Comparison of Clinical Outcomes and Day 30 Lymphocyte Recovery Between Two aGVHD Prophylaxis Regimens In Matched Unrelated Hematopoietic Stem Cell Transplant (MUD) Patients

Compared to HLA related hematopoietic stem cell transplants (HSCT), matched unrelated donor transplant (MUD) is associated with higher rates of transplant related mortality (TRM), primarily due to a higher incidence of acute graft versus host disease (aGVHD) and infections. Several investigators have shown that early lymphocyte recovery predicts less TRM, overall morality, aGVHD, and relapse post transplant, in HLA matched related HSCT. Only Lablanc et al demonstrated that Lymphocyte recovery at day 30(L30) is associated with improved outcomes in MUD patients, with the use of antibody mediated in-vivo lymphocyte depletion. We sought to compare clinical outcomes, L30, and the ability of L 30 to predict clinical outcomes in two contemporaneous cohorts of MUD patients treated with two different regimens for aGVHD prophylaxis.

We retrospectively evaluated all consecutive MUD patients at our institution, who received aGVHD prophylaxis regimen Mycophenolate Mofetil and Tacrolimus (MT) between January 2008 and June of 2010, {Group 1(Grp 1), N =70 }. The second group (Grp2, N=40) received Tacrolimus, Sirolimus and Thymoglobulin on phase II protocol (TST), between July 2008 and June 2010. Thymoglobulin was administered at a total dose of 4.5mg/kg on days -3,-2, & -1. Clinical outcomes and L30 were compared between the groups using chi square test. We evaluated the impact of L30 above or below 400/microliter (mic) on 6 month all cause mortality, TRM, relapse, aGVHD and infections in each group separately using log rank test.

Groups 1 and 2 were not significantly different with respect to age, CMV status and gender for both donor and recipient. Groups were unbalanced for hematological diagnosis. There was more advanced disease in Grp1 and more HLA mismatches in Grp2. Conditioning regimens included Busulphan/Fludarabine with or without Total Body Irradiation (TBI), Fludarabine/Melplan/TBI, Etoposide/TBI, Cytoxan/TBI, and Rituxan, Carmustine, Cytarabine, Etoposide and Melphan (R BEAM). The incidence of aGVHD (Grades I-IV) was significantly higher in Grp1 vs Grp2 (74% vs 26%, P=0.001). CMV reactivation, 6 months mortality and TRM were not significantly different between the 2 groups (P=0.58), (P=0.2), (P=0.26) respectively. A marginally significant increase in relapse was noted in Grp2 (P=0.046). Compared to Grp1, Grp2 had a significantly lower proportion of patients with L30 greater than 400/mic (Grp1 50% vs Grp2 74%, P=0.01). However this difference disappeared on day 60 (Grp1 67% vs Grp2 76% P=0.32), day 90 (Grp1 71% vs Grp2 75% P=0.66) and day 180 (Grp1 87% vs Grp 2 92% P=0.55) post transplant. More EBV reactivations occurred in Grp2 (20% vs 4%, P= 0.008). In a multivariate model, gender, CMV status, age (for both donor & recipient), and donors CD34+ counts, diagnosis at transplant, disease status at MUD and the degree of mismatch were not independent predictors of L30. In Grp 1, L30 above 400/mic was significantly associated with a lower all cause mortality (HR 0.2, CI= 0.06–0.82), lower TRM (HR=0.16, CI=0.042-0.61) at 6 months, and a non-significant decrease in the incidence of aGVHD (HR 0.6 CI 0.26–1.46). However, in Grp2 L30 above 400/mic was not associated with the same clinical outcomes. L30 (above or below 400/mic) was also not associated with CMV or EBV reactivation in either group.

Compared to aGVHD prophylactic regimen MT, the use of triple immune suppression TST was associated with less aGVHD, and lower lymphocyte recovery at day 30 post transplant. L30 above 400/mic predicted less overall mortality and TRM at 6 months in Grp1. Further studies exploring recovery and kinetics of lymphocyte subsets may explain the difference in the ability of L30 to predict clinical outcomes between the two groups.

Off Label Use: Bortezomib is currently not approved for maintenance therapy after Autologous stem cells transplant. Abidi: Millennium: Speakers Bureau. Lum: Transtarget Inc: Equity Ownership. Al-Kadhimi: Genzyme Pharmaceutical: Research Funding.