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.

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.

Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia.

Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205.

An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.

Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889.

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.

Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab.

CD52 is expressed on malignant cells in lymphoplasmacytic lymphoma (LPL), including IgM-secreting Waldenström macroglobulinemia (WM). We examined the activity of alemtuzumab in 28 symptomatic LPL (27 IgM and 1 IgA) patients. The median prior number of therapies for these patients was 2 (range, 0-5) and 43% had refractory disease. Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing, and also received hydrocortisone, acyclovir, and Bactrim or equivalent prophylaxis. Patients had a complete response (n = 1), a partial response (n = 9), or a MR (n = 11) for an overall and major response rate of 75% and 36%, respectively. Median serum Ig decreased from 3510 to 1460 mg/dL (P < .001 at best response). With a median follow-up of 64 months, the median time to progression was 14.5 months. Hematologic and infectious complications, including CMV reactivation, were more common in previously treated patients and were indirectly associated with 3 deaths. Long-term follow-up revealed late-onset autoimmune thrombocytopenia (AITP) in 4 patients at a median of 13.6 months after therapy, which contributed to 1 death. Alemtuzumab is an active therapy in patients with LPL, but short- and long-term toxicities need to be carefully weighed against other available treatment options. Late AITP is a newly recognized complication of alemtuzumab in this patient population. This study is registered at www.clinicaltrials.gov as NCT00142181.

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.

The risk of Parkinson's disease in type 1 Gaucher disease.

In Gaucher disease, defective lysosomal glucocerebrosidase due to mutations in the GBA1 gene results in lysosomal accumulation of glucocerebroside in mononuclear phagocytes and a multisystemic phenotype. Observations of occurrence of Parkinson's disease in some patients with non-neuronopathic type 1 Gaucher disease (GD1) and their first degree relatives has led to the identification of GBA1 heterozygous mutations as a genetic risk factor for idiopathic Parkinson's disease (PD). However, the magnitude of risk of PD in patients with known GD1 has not been determined, and it is not known whether GD1/PD represents a specific sub-phenotype of GD1 with distinctive genotype/phenotype characteristics. We estimated the risk of PD in a cohort of 444 consecutively evaluated patients with GD1 compared to that in the general population. Eleven patients developed parkinsonian syndrome during a 12-year follow-up period. The adjusted life-time risk ratio of PD in GD1 compared to that in the general population was 21.4 [95% confidence interval (95% CI) 10.7-38.3], with a higher risk in men compared to women. In our cohort, GD1/Parkinson's disease phenotype (GD1/PD) was characterized by higher GD1 severity score, due to higher incidence of avascular osteonecrosis. The clinical spectrum of PD varied from mild to potentially life-threatening disease. All but one patient with GD1/PD phenotype had at least one N370S GBA1 allele. In conclusion, compared to the general population, patients with GD1 have an almost 20-fold increased life-time risk of developing PD.

Iron deficiency anemia from iron malabsorption caused by proton pump inhibitors.

Background: Iron deficiency anemia without evidence for blood loss can present a diagnostic challenge. Proton pump inhibitors have been associated with iron deficiency anemia for many years, yet the relationship between the two until recently was not fully understood. Treatment recommendations are lacking. Methods and methods: This study evaluated 43 iron deficient patients who were taking proton pump inhibitors, 41 of whom were unresponsive to oral iron, and for whom no etiology for the iron deficiency could be found. Two patients who had hereditary hemochromatosis never were treated with oral iron. Results: Forty-three patients taking a proton pump inhibitor had elevated serum gastrin ≥100 pg/mL. Upon treatment with intravenous iron, 95% (41/43) responded with increased hemoglobin concentration ≥2 g/dL. Improvements were also achieved in the mean corpuscular volume, ferritin, and transferrin saturation. Conclusions: These findings suggest that proton pump inhibitors have been an under-recognized cause for iron deficiency anemia and need to be considered in patients who are taking a proton pump inhibitor. The iron deficiency does correct with intravenous iron replacement.

Etiologies of Thrombocytopenia in the Community Hospital: The Experience of 1 Hematologist.

BACKGROUND: Thrombocytopenia in hospitalized patients is a common cause for hematologic consultation. Our experience in the community hospital setting can inform treating physicians of the causes for and need to treat thrombocytopenia. Here we describe our clinical experience from 2 community hospitals over a 22-month period, wherein a single hematologist was consulted for 97 cases of thrombocytopenia in 93 patients. METHODS: Referred patients underwent history, physical, review of old records and imaging, relevant laboratory testing, review of the peripheral smear, and a bone marrow aspirate and biopsy if clinically indicated. RESULTS: Thirty-five patients had a primary hematologic cause for their thrombocytopenia. Fifty-one had secondary causes for thrombocytopenia. Eleven patients had no discernible etiology for their thrombocytopenia. The most common hematologic diagnoses were immune thrombocytopenia purpura (n = 12), heparin-induced thrombocytopenia (n = 6), in vitro platelet clumping (n = 4), quite remarkably acute progranulocytic leukemia (n = 4), and thrombotic thrombocytopenia purpura (n = 3). The latter 3 were immediately diagnosed by reviewing the peripheral smear, which led to appropriate therapy. The most common nonhematologic etiologies were liver disease (n = 21), bacterial sepsis (n = 12), and oral medication (n = 7). Although the thrombocytopenia was mostly nonacute, immediate hematologic interventions were needed for 21 patients. Four patients died, none from complications of thrombocytopenia. CONCLUSIONS: Thrombocytopenia in hospitalized patients requires consideration of multiple etiologies and review of the peripheral smear. Liver disease is often overlooked as a cause for thrombocytopenia.

Depressive symptoms and myeloproliferative neoplasms: Understanding the confounding factor in a complex condition.

BACKGROUND: Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, have severe function-limiting symptom burden that is experienced by the majority of patients. Previous studies have suggested that depression may be present in over a quarter of MPN patients, but to date no studies have evaluated the relationship between depression and other variables such as symptoms. METHODS: A 70-item internet based survey regarding fatigue and mood symptoms was developed by a multidisciplinary team of MPN investigators, patients and patient advocates including Patient Health Questionnaire and the Myeloproliferative Neoplasm Symptom Assessment Form was completed by over 1300 patients with MPN diagnosis. RESULTS: There were 309 respondents (23%) with PHQ-2 scores ≥ 3. In this analysis, we found worse systemic symptom burden in individuals reporting depressive symptoms. CONCLUSION: This analysis suggests the importance of depression in contributing to as well as confounding symptomatology in MPN patients, and suggests that this critical variable should also be addressed by clinicians and researchers alike when comprehensively assessing symptom burden etiologies.

The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients.

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross-sectional study. In addition, the relative risk (RR) of cancer in patients compared with age-, sex-, and ethnic-group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17-54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49-6.79), and overall cancer risk (RR 1.80, 95% CI 1.32-2.40) was increased. Homozygous N370S GD leads to adult-onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma.