CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: February 07, 2024
Expiration: February 06, 2025
Introduction to MF
MF is an uncommon blood cancer that belongs to the family of myeloproliferative neoplasms. Nearly 60% of patients with MF present with primary MF, whereas 40% of patients develop MF as a transformation from either essential thrombocythemia or polycythemia vera. In 2023, we continued to treat patients with primary or secondary MF the same, without specific guidelines that differentiate them. Although patients with MF may harbor different driver mutations, all current approved therapies are neutral to driver mutation, whether it be in JAK2, CALR, or MPL.1,2
MF Management Goals
Our goals in managing patients with MF are to minimize or reduce spleen enlargement, minimize or improve MF-related symptoms, and improve quality and quantity of life. For each patient, this is a moving target. Patients will have a different emphasis for each of those domains as they approach their own care, with each patient at a different point in their therapeutic timeline. It is important to discuss goals of management with every patient, including potential use of more aggressive therapeutic options.
Treatment of MF Based on Risk and Symptoms/Signs
In general, prognostic scoring systems are used to designate patients as having lower- or higher-risk MF.3 For patients with lower-risk disease, healthcare professionals focus on symptom management and observation, as well as management of cytopenias or other disease manifestations. Lower-risk patients may benefit from early intervention with a JAK inhibitor and early referral for allogeneic stem cell transplantation with curative intent. For patients who are transplant eligible, transplant is offered to those after a bridge of a JAK inhibitor; individuals who are not transplant eligible are usually offered long-term therapy with a JAK inhibitor.
Patients with higher-risk disease (ie, those classified as intermediate-2 or high risk based on prognostic scoring models) often require more immediate therapy. Currently, 4 JAK inhibitors are approved by the FDA for managing patients with MF.
Based on these indications and clinical data, the first point of decision-making is based on platelet count. For patients with severe thrombocytopenia, or a platelet count <50 x 109/L, pacritinib is preferred, and momelotinib may be considered. For patients with platelet counts >50 x 109/L, all JAK inhibitors are approved, with ruxolitinib preferred as first-line therapy. Of course, patients who are transplant eligible should be referred to a transplant physician as early as possible to evaluate their candidacy for a transplant.
Ruxolitinib and Fedratinib for Patients With Higher-Risk MF
This slide shows key efficacy data with ruxolitinib and fedratinib. Note that cross-trial comparisons can be problematic due to a variety of factors.
PERSIST-1 and PERSIST-2: Phase III Trials of Pacritinib for MF
In 2022, pacritinib was approved as therapy for patients with severe thrombocytopenia and MF; it also is listed by guidelines as a possible option for patients with platelet counts >50 x 109/L as a category 2B agent.3 Pacritinib was assessed in the phase III PERSIST-14 and PERSIST-2 studies.5
PERSIST-2: Spleen/Symptom Response
The PERSIST-2 study included patients with severe thrombocytopenia (platelets ≤100 x 109/L). In patients with platelets <50 x 109/L, pacritinib was superior to the control arm (best available therapy) in SVR35 (29% vs 3%) and ≥50% reduction in modified TSS (23% vs 13%).5
PERSIST-2: Hematologic Stability/Improvement
Pacritinib also was associated with an improvement in anemia vs best available therapy. This was noted as improvement in baseline Hgb in patients with anemia, a reduction in transfusion independence, and a reduction in transfusion burden in patients who were transfusion dependent. Based on these findings, healthcare professionals believe there can be an additional gain of Hgb improvement for some patients who receive pacritinib.5
Let’s return to one of our earlier patient cases.
Selected Novel Therapies in Trials for MF
The field of MF has evolved, with many novel agents currently being investigated either as monotherapy or in combination with ruxolitinib, both in the JAK inhibitor–naive setting and after JAK inhibitor failure. Although we have 4 approved JAK inhibitors that have significantly changed the way we approach the management of MF, there are still unmet needs.6
Many patients are primary refractory to JAK inhibitors, and others have suboptimal responses. A large number of patients continue to relapse after therapy with short-duration JAK inhibitors. As a result, healthcare professionals would welcome improved options leading to higher-quality responses. Hopefully, many of the agents under investigation can induce faster and more durable responses that eventually can be disease modifying.7
Many agents are under investigation, including those with unique mechanisms of action. At ASH 2023, late-phase clinical trial data were presented in the JAK inhibitor–naive setting that appear very promising.
TRANSFORM-1: Navitoclax + Ruxolitinib vs Placebo + Ruxolitinib in Previously Untreated MF
Navitoclax is a unique BCL-xL and BCL-2 inhibitor that was studied in single-agent settings, as well as in combination with ruxolitinib in the second-line setting, where it demonstrated significant activity in the phase II REFINE study.8
During ASH 2023, results from the randomized phase III TRANSFORM-1 study were presented. In this trial, 252 patients with symptomatic, JAK inhibitor–naive, intermediate-2–risk/high-risk MF and splenomegaly were randomized to receive either navitoclax plus ruxolitinib or placebo plus ruxolitinib. Dosing of both navitoclax and ruxolitinib was based on baseline platelet count. The primary endpoint was SVR35 at 24 weeks. A key secondary endpoint was change in TSS from baseline to Week 24 (NCT04472598).9
TRANSFORM-1: SVR35 at Week 24
This study showed that the primary endpoint was reached, in that the combination of navitoclax plus ruxolitinib achieved nearly double the rate of SVR35 at 24 weeks vs the control arm (63.2% vs 31.5%; P <.0001). This was an overwhelmingly positive study in this regard, which is an exciting finding.9
TRANSFORM-1: TSS at Week 24
However, the study did not reach the key secondary endpoint of significant symptom improvement with the combination (mean change in TSS at Week 24 -9.7 vs -11.1 with the control arm; P = .2852). The significance of this is still being debated, and additional analyses are underway.9
TRANSFORM-1: Safety
More grade ≥3 AEs occurred among patients receiving navitoclax plus ruxolitinib vs placebo (85% vs 70%), particularly grade ≥3 thrombocytopenia (51% vs 15%) and neutropenia (38% vs 4%). Dose reductions/interruptions most frequently occurred because of thrombocytopenia. The significance of this again is being debated; it will be important to understand how best to mitigate specific AEs when this combination is applied in practice.9
MANIFEST-2: Pelabresib + Ruxolitinib vs Placebo + Ruxolitinib for JAK Inhibitor–Naive MF
Another study presented at ASH 2023 was the MANIFEST-2 trial, in which 431 patients with symptomatic, JAK inhibitor–naive, intermediate-2–risk/high-risk MF and splenomegaly were randomized to receive the combination of pelabresib plus ruxolitinib or placebo plus ruxolitinib. Pelabresib is a BET inhibitor that demonstrated promising single-agent activity in a phase II study. 10,11
For MANIFEST-2, the primary endpoint was SVR35 at Week 24, with the key secondary endpoint again symptom improvement at Week 24.
MANIFEST-2: SVR35 at Week 24
This study was also positive for the primary endpoint, demonstrating a doubling in SVR35 at Week 24 with pelabresib plus ruxolitinib vs placebo plus ruxolitinib (65.9% vs 35.2%; P <.001).10
MANIFEST-2: TSS at Week 24
Unfortunately, symptom improvement did not meet statistical significance with combination therapy vs control (TSS50 52.3% vs 46.3% at Week 24; P = .216). The importance of this, as well as the significance of spleen reduction without meeting the secondary symptom endpoint, remains to be debated in the medical field and with regulatory bodies.10
MANIFEST-2: Safety
No new safety signals were observed. Grade ≥3 AE rates were similar between arms (49.1% with the combination vs 57.5% with control). Of interest, certain AEs were numerically fewer with combination therapy vs control treatment. These data demonstrate pelabresib plus ruxolitinib as a safe and effective combination that might result in deeper responses in selected patients.10
Now, let’s return to an earlier question on this topic.
JAK Inhibitor Failure: Response-Adaptive Therapy
Given the evolution in the treatment landscape for MF, it is now important to consider how to sequence therapy and treat in the second-line setting.
For patients who received a single JAK inhibitor as first-line therapy and develop refractory disease, it is reasonable to offer them an alternative JAK inhibitor.
Patients who responded suboptimally to JAK inhibitor monotherapy in the first-line setting may be ideal patients for combination therapy after dose optimization. In the future, we might start with combinations in the majority of patients, which could change our treatment paradigm significantly. For now, for patients with multiple JAK inhibitor failures,we should consider non–JAK inhibitor agents.
Response Criteria for MF Are Difficult to Apply in Daily Clinical Practice
Many clinical trials have defined what an ideal response to treatment is for patients with MF; however, many patients do not necessarily meet these response criteria. They often have responses that are not negative, but are not optimal. Moreover, there are patients who are not sensitive to therapy.12
There has not been equal investment in describing what is a suboptimal or less-than-ideal response. However, a general understanding is that patients who do not achieve an SVR by a certain volumetric loss or did not achieve symptom improvement are considered suboptimal responders. Of course, the definition of suboptimal response changes as we have more options.
Defining Ruxolitinib Failure in Clinical Practice
Ruxolitinib failure remains a question that healthcare professionals are faced with every day as we manage patients. Patients who are truly primary refractory to a first-line JAK inhibitor are ideal patients to switch therapy.
Other patients may respond and then lose that response or can no longer tolerate the drug. There are also patients who progress beyond MF into blast phase or acute leukemia who need completely different approaches to their cancer therapy. It is important to consider the type of resistance or intolerance to treatment a patient experiences when selecting subsequent lines of therapy. This is becoming more relevant, as we have multiple JAK inhibitors that are approved beyond ruxolitinib failure and emerging investigational combinations that might be approved in the setting.13
JAK Inhibitor Efficacy and Tolerability in MF: Meta-analysis
Three other JAK inhibitors are approved and being used in the second-line setting following ruxolitinib failure. Recently, a meta-analysis assessed randomized, controlled trials with JAK inhibitors vs ruxolitinib, as shown on this slide.14
Fedratinib was approved based on the JAKARTA study.15 This agent may be an option for patients who have intolerance to or failure with ruxolitinib.
Pacritinib also is approved and has been studied in the second-line setting, where it continues to be an active agent after ruxolitinib, especially in patients with cytopenias.
Momelotinib is the most recent addition to this list of options. In second-line studies, momelotinib showed significant activity and improvement in anemia. Let’s have a closer look at the data with this novel agent.
MOMENTUM: Momelotinib for Patients With MF, Anemia, and Previous JAK Inhibitor Therapy
The FDA approval of momelotinib was based on the phase III MOMENTUM trial, in which 195 patients with symptomatic, intermediate-1/2–risk or high-risk MF; Hgb <10 g/dL; splenomegaly; and previous JAK inhibitor therapy were randomized to receive momelotinib or danazol.16 The primary endpoint was symptom improvement at Week 24, and key secondary endpoints were transfusion independence and spleen response.
MOMENTUM: Efficacy
This study met its primary endpoint, demonstrating superiority of momelotinib vs danazol in TSS response rate (25% vs 9%; P = .0095). Momelotinib also was associated with significant improvements in the transfusion independence rate (30% vs 20%; P = .0116) and SVR35 (22% vs 3%, P = .0011).16
In addition to the results for the MOMENTUM study, the SIMPLIFY-I study compared ruxolitinib with momelotinib in the first-line setting, and momelotinib was shown to be noninferior to ruxolitinib in SVR.17 The FDA approval for momelotinib was line agnostic.
MOMENTUM: Transfusion Independence Rate at Week 24 and Mean Hgb Over Time
Looking more closely at the anemia results from the MOMENTUM study, momelotinib significantly improved the transfusion independence rate at Week 24 vs danazol. When patients crossed over from danazol to momelotinib at Week 24, there also was an advantage in transfusion independence.16
Before continuing, let’s return to our patient case from earlier in the activity, in which a patient with anemia had experienced ruxolitinib failure.
Additional Agents and Combinations in Phase III Trials for Patients With JAK Inhibitor Failure
There are several agents and combinations in phase III trials for treating patients who previously have received a JAK inhibitor. We previously discussed navitoclax and the TRANSFORM-1 data; navitoclax also is being assessed in combination with ruxolitinib in patients with MF relapsed or refractory to ruxolitinib in the phase III TRANSFORM-2 trial.
Imetelstat (a telomerase inhibitor) currently is being assessed in a randomized phase III study for patients with JAK inhibitor failure. Navtemadlin is a unique MDM2 inhibitor currently being evaluated in a randomized phase III study, as well.
INDEPENDENCE: Luspatercept in Patients With MF and Anemia Receiving JAK Inhibitor Therapy
Another promising agent is luspatercept, which is used to manage anemia. This agent has been approved in several other hematologic malignancies and currently is being investigated in the phase III INDEPENDENCE study in MF in combination with JAK inhibitors in patients who continue to manifest anemia. If this study is positive, patients receiving JAK inhibitors also will be able to receive luspatercept to improve their anemia, which may allow them to remain on JAK inhibitor therapy longer, thereby improving the quality responses and quality of their lives.
Tagraxofusp (CD123 Inhibitor): Phase I/II Study in R/R MF After JAK Inhibitor
Many other agents are in development for treating MF that are novel and not dependent on the JAK/STAT pathway. One example is tagraxofusp, which has completed phase II studies and now is being explored in late-phase clinical trials. This is a selective CD123-binding peptide that delivers a payload of diphtheria toxin and results in cellular toxicity, showing activity in spleen reduction and symptom improvement. Of importance, there was also a remarkable improvement in survival in the patient cohort in which it was studied, and hopefully this will be investigated further in the future.18
Healthcare professionals are looking forward to seeing how these agents with unique mechanisms of action change the standard-of-care therapy for MF in the next few years.
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