Significant Difference In Non-relapse Mortality Research Articles

Matched Unrelated Donor Transplantation Is Curative In Selected Patients with Diffuse Large B Cell Lymphoma: A Report of the Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT)

AbstractAbstract 363Matched unrelated donor stem cell transplantation (MUD-SCT) has recently become a therapeutic option for patients with B cell diffuse large cell lymphoma (DLBCL) who fail other conventional therapies and do not have a matched sibling donor available. We present retrospective data of 473 DLBCL patients, 285 males and 188 females, aged 18 to 69 years (median 46 years), treated with matched sibling (n=301) or matched unrelated (n=172) SCT between January 2000 and December 2007 and reported to the EBMT registry. Median time from diagnosis to allograft was 25 months (range 2 – 203). Fifty-seven percent of the patients had failed previous autologous SCT, and 12% were transplanted in chemorefractory disease. After a median follow up of 41 months, the estimated 3-year non-relapse mortality (NRM), relapse rate (RR), progression free survival (PFS) and overall survival (OS) for the whole series were 37%, 32%, 31% and 40%, respectively. There were no statistically significant differences in patient age, disease status at transplantation, stem cell source and intensity of conditioning regimen between the Sib and the MUD cohorts (summarized in Table 1).However, a higher number of patients undergoing MUD have already failed an autograft (66% vs 52%, p=0.004), and T cell depleted grafts were more frequently used in the MUD cohort. Acute GvHD occurred in 48% of patients treated with a sib allograft vs 54% in those receiving a MUD (p=n.s). Interestingly, there were no statistically significant differences in NRM and RR between the Sib and the MUD groups (3 yr NRM=38% vs 37%, RR approached 38% vs 34%), resulting in a similar 3-year PFS and OS (32% vs 29% and 42% vs 35%, respectively). Multivariate analysis identified refractory disease (p = 0.001, RR 3.2; CI=1.3-3.5), poor performance status (p = 0.017, RR 1.9; CI=1.1-3.4) and age at transplantation > 50 years (p = 0.015, RR1.5; CI=1.1-2.1) as independent adverse prognostic factors for NRM and time from diagnosis to SCT < 36 months (p = 0.02, RR 1.5; CI=1.1-2.1), a previously failed autologous SCT (p = 0.026, RR .4; CI=1.1-1.9), refractory disease (p = 0.003, RR 2; CI=1.3-3.1), poor performance status (p = 0.0001, RR 3.5; CI=2.1-5.6) and T cell depletion (p = 0.001, RR 2; CI=1.3-2.9) as adverse prognostic factors for RR. A previous autologous SCT, poor performance status and refractory disease at transplantation were found to be significantly associated with a shorter PFS (p=0.04, RR 1.3; CI=1-1.6; p=0.0001, RR 2.4; CI=1.6-3.4; p=0.000,RR 2.1; CI=1.5-2.9, respectively) and refractory disease (p=0.0001, RR 2.2; CI=1.6-3.1) and poor performance status at the time of SCT (p=0.0001, RR 2.5; CI=1.7-3.6) with a shorter OS. Patients allografted from MUD tended to have a slightly increased risk of overall mortality in multivariate analysis, but this was not statistically significant (p=0.06, RR 1.2; CI=0.95-1.6). In conclusion, MUD SCT provides a curative option, not significantly inferior to that obtained with a matched sibling transplant, for selected patients with DLBCL who have failed conventional therapies, including autograft. Similarly, the type of conditioning regimen was not found to have a significant impact on patient outcome.Table 1Clinical characteristics Sib vs MUDSib (n = 301)MUD (n= 172)pAge (median, years)4645N.S.Previous ASCT48%33%0.004Refractory disease12%12%N.S.Poor P.S.13%7%0.06RIC/CC57%/43%56%/42%N.S.SC source BM/PB20%/80%22%/78%N.S.ATG/ALG15%46%<0.001in vivoüT-cellüdepletion12%20%0.03ex vivoüT-cellüdepletion5%12%0.03ASCT. Autologous stem cell transplantation; PS. Performance status; RIC. Reduced intensity conditioning; CC. Conventional conditioning; SC. Stem cell; BM. Bone marrow; PB. Peripheral blood; ATG/ALG. Anti-thymocyte globulin/ALG. Anti-lymphocyte globulin. Disclosures:No relevant conflicts of interest to declare.

Markedly Reduced Overall Survival of CYP2C19 *2/*2 Homozygotes After Myeloablative Hematopoietic Stem Cell Transplantation

AbstractAbstract 520Patients with allelic variations of cytochrome P450 enzymes that affect drug metabolism have been shown to have worse outcomes after hematopoietic stem cell transplantation (HSCT). One study demonstrated higher treatment-related mortality in carriers of the cytochrome P450 2C19 (CYP2C19) loss-of-function allele, *2, however the underlying cause remains unclear. Extensive metabolizers (EM) have two wild-type alleles of CYP2C19 (i.e., *1/*1), while intermediate metabolizers (IM) and poor metabolizers (PM) are heterozygous or homozygous for common allelic variants of CYP2C19 that produce null mutations (i.e., *1/*2, *1/*3 for IM and *2/*2, *2/*3 and *3/*3 for PM). We hypothesized that allelic variations in CYP2C19 may lead to worse outcomes after HSCT due to altered metabolism of CYP2C19 substrates or other drugs commonly given to patients receiving HSCT. We analyzed DNA samples from 344 patients who received high-dose CPA conditioning and total body irradiation prior to allogeneic HSCT between 2002 and 2008. Genotyping was performed to detect the *1,*2 and *3 allelic variants of CYP2C19. Non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) were determined for EM, IM and PM. We collected kidney and liver function test results and recorded all medications in the PM group. The EM, IM and PM phenotype was found in 249 (72.4%), 83 (24.1%) and 12 (3.5%) patients, respectively. CYP2C19 PM had significantly worse overall survival (3-yr: 25%) than EM and IM (55%) (Figure, adjusted HR=2.78, p=0.004). PFS was also significantly worse in PM (3-yr: 25%) versus EM and IM (53%) (adjusted HR=2.38, p=0.008). No significant difference in NRM and relapse was seen (p=0.10 and p=0.42, respectively). Compared to the three surviving patients, the nine PM who died had higher maximum post-transplant concentrations of creatinine (2.59 ± 2.33 mg/dl vs. 1.37 ± 0.06 mg/dl), total bilirubin (16.7 ± 18.4 mg/dl vs. 1.5 ± 0.8 mg/dl), AST (310 ± 144 U/l vs. 156 ± 107 U/l), and alkaline phosphatase (787 ± 811 U/l vs. 207 ± 84 U/l). A total of 192 different medications were administered to the twelve PM. Of the drugs metabolized by CYP2C19, seven of the nine patients who died received voriconazole and four received omeprazole. None of the three surviving patients received either drug. The significantly worse overall survival in CYP2C19 *2 homozygotes who carry two non-functional alleles may have multiple causes, one of them being administration of triazole drugs, in particular voriconazole. Voriconazole is an effective antifungal commonly given to patients after HSCT. It undergoes extensive hepatic metabolism, primarily by CYP2C19. PM have significantly higher concentrations of voriconazole than EM and IM, which may not only lead to direct voriconazole toxicity but also to exacerbated drug-drug interactions and altered concentrations of immunosuppressants and antibiotics. Since more than a thousand patients who receive HSCT each year are homozygous for CYP2C19 *2, further investigation into the causes of poor outcomes in this patient subset is warranted. In the interim, we propose testing for the CYP2C19 *2 allele in patients undergoing HSCT and careful monitoring of drug levels in the homozygotes, in particular voriconazole and immunosuppressants.Overall survival by CYP2C19 Genotype. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Abstract 3375Poster Board III-263Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients.We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo.Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT.Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001).There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD.In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures:Delgado:Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.