Despite the identification of JAK mutations and the development of targeted inhibitors, there remain significant unmet needs for patients with myeloproliferative neoplasms. Identification of the myeloproliferative neoplasm populations not currently benefiting from JAK inhibitor therapy highlights the therapeutic deficits still present in this heterogeneous stem cell malignancy. While JAK inhibition has provided significant benefits for patients with intermediate-2 or high-risk myelofibrosis and in patients with polycythemia vera in the second-line setting, JAK inhibitor monotherapy is not approved and not appropriate for all patients with myeloproliferative neoplasms. Continued investigation into additional JAK inhibitors, combination therapy, and novel pathway therapeutics remains key to improving outcomes for all patients with myeloproliferative neoplasms. While therapeutic advances in the JAK inhibitor arena or involving alternative pathways are crucial to improving outcomes in myeloproliferative neoplasms, it is also important to reconsider the role of constitutional symptoms in affected patients as an indication for treatment with agents, such as JAK inhibitors, that can mitigate these debilitating symptoms. In this review, we demonstrate the evolving landscape of clinical investigations that address the important therapeutic needs of patients with myeloproliferative neoplasms.
Myeloproliferative neoplasms are a group of myeloid malignancies caused by a hematopoietic stem cell clonal proliferation, the main result of which is primarily either erythrocytosis in polycythemia vera, thrombocytosis in essential thrombocythemia, or progressive cytopenias and splenomegaly in primary myelofibrosis. This group of neoplasms is characterized by a lack of the BCR-ABL fusion protein that is associated with chronic myelogenous leukemia; instead, they are identified with one of three mutually exclusive mutations: JAK2 (Figure), CALR, or MPL. The identification of these mutations has led, through the subsequent development of JAK inhibitors, to changes in diagnostic paradigms,[6,7] prognostication,[8,9] and therapeutic interventions.
The COMFORT-1 and COMFORT-2 trials demonstrated that the JAK1/2 inhibitor ruxolitinib, when used in intermediate-2 or high-risk myelofibrosis, reduced spleen size, improved myelofibrosis-related symptom burden, and improved overall survival (OS).[10,11] The success of JAK2 inhibition in myelofibrosis brings into focus new areas of unmet need in the myeloproliferative neoplasm population. The first group with one of these current unmet needs are those patients who are not candidates for JAK inhibition with ruxolitinib. These patients are deemed not to be candidates either because at baseline they have a disease for which ruxolitinib has not been approved, including high-risk polycythemia vera or essential thrombocythemia, which require first-line cytoreductive therapy, or because they have drug-limiting cytopenias that preclude ruxolitinib use.
Another myeloproliferative neoplasm population with an unmet need comprises those patients for whom JAK inhibitor monotherapy is not effective, or is not effective enough. This group includes patients with advanced myeloproliferative neoplasms (accelerated phase, blast phase, or post–myeloproliferative neoplasm acute myeloid leukemia) characterized by poor outcomes and aggressive disease. These patients need the benefit of JAK inhibition to be incorporated into the context of combination therapy for disease management.
Lastly, there remains the unmet need of myeloproliferative neoplasm patients who have a high systemic symptom burden that requires interventions specifically targeting symptom mitigation. In this review, we demonstrate the evolving landscape of clinical investigation as researchers and clinicians attempt to address the important therapeutic needs of patients with myeloproliferative neoplasms.
Frontline Therapy in Polycythemia Vera
Although ruxolitinib has been approved for use in patients with myelofibrosis, this drug has a limited role in patients with polycythemia vera or essential thrombocythemia. Ruxolitinib is approved for management of polycythemia vera only in patients who have failed prior therapy or who are intolerant of hydroxyurea (HU) pharmacotherapy.
For patients with polycythemia vera, management begins with risk stratification based on age and history of thrombosis. Cytoreduction with pharmacotherapy is recommended for high-risk patients. There are two options for frontline cytoreductive therapy in polycythemia vera and essential thrombocythemia: HU, an oral antimetabolite, or interferon-alfa (IFN), a subcutaneous immunotherapy (Table 1).
A study of 261 polycythemia vera patients treated with HU for a median of 4.4 years demonstrated a high hematologic response rate of 90% (complete responses [CRs], 24%, and partial responses [PRs], 66%) after a median of 4.6 months of therapy. Median OS with HU was 19 years. Survival was not affected by the ability to attain a CR or PR to therapy; however, inability to achieve a white blood cell count response was associated with decreased survival. Intolerance of HU was uncommon, occurring in 13% of patients, and did not affect survival or risk of transformation.
IFN, specifically recombinant IFN (rIFN) has demonstrated response in patients with myeloproliferative neoplasms. A study of 55 patients with polycythemia vera previously treated with phlebotomy with or without HU and followed for a median of 13 years after initiation of rIFN revealed hematologic response with normalization of platelet count (< 400 × 109/L) in all patients by 1 year, despite 75% of participants having thrombocytosis at drug initiation; the study also showed decreased spleen size in 27 of 30 patients who had baseline splenomegaly. During the study, no patients had thrombohemorrhagic events. Long-term retrospective data on rIFN in 102 Danish patients with myeloproliferative neoplasms, with a median follow-up of 42 months, demonstrated high rates of complete hematologic response (in essential thrombocythemia, 95%; in polycythemia vera, 68%), and 74% of patients demonstrated a decline in JAK2 V617F allele burden. Pegylated IFN (PEG) has been shown to increase regulatory T cells and decrease JAK2 allelic burden. This ability to augment the immune system and decrease the allele burden suggests a disease-modifying effect of IFN.
One observational prospective study followed 136 patients with polycythemia vera who received treatment with either IFN or HU. The overall hematologic response rate was similar for the IFN group and the HU group (70.3% and 70.8%, respectively). A molecular response, shown by a decreased JAK2 V617F allele burden, was more common in the IFN group than in the HU group (54.7% vs 19.4%). The IFN group demonstrated decreased phlebotomy needs and greater improvement in systemic symptoms (vasomotor symptoms, distal paresthesia, and erythromelalgia) compared with the HU group. In patients with a JAK2 mutation, better 5-year progression-free survival (PFS) was seen in the IFN group than in the HU group (75.9% vs 47.6%).
One distinct difference between HU and IFN is the associated risk of secondary malignancies. A retrospective review of 196 patients with myeloproliferative neoplasms treated either with HU, IFN, or both revealed a complete hematologic response in 64.4% of those treated with HU and in 78.9% of those treated with IFN. Treatment with HU was associated with a greater risk of secondary malignancies— including acute myeloid leukemia, myelodysplastic syndrome, and skin cancers—compared with IFN (25% vs 8%); however, the patients treated with HU were older than those in the IFN group. The concern for leukemic transformation resulting from treatment with HU has led the European LeukemiaNet (ELN) to caution against using HU in young patients (< 40 years) and has led others to advocate for prioritizing IFN as the treatment of choice for effecting cytoreduction in polycythemia vera.
Two ongoing phase III studies are attempting to identify the ideal upfront therapy for polycythemia vera and essential thrombocythemia. The PROUD-PV study is a phase III randomized controlled trial comparing ropeginterferon alfa-2b with HU in polycythemia vera. Two hundred fifty-seven patients with polycythemia vera have enrolled. Results of the study are awaited. The Myeloproliferative Disorders Research Consortium phase III trial of frontline PEG vs HU is ongoing in patients with high-risk polycythemia vera or essential thombocythemia. Patients with high-risk newly diagnosed polycythemia vera or essential thrombocythemia, with less than 3 months of prior HU therapy, were enrolled and randomized to either HU or PEG. The primary endpoint was complete hematologic response rate based on ELN criteria. Although 168 patients have enrolled, a planned interim analysis of 75 patients was completed. There was a higher average age in the HU group (66 years, compared with 56 years in the PEG group; P < .01). Overall response rate was 69% in the HU group and 81% in the PEG group (P = .6). Reduction in palpable splenomegaly at 12 months was more common in the PEG group (71%, compared with 29% in the HU group), and phlebotomy independence was more common in the HU group (0% phlebotomy use, compared with 20% in the PEG group). Both groups demonstrated reductions in myeloproliferative neoplasm symptoms, as shown by the myeloproliferative neoplasm symptom assessment form (MPN-SAF) total symptom score (TSS). Further and final results are awaited.
Until these phase III studies report their results, the optimal frontline cytoreductive therapy for polycythemia vera and essential thrombocythemia will remain contested. Since the current evidence does not reveal the ideal frontline cytoreductive therapy for polycythemia vera or essential thrombocythemia, we endorse HU or IFN based on patient preference with regard to toxicity profile and ease of administration. We do recommend adherence to the ELN guidelines that advise caution with regard to HU use in younger patients (< 40 years).
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