Graft-versus-host disease and impact on relapse in myelofibrosis undergoing hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment for myelofibrosis (MF). Relapse occurs in 10-30% and remains a major factor for dismal outcomes. Previous work suggested that graft-versus-host disease (GVHD) might be associated with risk of relapse. This study included 341 patients undergoing their first (n = 308) or second (n = 33) alloHSCT. Anti-T-lymphocyte or antithymocyte globulin was used for GVHD prophylaxis in almost all patients. Median time to neutrophile and platelet engraftment was 13 days and 19 days, respectively. The cumulative incidence of acute GVHD grade II-IV was 41% (median, 31 days; range, 7-112). Grade III-IV acute GVHD was observed in 22%. The cumulative incidence of chronic GVHD was 61%. Liver was affected in 23% of acute GVHD cases and 46% of chronic GVHD cases. Severe acute GVHD was associated with high non-relapse mortality. The development of acute GVHD grade II and moderate GVHD was an independent factor for reduced risk for relapse after transplantation without increased risk for non-relapse mortality, while especially acute GVHD grade IV was associated with high non-relapse mortality. Last, we identified that ongoing response to ruxolitinib, accelerated-phase MF at time of transplantation and splenectomy prior to transplantation were independent predictors for relapse.

Development and Validation of a Concise Objectifiable Risk Evaluation Score for Non-Relapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation.

We aimed to develop a concise objectifiable risk evaluation (CORE) tool for predicting non-relapse mortality (NRM) and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HCT). A total of 1120 adult patients who had undergone allo-HCT at our center between 2013 and 2020 were divided into training, first, and second validation cohorts. Objectifiable, patient-related factors impacting NRM in univariate and multivariate analyses were: serum albumin, serum creatinine, serum C-reactive protein (CRP), heart function (LVEF), lung function (VC, FEV1), and patient age. Hazard ratios were assigned points (0-3) based on their impact on NRM and summed to the individual CORE HCT score. The CORE HCT score stratified patients into three distinct low-, intermediate-, and high-risk groups with two-year NRM rates of 9%, 22%, and 46%, respectively, and OS rates of 73%, 55%, and 35%, respectively (p < 0.001). These findings were confirmed in a first and a second recently treated validation cohort. Importantly, the CORE HCT score remained informative across various conditioning intensities, disease-specific subgroups, and donor types, but did not impact relapse incidence. A comparison of CORE HCT vs. HCT Comorbidity Index (HCT-CI) in the second validation cohort revealed better performance of the CORE HCT score with c-statistics for NRM and OS of 0.666 (SE 0.05, p = 0.001) and 0.675 (SE 0.039, p < 0.001) vs. 0.431 (SE 0.057, p = 0.223) and 0.535 (SE 0.042, p = 0.411), respectively. The CORE HCT score is a concise and objectifiable risk evaluation tool for adult patients undergoing allo-HCT for malignant disease. External multicenter validation is underway.

Allogeneic hematopoetic stem cell transplant for patients with refractory T-Cell lymphomas.

OBJECTIVE: Allogeneic stem cell transplantation (allo-SCT) may have a curative potential due to the graft versus lymphoma effect. In this study, we aimed to compare transplant outcomes between refractory-T-NHL (ref-NHL) and Chemosensitive-T-NHL (CS-T-NHL). MATERIALS AND METHODS: We retrospectively reviewed the records of 26 ref-NHL and 29 CS-T-NHL consecutive patients who underwent allo-SCT at our center and compared the transplant outcomes between the groups. RESULTS: All patients were heavily pretreated with 27% of patients relapsing post-auto-SCT and two patients in the ref-T-NHL post-allo-SCT. Patients were transplanted mainly from unrelated donors. There were no differences in leucocytes and platelet engraftment between the two groups. At 3 years, the relapse incidence was 34% in Ref-TNHL and 19% in CS-TNHL (p = .33), with non-relapse mortality rates of 28% and 22%, respectively (p = .52). Female patients and those with a previous auto-SCT had lower relapse incidence (p = .045, p = .003). The 3-year overall survival was 39% in Ref-TNHL and 56% in CS-TNHL (p = .15). Trends for improved progression-free survival (PFS) and graft-versus-host disease relapse-free survival (GRFS) were observed in the CS-TNHL group (PFS: 60% vs. 30%, p = .075; GRFS: 38% vs. 21%, p = .1). CONCLUSION: Acknowledging the retrospective nature of our study, our results indicate that allo-SCT has a curative potential in patients with T-NHL even in refractory status.

Spleen volume and length determined by computed tomography impact outcome after allogeneic stem cell transplantation for myelofibrosis.

Splenomegaly is a hallmark of myelofibrosis (MF), and reports on the impact of spleen size on the outcome of allo-HSCT have been conflicting, possibly due to differences in methods of assessment. We retrospectively analysed the impact of spleen volume and length measured by computed tomography on allo-HSCT outcome in 93 patients, 74% of whom had prior ruxolitinib treatment. Median spleen volume and length were 1.58 dm3 and 20 cm, respectively. We found a strong correlation between spleen volume and length (Pearson's r = 0.95, p < 0.001), Spearman (rho = 0.96, p < 0.001). After a median follow-up of 41.7 months, 5-year overall and disease-free survival were 66% and 59%, respectively. Spleen size did not impact overall survival or non-relapse mortality. Larger spleen volume and length as continuous variables were associated with slower platelet and leucocyte engraftment and a higher risk of disease relapse in univariate and multivariate analyses. Spleen length measured precisely by imaging is a good surrogate for spleen volume. In the era of JAK inhibitors, larger spleen size reflects advanced disease in MF and is associated with an increased risk of relapse but has no impact on non-relapse mortality and overall survival after allo-HSCT.

Individualized busulfan dosing improves outcomes compared to fixed-dose administration in pre-transplant minimal residual disease-positive acute myeloid leukemia patients with intermediate-risk undergoing allogeneic stem cell transplantation in CR.

Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. Eighty-seven patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. Thirty-two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n = 18/25 (72%); decreased: n = 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2%-19% vs. 35%, 23%-49% p = 0.02), improved 3-year leukemia-free survival (LFS) (78%, 54%-91% vs. 55%, 40%-70% p = 0.009) and - overall survival (OS) (82%, 60%-93% vs. 69%, 54%-81% p = 0.05) after individualized compared to fixed Bu. Non-relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p = 0.044), LFS (HR 3.6, p = 0.018) and relapses (HR 3.6, p = 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p = 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity.

Impact of Anti-T-lymphocyte globulin dosing on GVHD and Immune reconstitution in matched unrelated myeloablative peripheral blood stem cell transplantation.

Data on the influence of different Anti-lymphocyte globulin (ATLG) doses on graft versus host disease (GVHD) incidence and immune reconstitution in matched unrelated (MUD) allogeneic Stem cell transplantation (allo-SCT) is limited. This retrospective study conducted at the University Medical-Center Hamburg compares GVHD and Immune reconstitution after myeloablative MUD (HLA 10/10) PBSC allogeneic stem cell transplant between 30 mg/Kg (n = 73) and 60 mg/Kg (n = 216) ATLG. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100, and 180 posttransplant. Neutrophil and platelet engraftments were significantly delayed in the 60 mg/kg group with a higher Cumulative incidence of Infections (67% vs 75% p = 0.049) and EBV (21% vs 41% p = 0.049) reactivation at day 100 in this group. In the 30 mg/kg group, we observed a faster reconstitution of naïve-B cells (p < 0.0001) and γδ T cells (p = 0.045) at day+30 and a faster naïve helper T-cell (p = 0.046), NK-cells (p = 0.035), and naïve B-cell reconstitution (p = 0.009) at day+180. There were no significant differences in aGVHD, cGVHD, NRM, RI, PFS, and OS between the groups. The choice of ATLG dose has significant impact on IR but not on GVHD after MUD-allo-SCT. Higher doses are associated with delayed engraftment and increased infections.

Post-Transplantation Day +100 Minimal Residual Disease Detection Rather Than Mixed Chimerism Predicts Relapses after Allogeneic Stem Cell Transplantation for Intermediate-Risk Acute Myelogenous Leukemia Patients Undergoing Transplantation in Complete Remission.

Chimerism and minimal residual disease (MRD) are suggested to be prognostic for post-transplantation relapse in patients with acute myelogenous leukemia (AML). Nevertheless, the predictive value of both approaches in homogeneous populations remains underinvestigated. Here we suggest that MRD may have greater predictive value for relapse than mixed chimerism (MC) in intermediate-risk AML patients. Seventy-nine patients with intermediate-risk AML (40 males; median age, 57 years [range, 19 to 77 years]) were included. MRD detection on day +100 was performed in bone marrow via multiparameter flow cytometry (MFC) and quantitative real-time PCR (qPCR) for patients with an NPM1 mutation. Chimerism analysis was performed in peripheral blood. MC was defined as the persistence of <99.9% of donor alleles. The area under the receiver operating characteristic curve was highest for qPCR-MRD (.93), followed by MFC-MRD (.80) and MC (.65). The highest rate of relapse at 3 years was observed in day +100 qPCR-MRD-positive patients (100%), followed by MFC-MRD-positive patients (55%; P < .001). No patients with MC and without detectable MRD experienced relapse. The median 3-year overall survival (OS) and leukemia-free survival (LFS) for patients with MC without detectable MRD were both 86% (range, 61% to 96%), significantly higher than the values in day +100 MFC-MRD-positive patients (OS, 61% [range, 36% to 84%]; LFS: 30% [range, 11% to 59%]) and with day +100 qPCR-MRD-positive patients (OS: 17% [range, 3% to 56%], P = .001; LFS: 0%, P < .001). In patients with intermediate-risk AML, the qPCR-MRD on day +100 was highly predictive for relapse and long-term survival after allogeneic stem cell transplantation, followed closely by MFC-MRD. In contrast, chimerism status had limited predictive potential. Thus, molecular and flow cytometry MRD monitoring rather than MC in the first several months post-transplantation can identify patients at increased risk of relapse who may benefit from early post-transplantation preemptive intervention.

Post-Transplantation Multicolored Flow Cytometry-Minimal Residual Disease Status on Day 100 Predicts Outcomes for Patients With Refractory Acute Myeloid Leukemia.

Patients with relapsed/refractory acute myeloid leukemia (AML) have a dismal prognosis. Allogeneic stem cell transplantation (allo-SCT) provides a curative approach; however, the overall survival (OS) remains low (20% to 40%). In this setting, although some effective approaches have been evaluated in recent years, the management of such patients still remains challenging. In this study we evaluated the predictive role of post-transplant day 100 minimal residual disease (MRD) detection for post-transplantation outcomes for patients with refractory AML. Fifty-six adult patients with refractory AML (median age 58, range 20-76; male, 61%) who underwent allo-SCT were included in this retrospective monocentric study. Twenty-nine patients (52%) received fludarabine, amsacrine, and cytarabine (FLAMSA)-based conditioning. MRD was assessed using multicolored flow cytometry (MFC) according to European Leukemia Net guidelines ("different from normal" and leukemia-associated phenotype). The sensitivity of the method was 10-4 to 10-5. The median marrow blast count at allo-SCT was 25% (range 6% to 91%). At day 100 after transplantation, 40 patients (71%) experienced MFC-MRD negativity, and 16 patients (29%) were MRD positive. All included patients survived at least 100 days after transplantation without relapse. Univariate and multivariate analysis based on Kaplan-Meier and Cox proportional hazards method were performed. The median follow-up was 16 months (range 3 to 66). The post-transplantation day 100 MRD-negative patients instead received 2 allografts (27% versus 6%, P = .08). In multivariate analysis, day 100 MRD status (negative versus positive) (OS: 0.23 [0.1 to 0.54], P =0.001; relapses: 0.20 [0.1 to 0.49], P = .0005) and FLAMSA versus other regimens (0.34 [0.1 to 0.83], P = .018; relapses: 0.43 [0.17 to 1.1], P = .07) independently impacted post-transplantation survival. We suggest that post-transplantation day 100 MFC-MRD detection plays predictive role in refractory AML patients and may help to define possible candidates for early post-transplantation interventions aiming to decrease the relapse risk and improve survival.

Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation.

Anti-T-cell lymphocyte globulin (ATLG) and posttransplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical Center Hamburg-Eppendorf (UKE) compares PTCy (n=123) and ATLG (n=476) after myeloablative allogeneic peripheral blood stem cell transplant. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations, GVHD and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. day 10, P<0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher Epstein-Barr virus reactivation in the ATLG arm and comparable cytomegalovirus reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was seen more often after PTCy (44% vs. 38%, P=0.005). ATLG resulted in a faster reconstitution of CD8+ T, NK, NKT and gdT cells while CD4 T cells and B cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B cells. Non-relapse mortality relapse incidence, disease-free survival, and overall survival did not differ significantly between both arms. Even though differences in IR were related to a decreased incidence of infection and moderate/severe cGVHD in the ATLG group they had no impact on any of the other long-term outcomes. However, it remains undetermined which regimen is better as GVHD prophylaxis.

Antibody response after vaccination against SARS-CoV-2 in adults with hematological malignancies: a systematic review and meta-analysis.

Vaccines against SARS-CoV-2 have shown remarkable efficacy and thus constitute an important preventive option against coronavirus disease 2019 (COVID-19), especially in fragile patients. We aimed to systematically analyze the outcomes of patients with hematological malignancies who received vaccination and to identify specific groups with differences in outcomes. The primary end point was antibody response after full vaccination (2 doses of mRNA or one dose of vectorbased vaccines). We identified 49 studies comprising 11,086 individuals. Overall risk of bias was low. The pooled response for hematological malignancies was 64% (95% confidence interval [CI]: 59-69; I²=93%) versus 96% (95% CI: 92-97; I²=44%) for solid cancer and 98% (95% CI: 96-99; I²=55%) for healthy controls (P<0.001). Outcome was different across hematological malignancies (P<0.001). The pooled response was 50% (95% CI: 43-57; I²=84%) for chronic lymphocytic leukemia, 76% (95% CI: 67-83; I²=92%) for multiple myeloma, 83% (95% CI: 69-91; I²=85%) for myeloproliferative neoplasms, 91% (95% CI: 82-96; I²=12%) for Hodgkin lymphoma, and 58% (95% CI: 44-70; I²=84%) for aggressive and 61% (95% CI: 48-72; I²=85%) for indolent non-Hodgkin lymphoma. The pooled response for allogeneic and autologous hematopoietic cell transplantation was 82% and 83%, respectively. Being in remission and prior COVID-19 showed significantly higher responses. Low pooled response was identified for active treatment (35%), anti-CD20 therapy ≤1 year (15%), Bruton kinase inhibition (23%), venetoclax (26%), ruxolitinib (42%), and chimeric antigen receptor T-cell therapy (42%). Studies on timing, value of boosters, and long-term efficacy are needed. This study is registered with PROSPERO (clinicaltrials gov. Identifier: CRD42021279051).

Enhanced Immune Reconstitution of γδ T Cells after Allogeneic Stem Cell Transplantation Overcomes the Negative Impact of Pretransplantation Minimal Residual Disease-Positive Status in Patients with Acute Myelogenous Leukemia.

Minimal/measurable residual disease (MRD) before allogeneic stem cell transplantation (allo-SCT) in patients with acute myelogenous leukemia (AML) is a poor risk factor for outcome. γδ T cells represent a unique minority lymphocyte population that is preferentially located in peripheral tissues, can recognize antigens in a non-MHC-restricted manner, and plays a "bridging" role between the innate and adaptive immune systems. In this study, we investigated a potential graft-versus-leukemia effect of γδ T cell reconstitution post-transplantation in AML patients with pretransplantation positive MRD status (MRD+). MRD assessment was performed in 202 patients using multicolored flow cytometry ("different from normal" strategy); 100 patients were deemed MRD+. Analysis for absolute concentrations of CD3+, CD4+, CD8+, natural killer, and γδ T cells were performed by flow cytometry according to an internal protocol at day +30 and +100 post-transplantation. Differences between categorical and continuous variables were determined using the chi-square and Student t test, respectively. The Mann-Whitney U test was used to compare medians of continuous variables. Spearman's correlation was used for nonparametric assessment of correlation between different cell subsets during immune reconstitution. Kaplan-Meier survival analysis and Cox regression analysis were used to investigate the associations between immune reconstitution and survival outcomes. Gray's analysis was used to compute incidences of relapse, nonrelapse mortality, and graft-versus-host disease (GVHD). The median follow-up of survivors was 28 months (range 3 to 59 months). Younger age (≤58 years) of recipient and donor (<30 years), sex mismatch, use of a matched donor, cytomegalovirus reactivation, and administration of antithymocyte globulin were associated with a faster γδ T cell reconstitution. In multivariable analysis for MRD+ patients, a higher than median level of γδ T cells on days +30 and +100 resulted in significantly improved leukemia-free survival (hazard ratio [HR], 0.42 [P = .007] and 0.42 [P = .011], respectively) and overall survival (HR, 0.44 [P = .038] and 0.33 [P = .009], respectively). Furthermore, a higher γδ T cell level on day +30 was associated with a significantly reduced risk of relapse (HR, 0.36; P = .019). No impact of γδ T cell level on relapse at days +30 and +100 could be seen in MRD-negative patients, and no correlation with occurrence of GVHD was observed. Our data indicate that enhanced immune reconstitution of γδ T cells post-transplantation may overcome the higher relapse risk of pretransplantation MRD+ status in patients with AML.

A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia.

Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.

Risk adapted therapeutic strategy in newly diagnosed acute myeloid leukemia: Refining the outcomes of ELN 2017 intermediate-risk patients.

INTRODUCTION: Despite advances in the treatment of acute myeloid leukemia (AML), cytotoxic chemotherapy remains the standard induction regimen. PATIENTS AND METHODS: In this single center retrospective study, we assessed outcomes of 99 consecutive adult AML patients treated with a risk-adapted strategy with a median follow-up of 35.5 months. RESULTS: We identified 24 (24 %), 55 (56 %) and 20 (20 %) patients classified as favorable-, intermediate-, and adverse- risk group respectively, according to the European LeukemiaNet (ELN) 2017 classification. Patients either received idarubicin and cytarabine induction chemotherapy with or without FLT3 inhibitors or hypomethylating agents based on age and comorbidity. The complete response (CR) rate was 76 % (82 % and 61 % in patients aged < 60 and ≥ 60, respectively). For the whole cohort, the 3-year overall survival (OS) was 53 %, being 62 % and 30 % in patients aged < 60 and ≥ 60, respectively. The 3-year leukemia-free survival (LFS) was 54 %, with 56 % and 45 % in patients aged < 60 and ≥ 60, respectively. The 3-year LFS were 58 %, 62 % and 25 % for patients within ELN favorable-, intermediate-, and adverse-risk groups respectively. Twenty-seven (36 %) out of 75 patients with intermediate- and adverse-risk disease underwent allogeneic hematopoietic cell transplantation (allo-HCT) in first CR with 92 % of them receiving post-transplant maintenance consisting of azacitidine in 19 (76 %) patients or sorafenib in 6 (24 %) patients. Of these patients younger than 60 years, the 3-year OS and LFS were 85 % and 69 %, respectively. CONCLUSION: These results indicate an improved OS for AML patients especially in intermediate-risk category who were treated with a total therapy consisting of induction chemotherapy followed by allo-HCT and post-transplant maintenance.

Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic stem-cell transplantation. Posttransplantation cyclophosphamide (PT/CY) has become standard prophylaxis of GVHD in T-replete haploidentical transplantation. The question is whether adding antithymocyte globulin (ATG) to PT/CY may further reduce the incidence of GVHD compared to PT/CY only. PATIENTS AND METHODS: We retrospectively studied 268 patients undergoing myeloablative haploidentical transplantation with thiotepa, busulfan, and fludarabine (TBF) conditioning. Sixty-nine patients (26%) received ATG. RESULTS: In the ATG group, 3% died due to GVHD versus 8% in the no ATG group. The 100-day and 1-year nonrelapse mortality (NRM) was 0% and 19%, respectively, in the whole cohort. On univariate analysis, the 1-year NRM was 8% versus 23% in patients receiving ATG and no ATG, respectively (P = .005). The no ATG group had a higher incidence of acute GVHD at 12 months compared to the ATG group (22% vs. 12%, respectively, P = .029). The ATG group had better overall survival at 12 months compared to the no ATG group (79% vs. 69%, P = .029). On multivariate analysis, adding ATG to PT/CY had no significant impact on any of the outcomes. A low disease risk index was associated with better overall survival and lower NRM, while Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥ 3 was associated with higher NRM. CONCLUSION: ATG can be safely used as part of the pretransplantation conditioning and does not increase the incidence of relapse or complications after transplantation.

Impact of the Conditioning Regimen Dose Intensity Before Autologous Stem Cell Transplantation on the Pulmonary Function Test Abnormalities in Patients With Lymphoma and Multiple Myeloma: Single Center Experience.

BACKGROUND: Most studies addressing the impact of hematopoietic stem cell transplantation (SCT) on pulmonary function test (PFT), and the various factors affecting that impact have been performed on the allogenic type. Few have addressed PFT changes in autologous SCT. This study describes PFT changes seen in autologous SCT recipients and addresses the various factors impacting these changes. PATIENTS AND METHODS: We reviewed the medical records of 223 consecutive adult autologous SCT recipients. We collected pre-transplant and post-transplant data, as well as PFT data and long-term mortality. RESULTS: A total of 123 patients with lymphoma receiving the BEAM (carmustine, etoposide, aracytin, and melphalan) conditioning regimen had a significant 5% drop in mean forced vital capacity and total lung capacity but no significant change in forced expiratory volume in one second/forced vital capacity ratio nor in diffusion lung capacity of carbon monoxide adjusted to volume. Fifteen percent of the patients with lymphoma had a clinically significant drop of 15% in their lung volume parameters. The patients with multiple myeloma receiving the melphalan conditioning regimen had no significant change in any of the PFT parameters. Smoking, baseline PFT parameters, and radiation did not affect lung function or mortality. CONCLUSIONS: Autologous SCT impact on lung function depends on the disease and conditioning regimen. It leads to a drop in lung volumes but no obstruction or decrease in diffusion in patients with lymphoma receiving the BEAM regimen. Autologous SCT did not affect lung functions in patients with multiple myeloma, and these patients may not need screening PFTs.

Safety and efficacy of four cycles of Brentuximab Vedotin as consolidation after autologous peripheral stem cell transplantation in relapsed/refractory Hodgkin lymphoma.

Brentuximab Vedotin (BV) is a chimeric anti-CD30 antibody, conjugated to anti-tubulin mono-methyl-auristatin. The AETHERA trial revealed increased PFS when BV is used as maintenance therapy for 16 cycles in high risk Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). However, this schedule is associated with high cost and significant toxicity. Our objective is to assess the safety and efficacy of four cycles Brentuximab Vedotin as consolidation after ASCT for relapsed/refractory (R/R) HL. We identified 20 consecutive adult patients with R/R HL treated with BV for four cycles as consolidation after ASCT. The indications for BV consolidation included primary refractory disease in 12 patients (60%), early relapse in 6 patients (30%) and extra-nodal involvement in two patients (10%). After a median follow up of 27 months, five (25%) patients relapsed. The median time to relapse was 6 months. Median PFS and OS were not reached. No significant toxicities were reported.

The role of candidate genetic polymorphisms in the interaction between voriconazole and cyclosporine in patients undergoing allogeneic hematopoietic cell transplantation: An explorative study.

PURPOSE: To evaluate polymorphisms in genes of drug metabolizing enzymes and transporters involved in cyclosporine and/or voriconazole disposition among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: DNA from forty patients was genotyped using the DMETPlus array. The average ratio of cyclosporine concentration/dose (C/D in (ng/mL)/(mg/kg)) per participant's weight was computed using available trough levels and daily doses. RESULTS: The C/D cyclosporine ratio was significantly higher when it was administered with voriconazole as compared to when it was administered alone: median: 116.75 vs. 25.40 (ng/mL)/(mg/kg) with and without voriconazole respectively, (P < 0.001). There was also a significant association between the C/D cyclosporine ratio combined with voriconazole and the ABCB1 2677 G > T > A (rs2032582) genetic polymorphism (P = 0.05). In parallel, ABCB1 variant allele carriers had higher creatinine in combination therapy with a median creatinine (mg/dL) of 0.74 vs. 0.56 for variant allele carriers vs. reference; P = 0.003. Interestingly, CYP2C9, CYP2C19, and CYP3A5 extensive metabolizers tended to be associated with lower cyclosporine C/D ratio when combined with voriconazole, but the results were not statistically significant. CONCLUSION: To the best of our knowledge, this is the first pharmacogenetic study on the interaction between voriconazole and cyclosporine in patients undergoing allo-HCT. Results suggest that the ABCB1 2677 G > T > A genetic polymorphism plays a role in this interaction with cyclosporine related nephrotoxicity. Pre-emptive genotyping for this genetic variant may be warranted for cyclosporine dose optimization. Larger studies are needed to potentially show significant associations with more candidate genes such as CYP3A4/5, CYP2C9, and CYP2C19, among others.

Assessment of Caries Index and Fluoride Intake in a Pediatric Middle Eastern Population.

AIMS: To assess the fluoride concentration in water sources and its association with caries index in children living in Tripoli, Lebanon. MATERIALS AND METHODS: The concentration of fluoride was measured in tap and bottled water using ion chromatography. For tap water, eight water sources were evaluated before and after domestic distribution during June and November 2016. For bottled water, seven brands available on the market were tested. Caries were recorded in 402 children using DMFT/dmft indices. A questionnaire was distributed to parents to gather information about sociodemographic characteristics, the source of water consumed, the consumption of fluoride supplements, fluoridate salt, tea and sweets, and the frequency of toothbrushing. RESULTS: The fluoride concentration in tap water was not significantly different from the optimal concentration (p value > 0.05). However, the amount of fluoride in bottled water (0.14 ± 0.698 mg/L) was significantly lower than the optimal amount of fluoride recommended by the World Health Organization for decay prevention (0.5-1 mg/L) (p value < 0.001). The prevalence of caries was elevated in children aged 5 years (90.5%) and 12 years (89.6%). The carious indices were lower in children who consume tap water, tea, and fluoridated salt and those who consume less sweet. CONCLUSION: Additional studies covering all Lebanese regions should be performed to develop a national policy concerning fluoride-based scientific evidences. CLINICAL SIGNIFICANCE: Pedodontists should take in consideration the source of water consumed by the patient before prescribing a fluoride supplementation to avoid an overconsumption. They should promote effective oral hygiene methods and nutritional education and encourage regular tea consumption as an affordable source of fluoride to prevent caries.