Q2 2022: Additional information and data in acute leukemia

May 27, 2022


Continued and posttransplant gilteritinib maintenance therapy was associated with sustained remission, led to better long-term survival than salvage chemotherapy, and featured an acceptable side effect profile over two years in patients with relapsed or refractory FLT3-mutation-positive AML. These findings need to be confirmed in larger trials as limitations of the study included the small number of patients who were assessed for pretransplant and posttransplant outcomes as well as the lack of a second randomization period and a placebo arm. (Ref: Perl AE, Larson RA, Podoltsev NA, et al. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial [published online ahead of print, 2022 Jan 26]. Blooddoi: 10.1182/blood.2021011583.)

Bleeding can be a significant concern that causes early morbidity and mortality in this patient group, so finding a way to identify those who are at the highest risk could aid in the development of strategies to improve overall patient outcomes. Pre-treatment risk factors were identified consistent with DIC-like [disseminated intravascular coagulation] coagulopathy, which predict grade 4 bleeding in patients with AML receiving intensive induction chemotherapy. (Ref: Versluis J, Pandey M, Flamand F, et al. Prediction of life-threatening and disabling bleeding in patients with AML receiving intensive induction chemotherapy [published online ahead of print, 2022 Jan 28]. Blood Adv. doi: 10.1182/blood​advances.2021006166.)

A combination regimen comprising venetoclax plus azacitidine appears to have similar efficacy as a frontline strategy for treatment-naïve patients with AML irrespective of FLT3 mutation status. A study showed that the combination approach was superior to azacitidine alone in terms of remission and survival regardless of whether FLT3 mutations were present. (Ref. Konopleva M, Thirman MJ, Pratz KW, et al. Impact of FLT3 mutation on outcomes after venetoclax and azacitidine for patients with treatment-naïve acute myeloid leukemia [published online ahead of print, 2022 Jan 21]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-21-3405.)

CAR-T cell therapy

A recent study showed that optimal (higher) fludarabine exposure before CD19-specific CAR T-cell therapy (tisagenlecleucel) in pediatric and young adult patients with R/R B-ALL is associated with lower relapse probability. This analysis should be replicated with other CAR T-cell products that use fludarabine-based LDC to identify the optimal fludarabine exposure for individual products. (Ref. https://doi.org/10.1182/bloodadvances.2021006418)

The addition of fludarabine to cyclophosphamide as a lymphodepleting regimen prior to CD19 CAR T-cell therapy significantly improved outcomes in patients with relapsed/refractory (r/r) B-cell ALL. Fludarabine exposure, previously shown to be highly variable when dosing is based on body surface area, is a predictor for survival in allogeneic hematopoietic cell transplantation. A study showed that one of the first identified controllable predictors for outcome, a fludarabine cumulative AUCT0−∞ ≥14 mg*h/L showed a strong correlation with improved leukemia-free survival and a lower incidence of both CD19-positive relapse and B-cell recovery. Optimization of fludarabine exposure in each individual patient, using therapeutic drug monitoring in the lymphodepleting regimen, may improve CD19 CAR T-cell persistence and clinical outcome of currently available commercial CAR T therapies. (Ref. https://doi.org/10.1182/bloodadvances.2021006700)

CD19-targeted CAR T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. Results of a study showed that pre-lymphodepletion blood counts, CRS severity and CRS-related cytokines independently affected hematopoietic recovery after CD19 CAR T-cell therapy. It also suggests that both patient selection and advancing CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy. (Ref. https://doi.org/10.1182/bloodadvances.2020004142)


Drug resistance and treatment failure in pediatric acute lymphoblastic leukemia (ALL) are in part driven by tumor heterogeneity and clonal evolution. Although bulk tumor genomic analyses have provided some insight into these processes, single-cell sequencing has emerged as a powerful technique to profile individual cells in unprecedented detail. Since the introduction of single-cell RNA sequencing, we now have the capability to capture not only transcriptomic, but also genomic, epigenetic, and proteomic variation between single cells separately and in combination. This rapidly evolving field has the potential to transform our understanding of the fundamental biology of pediatric ALL and guide the management of ALL patients to improve their clinical outcome. Here, we discuss the impact single-cell sequencing has had on our understanding of tumor heterogeneity and clonal evolution in ALL and provide examples of how single-cell technology can be integrated into the clinic to inform treatment decisions for children with high-risk disease. (Ref: https://journals.lww.com/hemasphere/Fulltext/2022/06000/The_Promise_of_Single_cell_Technology_in_Providing.14.aspx)

COVID-19 and cancer care

The American Association for Cancer Research (AACR) recently released a report that details the ways COVID-19 has affected cancer research and patient care and announces several initiatives to fully understand and mitigate these effects. Among the key negative effects highlighted in the report are significant delays in routine cancer screenings and impaired referrals for preliminary cancer diagnoses, which led to more patients being diagnosed with metastatic or inoperable cancers. If not reversed, this trend could increase future cancer morbidity and mortality. Severe disruptions in cancer research also occurred, resulting in lab closures, decreased participation in clinical trials, and loss of career opportunities among researchers.

The pandemic necessitated several patient-centric changes to cancer clinical trials, such as video visits.

The report also details how the cancer community pivoted to continue providing care to patients and the benefits of maintaining these types of care. For example, dramatic increases in telehealth during the pandemic led to 43% of users wanting to continue using this tool in the future. The pandemic also necessitated several patient-centric changes to cancer clinical trials, such as video visits, pharmaceutical shipments, and the relocation of scanning and testing sites to be more convenient to patients.

A major advance wrought by the success of the mRNA-based technology used to develop COVID-19 vaccines is renewed interest in applying this technology to the development of cancer vaccines.

Source: American Association for Cancer Research, February 9, 2022.