Gruppo Italiano Trapianto Di Midollo Osseo Research Articles

The Impact of Graft CD3 Cell/Regulatory T Cell Ratio on Acute Graft-versus-Host Disease and Post-Transplantation Outcome: A Prospective Multicenter Study of Patients with Acute Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation

Although it is well known that tumor site- or bone marrow-infiltrating regulatory T cells (Tregs) might be correlated with worse outcomes in solid tumors and acute leukemias by promoting immune surveillance escape, their contribution to the immediate post-allogeneic transplantation phase by peripheral blood (PB) allografts remains unclear. Moreover, the Treg content in stem cells harvested from PB has been suggested to be correlated with acute graft versus-host-disease (aGVHD) and immunologic recovery after allogeneic PB stem cell transplantation (allo-PBSCT). This study aimed to investigate the impact of the graft content of Tregs, as graft CD3+/Tregs ratio (gCD3/TregsR), on acute GVHD and post-allo-PBSCT outcomes. We prospectively enrolled 94 consecutive patients at 9 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) with acute myelogenous (n=71; 75%) or lymphoblastic (n=23; 25%) leukemia in complete remission who underwent matched related donor (n=35; 37%) or unrelated donor (n=59; 63%) allo-PBSCT. The median graft CD3+ cell, Treg, and gCD3/TregsR values were 196×106/kg body weight (range, 17 to 666×106/kg), 3×106/kg (range, 0.1 to 35×106/kg), and 71 (range, 1 to 1883), respectively. The discriminatory power of the gCD3/TregsR value to predict grade ≥II aGVHD was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC). Any grade and grade ≥II aGVHD occurred in 24 (26%) and 17 (18%) allo-PBSCT recipients, respectively. By ROC analysis, AUC (0.74; 95% confidence interval [CI], 0.608 to 0.866; P=.002) identified 70 as the optimal gCD3/TregsR cutoff value predicting the appearance of grade ≥II aGVHD with 76% sensitivity and 71% specificity. Patients were subdivided into a high (ROC curve value ≥70) gCD3/TregsR group (HR; n=48) and a low (ROC curve value <70) gCD3/TregsR group (LR; n=46). The incidence of grade II-IV aGVHD was lower in the LR group compared with the HR group (9% [4 of 46] versus 27% [13 of 48]) in both univariate analysis (odds ratio [OR], 4.8; 95% CI, 1.44 to 16.17; P=.015) and multivariate analysis (OR, 5.0; 95% CI, 1.34 to 18.93; P=.017), whereas no differences were documented taking into account aGVHD of any grade. The overall survival, disease-free survival, nonrelapse mortality, and relapse rates at 2 and 3 years were 61% and 54%, 62% and 55%, 15% and 23%, and 27% and 30%, respectively. Of note, gCD3/TregsR did not significantly correlate with relapse (P=.135). Taken together, our data from this prospective multicenter study confirm the value of Tregs in preventing aGVHD while maintaining the graft-versus-leukemia effect. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Development of an assay for cellular efflux of pharmaceutically active agents and its relevance to understanding drug interactions.

Drug interactions may dictate the failure or success of a treatment. Patients undergoing hematopoietic stem cell transplantation (HSCT) are exposed to various types of drugs, and understanding how these drugs interact is of the utmost importance. The pharmacokinetics of busulfan, melphalan, and cyclophosphamide, drugs commonly used for HSCT, are known to be affected by a variety of other drugs with differing molecular structures. We hypothesized that these structurally unrelated drugs affect the transport of DNA-alkylating agents. To test this hypothesis, we developed a flow cytometry assay that used 5-carboxyfluorescein diacetate acetoxymethyl ester, which is cleaved by nonspecific intracellular esterases to 5-carboxyfluorescein (5-CF), a fluorescent ligand for the drug transporter MRP1. A decreased 5-CF efflux in the presence of a test compound suggests competitive inhibition. We demonstrated that chlorambucil, 4-hydroperoxycyclophosphamide, ketoconazole, ethacrynic acid, everolimus, and sirolimus strongly inhibited 5-CF efflux in lymphoma and leukemia cell lines. The efflux of these drugs partially depends on the glutathione (GSH) level, and their cytotoxicity is synergistic with inhibited GSH synthesis. This is consistent with the hypothesis that their GSH-conjugated products are ligands of a common cellular drug transporter. Our results may explain clinical observations on the effects of various drugs on the pharmacokinetics and pharmacodynamics of alkylating agents, and the assay may be used to deduce interaction mechanisms of drugs transported by a common system.

Prediction of Allogeneic Stem Cell Transplantation Mortality in Patients with Acute Leukemia (AL) Using the AL- European Society for Blood and Marrow Transplantation (EBMT) Risk Score in the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO) Data Set: A Study on Behalf of the AL Working Party (ALWP) of the EBMT and GITMO

* AR and AN contributed equally to the abstractBackground: When considering a high risk, but potentially curative procedure, such as an allogeneic hematopoietic stem cell transplantation (HSCT), prognostic models may help decision making. We have previously developed the Acute Leukemia (AL)-EBMT score for prediction of mortality following allogeneic HSCT in AL patients (Shouval et al., JCO, 2015). The score is based on 10 variables including: disease status,Karnofsky performance status, recipient age, diagnosis, interval between diagnosis to HSCT, conditioning regimen, donor type, donor and recipient CMVserostatus combination, HSCT year, and center experience (HSCT/year). External validation of the score on an independent cohort of AL patients is of importance.Methods: This was a retrospective validation study on an independent cohort of AL patients from the Italian national transplantation network (GITMO). Inclusion criteria included adult AL patients, receiving an allogeneic HSCTbetween 2000-2014. Competing risks analysis was used to calculate the 2 years non-relapse related mortality (NRM) cumulative incidence, using the Gray test to test differences between ADT score groups. Overall survival (OS), and leukemia free survival (LFS) at 2 years were estimated using the Kaplan-Meier method; hazard ratios were computed between subgroups using Cox regression for OS and LFS and competing risk regression for NRM. Competing risk regression was used to compute NRM cumulative incidence rates, considering non-transplant mortality as the competing event. The predictive ability of the AL-EBMT score was assessed using time-dependent receiver-operator curves (AUC) analysis.Results: A total of 1,848 patients from 61 Italian transplant centers were analyzed. The median age was 45.9 (IQR 35.2-55). Indications for HSCT were Acute Myeloid Leukemia (67.8%) and Acute Lymphoblastic Leukemia (32.2%). The majority of patients were in first complete remission (60.6%), and received myeloablative conditioning (81.3%). Median follow-up was 2 years (1.9-2.1, 95% CI). The AL-EBMT score was categorized according totertiles (low, intermediate, high) on the original ALWP-EBMT cohort. Increasing score intervals corresponded with decreasing probability for 2 year OS (95% CI), ranging from 75.52% (70.69-80.68) to 36.93% (32.81-41.56), and increasing probability of 2 years NRM ranging from 10.9% (7.97-14.93) to 27.39% (23.84-31.48) (Table 1, Figure 1). The highest scoring group was associated with a hazard ratio (95% CI) of 2.89 (2.01-4.16) for 2 year NRM and 3.66 (2,85-4.72) for death at 2 years (Table 2). The categorized score discrimination (AUC) for 2 year OS, LFS, and NRM was 66.42, 66.15, and 67, respectively.Conclusion: This is the first study externally validating the AL-EBMT score. The score identified 3 distinctive risk groups and was predictive of survival related outcome. It can be used as a decision support tool when considering an allogeneic HSCT in acute leukemia patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES, and GITMO Position Paper.

Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas.

Factors Predicting Outcome after Allogeneic Stem Cell Transplantation in Primary Refractory Acute Myeloid Leukemia: A Retrospective Analysis of the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

BackgroundThe outcome of primary refractory (PRF) acute myeloid leukemia (AML) patients is poor with a minor proportion rescued by allogeneic hematopoietic stem cell transplantation (HSCT). The identification of pre-HSCT variables may help to identify PRF AML most likely to benefit from HSCT. The EBMT group reported factors predicting the outcome of 168 patients with PRF AML receiving an unrelated donor stem cell transplantation; 5-years OS was 22% and factors associated to an improved survival were the numbers of chemotherapy cycles (< 3), bone marrow blast infiltration <38% and patient CMVseropositivity. These clinical findings allowed to define 4 prognostic groups with survival rates ranging between 44% and 0% {Craddock, 2011). We performed a similar analysis focusing on PRF AML patients transplanted in Italy between 1999-2012 with a stem cell graft obtained by a sibling, unrelated donor and cord blood unit.Patients and study designWe analyzed the clinical outcome of 242 patients transplanted in 26 GITMO centers. Patients disease status at HCST included PRF AML defined as failure to achieve a complete response (CR) after one or more chemotherapy cycles containing active drugs on AML. The cytogenetic and molecular risk was defined according to the European LeukemiaNet. The main clinical and outcome follow up data were retrieved from the GITMO database. The main end-points of the study were overall survival (OS) and leukemia-free survival (LFS).ResultsThe median age at HSCT was 49 years (18-72) and 55% of patients were male. Before HSCT, 58% received ≤ 2 chemotherapy cycles. Median time from diagnosis to HSCT was 6 months (1-19) and in 85% was ≥ 3 months. An intermediate-II/adverse karyotype was detected in 58% of patients, > 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 60% and a pre-HSCT Karnofsky score < 90 was present in 43%. Donors were HLA identical sibling in 48% and matched unrelated in 19%, related mismatched in 19%, unrelated mismatched in 3% and cord blood in 11%. Anti-CMV antibodies were present in 87% of patients and in 65% of the donors. Conditioning regimen intensity was myeloablative or reduced in 69% and 31%, respectively; 49% of patients received T cell depletion (92% in vivo and 8% ex vivo). Neutrophils and platelets engraftment was achieved in 87% of patients after a median of 17 (9-52) and 17 (3-150) days, respectively.In all, 35 (14%) patients died within 30 days from HSCT. Of 207 patients evaluable for response, 138 (66%) achieved CR after a median time of 32 days (range 16-130) from HSCT and 69 did not (33%). Median survival of patient who achieved CR was 10 months while it was 2 months for those who did not. Seventy patients (51%) relapsed after a median time of 3 months (1-31), 64 died of disease, 6 survived and 2 of these latter reachieved CR. Sixty-eight patients (49%) maintained CR, 34(50%) died and 34 survived. A t the last follow up 42 patients were alive, 36 in CR and 6 with disease with a median follow up of 27 months (range 1,8-14). The median OS of the whole patient cohort was 5,7 months. At 3-years, the OS and LFS was 15% and 23% respectively.AGvHD was registered in 39% of patients (grade > 2 in 30% of cases) while cGVHD occurred in 29% (extended in 44% of cases). The 3-years cumulative incidence of NRM was 17%.By univariate analysis, the number of chemotherapy cycles to achieve CR (≤ 2), the time to HSCT (< 3 months), the cytogenetics risk favorable/intermediate I, the number of marrow blasts < 25% or the absence of blasts in the peripheral blood, the PS ≥ 90 and the lack of any form of T cell depletion, were all associated to a better survival. By multivariate analysis, the number of chemotherapy cycles, (Hazard Ratio (HR): 1.51; 95% confidence interval (CI): 1.04–2.19; P=0.029), the lack of T cell depletion (HR: 1.66; 95% CI: 1.15–2.40; P=0.007), the degree of BM or PB blast infiltration (HR: 1.59; 95% CI: 1.01–2.25; P=0.043), and the PS (HR: 1.46; 95% CI: 1.00–2.14; P=0.048) remained significantly associated with survival. On the basis of this multivariate analysis, we set up a new score predicting a different 3 years OS: score 0 (0 or 1 adverse prognostic factor, with 28% survival), score 1 (2 adverse prognostic factor, 17% survival); score 2 (2 or 3 adverse prognostic factors, 10% survival) (Figure 1)ConclusionThe clinical outcome of PRF AML remains poor. The new simple clinical GITMO score helps indentifying patients most likely will benefit or not from the HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pre-Transplant Ferritin, Albumin and Platelet Count Add Prognostic Information to Comorbidities for Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes: A Multi-Center Discovery-Validation Study

▪Albumin, ferritin, and peripheral blood counts broadly capture health status in patients undergoing allogeneic stem cell transplantation (HCT). Whether they add any prognostic information to the HCT-Comorbidity Index (HCT-CI) is unknown. We analyzed the independent prognostic role of a group of 5 biomarkers (ferritin, albumin, absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet (Plt) count) in pts given allogeneic HCT for hematologic malignancies.This was a multi-center, retrospective discovery-validation study comprising data from 3917 recipients of allogeneic HCT at the Fred Hutchinson Cancer Research Institute (FHCRC) (n=1789) and Dana Farber Cancer Institute (DF) (n=716) in the US and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) (n=1412) in Italy (Table 1). Proportional hazard models were used to estimate the hazards of non-relapse mortality (NRM) and survival after adjustment for the HCT-CI, donor type, CMV serostatus, regimen intensity, age, disease risk and Karnofsky Performance Status (KPS). These were stratified by institution. Model performances were tested by c-statistic estimates.In an initial analysis within the FHCRC population, ANC of <500 and Hgb of < 9 were not associated with outcomes in the models. Alternatively, ferritin >1000 (HR 1.98; p=0.0003) and >2500 (HR 1.97; p=0.0005); albumin <3.5 (HR 1.63; p<0.00001) and <3.0 (HR 1.73 p<0.0001); and Plt <100k (HR 1.65; p<0.0001), <50k (HR 1.52; p<0.0001) , and <20K (HR 1.54; p<0.008) were all statistically significantly associated with NRM.Results were validated in a larger population from DF and GITMO. In multivariate models, adjusted for previously mentioned variables, ferritin >2500 and incremental decreases in albumin and Plt counts had statistically significant associations with both NRM and survival (Table 2). Of note, HCT-CI scores (2, 3 and >4) also retained significant associations with NRM and survival in the presence of the three biomarker values and in both cohorts. Subsequent multivariate analyses stratified the whole cohort (n=3917) into a training (n=2352) and a validation (n=1407) set. In both sets, albumin <3.5, plts <100K, and ferritin >2500 had statistical significance associations with NRM and survival. Each of the three biomarker values were subsequently assigned a weight of 1 following the same equation used to develop the HCT-CI. The augmented HCT-CI/biomarker index had higher c-statistic estimate (0.61) for prediction of NRM compared to the HCT-CI alone (0.58) in the validation set.Ferritin, albumin, and Plt counts are simple and valid prognostic biomarkers for transplant outcomes and should be considered in combination with the HCT-CI in risk assessment prior to allogeneic HCT. The physiology behind these associations warrants further investigation to identify areas of intervention that may improve outcomes.Table 1:Pt characteristicsFHCRC(N=1789)DF/GITMO(N=2128)N (%)N (%)DonorRelated900 (50)1062 (50)Unrelated889 (50)1053 (50)Disease riskLow740 (41)866 (43)High1049 (59)1157 (57)Age< 501025 (57)1120 (53)≥ 50764 (43)1008 (47)ConditioningMA983 (55)1100 (52)RIC/NMA806 (45)1004 (48)Pt CMV-773 (43)505 (24)+1016 (57)1581 (76)KPS≤ 90691 (39)644 (33)90-1001098 (61)1304 (67)Table 2:Multivariate analysis showing the associations between biomarkers and NRM and survival.NRMSurvivalMarkerHR1P1HR1P1FHCRCAlbumin≥3.51.01.0<3.5 - 3.01.440.0021.45<0.0001<3.01.77<0.00011.77<0.0001Unk1.150.381.190.11Plts≥100K1.01.0<100K – 50K1.480.00071.280.003<50K – 20K1.490.0031.370.001<20K1.640.0051.580.0004Unk0.660.470.480.14Ferritin≤10001.01.0>1000 - 25001.600.031.700.0006>25002.080.0011.630.007Unk1.420.031.440.002HCT-CI01.01.011.290.121.310.0221.500.011.420.00132.29<0.00012.04<0.0001≥ 42.94<0.00012.42<0.0001DF/GITMOAlbumin≥3.51.01.0<3.5 - 3.01.600.00011.360.0005<3.02.77<0.00012.18<0.0001Unk1.610.011.110.49Plts≥100K1.01.0<100K – 50K1.080.561.020.85<50K – 20K1.170.281.210.06<20K1.380.041.350.009Unk0.640.100.820.28Ferritin≤10001.01.0>1000 - 25001.110.431.230.02>25001.600.0021.69<0.0001Unk1.130.331.120.19HCT-CI01.01.011.310.051.140.1921.290.101.250.0431.480.0061.460.0001≥ 41.74<0.00011.66<0.0001Unk=Unknown1Adjusted for donor , CMV serostatus , regimen intensity , age , disease risk , KPS ; stratified on institution. DisclosuresNo relevant conflicts of interest to declare.

Decision Analysis of Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome Stratified According to the Revised International Prognostic Scoring System (IPSS-R)

Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms that range from indolent conditions to forms very close to acute leukemia (AML). The International Prognostic Scoring System (IPSS) is the benchmark for clinical decision-making. Recently, the International Working Group for Prognosis in MDS (IWG-PM) defined 5 new cytogenetic risk groups on a large cohort of patients representing the basis for the revised IPSS (IPSS-R) together with refined categories for marrow blasts and cytopenias (Blood. 2012;120:2454-65). IPSS-R categorization enables more accurate definition of the prognosis of MDS patients, in particular those in low or intermediate-1 IPSS risk groups. Despite recent progress, the only curative treatment for MDS remains allogeneic stem cell transplantation (allo-SCT), which however involves a non-negligible risk of mortality/morbidity. Allo-SCT is not considered in patients with very low IPSS-R risk, whose median survival is 9 years. Conversely, eligible patients with high or very high IPSS-R risk, whose survival is 1–2 years, should be offered immediate transplantation. Uncertainty exists about the optimal timing of allo-SCT in the low and intermediate IPSS-R risk groups, and to address this issue we performed an ad hoc decision analysis. We analyzed two cohorts of MDS patients (age 18-70 years): i) 477 patients diagnosed with MDS at the Policlinico S. Matteo, Pavia, Italy between 2000–2010, who mostly received best supportive care; ii) 488 patients who received allo-SCT in the same period reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry. We adopted a continuous time multi-state Markov approach to model the natural history of the disease. Each IPSS-R risk group is represented by a state, and transition is allowed to the next state (to AML from very high risk) or to death. A transition intensity (i.e., instantaneous risk of moving to another state) is then estimated for each possible transition. Allo-SCT is modeled as a time-dependent covariate with 3 levels: i) no allo-SCT; ii) transplantation done no more than 3 months before; iii) transplantation done more than 3 months before. The effect of allo-SCT on survival was estimated by hazard ratios (HR) with respect to the no allo-SCT level. We examined two different policies: policy A) perform allo-SCT after t months since entering the low IPSS-R risk state or immediately in case of disease progression before the planned delay time t; policy B) perform allo-SCT after t months since entering the intermediate IPSS-R risk state or immediately in case of disease progression before the planned delay time t. For each policy, the expected survival of patients with different age at diagnosis was calculated. According to the model, a patient with a low IPSS-R risk is expected to spend 2.13 years in this risk group, and 2.39 years in the intermediate one. The cumulative incidence of progression from low to a higher IPSS-R risk was 27% at 3 years, while that of progression from intermediate to a higher risk was 39% at 3 years. Overall, expected survival times from diagnosis were higher under policy B vs policy A. Expected survival times were up to three years greater under policy B with respect to policy A for younger patients. When the waiting time before transplantation was progressively increased from 0 to 60 months, there was an increase in expected survival under policy A (in younger patients this increases by about two further years if transplant is delayed until 60 months in low IPSS-R risk state). Conversely, under policy B, delaying transplant further reduces expected survival, by up to about three years with a delay of 60 months after entering intermediate risk state or further progression to high risk state. In summary, this study suggests that a delayed transplantation strategy is advisable for patients with early disease, i.e. very low and low IPSS-R risk, whereas no further delay is advised for patients belonging to intermediate or higher risk categories. When indicated, setting the timing of intervention immediately after disease progression makes such a strategy easy to implement in the clinical practice. These results provide clinicians with a base of evidence to maximize the effectiveness of allo-SCT in MDS patients. DisclosuresNo relevant conflicts of interest to declare.

High Dose Therapy and Autologous Stem Cell Transplantation in Marginal Zone Lymphoma : An EBMT-FIL-Gimeto Retrospective Study

Introduction:The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphomas (MZL) is not fully elucidated. The aim of the present study was to determine the outcome of patients undergoing ASCT for relapsed/refractory MZL, and define prognostic factors affecting that outcome.Methods: Eligible for this study were patients with nodal, extra-nodal (MALT) or splenic MZL , aged ≥18 ears, who underwent a first ASCT between July 1994 and February 2013, and reported to the European Society for Blood and Marrow Transplantation (EBMT) registry, and/or the Fondazione Italiana Linfomi (FIL) and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) networks.Patients with a history of MZL transformation were excluded. Review of written diagnostic reports was mandatory for inclusion. Log rank tests were used to assess the impact of baseline characteristics on overall survival (OS) and event-free survival (EFS). In multivariate analysis, the effect of prognostic factors was evaluated using Cox regression models. Cumulative incidence of relapse (IR) and cumulative incidence of non-relapse mortality (NRM) were estimated with a competing-risk approach. Risk factors for IR and NRM were estimated by Pepe & Mori test or by Fine & Gray model.Results: The study included 199 patients, 111 patients (56%) with MALT lymphoma, 55 patients with nodal MZL (28%) and 33 patients (16%) with splenic MZL.. Median age at transplantation was 56 years (range, 25-71 years). Median time from diagnosis to ASCT was 2 years (0.1-28.0). Median number of prior therapies was 1 , (range 1-8) , including rituximab in 74%. 96% were transplanted with chemosensitive disease; 70 (37%) in CR1/PR1 ,113(59%) in CR/PR >1 and 7 in SD (4%) Median calendar year of ASCT was 2006, with 17,1% of transplants being performed before 2001. Total body irradiation-based high-dose regimen was used in 16 patients (8%), whilst 92% of the patients received high-dose chemotherapy only. Median follow-up was 4.1 years (0.1-19.1). Five-year cumulative incidence of relapse/progression (IR) and non-relapse mortality (NRM) were 38% (95%CI 30-45%) and 9 %( 95%CI 6-14%) respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% (95%CI 45-61%) and 73% (95%CI 65-79%), respectively.Multivariate analysis revealed age >65 years to be associated with shorter EFS and a shorter OS (HR=8.6, 95%CI 2.8-26.2, p<0.001 and HR=5.2,95%CI 1.9-14, p=0.001 respectively).Additionally, MZL predicted a shorter OS than MALT (HR=3.2, 95%CI 1.2-8.7, p=0.023). Notably, rituximab had no statistically significant effect on transplant outcome.Risk of secondary malignancies approached 6.8%.Conclusions: ASCT is a feasible and effective procedure when offered to MZL patients younger than 65 years, even in those previously exposed to rituximab. DisclosuresZaja:MedImmune: Research Funding.

Nilotinib For Steroid-Refractory Chronic Graft Versus Host Disease (SR-cGVHD): Preliminary Results Of a Phase I-II GITMO Study (Gruppo Italiano Trapianto di Midollo Osseo)

Chronic Graft versus Host Disease (cGvHD) is still the leading cause of late mortality in transplanted patients. Among the new drugs potentially useful in patients with steroid-refractory cGVHD (SR-cGVHD), the Tyrosine Kinase Inhibitor (TKI) Imatinib emerged as promising agent; however in our previous experiences, patient's frailty and their reduced haematological tolerance heavily limited the daily dose of Imatinib (median dose administered was 200 mg/day). Thus we planned to evaluate in the same setting a the safety and activity of a second generation TKI, such as Nilotinib (NIL), characterized by a better haematological tolerance and that could allow to treat SR-cGVHD patients with a higher relative dosage than Imatinib, thus achieving a better efficacy. Basing on this rational we designed a phase I-II study, aimed to individuate the maximum tolerated dose ( MTD) and the activity of NIL in patients with SR-cGVHD (ClinicalTrials.gov ID: NCT01810718). Primary endpoint of the phase I study was to define the dose limiting toxicity (DLT) of NIL, defined as the occurrence of any grade≥3 toxicity during at least one month of treatment. According to the Fibonacci standard 3+3 design, we started from an initial dose of 200 mg/day of NIL, up to a maximum of 600 mg/day. The drug has been supplied free of charge by Novartis Italia, Milan. In the phase II the MTD will be used to define the efficacy of NIL in SR-cGVHD patients, with similar characteristics of the previously Imatinib-treated population. Moreover all the patients enrolled in the phase I were allowed to continue NIL at the same dose, up to a cGVHD progression, if an objective improvement (OI) was documented after 3 months of treatment. We report here the preliminary results of a pre-planned interim analysis, during the phase I study, in 12 patients with SR-cGVHD who received NIL at low dose. The main characteristics of the enrolled patients are reported in table 1. Six patients received NIL 200mg/day and 6 NIL 300 mg/day. Two patients stopped NIL within 30 days: one due to cGVHD progression, the other had asymptomatic hypertransaminasemia (&gt;5xULN) which normalized 1 month after stopping NIL; these patients received an alternative treatment. In 3 cases severe adverse events (SAE) have been reported: 1 patient had extramedullary relapse of Acute Leukemia 8 months after start of NIL, while 2 patients have been hospitalized; one due to a transient cGVHD flare, without drug interruption, the second for a late cGVHD progression; he eventually died. The most frequent extrahematological toxicities (grade 1-2 according to CTCAE) were headache, nausea, pruritus, cramps, asthenia, constipation, while the main hematological abnormalities were represented by anemia grade 1 (5/12patients), neutropenia gr.1 (1/12 patients) and lymphocyte count increase gr.2 (1/12 patients). (tab.2) With a median F-U of 10 months (range 4-20), 10 patients are alive, while two died for cGVHD progression (7 and 9 months after the enrollment). After 3 months of treatment with NIL 6 patients (50%) achieved an OI and 4 (33%) a stable disease; all the 10 patients continued Nilotinib at the same dose until ≥6 months of treatment: after 6 months we observed 5 OI, 1 stable disease and 2 mixed responses (2 lung responses with skin failure), while in 2 the response evaluation is still ongoing. These preliminary data suggest that, like Imatinib, NIL at low doses is safe and effective in SR-cGVHD patients; up to day the MTD has not been still achieved, therefore only after the end of the phase I study we will be able to fully define the NIL activity. This study is supported by GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Disclosures: Off Label Use: Bendamustine.

Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma

Although the efficacy of plerixafor in peripheral blood stem cell (PBSC) mobilization has been explored in several studies, factors associated with successful plerixafor mobilization after administration of granulocyte-colony-stimulating factor (G-CSF), with or without chemotherapy, have not been investigated. We analyzed data on PBSC mobilization from a large Italian database of lymphoma and myeloma plerixafor-treated patients. Two endpoints were established to define successful mobilization: patients with at least 2 × 10(6) CD34+ cells/kg collected by three leukapheresis procedures and patients achieving a peak count of at least 20 × 10(6) CD34+ cells/L during mobilization. Plerixafor achieved successful mobilization in both predicted (n = 64) and proven poor mobilizers (PMs; n = 143), classified according to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) criteria. Successful mobilization was independent of type of mobilization (steady state or chemotherapy); age; sex; disease; number or type of chemotherapy regimens preceding plerixafor; radiation therapy; prior treatment with melphalan, carmustine, lenalidomide, and radioimmune conjugates; and laboratory variables. Multivariate analysis identified previous fludarabine treatment and premobilization platelet count as predictors of successful mobilization. This large, prospective, nationwide study confirmed plerixafor efficacy for mobilizing PBSCs when added to G-CSF with or without chemotherapy. Plerixafor can overcome negative effects of most predictors of poor mobilization to achieve satisfactory harvest both in predicted and proven PM.

In Vivo T Cell Depletion with Antithymocyte Globulin or Alemtuzumab for Unrelated Donor Stem Cell Transplantation with Reduced Intensity Conditioning: Results of a Multicenter Randomized Phase II Clinical Trial (The Global Study) From the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

AbstractAbstract 221 Background and aimIn vivo T cell depletion with either Antithymocyte Globulin (ATG) or Alemtuzumab (Alem) for GVHD prophylaxis is frequently included in reduced intensity conditioning (RIC). We recently reported the results of two Phase II studies performed by GITMO in high risk patients undergoing allogeneic stem cell transplantation (HSCT) using an unrelated donor (UD) after conditioning with either an ATG or Alem based RIC (Rambaldi et al.: Leukemia 2012). Since both these programs proved to be well tolerated and reasonably effective we compared them in a prospective randomized Phase II clinical trial (ClinicalTrial.gov Identifier: NCT00354120). Study design and PatientsThe composite primary end point was the efficacy (overall and event free survival) and the safety (infectious complications and GVHD) of the two conditioning regimens. In addition, the outcome of patients receiving an UD transplant was compared (by a time dependent analysis, correcting for time to transplant) to patients who were not randomized for the lack of a donor or any other reasons. From March 2005 to September 2008, 245 patients were registered into this study when the UD search was activated. Of these patients, 121 were randomized and 112 (AML n=27, NHL n=27, HD n=26, MDS n=14, B-CLL n=11, ALL n= 4, CML n= 2, and MF n= 1) underwent HSCT (median age 58 years, range 17–67). The 2 randomized groups were well balanced. All these patients were unfit for conventional transplants due to age (between 55 and 65 years for acute leukemias, myelodysplastic syndromes, chronic myeloid leukemia and myelofibrosis) or advanced disease (for Hodgkin and non-Hodgkin Lymphomas). A previous autologous transplant was performed in 49% of patients while 26% had received more than 3 courses of chemotherapy. Patients were randomized to the following RIC programs: program A, (Melphalan 30 mg/m2, Fludarabine 90 mg/m2, TBI 200cGy and Alem 80 mg) (n= 58) or program B, (Thiotepa 10 mg/Kg, Cyclophosphamide 100 mg/Kg, Melphalan 30 mg/m2 and ATG 7,5 mg/Kg) (n= 54). At transplant, 52 patients were in complete remission (CR), 38 patients were in partial remission (PR) while the remaining 22 patients had active disease. Of the 124 patients who were not randomized, 58 stopped the UD search because of death before randomization. Of the remaining 66 patients, 31 were transplanted with an alternative program and 35 were unable to proceed to HSCT. ResultsThe median time of neutrophil and platelet engraftment was similar in the 2 study arms (18 vs. 16 days and 18 vs. 18 days, respectively) but graft failure and graft rejection occurred most likely in arm A (9 vs. 1, p 0.036) and a better full donor chimerism in peripheral blood CD4+ cells was observed in arm B (93% vs. 68%, p 0.052). Of the 24 patients who had to be treated with DLI, 15 belonged to arm A and 9 to arm B (p 0.476). At day +100 the incidence of acute GVHD (> grade II) was slightly higher in the ATG arm (37% vs. 26%, p 0.224) but a higher incidence of late occurring acute GVHD occurred in the Alem arm, most likely because of DLI (5/6 patients, all with GVHD > grade III). The incidence of chronic GVHD was similar (40% and 41%) in both treatment arms. The immunologic reconstitution (time to CD4+ cells > 100/mcl) was slower in arm A (174 vs. 113 days, p 0.058) but no significant difference was observed in the incidence of viral, bacterial or fungal infections. A similar incidence of CMV disease (10% vs. 6% in arm A and B, respectively) and PTLD (5% in A vs. 11% in B) was observed. With a median follow up of 15 months (range 1–39), at 2 years, the non-relapse mortality (NRM) (36% vs. 35%) and the relapse rate (34% vs. 25%, p 0.294) do not differ in the 2 arms. Similarly, despite a trend for a better outcome for patients randomized to arm B, no significant difference was observed in terms of EFS (29% vs. 41%, p 0.295) and OS (36% vs. 52%, p 0,206) (Figure 1). By a multivariable model for the prediction of OS, a significant decrease of the risk of death was associated with the incidence of acute (p= 0.02) and chronic GVHD (p <0.001). At 3 years, the OS of randomized and non-randomized patients is similar (43% vs. 34%, p= ns). ConclusionA better engraftment and immune reconstitution as well as a trend for a lower relapse rate was observed in patients receiving an ATG based RIC. GVHD confirms its protective role on the risk of death confirming that an accurate dosing of in vivo T cell depleting agents is crucial for the long term clinical outcome after HSCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Validation of the Cibmtr Score in Predicting the Outcome of Hematopoietic Stem-Cell Transplantation in AML Patients Not in Complete Remission At the Time of Conditioning: A Retrospective Analysis On Behalf of the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

AbstractAbstract 2005 Background and AimThe dismal prognosis of AML patients undergoing allogeneic stem cell transplantation not in complete remission at time of conditioning poses challenging clinical decisions. In these patients, a recent, large retrospective analysis conducted by the CIBMTR showed that a myeloablative HCST can induce an overall 19% long term survival. Based on five adverse pretransplantation variables (first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics) this analysis allowed to set up a pre-HSCT score (from 0 to ≥3) able to identify four risk groups defining a 3-years overall survival (OS) probability ranging from 6% up to 42% (Duval M, JCO 2010). However, this CIBMTR analysis was limited to patients with the following characteristics: a) de novo AML or secondary AML to a previous MDS b) patients receiving a TBI or busulfan based myeloablative conditioning regimens (MAC) and a BM or PB derived stem cell graft. Here we report data obtained in Italy in a similar cohort of AML patients that also included those receiving a reduced-intensity conditioning (RIC) regimen and those grafted with a cord blood unit. Study design, patients and transplants characteristicsWe retrospectively analyzed data reported to the GITMO registry by 20 Italian centers on 523 AML patients who underwent a first HSCT being not in complete remission (CR) at time of conditioning, between 1999 and 2010. The median age at HSCT was 47,6 years (18–72), the male/female ratio 50%. At diagnosis 71,5% were de novo AML, 23% were secondary to a previous MDS/CMML, while in 5,5% the AML was therapy related or secondary to a previous CMN. Before HSCT conditioning, patients were primary refractory (PIF) in 34%, in first or subsequent untreated relapse in 45% and 16%, respectively or an untreated MDS to AML evolution in 5%. Before HSCT, 79% of PIF received ≥2 chemotherapy cycles and for relapsed patients the duration of the first CR was < 6 months in 50%. An intermediate-II or adverse karyotype was detected in 43% of patients, a greater than 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 53% and a pre-HSCT Karnofsky score less than 90 was present in 38%. The stem cell source was the PB in 65%, the bone marrow in 28% and the cord blood in 6%. Donors were HLA identical sibling or matched unrelated donor in 69%, a family or unrelated mismatched in 25% and a cord blood unit in 6%. Anti-CMV antibodies were present in 87% of patients and in 66% of the donors, while donor-recipient pair were sex-matched in 50% of the cases. More than 60% patients received a MAC and 37% a RIC program. ResultsAfter HSCT, a myeloid and platelets engraftment was achieved in 87% of patients after a median of 17 (9–63) and 18 (2–117) days, respectively. Acute GVHD (grade ≥2 60%) was registered in 46% while chronic GVHD developed in 31%. The median follow up of the whole patients cohort was 5,36 months (0.09–133) while that of survivors was 26 months (1–133) with 96 patients alive and 77 leukemia-free. A multivariate analysis identified 7 pre-HSCT adverse variables that significantly influenced survival: an AML secondary to a previous chronic myeloproliferative neoplasm or a therapy related AML (HR 1,83, 95%CI 1,14–2,96, p 0,013), a relapsed AML with a first CR duration < 6 months (HR 1,39, 95%CI 1,06–1,82, p 0,018), an AML with a PIF after ≥2 chemotherapy cycles pre-HSCT (HR 1,74, 95%CI 1,11–2,74, p 0,016), an intermediate II/adverse cytogenetics (HR1,71, 95%CI 1,11–2,62, p 0,015), BM blasts ≥25% or any level of PB at HSCT (HR 1,65, 95%CI, 1,31–2,07, p 0.000) and a mismatched related/unrelated donor (HR 1,56, 95%CI, 1,23–1,98, p 0.000). At 3-years, the OS and LFS of our patients was 16% and 21%. Interestingly, when applied to our results, the CIBMTR score was fully validated in our patients with a 3-year survival rate decreased from 40% (score 0, HR1) to 26% (score 1, HR 1,39; 95%CI 0.88–2,12, p 0,142), to 18% (score 2, HR 1,58; 95%CI 1–2,43, p 0,04) to 5% (score 3, HR 2,83; 95%CI 1,71–4,16, p 0,000) (Figure 1). ConclusionsOur results confirm that a) HSCT is a potentially curative option for a significant proportion of AML patients undergoing transplant not in remission, b) these patients may benefit from either a MAC or a RIC conditioning regimens and c) the CIBMTR score applied to this poor prognosis AML cohort is a useful tool for patient counseling and for planning the HSCT activity. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: A GITMO study

Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety-one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT.

Decision Analysis of Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome Stratified According to the Who Classification-Based Prognostic Scoring System (WPSS)

Abstract 116Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms that range from indolent conditions with a near normal life expectancy to forms very close to acute myeloid leukemia (AML). The WHO classification-based Prognostic Scoring System (WPSS) is able to classify MDS patients into five risk groups (very low, low, intermediate, high, and very high) with different median survival (from more than 10 to about 1 yr). Despite recent progress, the only curative treatment for MDS remains allogeneic stem cell transplantation (allo-SCT), which however involves a non-negligible risk of mortality and morbidity. Allo-SCT is not considered in patients with low WPSS risk, whose median survival is >10 yr. Conversely, eligible patients with high or very high WPSS risk, whose median survival is 1–2 yr, should be offered immediate transplantation. Uncertainty exists about the optimal timing of allo-SCT in the low and intermediate WPSS-risk groups, and to address this issue we performed an ad hoc decision analysis.We analyzed two cohorts of MDS patients: i) 615 patients diagnosed with MDS at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, between 1992–2007, who were followed regularly and mostly received best supportive care; ii) 405 patients who received allo-SCT between 1997–2007, reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry. In this latter cohort, variables were analyzed at the time of transplantation in patients undergoing allo-SCT upfront, and at the time of remission-induction chemotherapy in those receiving treatment before allo-SCT.We adopted a continuous time multi-state Markov approach to model the natural history of the disease. In this model, each WPSS risk group is represented by a state, and transition is allowed to the next state (to AML from very high risk) or to death. A transition intensity (i.e., instantaneous risk of moving to another state) is then estimated for each possible transition. Allo-SCT is modeled as a time-dependent covariate with 3 levels: i) no allo-SCT; ii) transplantation done no more than 3 months before; iii) transplantation done more than 3 months before. The effect of allo-SCT on survival was estimated by hazard ratios (HR) with respect to the no allo-SCT level. We examined two different policies: policy A) to perform allo-SCT after t months since entering the low-risk state or at the time of progression to intermediate risk; policy B) to perform allo-SCT after t months since entering the intermediate-risk state or at the time of progression to high risk. For each policy, the expected survival of patients with different age at diagnosis was calculated.According to the model, a patient with a low WPSS risk is expected to spend 6.2 years (95% CI, 5.5–7.0) in this risk group, and, in case of progression, 3.5 years (95% CI, 3.1–4.0) in the intermediate one. The cumulative incidence of progression from low to a higher WPSS risk was 9%, 31% and 41% at 1, 3 and 5 years, respectively, while that of progression from intermediate to a higher risk was 18%, 40% and 53% at 1, 3 and 5 years, respectively.Overall, expected survival times from diagnosis were higher under policy A vs policy B. Expected survival decreased with increasing age (from 30 to 65 yr) under policy A, while there was little effect of age under policy B. For younger patients, expected survival times were up to four years greater under policy A, while there was no estimated benefit for patients closer to age 65. When the waiting time before transplantation was progressively increased from 0 to 60 months, there was a small decrease in expected survival under policy A for younger patients. Conversely, varying the time of transplantation between 0–60 months did not substantially influence expected survival under policy B.These findings suggest that in eligible patients with low or intermediate WPSS-risk MDS there is no clear benefit in adopting a delayed transplantation strategy, as the risk of progression abolishes the expected gain in survival resulting from postponing the procedure. In particular, younger patients appear to benefit from early transplantation in the low risk state. This is at variance with a previous decision analysis based on the International Prognostic Scoring System (IPSS) (Blood. 2004;104:579–85), which concluded that for low and intermediate-1 IPSS-risk MDS, delayed allo-SCT was associated with maximal life expectancy.This paper is on behalf of GITMO investigators. Disclosures:No relevant conflicts of interest to declare.

Iron overload and iron chelation therapy in patients with myelodysplastic syndrome treated by allogeneic stem‐cell transplantation: Report from the working conference on iron chelation of the Gruppo Italiano Trapianto di Midollo Osseo

Many myelodysplastic syndrome (MDS) patients have a long history of transfusion before eventually undergoing transplantation and therefore are at high risk of developing parenchymal iron overload. Recently, retrospective studies suggested that iron overload has some prognostic impact in MDS patients treated by allogeneic stem-cell transplantation (allo-SCT) as previously observed in thalassemia. However, the optimal strategy to assess iron overload and to reduce iron burden during and after transplant procedure remains to be determined. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) promoted a consensus process aimed at providing clinical practice recommendations that can support the appropriate choice for iron overload assessment and for iron chelation therapy in MDS patients undergoing allo-SCT. A systematic review of the published literature (1990–2010) was performed. An Expert Panel was selected according to the framework elements of the NIH Consensus Development Program, comprising 10 physicians with different areas of expertise (iron metabolism, SCT, and MDS patient management/treatment). Based on the available scientific evidence and consensus among experts, clinical recommendations were formulated on appropriate assessment of iron body stores, selection of candidates to iron chelation therapy before and after allo-SCT, and treatment modalities.

Key concepts and critical issues on epoetin and filgrastim biosimilars. A position paper from the Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation

The term “biosimilars” (“follow-on biologics” in the USA) has been used by the European Medicines Agency (EMA) to describe officially-approved subsequent versions of innovator biotechnological products made by a different competitor after the patent and exclusivity rights have expired.1 Biosimilars pose a problem to the clinician who is bound to require guidance on how best to capitalize on these new pharmacological opportunities. In its mandate to promote the best hematologic care, the Italian Society of Hematology (SIE) and the affiliate societies SIES (Societa Italiana di Ematologia Sperimentale) and GITMO (Gruppo Italiano Trapianto di Midollo Osseo) convened an expert panel to produce a position paper on the two marketed biosimilars in hematology, i.e. epoetin and filgrastim. The panel of 8 experts was selected according to the conceptual framework elements of the NIH Consensus Development Program.2 Panel bias was minimized by eliminating from consideration strong advocates for or against the use of biosimilars. Each panel member was asked to disclose any tie he or she may have had with pharmaceutical companies manufacturing the drugs considered in the paper in the last five years. The project was conducted independently from any pharmaceutical company which sold either conventional drugs or biosimilars.

EBMT Risk Score Predicts Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Who Have Failed a Previous Transplantation Procedure

Increasing numbers of allogeneic hematopoietic stem cell transplantation (allo-SCT) are being performed for patients who have failed a previous allogeneic or autologous SCT. We investigated whether the EBMT risk score could predict outcome after a subsequent allo-SCT. We analyzed prognostic factors in 124 consecutive patients who underwent a second transplantation using an allogeneic donor at our institution. Patients with either a first autologous (N = 64) or first allogeneic (N = 60) SCT were included. Age, disease stage, time interval from diagnosis to transplantation, donor type, and donor-recipient sex combination were used to establish a score from 0 to 7 points, from which 3 groups were identified. The 5-year survival probability decreased from 51.7% for risk scores 0-3 (low, n = 25), to 29.3% for risk score 4 (intermediate, n = 42), and only 10.4% for risk scores 5-7 (high, n = 57), P = .001. We propose that the EBMT risk score can identify patients most likely to benefit from a second transplantation.

Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study

Transfusion-dependency affects the natural history of myelodysplastic syndromes. Secondary iron overload may concur to this effect. The relative impact of these factors on the outcome of patients with myelodysplastic syndrome receiving allogeneic stem-cell transplantation remains to be clarified. We retrospectively evaluated the prognostic effect of transfusion history and iron overload on the post-transplantation outcome of 357 patients with myelodysplastic syndrome reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry between 1997 and 2007. Transfusion-dependency was independently associated with reduced overall survival (hazard ratio=1.48, P=0.017) and increased non-relapse mortality (hazard ratio=1.68, P=0.024). The impact of transfusion-dependency was noted only in patients receiving myeloablative conditioning (overall survival: hazard ratio=1.76, P=0.003; non-relapse mortality: hazard ratio=1.70, P=0.02). There was an inverse relationship between transfusion burden and overall survival after transplantation (P=0.022); the outcome was significantly worse in subjects receiving more than 20 red cell units. In multivariate analysis, transfusion-dependency was found to be a risk factor for acute graft-versus-host disease (P=0.04). Among transfusion-dependent patients undergoing myeloablative allogeneic stem cell transplantation, pre-transplantation serum ferritin level had a significant effect on overall survival (P=0.01) and non-relapse mortality (P=0.03). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload. Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome.

Prophylaxis and Treatment of Invasive Fungal Diseases in Allogeneic Stem Cell Transplantation: Results of a Consensus Process by Gruppo Italiano Trapianto di Midollo Osseo (GITMO)

In recent years, prospective studies have been conducted to assess the role of prophylaxis and treatment of invasive fungal diseases (IFD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although results of these studies have been encouraging, they have been unable to generate a consensus for optimal prophylaxis and treatment of IFD in the complex scenario of allo-HSCT. A consensus process was undertaken to describe and evaluate current information and practice regarding key questions on IFD management in allo-HSCT recipients; these questions were selected according to the criterion of relevance by group discussion. The Panel produced recommendations for risk stratification, prophylaxis, monitoring, and therapy of IFD and identified top priority issues for further investigation. The definition of the level of risk for IFD associated with the various types and phases of transplantation and the implementation of surveillance and diagnostic strategies are the critical determinants of the antifungal prophylactic and therapeutic approach for allo-HSCT recipients.

Improved Outcomes Using Tacrolimus/Sirolimus for Graft-versus-Host Disease Prophylaxis with a Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX.