Donor Lymphocyte Infusions in Acute Lymphoblastic Leukemia: A Single-Center Retrospective Analysis

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Introduction Post-allogeneic hematopoietic cell transplantation (allo-HCT) relapse of acute lymphoblastic leukemia (ALL) is associated with a median overall survival (OS) inferior to 6 months. Limited evidence is available on the use of donor lymphocyte infusion (DLI) in ALL. In the setting of hematological relapse, DLI showed scarce efficacy (complete response rates around 30%, with OS being less than 15% at 3 years). The improvement of chimerism analysis, the advent of molecular measurable residual disease (MRD) monitoring and novel agents used in combination with DLI might change their role in post-allo-HCT relapse prevention and treatment. Methods We retrospectively analyzed clinical characteristics and outcome of all consecutive ALL patients receiving DLI in our Center in the last 10 years. Patients with a fully matched donor received a DLI starting dose of 1x106 /kg, while patients transplanted from a mismatched donor received a starting dose of 0,5 x 106/kg. Subsequent incremental doses after 4 to 6 weeks were infused in absence of GvHD. MRD analysis was performed with PCR for Ig/TCR gene rearrangements or BCR:ABL. R survival package was used for survival analysis. Results Since 2015, 45 adult ALL patients have undergone allo-HCT in our Center. Among these, 17 (37,8% - 9 male, 8 female) have received DLI. Diagnosis was T-ALL in 5 cases, Philadelphia-negative (Ph-) B-ALL in 8 cases and Ph+ B-ALL in 4 cases. Three patients were transplanted from a matched sibling donor, 9 from a matched unrelated donor (MUD), 2 from a mismatched UD (MMUD) and 3 from an haploidentical donor (HAPLO). Five patients received a TBI-based conditioning, 7 a myeloablative chemotherapy-based conditioning and 5 a reduced-intensity conditioning. All but 2 patients have received an in vivo T cell depletion either with ATG, or post-transplant cyclophosphamide (for MMUD and HAPLO). Median number of DLIs was 4 (range, 1-12), the median time from transplant to DLI was 218 days (range, 50 - 1076) and the median maximal dose infused was 2.5 x 106 CD3+/kg (0,5 - 50). Reason for DLI use was mixed chimerism in 3, MRD relapse in 9, and hematological relapse in 5 cases, respectively. The 3 patients with mixed chimerism had Ph- B-ALL and received a median of 5 DLIs (3-7) with no other therapy. Two of them regained full donor chimerism, being alive and MRD negative at the last follow-up (mFU 2388d), while one experienced hematological relapse after the third DLI and proceeded with further treatment and second allo-HCT. Among 9 patients receiving DLI for MRD relapse 4 had T-ALL, 3 had Ph- B-ALL and 2 had Ph+ B-ALL. They received a median of 4 DLIs (1-12); DLIs were given in association with TKI in Ph+ ALL patients, with blinatumomab in 1 Ph- ALL case, with nelarabine in 1 T-ALL patient and with off-label bortezomib in 1 T-ALL patient. Four (44,4%) patients (3 Ph+ B-ALL, 1 Ph- B-ALL) reached a sustained MRD negative remission (mFU 1006d) while all the others progressed rapidly after a median time of 1.3 months from the first DLI dose. Five patients received DLI for hematological relapse (extramedullary in 3 cases), 1 with T-ALL, 2 with Ph- B-ALL and 2 with Ph+ B-ALL. They received a median of 3 DLIs (2-4), given with TKI in Ph+ B-ALL, inotuzumab in Ph- ALL and radiotherapy in T-ALL. One Ph- B-ALL patient had partial remission and proceeded with further treatment, while the other 4 patients obtained CR. Three of them subsequently experienced hematological relapse with a median CR duration of 196 days. One T-ALL patient is still alive and in remission (FU 2819d). Median follow-up was 694 days (26 - 3354). 1-year OS and progression free survival (PFS) for the whole group were 79 % and 43.8 %, respectively, with a median PFS of 4 months from the first DLI. Two patients (1 MUD, 1 HAPLO) had grade 1 acute GvHD after 1 and 4 DLI respectively, and 3 patients developed chronic GvHD requiring steroids after a median time of 136 days (92- 291) from the last DLI dose. Conclusions Almost 40% of ALL patients transplanted at our Center needed DLI during their follow-up, with the main indication being MRD positivity. DLI can be an active and safe treatment for ALL, especially if used in the prophylactic/pre-emptive setting and in combination with other therapies. Better evaluation of DLI efficacy in prospective clinical trials is needed in the era of MRD monitoring and novel agents.

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