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Srdan Verstovsek, MD, PhD:
At the 2021 ASH annual meeting, several potentially practice-changing studies were presented that may directly improve outcomes in patients with MPN. I would like to begin the discussion with a promising new agent: pemigatinib.
Srdan Verstovsek, MD, PhD:
MLNFGFR1 is a rare and aggressive hematologic neoplasm, which typically is associated with eosinophilia.1 Patients can present with bone marrow involvement, extramedullary disease, or both. Some patients present in chronic-phase MPN and about one half reach the blastic phase (ie, AML) within a year or may have lymphoma at presentation. A standard therapy does not exist and prognosis is poor2: Overall life expectancy after a MLNFGFR1 diagnosis is approximately 1.5-2 years.
The key here is the FGFR1 involvement, which is a consequence of a translocation in chromosome 8.1 The 8p11 translocation activates the FGFR gene and makes FGFR1 the driving force behind the disease. In fact, MLNFGFR1 was previously known as 8p11 syndrome.
Pemigatinib is a FGFR1-3 inhibitor approved for adults with previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements, but it has activity in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.
Srdan Verstovsek, MD, PhD:
Pemigatinib was recently evaluated in the phase II FIGHT-203 study.3 This study enrolled 34 patients with MLN, either variant translocation or FGFR1 rearrangement, at least 1 prior treatment, and who had relapsed after or were ineligible for hematopoietic stem cell transplantation (HSCT). Pemigatinib was given at 13.5 mg once daily for 2 of every 3 weeks. The primary endpoint was complete response (CR), with secondary endpoints including overall response rate (ORR), cytogenetic responses, and safety.
Srdan Verstovsek, MD, PhD:
In this trial, 21% of patients had no morphologic evidence of disease in the bone marrow (molecular or cytogenetic abnormality only), 70% had a myeloid neoplasm (MPN, MDS/MPN, or AML), 2 had acute lymphoblastic leukemia, and 1 had mixed-phenotype acute leukemia. More than one half (55%, n = 18) presented in chronic phase (ie, no extramedullary disease), 39% (n = 13) presented in blast phase with or without extramedullary disease, and 6% (n = 2) presented with only molecular/cytogenetic abnormality.
Srdan Verstovsek, MD, PhD:
In this early-phase study, pemigatinib appeared to be highly effective. Of the patients that presented in chronic phase (n = 18), about 90% achieved a CR and 78% achieved complete cytogenetic response. Of note, responses seem very durable; the longest a patient has been on this study is approximately 4 years.
With chemotherapy, the standard goal is to provide a bridge to stem cell transplantation. Pemigatinib played this role in these patients with chronic phase MPN as eliminating disease can allow for the transplant.
Among 13 patients (59%) in the blastic phase, approximately 60% took 1 pill a day and eliminated disease (ie, a CR), and most achieved a complete cytogenetic response.
Treatment-emergent adverse events (TEAEs) were typical for this class of medications: low phosphate, alopecia, dry eyes, and gastrointestinal irritation with diarrhea, stomatitis, constipation, alkaline phosphatase increase, and decreased appetite. Interruptions and reductions of the pemigatinib dose were common (up to two thirds of patients), but discontinuations were rare (12% of patients).
Srdan Verstovsek, MD, PhD:
In patients with MLNFGFR1, pemigatinib produced high and durable response rates despite extensive use of prior treatment or HSCT. Approximately 75% of patients achieved a CR or a complete cytogenetic response, with less frequent, less durable responses in patients with blast phase. Of note, the median duration of response was not achieved yet.
These results suggest that pemigatinib is an effective therapy that may provide long-term control of the disease, giving an opportunity for patients to undergo HSCT as the ultimate goal. Patients who are not transplant candidates can continue to take the pill daily. Although further follow-up is needed to determine how long disease control lasts, these data are very promising.
Overall, pemigatinib was generally well tolerated and comparable to other FGFR inhibitors. Pemigatinib can be delivered for a long period of time, and this is shifting outcomes for patients. Instead of MLNFGFR1 being typically aggressive and deadly with average survival of 1.5-2 years, it may become chronic with a high percentage of CRs that open the door to transplantation.
It is hoped that in the not too distant future, pemigatinib might be approved for treating patients with MLNFGFR1.
Srdan Verstovsek, MD, PhD:
PV is a classic MPN and produces a high red blood cell (RBC) count in all patients.4 Patients with PV have an increased thrombotic risk that needs to be effectively decreased in everyday practice. Approximately 60% of patients also have a high white cell count and/or high platelets. PV may cause some systemic symptoms like itching, night sweating, and fatigue. In some patients, usually with advanced disease, it also can enlarge the spleen.
The standard practice approach to therapy for patients with PV, according to current National Comprehensive Cancer Network guidelines, is chemotherapy, hydroxyurea, or biological agent interferon (different preparations exist) with a goal of normalizing the RBC count to a hematocrit below 45%.5 Maintaining the hematocrit below 45% has been proven (in prospective randomized studies) to decrease the thrombotic risk, which thereby decreases the main risk of dying from PV. Other goals include control of white cell and platelet counts and a decrease in splenomegaly and PV-related symptoms, as these are issues that affect quality of life.
Srdan Verstovsek, MD, PhD:
In November 2021, there was a major development in the field of PV: The FDA approved ropeginterferon (interferon α-2b).6 It had been approved in Europe since 2019. This is the first interferon approved for this indication, although interferons of different types have been used off label for PV for decades. Because of the activity of interferons, guidelines have suggested them for patients with PV. For example, National Comprehensive Cancer Network guidelines state that either hydroxyurea or interferon should be used as therapy for PV patients.
Ropeginterferon is a very long-acting interferon. It is given subcutaneously every 2 weeks, and many patients transition after approximately a year to monthly injections. The demonstration of an approximately 75% complete hematologic response rate led to approval in the United States and Europe. A complete hematologic response means normalization of the hematocrit below 45% without any phlebotomy, with normalization of the white cell and platelet counts.
Srdan Verstovsek, MD, PhD:
Updated 5‑year results of the CONTINUATION‑PV study of ropeginterferon α‑2b in PV were reported at ASH 2021.7 CONTINUATION-PV is a continuation study of PROUD-PV that randomized patients with PV to either ropeginterferon α‑2b or hydroxyurea (n = 127, each arm). Patients were treatment-naive or hydroxyurea-experienced for fewer than 3 years with no resistance, intolerance, or CR to hydroxyurea therapy. Ropeginterferon α‑2b was administered as a subcutaneous injection every 2 weeks.
The results presented at ASH showed that patients with PV responded better to ropeginterferon α‑2b than to hydroxyurea or best available treatment, regardless of prior therapy or mutational status.7 At 5 years, complete hematologic response rates in the ropeginterferon α‑2b arm were similar in patients with and without prior hydroxyurea exposure—61.3% and 53.1%, respectively. By contrast, rates in the control arm were 36% vs 48%. This means that healthcare professionals can safely choose either hydroxyurea or ropeginterferon α‑2b or use them in sequence for their patients with PV.
Similar rates of complete hematologic response were also observed in the ropeginterferon α‑2b arm, regardless of baseline JAK2V617F allele burden.
Of importance, there has been a significant decrease in the JAK2 allele burden over time. In this study, 14% of the patients treated with ropeginterferon α‑2b had undetectable JAK2 mutation in their samples by 5 years. That provides hope for a functional cure in the future, potentially including drug holidays if patients can achieve a complete molecular response. Stopping therapy could even be considered.
Srdan Verstovsek, MD, PhD:
Now that it is approved, ropeginterferon α‑2b is clearly a very valuable therapy for PV patients and provides long-lasting control of blood cell counts. This decreases the thrombotic risk and possibly decreases the risk of transformation through molecular response. These goals will be further analyzed in the future, but for now, healthcare professionals finally have an approved interferon to use in their clinical management of patients with PV.
Srdan Verstovsek, MD, PhD:
As noted previously, polycythemia vera is characterized by a high RBC count (erythrocytosis) that requires control; the goal is to decrease the hematocrit to below 45%. Standard therapy is based on periodic phlebotomy, with or without cytoreductive therapy.5 Symptoms can be present and include an enlarged spleen and increased white cell and platelet counts.
PV is associated with suppression of hepcidin that may be due to expanded erythropoiesis and iron deficiency.8 Hepcidin is the master regulator of iron metabolism. Rusfertide is a new hepcidin mimetic that suppresses PV erythropoiesis, keeping iron in the liver, spleen, and lining of the gastrointestinal track so there is less available for erythropoiesis. Treatment with rusfertide has a goal of eliminating the need for phlebotomy.
Phlebotomy is therapeutically applied to all patients with PV, whether patients are low-risk and being managed only with phlebotomy or patients are on cytoreductive therapy with high-risk features. Although cytoreductive therapy aims to eliminate a need for phlebotomy, patients who are receiving hydroxyurea or interferon or ruxolitinib may need too many phlebotomies. There is an unmet need in many patients for more effective therapy whether they are on cytoreductive therapy or not.
Srdan Verstovsek, MD, PhD:
At the ASH 2021 meeting, Hoffman and colleagues9 presented results from a phase II study of rusfertide in patients with phlebotomy-dependent PV.9 This trial enrolled 63 patients who had at least 3 phlebotomies in the past 6 months, with or without concurrent cytoreductive therapy, and who were phlebotomized to a standard hematocrit <45% at the start of the study. The primary endpoint was maintenance of the hematocrit <45%.
In the dose-finding phase, weekly subcutaneous rusfertide doses from 10-120 mg were added to prior standard therapy. Then, in the blind withdrawal phase, patients were randomized to continue rusfertide or receive a placebo. A 36-month open-label extension phase was used to establish optimal dose and titration.
Srdan Verstovsek, MD, PhD:
Results showed that 84% of patients required no phlebotomies during the 28-week treatment period—a very high success rate! Only 14% required a single phlebotomy, and only 2% required 2 phlebotomies. Moreover, hematocrit <45% was maintained for 1.5 years, and a significant reduction in RBC count was seen as early as Week 4 (P <.01).
In patients on rusfertide, platelet and white blood cell (WBC) counts did not significantly increase during the treatment period. Patients experienced notable improvements in the MPN-TSS scores for fatigue, concentration, and itching.
Srdan Verstovsek, MD, PhD:
Giving rusfertide as a hepcidin mimetic enhances the natural control of iron, eliminating iron from the bone marrow, keeping it in the reticuloendothelial system. In this study, 18 months of treatment with rusfertide in patients with phlebotomy-dependent PV was associated with rapid, sustained, durable hematocrit control with no significant increase in platelets or WBCs. Moreover, rusfertide appears to be safe and well tolerated.
The great hope for this agent is that it will be able to rapidly (in a few weeks) eliminate the need for phlebotomy in almost all PV patients. That is highly clinically valuable. The VERIFY phase III trial is enrolling patients with PV with at least 3 phlebotomies in the prior 6 months or at least 5 in the last year (NCT05210790). The endpoints include elimination of phlebotomy and improvement in quality of life. If the phase III study succeeds, rusfertide will become an alternative choice or combination partner to hydroxyurea, interferon, or ruxolitinib.
Srdan Verstovsek, MD, PhD:
MF is much more aggressive than essential thrombocythemia and PV, which are the 2 other classic Philadelphia chromosome–negative MPN. In those MPN, the goal is to control the thrombotic risk because blood clots pose a mortal danger. By contrast, the goal in MF is to control the signs and symptoms of the disease: enlarged symptomatic spleen, poor quality of life, and poor bone marrow activity (anemia).5
Both approved JAK inhibitors—ruxolitinib and fedratinib—can control spleen size and symptoms but are not approved for use in patients with MF and platelet counts below 50 x 109/L because these medications worsen the thrombocythemia. The risk is that patients will require platelet transfusions or will be at increased risk of bleeding. That said, they are sometimes used off label in low-platelet patients.
Srdan Verstovsek, MD, PhD:
Pacritinib is an alternative JAK2 inhibitor. It is not myelosuppressive and is clinically active in patients with MF and low platelets.10 Pacritinib has demonstrated activity in patients with low platelets for control of the spleen and symptoms. Pacritinib recently was approved in the United States as therapy for MF patients with platelets below 50 x 109/L.
The phase III PERSIST-1 study of pacritinib in MF showed significant and durable spleen volume reduction (SVR) and symptom control irrespective of baseline platelet count vs best available therapy.11 Subsequently, the phase III PERSIST-2 study was initiated in patients with MF with a platelet count ≤100 × 109/L and palpable splenomegaly.12 Results showed that pacritinib 200 mg twice daily was significantly more effective than ruxolitinib or other best available therapy at reducing splenomegaly and symptoms. Response rates were 25% for pacritinib vs 14% for best available therapy (P = .08).13 A spleen volume reduction of at least 35% was seen in 18% of patients on the pacritinib arm vs 3% with best available therapy (P = .001).12
Srdan Verstovsek, MD, PhD:
At ASH 2021, Palmer and colleagues13 presented results from a retrospective analysis of PERSIST-2 focused on symptom reduction in patients with MF and moderate or severe thrombocytopenia.13 In this analysis (N = 221), the total symptom score (TSS) was modified to include tiredness. Results showed that pacritinib significantly reduced symptoms of thrombocytopenia vs best available therapy (including ruxolitinib) as seen in the modified TSS rates at Week 24 (P = .0038). Symptomatic control (ie, ~50% of symptoms gone) was achieved in 37% of patients on pacritinib vs 11% with best available therapy.
Of note, a subgroup analysis was done that focused on patients with platelets below 50 x 109/L.13 This is a rather different group of patients than those who typically receive ruxolitinib or fedratinib. All evaluated symptoms (physical, spleen, and cytokine related) were meaningfully improved with pacritinib vs best available therapy.
Srdan Verstovsek, MD, PhD:
Clearly, the results from PERSIST-2 show a significant advantage to treating patients with a platelet count ≤50 × 109/L with pacritinib, as this agent recently obtained accelerated approval for patients with intermediate or high-risk MF and a platelet count ≤50 × 109/L. Furthermore, because pacritinib is not myelosuppressive, it doesn’t decrease platelets or RBCs and can be given at a stable dose intensity with little need for dose adjustments.
Although pacritinib can be safely given, it can cause low-grade gastrointestinal toxicity, such as nausea or diarrhea. Prophylactic or preventative medications for these issues will allow patients to fully benefit from pacritinib. I’m looking forward to using pacritinib as an approved alternative to low-dose ruxolitinib for cytopenic MF patients in my practice.
Srdan Verstovsek, MD, PhD:
One of the most important and interesting drugs in development for MF is pelabresib (CPI-0610), a novel first-in-class, selective, oral, small-molecule inhibitor of the BET (bromodomain) proteins.14 Pelabresib modifies BET protein activity in bone marrow, which facilitates better control of inflammation in MF patients by decreasing cytokine production. Pelabresib also may improve other features of MF, such as decreasing the spleen size and improving bone marrow function by improving production of RBCs. In other words, it may affect the erythrocyte differentiation as well as the megakaryocyte differentiation, and thereby have multiple different benefits not only in quality of life but also on spleen size and anemia.
Srdan Verstovsek, MD, PhD:
MANIFEST is an ongoing, open-label phase II study evaluating the safety and efficacy of pelabresib in MF in different patient populations and cohorts. At ASH 2021, Kremyanskaya and colleagues15 presented results from arm 1 of MANIFEST (N = 86).15 This analysis encompassed patients with MF who are intolerant/refractory to or ineligible for a JAK inhibitor, with a platelet count ≥75 x 109/L, and who are either transfusion dependent with ≥2 units of RBC transfusions/month for 12 weeks or who are not transfusion dependent but have a baseline spleen size >450 cm3.
In both the transfusion-dependent and transfusion-independent cohorts of arm 1, pelabresib was given at a starting dose of 125 mg once daily for 2 weeks on, 1 week off. The primary endpoint for the transfusion-dependent patients was conversion to transfusion independence, whereas the primary endpoint for the nontransfusion dependent cohort was SVR35 at 24 weeks.
Srdan Verstovsek, MD, PhD:
Results from arm 1 showed that pelabresib was able to control spleen size in many patients. In the nontransfusion dependent cohort, 11% (7 patients) achieved SVR35 at Week 24. Of note, SVR35 is approximately a 50% reduction by palpation. The median spleen volume reduction was 24%.
Srdan Verstovsek, MD, PhD:
In this trial, many patients also improved their symptoms. In total, 18 of 64 patients (28%) achieved at least a 50% reduction in their baseline TSS score after 24 weeks. The median decrease in TSS was 40%.
Srdan Verstovsek, MD, PhD:
In addition, there appeared to be significant improvement in anemia, which is not seen with other drugs for MF. A hemoglobin response was seen in 38% of patients overall, with responses noted across patients who had failed or were ineligible for JAK inhibitors.
Four of the 25 patients who were transfusion dependent became transfusion independent, with a median duration of 41 weeks.
Srdan Verstovsek, MD, PhD:
In this preliminary analysis of pretreated patients with MF who are refractory to, intolerant of, or ineligible for JAK inhibitor therapy, pelabresib monotherapy demonstrated clinical activity that included spleen volume reduction, symptom reduction, and hemoglobin benefit. Fortunately, the TEAEs seen were primarily low-grade.
Overall, pelabresib is relatively unique in that it not only controls spleen size and symptoms, but it also improves bone marrow function by improving anemia. There are biological correlates suggesting a significant modification of disease biology as well (eg, an exploratory analysis showed improvement in bone marrow fibrosis in many patients within 6 months of starting this therapy).16
MANIFEST is an ongoing clinical trial as of February 2022, with 3 additional arms continuing treatment: Arm 2 is evaluating pelabresib as an add-on to ruxolitinib in patients with MF with suboptimal responses to ruxolitinib or with disease progression.16 Arm 3 is evaluating pelabresib plus ruxolitinib as first-line therapy in patients with MF. A fourth arm is evaluating pelabresib monotherapy for essential thrombocythemia (NCT02158858).
When previously untreated MF patients start ruxolitinib, they usually experience good control of the spleen and symptoms. In this phase II trial of pelabresib, so far, the combination of pelabresib and ruxolitinib from Day 1 appears to enhance spleen and symptom responses beyond ruxolitinib alone.16 The phase III MANIFEST-2 study is underway and will compare pelabresib plus ruxolitinib with ruxolitinib alone in JAK inhibitor–naive patients (estimated N = 310) (NCT04603495).
The bottom line is not only that pelabresib is active as a single agent with an ORR of ~20% in the second-line setting, but it is also a potential partner to ruxolitinib. Hopefully, many patients will participate in the phase III study to help clarify the potential role of pelabresib.
In addition to the promising results discussed so far, I’d like to briefly touch on several other studies from ASH 2021 that are of particular interest.
Srdan Verstovsek, MD, PhD:
Sotatercept is, in general terms, an inhibitor of transforming growth factor-β (TGF-β), relieving blockade on terminal erythroid differentiation, similar to luspatercept. Bose and colleagues17 presented final results from a phase II study of sotatercept for the treatment of anemia in patients with MPN-associated MF.17 In this open-label trial, 56 anemic patients with MF were treated with either sotatercept monotherapy (0.75 mg/kg or 1 mg/kg) (n = 34) or with 0.75 mg/kg in combination with a stable dose of ruxolitinib (n = 21). In both cohorts, anemia response was defined as transfusion independence in patients with transfusion dependence or an increase in hemoglobin of at least 1.5 g/dL for at least 12 weeks in patients who were not transfusion dependent.
In the results presented at ASH for sotatercept monotherapy, 8 of 27 evaluable patients (30%) responded, including 5 anemia responses and 3 patients who were transfusion dependent and became transfusion independent. The median duration of response was 23 months. Sotatercept was well tolerated, with grade 3 hypertension and limb or back pain possibly associated with it.
Of note, luspatercept is an approved therapy for certain patients with MDS.18 and is in a phase III study as an anemia drug for MF (NCT04717414). Currently, there are no approved drugs to treat anemia in MF, and this remains a major clinical unmet need.
Srdan Verstovsek, MD, PhD:
There is a real clinical need for an effective second-line therapy for patients with MF who fail ruxolitinib, and this is where navtemadlin may have a role.
Navtemadlin (KRT-232) is a first-in-class inhibitor of murine double minute 2 (MDM2). MDM2 is the primary negative regulator of the tumor-suppressing protein P53, a multicellular regulator of genetic expression in many cells. Increased expression of MDM2 has been observed in MPN CD34+ hematopoietic stem/progenitor cells.19 By inhibiting MDM2, navtemadlin may be able to restore the ability of P53 to mediate apoptosis of malignant cells.
At ASH 2021, Vachhani and colleagues20 presented results from a phase II study of different doses and schedules of navtemadlin in 113 patients with relapsed/refractory (R/R) MF.20 Results showed that driver mutations in JAK2, CALR, or MPL were reported in 81 (73%), 22 (19%) and 13 (12%) patients, respectively. Of note, 28 patients (25%) had mutations in ≥2 high-molecular-risk genes.
Of 65 evaluable patients, a best driver gene allele reduction of ≥20% associated with navtemadlin was observed in 22 patients (34%). Also, 19 patients (29%) achieved a complete allele reduction (ie, undetectable) in high-molecular risk or driver genes. Overall, driver allele reduction at any time was significantly correlated with spleen volume reduction.
It is clear that navtemadlin has some benefit in this setting, and I hope the ongoing studies continue to support this benefit and perhaps lead to approval for use in the clinic. The phase III BOREAS study is underway and is comparing navtemadlin to best available therapy in patients with MF who failed JAK inhibitors (estimated N = 385) (NCT03662126).
Srdan Verstovsek, MD, PhD:
Selinexor is an oral, small-molecule inhibitor of exportin 1 which is approved for the treatment of myeloma.21 Now, it is being evaluated as a second-line therapy for patients with MF who failed JAK inhibitors.
At ASH 2021, Tantravahi and colleagues22 presented results from a small open-label study of selinexor in patients with MF and resistance or intolerance to JAK inhibitor therapy (N = 12; planned N = 24).22 Overall, once weekly single-agent selinexor was active with sustained spleen responses. With the caveat that few patients have data to date, 3 patients had achieved ≥25% SVR (SVR25) by Week 12, and 2 patients achieved ≥35% SVR (SVR35) by Week 24. Of the 9 patients with more than 24 weeks of treatment, SVR25 occurred at any point in 4 patients, and SVR35 occurred at any point in 3 patients.
Long-term treatment with selinexor was well tolerated, with weight loss as the most common TEAE.
Srdan Verstovsek, MD, PhD:
Lastly, I’d like to discuss the TGFβ inhibitor AVID200. This is a selective inhibitor of TGFβ1/3 with picomolar potency and much higher selectivity vs TGFβ2. TGFβ1/3 signaling is associated with resistance to immune checkpoint inhibitor therapy, as well as with immunosuppression in the tumor microenvironment. Therefore, inhibiting TGFβ1/3 signaling should improve bone marrow function.
At ASH 2021, Mascarenhas and colleagues24 presented updated results from the first-in-human phase I/Ib study of AVID200 in patients with intermediate-2 or high-risk MF and resistance or intolerance to ruxolitinib (N = 22).24 In patients who received the 2 highest phase Ib doses, 70 mg and 180 mg, the median decrease in palpable spleen length was 10%, and the TSS was decreased by a median of 50%. Of note, 17 patients had platelet increases from baseline, and 2 normalized their platelet counts. Also, at 21 days posttreatment, all patients had elevated levels of TGFβ1, and TGFβ1/3 levels were dramatically reduced. No dose-limiting toxicities were observed. Grade 3/4 adverse events (AEs), including anemia, thrombocytopenia, and hemorrhage, were seen in many patients.
Right now, there is no approved agent to improve platelet counts in MF, and this is a significant clinical problem. I am optimistic that TGFβ1/3 inhibitors like AVID200 may be of benefit.
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