Biol Blood Marrow Transplant Research Articles

Graft-Versus-Host Disease (GvHD) Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation (haplo-PBSCT) Using Abatacept in Combination with Post-Transplant Cyclophosphamide (PTCy)

Background: Multiple studies demonstrated the efficacy of PTCy in achieving successful multiple-HLA-antigen mismatched (haploidentical) donor transplantation. However, acute GvHD (aGvHD) remains a major cause of morbidity and mortality after transplantation. Furthermore, many patients (pts) experience severe cytokine release syndrome (CRS) immediately after haplo-donor transplantation, which may be a greater risk after haplo-PBSCT. We hypothesized that adding co-stimulation blockade with abatacept (Abat) starting before transplantation to a standard GvHD prophylaxis regimen of PTCy, tacrolimus, and mycophenolate mofetil in haplo-PBSCT would be safe and effective in aGvHD prevention and decrease the incidence of cytokine release syndrome (CRS) associated with use of this cell source. Methods: This retrospective study included 50 recipients of haplo-PBSCT between 1/1/20, and 3/31/23, who received standard PTCy GvHD prophylaxis with (PTCY/Abat, n=22) or without (PTCy, n=28) the addition of Abat at a planned dose of 10 mg/kg/dose IV on days -1, +5, +14 (n=10) and +28 (n=12). Choice of donor, conditioning regimen, and use of Abat were per physician discretion. The PTCy GvHD regimen and pre- and post-transplant care of all pts were as previously described (Baker et al. Biol Blood Marrow Transplant. 2016;22:2047-55). Survival development of aGvHD or chronic GvHD (cGvHD), and engraftment success and kinetics were evaluated. CRS (Lee, et al. Blood 2014;124:188-95), aGvHD (Magic criteria, Harris et al. Biol Blood Marrow Transplant. 2016;22:4-10) and cGvHD (NIH consensus criteria, Jagasia et al. Biol Blood Marrow Transplant 2015;21:389-401) were scored per citations. Results: In total, 22 pts received PTCy/Abat. Ten pts did not receive day +28 Abat for insurance reasons. Twenty-eight pts received PTCy without abatacept. Pt characteristics and CRS grading are described in the Table. Although distributions of diagnosis, sex, and pt or donor ages were similar between cohorts, there was some imbalance, particularly in higher use of TBI myeloablative conditioning regimen for PTCy cohort (Table). The median follow-up of survivors is 10 months. In this analysis we found a non-significant trend to lower incidence (65% vs 88% p=0.079) and severity of CRS for PTCy/Abat recipients vs PTCy recipients (Table). Only 1 of 20 evaluable PTCy/Abat recipients developed grade 2 CRS vs 6 of 26 PTCy pts. PTCy/Abat recipients achieved faster ANC engraftment (median: 15 days, 95% CI: 14-16 vs 17 days, 95% CI: 16-18; p<0.0001 (Figure 1A)) and platelet recovery (median: 15 days, 95% CI 13-22 vs 24 days 95% CI 19-29; p=0.002). No pt in either group developed 1 o or 2 o graft failure. Median peripheral blood CD3 chimerism at day +28 was 100% (range, 57-100%) for PTCy/Abat pts and 100% (range, 85-100%) for PTCy pts. The cumulative incidence of any aGvHD was 71% for PTCy/Abat pts vs 73% for PTCy pts, (p=0.9). Grade II or III aGvHD occurred in 13/21 and 1/21 evaluable PTCy/Abat pts, and 12/26 and 3/26 evaluable PTCy pts, respectively. No grade IV or liver aGvHD occurred in either group. The median time of onset of aGvHD was 54 days for PTCy/Abat pts and 36 days for PTCy pts (p= 0.08). The cumulative incidence of any grade cGvHD trended higher in the PTCy/Abat group (81% vs 50% p=0.052). Also, the PTCy/Abat group had a higher incidence of severe grade cGvHD (6/13 vs 2/10 evaluable pts). The 200-day cumulative incidence of relapse was 35% for PTCy/Abat and 11% for PTCy (p=0.2). No statistically significant differences in overall survival, or relapse-free survival (Figure 1B) were detected for these two populations. Conclusions:The addition of Abat starting before haplo-PBSCT did not interfere with the aGvHD and engraftment protective effects of PTCy in this cohort. Abat initiated before PBSC infusion may reduce the risk and severity of CRS and was associated with earlier neutrophil and platelet recoveries. Although the incidence of aGvHD did not differ between the two groups, time of onset trended later among PTCy/Abat recipients. Larger pt populations will be needed to determine more accurately the effects of adding Abat to PTCy on relapse risk and cGvHD incidence and severity.

A Novel Prediction Model for BK Virus Associated Hemorrhagic Cystitis in Acute Leukemia Patients Following Allogenic Hematopoietic Cell Transplantation: A Retrospective Cohort Study

Introduction BK polyomavirus (BKV) has been associated with hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (HSCT). BK virus hemorrhagic cystitis (BKHC) is associated with high morbidity and higher mortality. Previous studies have identified several risk factors associated with BKHC (Biol Blood Marrow Transplant, 2022). However, these results are contradictory among studies, and the potential mechanisms of BKHC are still unclear. Therefore, an accurate systematic evaluation method for screening high-risk populations before the onset of BKHC is highly necessary. This study was designed to establish an efficient prediction model for BKHC in acute leukemia patients following HSCT, thereby facilitating identification and early intervention in patients at high risk of BKHC. Methods In our retrospective study, a cohort of 789 acute leukemia patients following allogenic hematopoietic cell transplantation in 2019 was included and further divided into a BKHC group and a non-BKHC group. Among these patients, 80% were assigned to the derivation cohort, and 20% were assigned to the validation cohort. We first calculated the univariate association of each variable with the occurrence of BKHC. Second, the variables with p values less than 0.05 in the univariate analysis were further included as candidate predictors in the multivariate analysis using a backward stepwise logistic regression model. The variables that remained in the final model based on the outcomes of the multivariate analysis in the derivation cohort were identified as independent risk factors. The discrimination power of the model was assessed in both derivation and validation cohorts through ROC curve (AUC), calibration curve and decision curve analyses. Results Among 789 acute leukemia patients following allogenic hematopoietic cell transplantation, 171 patients were diagnosed with BKHC 14 days post transplantation according to the European Conference on Infections in Leukemia (ECIL) definition of BKHC. Patients with early-onset HC occurring within 14 days post transplantation were excluded from the BKHC group. The incidence rate of developing BKHC after allo-HSCT was 21.7%. The median time from transplantation to BKHC development was 30 days. Using multivariable logistic regression methods with stepwise variable selection, four highly significant independent risk factors for developing BKHC were identified: use of ATG during the transplantation regimen (p=0.048; odds ratio [OR], 2.32; 95% confidence interval [CI], 0.025-1.71), use of bone marrow blood and peripheral blood as sources of stem cells (p<0.001; odds ratio [OR], 0.25; 95% confidence interval [CI], 0.025-1.71), age less than 30 years old (p=0.02; odds ratio [OR], 1.74; 95% confidence interval [CI], 0.089-1.021) and absolute lymphocyte count at 14 days post-transplantation less than 0.035×10 9/L (p=0.02; odds ratio [OR], 2.59; 95% confidence interval [CI], 0.31-1.62). The area under the ROC curve (AUC) was 0.741 (95% confidence interval [CI], 0.694-0.789). According to the calibration plots, the model-predicted probabilities showed a good correlation with actual observed frequencies in both the derivation and validation cohorts. Decision curve analysis indicated that the clinical implementation of this model could benefit BKHC patients. A BKV-associated HC Risk Index (BHRI) was constructed according to the regression coefficients. The patient cohort was divided into a high-risk group and a low-risk group according to risk scores. Kaplan‒Meier estimations of the probabilities of BKHC were significantly different between the two risk groups. Conclusions Patients with BKHC after allo-HSCT usually have high morbidity and higher mortality. A novel prediction model, BHRI, was developed and validated, and this is the first straightforward scoring system designed to evaluate the probability of patients developing BKHC after receiving allo-HSCT to treat hematological malignancies. This model can be effectively utilized to help improve the prognosis of BKHC patients by accelerating the early identification of patients at a high risk of developing BKHC and contributing to the appropriate implementation of timely medical support.

Allogeneic Stem Cell Transplantation in Adolescent and Adult Patients with Acute T Cell Lymphoblastic Leukemia / Lymphoma : Single Center Experience of 143 Patients

Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/-LL) is an aggressive hematological neoplasm originates from T-cell progenitors. T-ALL and T-LL are distinguished by the presence of more or <20% marrow blasts, respectively. Allogeneic hematopoietic cell transplantation (SCT) is typically recommended for adults with T-ALL in second or later complete remission (CR2+), but also may be offered to patients in first CR (CR1) with high-risk features. Our center reported previously outcomes of allogeneic HCT (allo-SCT) in 53 adolescent and young adults of T-ALL ( Biol Blood Marrow Transplant. 2012;18(12):1897-1904). Patients and Methods: We analyzed the outcomes of adults (age >14years) with T-ALL who received allo-SCT at King Faisal Specialist Hospital and Research Center between January 1985 and September 2018. Patients eligible for allo-SCT included HR patients in CR1 and any patient in > CR2 or relapse. Patients in CR1 had one or more of the following HR features: WBC count at presentation > 100,000/mm3, residual disease in bone marrow (BM) at day 14 postinduction, central nervous system (CNS) involvement at diagnosis and the need for more than one induction regimen to achieve CR1. Full-intensity conditioning regimens were used for all patients. The majority of patients (95.1%) received cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg), followed by 12 Gy of fractionated total body irradiation (TBI) given in 6 fractions. Seven patients (4.9%) received busulfan 16 mg/kg (1 mg/kg per dose orally every 6 hours over 4 consecutive days) and cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg).Short-course methotrexate plus cyclosporine (MTX/CSA) was the GVHD prophylaxis regimen used, in all patients. Results: 143 patients underwent allo-SCT and were included in this study; some of them were referred in CR for allo- SCT after undergoing induction chemotherapy outside our institution. Median age was 20 years (range, 14-52).Majority of patients were males 116 (80.6%). Extramedullary presentation was reported in 34 patients (23.8 %) with CNS involvement in 15 patients (10.5%). For SCT outcomes, the incidence rates for relapse 27.1%, acute GVHD 45.8%, grade II-IV acute GVHD was 29.9% and that of chronic GVHD was 38.9%, extensive chronic GVHD was 21.5%. GVHD relapse free survival (GRFS) was reported in 27.1%. The majority of relapses occurred within 1 year after SCT. The cumulative incidence of relapse (CIR) at 1 year was 22.4% 95% CI (15.9 - 29.5), at 2 years was 23.8.8% 95% CI (17.2 - 31) and at 5 years was 25.9% 95% CI (19 - 33.3). Other outcomes, Hemorrhagic cystitis (HC) was noted in 9.7%, sinusoidal obstruction syndrome (SOS) 9% The mean time for overall survival (OS) was 166.77 months (95% CI = 136.54 - 197), and the median survival time was 41 months (95% CI = 15 - 266). For the CR1 group was 205.63 months (95% CI = 166.59 - 244.66). At 10 years, OS of the CR1 group was 74.44 months (95% CI = 63.67 - 85.22), and for the > CR2 group was 35.36 months (95% CI = 24.39 - 46.32); p= 0.0001 PFS analysis showed, the overall mean survival time for disease progression at 5 years was 33.16 months (95% CI = 28.77 - 37.54), and the median survival time was 32 months (95% CI = 12 - 55). For the CR1 group was 39.82 months (95% CI = 34.54 - 45.09), and for the >CR2 group was 22.83 months (95% CI = 16.02 - 29.64), p < 0.0001. At 10 years, PFS for the CR1 group was 74.95 months (95% CI = 63.58 - 86.31), and for the >CR2 group was 41.24 months (95% CI = 27.37 - 55.11) with statistically significantly difference, p < 0.0001. On multivariate analysis, chronic GVHD was significantly associated with a lower OS (P=0.006) and PFS (P=0.01).Disease status at SCT remained significantly associated with PFS (P=0.02),but not OS (P=0.07). The presence of extramedullary disease and CNS involvement at diagnosis had no effect on the different outcomes. Conclusions: Allo-SCT could provide better disease control for HR patients with T-ALL/LL in CR1. Dismal outcomes are reported in patients beyond CR1 with early relapses post allo-SCT are almost inevitable. Better understanding of disease's molecular background in addition to MRD applications, could help to identify more patients in CR1 status who might benefit from allo-SCT. Post SCT strategies including maintenance or pre-emptive interventions might be needed to improve SCT outcomes for T-ALL

Preliminary Findings of a Phase Ib/II Trial Indicate Manageable Safety and Promising Efficacy for Mosunetuzumab in Combination with Lenalidomide (M+Len) in Previously Untreated (1L) Follicular Lymphoma (FL)

Background: First-line FL treatments typically include an anti-CD20 monoclonal antibody with alkylator-based chemotherapy. Despite encouraging efficacy, most patients (pts) eventually relapse; novel therapies that improve outcomes and prolong remission in 1L FL are needed. Also, chemotherapy-containing regimens may have substantial toxicities, emphasizing the need for new therapies with improved safety. Mosunetuzumab (M), a CD20xCD3 bispecific antibody that redirects T cells to eliminate malignant B cells, has shown manageable safety with high complete remission rates in pts with relapsed/refractory (R/R) FL after ≥2 prior lines of therapy (Budde et al. Lancet Oncol 2022). Lenalidomide (Len), a potent immunomodulatory agent, may have synergistic effects with M. Initial results from the CO41942 Phase Ib/II trial (NCT04246086) showed that M (intravenous) combined with Len had a manageable safety profile and encouraging chemotherapy-free anti-lymphoma activity in pts with R/R FL who had ≥1 prior line of therapy (Morschhauser et al. ASH 2021). We present preliminary safety, efficacy, and biomarker data from this ongoing trial of M (subcutaneous [SC]) combined with oral Len in pts with 1L FL who require systemic therapy. Methods: Pts with 1L FL requiring systemic therapy (investigator-assessed using GELF criteria) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 are included; target enrollment is 40 pts. Pts received 12 cycles of M+Len (cycle [C] 1, 21 days; C2-12, 28 days); in C1, 5mg of M was given on Day (D) 1, with the target dose (45mg) given on C1D8, C1D15, and on D1 of C2-12; Len (20mg) was given on D1-21 of C2-12 ( Figure A). Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses by PET-CT were investigator-assessed using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Flow cytometry (fluorescence-activated cell sorting) on whole blood was used to assess peripheral biomarkers. Results: At clinical cutoff date (CCOD; May 2, 2023), 37 pts were enrolled: 21 (56.8%) had been on the study for 0-3 months, 12 (32.4%) for 3-6 months, and 4 (10.8%) for 6-9 months. Median age was 62.0 (range 28-83) years and 20 (54.1%) pts were male. All pts had a baseline ECOG PS of ≤1; 32 (86.5%) had Ann Arbor stage III-IV; and 7 (18.9%), 13 (35.1%), and 17 (45.9%) had a FL International Prognostic Index score of 0-1 (low), 2 (intermediate), and 3-5 (high risk), respectively. All pts reported ≥1 treatment-emergent adverse event (TEAE); 12 (32.4%) had ≥1 serious TEAE. Two pts discontinued study treatment after the C1D15 dose, one pt due to uveitis and one pt due to tumor flare. TEAEs related to M or Len occurred in 36 (97.3%) and 29 (78.4%) pts, respectively. At least one Grade (Gr) 3-4 TEAE occurred in 16 (43.2%) pts, the most common being neutropenia (seven pts). No pts reported Gr 5 AEs. CRS occurred in 20 (54.1%) pts; all were Gr 1, except for one pt with Gr 2 CRS, and all events resolved (median CRS duration: 2 days [range 1-26]). CRS frequency was highest after C1D1 (32.4%), and steadily declined over subsequent days and cycles. No immune effector cell-associated neurotoxicity syndrome events were observed. To date, 27 pts were efficacy evaluable ( Figure B). Of 24 (88.9%) responders, 22 (81.5%) had a complete metabolic response (21 achieved by the first response assessment at end of C3), and two (7.4%) had a partial metabolic response. One pt (3.7%) had no response assessment by CCOD, and two (7.4%) had progressive disease but were recognized to have biopsy-proven transformed FL during C1 and C2. All responses were maintained at CCOD. Preliminary biomarker analyses of pt blood samples showed: increased CD69 and sustained HLA-DR expression in CD8 T cells, with modulation of CD8 subsets favoring central/effector memory phenotypes; sustained natural killer-cell activity; and minimal effects on CD4 T cells (except for lower PD-1 expression). Conclusions: This fixed-duration, chemotherapy-free M+Len regimen offers a convenient means for outpatient SC administration, and has a manageable early safety profile with promising anti-lymphoma activity in pts with 1L FL requiring systemic therapy, based on the preliminary data. Advancing M+Len into the first-line setting offers potential benefits in chemotherapy-naïve pts. Safety, efficacy, biomarker, and pharmacokinetic data from the complete cohort (40 pts) will be presented.

TCRαβ +/CD19 + - Depleted HLA-Haploidentical Hematopoietic Stem Cell Traansplantation in Pediatric Patient with Fanconi Anemia

Background Allogeneic hematopoietic stem cell transplantation (HSCT) currently represents the only proven treatment able to rescue bone marrow failure and prevent the occurrence of clonal evolution in patients with Fanconi Anemia (FA). If HSCT from HLA-identical related donor (MRD) is reported to be associated with better outcomes, this is not available for most patients. On the other hand, the identification of a fully matched unrelated donor (MUD) may be unsuccessful, or require times incompatible with a prompt treatment of the haematological condition. For patients who lack a MRD or MUD, the preferred donor choice is debated. HLA partially matched haploidentical donor (haplo) is virtually immediately available for all patients and haplo-HSCT has been reported over the last few years as a promising alternative for those patients. Following the favorable results already reported from our group of a cohort of pediatric and young adult FA patients underwent haplo-HSCT, based on the selective depletion of TCRαβ + and CD19 + cells graft manipulation, here we present the outcome of an enlarged cohort of patients who received HSCT in 3 different centers. Methods Patients diagnosed with FA and eligible for an allogeneic transplantation, but lacking a MRD or MUD, and with a suitable HLA-haploidentical donor were eligible to this study. The conditioning regimen included intravenous fludarabine, cyclophosphamide and single-dose total body irradiation for most patients. Pretransplant anti-T-lymphocyte globulin was administered in all patient to control in vivo bidirectional donor-recipient alloreactivity. Apheresis and graft manipulation were performed as previously reported (Li Pira, Biol Blood Marrow Transplant 2016). Results Thirty-five patients (19 males and 16 females) underwent haplo-HSCT between September 2011 and April 2023 in 3 different centers (Bambino Gesù Children's Hospital, Rome, Italy; Policlinico San Matteo, Pavia, Italy; Tokyo; National Center for Child Health and Development, Children's Cancer Center, Tokyo, Japan). Twenty-four patients have been previously reported (Strocchio, Blood Adv 2021). Details on patients and donor characteristics, graft composition and conditioning regimen are listed in table 1. One patient with clonal evolution and 1 with AML received fludarabine and AraC 3 weeks before the start of the conditioning. Primary engraftment was achieved in 33 patients (94.3%), with median time for neutrophil and platelet recovery of 12 days (range, 9-20 days) and 10 days (range, 7-14 days), respectively. Primary graft failure occurred in 2 patients and both were successfully transplanted from the other haploidentical parent. The monitoring of chimerism analysis confirmed a stable engraftment of donor hemopoiesis in all engrafted patients. Within 33 evaluable patients, 9 (27.3%) experienced grade 1-2 aGvHD (7 with stage I-II skin-only involvement, 1 with stage I lower gastrointestinal involvement) at a median time of 35.5 days (range, 16-67 days) after HSCT. One patient developed late-onset skin only grade 2 aGvHD at day +211 after HSCT. One patient (3%) experienced grade IV aGvHD (liver and gastrointestinal involvement) at day + 100 from HSCT, 4 weeks after the infusion of adenoviral-specific donor T cells; he is currently receiving ruxolitinib and the complete resolution of GvHD was obtained. Only one patient (3%), developed cGvHD with mild skin involvement. Thirteen patients (39.4%) experienced one or more viral infections or reactivations (6 cytomegalovirus, 4 herpesvirus-6, 2 adenovirus, 1 parainfluenzae); the specific antiviral treatment was administered with a complete resolution of infection in all cases. With a median follow up of 5.5 years (range, 0.6-11.4 years) all the patients are alive and with resolution of hematological complications. Except for the already reported vulvar intraepithelial neoplasia, no additional posttransplant malignancy was observed Conclusions Our data obtained from enlarged cohort of patients previously reported, confirm excellent results in terms of survival and a good rate of engraftment also in a multicenter setting. The low incidence of acute and chronic GvHD, a particularly detrimental complication in patients with DNA repair disorder, makes this approach attractive in this patient population. In FA patients lacking a standard donor, TCRab +/CD19 + haplo-HSCT is confirmed to be a promising strategy.

Impact of Pre-Transplant Molecular and Cytogenetic Remission on Outcomes of Allogeneic Stem Cell Transplant in Patients with Myelodysplastic Syndrome

Background: Allogeneic stem cell transplant (allo-SCT) carries a high relapse rate (~35% within 2 years) in patients (pts) with myelodysplastic syndrome (MDS). Pre-transplant measurable residual disease (MRD) increases the risk of relapse and death in acute myeloid leukemia (Thol et al, Blood 2018). However, the impact of pre-transplant MRD on post-transplant outcomes is less clear in MDS. Prior studies have compared outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) in pts with pre-transplant MRD persistence based on either cytogenetic remission alone or ultra-deep genomic sequencing with a limited 10-gene panel, suggesting reduced risk of relapse in pts receiving MAC (Festuccia et al, Biol Blood Marrow Transplant 2016; Dillon et al, JCO PO 2021). However, pre-transplant MRD assessment using a commercial next-generation sequencing (NGS) panel in addition to cytogenetic testing to assess post-transplant outcomes has not been evaluated in MDS. Methods: We conducted a multicenter retrospective review of MDS pts who underwent allo-SCT from 2015-2022. Pts with FISH/cytogenetic (FC) and/or molecular abnormalities at diagnosis and MRD assessment by commercial myeloid-panel NGS (with a variant-allele frequency detection limit up to 5%) and FC performed on peripheral blood (PB) or bone marrow (BM) aspirate within 3 months prior to transplant were included for analysis. The Kaplan-Meier method and log-rank tests were used to estimate overall survival (OS). Gray's test/cumulative incidence functions were used to estimate relapse-free survival (RFS) with non-relapse mortality (NRM) as competing risk. Results: Table 1 includes baseline pt characteristics. Of 81 pts, 69 pts (85.2%) had residual FC and/or molecular abnormalities (MRD+) at pre-transplant PB/BM assessment. Twelve (14.8%) pts were in both FC and molecular remission (MRD-) prior to transplant. With a median follow-up of 13.9 months [IQR 6.8 - 38.9], 43 (53%) died and 24 (30%) pts experienced a relapse. Twenty-three of 69 (33%) MRD+ pts had relapsed disease with a 38% cumulative incidence of relapse (CIR) at 2 years. In contrast, only 1/12 (8.3%) MRD- pts experienced a relapse after 7 years, with chromosomal loss of TP53 not present at initial diagnosis. CIR at 2 years was 33% and 41% (p=0.207) for MRD+ pts who received MAC vs RIC, respectively with NRM of 34.5% associated with MAC vs 28.2% for RIC (p=0.61). TP53 mutations were most frequently associated with relapse in 8/24 (33%) pts with a median OS of 9.8 months [8.2 - NR]. Besides the previously defined 10-gene panel (Dillon et al, JCO PO 2021), relapses were also driven by SRSF2, U2AF1, KRAS, SETBP1 and NF1 mutations present in the original clone. Six pts had DNMT3A, TET2 and/or ASXL1 (DTA) mutations only on pre-transplant NGS, with 2/6 pts relapsing without the re-emergence of DTA mutations. Median OS was not reached for MRD- pts and was 14.1 months [11.35-NR] for MRD+ pts, p = 0.061 [Fig.1]. OS probability at 2 years was 35% for MRD+ pts vs 75% for MRD- pts. Type of conditioning regimen, RIC vs MAC, did not impact OS (p= 0.6). An equal number of deaths, 35% each, were attributable to GvHD and relapse, respectively. Thirteen (30%) pts died from other causes, primarily infections and bleeding complications. NRM was 25% and 36% for MRD- and MRD+ cohorts, respectively. Pts received a median of 6 cycles [range, 2-36] of hypomethylating agent (HMA) +/- venetoclax prior to transplant with no association between the number of cycles and MRD status (p=0.80). The incidence of grade 3-4 acute GvHD and chronic GvHD requiring systemic therapy did not significantly differ, at 25% and 18.8% (p= 0.696) and 33.3% and 31.8% (p= 1.00) in MRD+ and MRD- pts, respectively. Conclusions: MRD assessment using commercially available NGS panels and cytogenetic testing that are routinely performed in MDS pts in real-world practice can predict risk of relapse. Pre-transplant MRD is associated with worse OS irrespective of the intensity of conditioning regimen. Although limited in statistical power due to a small sample size of MRD- pts in our cohort, further studies with a larger cohort are underway to better clarify the role of MRD on transplant outcomes in MDS. Our data also highlights that only a small minority of MDS pts (<15%) achieve complete molecular and cytogenetic remission at the time of transplant; strategies to eliminate the pre-transplant MDS clone are urgently needed.

Impact of Investigational Microbiome Therapeutic SER-155 on Pathogen Domination: Initial Results from a Phase 1b Study in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation (HCT)

Introduction: During allogeneic hematopoietic cell transplantation (allo-HCT), conditioning regimens disrupt the epithelial barrier of the gastrointestinal (GI) tract and broad-spectrum antibiotics cause microbiome disruption characterized by low microbial diversity and high abundance of pathogens that can dominate gut communities. Microbiome disruption is associated with increased translocation of pathogenic bacteria leading to risk of bloodstream infections (BSIs) and acute graft-vs-host disease (aGvHD). Nonclinical studies have demonstrated that domination with pathogens leads to immune activation and subsequent GvHD following exposure to bacterial antigens in the gut-associated lymphoid tissue [ Jenq 2015 Biol Blood Marrow Transplant, Stein-Thoeringer 2019 Science, Peled 2020 NEJM]. SER-155, an oral investigational cultivated microbiome therapeutic comprised of 16 bacterial Firmicutes strains, was designed to engraft in the GI tract, improve GI barrier integrity, and restructure the GI microbiome by introducing bacteria with immunomodulatory and anti-inflammatory properties and driving a reduction in abundance of proinflammatory bacteria [ Halvorsen 2021 OFID, 2022 Bone Marrow Transplant]. Herein, we present preliminary clinical data through Day 100 from an open-label cohort of a Phase 1b study in patients undergoing allo-HCT (NCT04995653) and compare the incidence of GI pathogen domination in this cohort to a historical cohort. Methods: Study patients received two treatment courses of SER-155 (before conditioning and after neutrophil engraftment), each comprised of microbiome conditioning with 4 days oral vancomycin (to facilitate engraftment of SER-155 strains into the GI microbiome) followed by 10 days of oral SER-155. The primary endpoint was safety. Stool samples collected pre- and post-HCT were used to evaluate secondary endpoints, including engraftment of SER-155 strains (following each course of SER-155) and GI pathogen domination, defined as a relative abundance of a specific taxa at ≥30% ( Peled, 2020). Engraftment of SER-155 strains was assessed via strain-specific molecular probes (NanoString). Relative abundance of Enterobacteriaceae, Enterococcaceae, Streptococcaceae and Staphylococcaceae was assessed with whole metagenomic shotgun sequencing (WMS). A post-hoc comparison of GI domination was made with a historical cohort of 459 HCT patients with similar patient characteristics from one of the study sites (MSKCC) using stool samples profiled by 16S-amplicon sequencing. Results: Fifteen adults (median age 67 years; 54% male) were enrolled and 13 received study drug. SER-155 was generally well-tolerated. Following each course of SER-155, the majority of the 16 strains in SER-155 were detected in evaluable patients (median = 11 strains in 8 patients before conditioning; median = 12 strains in 7 patients after neutrophil engraftment).Between the day of transplant (Day 0) and Day 30, GI domination with potentially pathogenic bacteria occurred in only 1 of 9 (11%) evaluable patients (Figure 1). In contrast, in the historical comparator cohort, 64% of patients (294 of 459) had pathogen domination during the same timeframe, with domination by Enterococcus being most common. Conclusions: The observation of SER-155 strain engraftment before transplant and low incidence of GI pathogen domination after transplant through Day 30 are encouraging, although these preliminary data are limited by the small size of this open-label cohort of HCT patients. These observations are consistent with the design and preclinical evaluation of SER-155, supporting further development of this investigational cultivated microbiome therapeutic. Enrollment in the second double-blind, randomized, placebo-controlled cohort (approximately 60 participants) has initiated following a preplanned review by the Data Safety Monitoring Committee.

Longitudinal Blood Count Analysis Reveals That Poor Graft Function after Pediatric Hematopoietic Cell Transplantation Is a Common Complication Associated with Poor Outcome

Background Poor graft function (PGF) is an important complication of allogeneic hematopoietic cell transplantation (allo-HCT), predisposing to infections, bleeding complications and mortality. The reported incidence and outcome of PGF differ between studies, which may partially be explained by differences in patient cohorts and HCT strategies. Pediatric HCT differs from the adults setting in several aspects, such as the underlying disease and use of relatively young donors, including cord blood. To date, however, information on the incidence and outcome of PGF in pediatric HCT recipients is limited. Aim To determine the incidence, risk factors and outcome of poor graft function in pediatric HCT recipients. Methods Longitudinal blood count and transfusion data from 63.219 measurements were retrieved from the Utrecht Patient Oriented Database (ten Berg et al., Clin Chem Lab Med, 2007) to investigate PGF in pediatric recipients of a first HCT. Patients with less than 5 measurements within the first 30 days or 10 measurements within the first 100 days post-HCT were excluded. In line with published definitions, PGF was defined as cytopenia and/or transfusion dependence for 3 consecutive days after day 28 in ≥2 lineages simultaneously, and patients with relapse, grade III-IV GvHD and/or rejection were excluded (Müskens et al., Blood Reviews, 2023). Cytopenias were defined as thrombocytes <20x10 9/L, neutrophils <0.5x10 9/L and hemoglobin <7 g/dL (Kong et al., Biol Blood Marrow Transplant, 2013). Individual and cohort-wide reconstitution patterns of thrombocytes, neutrophils, and hemoglobin after HCT were analyzed and used to identify patients with PGF. Cumulative incidence and survival analyses were conducted using the {survival} R package. Probability of overall survival (OS) and event-free survival (EFS), defined as retransplantation-free, stem-cell-boost free survival, were calculated using the Kaplan-Meier estimate and compared at one year using the log-rank test. Risk factors for PGF and EFS were assessed in univariable and multivariable Cox proportional hazard models. Results Among 348 pediatric recipients who met the inclusion criteria, we identified 53 patients that fulfilled the criteria for PGF, resulting in a cumulative incidence of 0.15 (95% confidence interval (CI): 0.11-0.18). Risk factors for PGF included HCT for hematological disease (p = 0.03) and from an HLA-mismatched donor (p < 0.01). No difference in PGF incidence was observed between recipients of cord blood and bone marrow donors. The one-year OS (1Y OS) of patients in the PGF group was 71% (95% CI: 59-85%), compared to 91% (95% CI: 87-94%) in the good graft function (GGF) group (p < 0.0001, Figure 1A). Infectious disease was the cause of death in 47% in the PGF group, compared to 27% in the GGF group (p = 0.21). The 1Y EFS was 53% (95% CI: 41-68%) in the PGF group, compared to 90% (95% CI: 86-93%) in the GGF group (p < 0.0001, Figure 1B). Conclusion PGF is a common complication in pediatric HCT recipients. No difference in PGF incidence was observed between bone marrow and cord blood grafts. Both patient-specific (underlying disease) and donor-specific (HLA-matching) may contribute to its pathophysiology. PGF patients show a marked reduction in overall and event-free survival, highlighting the need for therapeutic strategies to prevent and/or treat PGF after HCT.

Efficacy of Cord Blood Transplantation for the Management of Chronic Myelomonocytic Leukemia: A Registry-Based Study in Japan

Introduction Chronic myelomonocytic leukemia (CMML) is a challenging malignancy that shares characteristics with myelodysplastic syndromes and myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for CMML. Numerous studies have examined transplant outcomes and prognostic factors; however, the focus has primarily been on bone marrow transplantation (BMT) and peripheral blood stem cell transplantation, while cord blood transplantation (CBT) is understudied. To address this knowledge gap, we conducted a nationwide retrospective study to comprehensively compare the outcomes of unrelated BMT and single-unit umbilical CBT in patients with CMML. Methods Data were collected from the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The inclusion criteria were as follows: age of 16 years or higher, a diagnosis of CMML, and receipt of the first allo-HSCT between 2013 and 2019 through unrelated BMT from a human leukocyte antigen (HLA) 8/8-matched donor (UBMT group) or single-unit umbilical CBT (CBT group). The primary endpoint was overall survival (OS) after allo-HSCT, and the secondary endpoints included progression-free survival (PFS), cumulative incidences of relapse and non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host (GVHD)-free, relapse-free survival (GRFS). The impact of CBT versus unrelated BMT on outcomes was evaluated using inverse probability of treatment weighting (IPTW) analysis. In this analysis, the Cox proportional hazards regression model for OS, PFS, and GRFS and the Fine-Gray proportional hazards regression model for relapse, NRM, engraftment, and GVHD were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for all outcomes. The propensity score (PS) was calculated via logistic regression by using the following factors: age at allo-HSCT, sex, cytogenetic risk, disease status, days from diagnosis to allo-HSCT, and year of allo-HSCT. For the CBT group, the stabilized weights were calculated by dividing CBT prevalence by each individual's PS. Conversely, for the UBMT group, the weights were calculated by dividing the 1 minus prevalence of CBT by 1 minus each individual's PS. Results Between 2013 and 2021, 238 patients with CMML underwent their first allo-HSCT. Among them, 50 underwent HLA 8/8 allele-matched unrelated BMT (UBMT group) and 68 underwent single-unit umbilical CBT (CBT group). The median age at allo-HSCT was 58.5 (range: 26-75) years; the median follow-up period for survivors was 1,329.5 (range: 100-1,967) days. Intergroup differences in age at allo-HSCT, recipient sex, hematopoietic cell transplantation-specific comorbidity index, Eastern Cooperative Oncology Group performance status, cytogenetic risk, pre-transplant treatment, disease status at allo-HSCT, conditioning intensity, GVHD prophylaxis, and year of allo-HSCT were not significant. The transplantation outcomes are shown in Figure 1. There were no significant differences in the 3-year OS rate (UBMT: 51.0% [95% CI: 34.1-65.5%] vs CBT: 46.2% [95% CI: 33.2-58.1%]; P = 0.60; Figure 1A). IPTW analysis revealed no significant differences between the CBT and UBMT groups (HR: 1.21, 95% CI: 0.69-2.10, P = 0.51). PFS, relapse, NRM, and GRFS were not significantly different between the groups (Figure 1B-E). The neutrophil engraftment rate at 30 days was significantly higher in the UBMT group than in the CBT group (UBMT: 92.0% [95% CI: 78.9-97.1%] vs CBT: 79.4% [95% CI: 67.5-87.4%]; P < 0.01; Figure 1F). These observations associated with the secondary endpoints were concurrently corroborated by the IPTW analysis. Conclusion Our study suggests that CBT can serve as a viable treatment option, demonstrating efficacy comparable to that of unrelated BMT for patients with CMML. These findings underscore the improved outcomes over time after CBT in patients with CMML, which is a treatment previously perceived as inferior to other donor sources (Itonaga et al., Biol Blood Marrow Transplant. 2018;24:840-48). Further investigations are warranted to optimize transplantation strategies and improve outcomes in patients with CMML.

Impact of Allograft T-Cell (CD3) Dose on Outcomes When CD34 Cell Dose Is Capped: Analysis of 811 Consecutive Allogeneic PBSC Transplants from a Single Center

G-CSF mobilized PBSC allografts contain higher T-cell doses than bone marrow grafts and have been associated with a significantly higher risk of chronic GVHD. Higher CD34+ cell content in PBSC grafts has also been shown to predict higher rates of chronic GVHD and associated mortality 1,2 To mitigate this risk our center adopted a policy of capping CD34+ cell dose at 5 x 10e6/kg recipient weight for unmanipulated PBSC grafts. For this study, we assessed the effect of T-cell (CD3) dose administered under this capped CD34 strategy, on GVHD and other transplant outcomes. Consecutive first PBSC allografts for hematologic malignancy performed using the CD34 cap strategy between 2010 and 2022 (n=811) were included in this analysis. GVHD prophylaxis was tacrolimus/methotrexate for MRD and MUD and post-transplant cyclophosphamide based for Haplo. Patients receiving anti-T cell serotherapy or ex-vivo T-depletion were excluded. GVHD was uniformly assessed and graded by a dedicated practitioner for all cases. Patient characteristics were: median age 55 (18-80); 57% male; race -white 74%, black 21%, Asian 5%; diagnosis AML 38%, ALL 18%, MDS 18%, NHL 10%; donor type haplo 42%, MRD 32%, MUD 26%, %; high/v. high 25%, low/intermediate 73%; HCT-CI (0-2) 43%, (>3)57%, regimen - myeloablative 48%, RIC 31%, NMA 21%). Median follow-up for survivors was 64 (16-151) months. Median CD34 and CD3 doses infused were 5.0 x 10e6/kg (min 1.59) and 17.3 x 10e7/kg (range 1.2-83.3) respectively. Median CD3 dose infused were higher with female donors (20.5 vs 15.5 x 10e7/kg, p<0.001) and older donors (18.6 vs 15.9 x 10e7 for donors aged >38 vs <38, p<0.001). The effect of Infused CD3 dose was assessed in terciles (ranges 1.2-13.5, 13.6-22, 22.1-83.3 x 10e7/kg). Median peripheral blood donor CD3 chimerism was 100% for all CD3 dose terciles at d 30, through 180 post-transplant. On univariate analysis - estimated 3-year survival, DFS, NRM, relapse and acute GVHD incidence were not significantly different between the low, middle and high CD3 terciles. In contrast, the cumulative incidence (CI) of moderate-to-severe chronic GVHD at 3 years was significantly higher in the highest vs lowest tercile (36.8% vs 28.6%, p=0.042) (Fig 1), while severe chronic GVHD (14.5% vs 13%) was not significantly different. On stratified Cox multivariable analysis comparing the highest to the lowest CD3 dose terciles - survival, DFS, NRM, relapse and acute GVHD were not significantly different. Moderate-to-severe chronic GVHD was significantly higher in the highest versus lowest tercile (HR 1.53, p=0.005). In order to address specific effects of CD3 dose for particular donor groups, we analyzed incidence of chronic GVHD by CD3 dose terciles separately for the three donor types (MRD n=258, MUD n=210 and Haplo n=343). Whereas the CI of moderate-to-severe chronic GVHD was not significantly different for lowest versus highest CD3 tercile in MRD and Haplo transplant recipients, it was significantly higher for MUD recipients (50% vs 26%, p=0.008, GRFS 29% vs 9%, p=0.005). On multivariable analysis, risk of moderate-to-severe chronic GVHD was significantly higher for the highest versus lowest CD3 dose terciles (HR 2.62, p=0.002) and for the middle vs lowest terciles (HR1.77, p=0.043) in MUD patients (Fig 1). In contrast, CD3 dose had no significant impact on chronic GVHD for MRD and Haplo recipients. This large retrospective analysis of PBSC allografts using a CD34 cap (<5 x 10e6/kg) shows that this approach produced infused CD3 doses ranging between 1.2 and 83.3 x 10e6 /kg. The median and upper limit of infused CD3 dose was lower than previously reported by studies with no CD34 cap 2,3. CD3 dose had a significant impact on the rate of moderate-to-severe chronic GVHD in MUD recipients. A prospective comparison of capped versus uncapped CD34 dosing may help determine the value of this strategy in mitigating GVHD risk of PBSC grafts. These data suggest the need for more aggressive GVHD prophylaxis in patients infused with higher CD3 doses in MUD patients. 1. Mohty M, Bilger K, Jourdan E, et al. Leukemia. 2003;17(5):869-875. 2. Zaucha JM, Gooley T, Bensinger WI, et al. Blood. 2001;98(12):3221-3227. 3. Saad A, Lamb L, Wang T, et al. Biol Blood Marrow Transplant. 2019;25(9):1875-1883.

Mosunetuzumab Monotherapy Demonstrates Activity and a Manageable Safety Profile in Patients with Relapsed or Refractory Richter's Transformation

Background: Richter's transformation (RT) is characterized by the development of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly CD20+ large B-cell lymphoma. RT remains an unmet medical need with a poor prognosis and no standard of care. Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT02500407), fixed-duration mosunetuzumab monotherapy demonstrated notable efficacy and a manageable safety profile in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (Bartlett et al. Blood Advances 2023). We report the efficacy and safety of mosunetuzumab monotherapy in patients with R/R RT after a median follow-up of 8.7 (range: 1-37) months. Methods: Eligible patients with R/R RT and ≥1 prior therapies were enrolled. Patients with lymphocyte counts of ≥5000/µL were excluded. Mosunetuzumab was administered intravenously in 21-day cycles with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1mg; C1D8, 2mg; C1D15/C2D1, 60mg; C3D1 and onwards, 30mg). Hospitalization for treatment was not required. Patients achieving a complete response (CR) by C8 completed treatment without additional cycles; patients with a partial response (PR) or stable disease received a total of 17 cycles. The primary endpoints were safety and tolerability. Efficacy was a secondary endpoint and was assessed according to Cheson 2007 criteria. Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: Twenty patients with R/R RT were enrolled. Median age was 70 (range: 49-87) years, 95.0% of patients had Ann Arbor stage III/IV disease, and 70.0% had an International Prognostic Index score of ≥3. Median number of prior therapies was 2.5 (range: 1-10), 65.0% of patients had ≥2 prior therapies, and 45.0% had received prior treatment with a Bruton tyrosine kinase inhibitor. Overall, 80.0% of patients were refractory to their last therapy. Investigator-assessed overall response and CR rates were 40.0% and 20.0%, respectively. Of four patients with a CR, two had a CR ongoing for ≥20 months at data cut-off (duration of CR [DOCR] at data cut-off: 21.2 months [patient had disease progression at a later timepoint] and 34.2 months), and the other two patients had received a subsequent stem-cell transplant (DOCR with mosunetuzumab: 0.1 and 4.2 months) ( Figure). The four patients with a PR had individual durations of response of: 1.7, 2.1, 2.3, and 2.8 months. The most common adverse event (AE) was CRS (65.0%), and events were predominantly Grade (Gr) 1 (20.0%) or Gr 2 (40.0%); a Gr 3 event was reported after C1D15 in one patient (5.0%). CRS was primarily associated with treatment administration during C1 (C1D1, 15.0%; C1D15, 50.0%); a Gr 1 CRS event was reported in one patient (5.0%) during C2. Of the 14 patients with CRS, six (42.9%) received tocilizumab, three (21.4%) received low-flow oxygen, one (7.1%) received a single pressor, and four (28.6%) received steroids; of the patients who received steroids, two (14.3%) received both tocilizumab and steroids. One patient was admitted to the intensive care unit for the management of Gr 3 CRS. The median duration of CRS was 3 (range: 1‒9) days. All CRS events resolved. Neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and considered treatment-related, occurred in two patients (Gr 1 ICANS and Gr 2 lethargy, each n=1); both events resolved. ICANS occurred one day after a Gr 2 CRS event. No Gr 5 (fatal) AEs, or AEs leading to treatment discontinuation were reported. AEs of special interest included infections (35.0%), neutropenia (15.0%), thrombocytopenia (20.0%), and tumor flare events (10.0%). Conclusions: In patients with R/R RT, fixed-duration mosunetuzumab monotherapy demonstrates activity with durable responses and a manageable safety profile in a limited sample size of 20 patients. Treatment with mosunetuzumab warrants further study in this patient population with a high unmet medical need.

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (>5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

Efficacy and Safety of Elranatamab in Black Patients with Relapsed/Refractory Multiple Myeloma (RRMM): A Subgroup Analysis of the Magnetismm Studies

INTRODUCTION Multiple myeloma disproportionately impacts ethnic and racial minority groups, affecting both incidence and outcome. There is limited evidence-based data for clinical decision making for minority populations, including Black patients (Habr and Corsaro, Hematol Oncol 2022). Elranatamab is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the phase 2 registrational trial MagnetisMM-3, elranatamab demonstrated clinical efficacy in BCMA-naïve and BCMA-exposed patient populations. Here, we report the efficacy and safety of elranatamab in a pooled analysis of Black or African American patients with RRMM across 3 studies in the MagnetisMM program, including MagnetisMM-1 (MM-1; NCT03269136), MagnetisMM-3 (MM-3; NCT04649359), and MagnetisMM-9 (MM-9; NCT05014412). METHODS Eligible patients included in this pooled analysis had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody, and were either naïve or exposed to prior BCMA-directed therapy (antibody-drug conjugate [ADC] and/or CAR T-cells). All patients received subcutaneous elranatamab at the effective doses of 215-1000 µg/kg or fixed dose equivalent of 76 mg (MM-1) or 76 mg once-weekly (MM-3 and MM-9). Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Evaluation of overall response rate (ORR) was assessed per IMWG criteria. Adverse events (AEs) and laboratory abnormalities were graded by National Cancer Institute Common Terminology Criteria for AEs v4.03 (MM-1) or v5.0 (MM-3 and MM-9). American Society for Transplantation and Cellular Therapy criteria (Lee DW, et al. Biol Blood Marrow Transplant 2019) were used for grading cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). RESULTS Of 24 Black or African American patients in the pooled analysis who received elranatamab, the median age was 61.5 years (36-76), 75.0% had R-ISS Stage I or II disease, 79.2% had prior stem cell transplant, and 91.7% patients had an Eastern Cooperative Oncology performance status of 0 or 1. Patients had a median of 6 prior lines of therapy (range, 2-14), with 91.7% and 45.8% having triple-class and penta-drug refractory disease, respectively. Seven patients (29.2%) received prior BCMA-directed therapy as either an antibody-drug conjugate (ADC; n=5), CAR-T (n=4), or both (n=2). After a median follow-up of 13.3 months, the median duration of treatment was 9.0 months; 6 (25%) patients were still on treatment. The most common reasons for treatment discontinuation were progressive disease (41.7%), AEs (12.5%), and death (12.5%). The ORR was 58.3%, with 41.7% of patients achieving complete responses (CR) or better (Table). The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were 18.4, 14.4, and 21.2 months, respectively. Common treatment-emergent AEs (TEAEs) included CRS, anemia, and neutropenia (Table). Infections were reported in 15 patients (any grade, 62.5%; grade 3/4, 20.8%). Two cases of ICANS (both grade 2) were reported. One patient died due to disease progression (metastases to meninges), and four patients died due to a TEAE other than disease progression: 1 patient each due to COVID-19, septic shock, sudden death, and pulmonary embolism. CONCLUSIONS Elranatamab demonstrated clinical activity and a manageable safety profile in Black or African American patients with RRMM, supporting the use of elranatamab in this subgroup of patients. Efficacy and safety results are comparable to those observed for the overall population of patients treated with elranatamab in the phase 2 MagnestisMM-3 trial. No new safety signals were observed.

Dexamethasone is Associated with a Lower Incidence and Severity of Cytokine Release Syndrome Compared with Other Corticosteroid Regimens When Given as Premedication for Glofitamab Monotherapy in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

Glofitamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma: Extended Follow-Up from a Pivotal Phase II Study and Subgroup Analyses in Patients with Prior Chimeric Antigen Receptor T-Cell Therapy and by Baseline Total Metabolic Tumor Volume

Background: Glofitamab is a CD20xCD3 bispecific antibody with a 2:1 (CD20:CD3) format that engages and redirects T cells to eliminate B cells. In a pivotal Phase II study (NCT03075696), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and had a manageable safety profile in patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL; Dickinson et al. N Engl J Med 2022). Here, we present an extended follow up, as well as subgroup analyses in patients with prior chimeric antigen receptor (CAR) T-cell therapy and by baseline total metabolic tumor volume (TMTV). Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D) 1 of Cycle (C) 1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles; total of 8.3 months). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson et al. J Clin Oncol 2014). Cytokine release syndrome (CRS) events were assessed using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Exploratory analyses were performed to investigate the association between TMTV at baseline and progression-free survival (PFS) and CRS. As there is currently no consensus on the method for standardized uptake value (SUV) thresholding in non-Hodgkin's lymphoma, a variety of methods are used in clinical studies (Keijzer et al. Comput Struct Biotechnol J 2023). Here, we used IRC-assessed TMTV derived from baseline positron emission tomography images using a semi-automatic method with a threshold for TMTV of 2x the SUV mean of the liver. Results: As of May 1, 2023, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics were as previously presented (Dickinson et al. N Engl J Med 2022): median prior therapies received was 3 (range: 2-7); 33% of patients had received prior CAR T-cell therapy, and 85% were refractory to their most recent regimen. Median time on study was 25.8 months (range: 0-35). The IRC-assessed overall response and CR rates were 52% and 40%, respectively. The majority of CRs (40/62; 65%) were ongoing at data cut-off. Median duration of CR (DoCR) was 26.9 months (95% confidence interval [CI]: 18.4-not evaluable [NE]); an estimated 67% of patients with a CR at any time remained in remission at 18 months. PFS and overall survival rates at 12 months in patients with a CR at end of treatment (EOT) were 80% and 90%, respectively. In patients with prior CAR T-cell therapy (n=52), CR rates were consistent with the overall population (N=155; 37% vs 40%, respectively) and median DoCR was 22.0 months (95% CI: 6.7-NE). The safety profile of glofitamab was consistent with what has been described previously, with no new safety signals observed. Baseline TMTV was available for 144 patients and the median was 128.7mL (range: 0-3820; data cut-off: January 16, 2023). Higher TMTV was associated with an increased risk of experiencing a Grade ≥2 CRS event. The proportion of patients with Grade ≥2 CRS events in the first, second, third, and fourth TMTV quartiles was 2.8%, 11.1%, 16.7%, and 38.9%, respectively (Chi-square=16.273; degrees of freedom=1; p<0.0001). Patients with a baseline TMTV above or equal to the median (n=72) had a 12-month PFS rate of 16.8% (95% CI: 9.7-29.1), compared with 50.1% (95% CI: 39.5- 63.7) amongst patients with a baseline TMTV below the median (n=72; hazard ratio: 2.6, 95% CI: 1.7-3.9; Figure). Conclusions: Glofitamab continued to demonstrate durable responses in patients with R/R LBCL, with most patients with CR at EOT still in remission, and no new safety signals observed. These data indicate that there may be potential for favorable long-term outcomes with fixed-duration glofitamab for R/R LBCL. CR rates in patients with prior CAR T-cell therapy were durable and consistent with the overall population. Data from the subgroup analyses showed that higher baseline TMTV was associated with an increased risk of Grade ≥2 CRS and suggested that baseline TMTV may be prognostic for PFS. Updated analyses, with a follow-up of approximately 24 months post EOT, and further TMTV exploratory analyses will be presented.

Mosunetuzumab and Polatuzumab Vedotin Demonstrates Preliminary Efficacy in Elderly Unfit/Frail Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Treatment options for elderly unfit/frail (U/F) patients (pts) with diffuse large B-cell lymphoma (DLBCL) are often limited due to comorbidities or functional decline. Less toxic, efficacious alternatives to full-dose chemoimmunotherapy (CIT) are needed. Mosunetuzumab (Mosun) is a first-in-class CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells. Mosun monotherapy has demonstrated efficacy, durable complete responses (CR), and manageable safety in U/F pts with untreated DLBCL (NCT03677154; Olszewski et al. ASH 2022). Subgroup analysis from an ongoing Phase Ib/II study (NCT03671018) of Mosun plus polatuzumab vedotin (Pola; M-Pola) in pts with relapsed/refractory DLBCL demonstrated efficacy and a manageable safety profile in pts ≥65 years (yrs) (Olszewski et al. ASH 2022). We report preliminary efficacy and safety data from the M-Pola cohort of study NCT03677154 in elderly U/F pts with newly diagnosed DLBCL. Methods: Eligible pts were ≥80 yrs, or 65-79 yrs and ineligible for full-dose CIT/unfit per simplified Geriatric Assessment (sGA; Merli et al. J Clin Oncol 2021) ( Table). Pre-phase prednisone was allowed. Pts were enrolled in two safety cohorts with escalating doses of Mosun subcutaneous (SC; Cohort 1 and 2), followed by an expansion (Exp) phase. Pts received Cycle (C) 1 step-up dosing with Mosun SC on Day (D) 1/8/15 (Cohort 1: 5/15/45mg; Cohort 2 and Exp: 5/45/45mg) then 45mg on D1 of C2-8 plus 1.8mg/kg intravenous Pola on D1 of C1-6. Pts with CR stopped Mosun after 8 cycles; pts with partial response (PR) or stable disease could continue Mosun for up to 17 cycles in the absence of progressive disease (PD). Primary endpoints included safety and objective response rate (ORR) by independent review committee (IRC; assessed by positron emission tomography-computed tomography [Lugano 2014 criteria]) at end of treatment (EOT). CR rate, progression-free survival, and overall survival were secondary endpoints (IRC- and investigator [INV]-assessed). Best overall response (BOR) and EOT responses are reported in pts who received first treatment with a sufficient time interval to be eligible for the relevant response evaluation. Cytokine release syndrome (CRS) was assessed by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: Pts were enrolled from Feb 2021 to Jan 2023. As of the clinical cutoff date (CCOD; Feb 17, 2023), 108 pts received M-Pola (Cohort 1: n=7; Cohort 2: n=13; Exp: n=88). Median age was 81 yrs (range: 66-94); 52% of pts were female; 81% had an ECOG PS of 0-1; and 66% had Ann Arbor stage III-IV disease. Per sGA, 59% were unfit and 40% frail ( Table). Median (range) number of cycles was 7.5 (1-14) for Mosun and 6 (1-6) for Pola. Most frequent treatment-emergent adverse events (AEs) (≥20%) were neutropenia (32%), CRS (30%), and injection site reaction (20%). Grade (Gr) 3-4 AEs occurred in 43% of pts (most frequent: neutropenia [28%]). Serious AEs occurred in 41% of pts; most frequent (≥5%) were CRS (14%) and infections (21%), including COVID-19 pneumonia (10%) and COVID-19 infection (7%). Most CRS events occurred in C1; 30/32 pts had Gr 1-2 events; two pts had Gr 3 events. All CRS events resolved within a median of 2 days (range: 1-6); management included tocilizumab (7/32) and corticosteroids (3/32). AEs leading to discontinuation of Mosun or Pola occurred in 15% and 12% of pts, respectively. Fatal AEs occurred in 15 pts (14%): eight COVID-19/COVID-19 pneumonia events; two unexplained deaths; and one event each of Staphylococcal bacteremia, sepsis, pneumonia, pulmonary embolism, and suicide. Range of onset date for fatal AEs was D8-251. At the CCOD, median follow-up was 7.5 months (range: 0-21). In 90 evaluable pts from Cohort 2 and Exp, BOR and best CR rate per INV were 80% (72/90) and 61% (55/90), respectively. EOT response assessments per INV in 56 evaluable pts showed ORR in 55% (31/56); CR in 45% (25/56); PD in 9% (5/56); PR in 11% (6/56); and 36% (20/56) without EOT assessment (withdrawal of consent: 4/20; AEs: 13/20; early discontinuation per INV: 2/20; PD in C1: 1/20) ( Figure). Conclusions: Chemotherapy-freeM-Pola demonstrated preliminary efficacy in elderly U/F pts with previously untreated DLBCL. Overall, the safety profile of M-Pola was consistent with that of the individual drugs. However, COVID-19 remains a high risk in elderly U/F pts treated for DLBCL. Biomarker analyses and long-term follow-up data will be presented.

Pre-Transplant Measurable Residual Disease (MRD) Detection of KMT2A-rearranged Acute Myeloid Leukemia Is Strongly Associated with Inferior Post-Transplant Outcome

Introduction KMT2A-rearranged ( KMT2Ar ) acute myeloid leukemia (AML) is associated with inferior survival and allogeneic hematopoietic cell transplant (HCT) in first remission (CR1) is an important post-remission objective (Issa et al, Blood Cancer Journal 2021). Despite HCT, however, the relapse risk is ~50% (Menghrajani et al, Blood Adv. 2022). Several small cohort studies have described the prognostic utility of pre-HCT MRD assessment using real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR), but currently, this is not standard practice (Scholl et al, Haematologica 2005; Huang et al, Med Sci Monitor 2016; Liu et al, Biol Blood Marrow Transplant 2014; Heuser et al, Blood 2021). A significant barrier to widespread implementation of KMT2A::X MRD monitoring is the presence of diverse fusion-partner genes and varied breakpoint regions. The potential to detect and pre-emptively target pre-HCT KMT2A::X MRD has relevance with the development of menin inhibitors, which have been shown to be active in the clinic (Issa et al, Nature 2023). In the current work, we report the prognostic impact of pre-HCT KMT2A::X MRD detection by RT-qPCR and the relationship with post-HCT outcome in adults with KMT2Ar AML. We also describe a novel 3 common primer/probe KMT2A::X reverse transcription digital PCR (RT-dPCR) MRD assay as a simplified dPCR alternative to MRD monitoring. Methods Archived pre-HCT cDNA were available from 54 patients treated in the UK (including UK NCRI AML17 and AML19) and Australia. Samples were analyzed by RT-qPCR using previously described methods in 45 patients (Abildgaard et al, Eur J Haematol. 2013), and RT-dPCR in 9 patients (Ivey, unpublished 2023). The RT-dPCR method, which uses a common 3 primer/probe set to capture breakpoints within KMT2A obviating the need for fusion-gene specific plasmid standards, showed high concordance with RT-qPCR across 20 samples (R 2=0.9915) . Copy numbers were expressed per 100 ABL copies. Assay sensitivity was ~0.001%. Survival outcomes were estimated using the Kaplan-Meier method for relapse-free survival (RFS, date of HCT to relapse or death from any cause) and overall survival (OS, date of HCT to death or last follow-up). Cox proportional hazards was used to assess variables impacting RFS and OS. Categorical variables were calculated using Fisher exact test and continuous variables using Mann-Whitney-U test. The study was approved by human research ethics committees (AUS 21/26; UK 14/WA/1056, NC10.13). Results A total of 54 patients with KMT2Ar AML underwent HCT between 2010-2022. Median age was 43 years (range, 17-70), 63% were female, 94% had de novo AML, all had received prior intensive chemotherapy and 76% were transplanted in CR1, 50% with myeloablative conditioning. KMT2A::X subtypes included t(9;11)/ KMT2A::MLLT3 in 35%, t(6;11)/ KMT2A::AFDN in 26%, t(11;19)/ KMT2A::ELL in 13% and KMT2A::MLLT1 in 5%, t(10;11)/ KMT2A::MLLT10 in 17% and other rare KMT2A::X variants in 4%. Pre-HCT MRD was detected (MRD-pos) in 46% of patients (25 of 54) at a median level of 0.3 copies/100ABL (range, 0.006-35.0394). The frequency of post-HCT relapse was significantly higher in patients with RT-qPCR/RT-dPCR levels ≥0.01% pre-HCT (68% relapsed vs 24% if MRD-neg, p=0.002) (Figure 1). Median time to relapse was 4.7 months (range, 0.8-22.5), with 100% of patients (22 of 22 with available molecular status at relapse) retaining the KMT2A::X variant at relapse. With median follow-up time of 37 months, pre-HCT KMT2A::X MRD-pos was associated with significantly inferior 2-year RFS (19% vs. 63%, p=0.0013) (Figure 2) and 2-year OS (47% vs. 69%, p=0.031). On univariate analysis, variables associated with inferior RFS were pre-HCT MRD-pos status (hazard ratio (HR) 3.2 [95% confidence interval (CI) 1.5-6.9], p=0.002) and transplant in second remission vs. CR1 (HR 2.6 [95% CI 1.2-5.5], p=0.01), however, pre-HCT MRD-pos status was the only variable associated with inferior RFS on multivariate analysis (HR 2.8 [95% CI 1.3-6.1], p=0.01). Conclusions Pre-HCT KMT2A::X MRD detection by RT-qPCR and RT-dPCR is a robust prognostic indicator of post-transplant relapse and inferior survival outcome. Targeting patients with KMT2A::X MRD positive disease pre-HCT using novel menin inhibitors is currently the subject of an enrolling clinical trial (AMLM26 INTERCEPT) (ACTRN12621000439842).

Glofitamab (Glofit) Plus R-CHOP Has a Favorable Safety Profile and Induces High Response Rates in Patients with Previously Untreated (1L) Large B-Cell Lymphoma (LBCL) Defined As High Risk By Circulating Tumor DNA (ctDNA) Dynamics: Preliminary Safety and Efficacy Results

Background: Up to one-third of patients (pts) with 1L LBCL treated with R-CHOP do not achieve long-term remission or cure depending on disease stage. Outcome prediction beyond the International Prognostic Index (IPI) score is difficult due to the lack of reproducibility of common biomarkers. ctDNA offers potential as a sensitive biomarker to identify newly diagnosed pts with suboptimal chemoimmunotherapy responses. Reduction of ctDNA levels after 1-2 therapy cycles in pts with 1L diffuse LBCL (DLBCL) is associated with improved survival (Kurtz et al. J Clin Oncol 2018). Whether early intervention can improve outcomes of pts with elevated on-treatment ctDNA levels is unknown. Glofitamab, a CD20xCD3 bispecific antibody, engages and redirects T cells to eliminate B cells and has received FDA and EMA approval as monotherapy for relapsed/refractory DLBCL after ≥2 prior lines of therapy. Glofit + R-CHOP has favorable safety and efficacy in 1L DLBCL (Topp et al. ASH 2022). We report initial safety and efficacy from a Phase II open-label prospective trial (NCT04980222) evaluating glofit + R-CHOP in pts with 1L LBCL defined as high risk by ctDNA dynamics. Methods: Eligible pts had 1L CD20+ LBCL, Eastern Cooperative Oncology Group performance status 0-2, and IPI 0-5 (IPI 0 for pts with bulky disease; IPI 2-5 for USA pts). During ctDNA screening, pts received R-CHOP on Day (D)1 of Cycle (C)1 and C2 (21-day cycles). In pts defined as high risk by ctDNA (<2-log [100×-fold] reduction in plasma ctDNA after 1 R-CHOP cycle), R-CHOP was continued to C6, and glofitamab was administered as step-up dosing in C3 (D8, 2.5mg; D15, 10mg), at target dose (30mg) on D8 of C4-6, and on D1 of C7-10 (21-day cycles). Hospitalization for the first dose of glofitamab to assess cytokine release syndrome (CRS) was at the investigator's discretion; granulocyte colony-stimulating factors were advised for neutropenia prophylaxis. Real-time ctDNA analysis was performed centrally (AVENIO Oncology Assay for Non-Hodgkin's Lymphoma; Stokowski et al. ASH 2022). The primary endpoint was complete response (CR) at end of treatment (EOT). Responses were investigator-assessed after C2 and at EOT by positron emission tomography using Lugano criteria (Cheson et al. J Clin Oncol 2014). CRS was graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019); other adverse events (AEs) were assessed by CTCAE v5.0. Results: At data cut-off (May 25, 2023), of 121 pts screened, 24 (19.8%) were defined as high risk by ctDNA (low risk, 47 [38.8%] pts; missing/not evaluable, 49 [40.5%] pts) and received ≥1 dose of study drug from C3D1 (safety population). Of the 24 high-risk pts, 15 reached the EOT assessment (14 pts completed treatment; 1 pt discontinued due to progressive disease [PD]), and 9 pts were ongoing on treatment. Of 24 pts, 2 pts had double-hit and 4 pts had triple-hit cytogenetics; median age was 61.5 years (range: 39-77); 15 (62.5%) pts had IPI 1-2 (IPI 1: 12.5%, IPI 2: 50.0%) and 9 (37.5%) pts had IPI 3-5 (IPI 3: 25.0%, IPI 4: 8.3%, IPI 5: 4.2%). In the safety population, 20 (83.3%) pts had AEs of any Grade (Gr); 15 (62.5%) pts had Gr 3/4 AEs, including neutropenia (11 [45.8%] pts); febrile neutropenia was not observed ( Table). The most common (>20%) treatment-emergent AEs (any Gr) were neutropenia (13 [54.2%] pts) and diarrhea (6 [25.0%] pts). No Gr 5 AEs were reported. Nine (37.5%) pts experienced 17 serious AEs (14 glofitamab-related) including 7 CRS events.Gr ≥3 glofitamab-related AEs occurred in 8 (33.3%) pts. CRS events occurred in 5 (20.8%) pts: 4 (16.7%) pts had Gr 1 fever, 1 (4.2%) pt had Gr 2 fever and hypotension. CRS events occurred early and resolved at data cut-off; treatment (tocilizumab and dexamethasone) was administered for the Gr 2 CRS event only. One (4.2%) pt had a non-immunotoxic Gr 3 neurologic AE (presyncope, glofitamab-unrelated) that resolved by data cut-off. One pt died due to PD during treatment follow-up after discontinuing glofitamab. The interim CR rate was 46.7% (95% confidence interval [CI]: 21.3-73.4); CR at EOT was 80.0% (95% CI: 51.9-95.7) and the interim and EOT overall response rate were both 93.3% (95% CI: 68.1-99.8) ( Figure) . Conclusions: Glofit + R-CHOP in 1L LBCL defined as high risk by ctDNA, had a manageable safety profile and induced high response rates at the interim analysis and at EOT. Dynamic on-treatment risk assessment using ctDNA offers potential to identify high-risk pts with LBCL, independent of baseline characteristics.

Tocilizumab Prophylaxis for Patients Treated with Teclistamab: A Single-Center Experience

Background: Teclistamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, is the first-in-class FDA approved treatment for relapsed/refractory multiple myeloma (RRMM). Early studies of teclistamab have shown high rates of response along with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) (Moreau et al. NEJM 2022). Emerging data from 28 RRMM patients treated with the bispecific antibody cevostamab (targeting FcRH5 and CD3) indicate that use of prophylactic tocilizumab, an anti-IL6 monoclonal antibody, can reduce the risk of developing CRS significantly, without impacting its anti-myeloma activity (Trudel et al. Blood 2022). Preliminary data from 14 patients treated with prophylactic tocilizumab prior to teclistamab were presented at ASCO 2023, suggested reduced CRS risk and no new safety signals (van de Donk et al. J Clin Oncol). We were motivated to administer a single dose prophylactic tocilizumab prior to the first teclistamab step-up dose in a real-world setting including 31 patients. Methods: This single-center study includes all RRMM patients treated with teclistamab in the real-world setting at the University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center between FDA approval (October 25, 2022) and data cutoff (July 21, 2023). Patients were prospectively followed for safety and efficacy outcomes. The primary aim was to investigate the effect on CRS which was assessed by the standard Lee ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Other adverse events were graded according to CTCAE V5.0. P-values were calculated using Fisher's exact test. Results: At the time of data cutoff 31 patients had received teclistamab. The median age was 71 (range 50-84) and 10 (32%) patients were 75 or older. Nine (29%) patients were black and eight (26%) were Hispanic ethnicity. A total of 24 (77%) patients had extramedullary disease, 17 (55%; p<0.01) of which had soft tissue plasmacytomas. Twenty-six (84%) met at least one exclusion criteria for the MAJESTEC-1 trial. In this population we observed a low rate of CRS (13%: binomial 95%CI 4%-30%; p<0.01) and ICANS (10%: 2%-26%); CRS was limited to grade 1 and there was 1 episode of grade 2 neurotoxicity. IgG <400 mg/dL occurred in 21 (68%) of the patients and documented infections occurred in eight (26%) of patients. Neutropenia was observed in 27 (87%) patients, including 20 (65%) with Grade 3 or higher. Among 30 patients with secretory disease, the best overall response rate (ORR) was 15/30 (50%: 31%-69%). Based on standard response criteria, we found 9 (30%: 15%-49%) complete response, 4 (13%: 4%-31%) partial response, 11 (37%: 20%-56%) stable disease, and 4 (13%: 4%-31%) progressive disease. Median follow-up was 109 days (range 9-225) and median duration of response was not reached. At time of data cutoff, 17 (55%) of patients were currently receiving teclistamab therapy. Conclusions: Our findings suggest that tocilizumab may be effective as a preventative, rather than reactive, measure for patients treated with teclistamab. Larger studies are needed to confirm and expand on our results.

New Tocilizumab (TCZ) Dosing Guidance for T-Cell Engaging Bispecific Antibody-Related Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL): Insights from Pooled Clinical Trial Safety Experience and Quantitative Clinical Pharmacology (qCP) Analyses

Background: Mosunetuzumab (Mosun), approved for treatment of pts with R/R follicular lymphoma (FL) and ≥2 prior therapies, and glofitamab (Glofit), approved for treatment of pts with R/R diffuse large B-cell lymphoma, or large B-cell lymphoma arising from FL, and ≥2 prior therapies, are CD20xCD3 T-cell engaging bispecific antibodies that redirect T cells to eliminate B cells. CRS is a common on-target adverse event observed with bispecific antibodies and associated with exposure. TCZ, a humanized anti-interleukin-6 (IL-6) receptor, is often used for CRS management. TCZ dosing recommendations derived from CAR T-cell studies (Le et al. Oncologist 2018) may not be optimal for bispecific antibody-treated pts. Using TCZ clinical usage patterns in Mosun- or Glofit-treated pts with R/R B-NHL, qCP, and cytokine analyses, we explored a new TCZ dosing regimen for CRS management (for pts >30 kg body weight). Methods: Pooled safety data from seven Phase I/II studies evaluating Mosun or Glofit in pts with R/R B-NHL were analyzed. CRS was graded using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Modeling was used to predict TCZ concentrations (conc) and soluble IL-6 receptor (s-IL6R) occupancy over time, following administration of different TCZ dosing regimens in a subset of pts. Downstream cytokine pharmacodynamic responses (IL-6 and C-reactive protein [CRP]) were evaluated graphically post-TCZ dosing. Results: Data from 733 Mosun- and 772 Glofit-treated pts across different Mosun/Glofit dose levels were analyzed; of these, 232 (31.7%) and 427 (55.3%) pts, respectively, had ≥1 CRS event, and 36/232 (15.5%) and 140/427 (32.8%) pts received TCZ for CRS management. CRS events were mainly Grade 1/2 and occurred during the first treatment cycle. Most pts who received TCZ for CRS received ≤2 doses of TCZ overall (Mosun: 94.4%; Glofit: 84.2%) ( Table), and 1 dose of TCZ for the management of a single CRS event (Mosun: 91.7%; Glofit: 84.9%). CRS resolution was achieved within 3 days of TCZ administration in 75.0% and 66.9% of Mosun- and Glofit-treated pts, respectively. By then, a reduction in IL-6 and CRP levels was also observed. In a prior pharmacokinetic (PK) analysis of TCZ in pts with CAR T-cell-associated CRS, predicted TCZ conc after administration of 4 intravenous (IV) TCZ doses of 8 mg/kg every 8 hours (q8h) was generally below 649 μg/mL, the observed maximum conc in healthy volunteers and “safety threshold” used by the FDA (Le et al. Oncologist 2018). qCP analyses of TCZ PK and s-IL6R data from 67 pts who received TCZ for CRS management following treatment with Mosun or Glofit indicated that this TCZ regimen may exceed the safety threshold, in part because maximum TCZ conc is one-third lower in pts with CAR T-cell-induced CRS vs bispecific antibody-induced CRS. In addition, typical bispecific antibody regimens involve multiple doses compared with a single CAR T-cell infusion, with the potential for multiple CRS events requiring TCZ treatment; therefore, TCZ accumulation must be considered. qCP simulations predicted that for 1 x 8 mg/kg dose, median duration of >90% s-IL6R saturation was 28 (range: 14-28) days ( Table). Furthermore, simulations indicated that ≤2 consecutive TCZ doses q8h per CRS event and a maximum of 3 TCZ doses within a 6-week time period maintain the TCZ conc below the FDA safety threshold, while ensuring sustained s-IL6R occupancy ( Table). Conclusions: qCP results and clinical experience in Mosun and Glofit studies support a TCZ dosing regimen of ≤2 IV doses of 8 mg/kg per CRS event administered q8h, not exceeding a total of 3 doses within a 6-week period. Further improvement in CRS management and symptom resolution with additional TCZ doses is unlikely given the predicted duration of s-IL6R occupancy and observed rapid decline in systemic inflammatory markers post dosing. This proposed TCZ dosing regimen reflects TCZ usage patterns in clinical trials evaluating Mosun and Glofit, and is included in their Summaries of Product Characteristics. In patients with R/R B-NHL receiving bispecific antibody treatment, TCZ is generally suitable for management of acute CRS, and balances risk-benefit for potential scenarios involving multiple TCZ administrations for pts with CRS recurrence. This recommendation considers TCZ safety factors, the unique PK properties of TCZ in this setting and the expected duration of activity based on pharmacological modeling of target binding (s-IL6R occupancy).