Chronic graft-versus-host disease (cGVHD), a common complication after stem cell transplant (SCT), has an impact on morbidity and survival. Previous classification of cGVHD has not been reproducible or prognostic for nonrelapse mortality (NRM). Recently the National Institutes of Health (NIH) consensus criteria were proposed, but the ability of this classification to predict outcome of various subtypes of cGVHD is unknown. Patients (N = 110) undergoing an SCT for a hematologic malignancy and surviving until day 100 posttransplant from 2001 to 2003 were studied. The overall survival (OS) using a landmark analysis at day 100 was 44% versus 66% (no GVHD vs. GVHD, P = .026). The OS of patients with various types of GVHD as proposed by the NIH criteria were significantly different (P < .0001). In a univariate analyses, this was more apparent when patients with any acute features of GVHD were compared to classic cGVHD (3-year OS 46% vs. 68%, P = .033). The 3-year NRM for the entire cohort was 21%, and was not affected by presence or absence of GVHD or subtypes of GVHD. In a multivariable analysis, extensive cGVHD (hazard ratio [HR] 0.35, P = .015) and having any acute feature of GVHD after day 100 (HR 3.36, P = .0144) were significant independent predictors of survival. The OS with different NIH subtypes of GVHD after day 100 from SCT varies, and is superior for patients with classic cGVHD.

Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant non-hematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to inter-individual differences in the development of gastrointestinal complications of HDM, we analyzed single-nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and twenty in SLC7A8 were genotyped. Multiple analyses indicated that one SNP in the first intron of SLC7A5, rs4240803, significantly associated with TPN use (OR= 0.45, 95% CI 0.25 – 0.79, p = 0.007). Further, every haplotype that correlated with TPN requirement incorporated this SNP. These results suggest that variability in melphalan transport impacts mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.

New agents with a variety of mechanisms of activity offer promising therapeutic options for patients with advanced HCC.

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BACKGROUND: cGVHD, defined as GVHD after day 100 from allogeneic stem cell transplant (SCT), is a common complication, with impact on morbidity and survival. cGVHD has been previously classified as limited or extensive using Glucksberg criteria, which have not been reproducible or prognostic for late non-relapse mortality (NRM). Recently the NIH consensus criteria were proposed, but the ability of this classification to predict outcome of various subtypes of cGVHD is unknown. HYPOTHESES: Do various subtypes of GVHD affect overall survival (OS) or NRM in patients (pts) with GVHD after day 100 from SCT? Is the NIH severity scale sensitive to change in cGVHD? Does the NIH severity scale predict OS or NRM? METHOD: Pts undergoing their 1st SCT for a hematological malignancy from 1/2001 and 12/2003 were studied. 110 pts alive beyond day 100 after SCT met criteria for the retrospective study, and excluded pts who recieved donor lymphocyte infusion or a 2nd SCT. GVHD after day 100 was classified using NIH consensus criteria as follows: persistent acute GVHD (aGVHD) (assigned at day 100), recurrent aGVHD, delayed aGVHD, classic cGVHD, overlap GVHD (all assigned at time of onset). Severity scores were assigned to pts with classic and overlap GVHD at onset and peak. Survival was measured as OS from time of transplant and time of onset of GVHD. Cumulative NRM was also computed. RESULT: 37 (34%) had no GVHD and 73 (66%) pts had GVHD. The OS was 44% vs. 66% (no GVHD vs. GVHD, P=0.026). Time to death was shorter in pts without GVHD (0.73 yrs vs. 1.27 yrs, P=0.002). Of the 73 pts with GVHD, 14 (19%) had limited and 59 (80%) had extensive cGVHD. Pts with limited GVHD were reclassified as persistent aGVHD (1, 7%), recurrent aGVHD (4, 29%), and classic cGVHD (9, 64%).Pts with extensive cGVHD were reclassified as persistent (2, 3%), delayed (2, 3%), recurrent (18, 31%), classic chronic (22, 37%) and overlap GVHD (15, 26%). 31 (42%) had no worsening and 42 (58%) pts had worsening of GVHD. 65% of pts with classic cGVHD (22/31) had worsening compared to other types (20 of 42, 47%) (P=0.046). Severity score increased in 12 of 31 pts (39%) who had clinical worsening of GVHD (kappa coefficient=0.31). The OS of pts with various types of GVHD as proposed by the NIH criteria were significantly different (P<0.0001). This was more apparent when pts with any acute features of GVHD were compared to classic cGVHD (3-yr OS 47% vs. 66%, P=0.0015). This effect persisted even when survival was measured from onset of GVHD (P=0.0336). Severity at onset or peak of GVHD activity in pts with classic and overlap GVHD did not impact the survival. The 3-yr NRM (with relapse as a competing risk) for the entire cohort was 21% and was not affected by presence or absence of GVHD, or subtypes of GVHD. Significant variables using Cox model with time dependent covariates were any aGVHD feature after day 100 (HR 5.273, P=0.0004), and extensive cGVHD (HR 0.284, P=0.0041). CONCLUSION: The OS with different NIH subtypes of GVHD after day 100 from SCT varies and is superior for pts with classic cGVHD. Global severity score may be useful as a descriptive clinical indicator of morbidity and the need for immunosuppressive therapy, but within the limits of our study, this score has no prognostic value with respect to survival and did not change with clinical worsening of GVHD.