Chronic Myeloproliferative Neoplasms Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Chronic Myeloproliferative Neoplasms (MPN)

The chronic MPN consist of chronic myelogenous leukemia, polycythemia vera (p. vera), primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia.[1] All of these disorders involve dysregulation at the multipotent hematopoietic stem cell (CD34), with one or more of the following shared features:

• Overproduction of one or several blood elements with dominance of a transformed clone.
• Hypercellular marrow/marrow fibrosis.
• Cytogenetic abnormalities.
• Thrombotic and/or hemorrhagic diatheses.[2]
• Extramedullary hematopoiesis (liver/spleen).
• Transformation to acute leukemia.
• Overlapping clinical features.

Chronic MPN usually occur sporadically; however, familial clusters of MPN have been reported. These familial clusters include autosomal-dominant inheritance and autosomal-recessive inheritance.[3] Patients with p. vera and essential thrombocythemia have marked increases of red blood cell and platelet production, respectively. Treatment is directed at reducing the excessive numbers of blood cells. Both p. vera and essential thrombocythemia can develop a spent phase late in their courses that resembles primary myelofibrosis with cytopenias and marrow hypoplasia and fibrosis.[4] A specific point mutation in one copy of the JAK2 V617F gene, a cytoplasmic tyrosine kinase, on chromosome 9, has been identified in most patients with p. vera, essential thrombocythemia, and idiopathic myelofibrosis.[5] Other single nucleotide variants were associated with mutations in genes encoding calreticulin (CALR) and the thrombopoietin receptor (MPL).[6,7] Researchers are pursuing specific targeting of this aberrant protein as well as new targets based on next-generation sequencing of the genome.[8]

Leukemic transformation from Philadelphia chromosome–negative myeloproliferative neoplasms is defined as having 20% or greater myeloblasts in the blood or marrow (MPN-blast phase) and having no standard approach and a poor prognosis (3- to 5-month median survival).[9] Allogeneic stem cell transplantation has resulted in anecdotal long-term survivors, but this approach is often not feasible in older patients with comorbid conditions or lack of initial response to leukemic induction therapy.[10]

References:

1. Spivak JL: Myeloproliferative Neoplasms. N Engl J Med 376 (22): 2168-2181, 2017.
2. Hultcrantz M, Björkholm M, Dickman PW, et al.: Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms: A Population-Based Cohort Study. Ann Intern Med 168 (5): 317-325, 2018.
3. Ranjan A, Penninga E, Jelsig AM, et al.: Inheritance of the chronic myeloproliferative neoplasms. A systematic review. Clin Genet 83 (2): 99-107, 2013.
4. Tefferi A, Barbui T: Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 92 (1): 94-108, 2017.
5. James C, Ugo V, Le Couédic JP, et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434 (7037): 1144-8, 2005.
6. Lundberg P, Karow A, Nienhold R, et al.: Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 123 (14): 2220-8, 2014.
7. Tefferi A, Vannucchi AM: Genetic Risk Assessment in Myeloproliferative Neoplasms. Mayo Clin Proc 92 (8): 1283-1290, 2017.
8. Grinfeld J, Nangalia J, Baxter EJ, et al.: Classification and Personalized Prognosis in Myeloproliferative Neoplasms. N Engl J Med 379 (15): 1416-1430, 2018.
9. Mascarenhas J, Heaney ML, Najfeld V, et al.: Proposed criteria for response assessment in patients treated in clinical trials for myeloproliferative neoplasms in blast phase (MPN-BP): formal recommendations from the post-myeloproliferative neoplasm acute myeloid leukemia consortium. Leuk Res 36 (12): 1500-4, 2012.
10. Alchalby H, Zabelina T, Stübig T, et al.: Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 20 (2): 279-81, 2014.

Chronic Myelogenous Leukemia

Refer to the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.

Polycythemia Vera

Disease Overview

The proposed revised World Health Organization criteria for the diagnosis of polycythemia vera (p. vera) requires two major criteria and one minor criterion or the first major criterion together with two minor criteria.[1]

Major Criteria

1. Hemoglobin of more than 18.5 g/dL in men, 16.5 g/dL in women, or elevated red cell mass greater than 25% above mean normal predicted value.
2. Presence of JAK2 V617F or other functionally similar mutations, such as the exon 12 mutation of JAK2.

Minor Criteria

1. Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
2. Serum erythropoietin level below normal range.
3. Endogenous erythroid colony formation in vitro.

Other confirmatory findings no longer required for diagnosis include the following:[2,3,4]

• Oxygen saturation with arterial blood gas greater than 92%.
• Splenomegaly.
• Thrombocytosis (>400,000 platelets/mm³).
• Leukocytosis (>12,000/mm³).
• Leukocyte alkaline phosphatase (>100 units in the absence of fever or infection).

There is no staging system for this disease.

Patients have an increased risk of cardiovascular and thrombotic events [5] and transformation to acute myelogenous leukemia or primary myelofibrosis.[6,7,8] Age older than 65 years, leukocytosis, and a history of vascular events (bleeding or thrombosis) are associated with a poor prognosis.[6,9,10] Patients younger than 40 years have a more indolent course, with fewer thrombotic events or transformation to acute leukemia.[11]

Treatment Overview

The primary therapy for p. vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45%; this recommendation was confirmed in a randomized, prospective trial, which demonstrated lower rates of cardiovascular death and major thrombosis using this hematocrit target.[12,13] The target level for women may need to be lower (e.g., hematocrit <40%), but there are no empiric data to confirm this recommendation.[14]

Complications of phlebotomy include the following:

• Progressive and sometimes extreme thrombocytosis and symptomatology related to chronic iron deficiency, including pica, angular stomatitis, and glossitis.
• Dysphagia that is the result of esophageal webs (very rare).
• Possibly muscle weakness.

In addition, progressive splenomegaly or pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. (Refer to the PDQ summary on Pruritus for more information.) If phlebotomy becomes impractical, hydroxyurea or interferon-alpha can be added to control the disease.

The Polycythemia Vera Study Group randomly assigned more than 400 patients to phlebotomy (target hematocrit <45), radioisotope phosphorous 32 (32P) (2.7 mg/m² administered intravenously every 12 weeks as needed), or chlorambucil (10 mg administered by mouth daily for 6 weeks, then given daily on alternate months).[15] The median survival for the phlebotomy group (13.9 years) and the radioisotope 32P group (11.8 years) was significantly better than that of the chlorambucil group (8.9 years), primarily because of excessive late deaths from leukemia or other hematologic malignancies.[15][Level of evidence A1] Because of these concerns, many clinicians use hydroxyurea for patients who require cytoreductive therapy that is caused by massive splenomegaly, a high phlebotomy requirement, or excessive thrombocytosis.[15]

In a pooled analysis of 16 different trials, interferon-alpha therapy resulted in avoidance of phlebotomy in 50% of patients, with 80% of patients experiencing marked reduction of splenomegaly.[16][Level of evidence C3] Interferon posed problems of cost, side effects, and parenteral route of administration, but no cases of acute leukemia were seen in this analysis. In a phase II study (NCT01259856), 50 patients with p. vera who required therapy with hydroxyurea and had either an inadequate response or unacceptable side effects received pegylated interferon alpha-2a. The complete response rate was 22% and the partial response rate was 38%, with only a 14% discontinuation rate from side effects.[17][Level of evidence C3]

Patients who required therapy with hydroxyurea but had either an inadequate response or unacceptable side effects were randomly assigned to receive ruxolitinib or standard therapy (interferon, chlorambucil, or busulfan). Ruxolitinib provided better control of hematocrit (60% vs. 20%; P < .001), reduction of spleen volume (38% vs. 1%; P < .001) and reduction of symptom score by 50% (49% vs. 5%; P < .001).[18][Level of evidence B3]

In patients previously treated with hydroxyurea, ruxolitinib and interferon have not been compared in a randomized trial.

Patients with p. vera and no splenomegaly in whom hydroxyurea failed were studied in a randomized prospective trial of 173 participants.[19] Patients were randomly assigned to receive ruxolitinib (the JAK2 inhibitor) versus best available therapy (such as interferon, higher doses of hydroxyurea, or no treatment). Hematocrit control was achieved in 62% of ruxolitinib-treated patients versus 19% of controls (hazard ratio, 7.28; 95% confidence interval [CI], 3.43‒15.45; P < .001).[19][Level of evidence B3]

In a Cochrane review of two randomized studies of 630 patients with no clear indication or contraindication for aspirin, those receiving 100 mg of aspirin versus placebo had reduction of fatal thrombotic events, but this benefit was not statistically significant (odds ratio, 0.20; 95% CI, 0.03–1.14).[20] A retrospective review of 105 patients who underwent surgery documented that 8% of them had thromboembolisms and 7% of them had major hemorrhages with previous cytoreduction by phlebotomy and postoperative subcutaneous heparin in one half of the patients.[21]

Guidelines based on anecdotal reports have been developed for the management of pregnant patients with p. vera.[3]

Treatment options include the following:

1. Phlebotomy.[12]
2. Hydroxyurea (alone or with phlebotomy).[14,15]
3. Interferon-alpha [16,22,23,24] and pegylated interferon-alpha.[17,25,26]
4. Ruxolitinib.[19]
5. Rarely, chlorambucil or busulfan may be required, especially if interferon or hydroxyurea are not tolerated, as is often seen in patients older than 70 years.[2]
6. Low-dose aspirin (≤100 mg) daily, unless contraindicated by major bleeding or gastric intolerance.[9,20]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 115 (17): 3842-7, 2009.
2. Streiff MB, Smith B, Spivak JL: The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood 99 (4): 1144-9, 2002.
3. McMullin MF, Bareford D, Campbell P, et al.: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130 (2): 174-95, 2005.
4. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
5. Hultcrantz M, Björkholm M, Dickman PW, et al.: Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms: A Population-Based Cohort Study. Ann Intern Med 168 (5): 317-325, 2018.
6. Marchioli R, Finazzi G, Landolfi R, et al.: Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23 (10): 2224-32, 2005.
7. Elliott MA, Tefferi A: Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 128 (3): 275-90, 2005.
8. Chait Y, Condat B, Cazals-Hatem D, et al.: Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol 129 (4): 553-60, 2005.
9. Finazzi G, Barbui T: How I treat patients with polycythemia vera. Blood 109 (12): 5104-11, 2007.
10. Bonicelli G, Abdulkarim K, Mounier M, et al.: Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients. Br J Haematol 160 (2): 251-4, 2013.
11. Boddu P, Masarova L, Verstovsek S, et al.: Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms. Ann Hematol 97 (1): 109-121, 2018.
12. Berk PD, Goldberg JD, Donovan PB, et al.: Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 23 (2): 132-43, 1986.
13. Marchioli R, Finazzi G, Specchia G, et al.: Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 368 (1): 22-33, 2013.
14. Lamy T, Devillers A, Bernard M, et al.: Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 102 (1): 14-20, 1997.
15. Kaplan ME, Mack K, Goldberg JD, et al.: Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol 23 (3): 167-71, 1986.
16. Lengfelder E, Berger U, Hehlmann R: Interferon alpha in the treatment of polycythemia vera. Ann Hematol 79 (3): 103-9, 2000.
17. Yacoub A, Mascarenhas J, Kosiorek H, et al.: Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood 134 (18): 1498-1509, 2019.
18. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al.: Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372 (5): 426-35, 2015.
19. Passamonti F, Griesshammer M, Palandri F, et al.: Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 18 (1): 88-99, 2017.
20. Squizzato A, Romualdi E, Passamonti F, et al.: Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 4: CD006503, 2013.
21. Ruggeri M, Rodeghiero F, Tosetto A, et al.: Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 111 (2): 666-71, 2008.
22. Silver RT: Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 107 (3): 451-8, 2006.
23. Quintás-Cardama A, Kantarjian HM, Giles F, et al.: Pegylated interferon therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders. Semin Thromb Hemost 32 (4 Pt 2): 409-16, 2006.
24. Huang BT, Zeng QC, Zhao WH, et al.: Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. Leuk Res 38 (10): 1177-83, 2014.
25. Quintás-Cardama A, Kantarjian H, Manshouri T, et al.: Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 27 (32): 5418-24, 2009.
26. Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al.: Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 122 (6): 893-901, 2013.

Primary Myelofibrosis

Disease Overview

Primary myelofibrosis (also known as agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis, myelosclerosis with myeloid metaplasia, and idiopathic myelofibrosis) is characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardrop-shaped red blood cells.[1] In its early phase, the disease is characterized by elevated numbers of CD34-positive cells in the marrow, while the later phases involve marrow fibrosis with decreasing CD34 cells in the marrow and a corresponding increase in splenic and liver engorgement with CD34 cells.

As distinguished from chronic myelogenous leukemia (CML), primary myelofibrosis usually presents as follows:[2]

• A white blood cell count smaller than 30,000/mm³.
• Prominent teardrops on peripheral smear.
• Normocellular or hypocellular marrow with moderate to marked fibrosis.
• An absence of the Philadelphia chromosome or the BCR/ABL translocation.
• Frequent positivity for the JAK2 mutation, the MPL mutation, or the CALR gene mutation (identifying 70% of patients).[3,4,5]

In addition to the clonal proliferation of a multipotent hematopoietic progenitor cell, an event common to all chronic myeloproliferative neoplasms, myeloid metaplasia is characterized by colonization of extramedullary sites such as the spleen or liver.[6,7]

Most patients are older than 60 years at diagnosis, and 33% of patients are asymptomatic at presentation. Splenomegaly, sometimes massive, is a characteristic finding. Patients younger than 40 years have a more indolent course, with fewer thrombotic events or transformation to acute leukemia.[8]

Symptoms include the following:

• Splenic pain.
• Early satiety.
• Anemia.
• Bone pain.
• Fatigue.
• Fever.
• Night sweats.
• Weight loss.

(Refer to the PDQ summaries on Cancer Pain; Fatigue; Hot Flashes and Night Sweats; and Nutrition for information on many of the symptoms listed above.)

The proposed World Health Organization criteria for the diagnosis of primary myelofibrosis requires all three major criteria and two minor criteria.[9]

Major Criteria

1. Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis; or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (so-called prefibrotic cellular-phase disease).
2. Not meeting criteria for polycythemia vera (p. vera), CML, myelodysplastic syndrome, or other myeloid neoplasm.
3. Demonstration of JAK2 V617F or other clonal marker; or, in the absence of a clonal marker, no evidence of bone marrow fibrosis caused by an underlying inflammatory disease or another neoplastic disease. About 60% of patients with primary myelofibrosis carry a JAK2 mutation, and about 5% to 10% of the patients have activating mutations in the thrombopoietin receptor gene, MPL. More than half of the patients without JAK2 or MPL carry a somatic mutation of the CALR gene, which is associated with a more indolent clinical course than is seen with JAK2 or MPL mutations.[3,4,5,10,11,12]

Minor Criteria

1. Leukoerythroblastosis.
2. Increased serum level of lactate dehydrogenase.
3. Anemia.
4. Palpable splenomegaly.

The median survival is 3.5 years to 5.5 years, but patients younger than 55 years have a median survival of 11 years.[6,7] The major causes of death include the following:[13]

• Progressive marrow failure.
• Transformation to acute nonlymphoblastic leukemia.[14]
• Infection.
• Thrombohemorrhagic events.[15]
• Heart failure.
• Portal hypertension.

Fatal and nonfatal thrombosis was associated with age older than 60 years and JAK2 V617F positivity in a multivariable analysis of 707 patients followed from 1973 to 2008.[16] Bone marrow examination including cytogenetic testing may exclude other causes of myelophthisis, such as CML, myelodysplastic syndrome, metastatic cancer, lymphomas, and plasma cell disorders.[7] In acute myelofibrosis, patients present with pancytopenia but no splenomegaly or peripheral blood myelophthisis. Peripheral blood or marrow monocytosis is suggestive for myelodysplasia in this setting.

There is no staging system for this disease.

Prognostic factors include the following:[17,18,19,20,21]

• Age 65 years or older.
• Anemia (hemoglobin <10 g/dL).
• Constitutional symptoms: fever, night sweats, or weight loss.
• Leukocytosis (white blood cell count >25 × 10⁹ /L).
• Circulating blasts of at least 1%.

Patients without any of the adverse features, excluding age, have a median survival of more than 10 to 15 years, but the presence of any two of the adverse features lowers the median survival to less than 4 years.[22,23] International prognostic scoring systems incorporate the aforementioned prognostic factors.[22,24] Thrombocytopenia (platelets <50 × 10⁹ /L) is a very poor prognostic factor for primary myelofibrosis and for myelofibrosis following thrombocythemia or p. vera.[25]

Karyotype abnormalities can also affect prognosis. In a retrospective series, the 13q and 20q deletions and trisomy 9 correlated with improved survival and no leukemia transformation in comparison with the worse prognosis with trisomy 8, complex karyotype, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.[16,26]

Treatment Overview

Asymptomatic low-risk patients (based on the aforementioned prognostic systems) should be monitored with a watchful waiting approach. The development of symptomatic anemia, marked leukocytosis, drenching night sweats, weight loss, fever, or symptomatic splenomegaly would warrant therapeutic intervention.

The profound anemia that develops in this disease usually requires red blood cell transfusion. Red blood cell survival is markedly decreased in some patients; this can sometimes be treated with glucocorticoids. Disease-associated anemia may occasionally respond to the following:[7,27,28,29]

• Erythropoietic growth factors. Erythropoietin and darbepoetin are less likely to help when patients are transfusion dependent or manifest a serum erythropoietin level greater than 125 U/L.[30,31]
• Prednisone (40–80 mg/day).
• Danazol (600 mg/day).
• Thalidomide (50 mg/day) with or without prednisone.[32] Patients on thalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.
• Lenalidomide (10 mg/day) with or without prednisone.[33,34,35] In the presence of del(5q), lenalidomide with or without prednisone, can reverse anemia and splenomegaly in most patients.[33,34,35] However, patients on lenalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.
• Pomalidomide.[36] Patients on pomalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.

Ruxolitinib, an inhibitor of JAK1 and JAK2, can reduce the splenomegaly and debilitating symptoms of weight loss, fatigue, and night sweats for patients with JAK2-positive or JAK2-negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–p. vera myelofibrosis.[37]

In two prospective, randomized trials, 528 higher-risk patients were randomly assigned to ruxolitinib or to either placebo (COMFORT-I [NCT00952289]) or best available therapy (COMFORT-II [NCT00934544]). At 48 weeks, patients on ruxolitinib had a decrease of 30% to 40% in mean spleen volume compared with an increase of 7% to 8% in the control patients.[38][Level of evidence B3]; [39][Level of evidence B3] Ruxolitinib also improved overall quality-of-life measures, with low toxic effects in both studies, but with no benefit in overall survival in the initial reports. Additional follow-up in both studies (5 years in COMFORT-I and in COMFORT-II) showed a survival benefit (statistically significant only for COMFORT-I) among ruxolitinib-treated patients compared with control patients (COMFORT-I hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.50–0.96; P = .025; and COMFORT-II HR, 0.67; 95% CI, 0.44–1.02; P = .06).[40,41][Level of evidence A1] Clinical benefits were observed across a wide variety of clinical subgroups.[42,43] Discontinuation of ruxolitinib results in a rapid worsening of splenomegaly and the recurrence of systemic symptoms.[38,39,44] Ruxolitinib does not reverse bone marrow fibrosis or induce histologic or cytogenetic remissions. Aggressive B-cell lymphomas have occurred among patients treated with ruxolitinib when a preexisting clonal B-cell population was identified at diagnosis in conjunction with myelofibrosis.[45]

Painful splenomegaly can be treated temporarily with ruxolitinib, hydroxyurea, thalidomide, lenalidomide, cladribine, or radiation therapy, but sometimes requires splenectomy.[29,46,47] The decision to perform splenectomy represents a weighing of the benefits (i.e., reduction of symptoms, decreased portal hypertension, and less need for red blood cell transfusions lasting for 1 to 2 years) versus the debits (i.e., postoperative mortality of 10% and morbidity of 30% caused by infection, bleeding, or thrombosis; no benefit for thrombocytopenia; and accelerated progression to the blast-crisis phase that was seen by some investigators but not others).[7,46]

After splenectomy, many physicians use anticoagulation therapy for 4 to 6 weeks to reduce portal vein thrombosis, and hydroxyurea can be utilized to reduce high platelet levels (>1 million).[48] However, data from a retrospective review of 150 patients who underwent surgery provided documentation that 8% of the patients had a thromboembolism and 7% had a major hemorrhage with prior cytoreduction and postoperative subcutaneous heparin used in one half of the patients.[49]

Hydroxyurea is useful in patients with splenomegaly but may have a potential leukemogenic effect.[7] In patients with thrombocytosis and hepatomegaly after splenectomy, cladribine has shown responses as an alternative to hydroxyurea.[50] The use of interferon-alpha can result in hematologic responses, including reduction in spleen size in 30% to 50% of patients, though many patients do not tolerate this medication.[51,52] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[27,28,29,53,54,55][Level of evidence C3]

A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable donor is available.[56,57,58,59,60,61] Allogeneic stem cell transplantation is the only potentially curative treatment available, but the associated morbidity and mortality limit its use to younger, high-risk patients.[59,62] Detection of the JAK2 mutation after transplantation is associated with a worse prognosis.[63]

Treatment options include the following:

1. Ruxolitinib.[38,39,44,64]
2. Clinical trials involving other JAK2 inhibitors.
3. Hydroxyurea.[6,7]
4. Allogeneic peripheral stem cell or bone marrow transplantation.[57,58,59,60,61]
5. Thalidomide.[27,32,53,54,55,56]
6. Lenalidomide.[29,33,34,35,55]
7. Pomalidomide.[36]
8. Splenectomy.[46,65]
9. Splenic radiation therapy or radiation to sites of symptomatic extramedullary hematopoiesis (e.g., large lymph nodes, cord compression).[7]
10. Cladribine.[50]
11. Interferon-alpha.[51,52]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Hennessy BT, Thomas DA, Giles FJ, et al.: New approaches in the treatment of myelofibrosis. Cancer 103 (1): 32-43, 2005.
2. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
3. Cazzola M, Kralovics R: From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 123 (24): 3714-9, 2014.
4. Rumi E, Pietra D, Ferretti V, et al.: JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 123 (10): 1544-51, 2014.
5. Rotunno G, Mannarelli C, Guglielmelli P, et al.: Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123 (10): 1552-5, 2014.
6. Barosi G: Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 17 (9): 2954-70, 1999.
7. Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med 342 (17): 1255-65, 2000.
8. Boddu P, Masarova L, Verstovsek S, et al.: Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms. Ann Hematol 97 (1): 109-121, 2018.
9. Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 115 (17): 3842-7, 2009.
10. Klampfl T, Gisslinger H, Harutyunyan AS, et al.: Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369 (25): 2379-90, 2013.
11. Nangalia J, Massie CE, Baxter EJ, et al.: Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369 (25): 2391-405, 2013.
12. Guglielmelli P, Lasho TL, Rotunno G, et al.: The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 28 (9): 1804-10, 2014.
13. Chim CS, Kwong YL, Lie AK, et al.: Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia. Arch Intern Med 165 (22): 2651-8, 2005 Dec 12-26.
14. Odenike O: How I treat the blast phase of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood 132 (22): 2339-2350, 2018.
15. Hultcrantz M, Björkholm M, Dickman PW, et al.: Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms: A Population-Based Cohort Study. Ann Intern Med 168 (5): 317-325, 2018.
16. Hussein K, Pardanani AD, Van Dyke DL, et al.: International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood 115 (3): 496-9, 2010.
17. Cervantes F, Barosi G, Demory JL, et al.: Myelofibrosis with myeloid metaplasia in young individuals: disease characteristics, prognostic factors and identification of risk groups. Br J Haematol 102 (3): 684-90, 1998.
18. Strasser-Weippl K, Steurer M, Kees M, et al.: Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score. Leuk Lymphoma 47 (3): 441-50, 2006.
19. Tefferi A: Survivorship and prognosis in myelofibrosis with myeloid metaplasia. Leuk Lymphoma 47 (3): 379-80, 2006.
20. Tam CS, Kantarjian H, Cortes J, et al.: Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol 27 (33): 5587-93, 2009.
21. Morel P, Duhamel A, Hivert B, et al.: Identification during the follow-up of time-dependent prognostic factors for the competing risks of death and blast phase in primary myelofibrosis: a study of 172 patients. Blood 115 (22): 4350-5, 2010.
22. Cervantes F, Dupriez B, Pereira A, et al.: New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113 (13): 2895-901, 2009.
23. Tefferi A, Lasho TL, Jimma T, et al.: One thousand patients with primary myelofibrosis: the mayo clinic experience. Mayo Clin Proc 87 (1): 25-33, 2012.
24. Gangat N, Caramazza D, Vaidya R, et al.: DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 29 (4): 392-7, 2011.
25. Masarova L, Alhuraiji A, Bose P, et al.: Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis. Eur J Haematol 100 (3): 257-263, 2018.
26. Caramazza D, Begna KH, Gangat N, et al.: Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia 25 (1): 82-8, 2011.
27. Giovanni B, Michelle E, Letizia C, et al.: Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma 43 (12): 2301-7, 2002.
28. Marchetti M, Barosi G, Balestri F, et al.: Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol 22 (3): 424-31, 2004.
29. Tefferi A, Cortes J, Verstovsek S, et al.: Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 108 (4): 1158-64, 2006.
30. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC, et al.: Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 127 (4): 399-403, 2004.
31. Huang J, Tefferi A: Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol 83 (2): 154-5, 2009.
32. Thomas DA, Giles FJ, Albitar M, et al.: Thalidomide therapy for myelofibrosis with myeloid metaplasia. Cancer 106 (9): 1974-84, 2006.
33. Tefferi A, Lasho TL, Mesa RA, et al.: Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia 21 (8): 1827-8, 2007.
34. Mesa RA, Yao X, Cripe LD, et al.: Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 116 (22): 4436-8, 2010.
35. Quintás-Cardama A, Kantarjian HM, Manshouri T, et al.: Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol 27 (28): 4760-6, 2009.
36. Begna KH, Mesa RA, Pardanani A, et al.: A phase-2 trial of low-dose pomalidomide in myelofibrosis. Leukemia 25 (2): 301-4, 2011.
37. Verstovsek S, Kantarjian H, Mesa RA, et al.: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363 (12): 1117-27, 2010.
38. Harrison C, Kiladjian JJ, Al-Ali HK, et al.: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366 (9): 787-98, 2012.
39. Verstovsek S, Mesa RA, Gotlib J, et al.: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366 (9): 799-807, 2012.
40. Verstovsek S, Mesa RA, Gotlib J, et al.: Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol 10 (1): 55, 2017.
41. Harrison CN, Vannucchi AM, Kiladjian JJ, et al.: Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia 30 (8): 1701-7, 2016.
42. Mascarenhas J, Hoffman R: A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood 121 (24): 4832-7, 2013.
43. Verstovsek S, Mesa RA, Gotlib J, et al.: The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis. Br J Haematol 161 (4): 508-16, 2013.
44. Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 365 (15): 1455-7, 2011.
45. Porpaczy E, Tripolt S, Hoelbl-Kovacic A, et al.: Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy. Blood 132 (7): 694-706, 2018.
46. 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 91 (10): 3630-6, 1998.
47. Lavrenkov K, Krepel-Volsky S, Levi I, et al.: Low dose palliative radiotherapy for splenomegaly in hematologic disorders. Leuk Lymphoma 53 (3): 430-4, 2012.
48. Mesa RA, Nagorney DS, Schwager S, et al.: Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer 107 (2): 361-70, 2006.
49. Ruggeri M, Rodeghiero F, Tosetto A, et al.: Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 111 (2): 666-71, 2008.
50. Tefferi A, Mesa RA, Nagorney DM, et al.: Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 95 (7): 2226-33, 2000.
51. Sacchi S: The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leuk Lymphoma 19 (1-2): 13-20, 1995.
52. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
53. Strupp C, Germing U, Scherer A, et al.: Thalidomide for the treatment of idiopathic myelofibrosis. Eur J Haematol 72 (1): 52-7, 2004.
54. Mesa RA, Elliott MA, Schroeder G, et al.: Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc 79 (7): 883-9, 2004.
55. Jabbour E, Thomas D, Kantarjian H, et al.: Comparison of thalidomide and lenalidomide as therapy for myelofibrosis. Blood 118 (4): 899-902, 2011.
56. Guardiola P, Anderson JE, Bandini G, et al.: Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood 93 (9): 2831-8, 1999.
57. Deeg HJ, Gooley TA, Flowers ME, et al.: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 102 (12): 3912-8, 2003.
58. Daly A, Song K, Nevill T, et al.: Stem cell transplantation for myelofibrosis: a report from two Canadian centers. Bone Marrow Transplant 32 (1): 35-40, 2003.
59. Gupta V, Hari P, Hoffman R: Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 120 (7): 1367-79, 2012.
60. Kröger N, Holler E, Kobbe G, et al.: Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 114 (26): 5264-70, 2009.
61. Abelsson J, Merup M, Birgegård G, et al.: The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 47 (3): 380-6, 2012.
62. Alchalby H, Yunus DR, Zabelina T, et al.: Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol 157 (1): 75-85, 2012.
63. Alchalby H, Badbaran A, Zabelina T, et al.: Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood 116 (18): 3572-81, 2010.
64. Verstovsek S: Janus-activated kinase 2 inhibitors: a new era of targeted therapies providing significant clinical benefit for Philadelphia chromosome-negative myeloproliferative neoplasms. J Clin Oncol 29 (7): 781-3, 2011.
65. Tefferi A, Silverstein MN, Li CY: 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. Br J Haematol 99 (2): 352-7, 1997.

Essential Thrombocythemia

Disease Overview

The proposed revised World Health Organization (WHO) criteria for the diagnosis of essential thrombocythemia requires the following criteria:[1]

Criteria

1. Sustained platelet count of at least 450 × 10⁹ /L.
2. Bone marrow biopsy showing predominant proliferation of enlarged mature megakaryocytes; no significant increase of granulocytic or erythroid precursors. This finding distinguishes essential thrombocythemia from another entity with thrombocytosis, namely prefibrotic primary myelofibrosis, which is identified by increased granulocytic or erythroid precursors, atypical megakaryocytes, and increased bone marrow cellularity.

   Patients with prefibrotic primary myelofibrosis have a worse survival than patients with essential thrombocythemia because of an increased progression to myelofibrosis and increased progression to acute myelogenous leukemia.[2,3,4] Patients with prefibrotic primary myelofibrosis may also have a higher tendency to bleed, which can be exacerbated by low-dose aspirin.[5]

3. Not meeting criteria for polycythemia vera (p. vera), primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
4. Demonstration of JAK2 V617F mutation or myeloproliferative leukemia (MPL) exon 10 mutation.[6] In the absence of a clonal marker, there must be no evidence for reactive thrombocytosis. In particular, with a decreased serum ferritin, there must be no increase in hemoglobin level to p. vera range with iron replacement therapy. In the presence of a JAK2 or MPL mutation and exclusion of other myeloproliferative or myelodysplastic features, a bone marrow aspirate/biopsy may not be mandatory for a diagnosis.[7] About 60% of patients with essential thrombocythemia carry a JAK2 mutation, and about 5% to 10% of the patients have activating mutations in the thrombopoietin receptor gene, MPL. About 70% of the patients without JAK2 or MPL mutations carry a somatic mutation of the CALR gene, which is associated with a more indolent clinical course than is seen with JAK2 or MPL mutations.[8,9,10,11,12]

Patients older than 60 years or those with a previous thrombotic episode or with leukocytosis have as much as a 25% chance of developing cerebral, cardiac, or peripheral arterial thromboses and, less often, a chance of developing a pulmonary embolism or deep venous thrombosis.[2,13,14,15] Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (<10%) with long-term follow-up. Patients younger than 40 years have a more indolent course, with fewer thrombotic events or transformation to acute leukemia.[16] A multivariable analysis in several cohorts that included almost 1,500 patients showed worse outcomes for males, with a hazard ratio (HR) of 1.5 (confidence interval [CI], 1.1‒2.5).[17]

There is no staging system for this disease.

Untreated essential thrombocythemia means that a patient is newly diagnosed and has had no previous treatment except supportive care.

Treatment Overview

Controversy is considerable regarding whether asymptomatic patients with essential thrombocythemia require treatment.[18] In a case-controlled, observational study of 65 low-risk patients (age <60 years, platelet count <1,500 × 10⁹ /L, and no history of thrombosis or hemorrhage) with a median follow-up of 4.1 years, the thrombotic risk of 1.91 cases per 100 patient years and hemorrhagic risk of 1.12 cases per 100 patient years was not increased any more than in the normal controls.[19]

1. A prospective randomized trial of 382 patients aged 40 to 59 years with essential thrombocythemia and without high-risk factors (no history of thrombosis or bleeding, no hypertension, no diabetes, platelet count ≤ 1,500 × 10⁹ /L) were randomly assigned to receive aspirin alone versus hydroxyurea plus aspirin.[20]
   • After a median follow-up of 73 months, there was no difference in thrombosis, hemorrhage, or survival (HR, 0.98; 95% CI, 0.42‒2.25; P = 1.0).[20][Level of evidence B1] Patients younger than 60 years who lacked high-risk factors did not benefit from the addition of hydroxyurea to aspirin.
2. A randomized trial of patients with essential thrombocythemia and a high risk of thrombosis compared treatment with hydroxyurea titrated to attain a platelet count below 600,000/mm³ with a control group that received no therapy. Hydroxyurea was found to be effective in preventing thrombotic episodes (4% vs. 24%).[13][Level of evidence B3]
   • A retrospective analysis of this trial found that antiplatelet drugs had no significant influence on the outcome. Resistance to hydroxyurea is defined as a platelet count of greater than 600,000/μL after 3 months of at least 2 g per day of hydroxyurea or a platelet count greater than 400,000/µL and a white blood cell count of less than 2,500/µL or a hemoglobin less than 10 g/dL at any dose of hydroxyurea.[21]
3. A prospective randomized trial in the United Kingdom (UK) of 809 patients compared hydroxyurea plus aspirin with anagrelide plus aspirin.[22]
   • Although the platelet-lowering effect was equivalent, the anagrelide group had significantly more thrombotic and hemorrhagic events (HR, 1.57; P = .03) and more myelofibrosis (HR, 2.92; P = .01).
   • No differences were seen for subsequent myelodysplasia or acute leukemia in this trial.[23][Level of evidence B1]
4. Another prospective randomized trial also compared hydroxyurea and anagrelide in 259 previously untreated and high-risk patients.[24] In this central European trial, the diagnosis of essential thrombocythemia was made by the WHO recommendations, not by the Polycythemia Vera Study Group criteria as in the UK study. This means that patients with leukocytosis and a diagnosis of early prefibrotic myelofibrosis (both groups with much higher rates of thrombosis) were excluded from the central European trial.
   • In this analysis, there were no differences in outcome for thrombotic or hemorrhagic events.[24][Level of evidence B1]

These randomized prospective trials establish the efficacy and safety for the use of hydroxyurea for patients with high-risk essential thrombocythemia (age >60 years + platelet count >1,000 × 10⁹ /L or >1,500 × 10⁹ /L). For patients diagnosed by WHO standards (excluding patients with leukocytosis and prefibrotic myelofibrosis by bone marrow biopsy), anagrelide represents a reasonable alternative therapy. The addition of aspirin to cytoreductive therapies like hydroxyurea or anagrelide remains controversial, but a retrospective anecdotal report suggested reduction in thrombosis for patients older than 60 years.[25] In a phase II study (NCT01259856), 65 patients with essential thrombocythemia who required therapy with hydroxyurea and had either an inadequate response or unacceptable side effects received pegylated interferon alpha-2a. The complete response (CR) rate was 43% and the partial response rate was 26%, with only a 14% discontinuation rate from side effects. The CALR-mutated patients had a significantly higher CR rate than patients without a CALR mutation (57% vs. 28%).[26][Level of evidence C3] Unlike results for p. vera or myelofibrosis, ruxolitinib was not helpful for patients resistant to hydroxyurea.[27]

Many clinicians use hydroxyurea or platelet apheresis prior to elective surgery to reduce the platelet count and to prevent postoperative thromboembolism. No prospective or randomized trials document the value of this approach.

Among low-risk patients (defined as age ≤60 years with no prior thrombotic episodes), a retrospective review of 300 patients showed benefit for antiplatelet agents in reducing venous thrombosis in JAK2-positive cases and in reducing arterial thrombosis in patients with cardiovascular risk factors.[28] Balancing the risks and benefits of aspirin for low-risk patients can be difficult.[29] In an extrapolation of the data from trials of p. vera, low-dose aspirin to prevent vascular events has been suggested, but there are no data from clinical trials to address this issue.[30,31]

Treatment options include the following:

1. No treatment, unless complications develop, if patients are asymptomatic, younger than 60 years, and have a platelet count of less than 1,500 × 10⁹ /L.
2. Hydroxyurea.[13]
3. Interferon-alpha [32,33,34,35] or pegylated interferon-alpha.[36,37]
4. Anagrelide.[23,38]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 115 (17): 3842-7, 2009.
2. Passamonti F, Thiele J, Girodon F, et al.: A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood 120 (6): 1197-201, 2012.
3. Barbui T, Thiele J, Carobbio A, et al.: Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. Blood 120 (3): 569-71, 2012.
4. Barbui T, Thiele J, Passamonti F, et al.: Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol 29 (23): 3179-84, 2011.
5. Finazzi G, Carobbio A, Thiele J, et al.: Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia 26 (4): 716-9, 2012.
6. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006.
7. Harrison CN, Bareford D, Butt N, et al.: Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 149 (3): 352-75, 2010.
8. Klampfl T, Gisslinger H, Harutyunyan AS, et al.: Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369 (25): 2379-90, 2013.
9. Nangalia J, Massie CE, Baxter EJ, et al.: Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369 (25): 2391-405, 2013.
10. Cazzola M, Kralovics R: From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 123 (24): 3714-9, 2014.
11. Rumi E, Pietra D, Ferretti V, et al.: JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 123 (10): 1544-51, 2014.
12. Rotunno G, Mannarelli C, Guglielmelli P, et al.: Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123 (10): 1552-5, 2014.
13. Cortelazzo S, Finazzi G, Ruggeri M, et al.: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332 (17): 1132-6, 1995.
14. Harrison C, Kiladjian JJ, Al-Ali HK, et al.: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366 (9): 787-98, 2012.
15. Hultcrantz M, Björkholm M, Dickman PW, et al.: Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms: A Population-Based Cohort Study. Ann Intern Med 168 (5): 317-325, 2018.
16. Boddu P, Masarova L, Verstovsek S, et al.: Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms. Ann Hematol 97 (1): 109-121, 2018.
17. Tefferi A, Betti S, Barraco D, et al.: Gender and survival in essential thrombocythemia: A two-center study of 1,494 patients. Am J Hematol 92 (11): 1193-1197, 2017.
18. Masarova L, Verstovsek S: Therapeutic Approach to Young Patients With Low-Risk Essential Thrombocythemia: Primum Non Nocere. J Clin Oncol : JCO2018793497, 2018.
19. Ruggeri M, Finazzi G, Tosetto A, et al.: No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 103 (3): 772-7, 1998.
20. Godfrey AL, Campbell PJ, MacLean C, et al.: Hydroxycarbamide Plus Aspirin Versus Aspirin Alone in Patients With Essential Thrombocythemia Age 40 to 59 Years Without High-Risk Features. J Clin Oncol 36 (34): 3361-3369, 2018.
21. Barosi G, Besses C, Birgegard G, et al.: A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia 21 (2): 277-80, 2007.
22. Harrison CN, Campbell PJ, Buck G, et al.: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353 (1): 33-45, 2005.
23. Green A, Campbell P, Buck G: The Medical Research Council PT1 trial in essential thrombocythemia. [Abstract] Blood 104 (11): A-6, 2004.
24. Gisslinger H, Gotic M, Holowiecki J, et al.: Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 121 (10): 1720-8, 2013.
25. Alvarez-Larrán A, Pereira A, Arellano-Rodrigo E, et al.: Cytoreduction plus low-dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high-risk essential thrombocythaemia: an observational study. Br J Haematol 161 (6): 865-71, 2013.
26. Yacoub A, Mascarenhas J, Kosiorek H, et al.: Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood 134 (18): 1498-1509, 2019.
27. Harrison CN, Mead AJ, Panchal A, et al.: Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood 130 (17): 1889-1897, 2017.
28. Alvarez-Larrán A, Cervantes F, Pereira A, et al.: Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 116 (8): 1205-10; quiz 1387, 2010.
29. Harrison C, Barbui T: Aspirin in low-risk essential thrombocythemia, not so simple after all? Leuk Res 35 (3): 286-9, 2011.
30. Finazzi G: How to manage essential thrombocythemia. Leukemia 26 (5): 875-82, 2012.
31. Squizzato A, Romualdi E, Passamonti F, et al.: Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 4: CD006503, 2013.
32. Sacchi S: The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leuk Lymphoma 19 (1-2): 13-20, 1995.
33. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
34. Huang BT, Zeng QC, Zhao WH, et al.: Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. Leuk Res 38 (10): 1177-83, 2014.
35. Masarova L, Patel KP, Newberry KJ, et al.: Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol 4 (4): e165-e175, 2017.
36. Quintás-Cardama A, Kantarjian H, Manshouri T, et al.: Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 27 (32): 5418-24, 2009.
37. Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al.: Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 122 (6): 893-901, 2013.
38. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med 92 (1): 69-76, 1992.

Chronic Neutrophilic Leukemia (CNL)

Disease Overview

CNL is a rare chronic myeloproliferative neoplasm of unknown etiology, characterized by sustained peripheral blood neutrophilia (>25 × 10⁹ /L) and hepatosplenomegaly.[1,2] The bone marrow is hypercellular. No significant dysplasia is in any of the cell lineages, and bone marrow fibrosis is uncommon.[1,2] Cytogenetic studies are normal in nearly 90% of the patients. In the remaining patients, clonal karyotypic abnormalities may include +8, +9, del (20q) and del(11q).[1,3,4,5] There is no Philadelphia chromosome or BCR/ABL fusion gene. CNL is a slowly progressive disorder, and the survival of patients is variable, ranging from 6 months to more than 20 years.

Treatment Overview

Until the last few years, the treatment of CNL focused on disease control rather than cure. Once the disease progressed to a more aggressive leukemia, there was typically little chance of obtaining a long-lasting remission because of the older age of most patients, as well as the acquisition of multiple poor prognostic cytogenetic abnormalities. Allogeneic bone marrow transplantation represents a potentially curative treatment modality in the management of this disorder.[6,7,8] Varying success has been reported with the use of traditional chemotherapies including hydroxyurea and interferon.[9]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Imbert M, Bain B, Pierre R, et al.: Chronic neutrophilic leukemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 27-8.
2. Zittoun R, Réa D, Ngoc LH, et al.: Chronic neutrophilic leukemia. A study of four cases. Ann Hematol 68 (2): 55-60, 1994.
3. Froberg MK, Brunning RD, Dorion P, et al.: Demonstration of clonality in neutrophils using FISH in a case of chronic neutrophilic leukemia. Leukemia 12 (4): 623-6, 1998.
4. Yanagisawa K, Ohminami H, Sato M, et al.: Neoplastic involvement of granulocytic lineage, not granulocytic-monocytic, monocytic, or erythrocytic lineage, in a patient with chronic neutrophilic leukemia. Am J Hematol 57 (3): 221-4, 1998.
5. Matano S, Nakamura S, Kobayashi K, et al.: Deletion of the long arm of chromosome 20 in a patient with chronic neutrophilic leukemia: cytogenetic findings in chronic neutrophilic leukemia. Am J Hematol 54 (1): 72-5, 1997.
6. Piliotis E, Kutas G, Lipton JH: Allogeneic bone marrow transplantation in the management of chronic neutrophilic leukemia. Leuk Lymphoma 43 (10): 2051-4, 2002.
7. Hasle H, Olesen G, Kerndrup G, et al.: Chronic neutrophil leukaemia in adolescence and young adulthood. Br J Haematol 94 (4): 628-30, 1996.
8. Böhm J, Schaefer HE: Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease. J Clin Pathol 55 (11): 862-4, 2002.
9. Elliott MA, Dewald GW, Tefferi A, et al.: Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study. Leukemia 15 (1): 35-40, 2001.

Chronic Eosinophilic Leukemia (CEL)

Disease Overview

CEL is a chronic myeloproliferative neoplasm of unknown etiology in which a clonal proliferation of eosinophilic precursors results in persistently increased numbers of eosinophils in the blood, bone marrow, and peripheral tissues. In CEL, the eosinophil count is greater than or equal to 1.5 × 10⁹ /L in the blood.[1] To make a diagnosis of CEL, there should be evidence for clonality of the eosinophils or an increase in blasts in the blood or bone marrow. In many cases, however, it is impossible to prove clonality of the eosinophils, in which case, if there is no increase in blast cells, the diagnosis of idiopathic hypereosinophilic syndrome (HES) is preferred. Because of the difficulty in distinguishing CEL from HES, the true incidence of these diseases is unknown, although they are rare. In about 10% of patients, eosinophilia is detected incidentally. In others, the constitutional symptoms found include the following:[1,2]

• Fever.
• Fatigue.
• Cough.
• Angioedema.
• Muscle pains.
• Pruritus.
• Diarrhea.

No single or specific cytogenetic or molecular genetic abnormality has been identified in CEL.

(Refer to the PDQ summaries on Hot Flashes and Night Sweats; Fatigue; Cardiopulmonary Syndromes; Pruritus; and Gastrointestinal Complications for information on many of the symptoms listed above.)

Treatment Overview

The optimal treatment of CEL remains uncertain, partially on account of the rare incidence of this chronic myeloproliferative neoplasm and the variable clinical course, which can range from cases with decades of stable disease to cases with rapid progression to acute leukemia. Case reports suggest that treatment options include bone marrow transplantation and interferon-alpha.[3,4]

Treatment of HES has included the following:[5,6]

• Corticosteroids.
• Chemotherapeutic agents such as hydroxyurea, cyclophosphamide, and vincristine.
• Interferon-alpha.

Case reports suggest symptomatic responses to imatinib mesylate for patients with HES who have not responded to conventional options.[6,7,8][Level of evidence C3] Imatinib mesylate acts as an inhibitor of a novel fusion tyrosine kinase, FIP1L1-PDGFR alpha fusion tyrosine kinase, which results as a consequence of an interstitial chromosomal deletion.[6,9][Level of evidence C3] HES with the FIP1L1-PDGFR alpha fusion tyrosine kinase translocation has been shown to respond to low-dose imatinib mesylate.[9]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Bain B, Pierre P, Imbert M, et al.: Chronic eosinophillic leukaemia and the hypereosinophillic syndrome. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 29-31.
2. Weller PF, Bubley GJ: The idiopathic hypereosinophilic syndrome. Blood 83 (10): 2759-79, 1994.
3. Basara N, Markova J, Schmetzer B, et al.: Chronic eosinophilic leukemia: successful treatment with an unrelated bone marrow transplantation. Leuk Lymphoma 32 (1-2): 189-93, 1998.
4. Yamada O, Kitahara K, Imamura K, et al.: Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation. Am J Hematol 58 (2): 137-41, 1998.
5. Butterfield JH, Gleich GJ: Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome. Ann Intern Med 121 (9): 648-53, 1994.
6. Gotlib J, Cools J, Malone JM, et al.: The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 103 (8): 2879-91, 2004.
7. Gleich GJ, Leiferman KM, Pardanani A, et al.: Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 359 (9317): 1577-8, 2002.
8. Ault P, Cortes J, Koller C, et al.: Response of idiopathic hypereosinophilic syndrome to treatment with imatinib mesylate. Leuk Res 26 (9): 881-4, 2002.
9. Cools J, DeAngelo DJ, Gotlib J, et al.: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348 (13): 1201-14, 2003.

Latest Updates to This Summary (11 / 04 / 2020)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myeloproliferative neoplasms. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Chronic Myeloproliferative Neoplasms Treatment are:

• Aaron Gerds, MD (Cleveland Clinic Taussig Cancer Institute)
• Eric J. Seifter, MD (Johns Hopkins University)
• Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Chronic Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389291]

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Last Revised: 2020-11-04