After allogeneic HCT, 14 - 17% of patients die primarily due to infections. The impact of AMI on transplant outcome and risk factors for AMI has not been well assessed in the current era of antifungal agents. To assess this, the CIBMTR analyzed characteristics and outcomes of patients receiving allogeneic HCT from 1995 - 2008. Cases (n = 124) had a Zygomycetes [n = 72 (58%)] or Fusarium [n = 52 (42%)] AMI between day 0 - 365 after HCT. A control (ctl) cohort (n = 11856) included all patients from the same 66 centers as cases. HCT indication was malignancy in 106 (85%) cases and 9603 (81%) ctl. The median (range) follow-up of cases and ctl is 61 (13 – 132) and 62 months (1 – 186), respectively. Cases were older [41 yrs (1 – 68) vs 34 yrs (1 – 79); p = 0.004] and more likely to have a KPS <90% at HCT [cases = 50 (40%); ctl = 3330 (28%); p = 0.009]. Similar numbers of cases occurred before and after May 2002 when voriconazole was FDA approved [1995 – Apr 2002 = 60 (48%); May 2002 – 2008 = 64 (52%)]. Systemic antifungal prophylaxis (Table 1) was similar between cases and ctl (p = 0.64). The median time from HCT to AMI was 48 days (0 – 363) with most occurring between day 0 – 100 [day 0 – 30 = 49 (40%); day 31 – 60 = 18 (15%); day 61 – 100 = 22 (18%)]. AMI diagnosis significantly impacted 1-year survival (OS) with a probability (95% CI) for cases of only 22% (15 – 29) compared to 65% (64 – 65) for ctl [p <0.001]. OS after the diagnosis of AMI was dismal at 52% (42 – 60) by 30 days following AMI and 27% (20 – 35) by day 100. In multivariate analysis of OS, AMI increased the risk of death 6-fold (p<0.0001) regardless of the site (Blood, GI, Respiratory, Other) or the timing of infection. Compared to ctl, AMI beyond 100 days resulted in inferior survival vs AMI between day 0 - 30 [RR of death 11.78 (7.76 – 17.87) vs 5.67 (4.14 – 7.77); p = 0.006]. In multivariate analysis, time dependent factors occurring before and which increase the risk of AMI include grade II – IV acute GVHD [1.71 (1.13 – 2.58), p = 0.01], chronic GVHD [2.40 (1.21 – 4.75), p = 0.01], and prior Aspergillus infection [7.29 (3.70 – 13.38), p<0.001]. The only other significant factor for developing AMI was KPS <90% [1.92 (1.34 – 2.77), p = 0.0004]. Year of HCT, co-morbid conditions, stem cell source, disease/disease status, age, donor/recipient CMV serostatus and conditioning intensity were not significant. In conclusion, AMI occurs infrequently but appears similar in the current antifungal era and remains associated with high morbidity.TableAntifungal Prophylaxis reported in Cases with AMI and ControlsAntifungal AgentCases [N(%)]Controls [N(%)]None19 (15)2000 (17)Fluconazole57 (46)6264 (53)Amphotericin27 (22)1782 (15)Voriconazole9 (7)683 (6)Echinocandin1 (<1)158 (1)Other, including trials11 (9)969 (8) Open table in a new tab

Currently, there is no well-accepted rating system for reliably predicting which HLA-mismatched (MM) unrelated donor should be selected for a patient without an HLA allele-matched donor. We evaluated the ability of an MM ranking system, HistoCheck, to predict the risk associated with HLA class 1 disparity in a population of 744 single allele or antigen HLA-A, -B, or -C MM myeloablative unrelated donor hematopoietic stem cell transplantation recipients with acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome, facilitated through the National Marrow Donor Program between 1988 and 2003. Multivariate models were used to adjust for other significant clinical risk factors. HLA MMs were scored using the HistoCheck Web-based tool, and the patients were divided into 4 quartiles: dissimilarity score (DSS) 1.04-2.84 (allele MM), DSS >2.84-13.75 (allele and antigen MM), DSS >13.75-19.39 (antigen MM), and DSS >19.39-36.62 (antigen MM). Using the lowest scoring quartile as the reference, the DSS groups were evaluated for associations with relapse, treatment-related mortality, acute and chronic graft-versus-host disease, leukemia-free survival, and overall survival in the entire cohort and also in subset analyses by disease and disease stage. No significant associations were found between DSS and any outcomes in the overall cohort using the quartile categories or treating DSS as a continuous variable. Higher DSS scores were associated with decreased engraftment in early-stage disease (P = .0003), but not in other disease stages. In summary, DSS does not correlate with transplantation outcomes, and the HistoCheck scoring system does not provide an effective technique for ranking HLA class I MM. The dataset used in this study is available to evaluate new algorithms proposed for donor selection. Biol Blood Marrow Transplant 18: 739-746 (2012) (C) 2012 American Society for Blood and Marrow Transplantation

In the era of allelic typing and with bone marrow transplantation (BMT) in CR1 restricted to patients at higher risk of treatment failure, it is important to evaluate whether BMT using alternative family donors is equivalent to using an HLA-matched sibling donor (MSD) or an unrelated donor (URD). We compared the outcomes of patients <18y reported to CIBMTR from 1993–2006 with AML, ALL, CML and MDS undergoing a first allogeneic BMT. Donors were MSD (N = 1208), URD (N = 266) or a mismatched related donor (mmRD), either a 1 antigen mismatch at HLA-A, B or DRB1 (N = 97) or phenotypically matched related donor (N = 54). mmRD were typed by serological or DNA-based methods with all results verified by lab report review. URD were all 8/8 allelic matches at HLA-A,B,C,DRB1 through the NMDP retrospective typing program. All patients received myeloablative conditioning, T-cell replete bone marrow grafts and calcineurin inhibitor-based GVHD prophylaxis. Recipients of URD had more intermediate/advanced disease (p<0.01), were transplanted later after diagnosis (p<0.01) and more received TBI (p<0.01). There were no significant differences (p<0.01) between the phenotypically matched and 1-Ag mismatched related donor groups, so they were combined in the final multivariate model (as mmRD). Recipients of MSD had less acute GVHD grades 3–4, chronic GVHD, 100-day mortality, TRM and overall mortality (OM) as well as increased DFS compared with both the URD and mmRD groups (Table). Relapse rates were similar for all groups. Comparisons between the mmRD and URD groups did not detect a difference in acute GVHD grades 3–4, chronic GVHD, TRM, 100-day mortality, OM, DFS and relapse (Table). In this large cohort of paediatric patients, MSD have superior outcomes to either mmRD or URD. An 8/8 allelic matched URD results in outcome similar to mmRD. A family donor is an acceptable alternative to an allelic matched URD, but does not result in the same outcome as a MSD.Tabled 1Pairwise comparisons of mmRD vs. MSD and URD vs. mmRDOutcomemmRD vs. MSD OR/RR∗OR for 100-day mortality. RR for all other outcomes. (95%CI), pURD vs. mmRD OR/RR∗OR for 100-day mortality. RR for all other outcomes. (95%CI), p100-day mortality2.54 (1.55-4.17), <0.010.95 (0.54-1.66), 0.85Overall mortality1.48 (1.12-1.97), <0.010.98 (0.72-1.33), 0.87Disease-free survival1.38 (1.09-1.75), 0.011.02 (0.77-1.35), 0.90TRM3.01 (2.10-4.33), <0.011.16 (0.77-1.64), 0.74Relapse0.90 (0.65-1.24), 0.521.09 (0.74-1.60), 0.66Acute GVHD III-IV3.41 (2.38-4.89), <0.010.75 (0.49-1.14), 0.18Chronic GVHD3.09 (2.24-4.27), <0.011.27 (0.88-1.82), 0.20∗ OR for 100-day mortality. RR for all other outcomes. Open table in a new tab

We report outcomes of 932 recipients (rcpts) of UD PBSC HCT facilitated by NMDP from 1999 through 2003 (median f/u 3.3 yrs). Indications were AML (419 rcpts), ALL (185 rcpts), CML (134 rcpts), and MDS (194 rcpts). Preparative regimens included myeloablative (MA, N = 611), reduced intensity (RI, N = 160), and non-myeloablative (NMA, N = 161). Distributions of HLA-match grade, CMV status, Karnofsky scores (KS), and donor characteristics were similar between the preparative regimens, however, fewer rcpts with advanced disease received NMA (p = 0.035), while more rcpts with coexisting diseases received RI and NMA regimens (p < 0.001). The age of rcpts receiving RI and NMA regimens was substantially higher than rcpts receiving MA regimens (median RI 56 yo, NMA 57 yo, MA 38 yo, p < 0.001). Optimal cell dose cutpoints for TNC, MNC and CD34+ were determined based on Martingale residuals from Cox regression analyses. For MA rcpts, CD34+ counts >3.8 × 106/kg improved day +25 neutrophil and day +60 platelet engraftment; higher infused TNC doses (>6.9 × 108/kg) predicted decreased grade III-IV aGVHD, while improved overall survival (OS) and reduced TRM (RR 0.55) were seen with MNC doses >4.4 × 108/kg. For RI and NMA rcpts, OS was higher and TRM was decreased in those receiving >3.8 × 106 CD34+cells/kg. Of note, cGVHD was not increased with higher cell doses in rcpts of any type of preparative regimen. Additional predictors of improved OS included early disease, and for MA rcpts only, HLA-matched donors, KS ≥ 90, and CsA-based GVHD prophylaxis. Three year OS and DFS of rcpts receiving MA, RI, and NMA approaches were similar (33, 35, and 32% OS; 33, 30, and 29% DFS: MA, RI, and NMA, respectively). Higher risk of relapse at 3 yrs in RI and NMA approaches (35, 37 vs. 24% RI, NMA, MA, respectively, p < 0.001) was offset by higher 3 yr TRM using MA regimens (43 vs. 34, 34% MA, RI, NMA, respectively, p = 0.008). Sub-analyses of 1) rcpts with AML-CR1, 2) rcpts with AML/MDS/CML (excluding ALL), or 3) rcpts between the ages of 40–60 with AML/MDS also showed similar survival with MA vs. RI vs. NMA approaches. In summary, rcpts of UD PBSC HCT receiving preparative regimens differing in intensity experienced similar survival. Higher cell doses resulted in more rapid engraftment, less severe aGVHD (MA rcpts), and better 3 year OS (37 vs. 18%, MA; 36 vs. 21% RI/NMA, p < 0.001), but did not increase the risk of cGVHD.

Bariatric surgery has become an important means to reduce obesity and its related morbidity. Bariatric surgeries in the US have increased from 14,000 in 1998 to 140,000 in 2004. Malabsorption and achlorhydria can complicate bariatric surgery and may lead to iron deficiency and anemia. In this setting, little is known about the prevalence and severity of anemia and the efficacy of oral iron replacement, a common part of post-surgical management. We reviewed the records at our institution of a large number (n=1125; 126 men; 999 women) of patients followed for up to 4 yrs post-procedure for the development of anemia and assessment of vitamin levels and iron stores.

Non-myeloablative allogeneic SCT is associated with acute GVHD rates similar to conventional allografting which adversely impacts the survival of elderly patients typically receiving this therapy. In an attempt to modify the incidence of GVHD, we have developed conditioning regimens combining Thymoglobulin (THY) with low dose TBI in patients with hematologic malignancies. We report outcomes of two patient cohorts transplanted using either THY 2.5 mg/kg/day (day −4 to −1) with 2-Gy TBI on day 0 in cohort 1 (n=16) or THY 2.5 mg/kg/day (day−10 to −7) with 4.5-Gy TBI (day -1 to 0; 1.5 Gy fractions) in cohort 2 (n=7). This later modification was instituted because of early relapse and/or graft rejection seen in some patients in cohort 1. The patients received SCT from either matched sibling (MSD; n=14, all GCSF mobilized) or URD (n=9, marrow in 6). GVHD prophylaxis consisted of tacrolimus + methotrexate (day 1,3 & 6) in cohort 1 and tacrolimus + mycophenolate mofetil (day 0–30) in cohort 2. There were 8 female patients; median age was 57 years (range 70–43). Diseases treated were MM (9), NHL (6), CLL/SLL (3), AML (2) and other (3). A median of 3 (range 1–5) prior therapies had been given; 12 (52%) patients had failed a prior autograft. Disease status at transplant was, CR (4), Persistent disease (13) untreated relapse (6). No treatment-related grade IV or V toxicities were seen. Combined overall day-100 survival in the two cohorts is 87% (95% confidence interval 72–100%); and 1-year survival is 81% (95% CI 62–100%) in cohort 1. With a median follow-up of 32 months (range 44–13 mo) in cohort 1 and 6 mo (9–2 mo) in cohort 2, 16/23 (70%) patients are alive (6 died of progression and one of infection; 5 deaths were seen in cohort 1). 15/16 (93%) surviving patients are without disease progression (10 in CR). 11/23 (48%) are event-free (DLI, relapse or death), 8 of these were transplanted with URD. Only 3/23 patients (all receiving URD-PBSCT) developed steroid responsive GII–III AGVHD. Chronic GVHD developed in 7 patients undergoing URD-SCT. Graft rejection was seen in cohort 1 (3; all with disease relapse) but not in cohort 2. Hematopoietic chimerism as measured by PCR for STR loci in blood at day 30 was 95% (range 53–100) donor derived in all patients; 95% (68–100) at day 60, 95% (25–100) at day 90 and 95% around day 180 (1–100). The surviving patients are >90% donor chimeric in blood (8 URD, 7 MSD). WBC subset chimerism analysis at 30, 60 and 90 days showed similar neutrophil (96, 94, 96 vs. 96, 95, 98 %; P= 0.40) but superior T cell (96, 100, 99 vs. 85, 86, 71; P= 0.018) engraftment in cohort 2 when compared with cohort 1. There was rapid normalization of NK cell (CD3−, 56+) counts in patients with URD BMT compared with T cells (CD3+, 56−); median 46/μ L & 140 vs. 20 & 240 at 4 and 8 weeks. Ten patients (all MSD; 9 in cohort 1) received DLI, for mixed chimerism (4) or persistent disease (6). Six patients had increased donor chimerism following DLI, however only 4 developed GVHD requiring therapy. In conclusion, selected patients conditioned with reduced intensity TBI in combination with THY achieve rapid and sustained engraftment with minimal acute GVHD, especially when an URD is used.

More than 56,000 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed this year in the United States. Despite advances in treatment modalities such as radiation, biologic agents, and cytotoxic chemotherapeutic regimens, only 25–30% of these patients will be cured of their disease. Standard salvage regimens such as DHAP, ESHAP, ICE and EPOCH have proven efficacy at the cost of increasing toxicity and hospitalization costs. The reported response rates for these are on the order of 50–75% as first-line salvage regimens. However, as our aging patient population develops worsening performance status and co-morbidities, it seems appropriate to develop effective lymphoma treatments, which have fewer toxicities and lower costs for administration. One approach is to combine non-myelosuppressive therapies. One non-myelosuppressive agent, which has efficacy in lymphoma, is gallium nitrate. Investigation of gallium nitrate for cancer treatment dates back to the 1970’s. While it is currently approved for the treatment of bisphosphonate resistant hypercalcemia of malignancy, it has also been shown to inhibit ribonucleotide reductase and bind transferrin and potentially complex with the transferrin receptor, which is highly expressed in intermediate and aggressive histology lymphomas. It appears that the binding of the transferrin receptor on the lymphocyte as well as its inhibition of ribonucleotide reductase, eventually impairs iron metabolism, which is a necessary component of the intracellular cytochrome systems/mitochondrial function and ultimately oxidative phosphorylation. The current study is a phase II clinical trial investigating the combination of gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. The gallium nitrate is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients must have proven relapsed or refractory disease and have a SWOG PS <3. Patients may have failed prior ASCT or allogeneic SCT. The accrual goal is 37 patients. We have enrolled 14 patients on study to date and have 12 evaluable patients; as part of the ongoing safety evaluation for this study, we have the following results: ORR 9/12 (75%); CR 2/12 (17%); PR 7/12 (58%); SD 2/12 (17%); and PD 1/12 (8%). Most of these patients were refractory to prior salvage regimens 8/12 (67%), including ESHAP, DHAP or high-dose cyclophosphamide. No patients developed grade 3 or 4 toxicities, with the exception of grade 4 lymphopenia and grade 3 anemia (most likely due to transferrin receptor binding). Conclusions: gallium nitrate, rituximab and dexamethasone (GaRD) appears to be an effective and relatively non-toxic salvage regimen for patients with relapsed DLBCL, MCL or transformed FL.

There is considerable effort to develop more sensitive methods to detect minimal residual disease (MRD) in bone marrow and blood samples of persons with cancer. Results of MRD-testing are used to predict clinical outcome and determine if more anti-cancer therapy is needed. Mathematical models were developed to assess factors affecting sensitivity and specificity of MRD-testing at diverse cancer cell prevalences. Modeling results and predictions were compared to results of large published studies.Accuracy of MRD-testing depends on cancer cell prevalence and distribution in the blood or bone marrow of the subject, sensitivity and specificity of the MRD-test and sample size. In subjects with low cancer cell prevalences (< or = 10(-4)) results of MRD testing are likely inaccurate. Increasingly sensitive MRD-tests are only marginally useful; the major obstacle to accuracy is inadequate sampling. Increasing sensitivity of methods to detect MRD is unlikely sufficient to increase accuracy of MRD-testing. In contrast, increased sampling (size and frequency) and assigning a high cut-off value (for example, > or = 10(-3)) to declare a MRD-test positive will increase sensitivity and specificity, respectively.