ABSTRACT
Natural killer (NK) cells are expanded in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors (TKI) and exert cytotoxicity. The inherited repertoire of killer immunoglobulin-like receptors (KIR) may influence response to TKI. We investigated the impact of KIR-genotype on outcome in 166 chronic phase CML patients on first-line imatinib treatment. We validated our findings in an independent patient group. On multivariate analysis, KIR2DS1 genotype (RR=1.51, P=0.03) and Sokal risk score (low-risk RR=1, intermediate-risk RR=1.53, P=0.04, high-risk RR=1.69, P=0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR=3.1, P=0.03) and overall survival (OS) (RR=2.6, P=0.04). The association between KIR2DS1 and CCyR, PFS and OS was validated by KIR genotyping in 174 CML patients on first-line imatinib in the UK multi-center SPIRIT-1 trial; in this cohort, KIR2DS1(+) patients had significantly lower 2-year probabilities of achieving CCyR (76.9 vs 87.9%, P=0.003), PFS (85.3 vs 98.1%, P=0.007) and OS (94.4 vs 100%, P=0.015) than KIR2DS1(-) patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P=0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Receptors, KIR/genetics , Adolescent , Adult , Aged , Benzamides , Female , Genotype , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , Remission Induction , Survival AnalysisSubject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Octamer Transcription Factor-1/genetics , Piperazines/therapeutic use , Polymorphism, Single Nucleotide/genetics , Pyrimidines/therapeutic use , Benzamides , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Octamer Transcription Factor-1/metabolism , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the 'donor' group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21-60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11-55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7-48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56-98%; P=0.0003) among the nontransplanted patients. In an 'intention-to-treat' analysis, the Kaplan-Meier estimate of PFS was significantly higher in the 'donor' group as compared to the 'no-donor' group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15-0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.
Subject(s)
Multiple Myeloma/therapy , Neoplasm Recurrence, Local/therapy , Salvage Therapy/methods , Transplantation Conditioning/methods , Adult , Aged , Female , Graft vs Host Disease , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Stem Cell Transplantation , Transplantation, HomologousSubject(s)
Graft vs Tumor Effect , Leukemia, Prolymphocytic/therapy , Leukemia, T-Cell/therapy , Stem Cell Transplantation/adverse effects , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Follow-Up Studies , Graft vs Host Disease/diagnosis , Graft vs Host Disease/therapy , HLA Antigens/analysis , Humans , Leukemia, Prolymphocytic/diagnosis , Leukemia, T-Cell/diagnosis , Male , Prednisone/therapeutic use , Remission Induction , Siblings , Time Factors , Tissue Donors , Transplantation Conditioning/methods , Transplantation, Homologous , Treatment Outcome , Vincristine/therapeutic useABSTRACT
Using a genetic randomization through a 'donor' vs 'no donor' comparison, the aim of this analysis was to assess the real benefit of reduced intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) among 95 adult high-risk acute myeloid leukemia (AML) patients. In an 'intention-to-treat' analysis, leukemia-free survival (LFS) was significantly higher in the 'donor' group as compared to the 'no donor' group (P=0.01; 54 vs 30% at 4 years). The latter held true when restricting the analysis to the 25 patients who could actually receive the RIC-allo-SCT (P=0.001). Overall transplant-related mortality in the 'transplant' group was 12%, with overall survival (OS) being significantly higher in the 'transplant' group as compared to the 'no transplant' group (P=0.01). Also, in the 'intention-to-treat' analysis, OS was significantly higher in the 'donor' group as compared to the 'no donor' group (P=0.04). In the multivariate analysis, actual performance of RIC-allo-SCT (P=0.001; RR=4.0; 95% CI, 1.7-9.6) was the strongest factor significantly predictive of an improved LFS. We conclude that if a matched related donor is identified, RIC-allo-SCT should be proposed for AML patients not eligible for standard myeloablative allo-SCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid/therapy , Tissue Donors , Transplantation Conditioning/methods , Acute Disease , Adult , Aged , Female , Humans , Leukemia, Myeloid/mortality , Male , Middle Aged , Recurrence , Retrospective Studies , Risk Factors , Survival Analysis , Transplantation, Homologous , Treatment OutcomeABSTRACT
The use of reduced intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) can result in a significant decrease in early procedure-related toxicity in patients not eligible for standard myeloablative regimens. However, acute graft-versus-host disease (aGVHD) remains a matter of concern after RIC allo-SCT, and its incidence might be expected to be higher in elderly and high-risk patients. This report investigated mycophenolate mofetil (MMF) and cyclosporin A (CsA) combination (n=14) in comparison to CsA alone (n=20) for GVHD prophylaxis in cancer patients aged over 50 years (27 haematological malignancies and seven solid tumours) receiving an HLA-identical sibling antithymocyte-globulin (ATG)-based RIC allo-SCT. Baseline demographic characteristics and risk factors for aGVHD were comparable between both groups. Although MMF administration was not associated with any significant toxicity, the cumulative incidence of any form of GVHD was comparable between both groups (cumulative incidence of grade II-IV aGVHD, 50% (95% CI, 28-72%) for CsA alone, as compared to 64% (95% CI, 39-89%) to CsA and MMF, P=NS), suggesting that adjunction of MMF to CsA is feasible, but does not translate towards a significant reduction of aGVHD, at least in the context ATG-based RIC allo-SCT.
