Outcomes of therapeutic plasma exchange for the treatment of patients with multiple myeloma cast nephropathy.

Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3 months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6 months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6 months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p = 0.006), and achievement of ≥VGPR (OR 21.7 p < 0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p = 0.09). With a median follow-up of 36.4 months, the median overall survival (OS) was 11 months. On multivariable analysis, achievement of renal response (hazard ratio [HR] 0.3, p < 0.0001) and newly diagnosed disease (NDMM; HR 0.43, p = 0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p = 0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.

A multi-center analysis of the impact of DA-EPOCH-R dose-adjustment on clinical outcomes of patients with double/triple-hit lymphoma.

Patients with double- and triple-hit lymphomas (DHL/THL) have inferior outcomes with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and higher-intensity regimens such as dose-adjusted (DA)-EPOCH-R are standard. Dose-intensification of DA-EPOCH-R is guided by hematologic toxicity, without conclusive benefit for DHL/THL patients. To determine if cumulative doses of DA-EPOCH-R or compliance with dose adjustment impacts survival, we retrospectively evaluated detailed clinical data from 109 adult (age ≥18 years) patients with DHL/THL treated with ≥4 cycles of induction DA-EPOCH-R from 2014 to 2019 at six centers. A comprehensive multivariate analysis was performed. Survival outcomes for the entire cohort were comparable to historical estimates for DHL/THL treated with this regimen (median follow-up 27.9 months). Overall survival (OS) and progression-free survival (PFS) were not significantly associated with cumulative chemotherapy dose, dose escalation, or compliance with dose adjustment. Heterogeneous dosing practices were observed. Prospective investigation is warranted to evaluate the practice of dose adjustment of R-EPOCH for patients with DHL/THL.

Incidence and Management of Carfilzomib-induced Cardiovascular Toxicity; A Systematic Review and Meta-analysis.

BACKGROUND: The ASPIRE and ENDEAVOUR trials have shown cardiovascular adverse effects in patients treated with carfilzomib-based regimens. Therefore, we conducted this meta- analysis of published clinical trials to identify the cumulative incidence and risk of cardiovascular adverse effects due to carfilzomib. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed, and we identified 45 prospective trials of carfilzomib with data on 5583 patients. Among all patients being treated with carfilzomib (N=5,583), 8.9% sustained all grade cardiotoxicity, while 4.4% sustained high-grade cardiotoxicity. All-grade hypertension was present in 13.2%, while the incidence of high-grade hypertension was 5.3%. RESULTS: The observed incidences of all-grade heart failure, edema, and ischemia were 5.1%, 20.7%, and 4.6%, respectively. Likewise, for high-grade heart failure and edema observed incidence was 3.2%, and 2.7%, respectively. There was no difference in the event rate of all and highgrade cardiotoxicity between newly diagnosed multiple myeloma and relapsed/refractory (p-value 0.42 and 0.86, respectively). Likewise, we did not observe any difference in the event rate of all and high-grade cardiotoxicity when carfilzomib was used as a single agent versus when used in combination therapy with other agents (p-value 0.43 and 0.73, respectively). CONCLUSION: Carfilzomib is associated with a significant risk of cardiovascular toxicity and hypertension. With the increasing utilization of carfilzomib, it is critical for primary care physicians, oncologists and cardiologists to be aware of the risk of cardiotoxicity associated with the use of carfilzomib to recognize and treat baseline cardiovascular risk factors in such patients.

Eculizumab for transplant-associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients.

OBJECTIVE: To evaluate response rates and survival in adults with transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with eculizumab (ECU). METHODS: Patients were identified retrospectively and data collected through HSCT and pharmacy databases. RESULTS: Ten patients with TA-TMA after allogeneic HSCT were treated with ECU between 2013 and 2016. TA-TMA was diagnosed at a median of 93 days post-HSCT. Organ-specific injury was documented in all ten patients at time of TA-TMA diagnosis, the most common being renal dysfunction (90%). Acute GVHD (70%) and active infection (80%) were common at time of diagnosis. The median time to ECU initiation from TA-TMA diagnosis was 4 days. Seven patients received ECU as first-line therapy in combination with other treatment modalities, while three patients were treated with ECU as second-line therapy. ECU was well tolerated with the exception of one case of severe skin rash leading to discontinuation. ECU achieved an overall hematologic response rate of 70% and an overall survival rate of 60%. One patient achieved a complete response with corresponding organ recovery. CONCLUSION: Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.

A review of CD19-targeted immunotherapies for relapsed or refractory acute lymphoblastic leukemia.

Aim Novel immunotherapies have generated high response rates and unique adverse effects among patients with relapsed or refractory acute lymphoblastic leukemia. Therapies engaging endogenous T-cells against acute lymphoblastic leukemia are emerging for children and adults with various poor prognostic factors, thus accurate knowledge of immunotherapies is necessary for their effective implementation in the future. In this review, we evaluate clinical trial data regarding chimeric antigen receptor T-cells and blinatumomab, for the treatment of relapsed or refractory acute lymphoblastic leukemia. Summary In the relapsed or refractory setting, response rates rapidly diminish after subsequent lines of chemotherapy and cumulative toxicities may cause significant patient harm. Immunotherapies provide an approach to improve response rates and minimize traditional toxicities via novel mechanisms of action. Two therapies targeting CD19 antigens expressed on B-cell acute lymphoblastic leukemia lineages, chimeric antigen receptor T-cells, and blinatumomab have induced complete remissions among high-risk patient populations, especially those refractory to multiple therapies. Adverse effects such as cytokine release syndrome and neurologic sequelae remain serious precautions of each therapy. Conclusion Knowledge of immunotherapy mechanisms and clinical outcomes associated with immunotherapies is critical for the optimization of treating patients with relapsed or refractory acute lymphoblastic leukemia. Future use of chimeric antigen receptor T-cells and blinatumomab demands proper assessment of a patient's disease and treatment history in addition to unique monitoring and supportive care interventions.