Impact of posttransplant cyclophosphamide-based GVHD prophylaxis in patients 70 years and older: an update from BMT CTN 1703 Open Access

Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard therapy option for advanced hematologic malignancies. Although the median age at diagnosis for hematologic malignancies is 70 years, patients aged ≥70 years represent fewer than 15% of individuals undergoing allo-HCT in the United States.^1,2 Identifying HCT platforms with an optimal therapeutic window (ie, disease control and low risk of morbidity and nonrelapse mortality [NRM]) is an unmet need for improving outcomes of older patients.

Graft-versus-host disease (GVHD) is a common cause of allo-HCT morbidity and mortality and is thought to affect older adults more significantly.^3-5 The BMT CTN 1703 trial investigated an experimental GVHD prophylaxis regimen including posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil (PTCy) in adults undergoing allo-HCT with matched related or 7-8/8 HLA–matched unrelated donors after reduced intensity conditioning (RIC).⁶ Patients were randomized 1:1 to PTCy or tacrolimus and methotrexate (Tac/MTX); the primary end point was GVHD-free, relapse-free survival (GRFS). The study demonstrated superior 1-year GRFS with PTCy, establishing it as a new standard of care for GVHD prevention after RIC allo-HCT.

Given that the use of allo-HCT in older adults is often limited by concerns for HCT-related toxicity, we performed a post hoc analysis of adults aged ≥70 years enrolled in BMT CTN 1703 to evaluate the impact of PTCy in this population.

Study design and end points for the BMT CTN 1703 trial are published.⁶ In brief, the experimental regimen (PTCy) consisted of cyclophosphamide (50 mg/kg per day) on days 3 and 4, tacrolimus starting on day 5, and mycophenolate mofetil from day 5 to day 35 after allo-HCT. The standard regimen (Tac/MTX) consisted of tacrolimus, starting 3 days before HCT, and methotrexate on days 1, 3, 6, and 11 after allo-HCT. The protocol was approved by the institutional review board of the National Marrow Donor Program, and all patients provided a written informed consent.

The current analysis includes all patients aged ≥70 years treated on BMT CTN 1703. The primary end point was GRFS (events included grade 3 to 4 acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse/progression, and death) at 1 year. Secondary end points included acute and chronic GVHD, GVHD-free survival (GFS), relapse/progression, RFS, NRM, engraftment, infections, overall survival (OS), and quality of life (QOL). QOL was assessed at enrollment and on days 100, 180, and 365 using the Lee Chronic GVHD Symptom Scale and Patient-Reported Outcomes Measurement Information System subscales for physical function, gastrointestinal symptoms, and satisfaction with participation in social roles.

GRFS was compared between arms in the intention-to-treat population; secondary end points were analyzed in the transplanted population. Patients were classified into treatment groups by their randomized assignments for all analyses. Rates of GRFS, GVHD, GFS, relapse/progression, RFS, NRM, and OS were compared between arms using multivariable Cox models adjusted for donor type, disease risk index, HCT-specific comorbidity index, Karnofsky performance status, planned conditioning regimen, and planned use of posttransplant antileukemia maintenance therapy (declared before randomization). Adjusted survival probability estimates were generated for GRFS, GFS, RFS, and OS, whereas adjusted cumulative incidence estimates were produced for GVHD, relapse/progression, and NRM. Four patients had missing values for the HCT-specific comorbidity index; the median score was imputed for these patients in the regression models. A significance level of 5% was used for all statistical tests.^7,8 Key end points including GRFS, GFS, RFS, and OS were also described using Kaplan-Meier survival estimates and compared between arms using log-rank tests as a supplementary analysis. These results are reported in the supplemental Data (supplemental Figure 12).

All patients enrolled in the BMT CTN 1703 trial have consented with institutional review board approval at each site. For this subanalysis of a deidentified data set, no institutional review board approval was required at the primary site, Medical College of Wisconsin.

Ninety-six of 431 patients enrolled in BMT CTN 1703 were ≥70 years old. Median ages at randomization were 72 (range, 70.1-78.6) years and 73 (range, 70.1-77.4) years in the PTCy (N = 43) and Tac/MTX arms (N = 53), respectively. Notably, 88% and 85% had a matched unrelated donor, and 46% and 40% received fludarabine/melphalan conditioning, respectively (Table 1). Conditioning therapy dosing details are provided in the supplemental Data.

Patients assigned to PTCy experienced improved GRFS than those assigned to Tac/MTX (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.13-0.55; P < .001) (Figure 1A). The adjusted 1-year GRFS was 67.1% (95% CI, 51.8-78.5) with PTCy and 29.5% (95% CI, 18.9-40.8) with Tac/MTX. PTCy recipients had significantly lower mortality risk (HR, 0.08; 95% CI, 0.02-0.33; P = .001). The adjusted 1-year OS with PTCy was 94.3% (95% CI, 85.0-97.9) vs 60.2% (95% CI, 48.2-70.3) with Tac/MTX (Figure 1B).

GVHD was a major secondary end point. Grade 2 to 4 acute GVHD was frequent in both arms. The day 100 cumulative incidence of grade 2 to 4 acute GVHD was 58.1% (95% CI, 44.6-69.3) with PTCy and 37.1% (95% CI, 26.3-47.8) with Tac/MTX (supplemental Figure 1). Grade 3 to 4 acute GVHD was not observed in patients assigned to PTCy; the cumulative incidence with PTCy was 0% vs 9.9% (95% CI, 3.6-20.1) with Tac/MTX (supplemental Figure 2). Chronic GVHD was not found to be different between the groups. The cumulative incidence of chronic GVHD at 1 year was 23.5% (95% CI, 11.9-37.3) with PTCy and 30.5% (95% CI, 19.6-42.0) with Tac/MTX. The cumulative incidence of chronic GVHD requiring immunosuppression at 1 year was 17.9% (95% CI, 8.1-30.9) with PTCy and 23.8% (95% CI, 14.1-34.9) with Tac/MTX (supplemental Figure 3). Using the Lee Chronic GVHD Symptom Scale survey, PTCy-treated patients had stable symptom scores through 1 year whereas those receiving Tax/MTX trended toward increasing symptoms at day 100 and beyond (supplemental Figure 4).⁹ Overall, PTCy recipients experienced improved GFS compared with Tac/MTX (HR, 0.25; 95% CI, 0.11-0.56; P = .001). The adjusted 1-year GFS with PTCy was 75.8% (95% CI, 60.8-85.7) vs 41.0% (95% CI, 28.7-52.9) with Tac/MTX (Figure 2A).

PTCy recipients had significantly lower relapse or progression risk (HR, 0.30; 95% CI, 0.10-0.88). The incidence of relapse/progression at 1 year was 14.3% (95% CI, 6.2-25.6) with PTCy and 29.3% (95% CI, 18.8-40.6) with Tac/MTX (supplemental Figure 5). Overall, PTCy recipients had improved RFS compared with Tac/MTX (HR, 0.27; 95% CI, 0.12-0.64). The adjusted 1-year RFS with PTCy was 80.5% (95% CI, 66.2-89.2) vs 50.3% (95% CI, 37.2-62.0) with Tac/MTX (Figure 2B).

Full donor cell engraftment, defined as >95% donor cells, was similar between groups at day 28. The proportion with full donor chimerism was 75% with PTCy and 62% with Tac/MTX (P = .171) (supplemental Figure 6). The cumulative incidence of neutrophil recovery (≥500/μL) was similar between groups at day 28; however, the incidence of sustained platelet recovery (≥20 × 10³/μL) was lower in PTCy-treated patients at day 28 (supplemental Figure 7). The cumulative incidence of BMT CTN grade 2 to 3 infections and grade 3 infections was similar between groups (supplemental Figure 8). Organ toxicity did not differ significantly between arms, including toxicities in organs considered vulnerable to cyclophosphamide toxicity. The incidence of grade 3 to 5 cardiac events was 30.2% and 34% with PTCy and Tac/MTX, respectively. Corresponding rates of grade 3 to 5 renal events were 14.0% and 15.1% and of grade 3 to 5 respiratory events were 11.6% and 24.5% (supplemental Figure 9). PROMIS (Patient-Reported Outcomes Measurement Information System) Physical Function scores indicate that both groups regained baseline function by 1 year after transplant (supplemental Figure 10).

PTCy recipients experienced a lower NRM risk than those receiving Tac/MTX (HR, 0.19; 95% CI, 0.040-0.94; P = .04). The 1-year NRM with PTCy was 4.7% (95% CI, 0.8-14.7) vs 19.4% (95% CI, 10.5-30.3) with Tac/MTX (Figure 2C). Overall, at 1 year, the probability of being alive, relapse-free, and off immunosuppression was significantly higher with PTCy at 60% (95% CI, 44.8-75.2) than 38.8% (95% CI, 25.1-52.4) with Tac/MTX (P = .046).

By 1 year, 4 patients (8%) assigned to PTCy died, 2 from relapse, and 1 each from organ failure and hemorrhage. Eighteen patients (34%) assigned to Tac/MTX died, 9 from relapse, 6 from infections, and 1 each from GVHD, hemorrhage, and shock (supplemental Figure 11).

This post hoc analysis of transplant recipients aged ≥70 years treated on BMT CTN 1703 demonstrates that PTCy significantly mitigates allo-HCT–related toxicities and potentially affects relapse, leading to impressive 1-year OS. These results further support the use of PTCy as standard of care for GVHD prophylaxis, namely in older adult populations.

PTCy retained its GVHD protective effect without increasing transplant-related fatalities in this older population. The ability to successfully discontinue immunosuppression could explain this finding, particularly regarding infectious deaths. Finally, by 1 year, PTCy-treated patients experienced low chronic GVHD symptom burden and recovered their physical function, mitigating concerns about adverse effects on QOL.

Going forward, PTCy-treated patients continued to experience similar rates of infection and organ toxicities compared with the Tac/MTX cohort. Furthermore, with PTCy, blood cell recovery kinetics seem delayed in comparison with Tac/MTX. This analysis largely included older adults with limited comorbidities; therefore, older adults with more comorbid conditions may face additional risk than what was presented here. Efforts to reduce the toxicity of the PTCy platform will further enhance access to allo-HCT, particularly for older adults who are more likely to be excluded owing to comorbidities.

Overall, although this study has limitations, including the small number of patients in the comparison arms, and the study was not powered to compare arms in this subgroup, the low rates of NRM and high 1-year OS observed in the prospectively treated older cohort warrant greater consideration for allo-HCT in patients aged ≥70 years. Particularly with recent advancements in the management of acute leukemias and myelodysplastic syndrome, there is now potential for a larger proportion of older adults to achieve meaningful responses that could then allow for a potentially curative, consolidative RIC allo-HCT.^10-12 

This work was supported by grants U10HL069294 and U24HL138660) (M.M.H.) from the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI); grant U24-CA76518 (Center for International Blood and Marrow Transplant Research [CIBMTR]) from the NCI, the NHLBI, and the National Institute of Allergy and Infectious Diseases; and by contract HHSH234200637015C (CIBMTR) from the Health Resources and Services Administration and the Department of Health and Human Services.

Contribution: S.A., M.J.M., Q.L., J.B.-M., S.G.H., and M.H. contributed to the design of the research, analysis of the results, and initial draft of the manuscript; M.M.A.M., L.R., H.E., M.G., K.T.L., B.C.S., A.W.L., M.S., A.M.A., O.H.T., M.-A.P., A.R., A.B., N.E.J., J.M.Y., K.A., L.S.K., Y.A.E., R.R., W.C., E.L., W.S., M.M.H., and R.J.J. provided critical revisions; and all authors provided final approval of the final manuscript version.

Conflict-of-interest disclosure: S.A. received research funding from Incyte. S.G.H. received research funding from Incyte and VITRAC Therapeutics and has held a consulting role for Sanofi, MaaT Pharma, and Ossium Health. M.M.H. received research funding from Incyte and Sanofi and has held a consulting role for Sobi. L.S.K. received research funding from Tessera Therapeutics, EMD Serono, Gilead Pharmaceuticals, and Regeneron Pharmaceuticals; has held a consulting role for Vertex; has served on the scientific advisory board for HiFiBiO Therapeutics; and received grant support from Bristol Myers Squibb. M.H. received research funding from ADC Therapeutics, Spectrum Pharmaceuticals, and Astellas Pharmaceuticals; has held a consulting role for ADC Therapeutics, Omeros, Bristol Myers Squibb, Kite, Genmab, CRISPR Therapeutics, AlloVir, Caribou, Autolus, Forte Biosciences, and Byondis; and served on a speakers' bureau for AstraZeneca, ADC Therapeutics, BeiGene, Kite, and Myeloid Therapeutics. The remaining authors declare no competing financial interests.

Correspondence: Sameem Abedin, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226; email: sabedin@mcw.edu.