Allogeneic hematopoietic cell transplantation without myeloablative conditioning for patients with advanced hematologic malignancies

G Gürman, M Arat, O Ilhan, N Konuk, M Beksaç, H Celebi, M Ozcan, O Arslan, C Ustün, H Akan, A Uysal, H Koç
Cytotherapy 2001, 3 (4): 253-60

BACKGROUND: The effect of allogeneic hematopoietic cell transplantation (alloHCT) on hematologic malignancies is based on the graft-versus-malignancy effect. Obtaining this effect with reduced toxicity has been possible by non-myeloablative (NMA) alloHCT. Once mixed chimeric status, and host versus graft with graft versus host tolerance are achieved, further strengthening of chimerism and graft-versus-malignancy effect can be obtained by donor lymphocyte infusions (DLIs) when needed.

METHODS: The patient group consisted of 13 patients with advanced hematological malignancies: seven had CML, four of them in blastic-, two in chronic- and the remainder in accelerated-phase; four patients with AML, refractory or in second remission state; one patient with primary refractory secondary AML; and one patient with ALL relapsed after alloHCT. Conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days and anti-T-lymphocyte globulin (ATG) 10 mg/kg/day for 4 days as immunosuppressive. Ara-C or Bu or melphalan were used as the cytoreductive component. All transplants were performed using HLA-identical sibling donors' peripheral blood hematopoietic cells, after priming with filgrastim. Post-transplant GvHD prophylaxis was achieved with CsA alone in 10 patients, and with CsA plus mycophenolate mofetil in the last three patients.

RESULTS: Median follow-up is 3 months (range, 0-20) for all the patients and 6 months (range, 2-15) for the live patients. Donor chimerism was shown in 10 patients, not regarding any pretransplant feature. DLIs were performed in seven patients after transplantation and two of them achieved complete chimeric status and molecular remission. Two CML patients in blastic phase (CML-BP), and the primary refractory secondary AML patient did not respond to procedure. In four patients, drug therapy in conventional doses was added to post-transplant DLIs for their relapsed or refractory diseases. Two patients with AML in second CR, and another CML-BP patient, relapsed or progressed after transplantation. A patient with CML-BP achieved CR and full donor chimerism after transplantation, but developed refractory post-transplant lymphoproliferative disease in the 19th month. Two patients with refractory AML, one patient with relapsed ALL and two patients with CML in chronic phase were in complete chimeric status and free of disease signs. Acute GvHD, Grade II-III, was observed in five patients, and two of them developed secondary progressive chronic GvHD subsequently. We observed one early death in a platelet transfusion refractory blastic phase CML patient due to intracranial hemorrhage. Procedure-related severe toxicity was not observed, either in standard-risk patients or stem-cell donors.

DISCUSSION: Establishing engraftment with donor chimerism was the first successful step in this approach. The second step, which was the result of the graft-versus-malignancy effect, could be seen in most of the patients, but was not sustained in all of them because of the aggressiveness of their malignancy. It can be suggested that the immunotherapeutic efficacy of this approach could be more successful, and with acceptable toxicity, when performed in patients with minimal residual disease. The role of NMA conditioning, and of the treatment in standard disease indications, remains to be determined in further studies.

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