Non-myeloablative (NMA) allogeneic hematopoietic stem cell transplantation was originally engineered with the hope to minimize severe transplant-related complications such as acute GVHD. However, reported incidences of acute GHVD in the literature thus far still range from 30-60%, and there is yet no consensus on the ideal NMA conditioning and GVHD prophylaxis that should be used. In 2000, we speculated that early achievement of therapeutic levels of FK-506 prior to graft infusion would not only promote engraftment, but also lessen the incidence of acute GVHD by 1) further abating the cytokine cascade and 2) inhibiting the activation of donor lymphocytes by host dendritic cells. With this concept in mind, we have designed an immunosuppressive conditioning regimen consisting of iv cyclophosphamide 300/m2 and iv fludarabine 30 mg/m2 given from D-8 to D-4, followed by infusion of 5 x 106 CD34+ cells/kg obtained from a 6/6 sibling donor on D0. FK-506 was started D-8 at 3 mg BID, and promptly adjusted to obtain 10-15 nmol/L; tapering was intiated on D+50, and completed by D+100 or +180 according to expected risk of relapse. Mycophenolate mofetil (MMF) 1000 mg BID was started 24h after graft reinfusion, and discontinued on D+50. We evaluated donor chimerism prospectively in recipients lymphocytes and neutrophils using short variable tandem repeat assay (GenePrint STR, Promega). DLIs were scheduled prospectively for incomplete chimerism and progressive disease. Patients were assessed 1-3x/week on an outpatient basis and admitted only when clinically required. Between 07/2000 and 07/2003, 63 patients have been enrolled, and follow-up > 3 months is available in 57 (M/F 32/25; median age 54 years, range 20-65). Indications for NMA transplant were age 55 years (N=29) or expected higher risk of toxicity (N=28). Diagnoses include MM (N=28), lymphoma (N=14), AML/MDS (N=10), ALL (N=2), CML (N=2), and CLL (N=1). FK-506 taper was completed by D+100 in 90% of patients, and complete donor chimerism achieved in 97% of evaluable cases (median time : 42 days). Only 1 patient with CML-AP on STI571 had primary graft failure; 4 patients required DLIs for persistent mixed chimerism. We report an overall incidence of acute GVHD of 9% (5/57; grade I, N =1; grade II, N=4; grades III-IV=0). With a mean follow-up time of 16 months (range 4-35), KM estimate incidence of extensive chronic GVHD is 74 8%, occurring at a median time of 142 days (range: 92-244). Our patients experience no mucositis, short cytopenias, exceedingly low transfusion requirements, and could be treated entirely on an outpatient basis in 90%. Excluding cases of progressive disease, we report 2 deaths related to transplant (fulminant hepatitis, systemic aspergillosis following immunosuppression for refractory chronic GVHD). A graft vs tumor effect is particularly observed in the MM subgroup, and strongly correlated with onset of chronic GVHD. In summary, our regimen is remarkably well tolerated, and allows administration of NMA allogeneic transplant as an outpatient for almost all recipients. We report a very low incidence (9%) of acute GVHD despite the advanced age of our cohort: the exact contribution of FK-506 in combination with MMF needs to be clarified in animal models. Finally, the high incidence of extensive chronic GVHD remains to be improved, perhaps by prolonged tapering of immunosuppression.
Full conference title:
American Society of Hematology 45th Annual Meeting
- ASH 45th (2003)