Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease

Abstract

Infusions of large numbers (> 10(8)/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 x 10(5) and 5 x 10(8). Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 x 10(7) (n = 8), 5 x 10(7) (n = 4), 1 x 10(8) (n = 3), and 5 x 10(8) (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 x 10(7)/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of > or = 5 x 10(7)/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 x 10(7)/kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.

Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse

“…This is in accordance with our previous experience in a larger group of patients, in whom we saw very few (3/44) relapses with a median and maximal follow-up of 29 and 89 months respectively (Dazzi et al, 2000a). This supports the notion that, until we have further experience with STI571, the use of DLI in compliance with the escalating dose regimen pioneered by the Memorial Sloan±Kettering group (Mackinnon et al, 1995;Dazzi et al, 2000b) may be the best way of treating CML patients who relapse after allo-SCT, defining relapse as one will.…”

Cytotoxic T‐lymphocyte (CTL) responses against acute or chronic myeloid leukemia

“…Based on these observations, attempts have been made to treat recurrence of leukemia after transplantation by the administration to the patient of T lymphocytes from the original stem cell donor (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Especially in chronic myeloid lexikemia (CML).…”

“…In patients with relapsed CML chronic phase, 70-80% complete remissions have been reported foUowing this treatment, most of which have been sustained remissions. AJthough there has been a clear association between the occurrence of acute GVHD following this treatment, and an itnti-leukemic effect, disappearance of the leukemic cells did not always coincide with the occurrence of GVHD, suggesting that GVL and GVHD reactivity after allogeneic SCT may be separated (27,28).…”

“…no anti-leukemic response is observed after donor lymphocyte infusion (27). This may in part be due to the fact that the clinical responses may take several weeks to months to occur, and that the exponential expansion of the cells in vivo exceeds the efficiency of the immune response (28). hi addition, it can be hypothesized that the leukemic cells are not appropriate antigen-presenting cells, and, therefore, fail to induce a sustained anti-leukemic response in vivo, leading to an abortive immune response without a clinical effect (29).…”

Nonmyeloablative Allogeneic Stem Cell Transplantation: Early Promise and Limitations

“…The importance of cytoreduction either prior to alloSCT or as part of the preparative regimen is also controversial. Extrapolating from the chronic myelogenous leukemia experience [9,10,45,46], durable responses from DLI are more frequent in the setting of less advanced disease. It has been shown that a state of minimal residual disease can be induced with high-dose chemotherapy and autologous stem cell rescue followed safely by immune therapy with a nonmyeloablative alloSCT.…”