Multicenter evaluation of the addition of eltrombopag to immunosuppressive therapy for adults with severe aplastic anemia.

Eltrombopag has been shown to improve response rates when added to standard therapy in adults with severe aplastic anemia in controlled trial settings. However, outcomes in real-world populations have mostly been examined in small retrospective studies. This robust, multicenter, retrospective cohort study across six academic health systems compared outcomes in patients who received immunosuppressive therapy with or without eltrombopag. The study included 82 patients who received front-line therapy from January 2014 to August 2021. Overall response rates at 6 months did not differ significantly for patients receiving eltrombopag versus immunosuppressive therapy alone (58% v. 65%, p = 0.56). However, complete response rates at 6 and 12 months were over two times higher in the eltrombopag arm (29% v. 12%, p = 0.06 and 48% v. 18%, p = 0.005). Rates of hepatotoxicity were similar across both arms. Eltrombopag addition did not impact overall survival (median not reached in either arm at 2 years, p = 0.86) or disease-free survival (median not reached v. 13.3 months at 2 years, p = 0.20). Eltrombopag may not produce as large of a benefit in real-world settings compared to controlled trial settings but may offer patients deeper responses with similar rates of toxicity to immunosuppressive therapy alone.

Outcomes with high dose cytarabine and mitoxantrone induction for adults with mixed phenotype acute leukemia.

The optimal induction strategy for mixed phenotype acute leukemia (MPAL) is unknown, though retrospective data has shown improved remission rates and overall survival with acute lymphoblastic leukemia (ALL)-based regimens. At Memorial Sloan Kettering Cancer Center (MSKCC), the most utilized induction regimen for MPAL is high dose cytarabine plus mitoxantrone ("ALL-2"), though outcomes with this regimen are not well described. In this study, outcomes to first-line induction chemotherapy in 24 patients at MSKCC with MPAL classified by 2016 World Health Organization criteria are reported. The overall response rate was 94 % (16 of 17) in patients receiving ALL-2, including 86 % (6 of 7) in patients with extramedullary disease. Thirteen patients who received ALL-2 induction proceeded to allogeneic hematopoietic cell transplant (allo-HCT). The most common toxicity associated with ALL-2 was febrile neutropenia, documented in 12 patients. With a median follow-up of 37 months, median overall survival was not reached in the ALL-2 cohort, and 3-year overall survival was 62 %. In multivariate analysis, age ≥ 60 years and MPAL with isolated extramedullary disease were associated with significantly worse overall survival (P = .009 and P = .01, respectively). These results support further prospective investigation of ALL-2 as a front-line induction regimen for adults with MPAL.

Multicenter comparison of first salvage chemotherapy versus novel therapy regimens in adult relapsed/refractory acute lymphoblastic leukemia.

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, Larson/CALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (p = .799). Similarly, there was no difference in the CR/CRi rate, with a CR/CRi in 18 patients (41.9%) versus 16 patients (47.1%) treated with salvage chemotherapy and novel therapy, respectively (p = .817). Age significantly impacted the probability of achieving CR/CRi with novel therapy versus chemotherapy. This analysis suggests the use of chemotherapy in first salvage still represents an appropriate treatment option, particularly for young fit patients, as the median OS was roughly 10 months regardless of whether patients received novel therapy or chemotherapy in first salvage. For the reported outcomes, 100% of patients in the novel therapy arm received a novel therapy (per design), whereas only 60.5% of patients in the chemotherapy arm required a novel therapy. Thus, 40% of patients did not require a novel therapy for similar OS. This analysis demonstrates that first-line chemotherapy can achieve similar results to novel therapies, especially now that novel therapies are available for subsequent relapses. However, this study has several limitations including younger age, increased CNS involvement, and higher blast percentage in the chemotherapy arm and potential confounders, including selection of treatment sequence as 43 patients (55.8%) ultimately received both chemotherapy and novel therapy. Therefore, a larger, prospective, randomized study with adequate chemotherapy comparators and availability of novel agents upon relapse is warranted to confirm these results.

Real-world management of targeted therapies in chronic lymphocytic leukemia.

The advent of novel targeted therapies, including B-cell receptor (BCR) pathway and B-cell lymphoma 2 (BCL2) inhibitors, has substantially changed the treatment paradigm for chronic lymphocytic leukemia (CLL). Although targeted therapies have improved outcomes compared to traditional chemoimmunotherapy in the front-line and relapsed or refractory settings, they are associated with resistance mutations and suboptimal outcomes in certain high-risk patients. Additionally, targeted therapies are associated with drug interactions and unique adverse effect profiles which can be challenging for patients and clinicians to manage. Ongoing studies continue to address questions regarding optimal sequencing of therapies, the role of treatment combinations, and the efficacy of next-generation novel agents. This review provides a comprehensive overview regarding the clinical management of targeted therapies for CLL and applies current literature to clinical practice.

Real-world comparison of immune checkpoint inhibitors in non-small cell lung cancer following platinum-based chemotherapy.

PURPOSE: Immunotherapy is a relatively new treatment modality for advanced non-small cell lung cancer following platinum-based chemotherapy. Nivolumab, pembrolizumab, and atezolizumab demonstrated superior outcomes and improved tolerability compared to standard treatment in randomized controlled trials; however, these studies vary significantly in inclusion criteria and study design. To our knowledge, the efficacy and safety of nivolumab and atezolizumab following platinum-based chemotherapy have not been directly compared to one another in a real-world clinic setting. METHODS: We retrospectively compared immunotherapy response rates and toxicity in patients with stage IV or recurrent non-small cell lung cancer following progression during or after platinum-based chemotherapy. RESULTS: Among 124 eligible patients, the objective response rate was 14.8% in the nivolumab group (n = 81) vs. 13.9% in the atezolizumab group (n = 43) (p = 0.897). Median overall survival was 8.4 months with nivolumab (95% confidence interval (CI), 6.3 to 11.2) vs. 6.5 months with atezolizumab (95% CI, 4.7 to not reached). Median progression free survival was 2.2 months (95% CI, 1.7 to 2.8) and 2.0 months (95% CI, 1.8 to 2.7) in the nivolumab and atezolizumab groups, respectively. Treatment-related adverse events occurred in 70.4% of patients in the nivolumab group and 65.1% in the atezolizumab group. CONCLUSIONS: There was no statistically significant difference in efficacy outcomes in patients with non-small cell lung cancer who received atezolizumab or nivolumab after progression during or after platinum-based chemotherapy. Response rates in this study were numerically lower than response rates observed in the landmark randomized controlled trials leading to approval of immunotherapy in this setting. Rates of treatment-related adverse events were similar between groups.

Impact of a vincristine dose cap on the incidence of neuropathies with DA-EPOCH-R for the treatment of aggressive lymphomas.

The CALGB/Alliance 50303 trial found a fivefold increase in the rate of severe neuropathies with DA-EPOCH-R compared to R-CHOP. A likely cause is a higher, uncapped dose of vincristine which is unique to DA-EPOCH-R. Due to a potential for increased toxicity and a paucity of literature confirming improved efficacy with higher vincristine doses, our institution implemented a 2 mg vincristine dose cap with DA-EPOCH-R. We conducted a single-center, retrospective cohort study assessing rates of neuropathy in patients receiving DA-EPOCH-R with or without a 2 mg vincristine dose cap. Patients who received a 2 mg vincristine dose cap had a significant reduction in the incidence of grade 2+ neuropathy (40.9% vs. 84.1%, p = .001) and a significantly longer time to onset of grade 2+ neuropathy (not reached vs. 63 days, p = .001). A vincristine dose cap of 2 mg per cycle may reduce the neurotoxicity-associated morbidity of DA-EPOCH-R.

Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia.

Internal tandem duplications and tyrosine kinase mutations in the fms-like tyrosine kinase 3 (FLT3) receptor can occur in acute myeloid leukemia (AML) and portend a poor prognosis. Midostaurin, a multikinase inhibitor that targets FLT3, demonstrated a survival benefit in FLT3-mutated AML in combination with front-line chemotherapy. Despite this advancement, the use of FLT3 inhibitors in clinical practice is complicated by significant drug-drug interactions and uncertainty about optimal timing, duration, and sequencing of therapy. As monotherapy, the utility of FLT3 inhibitors was initially limited by incomplete and transient clinical responses and the development of acquired resistance. This led to the development of more potent and selective FLT3 inhibitors designed to overcome common resistance mechanisms. One of these second generation FLT3 inhibitors, gilteritinib, is now FDA-approved for the treatment of relapsed or refractory AML. Now that multiple FLT3 inhibitors are commercially available, it is important to further delineate the role of these agents in the AML population. This review aims to provide a comprehensive overview of the role of FLT3 inhibitors in AML and apply the current literature to clinical practice.