Allogeneic Stem Cell Transplantation (ASCT) in CML with Partial T-Cell Depletion, No Prophylaxis for Graft-Versus-Host Disease (GvHD) and Preemptive DLI for Patients with Post-Transplant Minimal Residual Disease (MRD): An Alternative Approach in CML Transplantation with Low Morbidity and Long Term Disease Free Survival.
Authors: Zuckerman Tsila , Katz Tamar , Haddad Nuhad , Fineman Riva , Avivi Irit , Dann Eldad J. , Sahar Dvora , Oliven Ana , Hertz Ety , Ofran Yishay , Akria Luiza , Markovitz Michal , Faibish Tal , Rowe Jacob M. 
Published: October 2019

The introduction of imatinib mesylate has revolutionized the treatment of CML, but despite significant cytogenetic responses primary therapy failure and emergence of resistance pose a major obstacle to successful treatment. ASCT still has a pivotal role in the treatment of CML and reduction of morbidity and mortality remains an important focus of ongoing studies in CML. We conducted a prospective study with ablative conditioning and partial T cell depleted ASCT from a matched sibling donor with no post-transplant GvHD prophylaxis. This was followed by an escalated donor lymphocyte infusion (DLI) administered if there was evidence for the presence of MRD, as determined by FISH and PCR/RQ-PCR for bcr-abl. Patients and methods: 40 consecutive patients underwent ASCT for CML between 1999–2005. The transplant regimen contained busulfan (12mg/kg), cyclophosphamide (120 mg/kg), anti-thymocyte globulin (ATG-Fresenius) (25mg/kg) and fludarabine (200mg/kg) followed by an infusion of ≥5×106/kg of G-CSF-mobilized and positively selected CD34 cells and 1×105/kg T cells. No post-transplant GvHD prophylaxis was given. The presence of MRD was determined every 3 months. DLI was administered in escalated doses starting with 3×106/kg and escalating in increments up to 1×108/kg. Results: 40 patients, median age 38 (19–63), 35 transplanted in first chronic phase (CP), 1 in second CP and 4 in accelerated phase. Patients were transplanted at a median of 4 months from diagnosis (1–66). The median of positively selected CD34+ cells was 9×106 cells/kg (5–24). 39 patients engrafted neutrophils at a median of 11 days (9–25) and platelets at a median of 15 days (9–134). Primary non-engraftment occurred in one patient and late graft failure in two, all salvageable by back-up marrow in two patients or donor stem cell boost in a single patient. The median follow-up of the entire cohort is 44 months (6–84).

Overall Survival 80% Transplant Related Mortality (TRM) day 100 5% day > 100 10% Acute GvHD Post transplant (n = 38) Post DLI (n= 24) grade I-II 21% 21% grade II-III 0 8% grade IV 0 0 Chronic GvHD Post transplant (n = 38) Post DLI (n= 24) limited 2.6% 16% extensive 0 0 Need for DLI One dose 63% Two doses 31% ≥ Three doses 16% Disease-Free Survival Major cytogenetic response 6% Major molecular response 6% Complete cytogenetic and molecular response 88% Disease Progression 10%

None of the patients developed significant VOD. Post transplant acute GvHD developed in only 21% of patients and was confined to grade I–II, all responding to a short course of immunosuppression. Additional 7 out of the 24 patients receiving DLI developed acute GvHD. There was no grade IV or mortality from GvHD. At the time of this analysis all apart from 1 patient were able to stop immunosuppressive treatment for GvHD. There were no significant infectious complications in this group. All late TRM were secondary to autoimmune complications, unrelated to GvHD, and occurred in 5 patients (13% of all) at 6–14 months post transplant. These complications included: ITP, AIHA, autoimmune pneumonitis, nephritic syndrome, TTP and Kaposi sarcoma. The mortality from these complications was 80% (4 out of 5 patients). 4 patients developed blast crisis post transplant; 2 patients have died; and the others are currently in CR post salvage treatment, DLI and imatinib. Twenty five percent of patients attained complete molecular remission without ever needing DLI, while 75 % responded after DLI, mostly following a single dose. Two patients are in major cytogenetic response, one of whom received back-up marrow and for the other a DLI donor is not available. The two patients in major molecular response are awaiting DLI. Conclusions: Matched ASCT for CML can be performed with significantly reduced TRM and morbidity using partial T cell depletion, no GvHD prophylaxis and preemptive DLI. This regimen offers > 80% long-term curative potential. Programmed DLI is safe and associated with a low risk of GvHD. The late immunological complications pose a major risk. This appears to be related to an imbalance between B and T cell reconstitution and the precise mechanisms of this need to be elucidated. In the imatinib era ASCT using this approach may be reserved for patients not responding or resistant to the imatinib mesylate.