Abstract
Background:
Advanced MF/SS carries a poor prognosis with most therapies failing to provide a long-term benefit. Allogeneic hematopoietic cell transplantation may result in durable remissions or clinically meaningful downstaging in a subset of patients. However, the risk of transplant related mortality has substantially curbed enthusiasm in the use of conventional allogeneic transplantation for this disease. In this study, we describe a novel allogeneic transplant approach in which a G-CSF mobilized, unmanipulated PBSC allograft from HLA-matched siblings was infused after conditioning with a regimen customized to maximally cytoreduce the disease and to provide the necessary immunosuppression to achieve sustained donor immune engraftment needed for the generation of a graft-vs-tumor effect (GVT). We theorized that this outpatient based reduced intensity transplant regimen would provide the essential tumor-debulking and a strategy to achieve sufficient degrees of donor T-cell chimerism necessary to result in the generation of curative GVT effects in patients with the most advanced forms of MF/SS.
Patients and Methods:
Between January 2004 and May 2014, 5 subjects (median age of 57, range 27-59) with refractory, advanced stage (III and IV) MF/SS who had failed a median 3 prior treatment regimens (range 2-7) underwent PBSCT following mostly outpatient conditioning with alemtuzumab (total of 193 mg), and fludarabine (total of 125 mg/m2). On day 0, subjects received a G-CSF mobilized unmanipulated PBSC allograft from an HLA identical sibling. CSA alone was used as GVHD prophylaxis. Donor lymphocyte infusions (DLI) were given to all patients to convert T-cell chimerism from mixed to full donor and when necessary to boost a GVT effect.
Results:
All 5 subjects initially had mixed lympho-hematopoietic chimerism but eventually converted to full donor chimeras in both myeloid and T-cell lineages; full donor T-cell chimerism was achieved at a median 7 months post-transplant (Figure 1). 3/5 subjects never became neutropenic and the 2 subjects who developed neutropenia had rapid neutrophil recovery occurring after 5 and 7 days. No patients developed severe anemia or thrombocytopenia and none required RBC or platelet transfusion support.
No patients developed acute GVHD prior to DLI and only one (20%) developed acute GVHD (GI, grade IV) following DLI (the 2nd DLI for this patient). Three subjects (60%) developed limited cGVHD which resolved with short course of steroids.
At a median follow-up of 3 years, 4 subjects achieved a complete remission, documented by labs, skin biopsy, and imaging. Remissions were delayed in onset, occurring at median 8 months post-transplant (Figure 1). 3 subjects remain alive in remission 13, 11, and 3 years after transplant. One subject with a heavy smoking history died in remission 3 years post-transplant from a secondary head and neck squamous cell carcinoma, and one subject died 7 months post-transplant from grade IV GI GVHD which followed a 2nd DLI given to treat progressive disease (Table 1).
Among those at risk, 3 of 4 subjects (75%) developed CMV reactivation. None of the subjects developed CMV disease or PTLD.
Conclusions:
Our custom designed conditioning regimen 1) resulted in cytoreductive effects against advanced MF 2) proved to be immunosuppressive enough to allow sustained donor engraftment serving as a platform for subsequent DLIs which lead to curative GVT effects 3) could be performed in the outpatient setting avoiding severe neutropenia and its associated opportunistic infections and the need for platelet and RBC transfusion support. These data establish that long-term cures of even the most advanced refractory MF/SS can be achieved utilizing this alemtuzumab and fludarabine-based reduced intensity allogeneic hematopoietic cell transplant approach.
No relevant conflicts of interest to declare.
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