Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma.

PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients.

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study.

Hematotoxicity after chimeric antigen receptor (CAR) T-cell therapy is associated with infection and death but management remains unclear. We report results of 31 patients receiving hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic) for either sustained severe neutropenia of grade 4 (<0.5 × 109/L), sustained moderate neutropenia (≤1.5 × 109/L) and high risk of infection, or neutrophil count ≤2.0 × 109/L and active infection. Median time from CAR T-cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia before HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia (P = .007). All nonresponders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia (≤38 days; 85%) vs neutropenia >38 days before HSCB (44%; P = .029). In conclusion, early or prophylactic HSCB showed quick response and improved outcomes for sustained moderate to severe neutropenia after CAR-T.

Impact of Elevated LDH on Cystatin C-Based Glomerular Filtration Rate Estimates in Patients with Cancer.

Background: The determination of renal function is crucial for the clinical management of patients with cancer. The glomerular filtration rate (GFR) serves as a key parameter, estimated by creatinine clearance determination in 24-h collected urine (CrCl) as well as equation-based approaches (eGFR) relying on serum creatinine (eGFR CKD EPIcrea) or serum cystatin C (eGFR cystatin C). Serum creatinine and serum cystatin C levels differentially depend on muscle and tumor mass, respectively. Although muscle and tumor mass may thus represent confounding factors, comparative studies for eGFR estimate approaches in cancer patients are lacking. Methods: The present study retrospectively analyzed GFR estimates based on equations of creatinine (eGFRcr), cystatin C (eGFRcys) and combined creatinine-cystatin C levels (eGFRcr-cys) in a subset of patients. The associations of LDH with cystatin C or LDH with eGFRcr, eGFRcys and GFRcr-cys were explored. Results: The laboratory values of 123 consecutive patients were included. The median age was 59 (24−87) and 47.2% were female. There was a statistically significant difference in the mean of CKD EPIcrea (85.17 ± 21.63 mL/min/1.73 m2), CKD EPIcys (61.16 ± 26.03 mL/min/1.73 m2) and CKD EPIcrea-cys (70.42 ± 23.89 mL/min/1.73 m2) (p < 0.0001). Spearman's correlation analysis revealed a significant correlation of elevated plasma LDH >1.5 UNV and cystatin C values (r = 0.270, p < 0.01, n = 123). LDH values >1.5 UNV were associated with significantly lower CKD EPIcys (r = 0.184, p < 0.01) or CKD EPIcrea-cys (r = 0.226, p < 0.05) estimates compared to CKD EPIcrea. Conclusions: The inclusion of cystatin C as a biomarker led to a lower eGFR estimates compared to creatinine alone or in a combination of both cystatin C and creatinine. The level of cystatin C correlated with the level of LDH, suggesting that the use of cystatin C-based calculations of GFR in cancer patients with elevated LDH should be used with caution.

Sarcoidosis Following Hematopoietic Stem Cell Transplantation: Clinical Characteristics and HLA Associations.

Purpose: Extrinsic factors and genetic predisposition contribute to the etiology of sarcoidosis, converging in a phenotype of altered immune response associated with multisystemic inflammatory granulomatous tissue infiltration. Immunological reconstitution after hematopoietic stem cell transplantation (HSCT) may represent a unique window for the pathogenesis of the disease. We describe the incidence, clinicopathological features, and HLA associations of sarcoidosis after HSCT in a single-center cohort of patients, together with data from previously published cases. Methods: We retrospectively analyzed clinical characteristics and HLA haplotypes from allogeneic (allo) or autologous (auto) HSCT patients from January 2001 through May 2021 at the University Medicine Goettingen (UMG), and data from previously published cases. Results: A total number of 19 patients was identified. These included 4 patients from our center (3 allo HSCT and 1 auto HSCT) and 15 patients from the literature review. Thirteen patients had received an allo HSCT, and six patients had received an auto HSCT. Sarcoidosis occurred after a median interval of 20 (after allo HSCT) and 7 (after auto HSCT) months, respectively. The predominant HLA allele associated with sarcoidosis was HLA DRB1*03:01. Sarcoidosis involved the respiratory tract in 15 patients (three unknown, one without pulmonary involvement), and it was associated with graft-versus-host disease in 7 of 13 patients receiving allo HSCT. None of the donors or patients had a history of sarcoidosis before transplantation. Disease manifestations resolved with standard glucocorticoid treatment without long-term sequelae. Conclusion: Sarcoidosis may occur at low frequency during reconstitution of the immune system after HSCT. HLA allele associations reflect the associations observed in the general population, particularly with DRB1*03:01. Further insights into the interplay between Tcell reconstitution and the development of sarcoidosis could also provide novel approaches to an improved understanding of the pathogenesis in sarcoidosis.

Patterns of Late Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with T-Cell Prolymphocytic Leukemia.

Initial treatment with the monoclonal anti-CD52 antibody alemtuzumab induces responses in the majority of patients with T-cell prolymphocytic leukemia (T-PLL). In eligible patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an option to consolidate hematological remissions. Here, we report our experience with 10 patients who received allo-HSCT against T-PLL. Notably, 3 patients with complete remission at transplantation and durable full-donor chimerism relapsed at months 12, 59, and 84 after transplantation, respectively. This relapse was associated with rapid progressive leukemia in 1 patient and extralymphatic lymphoma growth in the other 2. Despite CD52 positivity at relapse, alemtuzumab retreatment, donor lymphocyte infusions, and/or chemotherapy including salvage therapy, allo-HSCT yielded a transient partial response, only. Alemtuzumab induction and consolidative allo-HSCT enabled prolonged disease-free survival in these patients but failed to procure cure.