Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem-Cell Transplantation for De Novo ALL in Adults

Conference Correspondent - EHA 2016

In the donor versus no-donor analysis of the UKALL12/E2993 trial in adult patients with acute lymphoblastic leukemia (ALL), survival benefits did not extend to older patients. At 2 years, myeloablative allogeneic hematopoietic cell transplant-related mortality (TRM) was 35%, which outweighed the reduction in relapse risk. To address this elevated TRM, reduced-intensity conditioning (RIC) has been introduced. In the current UK National Cancer Research Institute UKALL14 study, all patients over 40 years of age in complete remission, regardless of Philadelphia status and other high-risk factors, are considered “high risk” and are considered for RIC allogeneic hematopoietic stem-cell transplantation (alloHSCT) with a matched sibling or matched unrelated donor (MUD) after a 2-course induction and high-dose methotrexate.1 The primary end point in this study was event-free survival (EFS). Standard RIC was with fludarabine 30 mg/m2 days -6 to -2, melphalan 140 mg/m2 day -2, and alemtuzumab 30 mg days -2 to -1 (MUD) or day -1 (sibling). Cyclosporin A was used to prevent graft versus host disease (GVHD). Multilineage chimerism and minimal residual disease (MRD) were assessed every 3 months post-alloHSCT. Escalating doses of donor lymphocyte infusions (DLIs) were given for T-cell mixed chimerism or MRD. Of the total of 597 patients who enrolled to date, 173 were registered for an RIC alloHSCT and 122 have completed the transplant. Among the latter, 120 have sufficient follow-up data. Their median age was 51 years (range, 29-64 years). Donors were siblings in 39 patients and MUD in 81 patients. Median white blood count at diagnosis was 8.7 x 109/L (0.6-557). Fifty-seven (54%) of 106 evaluable patients had high-risk cytogenetics, and 26% were Philadelphia-positive. Eighteen (24%) of 74 with MRD data were MRD-positive pre-alloHSCT. Post-alloHSCT, myeloid engraftment occurred in 111 patients at a median of 14 days; 9 had missing data. No graft failures were reported. Acute GVHD occurred at grade 1 in 28% of patients and grade 2/3 in 10% of patients. Forty-seven patients developed chronic GVHD (40% of 117 patients surviving beyond D100): 20 limited and 27 extensive. Of 15 patients who suffered TRM, 8 died of infection, including 1 of posttransplant lymphoproliferative disease. TRM was not associated with age or donor type. Twenty-seven patients relapsed at a median of 230 days (97-1034) with a relapse risk of 28% (19%-38%) at 22 months post-alloHSCT. Of those, 16 (of 25 with data) had high-risk cytogenetics (EFS; P = 0.11) and 10 (of 19 with data) were MRD-positive pre-alloHSCT (EFS; hazard ratio, 2.41; P = 0.025). Serial MC data were available for 43 patients. By 6 months posttransplant, 79% of these patients achieved full donor total peripheral blood chimerism, whereas 35% achieved full donor chimerism in the T-cell compartment. With longer follow-up, 26 (60%) patients achieved full donor T-cell chimerism (median, 9 months), 10 after receiving DLI (38%). Kaplan Meier curves showed overall survival of 66% (95% confidence interval [CI], 55%-76%) and EFS of 59% (95% CI, 49%-69%) at 22 months median follow-up. Researchers concluded that these early data from the first large prospective study of RIC alloHSCT in older adults with ALL are promising. Severe GVHD and TRM were relatively low, leading to a higher EFS than expected for this age group.
  1. Okasha D, et al. EHA 2016. Abstract S819.