Leukemic Transformation in Myeloproliferative Neoplasms

SYMPOSIUM ON NEOPLASTIC HEMATOLOGY AND MEDICAL ONCOLOGY

Leukemic Transformation in Myeloproliferative Neoplasms: A Literature Review on Risk, Characteristics, and Outcome Meera Yogarajah, MD, and Ayalew Tefferi, MD From the Division of Hematology and Oncology, Brody School of Medicine, East Carolina University, Greenville, NC (M.Y.); and Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN (A.T.).

CME Activity Target Audience: The target audience for Mayo Clinic Proceedings is primarily internal medicine physicians and other clinicians who wish to advance their current knowledge of clinical medicine and who wish to stay abreast of advances in medical research. Statement of Need: General internists and primary care physicians must maintain an extensive knowledge base on a wide variety of topics covering all body systems as well as common and uncommon disorders. Mayo Clinic Proceedings aims to leverage the expertise of its authors to help physicians understand best practices in diagnosis and management of conditions encountered in the clinical setting. Accreditation: Mayo Clinic College of Medicine and Science is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Statement: Mayo Clinic College of Medicine and Science designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).TM Physicians should claim only the credit commensurate with the extent of their participation in the activity. Credit Statement: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Learning Objectives: On completion of this article, you should be able to (1) describe risk factors for leukemic transformation in myeloproliferative neoplasms; (2) review current experience in the outcome of patients with blast-phase myeloproliferative neoplasms; and (3) discuss current challenges in the treatment of blast-phase myeloproliferative neoplasms. Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional Development) must

ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation. In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry. The authors report no competing interests. Method of Participation: In order to claim credit, participants must complete the following: 1. Read the activity. 2. Complete the online CME Test and Evaluation. Participants must achieve a score of 80% on the CME Test. One retake is allowed. Visit www.mayoclinicproceedings.org, select CME, and then select CME articles to locate this article online to access the online process. On successful completion of the online test and evaluation, you can instantly download and print your certificate of credit. Estimated Time: The estimated time to complete each article is approximately 1 hour. Hardware/Software: PC or MAC with Internet access. Date of Release: 7/1/2017 Expiration Date: 6/30/2019 (Credit can no longer be offered after it has passed the expiration date.) Privacy Policy: http://www.mayoclinic.org/global/privacy.html Questions? Contact [email protected].

Abstract Myeloproliferative neoplasms (MPNs) operationally include essential thrombocythemia, polycythemia vera, primary myelofibrosis (PMF), and prefibrotic PMF. All 4 MPN variants might progress into blast-phase disease (MPN-BP). For essential thrombocythemia, reported risk factors for leukemic transformation include advanced age, extreme thrombocytosis, anemia, leukocytosis, and sequence variants/mutations involving TP53 and EZH2 (for expansion of gene symbols, see www.genenames.org); for polycythemia vera, advanced age, leukocytosis, abnormal karyotype, mutations involving SRSF2 and IDH2, and treatment with pipobroman, chlorambucil, or P32; and for PMF, increased blast percentage, thrombocytopenia, abnormal karyotype, triple-negative driver mutational status, and sequence variants/mutations involving SRSF2, RUNX1, CEBPA, and SH2B3. The reported median survival figures for MPN-BP range from 1.5 to 2.5 months in patients treated with supportive care only, from 2.5 to 10 months in those receiving hypomethylating agents or low-dose chemotherapy, and from 3.9 to 9.4 months in those receiving induction chemotherapy. Three-year survival after allogeneic stem cell transplant was reported in 16% to 33% of patients. These observations validate the extremely poor prognosis associated with MPN-BP and the lack of effective drug therapy and highlight the need for urgent assessment of therapeutic values of investigational agents. In the meantime, affected patients might be best served with aggressive chemotherapy followed by allogeneic stem cell transplant after adequate blast clearance. ª 2017 Mayo Foundation for Medical Education and Research

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LEUKEMIC TRANSFORMATION IN MYELOPROLIFERATIVE NEOPLASMS

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yeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by proliferative bone marrow with varying degrees of reticulin/ collagen fibrosis, extramedullary hematopoiesis, abnormal peripheral blood count, and constitutional symptoms that are presumed to be secondary to abnormally expressed inflammatory cytokines.1,2 The classical categories of MPN consists of chronic myeloid leukemia, primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV). Chronic myeloid leukemia is invariably associated with a specific genetic abnormality (BCR-ABL1) (for expansion of gene symbols, see www. genenames.org)3,4; accordingly, the other MPNs are operationally labeled as “BCR-ABL1enegative MPN,” and the World Health Organization (WHO) classification system currently recognizes 4 variants of BCR-ABL1enegative MPN: ET, PV, PMF, and prefibrotic PMF.5 There is considerable overlap among the 4 MPN variants in terms of symptomatology, laboratory findings, bone marrow morphology, and mutations, however, with marked differences in natural history and survival outcomes.5 Accordingly, diagnostic accuracy is prognostically relevant, especially in terms of differentiating WHO-defined ET from prefibrotic PMF and masked PV, which displays a higher risk of leukemic transformation.6,7 In general, the natural history of MPN might be interrupted by thrombohemorrhagic complications8 or disease transformation into post-ET or post-PV myelofibrosis (MF)9 or post-MPN acute leukemia, also known as blast-phase myeloproliferative neoplasms (MPN-BP).10,11 The typical definition of MPN-BP includes the documentation of 20% or more blasts in the peripheral blood or bone marrow.12 However, discordance in the content of peripheral blood vs bone marrow blasts is often seen.13 The propensity for leukemic transformation in MPN varies according to the MPN variant and is highest in PMF, with an incidence of 10% to 20% in the first 10 years of the disease14-16; lower in PV, with an estimated risk of 2.3% at 10 years and 7.9% at 20 years17; and lowest in ET, with less than 1% in the first decade of the disease.6,18 This varying incidence of MPN-BP was recently highlighted in a large study by Tefferi et al.10 Mayo Clin Proc. n July 2017;92(7):1118-1128 www.mayoclinicproceedings.org

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CHARACTERISTICS OF MPN-BP Blast-phase myeloproliferative neoplasms commonly involve the myeloid lineage with rare involvement of the lymphoid lineage. The characteristics of MPN-BP have been reported to be different, both morphologically and cytogenetically, from primary (de novo) acute myeloid leukemia (AML). According to the French-American-British (FAB) classification of AML, erythroleukemia (FAB-M6) and megakaryoblastic leukemia (FAB-M7) were the most common subtypes reported in MPN-BP.14,19 A Mayo Clinic study of patients with PMF found M7 (25.4%) to be the most common subtype followed by M0 (22.4%) and M2 (17.9%).19 The incidence of AML in postET or post-PV MF is similar to that of postPMF AML.19 Patients with PV and ET can also directly develop AML without going through the fibrotic phase of the disease.16,20 A karyotype in MPN-BP is often complex, and a favorable karyotype is infrequent. Common mutations described in MPN-BP include JAK2, IDH1/2, TP53, ASXL1, and TET2, whereas their counterparts in primary AML include N/KRAS, DNMT3a, NPM1, and FLT3.21-24 A study that analyzed genetic information in paired samples of chronic MPN-BP reported acquisition of TET2 mutation during blast transformation and presence of ASXL1 in both phases of the disease.22 JAK2 mutations are important in MPN pathogenesis, and clonal changes in JAK2 clones, during leukemic transformation, have been observed with acquisition of new mutations and, in certain instances, loss of the prevailing mutations.25,26 RISK FACTORS FOR LEUKEMIC TRANSFORMATION IN MPN Various clinical and genetic risk factors have been identified as being useful in predicting leukemic transformation in MPN (Table 1). RISK FACTORS FOR LEUKEMIC TRANSFORMATION IN PMF Conventional drug therapies have not resulted in prolongation of survival in PMF, and allogeneic stem cell transplant (ASCT) remains the definitive treatment for purposes of cure or prolongation of survival. Accordingly, identification of risk factors for inferior overall

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TABLE 1. Risk Factors for Leukemic Transformation Risk factors

Essential thrombocytosis

Polycythemia vera

Clinical

Age 60 y Thrombosis6

Age >70 y Age >61 y17

Laboratory

Platelets (1000
109/L)6,28 Anemia28,32 Leukocytosis (15
109/L)33,34

Leukocytes (15
109)17

Bone marrow

Prefibrotic primary myelofibrosis morphology, reticulin grading, and bone marrow cellularity6,34

27,28

Previous therapy

Myelofibrosis Age >65 y Red blood cell transfusion dependency31 White blood cells (>30
109/L)35 Platelets (<50
109/L)36 Peripheral blast (3%) and/or platelets (<100
109/L)37 IL-8, IL-2R38 C-reactive protein (>7 mg/L) and peripheral blast (>1%)30 Bone marrow blasts (10%)36

29

30

Cytogenetic abnormalities

None

Cytoreductive agents, pipobroman, P32, chlorambucil39 Abnormal karyotype17

Mutations

TP53, EZH233

SRSF2, IDH233

Abnormal karyotype35 Chromosome 17 aberrations36 Monosomal karyotype (1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q, del17p, 5, 7) and/or complex40 Unfavorable karyotype (complex karyotype or sole or 2 abnormalities that include þ8, 7/7q-, i(17q), 5/ 5q-, 12p-, inv(3), or 11q23 rearrangement)41,42 Del17p, 5, 7, and/or complex43 Triple-negative mutational status10 ASXL1, SRSF2, IDH1, or IDH244

IL-2R ¼ interleukin 2 receptor; IL-8 ¼ interleukin 8.

and leukemia-free survival is a critical step in the management of patients with PMF or post-ET or post-PV MF. In a study of 311 patients with PMF, independent risk factors for leukemic transformation included circulating blast of more than 3% and platelet count of less than 100
109/L.37 The same study also found no increased leukemogenicity from treatment with hydroxyurea, thalidomide, or many other drugs, although a potential detrimental effect from erythropoiesis stimulating agents, and danazol was suggested. Using the aforementioned 2 risk factors, the rate of leukemic transformation was only 6% in the absence of both risk factors and 18% in the presence of one or both risk factors. Leukocytosis (>30
109/L) was also identified as a risk factor for leukemic transformation in another 1120

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study.35 In a study by Passamonti et al,31 red blood cell (RBC) transfusion need was also identified as an independent risk factor for leukemic transformation, with an incidence of leukemic transformation at 7.4
100 persons per year in RBC-transfused patients vs 1.5
100 persons per year in nontransfused patients (P<.001). Other reported risk factors for leukemic transformation include increased serum interleukin 8 levels,38 C-reactive protein level of greater than 7 mg/L, age greater than 65 years, and peripheral blast count of more than 1%.30 The International Prognostic Scoring System45 and the Dynamic International Prognostic Scoring System (DIPSS)46 are currently used to risk stratify patients with PMF and predict survival. The DIPSS was further modified to DIPSS plus41 by including

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thrombocytopenia, unfavorable karyotype, and RBC transfusion need as additional risk factors. An analysis of risk factors for leukemic transformation, in the context of DIPSS plus, identified unfavorable karyotype and platelet count less than 100
109/L as being the most important: patients with no risk factors had a risk of leukemic transformation at 5 years of 6% and at 10 years of 12%, whereas the risk was substantially higher in patients with 1 or more risk factors at 18% and 31% at 5 and 10 years, respectively.35 Subsequent studies have confirmed the adverse effect of specific cytogenetic abnormalities, including monosomal and complex karyotypes.40 In a study of 793 patients with PMF, the 2-year rate of leukemic transformation was 29.4% in patients with monosomal karyotype compared with 8.3% in patients with complex karyotype.40 Mutually exclusive driver mutations upregulating the JAK-STAT signaling pathway are frequent in MPN. JAK2 mutations are almost always present in patients with PV, whereas their incidence in PMF and ET is similar and estimated at 60%.47 In ET and PMF, the remaining 40% of patients harbor either CALR (25%-35%)48-54 or MPL (3%8%) mutations.47 Approximately 10% to 15% of patients with ET or PMF do not express any one of the aforementioned 3 driver mutations and are often referred to as being “triple negative.”10,55 The prognostic role of driver mutations, in terms of leukemic transformation, is best recognized for PMF where a higher risk has been associated with triple negative and a lower risk with CALR type 1 mutation status.10 The most elaborate studies assessing the prognostic role of mutations comes from 2 patient cohorts from Mayo Clinic and Florence, Italy.44 These studies identified ASXL1, SRSF2, IDH1, or IDH2 mutations as independent risk factors for leukemic transformation. The contribution of these mutations in conferring high risk for leukemic transformation was reported in other studies as well.56-59 A Genetics-Based Prognostic Scoring System for PMF that integrated karyotype information and mutation status was recently reported in an abstract form at the American Society of Hematology annual meeting.60 Cytogenetic risk categorization included very Mayo Clin Proc. n July 2017;92(7):1118-1128 www.mayoclinicproceedings.org

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high (monosomal karyotype, inv(3), i(17q), 7/7q-, 11q, or 12p abnormalities), high (complex nonmonosomal, 2 abnormalities not included in the very high risk category, 5q-, þ8, other autosomal trisomies except þ9, and other sole abnormalities not included in other risk categories), intermediate (sole abnormalities of 20q-, 1qþ or any other sole translocation, and -Y or other sex chromosome abnormality), and low (normal or sole abnormalities of 13q- or þ9). Mutational status was considered favorable in the presence of CALR type 1/type 1elike variants and unfavorable in the presence of ASXL1, SRSF2, EZH2, and IDH1/2 mutations. The integration of karyotype and mutational status allowed risk stratification into high, intermediate 2, intermediate 1, and low risk groups, with the Genetics-Based Prognostic Scoring Systemeidentified high-risk group displaying the highest risk of leukemic transformation; leukemia-free survival was significantly different between the high-intermediate 2 group vs low-intermediate 1 group (median, 11.6 years vs not reached), and this was validated in another independent cohort.60 Most recently, a Mayo Clinic study of targeted sequencing in PMF identified ASXL1, SRSF2, CBL, and KIT mutations as interindependent risk factors for overall survival.57 Univariate analysis for leukemiafree survival identified SRSF2, RUNX1, CEBPA, SH2B3, and IDH2 mutations as risk factors, and the first 4 remained significant in that regard in multivariate analysis. RISK FACTORS FOR LEUKEMIC TRANSFORMATION IN PV It is now well established that treatment of patients with PV treated with P32, chlorambucil, or pipobroman results in a higher risk of leukemic transformation.39,61 Older age,17,29 leukocytosis,17,62 and abnormal karyotype17 have also been associated with a higher risk of leukemic transformation. A recent Mayo Clinic study evaluated 133 patients with PV, in which 5.4% had documented leukemic transformation.63 Sequence variants or mutations in PV other than JAK2, CALR, or MPL were seen in 52.6% of patients. ASXL1, SRSF2, and IDH2 were identified as adverse variants or mutations on the basis of their effect on overall, leukemia-free, or MF-free

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survival. In particular, SRSF2, IDH2, and RUNX1 mutations were associated with shortened leukemia-free survival in univariate analysis; SRSF2 and IDH2 mutations remained significant in multivariate analysis.

RISK FACTORS FOR LEUKEMIC TRANSFORMATION IN ET The reported incidence of leukemic transformation in ET has varied from less than 1% to almost 10% in some studies. In this regard, the 10-year rates from earlier studies have ranged from 2.6%27 to 8.3%-9.7%.33,64,65 More recent studies that have carefully excluded patients with prefibrotic PMF from their study population suggest a remarkably lower rate of less than 1% at 10 years and 2% in 15 years in WHO-defined ET.6,66 In regard to risk factors for leukemic transformation in ET, Gangat et al28 studied 605 consecutive patients and identified anemia with hemoglobin levels below sex-adjusted normal values, extreme thrombocytosis (1000
109/L), and age as continuous variables for leukemic transformation; the first 2 risk factors were included in a prognostic model that predicted leukemic transformation, and the particular risk was low at 0.4% when both risk factors were absent and was significantly higher at 4.8% and 6.5% in the presence of one or both risk factors, respectively (P<.001). Other risk factors for leukemic transformation in ET identified by other studies include leukocytosis (15
109/L),33,34 extreme thrombocytosis (1000
109/L),6,28 anemia,28,32,34 older age,27,28 and increased reticulin content or bone marrow cellularity6,34; it is possible that the last 2 parameters segregated with incorrectly diagnosed cases with prefibrotic PMF. The effect of cytoreductive drugs in leukemic transformation of patients with ET was examined in several studies including a cohort of 338 patients67 in which single agent treatment with hydroxyurea or busulfan did not appear to increase the risk of leukemic transformation. Many other retrospective studies have also validated the absence of convincing evidence for drug leukemogenicity in ET, although reports to the contrary are also noted.33 Regardless, there is general agreement on the absence of controlled data 1122

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that implicate any 1 drug or combination thereof as being leukemogenic in ET. More recent studies have examined the role of driver and other mutations in the development of leukemia in ET. Among the 3 MPN-associated driver mutations, MPL mutations have been associated with a higher risk of fibrotic progression but their effect on leukemic transformation was either not apparent68,69 or noted during longer-term follow-up.53 A Mayo Clinic study63 of targeted sequencing recently identified TP53, EZH2, SRSF2, and IDH2 variants or mutations as being associated with a higher risk of leukemic transformation in univariate analysis; TP53 and EZH2 remained significant in multivariate analysis. OUTCOME OF PATIENTS WITH MPN-BP The survival of patients with MPN-BP is generally considered to be extremely poor (Table 2). This is not unexpected, given its high-risk morphological and cytogenetic features compared with those of both chronic phase MPN and primary AML. Blast-phase myeloproliferative neoplasms are often, but not always, preceded by a fibrotic phase of the disease.36 In the largest retrospective review of 273 patients with MPN-BP treated with hypomethylating agents (n¼99), high-dose cytarabine (n¼71), or low-dose cytarabine (n¼52),81 progression-free or overall survival did not differ among the treatment groups; 46 patients subsequently received ASCT, with 27 in complete remission (CR), and median survival was longer in patients in CR vs patients not in CR (35.1 months vs 8.9 months). The authors also noted that treatment outcome had not changed between 1989 and 2016. In a similarly large study,19 we reported on 91 consecutive cases of MPN-BP; the overall outcome was poor, with a median survival of 2 to 3 months of the subgroup who received induction chemotherapy and responded faring a little better with a median survival of 6.2 months as opposed to 2.7 months of patients who did not respond to treatment (P¼NS). Only 1 patient had received ASCT and survived for more than 2 years.19 There are several other reports in the literature on MPN-BP. Tam et al16 reported on 74 patients and also documented

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99 pts, 7.8 mo, HMA, 52 pts, 8 mo, low dose

19 pts, 9.9 mo, azacytidine

21 pts, 6.9 mo, decitabine

18 pts, 0% response

18 pts, 17% response 15 pts, 6.6 mo

26 pts, 8 mo, azacitidine 6 pts, >9 mo, decitabine

8 pts, 2.5 mo, low dose 19 pts, 2.9 mo, low dose 12 pts, 7 mo, low dose

26 11 14 23 13 18 75 46 60 21 18 19 13 273 Thepot et al,70 2010 Mascarenhas et al,13 2010 Ciurea et al,71 2010 Noor et al,11 2011 Cherington et al,72 2012 Eghtedar et al,73 2012 Kennedy et al,74 2013 Alchalby et al,75 2014 Cahu et al,76 2014 Badar et al,77 2015 Pemmaraju et al,78 2015 Andriani et al,79 2015 Shanavas et al,80 2016 Chihara et al,81 2016

7 pts, 2.5 mo 48 pts, 2.1 mo 19 pts, 1.5 mo 23 91 74 Passamonti et al,20 2005 Mesa et al,19 2005 Tam et al,16 2008

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HMA ¼ hypomethylating agent; mOS ¼ median overall survival; OS ¼ overall survival; PFS ¼ progression-free survival; pts ¼ patients.

71 pts, 7.1 mo

13 pts, 32% 2-y OS 46 pts, 15.3 mo

17 pts, 47 mo 46 pts, 33% 3-y OS 60 pts, 16% 3-y OS

20 pts, 6 mo

13 pts, 9.4 mo

5 pts, >20 mo 14 pts, 31 mo 3 pts, 10.5 mo 8 pts, 75% 2-y PFS

1 pt, survived >70 d 1 pt, survived >57 mo 8 pts, 73% survival, median follow-up 31 mo 8 pts, 5.6 mo 24 pts, 3.9 mo 36 pts, 6 mo

Induction chemotherapy: n, mOS JAK2 inhibitor ruxolitinib HMA or low-dose chemotherapy: n, mOS Supportive care: n, mOS N Reference, study

TABLE 2. Survival Outcomes of Blast-Phase Myeloproliferative Neoplasms

responses to AML-like induction chemotherapy that were not, however, durable but with improved survival as compared with supportive care (median, 6 months vs 1.5 months); of note, patients who received ASCT at any point during their treatment had better survival than did those who did not receive ASCT, and the survival advantage was even more evident for early transplant with 73% survival at a median follow-up of 31 months; the authors identified older age, peripheral blasts of 20% or more, and previous splenectomy as independent risk factors for survival.16 Passamonti et al20 reported the outcome of MPN-BP after PV and found similar survival between patients who had received AML-like induction chemotherapy (median, 5.6 months) or palliation with low-dose chemotherapy (cytarabine or 6thioguanine) or supportive care (median, 2.5 months). Noor et al11 studied 23 patients with MPN-BP, among whom 20 received AML-like induction chemotherapy, with 12 achieving remission; median survival was higher in responding patients at 12.8 months compared with 2.9 months in patients who did not achieve remission; 3 patients underwent ASCT with a median survival of 10.5 months. The authors subsequently scanned the literature and gathered information on 112 patients with MPN-BP to identify favorable risk factors for survival: antecedent diagnosis of ET, absence of complex karyotype, age less than 60 years, and less than 3 previous therapies. In yet another study of 13 patients with MPN-BP, 11 were treated with AML-like induction chemotherapy, with 8 patients achieving complete response, reversal to chronic phase disease, or marrow blast clearance72; 8 patients underwent ASCT, including 5 patients with less than 5% blood and bone marrow blast, 2 patients with peripheral blasts, and 1 patient with more than 5% bone marrow blast; outcome in this small study was better in the absence of excess bone marrow blast, but patients with circulating blasts were still salvageable. Hypomethylating agents, such as azacitidine and decitabine, have also been shown to have activity in MPN-BP; in a study of 26 patients treated with azacitidine, a 38% response rate (median time to response,

Allogeneic stem cell transplant: n, mOS or survival

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9 months) with an overall median survival of 8 months was reported.70 In that study, the authors observed better responses in post-ET, as opposed to post-PV, MPN-BP, with no significant difference in overall survival.70 Another study reviewed patients with MPN-BP treated with azacytidine (75 mg/m2) and found that the observed median survival of 9.9 months was better than that of their historical controls79; once again, the median survival of patients who achieved CR was even better at 19.6 months. In a retrospective comparison to 6 patients treated with decitabine, the 5 who received low-intensity ASCT survived longer, with a median survival of more than 20 months.13 Similar observations were noted in another study of 14 patients with MPN-BP who received ASCT after first being chemotherapy-induced and 2-year survival was reported at 49%.71 Badar et al77 studied the use of decitabine in 21 patients with MPN-BP; 6 patients responded (3 CR, 2 near CR, and 1 partial response), and survival was better in responders vs nonresponders (median, 10.5 months vs 4 months); the authors did not find survival difference between decitabine-treated patients and historical controls treated with AML-like induction chemotherapy without ASCT. Kennedy et al74 adopted an approach of using curative intent treatment with induction chemotherapy followed by ASCT in fit and transplant-eligible patients. Seventy-five patients were included in the study, with 39 patients receiving AML-like induction chemotherapy followed by ASCT in eligible patients (17 of 39). The 36 other patients were treated with noncurative intent using hypomethylating agents, novel agents, or supportive care. Two-year survival was superior at 25.6% vs 3.1% in patients treated with curative intent. Furthermore, median survival was impressive at 47 months in patients who received ASCT and was not affected by the type of conditioning regimen. Induction chemotherapy without ASCT was unable to induce long-term remissions and resulted in a median survival of 9.4 months. The transplant cohort and the induction chemotherapy arm with responses but without transplant were compared, and survival was significantly better in the transplant group (2-year survival of 47% vs 15%; P¼.03). The median survival for 1124

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low-intensity regimens was 6.6 months. This study further stressed the importance of ASCT as an adjunct to induction chemotherapy. The MPN Subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation studied 46 patients with MPN-BP who received ASCT.75 At a median follow-up of 37.4 months, progression-free survival and overall survival at 3 years were 26% and 33%, respectively. The major determinant of survival after ASCT was achievement of CR before transplant (69% vs 22%; P¼.008). A study in France analyzed the outcomes of ASCT in patients with MPN-BP or myelodysplastic syndrome (MDS)/MPN-BP76; 60 patients were studied and overall survival and leukemia-free survival at 3 years were 16% and 9%, respectively. As expected, outcome was better in patients receiving transplant in CR, while intensity of the conditioning regimen did not affect survival.76 A Canadian MPN group conducted a study to evaluate the survival effect of ASCT in patients with MF previously exposed to JAK inhibitors80; their patient cohort of 100 included 13 who progressed into MPN-BP while receiving JAK inhibitor; patients with MPN-BP received AML-like induction chemotherapy or hypomethylating agents before transplant; 2-year post-ASCT survival was worst in patients with MPN-BP (32%), and the poor outcome was attributed to a higher relapse rate. In regard to ruxolitinib activity in MPN-BP, a phase 2 study was conducted in refractory AML, including 18 patients with MPN-BP and exhibited limited activity.73 INVESTIGATIONAL AGENTS Blast-phase myeloproliferative neoplasms are relatively resistant to conventional chemotherapy with the only curative hope being ASCT, as discussed above, necessitating the need to develop novel therapies. Bromodomain and extra terminal domain inhibitors (BETis) target epigenetic proteins in cancer and were studied in patient-derived MPN blast progenitor cells and exhibited activity inducing apoptosis and inhibiting growth82; furthermore, synergism was observed when BETis were combined with ruxolitinib. In another study, combination of BETi with heat shock protein 90 inhibitor

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exerted effects on ruxolitinib-persisting or ruxolitinib-resistant MPN blast cells. This was based on a previous finding reported by this team that heat shock protein 90 inhibitor reduces mutant JAK2, AKT, and c-RAF as well as induces apoptosis in JAKi-resistant MPN blast cells.83 CPX-351 is a liposome formulation of cytarabine and daunorubicin and recently received breakthrough therapy designation in May 2016 for therapy-related AML or AML with myelodysplasia-related changes. Ex vivo sensitivity using CPX-351 in leukemia cells from different sources exhibited activity against myeloid blasts derived from patients with MPN/MDS overlap.84 Moreover, the improved survival (median, w10 months with CPX-351 vs w6 months with the standard “7þ3” AML therapy; P¼.005) reported in the relevant phase III trial of CPX-351 involved older patients and high-risk AML, including therapy related and with antecedent MDS or chronic myelomonocytic leukemia.85 Accordingly, it makes sense to investigate the therapeutic value of CPX-351 in MPN-BP, which happens to be a form of secondary AML and usually affects older patients. CONCLUSION The prognosis of MPN- BP remains dismal and appears to be worse than that of primary AML. Drug therapy alone, although capable of inducing CRs in a minority of patients, is ineffective in securing long-term remissions. Furthermore, despite increasing information on mutational repertoire in MPN-BP, the promise for targeted therapy in the near future is currently slim. Durable remissions have been noted in few patients who managed to receive ASCT, but the overall experience with the particular treatment modality has been less than impressive. It is possible that one can reduce the case numbers with MPN-BP using MPN treatment that modifies the natural history of disease, but the particular scenario has yet to be realized. Current prognostic models for MPN are useful in predicting leukemic transformation, and incorporation of molecular information might lead to further refinement of these models. For now, the only hope for cure or long-term remission in MPN-BP remains ASCT, and every effort should be made to identify Mayo Clin Proc. n July 2017;92(7):1118-1128 www.mayoclinicproceedings.org

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patients with MPN who are at high risk for leukemic transformation so that they can be offered treatment with ASCT sooner rather than later. Abbreviations and Acronyms: AML = acute myeloid leukemia; ASCT = allogeneic stem cell transplant; BETi = bromodomain and extra terminal domain inhibitor; CR = complete remission; DIPSS = Dynamic International Prognostic Scoring System; ET = essential thrombocythemia; FAB = French-American-British; MDS = myelodysplastic syndrome; MF = myelofibrosis; MPN = myeloproliferative neoplasm; MPN-BP = blast-phase myeloproliferative neoplasm; PMF = primary myelofibrosis; PV = polycythemia vera; RBC = red blood cell; WHO = World Health Organization Correspondence: Address to Ayalew Tefferi, MD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Tefferi.ayalew@mayo. edu). Individual reprints of this article and a bound reprint of the entire Symposium on Neoplastic Hematology and Medical Oncology will be available for purchase from our website www.mayoclinicproceedings.org. The Symposium on Neoplastic Hematology and Medical Oncology will continue in an upcoming issue.

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