Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

Abstract

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

Keywords: Bone marrow transplantation; Post-transplantation cyclophosphamide; Primary immunodeficiency; Reduced-intensity conditioning.

Figure 1.

Kaplan-Meier curves of overall survival and acute grade III-IV GVHD-free, graft-failure-free survival for the cohort, n=20.

Figure 2.

Chimerism and phenotype reversal. A) Chimerism in myeloid and CD3+ T-cell subsets, expressed as the percentage of donor cells. Black lines show the median and interquartile range of myeloid (solid line) and CD3+ (dashed line) chimerism for the RIC arm cohort (n=18), excluding the patients with graft failure. Blue lines indicate the percentage of myeloid and CD3+ donor chimerism for P12 with secondary graft failure. P14 with primary graft failure is represented as a single, separate data plot (black star) for myeloid and CD3+ chimerism of 0% on day +28. Most recent chimerism data from patients with follow up beyond 1 year are listed in Table 4. B) Chimerism in CD4+ (solid line) and CD8+ (dashed line) T-cell subsets, shown as subsets shown in panel A for the cohort (n=18, in black), P12 (in blue), and P14 (black star). C) Phenotype reversal in engrafted survivors. For each patient, the left column shows pre-BMT phenotype and the right column post-BMT clinical status. Shading indicates the severity of disease manifestations: black - severe, dark gray - moderate, light gray - mild, white - absent. An X indicates that this disease manifestation could not be assessed, such as due to concomitant immunomodulatory immunoglobulin therapy. The dark gray/”moderate” category also includes historical disease manifestations that were inactive at the time of BMT but represent a significant part of the disease phenotype and indication for transplant, e.g. splenectomy for immune cytopenias (P2, P13), chemotherapy/radiation for lymphoma/lymphoproliferative disorder (P9), Guillain-Barre syndrome (P11). Viral mucocutaneous infections included HPV, HSV, VZV, and molluscum. P13 had significant post-BMT complications, including primary CMV infection resulting in pneumonitis. She also developed focal segmental glomerulosclerosis requiring immunosuppressive therapy. She has 100% donor chimerism across lineages and an underlying PID where full donor chimerism should result in full phenotype reversal. Therefore, the post-BMT grading for phenotype reversal in P13 reflects events likely not related to failure to reverse her disease phenotype, but rather complications in the setting of poor/slow immune reconstitution post-BMT.

Figure 3.

Post-BMT lymphocyte subset reconstitution, with box-and-whisker plot denoting median and range. Upper and lower limit of institution-specific adult normal range are demarcated for each subset. Patients who experienced graft failure are excluded from this analysis. Of evaluable patients, 47% attained >300 total T cells/ml and 65% attained >50 CD8+ T cells/ml by day +100, while 6% and 44% respectively attained >500 CD4+ T cells/ml by 6 months and 1 year post-BMT; these markers shown to predict survival and graft failure outcomes in young infants and children with severe combined immunodeficiency may not be applicable in an older more heterogeneous population.