Frequency and outcomes of obinutuzumab-induced thrombocytopenia.

Obinutuzumab is a third-generation anti-CD20 monoclonal antibody widely used in the treatment of B-lymphoproliferative disorders but infrequently associated with severe thrombocytopenia, which can be life-threatening. The pathophysiology is unclear, but platelet clearance can be extremely rapid (usually within 24 h). In a retrospective case series, we have identified four cases among 149 recipients of obinutuzumab-containing chemotherapy regimens between 2015 and 2022 treated for haematological malignancies in Canberra, Australia (frequency 2.7%). We illustrate four cases of obinutuzumab-induced thrombocytopenia with a review of the literature. Research is required to identify the pathophysiology and improve early recognition and management of the condition in the context of multiagent chemotherapy.

Chromosome microarray characterisation of chromosome arm 12p loss associated with complex molecular karyotype and recurrent adverse cytogenetic markers in multiple myeloma.

Copy number loss within chromosome 12 short arm (12p) has gained attention as an adverse cytogenetic marker in multiple myeloma. The prognostic significance and characterisation of the common minimal deleted region remains controversial between various studies with loss of CD27 proposed as the putative critical gene. We aimed to determine the frequency of 12p loss, its correlation with adverse cytogenetic markers further to define and characterise 12p deletions. Our study included a prospective cohort of 574 multiple myeloma patients referred for cytogenetic testing, including interphase fluorescence in situ hybridisation for IGH (14q32.33) translocations and chromosome microarray. Loss of 12p was detected in 54/574 (9.4%) patients and when compared with the non-12p loss group [520/574 (90.6%)], 12p loss patients demonstrated a statistically significant association with specific recurrent cytogenetic markers: complex molecular karyotypes (98.1% vs 45.2%), 1p loss (50.0% vs 20.2%), t(4;14) (20.4% vs 7.7%), 8p loss (37.0% vs 15.0%), 13/13q loss (70.4% vs 41.7%), and 17p loss (33.3% vs 6.5%). The size and location of 12p losses were heterogeneous with a common 0.88 Mb minimally deleted region that included ~9 genes from ETV6 to CDKN1B in 52/54 (~96.3%) patients but did not include CD27. Our findings support 12p loss being a secondary chromosome abnormality frequently co-occurring with adverse cytogenetic markers and complex molecular karyotypes indicative of chromosome instability.

Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients.

Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.

Activating the Antitumor Immune Response in Non-Hodgkin Lymphoma Using Immune Checkpoint Inhibitors.

Non-Hodgkin lymphomas comprise a heterogenous group of disorders which differ in biology. Although response rates are high in some groups, relapsed disease can be difficult to treat, and newer approaches are needed for this patient population. It is increasingly apparent that the immune system plays a significant role in the propagation and survival of malignant cells. Immune checkpoint blocking agents augment cytotoxic activity of the adaptive and innate immune systems and enhance tumor cell killing. Anti-PD-1 and anti-CTLA-4 antibodies have been tested as both single agents and combination therapy. Although success rates with anti-PD-1 antibodies are high in patients with Hodgkin lymphoma, the results are yet to be replicated in those with non-Hodgkin lymphomas. Some lymphoma histologies, such as primary mediastinal B cell lymphoma (PMBL), central nervous system, and testicular lymphomas and gray zone lymphoma, respond favorably to PD-1 blockade, but the response rates in most lymphoma subtypes are low. Other agents including those targeting the adaptive immune system such as TIM-3, TIGIT, and BTLA and innate immune system such as CD47 and KIR are therefore in trials to test alternative ways to activate the immune system. Patient selection based on tumor biology is likely to be a determining factor in treatment response in patients, and further research exploring optimal patient populations, newer targets, and combination therapy as well as identifying biomarkers is needed.

Outpatient rituximab, ifosfamide, etoposide (R-IE) in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation.

Patients with relapsed-refractory diffuse large B-cell lymphoma (RR-DLBCL) ineligible for autologous stem cell transplantation (autoSCT) have poor survival. Thirty transplant-ineligible patients older than 60 years were administered rituximab 375 mg/m2 day 1, ifosfamide 1333 mg/m2 days 1 to 3, and etoposide 80 mg/m2 days 1 to 3 (R-IE) every 21 days for 6 cycles plus 2 doses of rituximab. Revised international prognostic index 3-4 was seen in 53% and prior rituximab exposure in 60%. The complete and overall response rates were 55% and 76%, respectively. Median progression free survival (PFS) and overall survival were 23 and 24 months, respectively. Patients relapsing within 12 months of prior treatment had a median PFS of 2.5 months compared to 23 months for those relapsing beyond 12 months. Grade 3-4 thrombocytopenia and neutropenia occurred in one and eight patients, respectively. R-IE is an effective, well tolerated regimen in RR-DLBCL patients not fit for autoSCT.