Abstract
Abstract 3016FN2
Introduction
Hematopoietic stem cell transplantation from unrelated donors (UD) is an effective treatment for hematologic malignancies, but has been associated with relatively high rates of high non-relapsed mortality (NRM) in older and less physically fit patients. The development of reduced-intensity preparative regimens has allowed the extension of this form of treatment to older high risk patients. We hypothesized that a reduced–intensity preparative regimen with pre-transplant low-dose Alemtuzumab would reduce early NRM from regimen-related toxicity and GVHD respectively following UD transplantation, and the early use of donor lymphocyte infusion (DLI) without withdrawal of immunosuppression would promote complete donor T cell chimerism (DC) and thus improve control of the patient's malignancy. We tested this hypothesis in a prospective phase II study.
Methods
Thirty six patients were treated. Patient characteristics: median age, 59 years (range, 42–68 years), PBSC (n=34) or bone marrow (n=2); 10/10 HLA locus matched (n=33) or 9/10 matched (n=3); diagnoses AML= 14, CML= 3, MDS=4, MPS=2, NHL=8 CLL=3, and HD=1; CIBMTR disease risk high [n=7], intermediate [n=15], low [n=14]. The conditioning regimen was fludarabine (40mg/m2/d days -6, -5, -4, -3) and busulfan (16mg/kg or i.v. equivalent) for myeloid malignancies or fludarabine (30mg/m2/d days -5, -4, -3), cyclophosphamide (750mg/m2/d days -5, -4, -3), ± rituximab (days -13, -6, +1, +8) for lymphoid malignancies. Low dose subcutaneous alemtuzumab was administered to all patients at a total dose of 43mg over 3 days (-11, -10, -9). Post-grafting immunosuppression consisted of tacrolimus and methotrexate (5mg/m2 on days 1, 3, and 6).
Results
Donor engraftment occurred in 35/36 (97%) patients with median times to neutrophil and platelet recovery of 16 days (10–20) and 16 days (0–42), respectively. One patient expired prior to recovery secondary to a sagittal sinus thrombosis. Early mixed T cell chimerism generally occurred (median day +100 donor CD3 52% (0–100) and CD33 100% (0–100)), requiring donor lymphocyte infusion (DLI) (starting dose 1 × 107 CD3 cells/kg) in 30 of 36 patients (83%, median day 65 [range 36–576]), while 12 received ≥ 2 DLI. Complete DC (defined as ≥ 95% donor cells in peripheral blood CD3+ and CD33+ cells) was achieved at a median of 180 days (range, 33–426 days). Ten patients never achieved completed DC. Maximal cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 42% (14% grade III-IV) and that of chronic GVHD was 59% (12% severe) in patients who survived more than 100 days. Cumulative probability of non-relapse mortality at day 100 and one year was 3% and 14%, respectively. Estimated overall survival at day 100 and one year was 97% and 71%, respectively. CMV reactivation by quantitative PCR was observed in 18 of 24 (75%) at-risk patients. However, no CMV-related disease or mortality was observed. No fungal infections or infectious deaths were seen before day 100. The median hospital length of stay from start of preparative regimen through Day +30 and +100 was 9 days (1–31) and 13 days (1–52), respectively. With a median follow-up of 2.4 years, the probabilities of 2-yr overall (OS) and disease-free survival (DFS) are 57% and 38%, respectively. Patients who achieved complete DC had better OS (log-rank p-value=0.024) (see figure) than patients who failed to achieve this status. In Cox analysis, development of chronic GVHD had a protective effect, associated with decreased relapse (HR 0.150, p=0.089) and improved DFS (HR 0.342, p=0.081).
Conclusion
Low dose alemtuzumab based conditioning and preemptive DLI in order to promote complete donor T cell chimerism, results in low treatment related mortality and favorable survival outcomes in an older patient population with high-risk malignancies undergoing unrelated donor transplantation. The use of pre-emptive DLI while maintaining immunosuppressive therapy appears to control the incidence of severe GVHD and is not associated with an increased risk on infections.
Disclosures:
No relevant conflicts of interest to declare.
Preemptive DLI without withdrawal of immunosuppression to promote complete donor T-cell chimerism results in favorable outcomes for high-risk older recipients of alemtuzumab-containing reduced-intensity unrelated donor allogeneic transplant: a prospective phase II trial