Treating Anemic Patients With Myelofibrosis in the New Janus Kinase Inhibitor Era: Current Evidence and Real-world Implications

Anemia is a prevalent and burdensome clinical manifestation of myelofibrosis (MF) with a complex etiology. Most MF patients are anemic within 1 year of diagnosis, and nearly all become dependent on red blood cell transfusions over time.1 Anemia is associated with a reduced health-related quality of life (HRQoL) and shortened survival.2 Moreover, anemia and transfusion dependence are independent negative prognostic indicators incorporated into standard clinical MF risk scoring systems.3 While specific subsets of patients with MF may derive temporary anemia benefit from androgens (eg, danazol), corticosteroids (eg, prednisone), immunomodulators (eg, pomalidomide), or erythropoiesis-stimulating agents, the vast majority of patients will not achieve a prolonged response.2 The Janus kinase inhibitor (JAKi) ruxolitinib has been a decade-long standard of care for patients with intermediate- and high-risk MF due to its efficacy in reducing spleen size and improving disease-related symptoms; however, ruxolitinib is myelosuppressive and associated with dose-dependent worsening of anemia.4 More recently, the JAKi fedratinib and pacritinib have each been approved for the treatment of MF, having demonstrated spleen and symptom improvements compared with placebo or best available therapy.5,6 Like ruxolitinib, new-onset or worsening anemia is commonly reported with fedratinib treatment,5 whereas pacritinib is relatively nonmyelosuppressive.6 Notably, the investigational agent momelotinib is the first and only JAKi to also target the iron regulator activin A receptor type 1/activin receptor-like kinase-2 (ACVR1/ALK2), addressing the unmet need of anemia in MF patients in addition to the traditional treatment goals of JAK inhibition: reducing splenomegaly and symptom burden.2 Due to the lack of comparative information among these expanding treatment options, a systematic literature review and network meta-analysis (NMA) of 7 randomized controlled trials of JAKi in patients with MF (noted in Table 1) by Sureau et al evaluated the relative efficacy and tolerability of treatments, including endpoints of reduced spleen volume and adverse events due to hematologic toxicity, among others.7 This NMA demonstrated that ruxolitinib, momelotinib, and fedratinib were comparably efficacious in reducing spleen volume (with ruxolitinib and momelotinib providing significant improvements in achieving ≥35% spleen volume reduction at 24 weeks compared with pacritinib), while momelotinib was associated with significantly less grade 3/4 anemia compared with ruxolitinib, fedratinib, or pacritinib.7 However, this analysis did not include real-world studies, examine anemia-related benefits among treatments (such as decreased transfusion need), or evaluate the differential impact of therapies on the HRQoL and economic burden associated with anemia and transfusions in MF. Table 1 - Summary of the Impact of JAKi and Imetelstat on Transfusion Burden in Clinical and Real-world Studies of MF Treatment Publication Trial name/Data Source Number of Patients Anemia Rate Impact on Transfusion Burden Measurement Results Measurement Results Overall Change in %TI Patients From BL to W24 or End of Treatment Phase 3 clinical trials Ruxolitinib Verstovsek et al. N Engl J Med. 2012;366:799–807. COMFORT-1* Ruxolitinib (n = 155)Placebo (n = 154) Proportion of patients with grade 3 anemia during month 0–6 26.4% (ruxolitinib)10.7% (placebo) Proportion of patients who were TD at baseline who achieved TI during the study 41.2% (ruxolitinib) vs 46.9% (placebo) P = NR NR Proportion of patients with grade 4 anemia during month 0–6 11.5% (ruxolitinib)3.1% (placebo) Harrison et al. N Engl J Med. 2012;366:787–798. COMFORT-2* Ruxolitinib (n = 146)BAT (n = 73) Exposure-adjusted rate (event per 100 patient-years) of grade 3/4 anemia 21 (12.3) (ruxolitinib)5 (7.5) (BAT) Proportion of patients who received ≥1 RBC transfusion during the treatment period 51% (ruxolitinib) vs 38% (BAT) P = NR NR Al-Ali et al. haematologica 2016; 101:1065. JUMP Ruxolitinib (n = 1144) Proportion of patients with grade 3/4 anemia 33.0% NR NR NR Fedratinib Pardanani et al. JAMA Oncol. 2015;1:643–651. JAKARTA-1* Fedratinib 400 mg daily (n = 96)Fedratinib 500 mg daily(n = 97)Placebo (n = 96) Proportion of patients with grade 3/4 anemia 43% (fedratinib 400 mg)60% (fedratinib 500 mg)25% (placebo) Proportion of patients who were TD at baseline who achieved TI during follow-up 92.3% (fedratinib 400 mg and 500 mg pooled) vs 50% (placebo) P = NR –9% Pacritinib Mesa et al. Lancet Haematol. 2017;4:e225–e236. PERSIST-1* Pacritinib 400 mg (n = 220)BAT excluding JAKi (n = 107) Proportion of patients with grade 3/4 anemia through W24 17% (pacritinib 400 mg)15% (BAT) Proportion of patients who were TD at baseline who achieved TI during follow-up 25% (pacritinib 400 mg) vs 0% (BAT) P = 0.043 NR Mascarenhas et al. JAMA Oncol. 2018;4:652–659. PERSIST-2* Pacritinib 400 mg once daily (n = 75†)Pacritinib 200 mg twice daily (n = 74†)BAT (n = 72†) Proportion of patients with grade 3/4 anemia 27% (pacritinib 400 mg)22% (pacritinib 200 mg)14% (placebo) Proportion of patients not TI at baseline who had reduced transfusion burden at W24 20.5% (pacritinib 200 mg and 400 mg pooled) vs 8.6 (BAT) P = NR +1.3% (pacritinib 400 mg)+1.4% (pacritinib 200 mg)0% change (placebo) Momelotinib Mesa et al. J Clin Oncol. 2017;35:3844–3850. SIMPLIFY-1* Momelotinib (n = 215)Ruxolitinib (n = 217) Proportion of patients with grade 3/4 treatment-emergent anemia 5.6% (momelotinib)23.1% (ruxolitinib) Proportion of patients who were TI at W24 66.5% (momelotinib) vs 49.3% (ruxolitinib) P < 0.001 –2% (momelotinib)–21% (ruxolitinib) Proportion of patients who were TD at W24 30.2% (momelotinib) vs 40.1% (ruxolitinib) P = 0.019 Median rate of transfusion (units/month) 0 (momelotinib) vs 0.4 (ruxolitinib) P < 0.001 Harrison et al. Lancet Haematol. 2018;5:e73–e81. SIMPLIFY-2* Momelotinib (n = 104)BAT (n = 52) Proportion of patients with grade 3/4 treatment-emergent anemia 13.5% (momelotinib)13.5% (BAT) Proportion of patients who were TI at W24 43% (momelotinib) vs 21% (BAT) P = 0.0012 +12% (momelotinib)–16% (BAT) Phase 2 clinical trials Ruxolitinib Mead et al. Br J haematol. 2015;170:29–39. ROBUST Ruxolitinib (n = 48) Proportion of patients with grade 3/4 anemia 20.8% Proportion of patients who were TD at baseline achieved TI by the end of the study 17% (1 out of 6 evaluable patients) NR Talpaz et al. J Hematol Oncol. 2018;11:1–0. NCT01445769 Ruxolitinib (n = 45) Proportion of patients with grade 3/4 treatment- emergent anemia 20.0% Proportion of patients who were TI 66.7% (baseline)53.3% (by the end of treatment phase) -13% Talpaz et al. J Hematol Oncol. 2013;6:1–0. NCT01348490 Ruxolitinib (n = 50) Proportion of patients with grade 3/4 anemia 42.2% Proportion of patients who required RBC transfusion 40.0% (in 12 W before baseline)60.0% (during the treatment phase of the study) NR Ruxolitinib + lenalidomide Daver et al. Haematologica. 2015;100:1058. NCT01375140 Ruxolitinib and lenalidomide (n = 31) NR NR NR NR NR Fedratinib Harrison et al. Am J Hematol. 2020;95:594–603. JAKARTA-2 Fedratinib 400 mg (n = 97) Proportion of patients with grade 3/4 treatment- emergent anemia 38% Proportion of patients who had treatment-emergent TD 8% NR Pacritinib Gerds et al. Blood adv. 2020;4:5825–35. PACIFICA Pacritinib 100 mg QD(n = 52)Pacritinib 100 mg BID (n = 55)Pacritinib 200 mg BID (n = 54) Proportion of patients with grade 3/4 anemia 9.6% (pacritinib 100 mgQD)7.3% (pacritinib 100 mg BID)20.4% (pacritinib 200 mg BID) Proportion of patients with reduction in transfusion burden by 50% or greater 17.9% (pacritinib 100mgQD)35.5% (pacritinib 100 mg BID)14.7% (pacritinib 200 mg BID) NR Momelotinib Oh et al. Blood adv. 2020;4:4282–91. NCT02515630 Momelotinib (n = 41) Proportion of patients with grade 3 or above anemia 12% Proportion of patients achieved TI by W24 34% +34% Imetelstat Tefferi et al. N Engl J Med. 2015 Sep 3;373:908–19. NCT01731951 Imetelstat (n = 33) Proportion of patients with grade 3/4 treatment- emergent anemia 30% Proportion of patients who TD and who achieved TI 31% (4/13) NR Real-world studies NR‡ Masarova et al. Eur J haematol. 2018;100:257–63. University of Texas MD Anderson Cancer Center Overall (n = 1,269)Patients with platelet count > 100 × 109/L (n = 948)Patients with platelet count 50–100 × 109/L (n = 178)Patients with platelet count < 50 × 109/L (n = 145) Proportion of patients with anemia (hemoglobin 100 × 109/L)52% (patients with platelet count 50–100 × 109/L)68% (patients with platelet count 100 × 109/L)38% (patients with platelet count 50–100 × 109/L)62% (patients with platelet count < 50 × 109/L) NR NR‡ Masarova et al. Leuk Res. 2017;59:110–6. University of Texas MD Anderson Cancer Center PMF (n = 755)PET/MF(N = 163)PPV/MF (N = 181) Proportion of patients with anemia (hemoglobin < 10 g/dL) at baseline 43% (PMF)38%(PET/MF)41% (PPV/MF) Proportion of patients with TD at baseline 29% (PMF)17%(PET/MF)20% (PPV/MF) NR NR‡ Naqvi et al. Leuk Lymphoma. 2017;58:866–71. University of Texas MD Anderson Cancer Center PMF (n = 24)PET/MF (N = 4)PPV/MF (N = 7) NR NR NR NR NR All patients treated with ruxolitinib Kuykendall et al. Ann hematol. 2018;97:435–41. Lee Moffitt Cancer Center 64 Proportion of patients with anemia (hemoglobin < 10 g/dL) prior to ruxolitinib 51% NR NR NR Proportion of patients with anemia (hemoglobin < 10 g/dL) post ruxolitinib 70% NR‡ Kuykendall et al. Clin Lymphoma Myeloma Leuk. 2017;17:e45–53. Lee Moffitt Cancer Center 309 Proportion of patients with anemia OR TD at baseline 55% Proportion of patients with anemia OR TD at baseline 55% NR All patients treated with ruxolitinib Gerds et al. ASCO Ann meeting. 2020; e19539–e19539. Chart review 104 NR NR NR NR NR NR‡ Vallapureddy et al. Blood Cancer J. 2019;9:1–8. Mayo Clinic 1,306 Proportion of patients with moderate/severe anemia at first referral 54% Proportion of patients with TD at first referral 32% NR NR‡ Szuber et al. Am J Hematol. 2018;93:1474–84 Mayo Clinic PMF, age ≤ 40(n = 63)PMF, age 41–60 (n = 388)PMF, age >60 (n = 831) Proportion of patients with anemia (hemoglobin 60) Proportion of patients with TD at first referral 13% (PMF,age ≤ 40)24% (PMF, age 41–60)38% (PMF, age >60) NR NR‡ Pardanani et al. Am J Hematol. 2013;88:312–6. Mayo Clinic 203 Proportion of patients with anemia (hemoglobin < 10 g/dL) at first referral 59% Proportion of patients with TD at first referral 38% NR NR‡ Tefferi et al. Mayo Clin Proc. 2012;Vol. 87, No. 1, pp. 25–33 Mayo Clinic 1,000 Proportion of patients with anemia (hemoglobin < 10 g/dL) at first referral 54% Proportion of patients with TD at first referral 38% NR All patients treated with ruxolitinib Mascarenhas et al. J Med Econ. 2020;23:721–7. Optum, MarketScan, and SEER 290 Proportion of patients with anemia 36% (30 days after ruxolitinib initiation)53% (60 days after ruxolitinib initiation)60% (90 days after ruxolitinib initiation)66% (180 days after ruxolitinib initiation)53% (30 days after ruxolitinib discontinuation)65% (60 days after ruxolitinibdiscontinuation)69% (90 days after ruxolitinib discontinuation)77% (180 days after ruxolitinib discontinuation) NR NR NR NR‡ Vekeman et al. Leuk Lymphoma. 2015;56:2803–11. MarketScan and IMS PharMetrics TD patients with iron chelation therapy (n = 103)TD patients with iron chelation therapy (n = 468) Proportion of patients with anemia 86.4% (TD patients with iron chelation therapy)77.4% (TD patients with iron chelation therapy) Months from first MF diagnosis to TD, median (range): 2.9 (0.03, 33.80) (TD patients with iron chelation therapy)4.3 (0.03, 60.23) (TD patients with iron chelation therapy) NR NR‡ Yang et al. ASCO Ann meeting. 2016;e18556–e18556. Marketscan 1,658 NR NR Proportion of patients with RBC transfusion by line of therapy 13% (no therapy)25% (first-line therapy)32% (second-line therapy)35% (third-line therapy) NR All patients treated with ruxolitinib Pemmaraju et al. ASCO Ann meeting. 2020;e19535–e19535. Cardinal Health (chart review) 26 NR NR NR NR NR NR‡ Gimenez et al. J Med Econ. 2014;17:435–41. Three hospitals in Spain 33 NR NR Proportion of patients who needed transfusion Among splenomegaly symptomatic patients:33% (patients with constitutional symptoms and anemia)0% (patients with constitutional symptoms without anemia)21% (patients without constitutional symptoms with anemia)0% (patients without constitutional symptoms and anemia) Among splenomegaly asymptomatic patients:16% (patients with constitutional symptoms and anemia)2% (patients with constitutional symptoms without anemia)32% (patients without constitutional symptoms with anemia)0% (patients without constitutional symptoms and anemia) NR NR‡ Pastor-Galan et al. Med Clin. 2020;155:152–8. Spanish Registry of Myelofibrosis (GEM-MIE-2014-01) 1,000 Proportion of patients with anemia 36% NR NR NR All patients treated with ruxolitinib Palandri et al. Hematol Oncol.202;38:372–80. European Hematology centers 589 NR NR NR NR NR All patients treated with ruxolitinib Breccia et al. Ann Hematol. 2019;98:889–96. European Hematology centers 462 Proportion of patients with ruxolitinib inducted anemia 76% (any grade, any time)67% (any grade, at month 3)53% (any grade, at month 3) NR NR NR All patients treated with ruxolitinib Palandri et al. Br J Haematol. 2018;183:35–46. European Hematology centers 291 Proportion of patients developed anemia of any grade during ruxolitinib therapy 93 3% NR NR NR All patients treated with ruxolitinib Palandri et al. Oncotarget. 2017;8:79073. European Hematology centers 408 NR NR NR NR NR All patients treated with ruxolitinib Palandri et al. Cancer. 2020;126:1243–52. European Hematology centers 268 Proportion of patients with anemia (hemoglobin <10 g/dL) 51.5% (at the start of ruxolitinib)69.9% (at discontinuation of ruxolitinib) NR NR NR All patients treated with ruxolitinib Palandri et al. Hematol Oncol. 2018 Feb;36:285–90. European Hematology centers 70 Proportion of patients with ruxolitinib-induced anemia 45.7% Proportion of patients requiring occasional transfusion support 21.4% NR Proportion of patients acquired TD during ruxolitinib treatment 4.3% All patients treated with ruxolitinib Mazza et al. Leuk Lymphoma. 2017;58:138–44. Six institutions from the Apulia region in the south of Italy 65 Proportion of patients with mild anemia during ruxolitinib treatment 5% Proportion of patients who needed RBC transfusion 23% (before ruxolitinib)37% (during ruxolitinib)15% (after ruxolitinib) NR All patients treated with ruxolitinib Breccia et al.Ann Hematol. 2019;98:1933–6. Nine Italian hematological centers 53 Proportion of patients with grade 2 or above anemia during ruxolitinib treatment 45% NR NR NR All patients treated with ruxolitinib Breccia et al.Ann. Hematol. 2017;96:387–91. Nine Italian hematological centers 98 Proportion of patients experienced anemia of any grade 39.7% NR NR NR NR‡ Guglielmelli et al. Am J Hematol. 2016;91:918–922. Six Italian centers of the AGIMM consortium 490 Proportion of patients with anemia stratified by fibrosis grade 28.0% (overall)17.2% (grade 1 fibrosis)29.1% (grade 2 fibrosis)43.0% (grade 3 fibrosis) NR NR NR NR‡ Caocci et al. Int J Hematol. 2020;111:614–8. One Italian medical center 106 NR NR Median number of RBC units received 24 (TD patients with infection complication)15 (TD patients without infection complication) NR NR‡ Beauverd et al. Br J Haematol. 2016;175:37–42. Guy’s and St Thomas’ NHS Foundation Trust (UK) 43 Proportion of patients with anemia (hemoglobin < 10 g/dL) at referral 7.5% Proportion of patients with TD at referral 7% NR Proportion of patients who developed anemia during follow-up 17.6% All patients treated with ruxolitinib Barraco et al. Br J Haematol. 2020;191:764–74. The PASS (post-authorization safety study) study 259 Treatment-emergent anemia per 100 patient-years 3.8 NR NR NR *Randomized controlled trial included in network meta-analysis by Sureau et al.7†Only patients who completed at least 22 weeks of follow-up after randomization and before clinical hold were considered.‡Treatment information was not extracted for real-world studies where patients used various types of treatment or where treatment use was not reported.BAT = best available therapy; BID = twice per day; BL = baseline; JAKi = Janus kinase inhibitor; MF = myelofibrosis; NR = not reported; PET = postessential thrombocythemia; PMF = primary myelofibrosis; PPV = postpolycythemia vera; QD = once per day; RBC = red blood cell; TD = transfusion dependent; TI = transfusion independent; UK = United Kingdom; W = week. To address this, we conducted an expanded targeted literature review within the MEDLINE, Embase, Cochrane, NHS Economic Evaluation, and Health Technology Assessment databases to identify articles published between January 2011 and treatment of phase 2 and phase 3 clinical trials and real-world studies in MF in the United United or with at least patients per or approved ruxolitinib, fedratinib, and investigational momelotinib, as as the inhibitor and the MF treatments were A of were including real-world studies and clinical trials published study of the A review of the clinical trial that reported or in MF that momelotinib not only had the grade 3/4 anemia among JAKi also the in transfusion reported of treatment-emergent grade 3/4 anemia from to for momelotinib, to for ruxolitinib, 38% to for fedratinib, 7% to 27% for and 30% for the of patients from baseline to 24 or end of the treatment period decreased by 13% to 21% for ruxolitinib, decreased by for fedratinib, with a for and from a to a 12% for Notably, patients experienced a rate of transfusion at 24 compared with treated with ruxolitinib in the phase 3 trial P < and treated with best available therapy ruxolitinib) in P = patients experienced of transfusion dependence at 24 patients in P = where the median rate of transfusion was 0 with momelotinib compared with 0.4 with ruxolitinib P < targeted literature review also a of real-world the clinical burden associated with anemia and transfusions among patients with MF. we real-world of and including studies conducted in the studies, 3 and 2 conducted in 2 and 1 and 1 conducted of anemia and transfusion dependence the 24 real-world studies that reported among these MF 5% to of patients were anemic and 7% to were transfusion of ruxolitinib treatment due to anemia from 8% to and of ruxolitinib discontinuation due to anemia from 5% to we real-world studies and 1 clinical trial analysis that evaluated the between anemia and in patients with MF, include a of treatments Among of the 6 studies demonstrated an between anemia and shortened and a was in the study with the negative prognostic of anemia in Table 2 - Summary of the Impact of Anemia on Overall in Clinical and Real-world Studies of MF Publication Treatment Anemia Rate of Anemia vs P Guglielmelli et al. Am J Hematol. 2016;91:918–922. This study used 490 PMF patients with fibrosis grade 1 from 6 Italian centers of the AGIMM consortium to the prognostic impact of fibrosis of and were also NR P < P < Masarova et al. Leuk This study used patients with PMF, or who were to the University of Texas MD Anderson Cancer Center between and to and the and prognostic of PMF, and ruxolitinib, cell investigational 43% (PPV/MF) P = P = P = P = significant P = Palandri et al. Cancer. This study 268 patients who ruxolitinib between 2011 to 2018 from a of European The study for discontinuation and impact on Ruxolitinib after discontinuation of ruxolitinib P = P = Szuber et al. Am J Hematol. This study patients with myelofibrosis who were at between and The study the prognostic and among these NR 47% P = NR Tefferi et al. Mayo Clin Proc. This study 1,000 patients with PMF who were at Mayo Clinic between and This study reported clinical and for patients at of diagnosis and at from diagnosis, the of the including and in the of prognostic scoring and the prognostic impact of risk cell ruxolitinib, 54% P < 0.001 P < 0.001 Verstovsek et al. J Hematol Oncol. This study the in patients treated with ruxolitinib for myelofibrosis the from the 1 and Ruxolitinib or placebo or Ruxolitinib NR = best available therapy; = MF = myelofibrosis; NR = not reported; PET = postessential thrombocythemia; PMF = primary myelofibrosis; PPV = postpolycythemia the clinical burden associated with anemia and transfusion dependence has been in patients with MF, review to the impact of anemia and transfusions on HRQoL and economic in this specific we that from MF is in these from the that patients with MF had significantly dependent however, this study did not review for size per and did not address economic patients with with in with MF including transfusion burden is associated with significant HRQoL and economic with patients over 2 is needed to the HRQoL and economic impact to anemia and transfusion dependence in MF to the of therapies as as treatments that have the to address all of MF, including and with from Sureau et expanded targeted literature review the of ruxolitinib in addressing the unmet need among anemic patients with MF in real-world clinical MF patients ruxolitinib may treatment or treatment treatment or red blood cell transfusions the of nearly 50% of MF patients treated with ruxolitinib to as or erythropoiesis-stimulating the use of the median of ruxolitinib treatment in the real-world is in clinical While the for this of treatment may that adverse events anemia) and of treatment are The of treatment that address anemia in addition to the of MF may to Momelotinib of in addition to and to decreased the regulator of iron that is in MF and iron for Momelotinib may a or JAKi for anemic patients with MF, as its to of anemia and transfusion dependence in addition to spleen volume and symptoms has been demonstrated in phase 3 trials and by Sureau et therapies are in clinical that have demonstrated clinical anemia and of MF, including ruxolitinib an activin receptor ruxolitinib a and and ruxolitinib a Studies to address the in targeted literature review of the HRQoL and economic burden of anemia and transfusions in MF will to among the number of available and the MF treatment and the conducted the and the and the and the with from and Gerds has as a for and has received support from and and from and as a for and Kuykendall has received clinical from and and has on for and and are of is an of and Harrison has received clinical from and and has on and as a for and and is in of Momelotinib is by The targeted literature was by was by All or during this study are included in this published