilia. Although strict case definition of Ph+AML for research purposes may exclude patients with splenomegaly or basophilia,4 approximately one-quarter of patients with Ph+-AML are reported to have either splenomegaly1,3 or basophilia.1

Case Report The details of each patient are described in Tables 1 and 2. All patients, young and without comorbidities, presented with acute to subacute symptoms. The third patient had a history of stage IB right breast cancer diagnosed 3 years before presentation, which was treated with mastectomy, sentinel lymph node dissection, and adjuvant cyclophosphamide and doxorubicin (4 cycles); the patient subsequently underwent maintenance therapy with oral tamoxifen. All 3 patients had splenomegaly. The WBC count at presentation was 143,000/µL (66% blasts; 5% basophils) in the first patient (Figure 1); 159,000/µL (36% blasts; 0%–2% basophils) in the second patient; and 96,900/µL (12% blasts; 1% basophils) in the third patient. Bone marrow aspirate and biopsy revealed increased myeloblasts (>20%) in all patients; additionally the first patient had increased basophils (Figure 2). Immunophenotyping confirmed myeloid lineage and ruled out biphenotypic acute leukemia.8 Conventional cytogenetics and fluorescence in situ hybridization (FISH) studies detected a t(9;22)(q34;q11.2), consistent with the Ph chromosome, in the first and the second patients (Figure 3A). In addition, studies detected a subclone further characterized by a t(14;17)(q32;q24) in the first patient, which was confirmed by FISH to include disruption of the IGH locus at 14q32 (Figure 3B). FISH showed the presence of BCR-ABL in 17 of 17 cells in the third patient; however, a lack of mitotic cells prohibited conventional cytogenetic analysis. All of the patients received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib, and consolidation therapy with high-dose cytarabine (± imatinib). The first and the third patients did not receive imatinib during consolidation because of grade 3 hepatotoxicity and grade 3 diarrhea, respectively. The cytogenetic abnormalities had resolved at the time of allo-SCT in the first and the third patients, but persisted in

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Table 1 C  haracteristics of the Patients With Philadelphia Chromosome–Positive Acute Myeloid Leukemia Who Underwent SCT Age (y)/Sex

19/M

22/M

46/F

Peripheral WBCs/blasts

143,000/mcL; 66% blasts

159,000/mcL; 36% blasts

96,900/mcL; 12% blasts

Immunophenotype of blasts

Myeloid (positive: dim CD45, dim CD7, CD13, and bright CD 34)

Myeloid (positive: dim CD45, HLA-DR, dim CD7, dim and partial CD11c, CD13, CD33, and CD 34)

Myeloid (positive: CD45, dim CD7, CD11b, CD13, partial CD34, and CD117)

Cytogenetics at diagnosis

46,XY,t(9;22)(q34;q11.2) [16]/46,idem,t(14;17)(q32;q24)[4]

46,XY,t(9;22)(q34;q11.2)[20]

See footnote a

Inductionb

7 + 3c + imatinib

7 + 3 + imatinib

7 + 3 + imatinib

Cytogenetics after induction

46,XY[10]

46,XY,t(9;22)(q34;q11.2) [4]/46,XY[10]

46,XX[20]

Consolidation chemotherapy

1 cycle HDAC

3 cycles HDAC + imatinib

1 cycle HDAC

Cytogenetics before SCT

46,XY[10]

46,XY,t(9;22)(q34;q11.2) [13]/46,XY[7]

46,XX[20]

Type/timing of SCTb,d

MRD; 3 mo in CR1

MUD; 9 mo in morphologic but not cytogenetic remission

MRD; 4 mo in CR1

OSe

116 mo

113 mo

28 mo

Abbreviations: CR1, first complete remission; F, female; HDAC, high-dose cytarabine; M, male; MRD, matched related donor; MUD, matched unrelated donor; OS, overall survival from the time of diagnosis; SCT, stem cell transplantation; WBC, white blood cell. a Cytogenetics could not be performed because of lack of mitotic cells in the cell culture; fluorescence in situ hybridization study was positive for bcr/ abl fusion in 17/17 cells. b Timing of SCT is calculated from the time of diagnosis. c 7-day cytarabine and 3-day idarubicin. d For all patients, antigen matching was 10/10. e All patients are currently alive and experiencing complete remission.

the second patient. All of the patients underwent 10/10 HLA-matched allo-SCT (sibling donor for the first and the third patients and unrelated donor for the second patient). In all cases, peripheral blood progenitor cells were the graft source. In the first and second patients, cyclophosphamide (60 mg/ kg/d for 2 days) and total body irradiation (200 cGy twice daily for 3 days) were used as the conditioning regimen, whereas the third patient received busulfan (3.2 mg/kg/d for 4 days) and fludarabine (30 mg/m2/d for 5 days). For graft-versus-host disease (GVHD) prophylaxis, the first and the third patients received tacrolimus and mycophenolate mofetil, whereas the second patient received tacrolimus and methotrexate. All the patients had acute GVHD (grade 2 skin, grade 1 gut, and grade 1 skin in the first, second, and third patients, respectively). The first (limited disease) and third (extensive disease) patients also had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively.

Discussion The t(9;22)(q34;q11.2) translocation, which results in the Ph chromosome, can occur in AML as a de novo chromosomal aberration with or without additional abnormalities or as a therapyrelated event.2,9 In de novo cases, it may be present at AML diagnosis or relapse.1,10,11 In the present report, the first and the second patients had de novo chromosomal aberrations, whereas the third patient had therapy-related Ph+-AML. The occurrence of the Ph chromosome in AML with core-binding factor leukemia or with certain genetic aberrations, such as NPM1 mutations, may indicate a role as a cooperating mutation that enhances cell proliferation (class I mutation).10 Ph+-AMLs display varying degrees of maturation, are classifiable into different FrenchAmerican-British types, frequently express lymphoid markers, and demonstrate clonal rearrangement of the immunoglobulin or T-cell receptor genes.3 The few publications available on the treatment and outcome of patients with Ph+-AML suggest a poor response to anthracycline- and cytarabinecontaining regimens,2 high relapse rate, and dismal

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Table 2 M  olecular Characteristics of the Patients With Philadelphia Chromosome–Positive Acute Myeloid Leukemia Who Underwent Stem Cell Transplantation BCR-ABL Fusion After Induction Chemotherapy

BCR-ABL Fusion Before SCT

BCR-ABL Fusion After SCT

BCR-ABL Fusion at Last Follow-up

Positive in 98.0% of interphase cells

Negative

Negative

Negative

Negative

2

Positive in 92.5% of interphase cells

Positive in 6.0% of interphase cells

Positive in 33.5% of interphase cells

Negative

Negative

3

Positive in 100.0% of interphase cells

Negative

Negative

Negative

Negative

Patient Number

BCR-ABL Fusion at Diagnosis

1

BCR-ABL fusion was detected by fluorescence in situ hybridization. Results were considered positive if ≥2% of interphase cells exhibited the dual fusion BCR-ABL signal pattern. The quantitative real-time reverse transcriptase polymerase chain reaction/DNA amplification assay used for BCR-ABL fusion transcript was able to detect the p210 fusion transcript (derived from b2a2 or b3a2 translocation) and the p190 fusion transcript (derived from the e1a2 translocation). The test result was negative after stem cell transplantation and at last follow-up in the first and second patients. In the third patient, the test showed 95% p210 BCR-ABL (b3a2 translocation) in peripheral blood at diagnosis, which decreased to < 0.01% after induction. Immediately after transplant, there was sporadic p190 BCR-ABL1 (e1a2) but no p210. Subsequent tests, including the one at last follow-up, have been negative. In the third patient, no FLT3 and JAK2 V617F mutation was seen in the bone marrow specimen at diagnosis.

prognosis.1 Although a transient response with imatinib alone (n=2) and with chemotherapy (n=5) have been reported,1 several case reports have shown good responses to imatinib as a first-line therapy (initial dose, 400 mg/d)12 and as a salvage therapy after chemotherapy failure (initial dose, 600 mg/d).13,14 Use of imatinib for postremission maintenance therapy after induction chemotherapy has resulted in complete remissions lasting for 10 to 19 months.15,16 In one instance, combination leukemia-type chemotherapy and imatinib after

failure of induction therapy with single-agent imatinib resulted in a complete cytogenetic response. Consolidation chemotherapy and imatinib followed by postremission imatinib led to a complete molecular response, which continued 15 months from diagnosis.17 Taken together, these results indicate that imatinib can play a valuable role in postremission therapy, even when Ph+-AML is resistant to first-line single-agent imatinib. Ph+-AML with additional abnormalities, rather than Ph+-AML alone, may behave differently. Ph+-

Figure 1 Peripheral blood smear showing circulating blasts and baso-

Figure 2 Bone marrow aspirate revealing myeloblasts and basophils

phils in the first patient (Wright stain, original magnification ×600).

(Wright stain, original magnification ×1000).

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A

B

Figure 3 (A) Partial G-banded karyotype showing a t(9;22) (q34;q11.2), consistent with the Philadelphia chromosome. (B) Partial G-banded karyotype showing a t(14;17)(q32;q24) in the first patient.

AML with monosomy 7 is considered to be a worse risk and is associated with poor response to therapy and short duration of remission.18 Conversely, the presence of favorable-risk cytogenetics may be associated with better outcomes. Two cases of Ph+-AML in association with inv(16) had excellent outcomes with chemotherapy (alive in remission 3 years after diagnosis) and allo-SCT (alive in complete remission 18 months post-SCT), respectively.19 Similarly, allo-SCT and chemotherapy with or without imatinib resulted in complete remission at 22 and 70 months after diagnosis in 2 patients with Ph+-AML with t(8;21).10 A patient with acute promyelocytic leukemia with a Ph chromosome experienced complete remission with all-trans retinoic acid and chemotherapy for 4 years from diagnosis.20 Additionally, the presence of a Ph chromosome in patients with otherwise good-risk AML may21 indicate a poor prognosis.10 Only a few instances of allo-SCT have been reported in Ph+-AML. In one study, allo-SCT (n=7) resulted in a median overall survival of 12 months1 (patients’ characteristics are not available). In another study, 4 men (age, 18–44 years) were treated with AML-type induction chemotherapy, with further augmentation chemotherapy in 3 patients, followed by imatinib and consolidation chemotherapy. Two patients experienced molecular remission, whereas the other 2 experienced complete hematologic remission. Subsequently, these patients

received a cyclophosphamide (120 mg/kg) and total body irradiation (1320 cGy) preparative regimen, and sibling (n=2) or unrelated (n=2) peripheral (n=1) or bone marrow (n=3) allo-SCT. Two patients had acute GVHD and 3 had chronic GVHD, whereas 1 did not have either acute or chronic GVHD. At 6 to 24 months’ follow-up, all of the patients were alive in molecular remission; however, the long-term outcome was not reported.7 The present report shows that allo-SCT can result in long-term remission and possible cure in some patients with Ph+-AML. The second patient had experienced morphologic complete remission but not cytogenetic remission at the time of alloSCT, thus suggesting that allo-SCT can achieve cure even in such a setting. In addition to the overall advancement in the techniques of alloSCT and supportive care, the young age, absence of comorbidities and additional high-risk cytogenetics, incorporation of imatinib, and occurrence of GVHD (suggesting graft-versus-leukemia effect) in the present patients may have contributed to the excellent outcomes. Although the benefit of consolidation with high-dose cytarabine with or without imatinib before allo-SCT is unclear, this should at minimum be considered as an interim therapy while awaiting allo-SCT. The NCCN Clinical Practice Guidelines in Oncology for AML recommend treating Ph+-AML as myeloid blast-phase CML with tyrosine kinase inhibitor (alone or in combination with AML-type induction chemotherapy) followed by hematopoietic SCT, if feasible, or enrollment in a clinical trial (available at NCCN.org).22,23 In conclusion, Ph+-AML is a rare condition that is incompletely studied. Available reports, including this one, suggest that long-term remission is possible. The use of allo-SCT, with resultant graft-versusleukemia effect, and the addition of imatinib provide potentially curative properties.

References 1. Soupir CP, Vergilio JA, Dal Cin P, et al. Philadelphia chromosomepositive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol 2007;127:642–650. 2. Paietta E, Racevskis J, Bennett JM, et al. Biologic heterogeneity in Philadelphia chromosome-positive acute leukemia with myeloid morphology: the Eastern Cooperative Oncology Group experience. Leukemia 1998;12:1881–1885.

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Bhatt et al 3. Cuneo A, Ferrant A, Michaux JL, et al. Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features. Haematologica 1996;81:423–427. 4. Konoplev S, Yin CC, Kornblau SM, et al. Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia. Leuk Lymphoma 2013;54:138–144. 5. Frankfurt O, Platanias LC. Philadelphia chromosome positive acute myeloid leukemia or de novo chronic myeloid leukemiablast phase? Leuk Lymphoma 2013;54:1–2. 6. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2010;116:3409–3417. 7. Cho BS, Kim HJ, Lee S, et al. Successful interim therapy with imatinib prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute myeloid leukemia. Eur J Haematol 2007;79:170–173. 8. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995;9:1783–1786. 9. Pedersen-Bjergaard J, Brondum-Nielsen K, Karle H, Johansson B. Chemotherapy-related - late occurring - Philadelphia chromosome in AML, ALL and CML. Similar events related to treatment with DNA topoisomerase II inhibitors? Leukemia 1997;11:1571–1574. 10. Bacher U, Haferlach T, Alpermann T, et al. Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations. Br J Haematol 2011;152:713–720. 11. Chen Z, Morgan R, Notohamiprodjo M, et al. The Philadelphia chromosome as a secondary change in leukemia: three case reports and an overview of the literature. Cancer Genet Cytogenet 1998;101:148–151. 12. Ueda K, Horiike S, Zen K, et al. Complete cytogenetic and molecular response to treatment with imatinib mesylate for philadelphia chromosome positive acute myeloid leukemia with multilineage dysplasia. Leuk Lymphoma 2006;47:1967–1969. 13. Yip SF, Wan TS, Liu HS, et al. Philadelphia chromosome unmasked as a secondary genetic change in acute myeloid leukemia on imatinib treatment. Leukemia 2006;20:2050–2051.

Instructions for Completion To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/ node/48801; and 4) view/print certificate. After reading the article, you should be able to answer the following multiple-

Posttest Questions 1. Several clinical and laboratory features, albeit not diagnostic, may help to differentiate between Ph+-AML and blast crisis of CML. Which of the following features is suggestive of Ph+-AML and not blast crisis of CML? a. Presence of NPM1 mutation b. Presence of ABL1 mutation c . History of myeloproliferative disorder d. Presence of lymphoid markers

14. Drummond MW, Lush CJ, Vickers MA, et al. Imatinib mesylateinduced molecular remission of Philadelphia chromosomepositive myelodysplastic syndrome. Leukemia 2003;17:463–465. 15. Jentsch-Ullrich K, Pelz AF, Braun H, et al. Complete molecular remission in a patient with Philadelphia-chromosome positive acute myeloid leukemia after conventional therapy and imatinib. Haematologica 2004;89:ECR15. 16. Lazarevic V, Golovleva I, Nygren I, Wahlin A. Induction chemotherapy and post-remission imatinib therapy for de novo BCR-ABL-positive AML. Am J Hematol 2006;81:470–471. 17. Kondo T, Tasaka T, Sano F, et al. Philadelphia chromosomepositive acute myeloid leukemia (Ph + AML) treated with imatinib mesylate (IM): a report with IM plasma concentration and bcr-abl transcripts. Leuk Res 2009;33:e137–138. 18. Maddox AM, Keating MJ, Trujillo J, et al. Philadelphia chromosome-positive adult acute leukemia with monosomy of chromosome number seven: a subgroup with poor response to therapy. Leuk Res 1983;7:509–522. 19. Miura I, Takatsu H, Yamaguchi A, et al. Standard Ph chromosome, t(9;22)(q34;q11), as an additional change in a patient with acute myelomonocytic leukemia (M4Eo) associated with inv(16) (p13q22). Am J Hematol 1994;45:94–96. 20. Mozziconacci MJ, Sainty D, Gabert J, et al. The Philadelphia chromosome as a secondary abnormality in two cases of acute myeloid leukemia. Br J Haematol 1998;102:873–875. 21. Secker-Walker LM, Morgan GJ, Min T, et al. Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia. Report of two cases. Cancer Genet Cytogenet 1992;58:29–34. 22. O’Donnell MR, Tallman MS, Abboud CN, et al. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 2.2014. Available at: NCCN.org. Accessed May 21, 2014. 23. O’Brien S, Radich JP, Abboud CN, et al. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. Version 3.2014. Available at: NCCN.org. Accessed May 21, 2014.

choice questions. Credit cannot be obtained for tests completed on paper. You must be a registered user on NCCN.org. If you are not registered on NCCN.org, click on “New Member? Sign up here” link on the left hand side of the Web site to register. Only one answer is correct for each question. Once you successfully answer all posttest questions you will be able to view and/or print your certificate. Software requirements: Internet.

2. True or False: Additional cytogenetic abnormalities may affect the prognosis of patients with Ph+-AML. 3.  Treatment of Ph+-AML may include which of the following treatments? a. Anthracycline + cytarabine b. Imatinib c . Stem cell transplant d. All of the above

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