Conditioning with Fludarabine (Flu)-Alkylator Is More Effective Cytoreduction Than Cyclophosphamide-Total Body Irradiation (Cy/TBI) for Refractory, Progressive Chronic Lymphatic Leukemia (CLL).

Allografting is becoming a more frequent therapeutic consideration for symptomatic CLL. The most frequently used preparative regimen historically has been Cy/TBI but flu-based conditioning is a recently reported alternative. Two cases in which Cy/TBI failed to impact on high pre-transplant peripheral blood (PB) lymphocyte counts prompted us to compare the outcome of stem cell allografts after TBI and non-TBI-based conditioning in 11 patients (pts) from two institutions. All pts had flu-refractory CLL. Five pts received flu 25mg/m² with either melphalan 120mg/m² (n=4) or Cy 120mg/kg; the other six received Cy 120mg/kg with fractionated TBI 12Gy. The two groups were comparable for age (median 50 yr overall; range 42–57), number of prior therapies (4; 2–6), extent of marrow involvement pre-transplant (90%; 65–99%) and incidence of cytogenetic abnormalities (abnormal in 8/9 evaluable). PB stem cells were used in 10 pts and marrow in one, with cyclosporine/methotrexate as GVHD prophylaxis in 8 and Campath/tacrolimus in 3. All patients receiving flu-alkylator conditioning had substantial initial cytoreduction with disappearance of PB lymphocytosis (including 2 with >30x10⁹/L pre-transplant), reduction in marrow infiltration to 25%, 15% and <5% at days 30, 60 and 100 respectively. Three of 5 remain in complete remission (CR) at 12, 35 and 49 months; one relapsed at one year and one died of GVHD with minimal disease at 5 months. In contrast, 5 of 6 pts had no significant initial marrow cytoreduction, 2 of whom maintained PB lymphocyte counts >300 and 30x10⁹/L during the first month. Median marrow CLL involvement was 93%, 80% and 77% at days 30, 60 and 100 post transplant in this group. Two pts subsequently experienced late onset cytoreduction in the context of chronic GVHD but have yet to achieve CR; three died of progressive disease and one of GVHD. In vitro studies in one patient demonstrated resistance of CLL cells to irradiation. These preliminary data demonstrate that advanced CLL may be resistant to TBI and despite prior resistance to single agent flu, a combination of melphalan and flu may be the optimal cytoreductive regimen in this context.