A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma.

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy.

BACKGROUND: Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy. METHODS: The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL. RESULTS: A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P<.01) and progression-free survival (PFS) (1.9 vs 4.4 years; P<.01). In patients who underwent high-intensity induction followed by autologous stem cell transplantation (ASCT) in first remission, a CK was associated with poor OS (5.1 vs 11.6 years; P = .04) and PFS (3.6 vs 7.8 years; P<.01). Among patients with a CK, high-intensity induction had no effect on OS (4.5 vs 3.8 years; P = .77) nor PFS (2.3 vs 1.5 years; P = .46). Similarly, ASCT in first remission did not improve PFS (3.5 vs 1.2 years; P = .12) nor OS (5.1 vs 4.0 years; P = .27). On multivariable analyses with Ki-67 and MIPI, only CK was found to be predictive of OS (hazard ratio [HR], 1.98; 95% confidence interval [95% CI], 1.12-3.49 [P = .02]), whereas both CK (HR, 1.91; 95% CI, 1.17-3.12 [P = .01]) and Ki-67 >30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival. CONCLUSIONS: CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.

PI3K Inhibitors: Understanding Toxicity Mechanisms and Management.

The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms. Despite the therapeutic benefit, there have been concerns about the severe and sometimes fatal adverse effects of this class of drug. Several side effects are unusual and have poorly understood mechanisms; these include autoimmune dysfunction, opportunistic infections, skin toxicity, hypertension, and hyperglycemia. An understanding of these unusual toxicities, as well as a good grasp of management principles, will be important as more PI3K inhibitors are approved and become incorporated into routine practice.

Disaster 101: a novel approach to disaster medicine training for health professionals.

BACKGROUND: Despite efforts to improve preparedness training for health professionals, disaster medicine remains a peripheral component of traditional medical education in the United States (US) and is a rarely studied topic in the medical literature. OBJECTIVES: Using a pre-/post-test design, we measured the extent to which 4(th)-year medical students perceive, rapidly learn, and apply basic concepts of disaster medicine via a novel curriculum. METHODS: Via a modified Delphi technique, an expert curriculum panel developed a 90-min didactic training scenario and two 40-min training exercises for medical students: a hazardous material scene and a surprise mass casualty incident (MCI) scenario with 100 life-sized mannequins. Medical students were quizzed before and after the didactic training scenario about their perceptions and their disaster medicine knowledge. RESULTS: Students rated their overall knowledge as 3.76/10 pretest compared to 7.64/10 after the didactic program. Students' post-test scores improved by 54% and students participating in the MCI drill correctly tagged 94% of the victims in approximately 10 min. The average overall rating for the experience was 4.85/5. CONCLUSIONS: The results of this educational demonstration project reveal that students will value and can rapidly learn some core elements of disaster medicine via a novel addition to a medical school's curriculum. We believe the principle of a highly effective and well-received medical student course that can be easily added to a university curriculum has been demonstrated. Further research is needed to validate core competencies and performance-based education goals for US health professional trainees.