Syed Ali Abutalib, MD
Ruben A. Mesa, MD, FACP
HERE IS AN UPDATE on six different studies featured at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition. Topics focused on novel treatments for myelofibrosis, polycythemia vera and essential thrombocythemia, as well as systemic mastocytosis.
Myelofibrosis
ABSTRACT 686: Efficacy and safety of monthly intravenous (IV) PRM-151 in myelofibrosis, an open-label extension study in 18 patients who had been treated for up to 35 cycles (140 weeks)1
Mechanism of Action: PRM-151, a recombinant human pentraxin-2 molecule, has been shown to prevent and reverse fibrosis in animal models of myelofibrosis by targeting differentiation of fibrocytes from monocytes.
Background: In the first stage of a 2-stage trial, 27 subjects with primary myelofibrosis, post–essential thrombocythemia/polycythemia vera myelofibrosis, and grade 2 or 3 bone marrow fibrosis received PRM-151 at a dose of 10 mg/kg IV with or without ruxolitinib (Jakafi) for 6 cycles (24 weeks). A reduction in bone marrow fibrosis, decrease in symptoms (Myeloproliferative Neoplasm– Symptom Assessment Form [MPN-SAF] Total Symptom Score [TSS]), and reduction in palpable splenomegaly were observed, along with a favorable safety profile. Patients experiencing clinical benefit were allowed to continue treatment beyond 24 weeks.
Key Findings: Of the 18 patients, 9 received PRM-151 as a single agent and 9 received it in conjunction with ruxolitinib. A total of 8 patients had primary myelofibrosis and 10 had post–essential thrombocythemia/polycythemia vera myelofibrosis. Fifty percent had grade 3 bone marrow fibrosis. All patients experienced at least one adverse event, with eight patients reporting a possible study drug–related adverse event. No unexpected adverse events were observed, and no deaths were reported during the study period.
Patients in the PRM-151 monotherapy group showed similar improvements in MPN-SAF TSS and splenomegaly as those who received combination therapy. Improvement in bone marrow reticulin grade was observed in 5 of 7 patients with grade 2 bone marrow fibrosis at baseline and in 4 of 9 patients with grade 3 bone marrow fibrosis at baseline. Of those with grade 3 bone marrow fibrosis at baseline, 2 of 9 patients had a 2-grade reduction. In addition, 5 of 6 patients with grade 2 collagen fibrosis at baseline had a 1-grade reduction, with 2 improving to grade 0. Also, 2 of 7 patients with grade 3 collagen fibrosis had a reduction of 1 grade, with 1 of 7 improving to grade 0. Improvement in bone marrow reticulin grade was detected in four of seven patients, and collagen fibrosis grade was decreased in three of seven patients.
Clinical Implications: The efficacy and safety were established in 18 patients with myelofibrosis who received PRM-151 for a median of 31 months. A subsequent trial of single-agent PRM-151 at 3 dose levels has completed accrual and is ongoing, with data anticipated soon.
ABSTRACT 685: Imetelstat is effective treatment for patients (n = 117) with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to Janus kinase (JAK) inhibitor therapy: Results of a phase II multicenter randomized study of 2 dose levels (9.4 mg/kg or 4.7 mg/kg intravenously, every 3 weeks; MYF2001, ClinicalTrials.gov identifier NCT02426086)2
Mechanism of Action: Imetelstat, a 13-mer oligonucleotide that specifically targets the RNA template of human telomerase, is a potent competitive inhibitor of telomerase enzymatic activity.
Background: Primary study endpoints were spleen response rate (% achieving at least 35% spleen volume reduction by magnetic resonance imaging [MRI]) and symptom response rate (% achieving at least 50% reduction in TSS per MPN-SAF version 2 at week 24. Key secondary study endpoints included safety, overall survival, treatment response, molecular response, and pharmacokinetic and pharmacodynamic relationships.
“Imetelstat is an active agent for JAK inhibitor–pretreated patients with myelofibrosis, and given its unique mechanism of action, it warrants further testing in clinical trials alone or in combination.”— Syed Ali Abutalib, MD, and Ruben A. Mesa, MD, FACP
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Key Findings: At the time of clinical cutoff, patients were followed for a median of 22.6 months (0.2–27.4 months), including a median treatment duration of 6.2 months (0.0–27.2 months). Six patients (10.2%) in the 9.4-mg/kg arm had a spleen response per MRI, with no responses on the 4.7-mg/kg arm. A total of 19 patients who received the higher dose and 3 patients (6%) who received the lower dose had a symptom response (TSS reduction ≥ 50%).
The median overall survival in the 9.4-mg/kg arm has not been reached, whereas the median overall survival was 19.9 months in the 4.7-mg/kg arm. The 18-month survival rates were 76.7% and 62.9% for higher- and lower-dose arms, respectively. Sensitivity analyses censoring patients at the time of dose escalation for subsequent JAK inhibitor therapy or allogeneic hematopoietic cell transplant generated similar results. Grade 3 or 4 neutropenia and thrombocytopenia were more frequent with 9.4 mg/kg (34% and 42%, respectively) than 4.7 mg/kg (13% and 29%, respectively); most cytopenias resolved within 4 weeks. Grade 3 or 4 liver function test elevations were observed in 7 study patients. Imetelstat-related hepatic toxicities, confirmed by an independent hepatic review committee, were not observed.
Clinical Implications: The safety profile for imetelstat was considered acceptable for this poor-prognosis population. Imetelstat (9.4 mg/kg intravenously every 3 weeks) is an active agent for JAK inhibitor–pretreated patients with myelofibrosis, and given its unique mechanism of action, it warrants further testing in clinical trials alone or in combination.
ABSTRACT 4288: Survival advantage to allogeneic transplant in myelofibrosis with intermediate-1 or higher Dynamic International Prognostic Scoring System (DIPSS) score3
Background: Consideration of allogeneic transplant is recommended by international working groups and national guidelines for patients with myelofibrosis who are younger than age 70 and have intermediate-1 DIPSS score with adverse indicators, intermediate-2 DIPSS or high-risk disease for myelofibrosis—a recommendation made in the absence of clear data indicating the optimal timing of transplant for myelofibrosis.
Key Findings: This large multicenter retrospective study analyzed overall survival in patients with myelofibrosis treated with and without allogeneic transplantation. A total of 1,377 and 551 patients were included in the nontransplant and transplant arms, respectively. In the overall cohort, survival was higher with nontransplant than transplant in the early time period (relative risk [RR] = 0.34, P < .0001), but in late time period, survival was lower with nontransplant than transplant (RR = 2.37, P < .001). In the DIPSS low-risk myelofibrosis group, although survival was higher with nontransplant than transplant in the early time period (RR = 0.19, P =.007), survival was lower with nontransplant in the late time period, but the latter did not reach statistical significance (RR = 1.45, P =.39). In the DIPSS intermediate-1 risk group, a survival advantage was present with nontransplant treatments vs transplant in the early time period (RR = 0.27, P < .0001); however, survival was lower with nontransplant in the late time period (RR = 3.13, P < .0001). Similarly, in those with DIPSS intermediate-2 and high-risk myelofibrosis, survival advantage was observed with non-transplant in the early time period (RR = 0.41, P < .0001), but survival was lower with nontransplant in the late time period (RR = 2.82, P < .0001).
Clinical Implications: A long-term survival advantage with transplant was observed for subjects with intermediate-1 or higher risk myelofibrosis, but at the cost of potential early mortality. The magnitude of benefit increased as Dynamic International Prognostic Scoring System risk score increased. Although this retrospective study has limitations, the results have an impact on clinical practice by suggesting that transplantation could be considered earlier in the disease course and supports the recommendation for consideration of transplant in the setting of intermediate-1 risk myelofibrosis.
Polycythemia Vera and Essential Thrombocythemia
ABSTRACT 577: Open-label randomized trial of pegylated interferon alfa-2a (n = 82) vs hydroxyurea (n = 86) in the treatment of high-risk polycythemia vera and high-risk essential thrombocythemia, with long-term follow up4
Background: Patients were treated for up to 12 months to achieve partial response or complete response (European Leukemia Net/International Working Group–Myeloproliferative Neoplasms Research and Treatment response criteria). Patients who achieved a partial response/complete response continued therapy for up to a maximum of 6 years. The minimum follow-up was 1 year from the time the last patient was randomly assigned to treatment. The primary study objective was to compare the complete response rate following hydroxyurea vs pegylated interferon alfa-2a at 12 months with 3-month confirmation.
Key Findings: The final analysis of the Myeloproliferative Neoplasms Research Consortium 112 revealed that the complete response rates in patients with high-risk essential thrombocythemia/polycythemia vera treated with pegylated interferon alfa-2a and hydroxyurea at 12 and 24 months were similar. Pegylated interferon alfa-2a was associated with a higher rate of grade 3 or 4 toxicity. Both drugs appeared equally capable of modifying the natural history of high-risk essential thrombocythemia/polycythemia vera based upon their effects on spleen size, karyotypic abnormalities, histopathologic parameters, the low incidence of thrombotic complications, and disease evolution.
“This randomized trial continues to validate the efficacy and safety of pegylated interferon alfa-2a as a viable option for cytoreduction in high-risk essential thrombocythemia and polycythemia vera.”— Syed Ali Abutalib, MD, and Ruben A. Mesa, MD, FACP
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Clinical Implications: This randomized trial continues to validate the efficacy and safety of pegylated interferon alfa-2a as a viable option for cytoreduction in high-risk essential thrombocythemia and polycythemia vera. The study further supports current National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology, which include both agents as a consideration for front-line therapy. Studies with longer follow-up might be needed to differentiate which agent is preferred and in which patient group as front-line therapy.
ABSTRACT 578: Mutation-enhanced international prognostic systems for essential thrombocythemia mutation–enhanced International Prognostic System–essential thrombocythemia and polycythemia vera5
Background: The current study examines the possibility of integrating genetic (based on the availability of next-generation sequencing–derived mutation information) and clinical information for overall survival, leukemia-free, and myelofibrosis-free survival in patients with essential thrombocythemia (n = 502) and polycythemia vera (n = 404).
Key Findings: To optimize the number of informative cases, the two Mayo and Florence databases were subsequently combined and subjected to multivariable analysis; it confirmed the independent survival effect, in essential thrombocythemia, of SRSF2/SF3B1 mutations (hazard ratio [HR] = 2.8, 95% confidence interval [CI] = 1.8–4.3), age > 60 years (HR = 6.7, 95% CI = 4.8–9.4), and male sex (HR = 1.8, 95% CI = 1.4–2.4) and, in polycythemia vera, of SRSF2 mutations (HR = 7.0, 95% CI = 2.3–17.4), age > 60 years (HR = 5.7, 95% CI = 3.3–10.1), and leukocyte count ≥ 11 × 109/L (HR = 2.4, 95% CI = 1.5–3.9). The combined analysis also flagged independent prognostic contribution from abnormal karyotype in polycythemia vera (HR = 2.1, 95% CI = 1.1–3.6). High-risk–weighted risk point allocation resulted in new, mutation-enhanced four-tiered risk models for essential thrombocythemia (mutation-enhanced International Prognostic Systems–essential thrombocythemia based on mutations, age, and sex) and polycythemia vera (mutation-enhanced International Prognostic Systems–polycythemia vera–based on mutations, karyotype, leukocyte count, and age. Both models displayed high predictive accuracy and were internally validated by bootstrapping. The combined analysis also confirmed the impact of TP53 mutations on leukemia-free survival and U2AF1/SF3B1 mutations on myelofibrosis-free survival in essential thrombocythemia.
Clinical Implications: Spliceosome mutation information enhances survival prediction in essential thrombocythemia and polycythemia vera and identifies those at risk for fibrotic progression. The TP53 mutations predict leukemic transformation in essential thrombocythemia. These results assist in predicting patients with higher long-term risk of progression to life-threatening stages of disease.
Mastocytosis
ABSTRACT 351: Avapritinib improves symptoms of advanced systemic mastocytosis: Analyses of patient reported outcomes from the phase I EXPLORER study using the Advanced Systemic Mastocytosis Symptom Assessment Form (ASM SAF), a new patient-reported outcome questionnaire for advanced systemic mastocytosis6
Mechanism of Action: Avapritinib is a highly potent and selective inhibitor of the KIT D816V mutation.
Background: Patients received avapritinib at the recommended phase II dose (300 mg once daily) in continuous 28-day cycles. Patient-reported outcomes and KIT D816– mutant allele fraction in the blood were assessed serially. The ASM SAF assesses the severity of 8 symptoms (pruritus, flushing, spots, nausea, vomiting, diarrhea, abdominal pain, and fatigue) on a 0–10 scale, and 2 items assess the frequency of diarrhea and vomiting. The results are analyzed as a TSS, combining all 8 severity items (maximum symptom score = 80), and as a gastrointestinal (GI) domain (combining 4 symptoms: nausea, vomiting, diarrhea, abdominal pain; maximum score = 40) and skin domain (combining 3 symptoms: pruritus, flushing, spots; maximum score = 30).
Key Findings: As of June 2018, 25 patients were treated in part 2 of the study, and enrollment and follow-up continue. The median duration of avapritinib treatment was 5.7 months (range = 1.7+ to 10.3+ months). Reductions in ASM SAF TSS, GI, and Skin scores significantly correlated with improvement in quality-of-life questionnaire emotional and cognitive functioning scales (P values for Pearson correlation coefficients < .0001, < .0001, and .04 with emotional functioning and < .0001, .0001, and .04 with cognitive functioning, respectively). Among 18 patients with baseline Patient Global Impression–Severity (mean = 3.2; standard deviation = 1.15; range, 1–5), improvement in Patient Global Impression–Severity was highly associated with improvement in GI score (P = .0004). Decreases in KIT D816V–mutant allele fraction correlated with reduction in TSS (P = .04).
Clinical Implications: Currently, there are no approved agents that selectively target KIT D816V, and there are limited tools to assess symptom improvement in systemic mastocytosis. Avapritinib treatment resulted in meaningful symptom improvement as measured by the ASM SAF in overall symptoms (TSS), GI, and skin domains—as well as all individual symptoms—and improvement continued with a longer duration of treatment. Reduction in ASM SAF scores correlated with improvements in other patient-reported outcomes instruments, Patient Global Impression–Severity, and quality-of-life questionnaire, supporting the ASM SAF as a useful new tool to assess symptoms in patients with advanced systemic mastocytosis. Reduction in ASM SAF scores also correlated with decreases in KIT D816V–mutant allele fraction, indicating that reductions in disease burden may correlate with reduced disease symptoms and improved quality of life. These data warrant further development of avapritinib in advanced systemic mastocytosis as well as in indolent systemic mastocytosis and smoldering systemic mastocytosis, where the symptom burden and poor quality of life are the predominant disease manifestations. ■
Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; and Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Mesa is Professor of Medicine; Director, Mays Cancer Center at UT Health San Antonio MD Anderson; and Mays Family Foundation Distinguished University Presidential Chair.
DISCLOSURE: Drs. Abutalib and Mesa reported no conflicts of interest.
REFERENCES
1. Verstovsek S, Hasserjian RP, Pozdnyakova O, et al: PRM-151 in myelofibrosis: Efficacy and safety in an open label extension study. 2018 ASH Annual Meeting & Exposition. Abstract 686. Presented December 3, 2018.
2. Mascarenhas J, Rami RS, Cavo M, et al: Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to Janus kinase inhibitor therapy: Results of a phase 2 randomized study of two dose levels. 2018 ASH Annual Meeting & Exposition. Abstract 685. Presented December 3, 2018.
3. Gowin KL, Ballen KK, Ahn KW, et al: Survival advantage to allogeneic transplant in patients with myelofibrosis with intermediate-1 or higher DIPSS score. 2018 ASH Annual Meeting & Exposition. Abstract 4288. Presented December 3, 2018.
4. Mascarenhas J, Kosiorek HE, Prchal JT, et al: Results of the Myeloproliferative Neoplasms - Research Consortium (MPN-RC) 112 randomized trial of pegylated interferon alfa-2a vs hydroxyurea therapy for the treatment of high risk polycythemia vera and high risk essential thrombocythemia. 2018 ASH Annual Meeting & Exposition. Abstract 577. Presented December 3, 2018.
5. Tefferi A, Guglielmelli P, Lasho TL, et al: Mutation-enhanced international prognostic systems for essential thrombocythemia (MIPSS-ET) and polycythemia vera (MIPSS-PV). 2018 ASH Annual Meeting & Exposition. Abstract 578. Presented December 3, 2018.
6. Gotlib JR, Radia D, DeAngelo DJ, et al: Avapritinib, a potent and selective inhibitor of KIT D816V, improves symptoms of advanced systemic mastocytosis (AdvSM): Analyses of patient reported outcomes (PROs) from the phase 1 (EXPLORER) study using the AdvSM symptom assessment form, a new PRO questionnaire for AdvSM. 2018 ASH Annual Meeting & Exposition. Abstract 351. Presented December 3, 2018.
