Non-Myeloablative Allogeneic Transplantation Resulting in Clinical and Molecular Remission with Low Non-Relapse Mortality (NRM) in Patients with Advanced Stage Mycosis Fungoides (MF) and Sézary Syndrome (SS)

Abstract Introduction: The majority of patients with refractory, advanced stage MF or SS have a life expectancy less than 5 years. Currently, there is no curative therapy and none of the available therapies provides a long-term remission. We have performed allogeneic transplant in 29 patients as a prospective clinical study using a novel non-myeloablative preparative regimen to provide prolonged disease control. Patient and Transplant Regimen: This cohort included 11 patients with MF and 18 patients with SS. The median age was 62 years (range 20-75). These patients were heavily treated with a median number of prior systemic therapies of 5 (range 2-13). The median time from diagnosis to transplant was 33 months (range 9-147). Five patients had stage IIB disease and 24 patients (83%) had stage IV disease (21 with IVA and 3 with IVB). All 11 patients with MF had evidence of large cell transformation. All patients had active disease at the time of preparative regimen (skin: 100%, blood: 62%, lymph node: 62%). The patients received total skin electron beam therapy (TSEBT, 24-36 Gy) as part of preparative regimen for skin disease control, immediately followed by total lymphoid irradiation (TLI, 8 Gy) and rabbit anti-thymocyte globulin (ATG). All patients received G-CSF mobilized peripheral blood hematopoietic cells from either an HLA-matched related (n=11), HLA-matched unrelated (n=13) or HLA-mismatched unrelated (n=5) donor. Cyclosporine or tacrolimus and mycophenolate mofetil were used for GVHD prophylaxis. The entire protocol required only a 5-day inpatient stay during the infusion of ATG. Results: As planned, all patients received their allograft infusion as outpatient. Patients tolerated the immediate post-transplant period extremely well. Fifteen patients required hospital admission within 100 days after transplant, with a median length of hospital stay of 4 days. The most common cause for admission was delayed ATG reaction. At day +90, full donor chimerism (donor CD3+ > 95%) was achieved in 10 patients (34%) and mixed chimerism was found in 14 patients (48%). Of these 14 patients, 9 of them subsequently achieved full donor chimerism and 1 had secondary graft rejection. Five patients (17%) had primary graft rejection (donor At 3-month post transplant, 19 patients achieved a complete response and 7 had a partial response (ORR 90%). Two patients experienced disease progression immediately after transplant, and 1 patient had stable disease. The median post-transplant follow-up for the entire cohort was 22.2 months and for the surviving patients was 24.5 months. The 2-year OS and PFS were 76% (95% CI, 54–88%) and 50% (95% CI, 28–68%), respectively. Among the surviving 21 patients, 81% (n=17) were in CR at last follow-up (16 with durable CR lasting >1 year). Of the 8 deaths in this study cohort, 3 were from NRM, each due to acute GVHD, complications related to chronic GVHD, or secondary malignancy (B-cell acute lymphoblastic leukemia). The 1-year cumulative NRM was 3%. High-throughput sequencing (HTS) of TCRs CDR3 was used for minimal residual disease (MRD) monitoring (Sci. Transl. Med.5:214ra171, 2013) (ImmunoSEQ, Adaptive Biotech). Of the 24 patients assessed, 11 patients (46%) achieved molecular remission in the blood after transplant. The median time to achieve molecular remission in the blood was 60 days (range 30-540). Of these 11 patients, 10 of them also achieved molecular remission in the skin. The 2-year OS and PFS for patients who achieved molecular remission were 86% (95% CI, 34–98%) and 71% (95% CI, 26–92%), respectively. Conclusion: We have developed an effective novel preparatory regimen with low transplant related mortality for non-myeloablative allogeneic transplant in patients with advanced stage MF and SS. Using the utmost sensitive TCRs HTS method to assess MRD, we were able to demonstrate a potentially curative therapy with molecular remission in this patient population. Disclosures No relevant conflicts of interest to declare.