•Tisagenlecleucel responses in patients with r/r FL remain highly durable a year after primary analysis; no new safety signals were observed.•Low levels of LAG3+CD3+ exhausted T cells and higher ...levels of naïve CD8+ T cells were significantly associated with improved outcomes.
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Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor–positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval CI, 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.
Dreyling et al report on longer-term follow-up of the phase 2 ELARA trial of tisagenlecleucel (tisa-cel) for treatment of relapsed/refractory (R/R) follicular lymphoma (FL) in third-line or later therapy. They report on 97 patients treated with tisa-cel for R/R FL that relapsed after autologous transplantation. Median progression-free survival, duration of response, and overall survival were not reached after a median follow-up of 29 months, confirming durable efficacy, especially in patients achieving complete remission. Low levels of exhausted T cells and high levels of naïve CD8+ T cells predicted better outcomes.
Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients ...with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS hazard ratio 1.5 (1.1-2.2), p = 0.02. The median overall survival was 14.8 months 95% CI: 9-Not reached (NR) vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel. Keywords: BCMA CAR-T, Ide-cel, Relapsed/refractory myeloma, Radiation, Immunotherapy
Survivorship Care Plans (SCPs) may facilitate long-term care for cancer survivors, but their effectiveness has not been established in hematopoietic cell transplantation recipients. We evaluated the ...impact of individualized SCPs on patient-reported outcomes among transplant survivors. Adult (≥18 years at transplant) survivors who were 1-5 years post transplantation, proficient in English, and without relapse or secondary cancers were eligible for this multicenter randomized trial. SCPs were developed based on risk-factors and treatment exposures using patient data routinely submitted by transplant centers to the Center for International Blood and Marrow Transplant Research and published guidelines for long-term follow up of transplant survivors. Phone surveys assessing patient-reported outcomes were conducted at baseline and at 6 months. The primary end point was confidence in survivorship information, and secondary end points included cancer and treatment distress, knowledge of transplant exposures, health care utilization, and health-related quality of life. Of 495 patients enrolled, 458 completed a baseline survey and were randomized (care plan=231, standard care=227); 200 (87%) and 199 (88%) completed the 6-month assessments, respectively. Patients' characteristics were similar in the two arms. Participants on the care plan arm reported significantly lower distress scores at 6 months and an increase in the Mental Component Summary quality of life score assessed by the Short Form 12 (SF-12) instrument. No effect was observed on the end point of confidence in survivorship information or other secondary outcomes. Provision of individualized SCPs generated using registry data was associated with reduced distress and improved mental domain of quality of life among 1-5 year hematopoietic cell transplantation survivors. Trial registered at
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Background
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for various hematologic disorders. Alternative donor strategies such as mismatched unrelated ...donors (MMUD) offer the option of HSCT to patients lacking a human leukocyte antigen (HLA)-matched donor. We conducted a systematic review and meta-analysis to evaluate outcomes after MMUD-HSCT.
Methods
A literature search was performed on PubMed, Cochrane Library, and ClinicalTrials.gov from the inception date through April 6, 2022. After screening 2477 manuscripts, 19 studies were included. Data was extracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed.
Results
A total of 3336 patients from 19 studies were included. The median age was
52.1
years, and 53% of recipients were males. The graft source was bone marrow in 19% and peripheral blood stem cells in 81% of recipients. The median time to transplant from hematologic diagnosis was 10 (1-247) months. Hematologic diagnoses included myeloid (82.9%), lymphoid (41.1%), and other disorders (3%). The reduced intensity and myeloablative conditioning were used in 65.6% and 32% of recipients, respectively.
In-vivo
T-cell depletion was performed in 56.7% of the patients. Most patients had one (87.9%) or two (11.4%) antigen HLA-mismatch. The pooled 1-year overall survival (OS) was 63.9% (95% CI 0.57-0.71, n=1426/2706), and the pooled 3-year OS was 42.1% (95% CI 0.34.2-0.50, n=907/2355). The pooled progression-free survival was 46.6% (95% CI 0.39-0.55, n=1295/3253) after a median follow-up of 1.8 (range 1-6) years. The pooled relapse rate was 26.8% (95% CI 0.22-0.32, n=972/3253) after a median follow-up of 2.25 (1-3) years. The pooled incidence of acute (grade II-IV) graft-versus-host disease (GVHD) and chronic GVHD was 36.4% (95% CI 0.31-0.42, n=1131/3030) and 41.2% (95% CI 0.35-0.48, n=1337/3228), respectively. The pooled non-relapse mortality was 22.6% (95% CI 0.17-0.29, n=888/3196) after a median follow-up of 2.6 (1-5) years.
Conclusion
MMUD-HSCT has demonstrated favorable outcomes with an acceptable toxicity profile. It represents a promising option in patients lacking an HLA-matched or haploidentical donor and may expand HSCT access to underrepresented racial and ethnic populations.
Background
Natural killer (NK) cells play a vital role in early immune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT).
Methods
A literature search was performed on ...PubMed, Cochrane, and Clinical trials.gov through April 20, 2022. We included 21 studies reporting data on the impact of NK cells on outcomes after HSCT. Data was extracted following the PRISMA guidelines. Pooled analysis was done using the meta-package (Schwarzer et al.). Proportions with 95% confidence intervals (CI) were computed.
Results
We included 1785 patients from 21 studies investigating the impact of NK cell reconstitution post-HSCT (8 studies/1455 patients), stem cell graft NK cell content (4 studies/185 patients), therapeutic NK cell infusions post-HSCT (5 studies/74 patients), and pre-emptive/prophylactic NK cell infusions post-HSCT (4 studies/77 patients). Higher NK cell reconstitution was associated with a better 2-year overall survival (OS) (high: 77%, 95%CI 0.73-0.82 vs low: 55%, 95%CI 0.37-0.72; n=899), however, pooled analysis for relapse rate (RR) or graft versus host disease (GVHD) could not be performed due to insufficient data. Higher graft NK cell content demonstrated a trend towards a better pooled OS (high: 65.2%, 95%CI 0.47-0.81 vs low: 46.5%, 95%CI 0.24-0.70; n=157), lower RR (high: 16.9%, 95%CI 0.10-0.25 vs low: 33%, 95%CI 0.04-0.72; n=157), and lower acute GVHD incidence (high: 27.6%, 95%CI 0.20-0.36 vs low: 49.7%, 95%CI 0.26-0.74; n=157). Therapeutic NK or cytokine-induced killer (CIK) cell infusions for hematologic relapse post-HSCT reported an overall response rate (ORR) and complete response (CR) of 48.9% and 11% with CIK cell infusions and 82.8% and 44.8% with NK cell infusions, respectively. RR, acute GVHD, and chronic GVHD were observed in 55.6% and 51.7%, 34.5% and 20%, and 20.7% and 11.1% of patients with CIK and NK cell infusions, respectively. Pre-emptive donor-derived NK cell infusions to prevent relapse post-HSCT had promising outcomes with 1-year OS of 69%, CR rate of 42%, ORR of 77%, RR of 28%, and acute and chronic GVHD rates of 24.9% and 3.7%, respectively.
Conclusion
NK cells have a favorable impact on outcomes after HSCT. The optimal use of NK cell infusions post-HSCT may be in a pre-emptive fashion to prevent disease relapse.
After more than a decade of preclinical and clinical development, therapeutic infusion of mesenchymal stromal cells is now a leading investigational strategy for the treatment of acute ...graft-versus-host disease (GVHD). While their clinical use continues to expand, it is still unknown which of their immunomodulatory properties contributes most to their therapeutic activity. Herein we describe the proposed mechanisms, focusing on the inhibitory activity of mesenchymal stromal cells (MSCs) at immunologic checkpoints. A deeper understanding of the mechanism of action will allow us to design more effective treatment strategies.
The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who ...were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 17%) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 52%). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached NR vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.
We sought to study whether survival after haploidentical transplantation is comparable to that after matched unrelated donor transplantation for 822 patients aged 50-75 years with acute myeloid ...leukemia in first or second complete remission. One hundred and ninety-two patients received grafts from haploidentical donors (sibling 25%; offspring 75%) and 631 patients from matched unrelated donors aged 18-40 years. Patients' and disease characteristics of the two groups were similar except that recipients of matched unrelated donor transplantation were more likely to have poor risk cytogenetics and more likely to receive myeloablative conditioning regimens. Time from documented remission to transplant did not differ by donor type. Five-year overall survival was 32% and 42% after haploidentical and matched unrelated donor transplant, respectively (
=0.04). Multivariable analysis showed higher mortality (hazard ratio 1.27,
=0.04) and relapse (hazard ratio 1.32,
=0.04) after haploidentical transplantation, with similar non-relapse mortality risks. Chronic graft-
-host disease was higher after matched unrelated donor compared to haploidentical transplantation when bone marrow was the graft (hazard ratio 3.12,
<0.001), but when the graft was peripheral blood, there was no difference in the risk of chronic graft-
-host disease between donor types. These data support the view that matched unrelated donor transplant with donors younger than 40 years is to be preferred.
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell ...therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
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