Primary resistance to tyrosine kinase inhibitors (TKIs) is a significant barrier to optimal outcomes in chronic myeloid leukemia (CML), but factors contributing to response heterogeneity remain unclear. Using single-cell RNA (scRNA) sequencing, we identified 8 statistically significant features in pretreatment bone marrow, which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis [BC] transformation). Employing machine-learning, we identified leukemic stem cell (LSC) and natural killer (NK) cell gene expression profiles predicting imatinib response with >80% accuracy, including no false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor [ERP] expansion in vivo (P < .05), and a 2- to 10-fold (6.3-fold in group A vs 1.09-fold in group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared with myeloid progenitors (P < .001). These LSC features were lost with progressive resistance, and MYC- and IRF1-driven inflammatory regulons were evident in patients who progressed to transformation. Patients with MMR also exhibited a 56-fold expansion (P < .01) of a normally rare subset of hyperfunctional adaptive-like NK cells, which diminished with progressive resistance, whereas patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance. Finally, we developed antibody panels to validate our scRNA-seq findings. These panels may be useful for prospective studies of primary resistance, and in assessing the contribution of predetermined vs acquired factors in TKI response heterogeneity.

Patients with chronic lymphoid leukemia (CLL), even in the Omicron era and after vaccination, suffer from persistent COVID-19 infection, higher complications, and mortality compared with the general population. In this study, we evaluated retrospectively the effectiveness of nirmatrelvir + ritonavir among 1080 patients with CLL who were infected with severe acute respiratory syndrome coronavirus 2. Nirmatrelvir administration was associated with a reduction in COVID-19-related hospitalization or death by day 35. Specifically, the rate of COVID-19-related hospitalization or death in the treated group compared with the untreated group was 4.8% (14 out of 292) vs 10.2% (75 out of 733), respectively. Moreover, we report a 69% relative risk reduction in COVID-19-related hospitalization or death in patients with CLL at the age of ≥65 years. Multivariate analysis indicates that patients aged >65 years, patients who received heavy treatment (>2 previous treatments), patients with recent hospitalizations, intravenous immunoglobulin (IVIG) treatment, and comorbidity had significant improvement outcomes after treatment with nirmatrelvir.

Chimeric antigen receptor (CAR) T cells have transformed the care for patients with hematologic malignancies. Patients treated with CAR T cells may experience cardiovascular and pulmonary complications, which primarily occur in the setting of cytokine release syndrome. In addition, many patients considered for CAR T-cell therapy have preexisting cardiac and pulmonary comorbidities. Among patients with good functional status, these conditions should not prevent patients from being offered these lifesaving therapies. In this article, we use a case-based approach to discuss how we evaluate and optimize conditions for patients with cardiac and pulmonary risk factors before CAR T-cell therapy and manage cardiac and pulmonary complications that may arise with treatment.

Systemic steroids are the standard first-line treatment for acute graft-versus-host disease (aGVHD), but ∼50% of patients become steroid-refractory or dependent (SR/D). Ruxolitinib is the only Food and Drug Administration- and European Medicines Agency-approved therapy for patients with SR/D aGVHD. In the phase 3 REACH2 trial (NCT02913261), ruxolitinib demonstrated superior efficacy in SR/D aGVHD, with a significantly higher overall response rate (ORR) on day 28, durable ORR on day 56, and longer median overall survival compared with the best available therapy (BAT). Identifying biomarkers and clinical characteristics associated with increased probability of response can guide treatment decisions. In this exploratory analysis of the REACH2 study (first biomarker study), we developed baseline (pretreatment) and day 14 models to identify patient characteristics and biomarkers (12 aGVHD-associated cytokines/chemokines, 6 immune cell types, and 3 inflammatory proteins) before and during treatment, which affected the probability of response at day 28. Treatment with ruxolitinib, conditioning, skin involvement, and age were strongly associated with an increased likelihood of response in the ≥1 model. Lower levels of most aGVHD and immune cell markers at baseline were associated with an increased probability of response. In the day 14 model, levels of aGVHD markers at day 14, rather than changes from baseline, affected the probability of response. For both models, the bias-corrected area under the receiver operating characteristic values (baseline, 0.73; day 14, 0.80) indicated a high level of correspondence between the fitted and actual outcomes. Our results suggest potential prognostic value of selected biomarkers and patient characteristics.

With the global growing older adult population, clinicians face the common, yet complex challenge of how to evaluate and manage anemia in this population. Older age predisposes to common causes of anemia such as nutritional deficiencies, inflammatory disorders, chronic kidney disease, and hematologic malignancies. Failure to diagnose and appropriately manage anemia may result in decreased quality of life, impaired cognition, impaired mobility, and increased mortality. Anemia diagnosis in older adults presents a diagnostic conundrum because anemia may have a single cause, may be multifactorial, or may have no apparent cause even after an extensive evaluation. We believe a systematic approach to diagnosis ensures appropriate testing and avoids the pitfall of undertreatment and overtreatment. In this article we present our recommended approach through common scenarios for the management of anemia in the older adult.

The benefit associated with the incorporation of vincristine-corticosteroid pulses in maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing the frequency of vincristine-steroid pulses during maintenance for pediatric patients newly diagnosed with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from 25 publications (12 513 patients), and assessed the risk of bias. We created historical and contemporary subgroups; the latter included trials providing both a version of Protocol III from the early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.85-1.09), which differed significantly from historical trials (HR, 0.79; 95% CI, 0.68-0.91; P = .04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however increased odds of grade 3+ nonhepatic toxicity in the high-pulse frequency group (odds ratio, 1.31; 95% CI, 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide the development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance among patients not in clinical trials, particularly those experiencing toxicity.

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.

Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.

Hematopoietic stem cells (HSCs) are assumed to be rare, infrequently dividing, long-lived cells not involved in immediate recovery after transplantation. Here, we performed unprecedented high-density clonal tracking in nonhuman primates and found long-term persisting HSC clones to actively contribute during early neutrophil recovery, and to be the main source of blood production as early as 50 days after transplantation. Most surprisingly, we observed a rapid decline in the number of unique HSC clones, while persisting HSCs expanded, undergoing symmetric divisions to create identical siblings and formed clonal pools ex vivo as well as in vivo. In contrast to the currently assumed model of hematopoietic reconstitution, we provide evidence for contribution of HSCs in short-term recovery as well as symmetric expansion of individual clones into pools. These findings provide novel insights into HSC biology, informing the design of HSC transplantation and gene therapy studies.

Human T-cell leukemia virus type 1 (HTLV-1), also known as human T-lymphotropic virus type 1, causes the aggressive malignancy known as adult T-cell leukemia/lymphoma (ATL) in 5% of infected people and a chronic progressive inflammatory disease of the central nervous system, HTLV-1-associated myelopathy, in ∼0.3% to 4% of them, varying between regions where it is endemic. Reliable treatments are lacking for both conditions, although there have been promising recent advances in the prevention and treatment of ATL. Because ATL typically develops after several decades of infection, it is necessary to understand how the virus persists in the host despite a strong immune response, and how this persistence results in oncogenesis.