acute leukemia arising from the myeloproliferative disorders: challenge and opportunity

The bcr-abl–Negative Myeloproliferative DisordersThe bcr-abl–negative chronic myeloproliferative disorders (MPDs; polycythemia vera [PV], essential thrombocythe-

mia [ET], and primary myelofibrosis [PMF]), first described by William Dameshek in 1951,1 are currently in a period of rapid discovery regarding their pathogenetic mechanisms. The watershed moment for MPDs occurred in 2005 with the heavily publicized discovery of the JAK2V617F mutation.2-5 This latter point mutation, in the pseudo-kinase domain of JAK2 (a key component of the cell growth and differentiation JAK-STAT pathway), leads to constitutive activation of the pathway. Additional genetic mutations with potential pathogenetic implications have also been described, includ-ing the c-MPLW515L/K (in 5% of PMF and 1% of ET)6 and alternative mutations in the exon 12 of JAK2 in some patients who had PV previously identified as wild type for JAK2.7

The MPDs have a variable period of risk for vascular events and a long-term risk for transformation to an overt myelofibrotic phase, acute leukemia, or death (Figure 1). Current available therapies have rarely been able to affect this natural history beyond palliating symptoms or decreasing the risk for vascular events. This article focuses on the most advanced clinical scenario for patients who have MPD and the biology and consequence of blastic transformation.

Phenotype of Leukemic Transformation in the Myeloproliferative DisordersDisease progression in myeloproliferative disorders is the development of overt acute leukemia with a variable risk

(Table 1)8-15 among patients who have MPD, or what is most appropriately called a blast phase (Figure 1).8 Clinically, as

Division of Hematology, Mayo Clinic, Rochester, MN

Submitted: Mar 23, 2008; Revised: Apr 28, 2008; Accepted: May 8, 2008

Address for correspondence: Ruben A. Mesa, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905Fax: 507-266-4972; e-mail: [email protected]

Acute Leukemia Arising from the Myeloproliferative Disorders: Challenge and Opportunity

The classical myeloproliferative disorders (MPDs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis have an increasing predisposition to transform to overt acute leukemia or MPD-blast phase (MPD-BP). Current therapies for the MPDs are limited, and no therapy other than allogeneic stem cell transplantation (alloSCT) has clearly altered the natural history of these disorders. Pathogenetic mechanisms that lead to an MPD progressing to MPD-BP are incompletely understood but seem to correlate with the accumulation of additional karyotypic abnormalities as opposed to increases in MPD-associated molecular lesion burden (such as JAK2V617F). The development of MPD-BP is heralded by worsening cytopenias, constitutional symptoms, and a poor survival despite therapeutic intervention. Risk factors for developing MPD-BP include features at diagnosis (such as increased peripheral blood blasts, karyotypic abnormali-ties, and thrombocytopenia) and exposure to established agents that enhance leukemogenesis (ie, P-32 and alkylators). Multiple avenues of therapeutic investigation are ongoing to treat or prevent MPD-BP, including early alloSCT, hypomethylating agents, and JAK2 inhibition. An improved understanding of the pathogenetic underpinnings of MPD-BP are necessary if more effective targeted therapies are to be developed.

Clinical Leukemia, Vol. 2, No. 4, 252-256, 2008; DOI: 10.3816/CLK.2008.n.034Keywords: Acute myeloid leukemia, Blast phase, Leukemic transformation

Ruben A. Mesa

Comprehensive Review

Abstract

Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP,ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Clinical Leukemia • November 2008252

Clinical Leukemia • November 2008 253

patients progress, they tend to experience a decrease in the efficacy of intramedullary hematopoiesis as manifested by worsening throm-bocytopenia, worsening constitutional symptoms, and the potential development of functional neutropenia.17 Patients most commonly reach a blast phase after first having gone through a myelofibrotic phase, whether PMF or post–essential thrombocythemia/polycythe-mia vera myelofibrosis (post–ET/PV MF).17 Patients who have PV or ET have been known to develop a blast phase without a clearly distinct prodrome of myelofibrosis developing, however.18

Pathogenesis of Blastic Transformation in Myeloproliferative Disorders

The pathogenetic mechanisms of transformation to MPD blast phase (MPD-BP) remain unclear. Although a growing number of MPD-associated mutations lead to activation of the JAK-STAT pathway (ie, JAK2V617F, exon 12, and MPL mutations), it is unclear whether these are disease-initiating mutations.19 The mechanisms by which these mutations can lead to widely varying disease phenotypes, or what leads to disease progression, remains unclear.19 Available evidence has shown that (1) neither the pres-ence of a JAK2-V617F mutant20 nor an increased allele burden8 is more common in those who undergo MPD-BP, and (2) the majority,21 but not all,9 isolated acute leukemia clones obtained from patients who were previously JAK2-V167F mutant will have reverted to a JAK wild-type state. Whether these MPD mutations play some passive role in the subsequent development of other more aggressive clones is under investigation.

The transformation of CML from CP to BP is typically associ-ated with additional karyotypic abnormalities, which are indepen-dent of the bcr-abl translocation.22 We have shown that patients who have MPDs that eventually transform are more likely to have

karyotypic abnormalities at diagnosis and develop new abnormali-ties before MPD-BP.11,17 The process of MPD-BP might mirror CML-BC in that chromosomal instability and additional muta-tions are crucial for blastic transformation.

Defining Blastic Transformation from the Myeloproliferative DisordersWorld Health Organization Definition of Acute Leukemia

The complex implications of BP in patients who have a previ-ous MPD arises in part from lack of clear diagnostic guidance as to what constitutes acute leukemia in these patients. Patients who have all chronic myeloid disorders exist in a spectrum of disease severity from the point of their diagnosis to acute leukemia. What constitutes this latter threshold in between is an arbitrary set point in a biologic continuum. The World Health Organization in their classification

Clinical and Pathogenetic ChangesOccurring During Myeloproliferative

Disorder Progression

Figure 1

Evolution of an MPD to MPD-BP

Abbreviations: ET = essential thrombocythemia; LDH = lactate dehydrogenase; MPD = myelopro-liferative disorders; MPD-BP = MPD–blast phase; PV = polycythemia vera; PMF = primary myelofibrosis; Post–ET/PV MF = post–essential thrombocythemia/polycythemia vera myelofibrosis

Post–ET MF

Post–PV MF

PMF

MPD-BP

PMF

PV

ET

Clinically�Splenomegaly

�Anemia�Constitutional

symptoms�Fibrosis

Clinically�Platelets�LDH�Blasts

�Symptoms

Pathogenesis? JAK2V617F

? MPL mutations? Other drivers ofstromal reaction

Pathogenesis�Karyotype

changes? Role of JAK2

mutations? Contributionfrom therapy

Risk Factors at Presentation of PrimaryMyelofibrosis that Suggest High Risk

for Eventual Transformation (Myeloproliferative Disorders–Blast Phase)

Table 1

Demographics

Huang et al11

Huang et al11

Peripheral Blood

Huang et al11

Tefferi et al12

Huang et al11

Huang et al11

Huang et al11

Physical Examination Features

Huang et al11

Bone Marrow

Mesa et al10

Mesa et al10

Mesa et al10

Mesa et al10

Molecular Lesions

Tefferi et al8 Swierczek et al9

MyelofibrosisPrognostic Scores

Huang et al11

Huang et al11

Huang et al11

Age at diagnosis

Sex

Hemoglobin

Leukocyte count

Platelet count

Presence of blasts

Blast percentage

Splenomegaly

Cellularity

Reticulin fibrosis

Blast percentage

Karyotypic abnormalities(complex > 2 lesions)

JAK2V617F

MPL mutations

Lille score13

Cervantes score15

Mayo score14

Risk Factor

None

None

Yes, univariate only

Yes (> 15 × 109/L)

None

Yes

Yes (greatest when > 3%)

None

None

None

Yes

Yes

Low allele burden

No data available

None



Association withDeveloping MPD-BPStudy

Abbreviation: MPD-BP = myeloproliferative disorders-blast phase

of myeloid neoplasms in 2001 classified MPD-BP as acute myeloid leukemia (AML) with multilineage dysplasia.22 This subgroup was further divided into those who had a previous case of myelodysplastic syndrome (MDS) or an MPD/MDS overlap disorder.23 This defini-tion is most pertinent to those who have an MPD/MDS overlap dis-order (chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or MPD/MDS unclassifiable), yet it does not really address those who have previous PMF, post-ET/PV MF, or previous ET/PV.

The threshold for a diagnosis of achieving BP was 20% blood or marrow blasts or the presence of a acute leukemia–defining karyotypic lesions despite blast percentage (t[8;21][q22:q22], inv[16][p13;q22], t[16;16][p13;q22], or t[15;17][q22;q12]).23 One problem with these criteria is that although karyotypic abnor-malities are quite common among patients who have MPD-BP,17 it is less clear that these defining mutations play any role in a trans-formed MPD17 as opposed to de novo AML.

Assessing the Importance of Peripheral Blast Percentage

Patients who have MPDs, particularly PMF and post-ET/PV MF are predisposed to circulating myeloblasts in the peripheral blood.24,25 This latter phenomenon is true even when there is not a clear increase in bone marrow blast percentage. Reasons for this phenomenon relate to the abnormal trafficking of immature myeloid cells in these patients, which could orginate from abnormalities of the marrow stroma and is likely responsible for the increased circualting CD34+ cells in these patients.26 Clinically, patients have been shown to have increased peripheral blood blasts for long periods of time without evidence of BP occurring.27 Based on this phenomenon the International Working Group for Myelofibrosis Research and

Treatment (IWG-MRT) has included among their clinical trial cri-teria that a patient in a trial must have a sustained peripheral blood blast percentage > 20% for 4 weeks sustained before acute leukemia can be declared.28 Until more is known regarding the biologic under-pinnings of a change from an MPD to MPD-BP, arbitrary clinical cutoffs will remain somewhat cumbersome. Some patients can have a clinical phenotype of MPD-BP with 15% blasts and die from their disease, whereas others who have a higher blast burden might have a more indolent course.

Risk Factors for Blastic TransformationRisk Factors at Presentation

Risk factors for the development of MPD-BP have been of great interest for two main reasons. First, they can be used to identify patients at high risk for death from their disease to use more aggres-sive therapy, such as allogeneic stem cell transplantation (alloSCT), earlier in the course of their disease.29 Second, they can be used to avoid unnecessary introduction of therapy for these patients earlier in the course of their disease, which could exacerbate this underly-ing predisposition to acute leukemia.18,30 Analysis of risk factors for MPD-BP are features present (ie, intrinsic to their MPD) at diagnosis or during the course of disease (including therapy).

Prognostication for patients who have MPDs, done at the time of diagnosis, can look at risk for vascular events (mainly for ET and PV), death, and development of blast phase (which unfortunately usually leads to rapid death). Of these latter endpoints, we focus on mortality and transformation. The most useful prognostic systems for MPDs (and particularly PMF) are those that have used informa-tion from the peripheral blood counts. The Lille criteria13 (based on aberrations in leukocyte count [< 4 or > 30 × 109/L] and/or anemia [hemoglobin < 10 g/dL]) can help distinguish survival into risk groups. The additive predictive power of thrombocytopenia (platelet count < 100 × 109/L) to the Lille criteria (the Mayo score14) adds discriminatory capacity. Although limited data exist on predicting eventual leukemic transformation, our group has


Myeloproliferative DisorderTherapies and Their Association with

Myeloproliferative Disorders–Blast Phase

Table 2

Medical

Finazzi et al18

Huang et al11

Huang et al11

Petti et al33

Najean and Rain34

Kiladjian et al31

Osgood31

Parmentier32

Huang et al11

Surgical

Barosi et al37

Mesa et al38

Hydroxyurea

Erythropoiesis-stimulating agents

Androgens

Melphalan

Pipobroman

Phosphorus-32

Thalidomide

Splenectomy

Therapy

Only as combination therapy

Higher rate of blastic transformationin PMF patients treated with ESAs

Higher rates of transformationin PMF, especially with danazol

Higher rates of transformationin trials of patients with PMF

Higher leukemia ratesin treated patients with PV

Clear and undisputed increasedrisk for transformation with use

No increased rate seen

Conflicting reports, but noclear link established

AssociationStudy

Abbreviations: ESAs = erythroid-stimulating agents; PMF = primary myelofibrosis; PV = polycythemia vera

Medical Options for MyeloproliferativeDisorders–Blast Phase17

Table 3

Supportive Care

Non-InductionChemotherapy

InductionChemotherapy

Antibody Therapy

• Transfusions• ± Hydroxyurea• ± Antibiotic support

• Weekly vincristine• Oral alkylators• Low-dose Ara-C• Oral etoposide

• Ara-C+ anthracycline (7 days)• High-dose Ara-C (> 1000 mg/m2/dose)• Mitoxantrone/etoposide/ high-dose Ara-C

• Gemtuzumab

Composition

2.1 (1.1-3.4)

2.9 (0.8-5.3)

3.9 (1.6-8.9)

2.5 (0.7-3.5)

Median Survival,Months (Range)*Therapy

*Median survivals according to Mayo Clinic Series.Abbreviation: Ara-C = cytarabine

AML Arising from MPDs

254


Ruben A. Mesa

255

shown that (1) low JAK2V617F allele burden,8 (2) peripheral blast percentage > 3%,11 and (3) thrombocytopenia present at diagno-sis11 are associated with higher risk for MPD-BP in these patients. Additionally, our IWG-MRT analysis would suggest that patients who eventually transform are more likely to have higher lactate dehydrogenase levels and more karyotypic abnormalities.10 No uniform prognostic score for MPD-BP yet exists (Table 1).

Influence of Therapy on the Development of Myeloproliferative Disorders–Blast Phase

The potential of therapy to accelerate the development of MPD-BP has long been a concern in patients who have MPD. Therapy-related acute leukemia has long been a concern with chemotherapy of malig-nant neoplasms and is of greater concern in patients who have underly-ing myeloid disorders (Table 2).10,28-33,35,36 Specific to MPDs, the use of myelosuppressive therapy with radioactive phosphorus (P-32)31,32 is most clearly associated with increased risk for MPD-BP, along with alkylator therapy, such as melphalan33 and pipobroman.34,35 Much controversy exists regarding the agent hydroxyurea, a valid and effica-cious myelosuppressive agent demonstrated to decrease risk for vascular events in patients who have ET and PV. Despite much discussion, evidence now suggests that single-agent hydoxyurea is not a significant contributor to leukemic transformation. Hydroxyurea has not been shown to be leukemogenic in the unrelated disorder of sickle cell anemia.36 There might be a synergistic leukemogenic potential role of hydroxyurea, however, in patients who then go on to receive other treatments.18 In the end there is no way to definitively negate a slight role of hydoxyurea on the risk for leukemic transformation; therefore, patients should be counseled accordingly. There are other agents with no suggestion of leukemogenicity (acetylsalicylic acid, anagrelide, and interferon).11 Our recent analysis suggested an independently increased risk for MPD-BP among patients exposed to erythroid-stimulating agents and androgen (particularly danazol).11 This risk was indepen-dent of anemia and was significant in multifactorial analysis. Whether there is a causal role remains unclear, and these single-institution observations do require further validation. Finally, patients who have undergone splenectomy for PMF have been reported in some series to have higher rates of transformation,37 but it remains unclear whether this might be merely an association in patients who have a more aggres-sive disease course.38

Clinical Course and Therapy of Myeloproliferative Disorders–Blast Phase

When a patient progresses to MPD-BP, significant morbidity and mortality usually follow.17 Clinically, patients have all of the challeng-ing peripheral blood cytopenias typical in de novo acute leukemia. Additionally, they face the significant debilitation, cachexia, and poor performance status already present from their MPD. They frequently have significant splenomegaly contributing to symptoms and to transfusion resistance.

Patients who have MPD-BP frequently have multiple features that are considered characteristic of high-risk acute leukemia, specifically advanced age, antecedent myeloid disorder, and complex and poor-risk karyotypic abnormalities.17 It is not surprising, therefore, that therapy for these patients has been disappointing. We have previously

demonstrated that aggressive therapy (with myelosuppressive induc-tion intent) did not seem to offer any survival benefit over purely supportive care (transfusions with or without hydroxyurea). Details of therapies and outcomes are listed in Table 3. Patients who under-went induction therapy had a 40% chance of returning to a more chronic-appearing phase of PMF but without any clear effect on sur-vival. Induction therapy might only provide a cosmetic cytoreduction in blasts without meaningful effect.17 Interestingly, an IWG-MRT analysis showed patients who died from MPD-BP or PMF complica-tions had a similar survival from their PMF diagnosis.10

The reasons for the lack of success of therapy in MPD-BP are many and include intrinsic drug resistance, lack of tolerability, and death from exacerbation of comorbidities. Given the dire conse-quence of transformation, if aggressive disease-altering therapy is to be used (ie, alloSCT39) it should be used before the patient devel-ops MPD-BP. Even in transplantation candidates, pretransplanta-tion induction might be needed for cytoreduction. It is an arduous and frequently unsuccessful path for a patient to have induction therapy followed by alloSCT in MPD-BP.

Because of the dire outcomes with MPD-BP therapy, the interest in novel therapeutic options is great. Many separate approaches are being investigated. The first is the use of JAK2 inhibitors (Table 4).40-47 Although it is unclear whether MPD-associated mutations might play a role in developing MPD-BP, perhaps inhibition here might still have some efficacy (ie, analogous to imatinib mesylate from CML-BP48). More likely, however, these agents might play a role in preventing even-tual transformation. Additional avenues of exploration include using hypomethylation agents (such as azacytidine and decitabine41,42), which have been used in high-risk MDS, or farnesyltransferase inhibi-tors (such as tipifarnib43), which have been active in elderly patients with AML.49 Clofarabine, active in high-risk AML and MDS, is also of interest and deserves investigation.50 We have previously demonstrated that the heat-shock protein–90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) can help abrogate cytarabine (Ara-C) resistance in primary cells of patients who have MPD-BP.44 A multicenter phase I clinical trial is ongoing using combination treatment with 17-AAG and Ara-C for patients who have high-risk acute leukemia and MPD-BP. Patients who have MPD-BP should be considered for appropriate high-risk acute leukemia trials or, if not a

Novel Therapies Under Investigation forMyeloproliferative Disorders–Blast Phase

Table 4

Mesa et al44

Mesa et al43

Verstovsek et al45

Verstovsek et al46

Lasho et al47

Odenike et al41

Quintas-Cardama et al42

17-AAG with Ara-C

Tipifarnib

INCB018424

XL019

TG101348

Aza C

Decitabine

Agent

Heat-shock protein–90

Farnesyltransferase

JAK2 inhibitor

JAK2 inhibitor

JAK2 inhibitor

Hypomethylating agent

Hypomethylating agent

TargetStudy

Abbreviation: 17-AAG = 17-allylamino-17-demethoxygeldanamycin; Ara-C = cytarabine; Aza C = azacytidine

candidate for these trials, should be offered supportive care given the lack of benefit with currently available agents.

ConclusionThe progression of patients to MPD-BP is an extremely serious

development, both symptomatically and prognostically. Although we have a partial understanding of risk factors for eventual trans-formation, we have an incomplete understanding as to the patho-genetic mechanisms of disease progression. Because of the rapid mortality and resistance to current therapies observed in patients who have MPD-BP, the need for novel and targeted therapy for these patients is great. A better understanding of mechanisms of clonal progression is required to identify valid therapeutic targets. It is hoped that blockade of JAK2 earlier in the course of an MPD will delay or inhibit disease progression, yet whether this will occur depends on long-term follow-up on current JAK2 inhibitor trials. Because of the uncertain role that the JAK-STAT pathway main-tains in the process of leukemic transformation, the need for further study into mechanisms of disease progression is crucial.

References 1. Damashek W. Some speculations on the myeloproliferative syndrome. Blood 1951;

6:372-5. 2. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2

in human myeloproliferative disorders. Lancet 2005; 365:1054-61. 3. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in

myeloproliferative disorders. N Engl J Med 2005; 352:1779-90. 4. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to consti-

tutive signalling causes polycythaemia vera. Nature 2005; 434:1144-8. 5. Levine RL, Wadleigh M, Cools J. Activating mutation in the tyrosine kinase JAK2 in

polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metapla-sia. Cancer Cell 2005; 7:387-97.

6. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108:3472-6.

7. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356:459-68.

8. Tefferi A, Lasho TL, Huang J, et al. Low JAK2V617F allele burden in primary myelo-fibrosis, compared to either a higher allele burden or unmutated status, predicts inferior overall and leukemia-free survival. Leukemia 2007; 22:756-61.

9. Swierczek SI, Yoon D, Prchal JT. Blast transformation in a patient with primary myelo-fibrosis initiated from JAK2 V617F progenitor. Blood 2007; 110: (Abstract 4665).

10. Mesa RA, Cervantes F, Verstovsek S, et al. Clinical evolution to primary myelofibrosis - blast phase: an International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) collaborative retrospective analysis. Blood 2007; 110:210 (Abstract 682).

11. Huang J, Li C-Y, Mesa RA, et al. Erythropoiesis stimulating agents and the risk of leu-kemic transformation in primary myelofibrosis. Blood. 2007; 110:170a (Abstract 554).

12. Tefferi A, Gangat N, Wolanskyj AP, et al. Choosing the right patients for clinical trials in essential thrombocythemia or polycythemia vera: leukemic or fibrotic transformation risk assessment among 1061 patients from a single institution. Blood 2007; 110:1038A (Abstract 3546).

13. Dupriez B, Morel P, Demory JL, et al. Prognostic factors in agnogenic myeloid metapla-sia: a report on 195 cases with a new scoring system. Blood 1996; 588:1013-8.

14. Dingli D, Schwager SM, Mesa RA, et al. Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer 2006; 106:623-30.

15. Cervantes F. Prognostic factors and current practice in treatment of myelofibrosis with myeloid metaplasia: an update anno 2000. Pathol Biol (Paris). 2001; 49:148-52.

16. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post poly-cythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofi-brosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res 2007; 31:737-40.

17. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 2005; 105:973-7.

18. Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005; 105:2664-70.

19. Levine RL, Pardanani A, Tefferi A, et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007; 7:673-83.

20. Mesa RA, Powell H, Lasho T, et al. JAK2(V617F) and leukemic transformation in myelofibrosis with myeloid metaplasia. Leuk Res 2006; 30:1457-60.

21. Theocharides A, Boissinot M, Girodon F, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007; 110:375-9.

22. Vardiman JW, Brunning RD, Harris NL. WHO histological classification of chronic myeloproliferative diseases. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization classification of tumors: Tumours of the haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer (IARC) Press; 2001:17-44.

23. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100:2292-302.

24. Cervantes F. Myelofibrosis: biology and treatment options. Eur J Haematol Suppl 2007:13-7.

25. Cervantes F, Mesa R, Barosi G. New and old treatment modalities in primary myelofi-brosis. Cancer J 2007; 13:377-83.

26. Barosi G, Viarengo G, Pecci A, et al. Diagnostic and clinical relevance of the number of circulating CD34(+) cells in myelofibrosis with myeloid metaplasia. Blood 2001; 98:3249-55.

27. Cervantes F, Pereira A, Esteve J, et al. Identification of ‘short-lived’ and ‘long-lived’ patients at presentation of idiopathic myelofibrosis. Br J Haematol 1997; 97:635-40.

28. Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 2006; 108:1497-503.

29. Kroger N, Zabelina T, Schieder H, et al. Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. Br J Haematol 2005; 128:690-7.

30. Wolanskyj AP, Schwager SM, McClure RF, et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006; 81:159-66.

31. Osgood EE. Contrasting incidence of acute monocytic and granulocytic leukemias in P32-treated patients with polycythemia vera and chronic lymphocytic leukemia. J Lab Clin Med 1964; 64:560-73.

32. Parmentier C. Use and risks of phosphorus-32 in the treatment of polycythaemia vera. Eur J Nucl Med Mol Imaging 2003; 30:1413-7.

33. Petti MC, Latagliata R, Spadea T, et al. Melphalan treatment in patients with myelofi-brosis with myeloid metaplasia. Br J Haematol 2002; 116:576-81.

34. Najean Y, Rain JD. Treatment of polycythemia vera: the use of hydroxyurea and pipobro-man in 292 patients under the age of 65 years. Blood 1997; 90:3370-7.

35. Kiladjian JJ, Rain JD, Bernard JF, et al. Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost 2006; 32:417-21.

36. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and mor-bidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment [published erratum appears in: JAMA 2003; 290:756]. JAMA 2003; 289:1645-51.

37. Barosi G, Ambrosetti A, Centra A, et al. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia. Blood 1998; 91:3630-6.

38. Mesa RA, Nagorney DS, Schwager S, et al. Palliative goals, patient selection, and peri-operative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer 2006; 107:361-70.

39. van Besien K, Deeg HJ. Hematopoietic stem cell transplantation for myelofibrosis. Semin Oncol 2005; 32:414-21.

40. Pardanani A. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia 2007; 22:23-30.

41. Odenike OM, Godwin JE, van Besien K, et al. Phase II study of decitabine in myelofi-brosis with myeloid metaplasia. Blood 2006; 108: (Abstract 4923).

42. Quintas-Cardama A, Kantarjian H, Garcia-Manero G, et al. A phase II study of azaciti-dine (Vidaza) for patients with myelofibrosis (MF). Blood 2006; 108:2706.

43. Mesa RA, Camoriano JK, Geyer SM, et al. A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia 2007; 21:1964-70.

44. Mesa RA, Loegering D, Powell HL, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Blood 2005; 106:318-27.

45. Verstovsek S, Kantarjian H, Pardanani A, et al. INCB018424, an oral, selective JAK2 inhibitor, shows significant clinical activity in a phase i/ii study in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibro-sis (Post-PV/ET MF). Blood 2007; 110:171a (Abstract 558).

46. Verstovsek S, Pardanani AD, Shah NP, et al. A phase i study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis and post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 2007; 110:170a (Abstract 553).

47. Lasho TL, Finke C, Hood JD, et al. Primary cell experiments with TG101348, a JAK2-selective inhibitor, in the presence of myeloproliferative disorder-associated JAK2V617F, MPLW515L/K, and JAK2 exon 12 mutations. Blood 2007; 110:1036A (Abstract 3541).

48. 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 lympho-blastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344:1038-42.

49. Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007; 109:1387-94.

50. Faderl S, Verstovsek S, Cortes J, et al. Clofarabine and cytarabine combination as induc-tion therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood 2006; 108:45-51.


AML Arising from MPDs

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acute leukemia arising from the myeloproliferative disorders: challenge and opportunity

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