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Management of thrombocytopenia in patients with myelofibrosis

Apr 2, 2020

Myelofibrosis (MF) is a progressive disease that can either appear de novo(primary MF [PMF]) or occur following a prior diagnosis of essential thrombocythemia (post-ET MF [PET-MF]) or polycythemia vera (post-PV MF [PPV-MF]). Initially, many patients with MF (30%) are asymptomatic, though a heterogeneous spectrum of clinical signs and symptoms subsequently develop, including symptomatic splenomegaly, constitutional symptoms such as fever, night sweats, and weight loss, bone pain, itching, thrombotic events, and ineffective hematopoiesis, correlating with reduced overall survival. 1

Our understanding of the genomic landscape of myeloproliferative neoplasms (MPNs) such as MF has increased in the last 10–15 years, indicating potential prognostic markers as well as therapeutic targets. For example, driver mutations in the JAK2, MPL, and CALRgenes affect Janus Kinase 2 (JAK2) signal transducer and activator of transcription (STAT) pathways and subclonal mutations, including those in high-molecular risk (HMR) genes ASXL1, IDH1/2, EZH2, and SRSF2, which are associated with poor prognosis. Additionally, in PMF, an association between U2AF1mutations, thrombocytopenia, and poor survival has been noted, indicating the potential role of U2AF1in risk-stratification. 1

Current risk stratification and prognostic scoring is based on clinical and laboratory parameters. The International Prognostic Scoring System (IPSS) is used at diagnosis, whereas the dynamic IPSS (DIPSS) and DIPSS-plus are used during the disease course. All scoring systems evaluate age, leukocyte count, circulating blast cells, hemoglobin, and presence of either one of three constitutional symptoms, though the DIPSS-plus also uses cytogenetic data, need for red blood cell transfusion, and platelet count. There are also newer scoring systems available incorporating mutation profiles, such as the mutation-enhanced IPSS 70 (MIPSS70), which considers platelet counts, fibrosis grading, and data on driver/HMR mutations, and MIPSS70+ version 2.0, which incorporates U2AF1Q157 as a HMR mutation. 1

Patients often present with cytopenias that worsen with the progression of disease and in response to cytoreductive treatment. Anemia is present in approximately 35% of patients with PMF and is included in all prognostic scoring systems. Therapies, such as corticosteroids and immunomodulatory drugs (IMiDs®), attempting to manage anemia in patients with PMF have so far failed to show efficacy. However, patients may also exhibit abnormal increases or decreases in platelet and white blood cell (WBC) counts. There are limited treatment options available for these patients, since many of the cytoreductive agents used innately cause cytopenias. Based on the unmet need for effective treatments that can be used in thrombocytopenic patients with MF, Guilia Benevolo and colleagues conducted a review of the current and emerging therapeutic interventions available for patients with MF with thrombocytopenia specifically. 1

Thrombocytopenia associated with MF

  • Thrombocytopenia is present in up to 25% of patients with PMF
    • Platelet count < 100 × 10 9/L: 16–26% of patients
    • Platelet count < 50 × 10 9/L: 11–16% of patients
      • These patients are often anemic and transfusion-dependent, have high blast count, and an increased risk for unfavorable karyotype
  • Thrombocytopenia in MF can be caused by different factors, such as ineffective megakaryocytopoiesis, splenomegaly, abnormal function of the spleen, and mutational status
  • Many approved treatments for PMF, such as hydroxyurea and JAK inhibitors, induce thrombocytopenia
  • Rates of thrombocytopenia increase over time due to the progressive nature of the disease
  • Thrombocytopenia is well established as a negative prognostic factor for patients with MF 2
    • Median overall survival (< 50 × 10 9/L vs> 100 × 10 9/L): 15 vs64 months
    • Median leukemia-free survival (< 50 × 10 9/L vs> 100 × 10 9/L): 13 vs52 months

Treatment options for thrombocytopenic patients with MF

JAK inhibitors

Ruxolitinib is an oral JAK1/2 inhibitor approved by the United States Food & Drug Administration(FDA) for the treatment of IPSS/DIPSS intermediate- and high-risk patients with MF-related splenomegaly and symptoms. 3However, as summarized in Table 1, the COMFORT-I and COMFORT-II trials found ruxolitinib led to high rates of thrombocytopenia, which is an on-target effect, therefore its use is restricted to patients with platelets > 50 × 10 9/L. 3-5Not surprisingly, dose reductions or discontinuation of ruxolitinib treatment due to thrombocytopenia is clinical reality and often results in a rapid recurrence of symptoms. More recent studies with ruxolitinib have shown a dose-escalation approach may mitigate the risk of worsening anemia and thrombocytopenia occurring with early ruxolitinib therapy ( Table 1). Other JAK inhibitors have subsequently been developed for the treatment of MF and their impact, specifically on thrombocytopenia, is shown in Table 1.

Table 1. Trials investigating JAK inhibitors for the treatment of patients with MF with thrombocytopenia

AE, adverse event; BAT, best available therapy; BID, twice daily; DIPSS, dynamic International Prognostic Scoring System; IPSS, International Prognostic Scoring System; JAK, Janus Kinase; MF, myelofibrosis; PET-MF, post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; TEAE, treatment-emergent adverse event

Therapeutic intervention

Trial name and design

Patient population

Key findings

Ruxolitinib

COMFORT-I 4

 

Randomized, double-blind, controlled phase III trial

 

Ruxolitinib (n = 155) vsplacebo (n = 154)

 

NCT00952289

Platelets: ≥ 100 × 10 9/L

 

Patients with intermediate-2 or high-risk MF as per IPSS/DIPSS

 

Ruxolitinib provided significant clinical benefits compared to placebo

 

Proportion of patients with a reduction in spleen volume of ≥ 35% at 24 weeks: 41.9% vs0.7%, p < 0.001

 

Ruxolitinib resulted in higher frequency of anemia and thrombocytopenia in the early part of treatment. Thrombocytopenia of any grade and Grade 3/4 was higher with ruxolitinib

  • Any grade: 70% vs31%
  • Grade 3/4: 13% vs1%

 

Dose adjustments led to low rates of discontinuation due to anemia or thrombocytopenia

COMFORT-II 5

 

Randomized controlled trial

 

Ruxolitinib (n = 146) vsBAT (n = 73)

 

NCT00934544

Platelets: ≥ 100 × 10 9/L

 

Patients with intermediate-2 and high-risk PMF, PET-MF, or PPV-MF as per IPSS/DIPSS

 

Continuous ruxolitinib led to reductions in splenomegaly and disease-related symptoms with modest toxic effects

Proportion of patients with a reduction in spleen volume of ≥ 35% at 48 weeks: 28% vs0%, p < 0.001

 

Thrombocytopenia of any grade and Grade 3/4 was higher with ruxolitinib

  • Any grade: 68% vs29%
  • Grade 3/4: 8% vs7%

 

Dose adjustments led to low rates of discontinuation due to anemia or thrombocytopenia

INCB 18424-261 6

 

Open-label, multicenter, single-arm phase II study

 

Ruxolitinib at incremental doses (n = 45)

 

NCT01445769

Platelets: ≥ 100 × 10 9/L

 

Patients with PMF, PET-MF, or PPV-MF

Median percentage change in spleen volume from baseline to Week 24: −17.3%

 

Most frequent Grade 3/4 TEAE was anemia (20.0%)

 

Eight patients (17.8%) developed thrombocytopenia, of which one patient had a Grade 3/4 event

 

Dose decreases due to anemia and thrombocytopenia were uncommon (11.1% and 6.7%, respectively)

Pacritinib

 

PERSIST-1 7

 

Phase III trial

 

Pacritinib 400 mg/day (n = 220) vsBAT (excluding JAK inhibitors; n = 107)

 

NCT01773187

 

 

No restriction on platelet count

 

Intermediate- or high-risk (by DIPSS) PMF, PET-MF, or PPV-MF

 

Patients were naïve to JAK2 inhibitors

 

Approximately 15% of patients in each arm had platelet counts < 50 × 10 9/L

Improvement in spleen responses in 17% of patients with platelet counts < 100 × 10 9/L and 23% with counts < 50 × 10 9/L

 

Most common Grade 3/4 AEs

  • Anemia: 17% vs15%
  • Thrombocytopenia: 12% vs11%

 

Pacritinib was well tolerated and improved symptom control, irrespective of baseline platelet count

PERSIST-2 8

 

Phase III trial

 

Pacritinib 400 mg/day (n = 75) vspacritinib 200 mg twice per day (n = 74) vsBAT (n = 72)

 

NCT02055781

 

Platelets: ≤ 100 × 10 9/L

 

Patients with MF and thrombocytopenia

 

Included patients with prior exposure to anti-JAK therapy (~50% of patients)

 

40–50% of patients had baseline platelet count of < 50 × 10 9/L

 

At Week 24, spleen volume responses of ≥ 35% (pacritinib vsBAT): 18% vs3%

 

Discontinuation due to thrombocytopenia occurred with pacritinib once daily (4%) and BAT (2%)

 

Most common Grade 3/4 AEs

  • Thrombocytopenia: 31% vs32% vs18%
  • Anemia: 27% vs22% vs14%

 

Pacritinib twice daily was more effective than BAT

PAC203 9

 

Phase II dose-finding study (n = 164)

 

Pacritinib: 200 mg BID vs100 mg BID or 100 mg once daily

 

Intermediate- or high-risk MF

 

Patients intolerant of, or resistant to, ruxolitinib

 

43% had platelet count < 50 × 10 9/L

 

Pacritinib (200 mg BID) was well tolerated with clinical activity, particularly in patients with severe thrombocytopenia at baseline

 

Spleen volume response ≥ 35%: 9.3% vs1.8% vs0.0%

 

Ongoing phase III study PACIFICA will evaluate PAC 200 mg BID vsphysician’s choice in patients with MF and severe thrombocytopenia who are naïve to, or had limited duration of, prior anti-JAK2 therapy

Momelotinib

 

 

SIMPLIFY-1 10

 

Randomized phase III trial

 

Momelotinib 200 mg/day (n = 215) vsruxolitinib (n = 217)

 

NCT01969838

Platelets: ≥ 50 × 10 9/L

 

Intermediate- or high-risk patients with MF

 

Patients who were naïve to JAK inhibitors

Momelotinib was non-inferior for spleen response but was associated with reduced transfusion requirement

 

Spleen volume response ≥ 35% at Week 24: 26.5% vs29% (p = 0.011)

 

Grade 3/4 thrombocytopenia: 7% of patients

SIMPLIFY-2 11

 

Randomized phase III trial

 

Momelotinib 200 mg/day (n = 104) vsBAT (n = 52)

 

NCT02101268

Patients with MF who were resistant or intolerant to ruxolitinib

Spleen response ≥ 35% for momelotinib was not superior to BAT (ruxolitinib in 89% of patients): 7% vs6%

 

Grade ≥ 3 thrombocytopenia: 7% vs6%

Fedratinib

JAKARTA 12

 

Double-blind, randomized, placebo-controlled phase III study

 

Fedratinib (400 mg or 500 mg) vsplacebo 

 

NCT01437787

Platelets: ≥ 50 × 10 9/L

 

Patients with intermediate- or high-risk PMF, PET-MF, or PPV-MF who were naïve to JAK inhibitors

Spleen volume responses with fedratinib in the 400mg cohort (thrombocyte counts < 100 × 10 9/L vs≥ 100 × 10 9/L): 36% vs49%

 

Grade 3/4 thrombocytopenia (fedratinib 400 mg vs500 mg/day): 17% vs27%

 

Fedratinib reduced splenomegaly and symptom burden in patients with MF but clinical development was discontinued due to toxic side effects

JAKARTA-2 13

 

Open-label, single-arm, non-randomized phase II trial

 

Fedratinib (400 mg/day, n = 97)

 

NCT01523171

Platelets: ≥ 50 × 10 9/L

 

Patients with intermediate- or high-risk PMF, PET-MF, or PPV-MF who were resistant/intolerant to ruxolitinib

Spleen volume responses with fedratinib (thrombocyte counts < 100 × 10 9/L vs≥ 100 × 10 9/L): 36% vs28%

 

Thrombocytopenia Grade 3/4: 22%

 

19% of patients discontinued due to AEs

 

 

IMiDs

IMiDs are a class of drugs that have immunomodulatory effects on the microenvironment, NK cells, and T cells. A summary of IMiDs tested in patients with MF is shown in Table 2, including established IMiDs such as thalidomide and lenalidomide, alone and in combinations, as well as second-generation agents, such as pomalidomide. These results have led to several ongoing trials including

  • thalidomide + ruxolitinib: phase II trial ( NCT03069326) in patients with PMF, PPV-MF, and PET-MF — early results in Table 2 14
  • pomalidomide + ruxolitinib: phase Ib/II trial ( NCT01644110), POMINC, MPNSG-0212, in patients with poor-risk MF — early results in Table 2 15

Table 2. Trials investigating IMiDs for the treatment of patients with MF with thrombocytopenia

AE, adverse event; MF, myelofibrosis; MPN, myeloproliferative neoplasm; PET-MF, post-essential thrombocythemia myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis

Therapeutic intervention

Study design

Patient population

Key findings

Thalidomide 16

 

 

Pooled analysis of patients treated on five phase II studies involving thalidomide ≥ 100 mg daily

Patients with PMF, PET-MF, or PPV-MF (n = 62)

38% of patients with thrombocytopenia had increased platelet counts

 

66% of patients discontinued within 6 months of treatment due to AEs

Thalidomide + prednisolone 17

 

 

Low dose thalidomide and a 3-month oral prednisone taper

Patients with PMF, PET-MF, or PPV-MF (n = 21)

Of eight patients with thrombocytopenia at baseline (< 100 × 10 9/L), all had improvements in platelet counts, six of which were ≥ 50%

 

The low doses of thalidomide here were better tolerated than prior studies

Thalidomide + ruxolitinib 14,18

 

 

Phase II study

 

NCT03069326

Platelets: ≥ 50 × 10 9/L

 

Patients with PMF, PPV-MF, and PET-MF who had received prior ruxolitinib

Combination was well tolerated overall, with increases in platelet counts in all patients with baseline thrombocytopenia

 

Grade 3/4 treatment-emergent events of special interest, were neutropenia in one patient and deep vein thrombosis in one patient

Lenalidomide 19

 

 

Results from two phase II studies

 

Patients with symptomatic MF

 

 

Overall response rate for thrombocytopenia: 50%

 

Increased platelet counts but more side effects, such as severe myelotoxicity

Lenalidomide + prednisone 20

 

Prospective, open-label phase II trial

 

NCT00352794

Patients with PMF (n = 40), including previously treated, relapsed or refractory disease, or newly diagnosed intermediate-/ high-risk

Grade 3/4 thrombocytopenia was observed in 13% of patients

 

No patients with baseline thrombocytopenia responded to treatment

Lenalidomide + ruxolitinib 21

 

 

NCT01375140

Patients with MF (n = 31)

Study terminated early due to failure to meet efficacy rule for treatment success. There was a high rate of early discontinuation due to hematologic AEs and simultaneous administration of both agents was difficult

Pomalidomide 22

 

 

RESUME

 

Phase III study

 

Pomalidomide (n = 152) vsplacebo (n = 77)

 

NCT01178281

Patients (n = 229) with MPN-associated MF and red blood cell transfusion dependence

Pomalidomide had no effect on rate/duration of red blood cell transfusion independence but did lead to significantly higher platelet responses compared to placebo (22% vs0%)

Pomalidomide + ruxolitinib 15,23

 

 

MPNSG-0212 trial

 

Single arm, open-label, multicenter phase Ib/II trial

 

NCT01644110

Patients with poor risk MF 

Combination was feasible. Step-wise increase in pomalidomide was safe and feasible. Disease stabilization

and improvements in cytopenia have been observed

Alternative treatment options

Other therapeutic interventions, including surgical options, are shown in Table 3.

Table 3. Therapeutic intervention options other than JAK inhibitors and IMiDs for patients with MF with thrombocytopenia

HSCT, hematopoietic stem cell transplant; MF, myelofibrosis; MPN, myeloproliferative neoplasm, PET-MF, post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis

Therapeutic intervention

Comment

Platelet transfusions 24

Reserved for patients with severe thrombocytopenia (< 10 × 10 9/L) and those with serious bleeding — not a long-term therapeutic option

Splenectomy 25

Splenectomy improved anemia and thrombocytopenia in 47% and 66% of patients with MPNs, respectively, and provides most benefits to patients with spleen pain and discomfort in addition to anemia and thrombocytopenia. However, in patients with MF, it is associated with high morbidity and mortality

PRM-151 26

PRM-151 is an anti-fibrotic agent. It is a recombinant intravenous form of pentraxin-2. In a phase II study looking at three doses of PRM-151 in patients previously treated with, or ineligible for ruxolitinib, improvements in thrombocytopenia were seen with PRM-151, with a reduction in platelet transfusions in 31–40% of patients who were transfusion dependent

Pegylated interferon alpha 27

In a retrospective study of 62 patients with primary and secondary MF, five of eight patients (62.5%) with thrombocytopenia had improved platelet counts and platelet counts were normalized in a further two patients. In the total cohort, nine patients (15%) developed thrombocytopenia

Allogeneic HSCT 28

Only curative treatment. Long-term survival rate is 40–65% and dependent on donor source. Reduced intensity conditioning in older patients provided 5-year OS rate of 67% in patients with PMF, PET-MF, or PPV-MF

Conclusion

  • JAK inhibitors cause thrombocytopenia as part of their on-target effect profile, which can be partly managed with dose reductions or interruptions
    • Spleen response and platelet reduction varies between JAK inhibitors, with pacritinib appearing to induce less spleen response and thrombocytopenia compared to other JAK inhibitors
  • IMiDs have been shown to reduce thrombocytopenia in patients with MF, however their toxicity profile restricts their clinical applicability
    • Ongoing trials are investigating whether combining an IMiD with ruxolitinib may be a novel treatment strategy
  • Anti-fibrotic agents, such as PRM-151, with or without a JAK inhibitor, may have efficacy but there are no currently accruing trials
  • Allogeneic hematopoietic stem cell transplant is the only curative measure, however post-transplant platelet counts can be low for a significant amount of time, and there is a high risk of morbidity and mortality. It is typically only considered for fit patients with high-risk disease or unfavorable cytogenetic features

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  2. Masarova L, Alhuraiji A, Bose P, et al. Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis. Eur J Haematol. 2018;100(3):257-263. DOI: 1111/ejh.13005
  3. S. Food and Drug Administration. JAKAFI label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202192s017lbl.pdf. Updated May 2019. Accessed Mar 13, 2020.
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  5. Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798. DOI: 1056/NEJMoa1110556
  6. Talpaz M, Erickson-Viitanen S, Hou K, et al. Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study. J Hematol Oncol. 2018;11:101. DOI: 1186/s13045-018-0642-0
  7. Mesa R, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e235-e236. DOI: 1016/S2352-3026(17)30027-3
  8. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. DOI: 1001/jamaoncol.2017.5818
  9. Gerds AT, Savona MR, Scott BL, et al. Results of PAC203: a randomized phase 2 dose-finding study and determination of the recommended dose of pacritinib. Blood. 2019;134(Supplement_1):667. DOI: 1182/blood-2019-129293
  10. Mesa RA, Kiladjian J-J, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naive patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. DOI: 1200/JCO.2017.73.4418
  11. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017;5(2):e73-81. DOI: 1016/S2352-3026(17)30237-5
  12. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. DOI: 1001/jamaoncol.2015.1590
  13. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-324. DOI: 1016/S2352-3026(17)30088-1
  14. Clinicaltrials.gov. A clinical study to test the effects of ruxolitinib and thalidomide combination for patients with myelofibrosis. https://clinicaltrials.gov/ct2/show/NCT03069326. Updated March 31, 2020. Accessed Mar 16, 2020.