Gergis, Usama

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

ABSTRACTBackgroundIn this study, we compared outcomes of intensified myeloablative conditioning regimens using large registry data from Japan (Japanese Society for Transplantation and Cellular Therapy) and the United States (Center for International Blood and Marrow Transplant Research).MethodsAdult patients who underwent their first myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia in remission between 2010 and 2018 using conditioning regimens of cyclophosphamide plus total‐body irradiation (CY/TBI), CY/TBI+cytarabine (AraC), or CY/TBI+etoposide (VP16) were included.ResultsThe acute myeloid leukemia (AML) cohort (N = 480, 38.8%) indicated that overall survival (OS) was poorer in CY/TBI+AraC (hazard ratio [HR] 1.46, p < 0.001) and CY/TBI+VP16 (HR 1.39, p = 0.059) compared to CY/TBI. Relapse was not suppressed, while treatment‐related mortality (TRM) was significantly higher (HR 1.78 and 1.74, p < 0.001 and 0.018, respectively). In the acute lymphoblastic leukemia (ALL) cohort (N = 3901, 61.2%), OS was comparable among these regimens. With intensified regimens, relapse was significantly suppressed in CY/TBI+VP16 (HR 0.74, p = 0.005), while TRM was higher (HR 1.21, p = 0.077). No interactions were observed regarding the country.ConclusionIn AML adding AraC and VP16 to CY/TBI had an adverse effect on OS. Conversely, in ALL, adding VP16 or AraC to CY/TBI did not affect survival, but the addition of VP16 reduced the risk of relapse.Clinical Trial RegistrationThe authors have confirmed clinical trial registration is not needed for this submission.

Background: In TRANSCEND CLL 004 (NCT03331198),monotherapy with liso-cel, an autologous, CD19-directed CAR T cell product (100 × 106 CAR+ T cells [dose level (DL) 2]), resulted in 43% ORR and 18% CR/CR with incomplete marrow recovery (CRi) rate per IRC in pts with third-line or later R/R CLL/SLL who had PD on Bruton tyrosine kinase inhibitor (BTKi) and failed venetoclax (Siddiqi T, et al. Lancet 2023). Ibr + other CAR T cell therapies has shown high ORR and reduced cytokine release syndrome (CRS) severity in pts with R/R CLL/SLL. In the phase 1 dose-escalation ibr combination cohort, DL2 was the recommended dose of liso-cel for expansion (Wierda WG, et al. Blood 2020). Here, we report results of liso-cel + ibr in pts with R/R CLL/SLL from TRANSCEND CLL 004. Methods: Eligible pts ≥ 18 y of age with CLL/SLL had ≥ 1 of the following: 1) receiving BTKi with PD at entry, 2) high-risk disease and &lt; CR after ≥ 6 mo on BTKi, 3) BTK/PLCγ2 mutation ± ibr PD, 4) prior BTKi with no contraindications to ibr, and 5) (per amendment) PD on BTKi and received prior venetoclax. At enrollment, pts started or continued ibr (420 mg daily or less for toxicity) through leukapheresis and for up to 90 d (or longer per investigator [inv]) after liso-cel (target dose of 50 × 106 CAR+ T cells [DL1] or DL2). Response was per inv by 2018 iwCLL criteria. Primary endpoint was CR/CRi rate at DL2; secondary endpoints included safety, ORR, duration of response (DOR), duration of CR/CRi (DOCR), time to response, time to CR/CRi, PFS, OS, and undetectable MRD (uMRD) rate in blood. Cellular kinetics was exploratory. Efficacy analyses were at DL2 and safety at DL1 + DL2. Treatment-emergent AEs (TEAE) occurred the latter of ≤ 90 days after liso-cel or ≤ 30 days of ibr completion. Liso-cel-treated pts who completed or withdrew from study could enroll in a separate long-term follow-up (LTFU) study (NCT03435796) for safety and OS ≤ 15 y after liso-cel. Results: A total of 65 pts underwent leukapheresis; 56 received ibr + liso-cel (DL1, n = 5; DL2, n = 51). At data cutoff (01/12/2024), 28 of 56 (50%) pts had discontinued the study, 11 (20%) completed the study, and 17 (30%) were ongoing; 5 of 28 (18%) eligible pts enrolled in LTFU. Median (IQR) on-study follow-up (including LTFU) was 24.8 mo (14.2-34.6). Median (range) age was 65 y (44-77); 55 (98%) pts had high-risk cytogenetics, such as del(17p) (n = 25), TP53 mutation (n = 24), and unmutated IGHV (n = 39); 43% had LDH ≥ ULN; and median (range) SPD was 27 cm2 (1-218). Pts had a median (range) of 5 (1-13) prior therapies (≤ 2, n = 13 [23%]). Median (range) time from leukapheresis to liso-cel availability was 25 d (17-79). Median (range) ibr exposure was 34 d (15-188) before and 94.5 d (6-1517) after liso-cel. At DL2, ORR (95% CI) was 86% (73.7-94.3), median (range) time to first response was 1.0 mo (0.9-6.0), and median (95% CI) DOR was 41.4 mo (23.3-not reached [NR]). CR/CRi rate (95% CI; primary endpoint) was 45% (31.1-59.7), median (range) time to first CR/CRi was 3.1 mo (0.9-12.1), and median (95% CI) DOCR was NR (26.6-NR). Median (95% CI) PFS and OS was 31.4 mo (20.1-NR) and NR (27.5-NR), respectively. uMRD rate (95% CI) in blood and marrow was 86% (73.7-94.3) and 84% (71.4-93.0), respectively. Grade (gr) ≥ 3 TEAEs occurred in 48 (86%) pts (most commonly neutropenia [52%] and anemia [41%]) with no gr 5 TEAEs. Liso-cel-related gr ≥ 3 TEAEs occurred in 32 (57%) pts and ibr-related gr ≥ 3 TEAEs in 24 (43%) pts including cardiovascular events of hypertension (7%) and atrial fibrillation (2%). Any-gr CRS occurred in 45 (80%) pts (gr ≥ 3, n = 2 [4%]) and any-gr neurological events (NE) in 23 (41%) pts (gr ≥ 3, n = 6 [11%]). Eight (14%) pts had gr ≥ 3 infections and 5 (9%) had second primary malignancies. Twenty-five (45%) pts had prolonged cytopenias (gr ≥ 3 at D30); most recovered to gr ≤ 2 by D90. Sixteen pts died after infusion (PD, n = 6; unknown, n = 6; COVID-19, n = 3; mixed septic/cardiogenic shock, n = 1). Liso-cel showed rapid expansion (median tmax, 10 d) and was detected up to 42 mo after infusion. Conclusions: Combined liso-cel + ibr demonstrated substantial efficacy with deep remissions (86% ORR, 45% CR rate, and 86% blood uMRD rate) and manageable safety in pts with R/R CLL/SLL. Though comparisons should be made with caution and there were differences in disease characteristics between cohorts, liso-cel + ibr showed a numerically higher ORR/CR rate and lower gr ≥ 3 CRS/NE rates vs liso-cel monotherapy, supporting the combination as a promising new therapeutic strategy for pts with R/R CLL/SLL.

Abstract We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P &lt; .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P &lt; 0.001) and overall response rate (71% vs 42%, P &lt; 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD ®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens. Methods This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2-4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed. Results At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at &lt; 3 mo, 52 [24.1%] pts at 3−&lt; 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm. Overall, incidence of gr 3/4 infections was high at &lt; 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at &lt; 3 mo, 18 [8.3%] pts at 3−&lt; 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at &lt; 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at &lt; 3 mo, 0 pts at 3−&lt; 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively. Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at &lt; 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−&lt; 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]). Conclusion In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

AbstractTo develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age &gt;50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels &lt;100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P &lt; .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P &lt; .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.