Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open-label study.

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.

Improvements in Health-related Quality of Life and Symptoms in Patients With Previously Untreated Chronic Lymphocytic Leukemia: Final Results From the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine.

BACKGROUND: We evaluated health-related quality of life (HRQoL) in patients with chronic lymphocytic leukemia (CLL) receiving first-line chemoimmunotherapy in the GIBB single-arm, Phase II study of obinutuzumab plus bendamustine (BG). MATERIALS AND METHODS: Patients received six 28-day cycles of BG and were followed for up to 27 months. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) and EORTC QLQ Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) questionnaires. Scores were linear-transformed to a 100-point scale, with clinically meaningful responses defined as a ≥ 10-point change from baseline. RESULTS: The patient-reported outcome (PRO) population comprised 98 patients (68.4% male; median age 61 years). EORTC QLQ-C30 global health status improvements were noted at all follow-up visits and were clinically meaningful 2 to 3 months after induction and at 3- and 27-months' follow-up. Clinically meaningful improvements were also observed for the EORTC QLQ-C30 role functioning, emotional functioning, fatigue and insomnia scales and the EORTC QLQ-CLL16 fatigue, disease symptoms and future health worries scales. Global health status was maintained throughout follow-up, and no clinically relevant deterioration in other HRQoL parameters was observed. CONCLUSION: PRO data from the GIBB study show improved overall HRQoL in patients with CLL who received first-line chemoimmunotherapy with BG.

Phase 2, multicenter GIBB study of obinutuzumab plus bendamustine in previously untreated patients with chronic lymphocytic leukemia.

The single-arm, multicenter, phase 2 GIBB study (NCT02320487) investigated bendamustine plus obinutuzumab (BG) in previously untreated CLL. Patients (N = 102) received six cycles of intravenous obinutuzumab (cycle [C] 1: 100 mg day 1/900 mg day 2, and 1000 mg days 8/15; C2-6 1000 mg day 1) plus bendamustine (C1 90 mg/m2 days 2/3; C2-6 days 1/2). Complete response (CR), the primary endpoint, was 50%, overall response 89%. Estimated 2-year progression-free survival (PFS) and overall survival (OS) were 86% and 97%, respectively. Following initial minimal residual disease (MRD) negativity, median MRD negativity duration was 28.9 months. Undetectable MRD (<10-4) was observed in up to 83% of evaluable patients in peripheral blood (any time) and 59% in bone marrow at response evaluation. Most common grade 3/4 adverse events (AEs) were neutropenia (25%; 5% febrile) and infusion-related reactions (9%). BG proved clinically active in CLL with high response, MRD negativity, and survival rates, consistent with other first-line studies of anti-CD20 antibody/bendamustine combinations.

Fostamatinib is an effective second-line therapy in patients with immune thrombocytopenia.

Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second-line therapy (after steroids ± immunoglobulins) versus third-or-later-line therapy (after ≥2 prior lines of therapy including a second-line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second-line and 54/113 (48%) third-or-later-line patients. Bleeding events were less frequent in second-line (28%) versus third-or-later-line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second-line than third-or-later-line therapy for ITP.

Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program.

Two randomized, double-blind, placebo-controlled studies demonstrated responses (≥50 000/µL) to fostamatinib in adults with long-standing immune thrombocytopenia (ITP). The long-term safety and efficacy of fostamatinib were evaluated in a follow-on, open-label extension (OLE) study. Patients received double-blind fostamatinib in the randomized trials, and responders continued the same dose, 100 to 150 mg BID, in the OLE study. Nonresponders received 100 mg BID for 4 weeks and could escalate to 150 mg BID at week 4. Endpoints included stable response, platelet count ≥50 000/µL at 4/6 biweekly (randomized trials) or 2/3 monthly visits (OLE), and overall response, ≥1 platelet count ≥50 000/µL during weeks 1 to 12. A total of 146 patients received fostamatinib including 123 in the OLE study. Median treatment duration was 6.7 months. Baseline median ITP duration was 8 years and median platelet count was 16 000/µL; prior treatments included thrombopoietic (TPO) agents (47%), splenectomy (35%), and rituximab (32%). Twenty-seven (18%) patients achieved a stable response with median duration of >28 months and a median platelet count of 89 000/µL. Sixty-four (44%) patients achieved an overall response (including stable responders) with a median platelet count of 63 000/µL and a median response duration of >28 months. Twenty-four of 71 (34%) patients who had failed TPO agents achieved overall responses to fostamatinib. The most common adverse events (AEs) were diarrhea, hypertension, nausea, epistaxis, and abnormal liver function tests. Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication. Almost half of the patients achieved an overall response, and most of these maintained their responses for >2 years. No new or increased frequency of AEs was seen at up to 31 months of treatment.

Comprehensively understanding fatigue in patients with myeloproliferative neoplasms.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) experience a high persistence, prevalence, and severity of fatigue. There is currently only limited information regarding factors that contribute to fatigue in patients with MPNs. METHODS: A 70-item, Internet-based survey regarding fatigue was developed by MPN investigators and patients/advocates and hosted by the Mayo Clinic Survey Research Center. RESULTS: Fatigue was found to be prevalent and severe among international survey respondents (1788 respondents). Higher body mass index (P<.001), current use of alcohol (P<.001), and current tobacco use (P = .0025) were found to be significantly associated with greater fatigue. Moderate/severe fatigue was present more frequently in those individuals who did not exercise compared with those who reported exercising at least once per week (P<.001). Medical comorbidities found to be significantly associated with greater fatigue included restless leg syndrome (P = .006), diabetes mellitus (P = .045), fibromyalgia (P < 0.001), chronic fatigue syndrome (P = .006), and chronic kidney disease (P = .02). Current use of antidepressants (P<.001), antihistamines (P = .0276), antianxiety medications (P = .0357), and prescription pain medications (P<.001) were found to be associated with worsened fatigue. Nearly 25% of respondents scored > 2 on the Patient Health Questionnaire, indicating a high probability of depression. Higher Brief Fatigue Inventory score, Myeloproliferative Neoplasm Total Symptom Score, and individual symptom items were all associated with a higher likelihood of depressive symptoms (P<.0001). CONCLUSIONS: The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. Patients with MPNs likely have a higher prevalence of mood disturbances compared with the general population, suggesting the need to assess and intervene in this domain.