Toxicity after blood and marrow transplantation (BMT) has interindividual variability that may be explained by common genetic polymorphisms in critical pathways. The glutathione-S-transferase (GST) isoenzymes detoxify the reactive oxygen species generated by chemotherapy agents and radiation. We investigated whether deletion polymorphisms in 2 GST genes (GSTM1 and GSTT1) were associated with toxicity after autologous or allogeneic BMT. The study population was selected from 699 consecutive BMT patients from 2 centers in Buffalo, NY, and Moscow, Russia, of whom 321 (203 autologous, 118 allogeneic BMT) had available banked samples and amplifiable DNA. Fifty percent of patients were homozygous null for GSTM1, which did not vary by center; however, the GSTT1 homozygous null deletion polymorphism occurred more frequently in patients treated in Moscow (38% versus 18%, P < .001). Overall grade 2-4 regimen-related toxicity occurred in 56%, with nearly 1 in 5 patients having 2 or more organ systems affected. Among autologous BMT patients, a deletion polymorphism in 1 or both genes was significantly associated with increased occurrence of overall toxicity (71% versus 56%, P = .034) and mucositis (74% versus 55%, P = .006). GSTM1 and/or GSTT1 deletion polymorphisms were not associated with toxicity after allogeneic BMT. Future studies may allow for individualized genetic risk stratification.
Donor lymphocyte infusions (DLI) are considered to be the treatment of choice in pts with relapses after allogeneic hematopoietic stem cell transplantation (HSCT). This kind of treatment is based on alloreactivity of donor lymphocytes, mediating a graft-versus-leukemia (GVL) effect. However, the relapses of acute leukemia in many cases are not susceptible to DLI. There were few reports that the concominant administration of cytokines (IL-2, IFN-alfa) and DLI is more efficient for conversion to complete donor chimerism (CC) from mixed chimerism (MC) and leads to remission in pts relapsed after HSCT, but the significance of this therapy is still not estimated. The aim of study was to evaluate the efficacy of DLI treatment combined with IL-2 i.v. administration for CC establishment and remission induction in pts with relapses after HSCT for hematological malignancies. 26 pts were treated with DLI for relapses after ASCT from related siblings in 2001–2007. 12 of them were included in the study. Median age was 25 y (16–44), 9 men/3 woman, 4 pts with AML, 1 - APL, 1 - ALL, 1 -ANL, 3 -CML, 2- MDS. 2 pt received reduced intensity HSCT, 10- conventional one. Median time to relapse was 12,5 months (3,5 – 48 months).10 pts demonstrated hematological relapses, 1 pt with APL and 1 pt with CML - molecular relapses. All pts with AL in overt relapse received chemotherapy first and then DLI was performed in aplasia. CML pts were treated with Hydrea and Glivec and then DLI were administrated. Median dose of infused DL was 6,34 x 108/kg (median 6 transfusions per pt) with median of CD3+ cells. Chimerism status was investigated on BM and PB using VNTR/STR analysis at relapse, before every DLI and monthly after DLI completion. All pts demonstrated MC in bone marrow before chemotherapy (median 74% of host DNA). 9 pts were still MC after chemotherapy and before DLI (median 38% of host DNA), 3 pts became CC before DLI. In all pts DLI were combined with IL-2 (2–6 MU with every DLI). In 6 pts with MC after chemotherapy only 1 (with CML) became CC after 1 course of DLI and developed aGVHD II–III and then cGVHD. 5 pts (with AL and MDS) after DLI were still MC remaining in hematological remission. One of them died of CMV infection. 2 pts recieved the 2nd course of DLI + IL-2, became CC and are still well and alive (1 - with cGVHD, 1 - without GVHD) for 30 months. For 2 pts (AML) with MC 2nd DLI course was not possible (donor was not available) and they received the course of IL-2 (5 days for 6 MU daily) in 2 months after DLI. The both are in complete remission with CC and cGVHD. 4 pts showed no effect and soon relapsed despite the 2nd DLI course in 2 pt and 2nd course of IL-2 in 1 pt. Despite the small and heterogenious group we may conclude, that DLI administration concomitantly with IL-2 leads to more prominent GVL effect and quick conversion from MC to CC. The interesting observation is that the additional infusions of IL-2 were effective for conversion to CC and remission induction in 3 of 4 pts resistant for DLI.
Background:Despite the decline in the overall incidence of COVID-19 in the world, patients with acute lymphoblastic leukemia (ALL) remain a vulnerable group of patients. Currently, coronavirus infection has predominantly mild course of the disease. However, a positive polymerase chain reaction (PCR) test for SARS-CoV-2 may interfere with treatment of leukemia, delaying therapy and increasing the risk of ALL relapse.
Treatment Related Mortality (TRM) due to BMT conditioning regimen-related toxicity (RRT) has decreased over the past decade, but still has a major impact on patient outcome. In addition, morbidity due to non-fatal toxicity has a major impact on increased length of stay, cost and treating toxicity, while decreasing acute quality-of-life. Several reports have associated individual polymorphisms and survival, TRM, hepatic toxicity and stomatitis. We hypothesized that genetic variability affecting metabolic and detoxifying enzyme activity might explain RRT inter-individual variability. The glutathione-S-transferase (GST) isoenzymes respond to oxidative stress by detoxifying the reactive oxygen species produced by many chemotherapeutic drugs and radiation therapy. We updated our previous single center report (Blood108:19a, 2006) of 496 first auto or allo BMT pts treated at RPCI from 1/1996 to 12/2002 with 203 additional pts meeting the same eligibility criteria and treated at an international center (NHC) from 1/1998 to 6/2007. Moderate to fatal toxicity was examined in association with GSTM1 and GSTT1 deletion genotypes. 290 patients (58%) from RPCI and 66 patients (33%) from NHC had available banked samples for genotyping. 268 RPCI patients and 54 NHC patients had samples yielding amplifiable DNA included in this analysis. 49% patients were homozygous null for GSTM1, 22% were homozygous null for GSTT1, and 7% were homozygous null for both GSTM1 and GSTT1; these genotype rates did not differ by center. 59% developed grade 2-4 RRT in any one or more organ sites (69% at NHC and 57% at RPCI, p>0.1). Comparison of patient characteristics between RPCI vs. NHC revealed significant differences between the 2 centers on age, donor relation, conditioning regimen intensity, diagnosis and KPS, therefore all analyses were adjusted for center effect. However, there were similar effects of genotype on RRT when stratified by center. GSTM1 deletion was associated with a significantly increased risk of overall grade 2-4 RRT (RR=1.6, 95%CI 1.04–2.6; p=0.03), with the same trend seen in both auto and allo BMT subgroups. In multivariate analysis, significant independent predictors of increased risk of grade 2–4 RRT were GSTM1 deletion (RR=1.78, 95%CI, 1.1–2.9, p=0.02) and unrelated allo donor (RR=6.7, 95% CI 1.3–35, p=0.03), with a trend toward a protective effect of improved performance status (KPS≥90 RR=0.6, 95%CI 0.4–1.03, p=0.07) after controlling for center, age, gender, diagnosis, conditioning regimen intensity and stem cell source. GSTM1 has been previously reported to be associated with TRM in unrelated allo BMT pts, however we now demonstrate this after auto and related allo BMT. GSTT1 deletion was not significantly associated with grade 2–4 RRT, confirming previous BMT studies. Individual organ toxicity (cardiac, bladder, pulmonary, hepatic, GI, CNS, stomatitis and renal) was also assessed: GSTM1 deletion was associated with a significantly increased risk of grade 2–4 Stomatitis RRT (RR=1.6, 95%CI 1.04–2.5, p=0.03). Genotype analysis of SNPs in additional metabolic enzyme pathways is ongoing. This is the first study evaluating RRT (overall and organ-specific) post auto, related and unrelated allo BMT. The ability to predict moderate, severe and fatal RRT after auto and/or allo BMT may improve outcomes by allowing for individualized conditioning regimens.
Monitoring of chimerism levels after hemopoietic stem cell transplantation (HSCT) has become a standard test for documentation of important clinical events such as engraftment, graft rejection or leukemic relapse. Sensitive and informative molecular techniques (PCR for STR/VNTR markers) are preferable methods for many laboratories for assessment of donor- or recipient-derived hemopoiesis. However, the sensitivity and specificity of this method may be improved using lineage-specific analysis. Separation of cell population allows not only to detect the kinetics of lineage engraftment but, in some cases, to reveal residual potentially malignant cells. We performed chimerism analysis in 10 pts with high risk haematological malignancies underwent alloHSCT in 2002–2004 ( 4pts - ALL, 3 of them - in 2-nd CR, 2pts - acute non-differentiated leukemia in 2-nd CR, 2 - AML in 2-nd CR, 1 pt with MDS and 1 pt - CML). 6 pts were transplanted after conventional conditioning (Busulfan 16 mg/kg and Cytoxan 120 mg/kg) and 4 - after reduced-intensity conditioning (Busulfan 8 mg/kg, Fludarabin 150 mg/m2 and ATG 40 mg/kg or Cytoxan 900 mg/m2). GVHD was prophylacted by Cyclosporin A (CSA) and Methotrexate(MTX) in 5 pts and Cy +MTX +Prednisone in 5 pts. The median follow-up was 339 days (90–600), median age was 32 yrs. The evaluation of chimerism was performed on bone marrow (BM) and following subpopulations of peripheral blood (PB): CD3+, CD19+ and granulocytes (GR) on +30, +60,+90, +180, +270, +360 days after HSCT using PCR-based method for VNTR/STR analysis. The analysed subpopulations have been obtained using immunomagnetic separation technique (Dynal). We also investigated the mononuclear fraction (MN) left after immunomagnetic separation for revealing of possible residual malignant cells. We revealed differencies in chimerism pattern in BM and PB cell populations. Only 4 pts showed complete chimerism (CC) in PB cell subsets while 7 patients had CC in BM on day+30. Four pts showed stable CC in all cell populations during all time of observation. Six pts demonstrated mixed chimerism (MC) in PB subpopulations (CD3+ - 6 pts, CD19+ - 4 pts, MN - 4 pts, GR - 2pts). Four of them showed stable or increasing donor signal (> 80%) and 2 pts expressed decreased donor chimerism (< 80%). In 4 pts with stable or decreasing MC CSA was cesated and 3 of them became CC to +180 d. 3 pts relapsed, 2 of them - with decreased donor chimerism in MN and CD3 subsets and one patient relapsed on day +90 despite CC in all cell populations. GVHD developed in 6 pts and always was predicted by CC in CD3+ subset. Pts with MC never demonstrated any GVHD. Conditioning regimen had no impact on chimerism status. In conclusion, investigation of chimerism in PB cell subsets permitted detection of minimal persistent recipient cell populations with high sensitivity than in BM. Close monitoring of chimerism allowed to identificate the patients with risk of relapse and convert them to CC using cessation of immunosupression.
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