Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study

For more than 30 years, umbilical cord blood (UCB) has been an important source of hematopoietic stem cells (HSCs) for use in allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is a particularly critical stem cell source for non-White patients who are underrepresented in the international adult donor registries.¹ Compared with transplants from adult donors, adult umbilical cord blood transplantation (UCBT) has been associated with increased early treatment-related morbidity and mortality stemming from delayed hematopoietic recovery and immunologic reconstitution. The advent of dual UCB grafts, refinement of pretransplant conditioning regimens, and improved supportive care have addressed many of the limitations of adult UCBT. However, delayed hematopoietic recovery remains a problem, resulting in increased use of resources.^2,3 Early-phase studies have demonstrated that ex vivo expansion of UCB stem cells before transplantation has the potential to address this critical shortcoming. By expanding both hematopoietic stem and progenitor cells, the time to neutrophil recovery after myeloablative conditioning can be even more rapid than the time after a mobilized peripheral blood stem cell (PBSC) graft.^4-7 

Omidubicel (Gamida Cell, Jerusalem, Israel) is a patient-specific cell product derived from a single banked UCB unit. It consists of an ex vivo expanded CD133⁺ fraction and a nonexpanded CD133^– fraction. Nicotinamide, the active agent in the culture system, inhibits differentiation and enhances functionality of cultured hematopoietic stem and progenitor cells. Preclinical studies demonstrated that when UCB-derived hematopoietic progenitor cells are cultured in the presence of nicotinamide and stimulatory hematopoietic cytokines, there is an outgrowth of phenotypically primitive CD34⁺CD38^– cells and a substantial increase in bone marrow (BM) homing and engraftment potential.⁸ The ability of nicotinamide to expand both committed and long-term repopulating HSCs was confirmed in early-phase studies of omidubicel.^6,9 In this study, we compared the outcomes of a myeloablative allo-HSCT using omidubicel with standard UCB grafts.

The trial was designed by the sponsor (Gamida Cell) in collaboration with a protocol steering committee. Enrollment began in January 2017 and was completed in January 2020. Random assignments were performed at the Emmes Company in a 1:1 ratio using minimization factors of age, center, disease risk index, and intention to use 1- or 2-unit UCB grafts if patients were randomly assigned to the control arm. As sites enrolled participants, they were randomly assigned using the centralized data entry system at Emmes Company. The primary end point was time to neutrophil engraftment. Secondary end points were platelet engraftment by 42 days, incidence of grade 2 to 3 bacterial or invasive fungal infection during the first 100 days, and days alive and out of the hospital for the first 100 days after transplantation. Additional planned end points included assessment of safety, nonrelapse mortality (NRM), relapse, overall survival (OS) and disease-free survival (DFS), acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), engraftment, and infectious complications. The trial was approved by the Institutional Review Boards of all participating institutions and the national regulatory authorities. All patients provided written informed consent. The study was performed in accordance with the International Conference on Harmonization, in agreement with local regulations and with the principals of Declaration of Helsinki.

Eligible patients were age 12 to 65 years with high-risk hematologic malignancies, were candidates for myeloablative allo-HSCT, and had no readily available matched sibling or matched unrelated adult donor. Patients with marked or 3+ BM fibrosis or chronic lymphocytic leukemia were excluded. Patients were required to have an available UCB unit HLA-matched at 4 or more loci (HLA-A, B at the antigen-level, and DRB1 at the allele level) with a total nucleated cell (TNC) count ≥1.8 × 10⁹, a TNC dose of ≥1.5 × 10⁷ cells per kg, and CD34⁺ cell count of ≥8 × 10⁶. This unit was designated for use before random assignments were made and was required to be used in both arms of the study. For patients randomly assigned to the control arm, a double cord blood graft was mandated when the omidubicel-designated unit (designated before random assignment and required to be used) was HLA-matched at 5 to 6/6 and contained <2.5 × 10⁷ TNCs per kg or <1.2 × 10⁵ CD34⁺ cells per kg, or were HLA 4/6 matched and contained <3.5 × 10⁷ TNCs per kg or <1.7 × 10⁵ CD34⁺ cells per kg. Patients were also required to have available backup cord blood unit(s). The presence of donor-specific antibodies to HLA-A, -B, -C, or DRB1 antigens (mean florescence intensity >3000) was not permitted. A detailed list of inclusion and exclusion criteria are provided in the protocol document (supplemental Material, available at the Blood Web site). Planned enrollment was 120 patients. In all, 125 patients were randomly assigned at 33 sites in North and South America, Europe, and Singapore. Participating centers and principal investigators are listed in supplemental Table 1. The population of 125 randomly assigned patients was analyzed as the intent-to-treat population (ITT), using the randomized treatment assignment. Of the 125 randomly assigned patients, 117 received an omidubicel or UCB transplant by day 90 after random assignment. This was the population that received transplants, which was also analyzed by treatment assignment. The as-treated population included 108 patients analyzed according to treatment received (Figure 1).

The omidubicel-designated unit was transported from the cord blood bank to a Current Good Manufacturing Practice–compliant cell-processing facility (Lonza, Walkersville, MD, or Gamida Cell, Jerusalem, Israel). Omidubicel was manufactured as previously described.⁶ Briefly, the unit underwent immunomagnetic bead selection for CD133⁺ cells. The CD133^–, T-cell–containing flow-through fraction was retained and recryopreserved. The CD133⁺ fraction was cultured in the presence of Flt-3 ligand, stem cell factor, thrombopoietin, interleukin-6, and nicotinamide for 21 ± 2 days and then cryopreserved. Both fractions were transported together to the transplantation center.

Three alternative myeloablative conditioning regimens were permitted for study participants: 2 contained total body irradiation and 1 contained chemotherapy only (Table 1). GVHD prophylaxis was provided by a calcineurin inhibitor (tacrolimus with target trough levels of 5-15 ng/mL or cyclosporine with target trough levels of 200-400 ng/mL) and mycophenolate mofetil 15 mg/kg 3 times per day (maximum daily dose, 3 g) starting 3 days before transplantation. Mycophenolate mofetil was continued for a minimum of 60 days and the calcineurin inhibitor for minimum of 100 days after transplantation in the absence of toxicity or relapse.

Granulocyte-colony stimulating factor (5 µg/kg of recipient body weight) was given once per day starting on day +1 after transplantation until the absolute neutrophil count exceeded 1000 cells per µL. Antiviral and antifungal prophylaxis were administered at the discretion of the transplantation center. Antibacterial prophylaxis after transplantation was required by protocol. The agent used was at the discretion of the transplant center.

Donor chimerism was performed by the local transplant center on whole blood, CD15⁺ myeloid, and CD3⁺ T cells using quantitative analysis of informative microsatellite DNA sequences. Quantitative assessment of CD3, CD4, CD8, natural killer (NK) and B-cell recovery was performed on a subset of patients by the transplant center (or designated referral laboratory) at 1, 2, 3, 6, and 12 months after transplantation. The time to engraftment of neutrophils ≥500 cells per µL and platelets >20 000/µL was defined according to Center for International Blood and Marrow Transplant Research (CIBMTR) standards, requiring donor chimerism for neutrophil engraftment. Grading of bacterial and invasive fungal infections was adapted from definitions in the Blood and Marrow Transplant Clinical Trials Network technical manual of procedures (supplemental Table 2).

The main comparisons of the primary and secondary end points as well as mortality end points were conducted using ITT analysis. Cox proportional hazards models were used in the analysis of DFS and OS, with randomly assigned treatment and disease risk as covariates in the model. The incidence of engraftment and engraftment kinetics were also calculated in the as-treated population. GVHD was assessed in the population that received a transplant and was defined as all patients randomly assigned to receive a UCBT, grouped by the treatment to which they were allocated. GVHD-free relapse-free survival (RFS) was evaluated in the as-treated population, grouped by treatment received. The primary end point (time to neutrophil engraftment) was compared between treatment groups using a Mann-Whitney–based statistic. A value of 43 days was assigned for patients who had received a transplant who did not engraft by 42 days after transplantation or patients who did not receive a transplant. P values for this and other protocol-specified ITT analyses were calculated using the rerandomization distribution.¹⁰ Sample size was chosen to provide at least 90% power for the primary end point analysis, based on information on engraftment times derived from the phase 2 study and the CIBMTR database.

Secondary end points of proportion of patients with grade 2 to 3 bacterial or invasive fungal infections up to 100 days posttransplant and proportion with platelet engraftment by 42 days were compared using cumulative incidence rates. Time out of hospital in the first 100 days was compared using the Mann-Whitney statistic. Differences in cumulative incidence were also analyzed for NRM and for relapse. For non-ITT analyses, neutrophil engraftment was compared using the Wilcoxon rank sum test or Fisher’s exact test, and time to platelet engraftment was compared using Gray’s test. GVHD for patients who received transplants was compared using a z test on the cumulative incidence difference. Infection densities were compared using the generalized estimating equation (GEE) approach for a linear model with 2 periods (0-30 and 31-365 days posttransplant) and a negative binomial link. The associations of CD34⁺ total cells and CD34⁺ dose with time to engraftment were evaluated using linear regression and correlation analyses of the log-transformed values. Immune reconstitution analyses were evaluated using Wilcoxon rank sum tests. P values for the multivariable models and non-ITT analyses were calculated using asymptotic methods. Confidence intervals (CIs) were calculated using bootstrap methods; the multivariable models and GEE models used asymptotic CIs. The multivariable Cox models, the GEE models, CD34⁺ associations with neutrophil engraftment, Gray’s test for platelet engraftment, GVHD-free RFS, and moderate-to-severe cGVHD analyses were post hoc analyses. The end points were evaluated after all evaluable patients completed 6 months of follow-up after transplantation; study follow-up is ongoing.

Demographics and baseline characteristics were well-balanced across the 2 arms (Table 1). In all, 125 patients (median age, 41 years; range, 13-65 years) were randomly assigned to receive omidubicel (n = 62) or standard single (33%) or double (67%) UCB grafts (n = 63). Ten patients randomly assigned to the omidubicel arm did not receive omidubicel per protocol. Eight patients randomly assigned to the standard UCB arm did not receive a transplant per protocol (Figure 1). Most patients had acute myeloid leukemia (48%) or acute lymphoblastic leukemia (33%). The disease risk index was moderate in 42% and high in 34% of patients. The study population was diverse with 16% Black, 14% Asian, 3% multiracial, and 13% Hispanic or Latino patients. Patients treated with omidubicel received a transplant at a median of 41 days after random assignment compared with 26 days for patients treated with standard UCBT.

Characteristics of the standard single and double cord blood grafts and the omidubicel grafts are shown in Figure 2. The median total CD34⁺ cell content of the control cord blood unit(s) and the omidubicel unit before expansion (as reported by the cord blood bank before cryopreservation) was 0.23 × 10⁸ cells (range, 0.11 × 10⁸ to 0.55 × 10⁸ cells) and 0.14 × 10⁸ cells (range, 0.09 × 10⁸ to 0.4 × 10⁸ cells), respectively. After expansion, the content of the omidubicel unit increased to a median 6.6 × 10⁸ CD34⁺ cells (range, 2.8 × 10⁸ to 39 × 10⁸ cells). Median CD34⁺ cell expansion was 130-fold (range, 32- to 233-fold). The median CD34⁺ cell dose of omidubicel and control grafts was 9.0 × 10⁶ cells per kg (range, 2.1 × 10⁶ to 47.6 × 10⁶ cells per kg) and 0.3 × 10⁶ cells per kg (range, 0.1 × 10⁶ to 1 × 10⁶ cells per kg), respectively. The CD3⁺ T cells in the omidubicel graft were contained solely in the unexpanded CD133^– fraction.

The median CD3⁺ content of the omidubicel grafts before cryopreservation was 210 × 10⁶ CD3⁺ cells (range, 71 × 10⁶ to 640 × 10⁶ cells), and 3 × 10⁶ CD3⁺ cells per kg (range, 1.1 × 10⁶ to 12.4 × 10⁶ CD3⁺ cells per kg). This compared with a median 412.9 × 10⁶ CD3⁺ cells (range, 4.4 × 10⁶ to 989.8 × 10⁶ CD3⁺ cells), and 4.6 × 10⁶ CD3⁺ cells per kg (range, 0 × 10⁶ to 14.8 × 10⁶ CD3⁺ cells per kg) for the control grafts. CD3 content was enumerated after thawing and before infusion from a subset of 25 control patients. Thus, the observed difference in CD3 content is underestimated because of additional cell loss after thawing the omidubicel product.

The median time to neutrophil recovery per ITT analysis was 12 days (95% CI, 10-14 days) for those randomly assigned to omidubicel and 22 days (95% CI, 19-25 days) for controls (P < .001) (Table 2). The cumulative incidence of neutrophil engraftment by day 42 after transplantation for patients receiving omidubicel (as-treated population, n = 52) was 96% at a median of 10 days (95% CI, 8-13 days) compared with 89% at a median of 20 days (95% CI, 18-24 days) for the controls (n = 56) (P < .001) (Figure 3A). For patients who received a transplant with omidubicel, higher total CD34⁺ cell counts and CD34⁺ cell doses (per weight) were associated with shorter times to neutrophil engraftment (Figure 4, correlations: total cells, r = –0.66; P < .001; cell dose, r = –0.62; P < .001).

The cumulative incidence of platelet engraftment by day 42 after transplantation for patients randomly assigned to omidubicel was 55% vs 35% for controls (P = .028) (Table 3). For the patients transplanted with omidubicel, the cumulative incidence of platelet engraftment by day 100 after transplantation was 83% at a median of 37 days (95% CI, 33-42 days) vs 73% at a median of 50 days (95% CI, 42-58 days) for the controls (P = .023) (Figure 3B).

Full donor chimerism (defined as >90% in the whole blood fraction) was observed at day +30 and day +100 after transplantation in all but 2 omidubicel recipients; one experienced early relapse and the other experienced primary graft failure. Six standard UCBT recipients experienced graft failure on day +42. The remaining evaluable standard UCBT recipients had full donor chimerism at day +30 and day +100 after transplantation.

Among the patients who received a transplant who were randomly assigned to omidubicel (n = 59) or standard cord blood (n = 58), the incidence of grade 2 to 4 aGVHD at day 100 was similar at 56% vs 43% (13% difference: 95% CI, −6% to 30%; P = .18), respectively (Figure 5A). Grade 3 to 4 aGVHD at day 100 was also similar in the omidubicel and control arms at 14% vs 21% (–7% difference; 95% CI, −21% to 7%; P = .33) (Figure 5B). The cumulative incidence of all cGVHD at 1 year was 35% for the omidubicel arm and 29% for the controls (6% difference; 95% CI, −14% to 25%; P = .57) (Figure 5C). The 1-year cumulative incidence of moderate-to-severe cGVHD was 27% for the omidubicel arm and 21% for the controls (6% difference; 95% CI, −11% to 24%; P = .49).

The median follow-up of all patients was 10 months after transplantation (range, 1-19 months). Using ITT analysis, the cumulative incidence of NRM at 210 days after random assignment was 11% for the omidubicel arm and 24% for the control arm (P = .09) (Figure 6A). The cumulative incidence of disease relapse at 15 months after random assignment was 25% for the omidubicel arm and 17% for the control arm (P = .32) (Figure 6B). During the time from random assignment to transplantation, relapse was reported in 4 patients allocated to the omidubicel arm and 4 patients allocated to the standard UCBT arm. Among these, relapse prevented 2 patients allocated to the omidubicel arm and 3 patients allocated to the UCBT arm from receiving a transplant by day 90 after random assignment (Figure 1).

The adjusted hazard ratio for treatment failure (relapse or death, inverse of RFS) with omidubicel vs standard UCB was 0.79 (95% CI, 0.45-1.38; P = .4). The adjusted hazard ratio for mortality with omidubicel vs standard UCB was 0.57 (95% CI, 0.3-1.1; P = .09) (Figure 6C-D). The 1-year GVHD-free RFS for the omidubicel arm was 36% and 45% for standard UCBT (P = .56).

Eleven deaths were reported among the as-treated population of patients who received a transplant with omidubicel, and 18 deaths among the patients treated with a standard UCB graft. As reported by the study investigators, 2 patients who received a transplant with omidubicel died of relapsed disease compared with 4 patients who received a transplant with a standard UCB graft. Among the treatment-related causes of death, GVHD was the setting for death for 4 patients in each group.

Patients randomly assigned to the omidubicel graft spent more days alive and out of hospital in the first 100 days after transplantation than those randomly assigned to UCBT; the median time was 61 days (range, 0-89 days) and 48 days (range, 0-84 days), respectively (P = .005). The median time from transplant to discharge from the hospital was 27 days for the omidubicel arm and 35 days for the control arm (P = .005). From random assignment and up to 100 days after transplantation, the cumulative incidence of first grade 2 to 3 bacterial or invasive fungal infections was 37% for patients randomly assigned to the omidubicel arm and 57% for patients who received the standard UCBT (P = .03) (Figure 7A). The cumulative incidence of first grade 3 viral infection during the first year after transplantation was also lower for those randomly assigned to the omidubicel arm (10% vs 26%; P = .02) (Figure 7B).

To account for the possibility of multiple infections per single patient and relative differences in periods of risk between the treatment groups, we compared infection density during the first year after transplantation. The risk ratio for all infections, irrespective of severity, was significantly lower among recipients of omidubicel compared with those who received standard UCBT. The same observation was made when bacterial and viral infections were analyzed individually (Figure 7C). Overall, fewer infections from all reported viral species were observed for omidubicel recipients (Figure 7D); however, these differences did not reach statistical significance. Invasive fungal infections were uncommon in both arms of the study.

The incidence of treatment-emergent serious adverse events (SAEs) possibly related to the stem cell product was similar in the 2 arms (40% for omidubicel and 41% for standard cord blood grafts). A breakdown of the treatment-emergent adverse events in both arms of the study is provided in supplemental Table 3. Those treatment-emergent events reported as related to the cord blood infusion are outlined in supplemental Table 4. After random assignment and before starting pretransplant conditioning, 10 serious adverse events (SAEs) were reported for those assigned to the omidubicel arm and 8 SAEs were reported for those assigned to a standard UCB graft.

Quantitative recovery of lymphoid subsets was monitored at 1, 3, 6, and 12 months after transplantation in subsets of patients on both arms of the study. Despite the lower numbers of CD3⁺ cells in patients on the omidubicel arm compared with those who received standard UCB grafts, the pace of recovery to normal levels of CD3⁺, CD4⁺, CD8⁺, CD19⁺, and CD56⁺/CD16⁺ NK cells was similar in both groups (supplemental Figure 1A-E).

Omidubicel is an ex vivo expanded, UCB-derived stem cell graft that was designed to address the major limitations of adult UCBT. There were 3 main findings from this multicenter randomized trial comparing omidubicel to a standard UCB graft. (1) The study confirmed that omidubicel safely addresses the most vexing limitation of UCBT, which is the delay in hematopoietic recovery. Omidubicel reduced the median time to neutrophil recovery by 10 days and the median time to platelet recovery by 13 days. (2) Omidubicel reduced the incidence of infectious complications and time spent in the hospital during the early posttransplantation period. (3) The study demonstrated the feasibility and safety of delivering a personalized, manufactured HSC product to transplantation centers around the world.

Multiple techniques designed to expand UCB stem and progenitor cells have been reported.^5-7,11-13 Omidubicel (previously known as NiCord) is the first drug to complete phase 3 testing, the results of which were consistent with observations from earlier studies that examined both safety and efficacy.^6,9 The omidubicel graft provides a CD34⁺ cell dose that is comparable to an adult mobilized PBSC graft. The 12-day median time to neutrophil recovery is similar to that for mobilized PB, suggesting that both graft sources are enriched for active hematopoietic progenitor cells.¹⁴ Furthermore, long-term follow-up from the earlier studies of omidubicel⁶ suggest robust, durable engraftment for more than 10 years, confirming the persistence and possible expansion of long-term repopulating cells during the ex vivo culture period. The clinical impact of reducing the time to hematopoietic recovery has been well characterized in the literature. A prospective multicenter study of BM vs PBSC grafts showed that a 5-day reduction in time to neutrophil recovery after PBSC graft translated into a reduction in bacterial infections.¹⁵ Conversely, a large multicenter study using the CIBMTR database demonstrated delayed hematopoietic recovery after standard adult UCBT resulted in prolonged hospital use.³ In line with the previous studies, rapid hematopoietic recovery after omidubicel transplantation translated into clinical benefit by reducing infections and time spent in the hospital during the first 100 days after transplantation. Importantly, although omidubicel grafts had a lower T-cell content, the recovery of T cells after transplantation is comparable to that with standard UCB, and the risk of viral infections was lower than that with standard UCB throughout the first year after transplantation. The reduced risk of viral infections for recipients of omidubicel was an unexpected finding and could perhaps be attributable to more robust NK cell reconstitution. Further studies of the T-cell receptor diversity are planned and may provide additional insight into this observation.

This study establishes for the first time, the feasibility of providing a personalized, ex vivo expanded HSC graft to recipients throughout the world. This was made possible with logistical support provided by both the sponsor and the regional UCB registries. For example, the National Marrow Donor Program provided participating centers with advice on selecting units that meet prespecified characteristics for expansion. Furthermore, they worked with the sponsor to facilitate transportation of the unit from the cord blood bank to the cell processing facility. Of note, although the added logistical complexity of producing an ex vivo expanded UCB graft led to a median 2-week delay in time from random assignment to transplantation, this did not result in an increased risk of pretransplant relapse. The study suggests that what is now possible with a commercial, personalized T-cell product in the form of chimeric antigen receptor T-cell therapy can be accomplished at the same scale with a personalized HSC graft.

The encouraging results of transplantation with omidubicel have important implications for minority populations in need of allo-HSCT. Forty-four percent of the patients treated on study were non-White, a population known to be underrepresented in the world-wide unrelated adult donor and UCB registries. The underrepresentation of UCB grafts from Black donors has necessitated the use of smaller units compared with those used for White recipients, which results in inferior outcome.¹⁶ UCB expansion technologies allow for the use of smaller, better matched units with the aim of improving outcome.

The study has important limitations. Although the progression-free survival (PFS) and OS end points trended higher for those receiving omidubicel, the study was not powered to detect a statistically significant difference in these critical end points. Adult UCBT trials have been notoriously difficult to complete, with many previous multicenter trials closing early because of incomplete accrual.^17,18 For this reason, alternative end points of clinical benefit were chosen to allow for a more realistic sample size. Use of resources for transplantation of UCB grafts has historically exceeded that for adult donor stem cell grafts. The reduction in time to engraftment, hospitalization duration, and infectious complications is expected to reduce the need to use resources over those for a standard UCB graft. Although data on use of resources are not presented in this report, those data have been captured and will allow for confirmation of this expectation. These, and other pressing questions such as the performance of omidubicel transplantation after reduced intensity conditioning and comparative outcomes to other graft sources and specific disease types will need to be addressed in future studies.

Hematopoietic recovery after transplantation with omidubicel was faster, reduced early transplant-related complications, and reduced the number of days patients were hospitalized compared with standard UCBT. The results of this trial demonstrate that omidubicel represents a major therapeutic advance and should be considered as a new standard of care for adult patients eligible for UCBT.

The authors thank Bruno Boulanger and Elena Maurer from BPE for their contribution to the CD34 correlative analyses, and Sarah Anderson, Alice Henning, Shashidhar Joshy, Laura Morrison, and Amarnath Vijayarangan from the Emmes Company for their support for statistical analyses. This work was supported by funding from Gamida Cell.

Contribution: E.G.-C., M.E.H., L.S.F., and G.S. conceived the study design and protocol; L.S.F., B.B., and S.W. performed statistical analyses; M.E.H. performed the research and wrote the manuscript; and M.E.H., P.J.S., C.C., C.B., R.H., R.T.M., A.R.R., N.A.K., J.M., D.V., G.J.S., C.A.L., W.Y.K.H., L.P.K., A.K., Y.K., N.H., O.F., T.P., I.S., B.B., S.W., L.S.F., E.G.-C., and G.S. collected, assembled, analyzed, and interpreted the data, reviewed and approved the manuscript, and are accountable for all aspects of the work.

Conflict-of-interest disclosure: M.E.H. served as consultant to AbbVie, CareDx, and Magenta, received honoraria from Kadmon, and received research funding from Gamida Cell. P.J.S. served as a consultant to CRISPR and received research funding from Gamida Cell, Atara Biotherapeutics, Amgen, Incyte, Takeda, Macrogenics, and Eisai. C.C. served as a consultant and member of the board of directors or advisory committee for Incyte, Kadmon, Jazz Pharmaceuticals, Medsenic, Generon, and Mesoblast. C.B. received research funding from Magenta, Gamida Cell, and Astex and is an advisor to AlloVir. R.T.M. received research funding from Novartis and Juno, data safety monitoring board membership for Novartis and Athersys, received honoraria from Incyte, Kite Pharma, Bristol Myers Squibb/Celgene, PACT Pharma, Orca BioSystems, and Omeros, has patents with and receives royalties from Athersys, and served as a consultant for Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and Allovir. A.R.R. received research funding from Pharmacyclics. J.M. received research funding from Novartis, Fresenius Biotech, Astellas, Bellicum Pharmaceuticals, Gamida Cell, and Pluristem, and received honoraria and served as a consultant for Kite Pharma, Juno, and AlloVir. G.J.S. served as a consultant for Agios, Amgen, AstraZeneca, Incyte, Novartis, and Ono, served on the speakers bureau for Celgene, Sanofi, Gilead, and Stemline, and received research funding from AbbVie, Actinium, Ariad, Astellas, Celgene, Celator, Constellation, Cyclacel, Daiichi Sankyo, Deciphera, DeltaFly, Forma, FujiFilm, Gamida Cell, Genentech, Roche, Geron, Jazz Pharmaceuticals, Karyopharm, Kite Pharma, Mateon, Medimmune, Onconova, Pfizer, Regimmune, Samus, Sangamo, Tolero, Trovagene, Kaiser Permanente, and Johnson & Johnson, and has equity in Bristol Myers Squibb and Pfizer. Y.K. was a member of the board of directors, advisory committee, or speakers bureau for Celgene, Seattle Genetics, Jazz Pharmaceuticals, and Takeda. G.S. served on an advisory committee for AbbVie, Hoffman-LaRoche, Helsinn, and Takeda. I.S. and E.G.-C. are employed by and have equity holdings in Gamida Cell. T.P. reports equity holdings in Gamida Cell. B.B. and S.W. are employed by Emmes Company. L.S.F. declares that Gertner Institute for Epidemiology and Health Policy Research received remuneration from Gamida Cell for the statistical consultation that he provided to the trial. The remaining authors declare no competing financial interests.

Correspondence: Mitchell E. Horwitz, Duke University Medical Center, 2400 Pratt St DUMC 3961, Durham, NC 27710; e-mail: mitchell.horwitz@duke.edu.