Q4 2022: Additional information and data in acute leukemia
This article by Larkin and colleagues describes a detailed analyses of survival differences between non-Hispanic Black adolescent and young adult (AYA) patients with AML vs non-Hispanic White patients. The authors compared non-Hispanic Black AYA patients with AML with non-Hispanic White patients treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. The authors compared early (<30 days) death rate, complete remission rate, and overall survival between the 2 groups, and they performed between-groups survival analyses across cytogenetic strata. They found that the outcome of Black AYA patients, especially those aged 18-29 years, was worse than the outcome of White patients receiving similar intensive therapy. The investigators concluded that reduced response rates to induction chemotherapy and leukemic clone persistence suggest a need for different treatment intensities and/or modalities in Black AYA patients with AML. They also call for a systematic change to patient care because of higher early death rates that are suggestive of a delay in diagnosis and treatment. Full article here.
The phase 3 QUAZAR AML-001 trial demonstrated that oral azacitidine (Oral-AZA) prolongs survival in patients with AML in remission after chemotherapy who are not candidates for stem cell transplantation. Döhner et al report on a subgroup analysis of Oral-AZA in patients with nucleophosmin 1 (NPM1) and FMS-related tyrosine kinase 3 (FLT3) mutations. Median survival is improved in all subgroups of patients with NPM1 or FLT3 mutations (alone or together) independent of other risk facts or measurable residual disease postinduction. Full article here or listen to podcast by clicking this link.
Wang et al present the results of a phase 3 study comparing gilteritinib plus azacitidine (GIL+AZA) to azacitidine alone (AZA) in newly diagnosed FLT3-mutated AML in patients ineligible for intensive induction therapy. GIL+AZA yielded higher remission rates, but neither event-free survival nor overall survival were significantly different, leading to the cessation of the trial for futility. Different approaches are required for unfit patients with FLT3-mutated AML. Full article here
Outcomes of older and unfit adults with AML differ significantly from their younger counterparts, owing to their adverse disease biology (complex karyotype, antecedent myelodysplastic syndrome) and age-related comorbidities.1 Recently, venetoclax-based lower intensity therapies were approved for newly diagnosed AML in older (aged ≥75 years) adults and/or those not eligible for intensive chemotherapy. Full article here
Restults from the Phase III ASAP trial: This is the first randomized controlled trial, which questioned the benefit of intensive remission induction CT prior to alloHCT for pts with r/r AML. Chemotherapy with high-dose cytarabine and mitoxantrone before alloHCT did not result in a higher overall success rate and did not confer a survival advantage. Watchful waiting followed by sequential conditioning and alloHCT resulted in comparable overall CR rates and survival. These data support sequential conditioning and alloHCT without prior remission induction CT whenever a stem cell donor is readily available. Finally, these results underline the importance of facilitating alloHCT as most effective anti-leukemic therapy in patients with r/r AML and stress the need for starting donor search at diagnosis. Full article here
Classification in AML: Existing classification and risk-stratification is primarily reliant on cytogenetic findings, which are present in less than half of patients with AML. A new research used 16 molecular subgroups of AML, classifies patients into three risk strata stratifies one in four patients with AML and achieves significant improvement in prognostic accuracy. Article here.
With the complex nature of NPM1mut AML, researchers developed a machine learning algorithm to identify as many as four combinations of co-mutated genes that could potentially affect overall survival. Results also demonstrated several independent prognostic factors, including a revised NPM1mut model, secondary or therapy-related AML, age over 60 years, and male gender. Article here.
Azacitidine and venetoclax (AZA-VEN) therapy in treatment-naïve AML is associated with toxicities, which often results in dose reductions. A study shows that reduced venetoclax exposure in AZA-VEN combination therapy for patients with treatment-naïve AML is efficient. The researchers noted their proposed 7+7 scheme of AZA-VEN compared favorably to the recommended 7+28 scheme. Though significant toxicity occurred even with reduced venetoclax exposure, subsequent dose reductions may be associated with favorable outcomes. Article here.
In the video, an updated analysis of the completed phase Ib portion of the study of ivosidenib combined with venetoclax, either with/without azacitidine, presented at ASCO 2022 is given. Lachowiez outlines the study design and enrollment criteria, then goes on to discuss adverse effects and response rates for the different patient groups. Finally, Lachowiez describes findings on IDH-1 clearance rates, overall survival, MRD, and the upcoming phase II expansion cohorts.
Bispecific antibodies retargeting T cells to malignant cells are emerging as highly effective options for several B-cell malignancies, but tumor heterogeneity and antigen loss reduce their effectiveness. Zhao et al tackle these problems by designing a trispecific antibody that can retarget T cells to cells expressing either CD19 or CD22 or both and demonstrates superior activity in vitro and in vivo over bispecific antibodies when the malignant cells express both antigens in preclinical models. The authors’ work holds potential promise as a new approach against B-cell acute lymphoblastic leukemia (B-ALL) when CD19 expression is heterogeneous. Full article here
Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive disease with suboptimal treatment options and a poor prognosis. Much of the literature derives from Japanese populations; however, ATLL is also seen in the Caribbean and amongst Caribbean immigrants to North America where recent reports highlight disparate prognostic and mutational profiles. This report by Zhao et al explores key transcriptional regulators between Japanese and North American ATLL cell lines and identifies ETS1 as a novel dominant oncogenic transcriptional regulator with overexpression in North American cell lines compared to Japanese cell lines. This distinction may identify novel treatment approaches for North American/Caribbean ATLL. Read full article here
Socioeconomic challenges in diagnosis and treatment of patients with ALL: some research highlight the significant impact of socioeconomic variables, including neighborhood SES, income, parental education, distance from treatment center, and occupation on disease outcomes in ALL. There is limited research on the socioeconomic challenges in adult populations across the cancer continuum and its underlying mechanisms, as well as diagnosis in both HMIC and LMIC settings and various age groups, thus there is a need for more conclusive research to better guide disease management. Read article here.
EZH2 drives retinoic acid resistance of variant APL: Cancer cell heterogeneity is a major driver of therapy resistance. To characterize resistant cells and their vulnerabilities, we studied the PLZF-RARA variant of acute promyelocytic leukemia, resistant to retinoic acid (RA), using single-cell multiomics. We uncovered transcriptional and chromatin heterogeneity in leukemia cells. We identified a subset of cells resistant to RA with proliferation, DNA replication, and repair signatures that depend on a fine-tuned E2F transcriptional network targeting the epigenetic regulator enhancer of zeste homolog 2 (EZH2). Epigenomic and functional analyses validated the driver role of EZH2 in RA resistance. Targeting pan-EZH2 activities (canonical/noncanonical) was necessary to eliminate leukemia relapse-initiating cells, which underlies a dependency of resistant cells on an EZH2 noncanonical activity and the necessity to degrade EZH2 to overcome resistance. Our study provides critical insights into the mechanisms of RA resistance that allow us to eliminate treatment-resistant leukemia cells by targeting EZH2, thus highlighting a potential targeted therapy approach. Beyond RA resistance and acute promyelocytic leukemia context, our study also demonstrates the power of single-cell multiomics to identify, characterize, and clear therapy-resistant cells. Article can be found here.
CAR T-cell therapy
Through clinical correlative analyses, Ghobadi and colleagues describe a novel genomic modification outside of the transmembrane and antigenic domains of CD19 that drives resistance to CD19-targeted immunotherapies. This new mechanism of antigen escape adds to the growing understanding of resistance to CAR T-cell therapy. Article here.
When the hematologist becomes the patient…
Here are three lessons I learned as a hematologist from being a patient:
- Be comfortable sitting with uncertainty.
- Offer silence as a gift to allow your patient to genuinely share deep fears.
- Recognize the inevitable ambiguity and polarized emotions that arise around questions of mortality.
Although our expertise as hematologists is needed during active chemotherapy, our compassion as healers is just as essential to help patients navigate the transition after therapy, when the emotional impact often comes to the fore.
Full article here.
Patient and physician perceptions of palliative care during transplant:
Patient and physician perceptions of what palliative care can offer may differ. Transplant patients with no direct experience with palliative care may not understand what it can offer in terms of symptom management and advance care planning. However, as patients are more likely to utilize palliative care during their transplant after receiving a consultation, increasing knowledge of palliative care in patients undergoing transplant may result in a wider uptake. Ending the stigma around palliative care and improving the relationship between healthcare professionals and their patients could also mean more patients becoming accepting of palliative care. In addition, the quality of palliative care consultations could be improved by increasing physician comfort in explaining diagnoses; this could be done by increasing clinical experience with HSCT and promoting relationships between palliative care physicians and hematologists.
Full article here.