Mild to moderate anemia is often present at MF diagnosis and can worsen with disease progression. Importantly, unlike JAK inhibitor treatment–related anemia discussed later in this review, MF-related anemia is associated with reduced overall survival, so proper management is essential [
14]. An overview of treatment recommendations for patients with MF-related anemia in my practice is presented in Fig.
1 [
16]. Patients should first be evaluated for contributing factors, including MF-related factors and exacerbating causes not directly related to MF. MF-related causes include reduced erythropoiesis, splenomegaly, and inflammatory cytokines [
12,
25]. Additionally, vitamin B
6, an essential element of heme synthesis, may be deficient in patients with primary or secondary MF, leading to anemia [
26]. Functional iron deficiency due to inflammation is also frequently observed in patients with MF [
27,
28], in which pro-inflammatory cytokine signaling upregulates hepcidin that in turn promotes storage of iron and ultimately iron-restricted anemia [
29]. Functional iron deficiency is identifiable by low transferrin saturation despite normal ferritin levels [
27,
28], and these patients should be treated with intravenous iron [
29]. In addition, new targeted therapies are in development to modulate hepcidin signaling, including the JAK1/JAK2 and type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2) inhibitor momelotinib (discussed in greater detail in the “
Treatment options for anemia resulting from JAK inhibition” section) [
30,
31] and the ACVR1/ALK2 inhibitor INCB000928 [
32]. Although seemingly very rare, cases of patients developing primary MF and autoimmune hemolytic anemia have been reported [
33]. Exacerbating causes not directly related to MF include underlying occult or gastrointestinal bleeding and deficiencies in iron folate and vitamin B
12, which can lead to megaloblastic anemia [
12,
25,
34,
35]. Deficiencies in iron folate and vitamin B
12 are not uncommon in elderly patient populations [
36] such as the MF population and are reversible via dietary or vitamin supplementation [
35]. For patients with contributing factors not related to MF, the underlying cause should be treated per appropriate guidelines, and patients should be treated normally for MF, regardless of anemia presence [
16,
35].
Management of patients with MF-related anemia begins with blood transfusions, with subsequent evaluation for additional anemia treatments [
16]. For patients with serum EPO < 500 mU/mL, erythropoiesis-stimulating agents (ESAs) are a viable option that offers clinical benefits [
16]. Up to half of the patients in this population may achieve an anemia response with ESAs, and dose escalation should be considered to achieve full benefit [
37]. Importantly, ESAs can be safely added to ruxolitinib to effectively improve anemia in some patients with MF [
38]. Additional treatment options are available for patients with serum EPO ≥ 500 mU/mL. The erythroid maturation agent, luspatercept, has demonstrated anemia benefits in patients with MF and myelodysplastic syndrome/MPN with ring sideroblasts who carry the SF3B1 mutation [
39,
40]. It is important to note that the studies that evaluated luspatercept in MF had small patient populations, and additional investigation is warranted to further evaluate safety and efficacy. Anabolic steroid medication such as danazol can also be used for the treatment of anemia in patients with MF [
16,
25]. Danazol treatment has been associated with an anemia response in these patients, including those who are transfusion-dependent [
41]. Immunomodulatory imide agents (IMiDs), such as thalidomide and lenalidomide, have also demonstrated an anemia benefit in patients with MF, including those who were transfusion-dependent [
42,
43]. However, this benefit was not observed in patients with myeloid metaplasia with MF who received thalidomide [
44] or those with MF treated with pomalidomide, another IMiD [
45]. Importantly, various treatments can be combined with ongoing ruxolitinib treatment, although the coadministration of IMiDs with steroids is currently a topic of debate. The combination of ruxolitinib with prednisone, thalidomide, and danazol has been associated with an anemia benefit in patients with MF [
46]. Similarly, luspatercept combined with ruxolitinib demonstrated transfusion independence in some patients with MF [
39]. Details for studies of ruxolitinib in combination with other agents, including ongoing/exploratory trials, are shown in Table
1.
Table 1
Key clinical trials featuring ruxolitinib-based combination therapy in patients with MF and anemia
(androgen) N = 14 | 2 (NCT01732445) | • Anemia (Hb < 10 g/dL) • Age ≥ 18 years • ECOG PS ≤ 2 • ANC ≥ 1 × 109/L • PLT, ≥ 50 × 109/L | • 4/5 (80%) JAKi-naive patients had stable or increasing Hb • 5/9 (56%) patients who had received JAKi had stable or increasing Hb | Hematologic grade ≥ 3 AEs: 71% (n = 10) Nonhematologic grade ≥ 3 AEs: 14% (n = 2) |
(TGFβ superfamily receptor ligand trap) N = 79 | 2 (NCT03194542) | • Anemia • Age ≥ 18 years • ECOG PS ≤ 2 • ANC ≥ 1 × 109/L • PLT, ≥ 50 × 109/L | • Mean Hb increase ≥ 1.5 g/dL from BL: NTD + RUX = 8/14 (57%); NTD, no RUX = 3/20 (15%) • RBC-TI ≥ 12 weeks during study: TD + RUX = 8/22 (36%); TD, no RUX = 4/21(19%) • ≥ 50% reduction in RBC transfusion burden: TD + RUX = 10/22 (46%); TD, no RUX = 8/21 (38%) | TRAEs in ≥ 5% of patients: • Hypertension, 13% • Bone pain, 9% • Diarrhea, 5% • 10% discontinued because of drug-related toxicity |
(TGFβ superfamily receptor ligand trap) Sotatercept monotherapy: n = 24 RUX combination cohort: n = 9 | 2 (NCT01712308) | • Anemia (Hb < 10 g/dL) • Age ≥ 18 years • Sporadic RBC transfusions, or TD | • ORR = TI + Hb increase ≥ 1.5 g/dL from BL for ≥ 12 consecutive weeks without RBC transfusion • 6/17 (35%) in sotatercept monotherapy cohort | TRAEs: • Grade 2 bilateral lower limb pain, n = 2 (1 patient in each cohort) • Hypertension, n = 1 |
• RUX combination cohort: ≥ 6 months RUX with stable dose for ≥ 2 months | • RUX combination cohort: ORR in 1/8 (12.5%) | |
(immunomodulatory agent) N = 23 (n = 15 evaluated) | 2 (NCT03069326) | • Age ≥ 18 years • ECOG PS ≤ 2 • ANC ≥ 1 × 109/L • PLT, ≥ 50 × 109/L • Suboptimal response, or refractory to RUX single-agent therapy • RUX treatment for ≥ 3 months, and stable dose for ≥ 4 weeks before enrollment | Cycle 3: • Trend toward increase in Hb over time | Nonhematologic grade ≥ 3 AEs: • Limb edema, diverticulitis, hypertension, syncope (n = 1 each) • Thromboembolic event and grade 3 neutropenia, n = 1 |
Prednisone, thalidomide, and danazol [ 46] N = 72 (n = 53 in combination therapy group) | Pilot study (ChiCTR1900025219) | • Age ≥ 18 years • SV ≥ 450 cm3 • Peripheral blood blasts < 10% • ECOG PS ≤ 2 • DIPSS: int-1, int-2, or high-risk • ANC ≥ 1 × 109/L • PLT, ≥ 50 × 109/L | Combo therapy group vs RUX monotherapy: • Anemia response: 56% vs 0% • Hb increase ≥ 10 g/L: 66% vs 0% • Hb increase ≥ 20 g/L: 38% vs 0% | Combo therapy group vs RUX monotherapy: • New or worsening anemia: 21% vs 58% • No grade 3/4 nonhematologic AEs occurred |
Erythropoiesis-stimulating agents [ 38] N = 59 | Retrospective study (completed) | • Anemia (Hb < 10 g/dL) • IPSS: int-2 or high (int-1 for some patients in compassionate use) | • Anemia response: 54% • Median time to anemia response: 4 mo | • Mild nausea, no other thrombotic events or toxicities reported |