Abstract
Background
Omidubicel is an advanced cell therapy derived from umbilical cord blood (UCB) for use in allogeneic hematopoietic cell transplantation (HCT). A recent randomized phase 3 clinical trial demonstrated faster engraftment, shorter hospitalizations, and lower rates of infections with omidubicel when compared to standard UCB transplantation in patients with high-risk hematologic malignancies (Horwitz et al., Blood 2021). Despite the proven clinical benefits of omidubicel, its impact on health-related quality of life (HRQL) from the patient’s perspective has not been described.
Objectives
This study reports on the analysis of patient-reported HRQL measures prospectively collected in the randomized phase 3 trial comparing omidubicel to standard UCB transplantation.
Study Design
A total of 108 patients at 33 international stem cell transplant centers received myeloablative allogeneic HCT with either omidubicel or standard UCB. Patients completed serial HRQL questionnaires at screening and on days 42, 100, 180, and 365 post-transplant. Administered HRQL surveys include the Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT), a 37-item cancer-specific questionnaire assessing physical, functional, emotional, social/family, and HCT–specific well-being, and the EuroQol 5-Dimension 3-Level, a 5-item generic HRQL survey. A mixed model with repeated measures was used to compare HRQL changes from baseline between treatment arms. The average change in HRQL scores over time was compared by estimating the difference in the area under the curve (AUC) in each treatment group.
Results
Seventy-five patients (omidubicel n = 37, standard UCB n = 38) who completed the FACT-BMT at baseline and on ≥1 follow-up visit were included in this study. Baseline characteristics were similar between treatment arms. Over the first year post-transplant, the AUCs of mean change in physical, functional, and total FACT-BMT scores indicated significantly better HRQL with omidubicel (P < .05), with mean differences across time points ranging from 1.4–3.1, 1.6–3.2, and 7.2–11.0 points, respectively. The minimal clinically important difference was exceeded on at least 1 time point for each of these measures. The HRQL improvements from omidubicel were observed as early as 42 days post-transplant and persisted at 1 year, indicating the potential long-term benefits of omidubicel on HRQL. Across all patients, adverse clinical outcomes such as grade 3 viral infections and lower rates of neutrophil engraftment were associated with worse HRQL scores. The observed improvements in HRQL measures may reflect the known clinical benefits of omidubicel.
Conclusions
Compared to standard UCB, allogeneic HCT with omidubicel resulted in significant and clinically meaningful improvements in patient-reported HRQL measures.
Graphical Abstract
Introduction
Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells that has expanded the access of allogeneic hematopoietic cell transplantation (HCT) for underrepresented patient populations. Nonetheless, UCB transplantation remains limited by the lower number of hematopoietic stem and progenitor cells, as well as the preponderance of naïve B and T cells, present in cord blood when compared to mobilized peripheral blood or bone marrow sources. This has led to higher rates of transplant-related mortality due to delayed engraftment and infectious complications [1,2].
Omidubicel is a novel umbilical cord–derived advanced cell therapy product comprising an ex vivo nicotinamide-expanded and enhanced CD133+ stem cell fraction and a non-expanded CD133− fraction containing mature lymphoid cells [3]. Culturing stem cells with nicotinamide has been shown to inhibit stem cell differentiation and improve bone marrow homing [4]. A multicenter, phase 3 randomized clinical trial was conducted comparing allogeneic HCT with omidubicel to standard UCB after myeloablative conditioning in patients with advanced hematologic malignancies [5]. This international study showed that transplantation with omidubicel resulted in faster neutrophil and platelet engraftment and shorter hospitalizations during the first 100 days following transplant. Omidubicel also led to a lower incidence of infectious complications, including grade 2/3 bacterial infections, grade 3 invasive fungal infections, and grade 3 viral infections. The rates of survival and graft-versus-host disease (GVHD) were similar between the treatment arms. Furthermore, recent reports have suggested rapid immune reconstitution and favorable long-term graft durability with omidubicel [6,7].
With the success of omidubicel and other recent advancements in the field of hematopoietic cell transplantation in improving objective transplant-related outcomes, there is an increasing focus on understanding how these novel transplantation techniques can impact health-related quality of life (HRQL) and improve the patient experience with transplantation. Prior studies have consistently demonstrated the profound and multidimensional impact that allogeneic HCT can have on patients’ HRQL in the early post-transplant period, which may continue to long-term impairment [8–11]. In this study, we compared the serially collected HRQL measures between patients who received allogeneic HCT with omidubicel versus standard UCB in the phase 3 randomized trial (ClinicalTrials.gov identifier: NCT02730299) [5]. This investigation complements the primary efficacy analysis from the clinical trial and may provide important insight for key stakeholders and decision-makers, including providers, payers, caregivers, and patients themselves.
MATERIALS AND METHODS
Study Design
The study design for the prospective, multicenter, randomized phase 3 clinical trial has previously been reported [5]. In brief, 125 patients with advanced hematologic malignancies were enrolled at 33 sites across North and South America, Europe, and Singapore. These patients were randomized 1:1 to receive either open-label omidubicel (n = 62) or control standard UCB units (n = 63) for allogeneic HCT. Minimization factors for randomization included age, treatment center, disease risk index, and intent to use 1- or 2-unit standard UCB grafts in the control arm. Among the randomized patients, 10 patients in the omidubicel arm and 8 in the control arm did not receive a transplant per protocol, leaving 108 patients in the as-treated population.
Three myeloablative conditioning regimens were permitted for the study (fludarabine 160 mg/m2 + thiotepa 10 mg/kg + total body irradiation 1350 cGy, fludarabine 75 mg/m2 + cyclophosphamide 120 mg/kg + total body irradiation 1320 cGy, or busulfan 12.8 mg/kg + fludarabine 150 mg/m2 + thiotepa 10 mg/kg). GVHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil starting 3 days prior to transplantation. The primary objective of the clinical trial was to compare the time to neutrophil engraftment after transplantation, which has been reported previously [5]. A planned exploratory objective was to describe and compare HRQL measures between the 2 treatment arms.
This study was approved by the institutional review boards at each respective research site. All patients gave written informed consent to be included in this study. The multicenter HRQL data were compiled as part of the clinical trial by Gamida Cell (Jerusalem, Israel) and The Emmes Company (Rockville, MD, USA). Statistical analysis was performed by Analysis Group, Inc. (Boston, MA, USA).
Study Population
Eligible study participants were 12–65 years of age and had a high-risk hematologic malignancy. Participants must have been candidates for an allogeneic HCT and must not have had a matched donor available. Exclusion criteria for the trial included chronic lymphocytic leukemia and the presence of 3+ fibrosis in the bone marrow. Between January 2017 and January 2020, 125 patients were randomized, and 108 patients received either omidubicel or standard UCB grafts for HCT (Figure 1) [5]. This HRQL study was performed on the as-treated population and included only those patients who had available HRQL data both at baseline and during at least 1 follow-up visit.
Figure 1.
CONSORT diagram depicting randomization and treatment of patients from the phase 3 clinical trial comparing allo-HCT with omidubicel versus standard UCB, as well as subsequent inclusion into the associated HRQL study. Allo-HCT indicates allogeneic hematopoietic stem cell transplantation; CBU, cord blood unit; HRQL, health-related quality of life; UCB, umbilical cord blood.
HRQL Questionnaires
Patient-reported HRQL measures were prospectively collected at the time of screening and at 42, 100, 180, and 365 days post-transplant. Two standardized HRQL instruments were utilized in this study. Functional Assessment of Cancer Therapy - General (FACT-G) version 4 is a 27-item cancer-specific HRQL questionnaire, which assesses the domains of physical, social/family, emotional, and functional wellness [12]. Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT) adds an additional BMT subscale to FACT-G [13]. The inclusion of this multidimensional questionnaire allows for detailed assessment of cancer-specific and transplant-specific HRQL concerns. EuroQol 5-Dimension 3-Level (EQ-5D-3L) is a generic, non–disease-specific, 5-item HRQL questionnaire evaluating mobility, self-care, usual activities, pain, and anxiety/depression [14]. This shorter questionnaire can easily be completed during clinic visits and allows for a general assessment of HRQL status. The shorter EQ-5D-3L questionnaires were completed by patients using self-administered instruments provided during clinic visits, while FACT-BMT questionnaires could also be completed electronically at home via a computer. Patients were instructed to fill out the questionnaires themselves rather than designating a surrogate. If a patient’s questionnaire was missing >50% of its responses, then the patient data for that entire questionnaire were considered to be missing. Higher questionnaire scores indicate better HRQL (FACT-G scores range from 0 to 108 points, FACT-BMT from 0 to 148 points, and EQ-5D-3L index score from 0 to 1).
Among cancer patients who undergo allogeneic HCT, the minimal clinically important difference (MCID) is defined as a change of ≥ 2 points in the FACT-G domain score, ≥ 5 points in the FACT-G total score, ≥ 2 points in the BMT subscale score, and ≥ 7 points in the FACT-BMT total score [13,15]. For measures of internal consistency, Cronbach alpha coefficients range from 0.85 to 0.92 for FACT-BMT in the transplant population [13]. The MCID of the EQ-5D-3L index score is defined as 0.07 points for general use; this has not been investigated specifically in transplant patients [16].
Statistical Analysis
Per the omidubicel phase 3 trial protocol, HRQL data were collected prospectively. However, statistical analyses for comparison of treatment arm differences were not prespecified in the trial analysis plan. The post hoc analyses described below were therefore conducted to compare treatment arm differences in HRQL. To assess balance, baseline characteristics were compared between the 2 treatment arms and between patients included and excluded from the HRQL study using t tests for continuous variables and chi-square tests for categorical variables.
Mixed models for repeat measures (MMRM) were used to compare changes in the HRQL measures over time between groups. The MMRM models included time, treatment group, and the interaction between treatment group and time and were further adjusted for baseline HRQL value, region (United States and not United States), age group, sex, race (white and non-white), HCT-specific comorbidity index, and primary cancer diagnosis. Correlations across repeated HRQL measures from the same individual were accounted for via an unstructured covariance matrix, which allows for possible changes in the variability of HRQL during follow-up. The area under the curve (AUC) for mean HRQL, which represents the average HRQL change over time, was compared between the treatment groups. This approach was selected due to the potential for HRQL scores to both worsen and improve over time such that no single time point would be representative of the full patient experience [17]. The time from transplant to first improvement or first worsening greater than the MCID was summarized in each treatment group using Kaplan-Meier analyses and compared between groups using the log-rank test. In these time-to-event analyses, patients with changes less than the MCID were censored at last follow-up.
The association between clinical outcomes and the change in HRQL measures from baseline to day 42 and day 100 post-transplant was assessed using multivariable linear regression models. Clinical outcomes of interest included neutrophil engraftment, platelet engraftment, infectious complications, grades II-IV acute GVHD, and length of hospitalization during the first 100 days post-transplant. The time points of 42 and 100 days post-transplant were selected for analysis as many of the clinical benefits associated with omidubicel occurred in the early post-transplant period. The regression models were adjusted for treatment group, baseline HRQL scores, region, age group, sex, race, HCT-specific comorbidity index, and primary cancer diagnosis. Changes in the scores of specific BMT subscale items from baseline to last assessment were evaluated using a similar linear regression model. All analyses were performed using R version 3.6.3. As these analyses were exploratory, there were no statistical adjustments for multiplicity.
RESULTS
Study Population
Seventy-five of the 108 patients in the as-treated population (69%) completed the FACT-BMT questionnaire both at baseline and on ≥ 1 follow-up visit and were thus included in this analysis (omidubicel, n = 37; standard UCB, n = 38). Sixty-eight patients (63%) completed the EQ-5D-3L survey at baseline and on ≥ 1 follow-up visit. For both FACT-BMT and EQ-5D-3L, the rate of survey completion decreased over time. Among the 75 included patients, the FACT-BMT completion rates were 100% at baseline, 81% at day 42, 84% at day 100, 68% at day 180, and 61% at day 365. The EQ-5D-3L completion rates were 89% at baseline, 77% at day 42, 76% at day 100, 61% at day 180, and 40% at day 365.
When comparing patients who were included (n = 75) versus those in the as-treated population who were excluded (n = 33), included patients had a higher incidence of platelet engraftment by day 42 after transplantation (90.7% versus 54.6%, P < .001), fewer days in the hospital during the first 100 days (43.6 versus 66.3 days, P < .001), and better 1-year overall survival (82.7% vs 42.4%, P < .001). There was no statistically significant difference in the rates of neutrophil engraftment, grades II-IV acute GVHD, chronic GVHD, or disease relapse.
Baseline Characteristics
Among the 75 patients included in this study, baseline characteristics were comparable between patients who received omidubicel versus standard UCB (Table 1). The mean age of the patients was 36 years and approximately 59% were male. Over 40% of the participants were non-White, highlighting a key underrepresented demographic. The most common indications for allogeneic HCT were acute myeloid leukemia (45%) and acute lymphoblastic leukemia (35%). Most patients (77%) had either intermediate or high-risk disease and 51% had a HCT comorbidity index of ≥ 3. When comparing availability of HRQL data over time, patients who received omidubicel tended to have comparable or fewer missing data than standard UCB (19% versus 18%, 14% versus 18%, 27% versus 37%, and 38% versus 40% on days 42, 100, 180, and 365, respectively).
Table 1.
Baseline Characteristics of Patients Included in the HRQL Study.
| Omidubicel (n = 37) | Standard UCB (n = 38) | P Value | ||
|---|---|---|---|---|
| Demographics | Age (years), mean ± SD | 37.3 ± 15.5 | 35.1 ± 14.8 | .54 |
| 12–17, n (%) | 5 (13.5%) | 5 (13.2%) | ||
| 18–39, n (%) | 15 (40.5%) | 16 (42.1%) | ||
| 40–65, n (%) | 17 (45.9%) | 17 (44.7%) | ||
| Male, n (%) | 20 (54.1%) | 24 (63.2%) | .57 | |
| Weight (kg), mean ± SD | 82.4 ± 20.5 | 79.7 ± 21.3 | .57 | |
| White, n (%) | 24 (64.9%) | 20 (52.6%) | .72 | |
| US participants, n (%) | 27 (73.0%) | 28 (73.7%) | >.99 | |
| Clinical measures | Primary diagnosis, n (%) | |||
| Acute myelogenous leukemia | 17 (45.9%) | 17 (44.7%) | .97 | |
| Acute lymphoblastic leukemia | 12 (32.4%) | 14 (36.8%) | ||
| Chronic myelogenous leukemia | 3 (8.1%) | 2 (5.3%) | ||
| Myelodysplastic syndrome | 3 (8.1%) | 2 (5.3%) | ||
| Lymphoma | 1 (2.7%) | 2 (5.3%) | ||
| Other | 1 (2.7%) | 1 (2.6%) | ||
| Disease risk index, n (%) | ||||
| Low risk | 11 (29.7%) | 6 (15.8%) | .31 | |
| Intermediate risk | 12 (32.4%) | 17 (44.7%) | ||
| High risk | 14 (37.8%) | 15 (39.5%) | ||
| HCT-specific comorbidity index, n (%) | ||||
| 0 | 8 (21.6%) | 6 (15.8%) | .81 | |
| 1–2 | 11 (29.7%) | 12 (31.6%) | ||
| 3+ | 18 (48.6%) | 20 (52.6%) | ||
Higher scores indicate better HRQL. HCT indicates hematopoietic stem cell transplantation; HRQL, health-related quality of life; SD, standard deviation; UCB, umbilical cord blood.
Regarding clinical outcomes of interest, in this sample, the median time to neutrophil engraftment was 10.0 days for omidubicel vs 19.5 days for standard UCB (P < .001). In addition, the omidubicel group had a lower rate of grade 3 viral infections (5.4% versus 31.6%, P < .01) and a higher rate of grades II-IV acute GVHD (64.9% versus 39.5%, P < .05) compared to standard UCB in the first year (Table 2). There were also fewer days in the hospital during the first 100 days (38 versus 49 days, P < .05). There were no differences in the rates of chronic GVHD, grades III-IV acute GVHD, or grade 2/3 bacterial infections and grade 3 fungal infections.
Table 2.
Comparison of the Frequencies of Clinical Outcomes (Prespecified Endpoints in the Phase 3 Study) Between the 2 Treatment Arms at 100 Days and 365 Days Post-transplant
| Omidubicel (n = 37) | Standard UCB (n = 38) | P Value | |
|---|---|---|---|
| Median time to engraftment, days (95% CI) | 10.0 (8.0 – 13.0) | 19.5 (18.0 – 25.0) | <.001* |
| During 1-year follow-up post-transplant | |||
| Neutrophil engraftment, n (%) | 37 (100%) | 35 (92.1%) | .240 |
| Platelet engraftment, n (%) | 36 (97.3%) | 32 (84.2%) | .108 |
| Grade 2/3 bacterial infections or invasive fungal infections (grade 3), n (%) | 20 (54.1%) | 25 (65.8%) | .423 |
| Grade 3 viral infection, n (%) | 2 (5.4%) | 12 (31.6%) | <.01* |
| Grades II-IV acute GVHD, n (%) | 24 (64.9%) | 15 (39.5%) | <.05* |
| Grades III-IV acute GVHD, n (%) | 4 (10.8%) | 5 (13.2%) | >.99 |
| Chronic GVHD, n (%) | 17 (46.0%) | 10 (26.3%) | .126 |
| First 100 days post-transplant | |||
| Neutrophil engraftment, n (%) | 37 (100%) | 35 (92.1%) | .240 |
| Platelet engraftment, n (%) | 36 (97.3%) | 31 (81.6%) | .056 |
| Grade 2/3 bacterial infections or grade 3 invasive fungal infections, n (%) | 18 (48.7%) | 21 (55.3%) | .732 |
| Grade 3 viral infection, n (%) | 1 (2.70%) | 6 (15.8%) | .108 |
| Grades II-IV acute GVHD, n (%) | 23 (62.2%) | 15 (39.5%) | .083 |
| Grades III-IV acute GVHD, n (%) | 4 (10.8%) | 5 (13.2%) | >.99 |
| Length of inpatient stay during the first 100 days post-transplant, mean ± SD | 38.0 ± 21.3 | 49.0 ± 24.0 | <.05* |
GVHD indicates graft-versus-host disease; SD, standard deviation; UCB, umbilical cord blood; CI, confidence interval.
Statistically significant difference.
HRQL Changes Over Time and Between Groups
Baseline HRQL measures including FACT-G total and domain scores, BMT subscale scores, FACT-BMT total scores, and EQ-5D-3L index scores, were similar between the 2 treatment arms (Table 3). An initial decline in mean scores from baseline to day 42 post-transplantation was observed in both treatment arms for all HRQL measures. The mean declines during this period were numerically smaller in the omidubicel arm compared to the standard UCB arm.
Table 3.
Mean HRQL Questionnaire Scores for Omidubicel Compared to Standard UCB at Screening. There were no statistically significant differences between the 2 groups.
| HRQL Measures, Mean ± SD | Omidubicel (n = 37) | Standard UCB (n = 38) | P Value |
|---|---|---|---|
| FACT-G total score | 80.2 ± 14.3 | 83.9 ± 11.9 | .22 |
| Physical well-being score | 22.3± 5.1 | 23.6 ± 4.5 | .26 |
| Social/family well-being score | 22.2 ± 5.2 | 24.1 ± 3.6 | .07 |
| Emotional well-being score | 18.1 ± 4.4 | 18.4 ± 3.6 | .72 |
| Functional well-being score | 17.6 ± 6.2 | 17.9 ± 5.7 | .84 |
| BMT subscale score | 28.2 ± 5.7 | 27.9 ± 6.6 | .82 |
| FACT-BMT total score | 108.4 ± 19.1 | 111.8 ± 17.3 | .42 |
| EQ-5D-3L index score | 0.86 ± 0.16 | 0.87 ± 0.13 | .70 |
BMT indicates bone marrow transplant; EQ-5D-3L, EuroQol 5-Dimension 3-Level; FACT-BMT, Functional Assessment of Cancer Therapy - Bone Marrow Transplant; FACT-G, Functional Assessment of Cancer Therapy - General; HRQL, health-related quality of life; SD, standard deviation; UCB, umbilical cord blood.
FACT-G Domain Scores
When assessing individual FACT-G domain scores, differences in the AUC of the mean change in physical well-being domain scores over time indicated better HRQL with omidubicel compared to standard UCB (P = .02), with mean differences across time points ranging from 1.5 to 3.1 points (Figure 2A). Differences greater than the MCID of 2 points were observed at days 180 and 365. Patients in the omidubicel arm also had better social/family and emotional HRQL, with mean differences across time points ranging from 0 to 1.3 points for social/family well-being and 0.5 to 1.4 points for emotional well-being (Figures 2B and 2C). However, these differences did not meet statistical significance or exceed the MCID. In the functional well-being domain, the AUC of mean change over time favored the omidubicel arm (P = .04), with mean differences between the 2 arms ranging from 1.7 to 3.2 points (Figure 2D). The MCID for the functional well-being domain was exceeded at day 42 only. In all FACT-G domains aside from social/family well-being, mean scores in the omidubicel arm were able to recover back to at least baseline scores by day 180. Regarding time to meaningful change—defined as change greater than or equal to the MCID—the time from transplant to first meaningful improvement of physical well-being scores was shorter for omidubicel compared to standard UCB (Supplemental Figure S1A). Correspondingly, the time from transplant to first meaningful worsening of physical well-being scores was longer in the omidubicel group (Supplemental Figure S1B). Significant differences in time to meaningful improvement or worsening were not detected for the other HRQL domains.
Figure 2.
Mean changes from baseline HRQL scores at predefined follow-up visits for omidubicel and standard UCB are reported for each of the 4 FACT-G domains: (A) physical well-being score, (B) social/family well-being score, (C) emotional well-being score, (D) functional well-being score. The difference in FACT-G domain scores between omidubicel and standard UCB at each respective time point are indicated below the x-axis. AUC indicates area under the curve; FACT-G, Functional Assessment of Cancer Therapy - General; HRQL, health-related quality of life; MCID, minimal clinically important difference; SE, standard error; UCB, umbilical cord blood. *This difference exceeded the MCID (2 points).
FACT-G Total, BMT Subscale, FACT-BMT Total, and EQ-5D-3L Scores
AUC differences in the mean change of FACT-G total scores indicated significantly better HRQL with omidubicel, with mean differences ranging from 6.0 to 6.9 points (P = .01). The MCID of 5 points was exceeded at all follow-up time points, beginning at day 42 up until day 365 post-transplantation (Figure 3A). Similarly, HRQL based on the mean change of BMT subscale scores over time was better in the omidubicel group compared to standard UCB (P = .04 for difference in AUCs), with mean differences ranging from 1.0 to 4.1 points across time points (Figure 3B). The improvements exceeded the MCID of 2 points at days 42, 100, and 180 and reconverged by day 365. Notably, under the BMT subscale question asking patients whether the transplant-related side effects were “worse than [they] had imagined,” the standard UCB arm had an increase in the proportion answering in the affirmative (i.e., “somewhat,” “quite a bit,” and “very much”) from 32% at baseline to 48% at last assessment. In contrast, the omidubicel arm had a reduction in the proportion of affirmative answers: from 34% at baseline to 22% at last assessment (Figure S2). The change in affirmative response from baseline to last assessment, measured as an item score derived from a Likert scale, was significantly different between the 2 arms (P = .046).
Figure 3.
Mean changes from baseline HRQL measures for the (A) FACT-G total score, (B) BMT subscale score, (C) FACT-BMT total score, and (D) EQ-5D-3L index score. The difference in HRQL scores between omidubicel and standard UCB at each respective time point are indicated below the x-axis. AUC indicates area under the curve; BMT, bone marrow transplant; EQ-5D-3L, EuroQol 5-Dimension 3-Level; FACT-BMT, Functional Assessment of Cancer Therapy - Bone Marrow Transplant; FACT-G, Functional Assessment of Cancer Therapy - General; HRQL, health-related quality of life; MCID, minimal clinically important difference; SE, standard error; UCB, umbilical cord blood. *This difference exceeded the MCID (5 points for FACT-G total score, 2 points for BMT subscale, 7 points for FACT-BMT total score, and 0.07 points for EQ-5D-3L index).
Finally, AUC differences of the mean change of FACT-BMT total scores indicated better HRQL with omidubicel (P = .01), with mean differences ranging from 7.2 to 11.0 points (Figure 3C). The MCID of 7 points for the FACT-BMT total score was exceeded at all follow-up time points from day 42 to day 365. The mean change of the EQ-5D-3L index was also numerically superior with omidubicel, with a difference that trended towards significance (P = .06 for difference in AUCs). The MCID for EQ-5D-3L was exceeded on days 100 and 180 (Figure 3D).
HRQL Associations with Clinical Outcomes
HRQL scores were analyzed for all patients regardless of treatment arm in the context of significant clinical outcomes at days 42 and 100. Achieving neutrophil engraftment by day 42 was associated with significantly better FACT-G emotional well-being at day 42 compared to baseline. Specifically, the mean change between baseline and day 42 was 8.1 points greater (95% confidence interval [CI], 2.5 to 13.6) for those who achieved engraftment versus those who did not. Earlier neutrophil engraftment was also associated with better FACT-G domain scores at day 42, but these differences did not reach statistical significance. Grades II-IV acute GVHD were associated with worse functional well-being (−3.7 points; 95% CI, −6.1 to −1.3), lower BMT subscale scores (−2.7 points; 95% CI, −5.1 to −0.3), and lower FACT-BMT total scores (−12.0 points; 95% CI, −20.2 to −3.8) at day 100.
With respect to infectious complications, in the entire study population, having a grade 3 viral infection in the first 42 days was associated with significantly worse emotional well-being (−6.0 points; 95% CI, −9.1 to −2.8) and numerically worse physical well-being, though the latter was not significant. Grade 2/3 bacterial or grade 3 invasive fungal infections were not associated with changes in HRQL measures at day 42 but were associated with worse physical well-being scores at day 100 (−3.2 points; 95% CI, −5.7 to −0.7). Finally, the total number of days hospitalized in the first 100 days, a prespecified secondary endpoint in the phase 3 trial, was associated with slightly worse physical (−0.1 points; 95% CI, −0.2 to −0.03), social/family well-being (−0.1 points; 95% CI, −0.2 to −0.03), FACT-G total (−0.2 points; 95% CI, −0.4 to −0.1), and FACT-BMT total (−0.3 points; 95% CI, −0.5 to −0.1) scores at day 100.
DISCUSSION
Omidubicel is an advanced cell therapy product that has demonstrated faster hematopoietic recovery and lower incidence of infectious complications when compared to standard UCB in allogeneic HCT. Despite the observed objective benefits with omidubicel, information regarding how this novel therapy impacts quality of life from the patient perspective has been lacking. Our study examines this question via an analysis of prospectively collected HRQL measures during the first year following allogeneic HCT in the phase 3 clinical trial comparing omidubicel to standard UCB.
Prior HRQL studies in allogeneic HCT have shown a reduction in quality of life measures across multiple domains, often reaching a nadir within the first 100 days after transplantation and returning to pretransplant levels by the 1-year mark [8,9,18]. In our study, the FACT-BMT domain and total scores all followed a similar downward trajectory in the early post-transplant period which corresponded to the expected early transplant-related toxicities. However, omidubicel tended to have a less precipitous initial decline in HRQL scores, and clinically meaningful differences were observed as early as 42 days after transplant. Notably, at 6 months post-transplant, physical well-being recovered back to baseline in patients who received omidubicel in contrast to the standard UCB group. In addition, the separations in physical well-being, FACT-G, and FACT-BMT scores between these 2 groups persisted at last follow-up on day 365, which may imply the presence of a more extended benefit and is consistent with prior studies suggesting long-term advantages with omidubicel [7,19].
In our study population with available HRQL data, there was a slight imbalance in clinical outcomes between the two treatment groups, reflecting the decreased rate of grade 3 viral infections, reduced duration of hospitalization, and numerically higher incidence of grades II-IV acute GVHD observed in the omidubicel arm of the full trial population. With the association between acute GVHD and poorer HRQL outcomes, this imbalance in acute GVHD that was skewed in favor of standard UCB would not have explained the HRQL benefit seen with omidubicel and instead may have led to an underestimation of its true effect size. However, it is plausible that the improvement in HRQL scores with omidubicel may be partially explained by the fewer number of days hospitalized and the lower rates of grade 3 viral infections. Adverse infectious events in the post-transplant period, including viral, bacterial, and fungal infections, are common and have been demonstrated to be associated with negative impacts on HRQL [20,21].
One of the main limitations of this study is the exclusion of patients (31%) from this study due to incomplete baseline or follow-up HRQL data. Patients who were excluded had slightly worse HRQL scores in most domains, as well as poorer clinical outcomes, including lower rates of platelet engraftment, longer hospitalizations, and worse survival. This is an expected association, as those patients with worse clinical status may be less likely to fill out HRQL surveys and are assumed to have poorer HRQL scores in most domains. Interestingly, the rate of missing HRQL data was more pronounced in the standard UCB group, suggesting that a selective loss of follow-up is more likely to create bias against omidubicel. While the HRQL burden may have been underestimated in both treatment arms, the specific HRQL benefits estimated for omidubicel compared to standard UCB are likely conservative relative to the true effect. In addition, the subjective nature of patient-centric assessments may make certain HRQL measures more prone to potential open-label bias due to patients’ greater optimism for an experimental intervention [22,23]. However, the true impact of open-label bias in this setting is uncertain, with a recent systemic review of 110 randomized controlled trials in prostate cancer failing to find evidence of significant bias related to the absence of blinding [24]. Finally, while the HRQL data were collected prospectively in the phase 3 trial, statistical analyses of HRQL measures were not prespecified, and the results reported here are based on post hoc analyses of the trial data.
Available literature on patient-reported quality of life measures with novel transplant and cell therapy products is limited. In recent years, there has been increasing importance placed on the inclusion of patient-reported outcomes in the assessment of novel therapeutics [25–27]. Our study showed that omidubicel was associated with meaningfully greater preservation or improvement of several important patient-reported HRQL measures when compared with standard UCB. Alongside statistically significant faster time to engraftment, lower infectious risks, and shorter hospitalizations, omidubicel appears to positively influence functional and physical well-being domains, as well as the overall HRQL measures. Across all patients, regardless of treatment group, adverse clinical events such as longer time to engraftment and grade 3 viral infections were associated with negative impacts on various HRQL domains. Overall, these findings suggest that HRQL following allogeneic HCT is sensitive to clinical outcomes and that the clinical benefits of omidubicel may be associated with important and concordant benefits on patient-centric HRQL measures that reflect the overall effects of treatment. The results of this study may be informative in guiding discussions with patients when considering the use of omidubicel.
Supplementary Material
Highlights.
Omidubicel significantly improved health-related quality of life (HRQL)
Improvements in HRQL started at 42 days post-transplant and persisted at 1 year
Physical well-being returned to baseline at 6 months with omidubicel
Shorter hospitalizations were associated with higher HRQL scores
Viral infections and graft-versus-host disease were associated with lower HRQL scores
ACKNOWLEDGMENTS
The authors would like to thank all of the patients, family members, coinvestigators, and research and clinical staff involved in this study. The authors would also like to acknowledge The Emmes Company for their support in data management, and Einat Galamidi-Cohen, who was involved in the initial clinical trial design while at Gamida Cell. Editorial support was provided by Evidence Scientific Solutions and funded by Gamida Cell. Author Chenyu Lin was supported by the NIH/NHLBI T32 training grant HL007057-46.
Financial Disclosure
Both the phase 3 clinical trial and this patient-reported outcome study were funded by Gamida Cell. Author C.L. was supported by the NIH/NHLBI T32 training grant HL007057-46.
Conflict of Interest
C.L., C.C., C.A.L., R.H., L.P.K., R.T.M., and W.Y.K.H. have no conflicts to declare. Ga.S., Y.S., Q.L., and J.S. are employees of Analysis Group, Inc., which received consulting fees from Gamida Cell to conduct this study. P.J.S. served as a consultant to CRISPR Therapeutics and Karyopharm Therapeutics, and has received research funding from Amgen, Atara Biotherapeutics, Eisai, Gamida Cell, Incyte, Karyopharm Therapeutics, MacroGenics, Pfizer, and Takeda Pharmaceutical Company Limited. C.G.B. has received research funding from Fate Therapeutics, Gamida Cell, and NantPharma, and consulting fees from AlloVir. Gu.S. has participated in advisory committees for AbbVie, Helsinn, Roche, and Takeda Pharmaceutical Company Limited. A.R.R. has received research funding from Pharmacyclics and medical expert witness consultancy fees from the U.S. Department of Justice, and has a sibling who is employed by Johnson & Johnson. R.M. and S.S. are employees of and own equity holdings with Gamida Cell. M.E.H. has received research funding from Gamida Cell. A.D.S. has received research funding from Enterome, Merck, Novartis, and Seres Therapeutics, honoraria from Abbott Nutrition, and research products from Clasado Biosciences and DSM.
Footnotes
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Data Sharing Statement
Agreement to Share Publication-Related Data and Data Sharing Statement: Individual participant data will not be shared. Queries about the data can be made to corresponding author or medicalinformation@gamidacell.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Agreement to Share Publication-Related Data and Data Sharing Statement: Individual participant data will not be shared. Queries about the data can be made to corresponding author or medicalinformation@gamidacell.com.