Posttransplantation relapse of pediatric chronic myelomonocytic leukemia cured using donor lymphocyte infusion (original) (raw)
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Bone Marrow Transplantation, 1997
plant procedures which are associated with high treatmentrelated morbidity and mortality. 1 However, immunologic graft-versus-leukemia (GVL) effects, 2 which play a major Thirty-two adults (median age 36 years) with leukemia (15 AML, eight CML, six ALL, three CLL) persisting role in long-term control of minimal residual disease and cure after allogeneic BMT, have been exploited or relapsing 1-40 months (median 4) after allogeneic BMT (20 matched siblings, eight unrelated, four family successfully to treat relapsed leukemia after allogeneic transplantation. 3-13 mismatch) underwent immunotherapy to elicit GVHD. This comprised one or more of: infusion of donor cells The various approaches to induction of GVL in the setting of relapsed disease have been abrupt cessation 6 or rapid taper-(n = 22), stopping cyclosporine (n = 14), and administration of interferon-␣2b (n = 15) or interleukin-2 (n = ing 12 of cyclosporine, infusion of donor leukocytes 3,5-11,13 or lymphokine-activated killer (LAK) cells, 4,13 and adminis-4). Eight acute leukemia patients received chemotherapy as well. The time from relapse to immunother-tration of cytokines such as interferon-␣ 10 and interleukin-2, 4,10,13 which have often been used in combination. Due apy was 0-1344 days (median 4). Acute and/or chronic GVHD developed in 17 patients. Response was not eval-to the difficult clinical situation most such patients are in, treatment approaches are heterogeneous and often have to uable in three patients due to early toxic death. There was no response in 10 patients, whereas 19 showed be individualized. 1 In most cases, effective GVL has been associated with objective response. Nine patients died due to toxicity and 10 due to progressive disease. Thirteen patients are clinically detectable graft-versus-host disease (GVHD), although there is evidence to show that a low dose of donor alive 4-58 months (median 14) after immunotherapy; 12 in remission (five AML, four chronic phase CML, cells can induce remission of chronic myeloid leukemia (CML) relapsing after T cell-depleted BMT without one ALL, one accelerated phase CML, one CLL) and one with progressive disease (accelerated phase CML). GVHD. 14 Additionally, whether immunotherapy is effective in the treatment of relapsed acute lymphoblastic Eleven of 13 patients who are alive had GVHD compared with six of 19 who died (P = 0.005, Fisher's exact leukemia (ALL) is controversial. 15 We have attempted to induce GVHD and long-term test). We conclude that with the exception of CML in myeloid blast crisis, immunotherapy is active in most remission of disease by adoptive immunotherapy and/or abrupt cessation of cyclosporine in 32 adult patients with types of acute and chronic leukemia relapsing after allogeneic BMT. It is associated with considerable toxicity. acute or chronic leukemia relapsing after allogeneic BMT. Ten of these patients with acute leukemia and two with Clinically obvious GVHD, especially chronic GVHD, results in a higher probability of survival. chronic lymphocytic leukemia/prolymphocytic leukemia (CLL/PLL) have been reported previously. 1,12
Experimental hematology, 1999
patients with chronic myeloid leukemia who relapsed after stem cell transplantation were studied. Seventeen patients were not treated before donor lymphocyte infusion (DLI), eight patients received interferon-a (IFN-a), and five underwent chemotherapy. The method of DLI was the bulk dose regimen. The median time between DLIs was 6 weeks. The median number of infusions was three; the median time from transplant to relapse was 17 months and from relapse to DLI 2 months. Eleven patients (37%) were in molecular/cytogenetic relapse, 14 (47%) in chronic phase, and five (16%) in accelerated or blastic phase. Seventeen patients (57%) developed acute graft-versus-host disease (GVHD). Chronic GVHD was observed in 15 of 24 (62%) patients. Four (13%) patients developed cytopenia after a median of 30 days. Nineteen (63%) patients achieved response, 15 of them developed GVHD. The response rate according to the disease phase was molecular or cytogenetic relapse: 91%, chronic phase: 57%, and accelerated or blastic phase: 20%. The median time to response was 6 months. Patients treated with IFN-a or no treatment as well as those who were in molecular/cytogenetic relapse and those who received a CD3 + cell dose <110 8 /kg and CD4 + <810 7 /kg had better survival. We conclude that patients who receive lower doses of lymphocytes have better survival. In some patients IFN-a seems to be a good choice to potentiate the graft-versus-leukemia (GVL) effect.
Blood, 1995
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-c...
Bone Marrow Transplantation, 1998
is well established as an effective therapy for relapse of CML post allogeneic BMT. Reports thus far have been mostly limited to patients who received DLT from a matched sibling donor. We compared the efficacy and toxicity of DLT in 30 patients who were treated with cells from their HLA-identical sibling (n = 18) or from their phenotypically HLA-matched unrelated marrow donor (n = 12). The overall probability of obtaining a cytogenetic remission was 69% (95%CI: 51-83%) and was not significantly different between the two groups. The disease stage at the time of DLT was the only factor associated with cytogenetic remission by multivariate analysis; patients treated in cytogenetic or molecular relapse (n = 11) were seven times more likely (RR = 7.4, 95%CI: 2.4-22.4, P = 0.0005) to respond compared to patients treated for hematologic relapse (n = 19). There was a trend towards more acute GVHD II-IV in the unrelated donor group (58 vs 39%, P = 0.09), but the probability of developing extensive chronic GVHD was not significantly different (56 vs 39%, P = 0.4). We conclude that transfusion of donor cells from HLAmatched volunteer donors does not appreciably increase the risk of GVHD compared with transfusion of cells from HLA-identical siblings in patients with CML who relapse following allogeneic BMT. Conversely, there is no evidence for an increased graft-versus-leukemia effect after DLT from volunteer donors.
Annals of Hematology, 2004
The infusion of lymphocytes from the original marrow donor (donor lymphocyte infusion [DLI]) reinduces complete remission in a high percentage of patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplant, and thus, is probably the best initial approach to their management. The major predictive factor for response is the disease stage at time of treatment, because patients in molecular or cytogenetic relapse fare better than those in hematologic relapse. Moreover, patients with a short interval between transplant and DLI have a higher probability of response than those with longer intervals. The durability of DLI-induced remissions has not yet been established, but they appear to be prolonged. The observation that DLI can be highly effective for patients in relapse has encouraged the recent development of new strategies designed to minimize the myeloablative regimen and exploit the immunotherapeutic component of the transplant. The principal complication associated with use of DLI is the occurrence of graft-versus-host disease (GVHD). Several approaches have been tested to reduce the incidence or impact of GVHD, based on the ex vivo depletion of alloreactive donor cells or the use of donor T cells transduced with a suicide gene. The incidence of GVHD can also be reduced by starting with low doses of donor cells and "escalating" subsequent doses as required. However, the identification of selective targets for leukemia-reactive immunity is probably the optimal strategy to resolve the problem of GVHD. Although currently minor histocompatibility antigens appear to be the most likely targets for DLI, several groups are focusing on the generation of leukemia-specific immunity. The results obtained by use of tumor-associated antigens presented by dendritic cells are encouraging and may lay the foundations for the use of adoptive immunotherapy in the autologous setting.
British Journal of Haematology, 2002
We report the results of 50 allogeneic transplantations from related (n ¼ 43) or unrelated (n ¼ 7) donors, performed for chronic myelomonocytic leukaemia (CMML) in 43 European centres. The median age at transplant was 44 years (range 19-61). Eighteen patients had excess blasts ranging from 5% to 30% at the time of transplantation. Two graft failures were observed (4%). Neutrophil (> 0AE5 · 10 9 /l) and platelet engraftment (> 50 · 10 9 /l) was reached after a median of 17 d (range 11-38) and 27 d (range 11-48) respectively. Acute graftversus-host disease (GvHD grade II-IV was seen in 35% of patients, while 20% developed severe-acute GvHD grade III/ IV. Twenty-six patients (52%) died of treatment-related causes. After a median follow-up of 40 months (range 11-110), the 5-year-estimated overall survival was 21% (95% CI: 15-27%) and the 5-year-estimated disease-free survival (DFS) was 18% (95% CI: 13-23%). Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, allogeneic transplantation and occurrence of acute GvHD favoured better DFS, but did not reach statistical significance. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute GvHD grade II-IV (24% vs 54%; P ¼ 0AE07), and for a higher relapse rate in patients with T cell-depleted grafts (62% vs 45%), suggesting a Ôgraft-versus-CMML effectÕ.