Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.

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.

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%. Result: 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 high-grade 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.

No abstract

BACKGROUND: High-grade B-cell lymphomas (HGBLs) with rearrangement of MYC and BCL2 and/or BCL6, known as "double-hit" or "triple-hit" B-cell lymphomas (DHL/THL), are an aggressive sub-type of non-Hodgkin mature B-cell lymphoma with chromosomal rearrangements involving MYC with BCL2 and/or BCL6 genes. DHL/THLs typically have poor outcomes and early relapses with first-line R-CHOP, and intensive induction chemoimmunotherapy regimens are associated with improved outcomes. Infusional dose-adjusted (DA)-R-EPOCH is commonly used, yet there is a lack of clear evidence that dose-adjustment enhances survival, and variations in compliance with dose-adjustment exist. DA-R-EPOCH has been incorporated as the backbone of prospective clinical trials testing the addition of novel agents for frontline management of DHL/THL, and these combinations may lead to a greater degree of myelosuppression that may disrupt dose-adjustments and hinder dose-escalations relative to using DA-R-EPOCH alone. Therefore, we sought to determine if patients with DHL/THL treated with induction DA-R-EPOCH have differences in clinical outcomes (OS, PFS, treatment-related adverse events and others) based upon compliance with dose-adjustment and cumulative doses of R-EPOCH administered. METHODS: Adult (age ≥18 years) patients with DHL/THL treated with induction DA-R-EPOCH chemoimmunotherapy from 2014 to 2019 at six collaborating medical centers were included in this study. To be included, patients must be without CNS-involvement at diagnosis, have received ≥4 cycles of DA-R-EPOCH, have adequate clinicopathologic data regarding chemoimmunotherapy dosing, survival, treatment response/remission status, cell counts, CNS and antimicrobial prophylaxis, admissions for cytopenias or IV antibiotics, and demographic data including age, international prognostic index (IPI), CNS-IPI, ECOG performance status, and cumulative illness rating score (CIRS, if available). An initial cycle of R-CHOP was permitted. De-identified data from participating sites were combined, and chemotherapy doses were aggregated and divided into quartiles based on cumulative doses of doxorubicin, etoposide, and cyclophosphamide received. Correlation between CIRS and dose was assessed by Spearman's correlation. OS and PFS were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: 109 total patients were included in this study. The median age was 63 years (range 29-83), and approximately 60% of patients were male, 58% were age 60 or older, 60% had an IPI score of ≥3, and 66% were Ann Arbor Stage IV at induction. For all patients, 2-year and 5-year OS rates were 75% (95% CI: 67-84%) and 70% (59-82%), with 27 total deaths in the study period. 2-year and 5-year PFS rates were 65% (56-75%) and 60% (49-72%), respectively. 94 of 109 patients received CNS prophylaxis (86%). 26 patients had received an initial cycle of R-CHOP (24%). PFS and OS were significantly worse for patients with higher risk IPI score (P = 0.03, 0.04, respectively), but there was no difference in PFS or OS based on CIRS score (P = 0.70, 0.60, respectively). 75 patients (68.8%) were dose-escalated while 34 patients (31.2%) were not; there was no difference in PFS (Fig 1) or OS (Fig 2) between these groups. When stratified by cumulative dose-level in quartiles, those who received the lowest cumulative doses (1st quartile) had a significantly reduced OS (1st, 2nd, 3rd and 4th quartile 2-year OS of 55%, 75%, 85%, and 84%, P = 0.046). Cause of death was largely from disease progression (74%), with only one treatment-related death in each dosing quartile. Dose intensity was not correlated with baseline CIRS score (R = -0.06, P = 0.56), but did correlate negatively with IPI (R = 0.22, P = 0.04). CONCLUSIONS: OS and PFS did not differ for DHL/THL patients treated with R-EPOCH with dose-escalation in at least one cycle as compared to those with no dose-escalation. Although cumulative doses beyond the 1st quartile were associated with improved OS, there was no significant difference between 2nd, 3rd and 4th quartiles. Dose-escalation was negatively associated with IPI scores but not CIRS scores. Further investigation into factors affecting adherence to dose-adjustment is warranted. The effect of adding novel agents to the DA-R-EPOCH backbone on dose-adjustment and cumulative doses of chemotherapeutic agents received should be evaluated in prospective clinical trials. Disclosures Haverkos: Viracta THerapeutics: Consultancy. Hughes:Acerta Pharma and HOPA: Research Funding; AstraZeneca: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Grover:Genentech: Research Funding; Tessa: Consultancy. Portell:Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy. Voorhees:AstraZeneca: Research Funding. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Kahl:Genentech: Consultancy; Pharmacyclics LLC: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Roche Laboratories Inc: Consultancy; Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.