Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.

BACKGROUND: Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. METHODS: In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. RESULTS: The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. CONCLUSIONS: In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.

BACKGROUND: In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome. METHODS: In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. RESULTS: At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. CONCLUSIONS: Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

The Myeloma Patient Outcome Scale is the first quality of life tool developed for clinical use and validated in patients with follicular lymphoma.

OBJECTIVES: The development of novel agents and an ageing population has led to an increasing number of patients with follicular lymphoma (FL) living longer with their disease. Health-related quality of life (HRQOL) is a priority for patients and should guide clinical decisions. The Myeloma Patient Outcome Scale (MyPOS), originally developed for myeloma, was validated in a cross-sectional survey recruiting 124 FL patients. METHODS: Content and construct validity, structural validity using confirmatory factor analyses, reliability and acceptability were evaluated. RESULTS: Three subscales were indicated: symptoms and function, emotional response, and healthcare support. MyPOS symptom and function scores were higher (worse) in participants with poorer ECOG performance status (F=26.2, P<.000) and discriminated between patients on and off treatment. Good convergent and discriminant validity in comparison to the EORTC-QLQ-C30 and FACT-Lym were demonstrated. Internal consistency was good; α coefficient 0.70-0.95 for the total MyPOS score and subscales. CONCLUSION: The MyPOS is valid, reliable and acceptable, and can be used to support clinical care of FL patients. This is the first measurement tool developed specially for use in clinical practice that has been validated for use in people with FL. Further longitudinal validation is now required to support its use in outcome measurement.

Life-threatening motor neurotoxicity in association with bortezomib.

Bortezomib has been licensed to be used in relapsed and refractory multiple myeloma. It is a promising agent for this incurable condition but our effort is to caution hematologists about the life-threatening neurotoxicity (grade 4) which was seen in two of six patients treated with this agent although the complication cannot definitely be attributed to bortezomib.

The impact of donor factors on primary non-engraftment in recipients of reduced intensity conditioned transplants from unrelated donors.

BACKGROUND AND OBJECTIVES: Primary graft failure is a serious complication following hematopoietic cell transplants, particularly when using unrelated donors. We analyzed factors affecting primary graft failure in recipients of hematopoietic cell transplants from unrelated donors, which were performed using reduced intensity conditioning. DESIGN AND METHODS: This was a retrospective analysis of 144 patients whose transplants took place between March 1998 and October 2004. The data were analyzed in January 2005. RESULTS: The median age of the patients was 51 years. The diagnoses were varied. Conditioning regimens were fludarabine, melphalan, campath (n=80), fludarabine, busulphan, campath (n=38), fludarabine, BEAM, campath (n=9) and other (n=17). The donor was 10/10 allele matched in 95/144 (66%) cases; 94 donated bone marrow and 50 peripheral blood stem cells. The 3-year probability of overall survival was 43%. The median follow-up was 724 days (range: 91-1651 days). Of evaluable patients, 7/140 (5%) failed to achieve myeloid engraftment. Primary graft failure was significantly associated with the use of a mismatched donor (6/47,13% versus 1/93, 1%, p=0.006), as well as: bone marrow as the source of stem cells (p=0.046), chronic myeloid leukemia compared to other diagnoses (p=0.022), and a female rather than a male donor (p=0.019). In multivariate analysis chronic myeloid leukemia, HLA mismatched and/or female donors remained significantly associated with primary graft failure. Single HLA mismatches were tolerated, however in multiply mismatched grafts, overall survival was worse (p=0.005); transplanted-related mortality (p=0.005) and chronic graft-versus-host disease (p=0.025) were increased. INTERPRETATION AND CONCLUSIONS: These data have implications for the choice of donor and stem cell source in transplants performed using reduced intensity conditioning regimens, suggesting that the use of bone marrow, female donors and HLA-mismatched grafts increase the risk of primary graft failure, and should be avoided in certain situations.

IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML.

Combined expression of costimulatory factors and proinflammatory cytokines stimulate effective immune-mediated tumor rejection in a variety of murine tumor models. Specifically, syngeneic tumor cells genetically modified to express B7.1 (CD80) have been shown to induce rejection of previously established murine solid tumors, and transduction with IL-2 can further increase survival. However, poor rates of gene transfer and inefficient expression of multiple transgenes encoded by single vectors have hampered the development of such autologous tumor cell vaccines for clinical trials in acute myeloid leukemia (AML) patients. Here we describe the development of a self-inactivating lentiviral vector encoding B7.1 and IL-2 as a single fusion protein postsynthetically cleaved to generate biologically active membrane-anchored B7.1 and secreted IL-2. This enables the efficient transduction of both established and primary AML blasts, resulting in expression of the transgenes in up to 98% of the cells following a single round of infection at an m.o.i. of 10. The combined expression of IL-2 and B7.1 in AML blasts enables increased stimulation of both allogeneic and autologous T cells. The stimulated lymphocytes secrete greater levels of Th1 cytokines and show evidence of specificity, as indicated by their increased proliferation in the presence of autologous AML compared to remission bone marrow cells.