Purpose The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors.Patients and Methods The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m(2)/d from days -4 to -2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day -3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0.Results Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after related and 42% after unrelated HCT, respectively. With a median follow-up of 44 months (range, 26 to 79 months), 51 patients were alive, of whom 48 were in complete remission (CR). Cumulative nonrelapse mortalities were 10% and 22%, and cumulative mortalities from disease progression were 47% and 33% at 2 years for related and unrelated recipients, respectively. Overall, 2-year survival was 48%, and disease-free survival was 44%.Patients receiving transplantation in CR1 had 2-year overall survivals of 44% after related and 63% after unrelated HCT, respectively. Conclusion We conclude that HCT from related and unrelated donors after low-dose TBI is a promising treatment for elderly patients with AML.

The safety and efficacy of 10/10 HLA antigen matched PBSC HCT from unrelated donors (URD)s after nonmyeloablative conditioning with fludarabine (3 x 30 mg/m2) and 2 Gy TBI (FLU/2 Gy TBI) followed by cyclosporine (CSP) and MMF (both given BID) for patients with hematologic malignancies ineligible for conventional HCT was previously demonstrated (Maris, Blood Vol 102, #6). Fifty-nine of the 71 pts who received PBSC grafts had sustained engraftment. In that study, the half-life of mycophenolate acid (active metabolite of MMF) was found to be 3 hours. This suggested that TID dosing of MMF could improve postgrafting immunosuppression and thereby increase engraftment rates. Subsequently, a trial of dose escalated MMF (15 mg/kg TID) while holding other HCT parameters constant was performed in 103 pts given PBSC grafts from URDs after FLU/2 Gy TBI, CSP and MMF, 15 mg/kg TID. The results in 69 patients with sufficient followup in this trial were compared to those in the previous 71 pts given MMF BID. Median (med) age of TID MMF pts was 58 (range 17–70) years and that of BID MMF pts was 54 (range 18–70) years. The med follow-up of pts given MMF TID and BID was 9 and 25 months. The med neutrophil nadir was 100/μl vs.740/μl (p = .01), but duration of absolute neutropenia was similar (8.5 vs 9 days, p = .43) for pts who received MMF TID and BID, respectively. There were trends toward less graft rejection at 1 year (7% vs.16%, p = .06) and higher peripheral blood donor CD3+ chimerism at day 28 after HCT (90% vs 75%, p = .09) with TID versus BID MMF. Other outcomes were not statistically different between TID versus BID patient groups: The cumulative probabilities (CP) of acute grades, II, III and IV GVHD were 40%, 11%, and 1% versus 41%, 10% and 3%, respectively. The CP of chronic GVHD requiring therapy were 40% and 44%, respectively. The Kaplan-Meier estimates at 1 year were 60% and 58% for overall survival, and 44% and 44% for progression free survival, respectively. The CP of relapse was 34% and 41%, respectively. The CP of nonrelapse mortality (NRM) at day 100 and at 1 year were 9% vs.11% and 22% vs.16%, respectively. We tentatively conclude that MMF dosing for URD PBSC grafts after FLU/2 Gy TBI can be safely increased from BID to TID without increasing toxicities, NRM, or relapse rates. TID compared to BID dosing of MMF in this setting may result in higher donor day 28 CD3+ chimerism values and sustained engraftment rates, while other outcomes were comparable. TableOutcomes after Nonmyeloablative Conditioning Using URDs: TID vs BID MMFTID MMF (n = 69)BID MMF (n = 71)P1 year Graft Rejection7%16%.06Day 28 T-cell Chimerism90%75%.09100 day aGVHD Grades II, III, IV40%, 11%, 1%41%, 10%, 3%.611-year CGVHD40%44%.351-year NRM22%16%.591-year Overall Survival60%58%.881-year Progression Free Survival44%44%.89 Open table in a new tab

Sixty-four patients (pts) with chemotherapy-refractory CLL who were ineligible for ablative allogeneic HCT due to age and/or comorbidities were given nonablative-HCT from related (n=44) or unrelated donors (n=20) between 1997-2003 (Table). Median pt age was 56 (range 44–69) years, interval from diagnosis to HCT was 4.4 (3–25) years, and number of prior regimens was 4 (range 1–12). Sixty-one pts were refractory to at least 1 regimen, 56 to fludarabine (FLU), 19 to alkylating agents, 14 to rituxumab and 4 to CAMPATH, and 2 had failed autologous HCT. Twenty-three pts (36%) had disease responsive to last chemotherapy [28% partial (PR) and 8% complete remission (CR)] while 34 were nonresponsive and 7 had untested relapse. Conditioning for HCT consisted of 2 Gy TBI alone (n=11) or combined with FLU (n=53), 90 mg/m2. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Pts received G-CSF mobilized peripheral blood mononuclear cells. After HCT, pts became neutropenic for a median of 11 days. Forty-four percent of pts had thrombocytopenia (<20,000 cells/ul). Three pts had graft rejection; 1 died with aplasia and 2 are alive with disease relapse. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic GVHD was 50% at 2-years. With median follow up of 24 (range 2.8–62.8) months, the overall response rate was 67% (50% in CR). URD-pts had significantly higher CR rate than MRD-pts. All 11 responding patients tested had molecular eradication of their disease. Overall, 39 patients are alive; 25 in CR, 5 in PR, 2 with stable disease, and 7 with relapse/progression. Twenty-five pts died, 10 from progression, 10 from infections ± GVHD, 2 from cardiac causes, 1 from metastatic lung cancer, 1 from cerebral stroke and 1 from rejection and aplasia. Estimated 2-year rates of non-relapse mortality, disease free survival, and overall survival were 22%, 52%, and 60% respectively. In multivariate analysis, high pretransplant comorbidity scores predicted higher non-relapse mortality and worse survival while bulky lymphadenopathy predicted increased risk of progression. CLL appears susceptible to graft-versus-leukemia effects particularly after URD grafts and nonablative-HCT should be explored in phase II trials in pts with FLU-refractory CLL.

We retrospectively analyzed the efficacy of unrelated HCT after nonmyeloablative conditioning with fludarabine 3 x 30 mg/m2 and 2 Gy total body irradiation as treatment for CML. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Data from 21 CML pts in CP1 (n=12), AP (n=5), CP2 (n=3), or BC (n=1) were analyzed. Median pt age was 54 (range, 33–66) years. Median time from diagnosis to HCT was 26 (range, 5–121) months. Two pts (in BC and in AP) had previously failed myeloablative allogeneic HCT. Four pts received marrow as stem cell source, and 17 G-PBMC. Two pts each had single HLA class 1-allele mismatches with their donor, the remaining were matched for 10/10 HLA antigens. One pt died before donor engraftment was evaluable. Donor engraftment at day 28 (defined as ≥ 5% donor T-cell chimerism) was observed in 18 of the 20 evaluable pts (90%), and was sustained in 11 of those (55%). All graft rejections were nonfatal and followed by autologous hematopoietic reconstitution. Day 28 T-cell chimerism was assessed in 19 pts. Eight of 9 pts with day 28 donor T-cell chimerism levels ≤ 40 rejected their grafts, compared with 1 of 10 pts with day 28 T-cell chimerism levels > 40%. The two marrow recipients who had not received chemotherapy prior to the HCT rejected their grafts. Eight of 11 (70%) patients with sustained engraftment (including 4 of 5 pts in CP1, 3 of 4 pts in AP, 1 of 2 pts CP2) achieved sustained complete cytogenetic remissions (CCR) (Table 1). In addition, another patient who had progressed to blast crisis after HCT achieved CCR and BCR/ABL molecular negativity by Q-PCR, following a short course of farnestyl transferase inhibitor and development of chronic GVHD. Analysis of minimal residual disease by Q-PCR in 6 pts with sustained CCR showed disappearance of BCR/ABL transcripts 84 to 524 days after HCT, consistent with graft-versus-tumor effects. Grade II-IV acute GVHD was seen in 11 pts and extensive chronic GVHD in 8. One pt transplanted in CP2 died of progressive disease (PD), and two pts transplanted in CP2 (n=1) and in AP (n=1) died of nonrelapse mortality (NRM), while in CCR. Three of 9 pts with graft rejection died of progressive disease, 5 were alive in CP, and 1 in AP at the time of the analysis. One hundred-day and two-year nonrelapse mortalities for all pts were 0% and 12%, respectively. Two year probability of overall survivals were 100% for pts transplanted in CP1, and 0% for those transplanted in more advanced stage. In summary, unrelated donor HCT following nonmyeloablative conditioning with fludarabine and low-dose TBI was feasible with low nonrelapse mortality. Sustained CCR were achieved in patients with stable engraftment, but graft rejection occurred in 45% of pts. Further efforts are being directed at reducing the risk of graft rejection by exclusive use of G-PBMC and increasing the intensity of pretransplant immunosuppression.

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.