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Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: .003; HR 2.16, 95% CI 1.29-3.61) and lower disease-free survival (DFS) (p: .002; HR 2.45, 95% CI 1.41-4.27), associated to a higher relapse incidence (p: .010; HR 2.23, 95% CI 1.21-4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

Traceability of patients who are candidates for Hematopoietic cell transplant (HCT) is crucial to ensure HCT program quality. Continuous knowledge of both a detailed registry from a HCT program and final exclusion causes can contribute to promoting a real-life vision and optimizing patient and donor selection. We analyzed epidemiological data reported in a 4 year-monocentric prospective registry, which included all patients presented as candidates for autologous (Auto) and/or allogeneic (Allo) HCT. A total of 543 patients were considered for HCT: 252 (42.4%) for Allo and 291 (57.6%) for Auto. A total of 98 (38.9%) patients were excluded from AlloHCT due to basal disease progression more commonly (18.2%). Seventy-six (30.2%) patients had an HLA identical sibling, whereas 147 (58.3%) patients had only Haplo. UD research was performed in 106 (42%) cases, significantly more often in myeloid than lymphoid malignancies (57% vs 28.7%, p

Background POEMS syndrome is a rare paraneoplastic disease caused by an underlying plasma cell disorder. The aim of this study is to describe clinical and biological features as well as outcomes in a series of patients in a real-world clinical setting. Methods We retrospectively analyzed 30 patients with POEMS syndrome consecutively diagnosed and treated at 8 hospitals in Catalonia, Spain, between 1996 and 2021. Medical records were reviewed for clinical and lab features at diagnosis, first-line treatment, autologous stem-cell transplantation (ASCT) and outcomes including progression-free (PFS) and overall survival (OS). Diagnosis was stablished according to published diagnostic criteria (Dispenzieri A, Am J Hematol 2011). Median follow up of alive patients was 13 years. Results Median age of the series was 65 years (range, 42-86). The median serum M-spike was 5 g/L. The heavy chain isotype was IgG in 43% of patients and IgA in 40%, while the light chain isotype was lambda in 87%. Four patients had more than 10% bone marrow plasma cells. VEGF was available in 18 patients and 16 of them (88%) had increased levels (3 times greater than the superior limit). All patients presented peripheral neuropathy, and other clinical features included organomegaly (22 patients), extravascular volume overload (22), endocrinopathy (20), skin lesions (18), thrombocytosis (18) osteosclerotic lesions (17), polycythemia (7), papilledema (7), pulmonary hypertension (4), portal hypertension (4), and Castleman disease (7). The median time between onset of symptoms and diagnosis was 6.3 months. Treatment information was available in 29 patients. Four patients had an isolated bone lesion and received only local radiation therapy, with hematologic and clinical response in 2 of them and a 10-year OS of 87%. Twenty-three patients underwent an ASCT: 15 after chemotherapy (with or without additional radiation therapy) and 8 upfront. Median age at the time of ASCT was 54 years. Conditioning prior to ASCT consisted in melphalan 200 mg/m2 in 74% of cases and 140 mg/m2 in 26%. Among 20 evaluable patients for hematologic response, 10 achieved a complete response and 10 obtained a partial response (PR). Eleven (55%) of these hematologic responding patients also obtained a significant organ improvement in a median time of 7 months after ASCT (range, 4–11). Nine patients (41.7%) progressed at a median time of 5 years after transplant, 5 of them received a second ASCT and 3 achieved at least a PR. After the second ASCT, only one patient clinically progressed after 38 months. All the remaining patients remained in response at the last follow-up evaluation. Median PFS and OS of the series were 6 and 12 years, respectively. Conclusions In conclusion, in our experience ASCT proved to be highly effective for patients with POEMS syndrome. When progression is confirmed after the first transplant, a second ASCT may be performed with potential clinical benefit.

Introduction Coronavirus Disease 2019 (COVID19) has shown higher mortality in patients with comorbidities, including cancer. First reports from China, Italy, and US showed mortality comprised between 20% and 40% in this specific population. However, the number of patients in these studies was limited and the percentage of hematological patients was underrepresented. In our study, we present a prospective evaluation of patients affected by solid and liquid tumors who were affected by COVID19 from the same geographical area and time period. Survival outcomes, prognostic risk factors, and effects of oncological treatments received were analyzed. Methods WAll consecutive oncological patients with age > 18 years old affected by COVID19 (confirmed by pharyngeal PCR test) who were hospitalized in 5 tertiary oncological referral centers in the Catalonia region were included in the study. The recruitment period started from 13/03/2020 to 24/04/2020. Two-hundred thirty-one patients were recruited. Thirty-three percent had hematological malignancies and 67% had solid tumors. The median age was 65 years (range 58-75 years). Female patients were 41%. Twenty-six percent of patients were not considered candidates to intensive care treatments (tracheal intubation) due to their advanced oncological status. Of the hematological cohort, lymphoid malignancies represented 36% of the population, multiple myeloma 20%; acute leukemias 15%; chronic lymphoproliferative diseases 12% and other malignancies 17%. At the time of infection, 11% of patients were receiving steroids (more than 0.5mg/kg/24 hours >15 days), 4% were on active immunosuppressive therapy (calcineurin inhibitors, sirolimus or mycophenolate mofetil) and 5% had grade >3 neutropenia. Most importantly, 61% were on active oncological treatment, 18% were on follow-up, 10% had been diagnosed without having received any treatment. Results At COVID19 diagnosis, 75% of patients had a fraction of inspired oxygen (FiO2) < 24% and 63% had fever. Only 16% had cough,16 % had mucous secretion and 12% had dyspnea. All the other symptoms (myalgia, diarrhea, anosmia, ageusia, fatigue, headache) had an incidence < 10%. Chest X-ray was abnormal in 60% of cases. Regarding in-hospital treatments, 85% received antibiotics, 76% hydroxychloroquine, 12% tocilizumab, 30% corticoids, 70% prophylactic anticoagulation and 55% oxygen support. The median duration of hospitalization was 9.00 days (range 5-16 days). WThe overall mortality rate was 26% with a non-significant difference between hematological (32%) and oncological (23%) patients (p-value = 0.23, figure 1). A significant difference was observed between patients who were candidates to intensive care treatments (21.5%) and not candidates (42.6%)(p-value = 0.0038, figure 1). The following risk factors were associated with decreased survival on multivariate analysis: having the oncological disease in progression (HR 3.33, 95%Confidence Interval (CI)= 1.73-6-41, p0.5mg/kg/24 hours) in the last 15 days (HR 3.76; 95%CI=1.69-8.40, p Severe respiratory insufficiency (defined as use of >50% FiO2 as oxygen support) was present or developed in 46% of patients. On multivariate analysis, the following factors were associated with a higher risk of developing severe respiratory insufficiency: use of steroids (>0.5mg/kg/24 hours) in the last 15 days (HR 2.36; 95%CI=1.12-4.97, p=0.023); age (HR 1.05, 95%CI= 1.01-1-08, p=0.009) and dyspnea at diagnosis (HR 3.95; 95%CI=1.77-8.78, p=0.001). Conclusion WCOVID19 is associated to increased mortality in patients affected by solid and liquid tumors. Being a candidate for intensive care treatments could improve survival while having progressive disease, older age and grade >3 neutropenia were considered negative factors. Interestingly, the use of steroids was associated to reduced survival if received within 15 days before COVID19 diagnosis, while it has protective effect when used as part of COVID19 therapy. Disclosures Mussetti: Novartis, Gilead: Honoraria, Research Funding. Sureda Balari:Gilead/Kite: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy. OffLabel Disclosure: Tocilizumab for COVID19

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

Background Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined. Patients and methods This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. Results We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1–93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2–3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6–5.2, p 20 mg/dL (OR 3.3, 95% CI 1.7–6.4, p

Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC. We also found an association between VEGFC expression and the patient cytogenetic risk group, with those with a worse prognosis having higher VEGFC expression levels. No correlation was observed between VEGFC expression and survival or complete remission. VEGFC expression strongly correlated with expression of the VEGF receptors FLT1, KDR, and NRP1. Thus, in this series, VEGFC expression was increased in AML-MRC and in subgroups with a poorer prognosis, but has no impact on survival.

The inflammasomes are macromolecular cytosolic complexes involved in the production of interleukin-1β (IL-1β) and IL-18 in response to several pathogen-derived stimuli. Such interleukins have been implicated in the origin of severe allogeneic stem cell transplant (allo-SCT) complications. We analyzed the relationship between the interindividual variability in inflammasome protein-encoding genes in donors and patients and clinical outcome after allo-SCT. Fourteen common genetic variants in 5 genes of the inflammasome, namely, NLRP1, NLRP2, NLRP3, CARD8, and CASP5, were genotyped in 133 human leukocyte antigen-identical sibling pairs undergoing allo-SCT. In the multivariate analysis, donor variants in NLRP2 and NLRP3 were the most important prognostic factors for the clinical outcome after allo-SCT. Thus, donor TT genotype at rs10925027 in NLRP3 was associated with disease relapse (odds ratio (OR) = 6.3, P = 1 × 10−7), and donor GG genotype at rs1043684 in NLRP2 was associated with nonrelapse mortality (OR = 4.4, P = 6 × 10−4) and overall survival (OR = 3.1, P = .001). In addition, patient AA genotype at rs5862 in NLRP1 was associated with nonrelapse mortality (OR = 2.8, P = .005) and overall survival (OR = 2.0, P = .009). These results suggest that inflammasome genetic variants are important prognostic factors for the outcome of allo-SCT. If validated in larger studies, including unrelated allo-SCT, NLRPs genotype would become an important factor in donor selection.

After allogeneic stem cell transplantation (allo-SCT) some patients develop persistent anemia in association with an inadequate erythropoietin (Epo) secretion. We determined the frequency and risk factors for this complication and the response to treatment with erythropoiesis stimulating proteins (ESP). Of 83 evaluable allo-SCT patients, 63 (76%) developed persistent anemia at a median of 34 (range: 30-244) days after allo-SCT. Forty-one (49%) patients had anemia considered as primary, and in all of them inadequate serum Epo levels (median 43.3, range: 2.5-134, mU/mL) were found. A high creatinine level during the first month after allo-SCT was associated with primary anemia (relative risk [RR] 2.5, P = .01). Of the 41 patients, 35 received ESP. Transfusion independence and an Hb level higher than 10 g/dL was achieved in 29 of 30 (97%) evaluable patients. Median ferritin levels at the beginning and at the end of the ESP treatment was 1628 (range: 168-5208) and 805 (range: 14-7443) ng/mL, respectively (P = .04). In conclusion, anemia associated with impaired Epo secretion after allo-SCT is more frequent than usually recognized and it is associated to early postransplantation renal damage. This complication easily reverts with ESP, which seems to contribute to reduce iron overload.

Objective The aim of this study was to determine whether nonmyeloablative transplants (NMT) result in complete and sustained donor engraftment in patients with progressive hematologic diseases compared to patients with stable disease or who are in remission. Materials and methods We prospectively monitored the kinetics of engrafting of T cells and myeloid cells in 10 consecutive adult patients with hematologic diseases submitted to NMT from an HLA-identical sibling donor. Patients were considered ineligible for conventional allogeneic transplantation because of age, concomitant diseases, or previous autologous transplant. Conditioning regimen and graft-vs-host disease posttransplant prophylaxis consisted of 2-Gy total-body irradiation plus fludarabine 30 mg/m 2 /day for 3 days, and cyclosporin and mycophenolate mofetil, respectively. Results One patient died in remission, and eight relapsed or progressed at a median of 68 days (15–335). On day +56, only 1 (11%) of 9 patients analyzed had achieved T-cell complete donor chimerism (CC), whereas 6 (67%) had achieved myeloid CC ( p =0.05). Median time for T-cell CC to occur was 110 days (56–150) compared with 42 days (28–100) to achieve myeloid CC ( p =0.002). The only parameter associated with T-cell CC was the status of the disease at the time of transplantation. Thus, 5 (100%) of 5 patients with stable disease or who were in remission before the transplant achieved T-cell CC compared with only 1 (20%) of 5 patients with progressive disease ( p =0.05). Conclusion Conditioning regimen based on fludarabine and 2-Gy total-body irradiation allows cell immunotherapy for old and medically infirm patients, but its antitumoral effect in patients with progressive hematologic disease is limited.

We used multiplex amplification of nine microsatellite sequences (PCR-STR) to analyse chimerism in pure populations of T cells and neutrophils from peripheral blood from 40 patients submitted to an allogeneic transplant, 22 having received a T-cell depleted (TCD) peripheral blood graft by means of CD34(+) selection (allo-PBT/CD34(+)), and 18, an unmodified graft (allo-SCT; 13 allogeneic bone marrow transplants and five allo-PBT). T-cell mixed chimerism (TcMC) was observed in 16 of the 22 (72.3%) patients receiving an allo-PBT/CD34(+), but in only one of the 18 (5.5%) patients receiving an allo-SCT (P=0.0001). TcMC was transient (n=6), stable (n=7), and associated with poor haematopoietic engraftment (n=4). All patients with TcMC who developed graft failure had more than 30% of host T cells. Myeloid MC (MyMC) was observed in four (19%) allo-PBT/CD34(+) patients and in three (17%) allo-SCT patients (P=NS). Five out of seven (71%) patients with MyMC relapsed, all of them diagnosed with myeloid malignancies, as compared with two of the 20 (10%) patients with complete donor chimerism (P0.0001). In conclusion, TcMC appears in a significant number of allo-PBT/CD34(+) patients and may be associated with poor engraftment when the percentage of host T cells is30%; likewise, MyMC appears in a small percentage of recipients of both allo-PBT/CD34(+) and allo-SCT patients, and is associated with leukaemia relapse in myeloid malignancies.

Myelofibrotic transformation is a known complication of essential thrombocythaemia (ET), but information on its incidence, presenting features and evolution is scarce. In a series of 195 patients with ET followed for a median of 7.2 years (range: 1.9-24), evolution into myelofibrosis with myeloid metaplasia (MMM) occurred in 13 cases, a median of 8 years (range: 3.6-20.2) from diagnosis. The actuarial probability of this complication was 2.7% (95% CI: 2.4-2.9) at 5 years, 8.3% (95% CI: 7.8-8.9) at 10 years, and 15.3% (95% CI: 6.1-24.5) at 15 years. Four patients had not been treated before developing MMM. The main features indicating this condition were the appearance of immature myeloid precursors in the peripheral blood, a decrease in the Hb value not related to treatment and increased serum lactate dehydrogenase levels, followed by a progressive decrease in the platelet count, increasing leucocytosis and progressive splenomegaly. No patient had constitutional symptoms, and none of five evaluable cases showed chromosome abnormalities in bone marrow or unstimulated blood. After a median the myelofibrotic transformation, three patients have died and four have not required treatment for MMM as yet.

Three single nucleotide polymorphisms (SNP) in the NOD2/CARD15 gene have been associated with the incidence and the severity of acute graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (SCT). We hypothesized that the clinical effect of SNP in NOD2/CARD15 might be different in patients submitted to T-cell-depleted allogeneic SCT, in which donor T cells, the main effectors of GVHD, are eliminated.SNP 8, 12 and 13 in NOD2/CARD15 were studied using a Taqman protocol in 85 patients undergoing HLA-identical, T-cell-depleted SCT and in 71 of their sibling donors.NOD2/CARD15 variants were present in nine (11%) patients and six (8%) donors. The incidences of acute GVHD and chronic GVHD were not associated with either the donors' or recipients' NOD2/CARD15 variants. In contrast, these genetic variants were associated with a lower disease-free survival (17% vs. 48%, p=0.03). Death due to pulmonary infection was more frequent in the group of patients with NOD2/CARD15 variants. In the multivariate analysis, only NOD2/CARD15 variants (RR 2.3, p=0.04) and older age (RR 2.2; p=0.04) were independent prognostic factors for disease-free survival.NOD2/CARD15 variants have a deleterious effect on clinical outcome in T-cell-depleted allogeneic SCT, which is independent of GVHD. These results supports the hypothesis that the detrimental effect of NOD2/CARD15 variants in such a transplant setting might be produced by an alteration of the innate immune system more than by activation of the adaptive immune system.

Dendritic cells (DC) play a key role in initiating immune reactions after allogeneic stem cell transplantation. The two main peripheral blood DC populations are myeloid (DC1) and lymphoplasmacytoid (DC2). A new subset of myeloid DC, expressing CD16, has been identified. We analyzed the number and CD86 expression of DC subsets in peripheral blood of 18 healthy donors, before and after granulocyte colony-stimulating factor (G-CSF) and in the inoculum of allogeneic peripheral blood transplants (allo-PBT; n=100) and allogeneic bone marrow transplants (allo-BMT; n=22). Granulocyte colony-stimulating factor administration increased the median number of DC1 (P=0.0007), of DC2 (P

Myelofibrotic transformation is a known complication of essential thrombocythaemia (ET), but information on its incidence, presenting features and evolution is scarce. In a series of 195 patients with ET followed for a median of 7.2 years (range: 1.9-24), evolution into myelofibrosis with myeloid metaplasia (MMM) occurred in 13 cases, a median of 8 years (range: 3.6-20.2) from diagnosis. The actuarial probability of this complication was 2.7% (95% CI: 2.4-2.9) at 5 years, 8.3% (95% CI: 7.8-8.9) at 10 years, and 15.3% (95% CI: 6.1-24.5) at 15 years. Four patients had not been treated before developing MMM. The main features indicating this condition were the appearance of immature myeloid precursors in the peripheral blood, a decrease in the Hb value not related to treatment and increased serum lactate dehydrogenase levels, followed by a progressive decrease in the platelet count, increasing leucocytosis and progressive splenomegaly. No patient had constitutional symptoms, and none of five evaluable cases showed chromosome abnormalities in bone marrow or unstimulated blood. After a median the myelofibrotic transformation, three patients have died and four have not required treatment for MMM as yet.

Hypercalcemia is a rare complication of chronic myeloid leukemia (CML), usually seen in the accelerated or blastic phases of the disease and associated with a poor prognosis. T-cell lymphoid phenotype is also an infrequent finding in the blast crisis (BC) of CML. A CML patient who had hypercalcemia as the presenting feature of a T-cell BC is reported. She was a 78 year-old woman who, at four months of CML diagnosis, developed weakness, bone pain, and mental confusion, with hypercalcemia being subsequently found. Although the peripheral blood and bone marrow were consistent with the chronic phase of CML, mediastinal enlargement, a soft tissue mass adjacent to the iliac bone, and multiple osteolytic lesions were seen. Serum levels of parathyroid hormone (PTH) and PTH-related peptide were normal, whereas the search for a second neoplasm was negative. The hypercalcemia initially responded to conventional treatment, but it reappeared two weeks later. Coincidentally, a high proportion of blast cells of T-cell origin at the cortical thymocyte stage were observed in the patient's peripheral blood and bone marrow, and she died shortly afterwards.

Dendritic cells (DCs) play a critical role in the regulation of alloimmune responses. Therefore, the number and function of these cells after allogeneic stem cell transplantation (allo-SCT) might influence patients’ outcome, an aspect scarcely investigated, particularly in the setting of reduced-intensity conditioning transplants (allo-RIC). Against this background, we studied DCs recovery in 92 patients (median age 50, range 17–67; male 57%), undergoing allo-RIC from HLA identical donors in five Spanish institutions between October 2002 and December 2004. Median follow up was 250 days (range, 25–708). Conditioning regimen consisted on fludarabine 150 mg/m2 + melphalan 140 mg/m2 for lymphoid malignancies (n=54), and fludarabine 150 mg/m2 + busulphan 10 mg/kg for myeloid malignancies (n=38); 71 (90%) patients had advanced disease. Peripheral blood samples were obtained at 1, 3, 6 and 12 months after transplant. DCs were identified as positive for HLA-DR and negative for lineage markers (CD3, CD14, CD19, and CD56). The expression of CD33, CD123 and CD16 was used to identify DC1, DC2 and DC CD16+ subsets, respectively; the immunophenotypic analysis being centralized at a single institution. The most significant association with clinical outcome was found with DC CD16+ levels at three months after transplantantation. Thus, at that time point, patients with a DC CD16+ count lower than the median (

Three single nucleotide polymorphisms (SNP) in NOD2/CARD15 have been associated with the incidence and severity of acute GVHD following allogeneic stem cell transplantation (allo-SCT). The potential clinical influence of SNP in NOD2/CARD15 in a model of allo-SCT with a low incidence of GVHD, such as T-cell depleted transplants (TCD), has not been studied. We analyzed the association of SNP in NOD2/CARD15 with the outcome of 84 patients undergoing allo-SCT with TCD by means of CD34+ selection. Results were compared with a concurrent group of 94 patients receiving an allo-SCT with unmanipulated grafts (Non-TCD). Transplants were performed in a single institution, donors were HLA identical siblings and all patients received myeloablative-conditioning regimen. Median follow-up was of 30.6 months (range, 0.2–112). SNP 8, 12 and 13 were analyzed by RT-PCR allelic discrimination method in all patients and in 137 donors. SNP in NOD2/CARD15 were detected in 13.8% of patients and in 10.7% of donors. Results of the association of patient’s NOD2/CARD15 genotype and outcome are given in the table. In TCD transplants, independent risk factors associated with event free survival in a multivariate analysis were: patient’s NOD2/CARD15 genotype (RR 2.7, p=0.02), patient’s age (RR 2.3, p=0.03) and conditioning with radiotherapy (RR 2.7, p=0.03). The only association of donor’s NOD2/CARD15 genotype with clinical outcome in the multivariate analysis was with acute GVHD (RR 3.3, p=0.03). In conclusion, polymorphisms in NOD2/CARD15 have a strong association with clinical outcome in TCD transplants, which is independent of GVHD. Overall group (n=178) SNP vs. WT P* TCD (n=84) SNP vs. WT P* Non-TCD (n=94) SNP vs. WT P* WT, wild type; N.S, non significant; * Log-rank test Acute GVHD II–IV 27 vs. 22 N.S 22 vs. 40 N.S 33 vs. 12 N.S Chronic GVHD 61 vs. 35 0.1 29 vs. 14 N.S 100 vs. 44 0.005 Event free survival 21 vs. 47 0.03 17 vs. 48 0.04 22 vs. 31 N.S Overall survival 30 vs. 59 0.01 33 vs. 56 0.04 30 vs. 48 N.S

Despite improvement in diagnosis and therapy, invasive fungal infections (IFI) remains one of the most important barriers to the success of allogeneic stem cell transplantation (allo-SCT). Mannan-binding lectin (MBL) gene polymorphisms have been associated with an increased risk of infections, particularly in immunocompromised patients. We analyzed the association of MBL gene polymorphisms with the incidence of IFI in 138 HLA identical donor-patient pairs, undergoing allo-SCT in our institution between March 1995 and December 2003. Median age at time of transplantation was 38 years (range 17 – 63); 73 (53%) patients were male. Diagnoses were AML (n=43), CML (n=23), ALL (n=19), NHL (n=18), and other hematological malignancies (n=35). 72 (52%) patients were in early phase of the disease and 66 (48%) in advanced phase. 129 (93%) donors were siblings and 9 (7%) unrelated. The source of stem cells was peripheral blood in 133 (96%) patients and bone marrow in 5 (4%). Conditioning regimen was myeloablative in 126 (91%) and non-myeloablative in 12 (9%). 71 patients (51%) received a T cell depleted graft by CD34+ selection, and in 67 (49%) cases the graft was unmanipulated. Six single nucleotide polymorphisms (−550 G/C, −221 C/G, 4 C/T, 52 CGT/TGT, 54 GGC/GAC and 57 GGA/GAA) in the MBL2 gene were genotyped using PCR and sequence specific primers. 22 (16%) donors and 21 (16%) patients of the 138 pairs carried O/O, LXA/LXA or LXA/O genotypes, which are related to a low production of MBL protein. After a median follow up of 21 moths, 25 (18%) patients developed an IFI, with an overall actuarial probability for this complication of 22%. In the univariate analysis, factors associated with a higher probability of IFI were: unmanipulated grafts (10% in CD34+ selected vs. 27% in unmanipulated grafts, p=0.001), aGVHD II–IV (9% vs. 30%, p=0.0007), and “low-producing” MBL donor genotype (14% vs. 41%, p=0.01). The group of patients with aGVHD II–IV and with a “low-producing” MBL donor genotype had an actuarial probability of IFI of 78% vs. 18% for the remaining patients (p=0.0003). No association between recipient’s MBL polymorphism and IFI was found. All variables with a p value < 0.2 in the univariate analysis were introduced in the multivariate analysis. Only two independent factors were associated with a higher incidence of IFI in the multivariate analysis: “low-producing” MBL donor genotype (RR 7.2, p=0.007) and aGVHD II–IV (RR 5.5, p=0.02). In conclusion, donor’s MBL gene polymorphism possesses strong predictive value for IFI. This finding could be useful for selecting the most appropriate donor. In addition, studies investigating primary anti-fungal prophylaxis in patients developing aGVHD II–IV and with a “low-producing” MBL donor genotype are warranted.