Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe.

BACKGROUND Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce. METHODS In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). RESULTS On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. CONCLUSIONS In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

The therapeutic concept of unleashing a pre-existing immune response against the tumor by the application of immune-checkpoint inhibitors (ICI) has resulted in long-term survival in advanced cancer patient subgroups. However, the majority of patients do not benefit from single-agent ICI and therefore new combination strategies are eagerly necessitated. In addition to conventional chemotherapy, kinase inhibitors as well as tumor-specific vaccinations are extensively investigated in combination with ICI to augment therapy responses. An unprecedented clinical outcome with chimeric antigen receptor (CAR-)T cell therapy has led to the approval for relapsed/refractory diffuse large B cell lymphoma and B cell acute lymphoblastic leukemia whereas response rates in solid tumors are unsatisfactory. Immune-checkpoints negatively impact CAR-T cell therapy in hematologic and solid malignancies and as a consequence provide a therapeutic target to overcome resistance. Established biomarkers such as programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) help to select patients who will benefit most from ICI, however, biomarker negativity does not exclude responses. Investigating alterations in the antigen presenting pathway as well as radiomics have the potential to determine tumor immunogenicity and response to ICI. Within this review we summarize the literature about specific combination partners for ICI and the applicability of artificial intelligence to predict ICI therapy responses

Novel models for prediction of benefit and toxicity with FOLFIRINOX treatment of pancreatic cancer using clinically available parameters.

BACKGROUND:Despite modern chemotherapy regimens, survival of pancreatic cancer patients remains dismal. Toxicity is a major concern and it is a challenge to upfront identify patients with the highest benefit from aggressive polychemotherapy. We aimed to evaluate ORR and side effects of the FOLFIRINOX regimen, highlighting dose modification and to explore possible prognostic response factors as a clinical tool. METHODS:This retrospective study includes 123 patients with metastatic PC that were treated with FOLFIRINOX between the years 2007 to 2016 in a single academic institution. Survival rates were analysed using the Kaplan-Meier method. Prognostic models including laboratory and clinical parameters were calculated using Cox proportional models in univariate and multivariate analyses. RESULTS:Median age at diagnosis was 64 years (47-78 years), 71 (57, 7%) were male and the majority had an ECOG performance status of 0 or 1 (63 patients; 83.7%). After a median follow up of 17.8 months, median progression free survival (PFS) and overall survival (OS) were 5.7 (4.55-6.84; 95%CI) and 11.8 months (9.35-14.24; 95%CI) respectively. Overall response rate with FOLFIRINOX was 34.9% and stable disease rate was 21.9%. Regarding Grade 3/4 side effects, 62 events, were reported in 37 patients. Looking at risk factors e.g. patient characteristics, tumor marker, inflammatory markers and body composition multivariate analyses proved CEA >4 elevation and BMI > 25 at the time point before palliative chemotherapy to be independent negative prognostic factors for OS. Grouping patients with no risk factor, one or two of these risk factors we analyzed a median OS of 17.4 moths, 9.6 months and 6.7 months (p<0.001) respectively. In addition we identified thrombocytosis and low BMI as predictors of early toxicity. CONCLUSION:This study identifies two easily available factors influencing overall survival with FOLFIRINOX therapy. By combining these two factors to create a score for OS, we propose a prognostic tool for physicians to identify patients, who are unlikely to benefit more from FOLFIRINOX or likely to experience toxicity

Two Cases of Pancytopenia with Coombs-Negative Hemolytic Anemia after Chimeric Antigen Receptor T-Cell Therapy

Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2–3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb’s tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism