Syed A. Abutalib, MD

HERE IS AN UPDATE on four different studies featured at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition. Topics focus on advanced systemic mastocytosis, diffuse large B-cell lymphoma (DLBCL), amyloidosis, and myeloproliferative neoplasms. 

Systemic Mastocytosis 

STUDY: Clinical activity in a phase I study of Blu-285 in 24 patients with advanced systemic mastocytosis¹ 

Mechanism of Action: BLU-285 is a specific oral inhibitor of KIT activation loop mutants including D816V. 

Key Findings: BLU-285 demonstrated significant clinical activity across all dose levels, with rapid and durable reductions in mast cell burden and D816V-mutant allele fraction relative to baseline. Most common adverse events were periorbital edema (43%), anemia, diarrhea, fatigue, peripheral edema (27% each), headache (23%), thrombocytopenia, and nausea (20% each). Grade ≥ 3 treatment-related adverse events occurring in at least two patients included neutropenia, anemia, and periorbital edema. BLU-285 at 300 mg orally 4-week cycles demonstrates considerable clinical activity in all advanced systemic mastocytosis subtypes, including patients who have failed to respond to midostaurin and other antineoplastic therapies. 

Conclusion: These encouraging phase I data validate selective targeting of KIT D816V, and favor further clinical testing of BLU- 285 in patients with advanced systemic mastocytosis. 

Lymphoma 

STUDY: Addition of polatuzumab vedotin to bendamustine and rituximab (BR; Rituxan) improves outcomes in transplant-ineligible patients with relapsed or refractory DLBCL vs BR alone: Results from a randomized phase II study² 

Mechanism of Action: Polatuzumab vedotin is an antibody-drug conjugate that delivers the microtubule inhibitor monomethyl auristatin E to CD79b-expressing cells. 

Key Findings: The primary aim of the study was to assess the efficacy of adding polatuzumab vedotin to BR (n = 40) vs BR alone (n = 40). The complete response rates were 43% vs 15% in the polatuzumab vedotin and BR vs BR arms, respectively. The median duration of response for polatuzumab vedotin and BR vs BR was 8.8 months (95% confidence interval [CI] = 4.5 months to not reached) vs 3.7 months (95% CI = 2.6–7.8 months), respectively. Median progression-free survival for polatuzumab vedotin and BR vs BR was 6.7 months (95% CI = 4.9–11.1 months) vs 2.0 months (95% CI = 1.5–3.7 months), with a stratified hazard ratio of 0.31 (95% CI = 0.18–0.55) and P value < .0001 (calculated by Cox regression and log rank, respectively). Although the study was not powered for survival analyses, the median overall survival for polatuzumab vedotin and BR vs BR alone was 11.8 months (95% CI = 9.5 months to not reached) vs 4.7 months (95% CI = 3.7–8.3 months), with a stratified hazard ratio of 0.35 (95% CI = 0.19–0.67) and P value of .0008. 

More grade 3/4 cytopenias were reported with polatuzumab vedotin and BR vs BR alone, but they were manageable, with similar transfusion rates between the two arms. Serious adverse events occurring in ≥ 10% of patients were infections (21% with polatuzumab vedotin and BR vs 26% with BR alone), febrile neutropenia (10% vs 5%), and pyrexia (10% vs 3%). Peripheral neuropathy occurred in 39% of patients treated with polatuzumab vedotin and BR (21% grade 1, 18% grade 2) vs 3% of patients treated with BR (3% grade 2) and led to polatuzumab vedotin discontinuation in one patient and dose reduction in two patients. 

Conclusion: The addition of polatuzumab vedotin to BR increased the overall response rate, progression-free survival, overall survival as well as provided significant clinical benefit with manageable toxicity in transplant-ineligible patients with relapsed or refractory DLBCL. 

Amyloidosis 

STUDY: Final analysis of the phase IA/B study of 11-1F4 in 27 patients with relapsed or refractory amyloid light-chain amyloidosis³ 

“Amyloid fibril–targeted therapy with 11-1F4 represents both a promising and innovative approach to the management of patients with amyloid light-chain amyloidosis.”

— Syed A. Abutalib, MD

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Mechanism of Action: 11-1F4 is an amyloid fibril–reactive monoclonal antibody that is designed to target amyloid deposits by directly binding to a conformational epitope present on human light-chain amyloid fibrils. 

Key Findings: Eight patients completed treatment in phase IA and 19 patients completed treatment in phase IB, with 26 patients evaluable for response. Overall, 5 of 8 evaluable patients demonstrated organ response after a single infusion of 11-1F4 in phase IA, and 11 of 18 evaluable patients showed organ response in phase IB. The median time to response was 2 weeks after the start of treatment, with a tendency to quicker response with higher dosages. All patients tolerated the given dose of 11-1F4 up to the highest dose level of 500 mg/m2 for both phase IA and phase IB. There were no drug-related grade 4 or 5 adverse events or dose-limiting toxicities. 

Conclusion: The monoclonal antibody 11-1F4 seems to be well tolerated and safe. Overall, amyloid fibril–targeted therapy with 11-1F4 represents both a promising and innovative approach to the management of patients with amyloid light-chain amyloidosis. Randomized trials to evaluate the agent’s efficacy are planned. 

Myeloproliferative Neoplasms 

STUDY: Open-label phase I study of single-agent oral idasanutlin (RG7388) in 12 patients with high-risk JAK2 V617F–positive polycythemia vera (11) and essential thrombocythemia (1) without prior JAK2 inhibitor therapy⁴ 

Mechanism of Action: MDM2, a negative regulator of p53 gene, is overexpressed in CD34-positive myeloproliferative neoplasm cells harboring wild-type p53. It is the target of idasanutlin, an MDM2 antagonist that results in upregulation of p53 and downstream activators of apoptosis. Baseline MDM2 levels were higher in study participants than in normal controls (P = .01). 

Key Findings: This phase I trial started with idasanutlin at two dose levels (100 mg and 150 mg) daily for 5 consecutive days and repeated every 28-day cycles. A dose-limiting toxicity was not identified for either dose level during cycle 1, and no hematologic treatment-emergent adverse events were seen at any time point. Three patients had grade 3 nonhematologic adverse effects. Patients who did not attain at least a partial response by modified European LeukemiaNet criteria after cycle 6 and met eligibility were able to continue receiving idasanutlin in combination with pegylated interferon-α at 45 μg weekly. 

The overall response rate by cycle 7 for the 9 evaluable patients was 77%. Of 10 evaluable patients, 7 achieved a ≥ 50% improvement in total symptom score from baseline. There were no thrombotic or major hemorrhagic episodes or progression to myelofibrosis. Bone marrow pathologic response was assessed in two patients after five cycles. One case showed histologic improvement, with normalization of overall marrow cellularity and megakaryocyte number, and less pronounced megakaryocytic atypia. One patient was eligible to receive combination therapy and achieved freedom from phlebotomy, normalization of palpable spleen (baseline 18 cm), and leukocyte count (baseline 44 109/L). This patient also attained a 20% reduction in JAK2 V617F–variant allele frequency. 

Conclusion: A global, multicenter, single-arm phase II trial of idasanutlin at a dose of 150 mg in patients with hydroxyurea-resistant/intolerant polycythemia vera is underway. ■

DISCLOSURE: Dr. Abutalib reported no conflicts of interest. 

REFERENCES 

1. DeAngelo DJ, Quiery AT, Radia D, et al: Clinical activity in a phase 1 study of Blu-285, a potent, highly selective inhibitor of KIT D816V in advanced systemic mastocytosis. 2017 ASH Annual Meeting. Plenary Abstract 2. Presented December 10, 2017. 

2. Sehn LH, Herrera AF, Matasar MJ, et al: Addition of polatuzumab vedotin to bendamustine and rituximab (BR) improves outcomes in transplant-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma versus BR alone: Results from a randomized phase 2 study. 2017 ASH Annual Meeting. Abstract 2821. Presented December 10, 2017. 

3. Edwards CV, Gould J, Langer AL, et al: Final analysis of the phase 1a/b study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with relapsed or refractory AL amyloidosis. 2017 ASH Annual Meeting. Abstract 509. Presented December 10, 2017. 

4. Mascarenhas J, Lu M, Virtgaym E, et al: Open label phase I study of single agent oral RG7388 (idasanutlin) in patients with polycythemia vera and essential thrombocythemia. 2017 ASH Annual Meeting. Abstract 254. Presented December 9, 2017.