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

General Information About Myeloproliferative Neoplasms

The categories of myeloproliferative neoplasms (MPN) include:[1]

• Chronic myeloid leukemia (CML).
• Polycythemia vera (PV).
• Essential thrombocythemia (ET).
• Overt and prefibrotic primary myelofibrosis (PMF).
• Chronic neutrophilic leukemia (CNL).
• Chronic eosinophilic leukemia not otherwise specified (CEL-NOS).
• MPN unclassifiable (MPN-U).

All of these disorders involve dysregulation at the multipotent hematopoietic stem cell, 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.

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 PV and ET have marked increases of red blood cell and platelet production. Treatment is directed at reducing the excessive numbers of blood cells. Both PV and ET can develop a spent phase during their courses that resembles PMF with cytopenias and marrow hypoplasia and fibrosis called post-PV/ET myelofibrosis.[4] A recurrent single nucleotide variant in one copy of the JAK2 gene, a cytoplasmic tyrosine kinase on chromosome 9, has been identified in most patients with PV, ET, and PMF.[5] Other single nucleotide variants were associated with genes encoding calreticulin (CALR) and the thrombopoietin receptor (MPL).[6,7]

There is no standard treatment approach for patients with progression from chronic-phase MPN to accelerated phase (blasts 10% to <20% in the peripheral blood or bone marrow) or blast phase (leukemic transformation, blasts ≥20% in the peripheral blood or bone marrow), and these patients have a poor prognosis (3- to 18-month median survival).[8] Allogeneic hematopoietic cell transplant has resulted in long-term survival, but this approach is often not feasible in older patients with comorbid conditions or lack of initial response to leukemic induction therapy.[9]

References:

1. Arber DA, Orazi A, Hasserjian RP, et al.: International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 140 (11): 1200-1228, 2022.
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. Barosi G, Mesa RA, Thiele J, et al.: Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 22 (2): 437-8, 2008.
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. Mudireddy M, Gangat N, Hanson CA, et al.: Validation of the WHO-defined 20% circulating blasts threshold for diagnosis of leukemic transformation in primary myelofibrosis. Blood Cancer J 8 (6): 57, 2018.
9. 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.

Treatment of Chronic Myeloid Leukemia

For information, see Chronic Myeloid Leukemia Treatment.

Treatment of Polycythemia Vera

Disease Overview for Polycythemia Vera (PV)

To establish a diagnosis of PV, the International Consensus Classification requires that the patient meet either all three major criteria or the first two major criteria with the minor criterion.[1]

Major Criteria

1. Hemoglobin greater than 16.5 g/dL in men or 16.0 g/dL in women, hematocrit greater than 49% in men or 48% in women, or elevated red cell mass greater than 25% above mean normal predicted value.
2. Presence of a JAK2 V617F variant or a JAK2 exon 12 variant.
3. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (panmyelosis), including prominent erythroid, granulocytic, and increase in pleomorphic, mature megakaryocytes without atypia.

Minor Criterion

1. Serum erythropoietin level below reference range.

There is no staging system for this disease.

Patients have an increased risk of cardiovascular and thrombotic events [2] and leukemic transformation (blast-phase disease) or post-PV myelofibrosis.[3,4,5] Age older than 67 years, leukocytosis (≥15 × 10⁹ /L), a history of thrombosis, and the presence of pathogenic variants (SRSF2) are associated with a poor prognosis.[6]

Treatment Option Overview for PV

The primary therapy for PV includes the use of phlebotomy or cytoreductive therapy to maintain the hematocrit below 45%. This approach was confirmed in a randomized prospective trial, which demonstrated lower rates of cardiovascular death and major thrombosis using this hematocrit target.[7]

Complications of phlebotomy include:

• Thrombocytosis and symptoms related to chronic iron deficiency, including pica, angular stomatitis, and glossitis.
• Dysphagia resulting from esophageal webs (very rare).
• Potential muscle weakness.

In addition, progressive splenomegaly and pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. For more information, see Pruritus.

If symptoms persist or phlebotomy is not tolerated, cytoreductive therapy can be added to control the disease.

Guidelines based on anecdotal reports have been developed for the management of pregnant patients with PV.[8]

Treatment Options for PV

Treatment options for PV include:

1. Phlebotomy.[7]
2. Hydroxyurea.[9]
3. Pegylated interferon alfa-2a.[10,11,12]
4. Ropeginterferon alfa-2B.[13,14]
5. Ruxolitinib.[15]
6. Low-dose aspirin (≤100 mg) daily, unless contraindicated by major bleeding or gastric intolerance.[16]

Frontline cytoreductive therapy

Early retrospective studies in patients with PV suggested a superior median survival with myelosuppressive therapy as opposed to either no treatment or treatment with phlebotomy alone. This observation was countered by concerns regarding the leukemogenicity of cytoreductive therapy. The Polycythemia Vera Study Group (PSVG) found that both chlorambucil and radioisotope phosphorous 32 can have leukemogenic potential and are detrimental to survival, but hydroxyurea does not have these effects.[9] Similarly, the leukemic potential of pipobroman and busulfan has been established.[17,18] The leukemogenic hazards of hydroxyurea are still being debated. In several large studies, no consistent association between exposure to hydroxyurea and leukemic transformation (blast-phase MPN) has been identified.

Evidence (frontline cytoreductive therapy):

1. In an analysis of 51 patients from the PSVG-08 study, the use of hydroxyurea, along with phlebotomy as needed, significantly reduced the risk of thrombosis compared with 134 patients treated with phlebotomy alone from the PSVG-01 study.[19]
   • During the first 7.25 years of observation, there were fewer thrombotic events in patients who received hydroxyurea (9.8%) compared with those who received phlebotomy alone (32.8%) (P = .18). There was no difference in the incidence of leukemic transformation between the two groups at that time point.
   • With further follow-up (median, 8.6 years; maximum, 15.3 years), leukemic transformation occurred in three patients who received hydroxyurea (5.9%) and two patients who received phlebotomy alone (1.5%) (P = .25). There was no significant difference in the incidence of post-PV myelofibrosis or overall survival between the two groups.[19][Level of evidence C3]
2. The randomized phase III MPN-RC 112 study (NCT01259856) included 87 patients with high-risk PV. Patients were randomly assigned to receive either hydroxyurea or pegylated interferon alfa.[20]
   • The complete response rates at 12 months were similar between patients who received hydroxyurea or pegylated interferon alfa (30% vs. 28%, respectively).[20][Level of evidence A3]
   • Thrombotic events and disease progression were infrequent in both arms, whereas grade 3 or 4 adverse events were more frequent for patients who received pegylated interferon alfa (46% vs. 28%).
3. The PROUD-PV study (NCT01949805) randomly assigned 257 patients with an indication for cytoreduction to receive either ropeginterferon alfa-2B or hydroxyurea. Patients could have previously received hydroxyurea for up to 3 years, but with suboptimal response or intolerance. After 1 year, patients could choose to continue study treatment in the CONTINUATION-PV trial (NCT02218047): patients either continued to receive ropeginterferon alfa-2B or received best-available treatment (hydroxyurea or another standard first-line treatment).[13]
   • In PROUD-PV, the 12-month complete hematological response rates were similar between the treatment groups (43% for ropeginterferon alfa-2B vs. 46% for hydroxyurea; P = .63).
   • In PROUD-PV, adverse events resulting in dose reduction occurred in 40% of the patients in the ropeginterferon alfa-2B group and 58% of patients in the hydroxyurea group. Serious treatment-related adverse events occurred in 3 of 127 patients (2%) in the ropeginterferon alfa-2B group and 5 of 127 patients (4%) in the hydroxyurea group.
   • In CONTINUATION-PV, the 5-year complete hematological response rate (with the last observation carried forward) was 72.6% (69 of 95 patients) in the ropeginterferon alfa-2B group and 52.6% (40 of 76 patients) in the best-available treatment group (rate ratio,1.43; 95% confidence interval [CI], 1.12–1.81; P = .004). The 5-year molecular response rate was 69.1% in the ropeginterferon alfa-2B group and 21.6% in the best-available treatment group (rate ratio, 3.04; 95% CI, 1.96–4.71; P < .0001). Also at 5 years, the median JAK2 V617F allele burden was better for the ropeginterferon alpha-2B group compared with the hydroxyurea group (8% vs. 44%, respectively; P < .0001).[14][Level of evidence A3]

Posthydroxyurea cytoreductive therapy

Evidence (posthydroxyurea cytoreductive therapy):

1. In the phase II MPN-RC 111 study (NCT01259817), 50 patients with PV received pegylated interferon alfa-2a. Patients had previously received hydroxyurea and had either an inadequate response or unacceptable side effects.[12]
   • The complete response rate was 22%, and the partial response rate was 38%. A total of 14% of patients discontinued treatment because of side effects.[12][Level of evidence C3]
2. In the open-label RESPONSE study (NCT01243944), patients with phlebotomy-dependent PV and palpable splenomegaly were randomly assigned to receive either ruxolitinib or standard therapy (interferon, pipobroman, anagrelide, immunomodulators, or no treatment/phlebotomy alone). Patients had previously received hydroxyurea but had either an inadequate response or unacceptable side effects.[21]
   • Ruxolitinib was superior to standard therapy with regards to phlebotomy-free control of hematocrit (60% vs. 20%; P < .001), reduction of spleen volume (38% vs. 1%; P < .001), and reduction in symptom score by 50% (49% vs. 5%; P < .001).[21][Level of evidence B3]
3. The follow-up open-label RESPONSE-2 study (NCT02038036) included 173 patients with phlebotomy-dependent PV without palpable splenomegaly who had either an inadequate response to or unacceptable side effects from hydroxyurea. Patients were randomly assigned to receive either ruxolitinib or best-available therapy (interferon, pipobroman, anagrelide, immunomodulators, or no treatment/phlebotomy alone).[15]
   • Hematocrit control was achieved in 62% of patients who received ruxolitinib and 19% of patients who received best-available therapy (hazard ratio [HR], 7.28; 95% CI, 3.43‒15.45; P < .001).[15][Level of evidence B3]
4. MAJIC-PV was a phase II study that randomly assigned 180 patients to receive either ruxolitinib or best-available therapy. Patients had experienced an inadequate response or unacceptable side effects from prior hydroxyurea therapy. Patients remained on study for up to 5 years without crossover.[22]
   • At 1 year, the complete response rate was 43% for patients who received ruxolitinib and 26% for patients who received best-available therapy (odds ratio, 2.12; 90% CI, 1.25–3.60; P = .02).[22][Level of evidence B1]
   • Thromboembolic event–free survival was significantly higher in the ruxolitinib group compared with the best-available therapy group (HR, 0.58; 95% CI, 0.35–0.94; P = .03).

No randomized trial has compared ruxolitinib with interferons in patients with PV who have previously received hydroxyurea.

Antiplatelet therapy

After controlling hematocrit with phlebotomy or cytoreductive therapy, the second principle in treating PV is the use of antiplatelet agents to reduce the risk of thrombosis.

Evidence (antiplatelet therapy):

1. The double-blind, randomized, phase III European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) studied the use of aspirin in patients with PV.[16]
   • Aspirin use was associated with a lower combined risk of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 % CI, 0.18–0.91).[16][Level of evidence B1]
   • The incidence of major bleeding was not significantly increased in the aspirin group.

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. Arber DA, Orazi A, Hasserjian RP, et al.: International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 140 (11): 1200-1228, 2022.
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. 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.
4. Elliott MA, Tefferi A: Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 128 (3): 275-90, 2005.
5. 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.
6. Tefferi A, Guglielmelli P, Lasho TL, et al.: Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera. Br J Haematol 189 (2): 291-302, 2020.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Gisslinger H, Klade C, Georgiev P, et al.: Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol 7 (3): e196-e208, 2020.
14. Kiladjian JJ, Klade C, Georgiev P, et al.: Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b. Leukemia 36 (5): 1408-1411, 2022.
15. 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.
16. Landolfi R, Marchioli R, Kutti J, et al.: Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350 (2): 114-24, 2004.
17. 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 105 (7): 2664-70, 2005.
18. Wang R, Shallis RM, Stempel JM, et al.: Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv 7 (5): 734-743, 2023.
19. Tremblay D, Kosiorek HE, Dueck AC, et al.: Evaluation of Therapeutic Strategies to Reduce the Number of Thrombotic Events in Patients With Polycythemia Vera and Essential Thrombocythemia. Front Oncol 10: 636675, 2020.
20. Mascarenhas J, Kosiorek HE, Prchal JT, et al.: A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood 139 (19): 2931-2941, 2022.
21. 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.
22. Harrison CN, Nangalia J, Boucher R, et al.: Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. J Clin Oncol 41 (19): 3534-3544, 2023.

Treatment of Essential Thrombocythemia

Disease Overview for Essential Thrombocythemia (ET)

To establish a diagnosis of ET, the revised World Health Organization (WHO) classification requires that the patient meet the following criteria:[1]

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 ET from another entity with thrombocytosis, namely prefibrotic primary myelofibrosis (PMF), which is identified by increased granulocytic or erythroid precursors, atypical megakaryocytes, and increased bone marrow cellularity.

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

3. Not meeting criteria for polycythemia vera (PV), PMF, chronic myeloid leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
4. Demonstration of a JAK2 V617F variant or an MPL exon 10 variant.[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 PV range with iron replacement therapy. If a JAK2 variant or an MPL variant is present and other myeloproliferative or myelodysplastic features are excluded, a bone marrow aspirate/biopsy may not be mandatory for diagnosis.[7] About 60% of patients with ET carry a JAK2 variant, and about 5% to 10% of the patients have activating variants in the MPL thrombopoietin receptor gene. About 70% of patients without JAK2 or MPL variants carry a somatic variant in the CALR gene, which is associated with a more indolent clinical course than that seen in patients with JAK2 or MPL variants.[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 men, with a hazard ratio (HR) of 1.5 (95% confidence interval [CI], 1.1‒2.5).[17]

There is no staging system for this disease.

Categorizing a patient as having untreated ET means that a patient is newly diagnosed and has had no previous treatment except supportive care.

Treatment Option Overview for ET

Initiation of therapy for patients with asymptomatic ET is controversial.[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 compared with normal controls.[19]

Treatment Options for ET

Treatment options for ET include:

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 alfa [20,21,22,23] or pegylated interferon alfa-2a.[24,25]
4. Anagrelide.[26,27]

Hydroxyurea

Evidence (hydroxyurea):

1. A prospective randomized trial included 382 patients aged 40 to 59 years with ET and without high-risk factors (no history of thrombosis or bleeding, no hypertension, no diabetes, platelet count ≤1,500 × 10⁹ /L). Patients were randomly assigned to receive aspirin alone or hydroxyurea plus aspirin.[28]
   • 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).[28][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 ET and a high risk of thrombosis compared treatment with hydroxyurea titrated to attain a platelet count below 600 × 10⁹ /L 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 was defined as (1) a platelet count of greater than 600 × 10⁹ /L after 3 months of at least 2 g per day of hydroxyurea or (2) a platelet count greater than 400 × 10⁹ /L and a white blood cell count of less than 2.5 × 10⁹ /L or a hemoglobin less than 10 g/dL at any dose of hydroxyurea.[29]
3. A prospective randomized trial in the United Kingdom of 809 patients compared hydroxyurea plus aspirin with anagrelide plus aspirin.[30]
   • 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.[27][Level of evidence B1]
4. Another prospective randomized trial also compared hydroxyurea with anagrelide in 259 previously untreated and high-risk patients.[31] In this central European trial, the diagnosis of ET was made by the WHO recommendations, not by the Polycythemia Vera Study Group criteria as in the U.K. 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.[31][Level of evidence B1]

These randomized prospective trials establish the efficacy and safety for the use of hydroxyurea for patients with high-risk ET (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.[32] In a phase II study (NCT01259856), 65 patients with ET who required therapy with hydroxyurea and had either an inadequate response or unacceptable side effects received pegylated interferon alfa-2a. The complete response rate was 43% and the partial response rate was 26%, with only a 14% discontinuation rate from side effects. Patients with a CALR variant had a significantly higher complete response rate than patients without a CALR variant (57% vs. 28%).[33][Level of evidence C3] Unlike results for PV or myelofibrosis, ruxolitinib was not helpful for patients resistant to hydroxyurea.[34]

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.[35] Balancing the risks and benefits of aspirin for low-risk patients can be difficult.[36] In an extrapolation of the data from trials of PV, low-dose aspirin to prevent vascular events has been suggested, but there are no data from clinical trials to address this issue.[37,38]

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. 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.
21. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
22. 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.
23. 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.
24. 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.
25. 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.
26. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med 92 (1): 69-76, 1992.
27. Green A, Campbell P, Buck G: The Medical Research Council PT1 trial in essential thrombocythemia. [Abstract] Blood 104 (11): A-6, 2004.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. Harrison C, Barbui T: Aspirin in low-risk essential thrombocythemia, not so simple after all? Leuk Res 35 (3): 286-9, 2011.
37. Finazzi G: How to manage essential thrombocythemia. Leukemia 26 (5): 875-82, 2012.
38. Squizzato A, Romualdi E, Passamonti F, et al.: Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 4: CD006503, 2013.

Treatment of Primary Myelofibrosis

Disease Overview for Primary Myelofibrosis (PMF)

PMF (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 myeloid leukemia (CML), PMF usually presents as follows:[2]

• A white blood cell count less than 30 × 10⁹ /L.
• 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.
• Identification of a JAK2, MPL, or CALR variant (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 of PMF include:

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

For more information about the symptoms listed above, see Fatigue, Hot Flashes and Night Sweats, and Nutrition in Cancer Care.

To establish a diagnosis of PMF, the World Health Organization classification requires that the patient meet all three major criteria and two minor criteria.[9]

Major Criteria

1. 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 (PV), 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 PMF carry a JAK2 variant, and about 5% to 10% of the patients have activating variants in the thrombopoietin receptor gene, MPL. More than half of the patients without JAK2 or MPL carry a somatic pathogenic variant in the CALR gene, which is associated with a more indolent clinical course than that seen in patients with JAK2 or MPL variants.[3,4,5,10,11,12]

Minor Criteria

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

The major causes of death include:[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:[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 (platelet count <50 × 10⁹ /L) is a very poor prognostic factor for PMF and for myelofibrosis following thrombocythemia or PV.[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 Option Overview for PMF

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 warrants 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:[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 receiving 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.

Treatment Options for PMF

Treatment options for PMF include:

1. Ruxolitinib.[37,38,39,40]
2. Clinical trials involving other JAK2 inhibitors.
3. Hydroxyurea.[6,7]
4. Allogeneic peripheral stem cell or bone marrow transplant.[41,42,43,44,45]
5. Thalidomide.[27,32,46,47,48,49]
6. Lenalidomide.[29,33,34,35,49]
7. Pomalidomide.[36]
8. Splenectomy.[50,51]
9. Splenic radiation therapy or radiation to sites of symptomatic extramedullary hematopoiesis (e.g., large lymph nodes, cord compression).[7]
10. Cladribine.[52]
11. Interferon alfa.[53,54]

Cytoreductive therapy

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 PMF, post–essential thrombocythemia myelofibrosis, or post-PV myelofibrosis.[55]

Evidence (cytoreductive therapy):

1. 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]).[37,38]
   • At 48 weeks, patients who received ruxolitinib had a decrease of 30% to 40% in mean spleen volume compared with an increase of 7% to 8% in the control patients.[37,38][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 patients who received ruxolitinib 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).[56,57][Level of evidence A1]
   • Clinical benefits were observed across a wide variety of clinical subgroups.[58,59]

Discontinuation of ruxolitinib results in a rapid worsening of splenomegaly and the recurrence of systemic symptoms.[37,38,39] Ruxolitinib does not reverse bone marrow fibrosis or induce histological 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.[60]

Treatment of splenomegaly

Painful splenomegaly can be treated temporarily with ruxolitinib, hydroxyurea, thalidomide, lenalidomide, cladribine, or radiation therapy, but sometimes requires splenectomy.[29,50,61] 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).[7,50]

After splenectomy, many physicians use anticoagulation therapy for 4 to 6 weeks to reduce portal vein thrombosis. Hydroxyurea can be used to reduce high platelet levels (>1 million).[62] However, in a retrospective review of 150 patients who underwent surgery, 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.[63]

Hydroxyurea is useful in patients with splenomegaly but may have a leukemogenic effect.[7] In patients with thrombocytosis and hepatomegaly after splenectomy, cladribine may be an alternative to hydroxyurea.[52] The use of interferon alfa may result in hematological responses, including reduction in spleen size in 30% to 50% of patients, though many patients do not tolerate this medication.[53,54] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[27,28,29,47,48,49][Level of evidence C3]

A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplant when a suitable donor is available.[41,42,43,44,45,46] Allogeneic stem cell transplant is the only potentially curative treatment available, but the associated morbidity and mortality limit its use to younger, high-risk patients.[44,64] Detection of a JAK2 variant after transplant is associated with a worse prognosis.[65]

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:

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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.
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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.
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37. 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.
38. 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.
39. Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 365 (15): 1455-7, 2011.
40. 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.
41. Deeg HJ, Gooley TA, Flowers ME, et al.: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 102 (12): 3912-8, 2003.
42. 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.
43. 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.
44. Gupta V, Hari P, Hoffman R: Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 120 (7): 1367-79, 2012.
45. 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.
46. 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.
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49. Jabbour E, Thomas D, Kantarjian H, et al.: Comparison of thalidomide and lenalidomide as therapy for myelofibrosis. Blood 118 (4): 899-902, 2011.
50. 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.
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52. 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.
53. 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.
54. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. 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.
65. 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.

Treatment of Chronic Neutrophilic Leukemia

Disease Overview for Chronic Neutrophilic Leukemia (CNL)

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 in patients with CNL. 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 ranges from 6 months to more than 20 years.

Treatment Option Overview for CNL

In the past, 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 transplant represents a potentially curative treatment modality for CNL.[6,7,8] Results vary 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.

Treatment of Chronic Eosinophilic Leukemia

Disease Overview for Chronic Eosinophilic Leukemia (CEL)

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.[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. However, in many cases, 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:[1,2]

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

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

For more information about the symptoms listed above, see Hot Flashes and Night Sweats, Fatigue, Cardiopulmonary Syndromes, Pruritus, and Gastrointestinal Complications.

Treatment Option Overview for CEL

CEL is rare, and the optimal treatment remains uncertain. The clinical course 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 transplant and interferon alfa.[3,4]

Treatment of HES has included corticosteroids, chemotherapeutic agents (e.g., hydroxyurea, cyclophosphamide, or vincristine), and interferon alfa.[5,6]

Case reports suggest that patients with HES who have not responded to conventional options may have symptomatic responses to imatinib mesylate.[6,7,8][Level of evidence C3] Imatinib mesylate acts as an inhibitor of a novel FIP1L1::PDGFRA fusion tyrosine kinase, which results as a consequence of an interstitial chromosomal deletion.[6,9][Level of evidence C3] HES with the FIP1L1::PDGFRA 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 (09 / 27 / 2024)

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.

This summary was renamed from Chronic Myeloproliferative Neoplasms Treatment.

General Information About Myeloproliferative Neoplasms (MPN)

Added Arber et al. as reference 1.

Added Barosi et al. as reference 4.

Revised text to state that there is no standard treatment approach for patients with progression from chronic-phase MPN to accelerated or blast phase, and these patients have a poor prognosis (cited Mudireddy et al. as reference 8).

Treatment of Polycythemia Vera

This section was extensively revised.

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 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 Myeloproliferative Neoplasms Treatment are:

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

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 Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloproliferative/hp/myeloproliferative-neoplasms-treatment. Accessed <MM/DD/YYYY>. [PMID: 26389291]

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Last Revised: 2024-09-27