Outcomes in patients with chronic lymphocytic leukemia and TP53 aberration who received first-line ibrutinib: a nationwide registry study from the Italian Medicines Agency.

In this analysis we describe the effectiveness of first-line ibrutinib in 747 patients with chronic lymphocytic leukemia (CLL) and TP53 aberrations in a nationwide study with a 100% capture of patients who received the study drug. Median age was 71 years (range 32-95). An estimated treatment persistence rate of 63.4% (95% CI 60.0%-67.0%) and survival rate of 82.6% (95% CI 79.9-85.4%) were recorded at 24 months. Disease progression or death were the reasons for discontinuation in 182/397 patients (45.8%). A higher risk of treatment discontinuation was found to be associated with age, ECOG-PS and pre-existing heart disease, whereas ECOG ≥ 1, age ≥ 70 years and male sex were associated with an increased risk of death. Median post-progression overall survival (OS) was 12.2 months (95% CI 9.2-22.0). Post-discontinuation median OS in patients who discontinued ibrutinib for other reasons was not reached (95% CI 42.3 months - NA). Ibrutinib was an effective first-line treatment for CLL and TP53 aberrations in patients treated at large academic centers and community practice hospitals. Clinical characteristics at baseline may influence the effectiveness of ibrutinib, whereas the experience of prescribing centers and multi-hit or single-hit TP53 aberrations had no impact on outcome in this high-risk population.

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.

Longitudinal Corneal Endothelial Cell Changes in Patients Undergoing Hematopoietic Stem Cell Transplantation.

PURPOSE: To evaluate longitudinally corneal endothelial cell changes in patients undergoing hematopoietic stem cell transplantation (HSCT) and to further investigate possible correlations with hematological and ocular characteristics. METHODS: Prospective observational study conducted at a single center. All patients underwent a comprehensive ophthalmological examination, before and after HSCT, including slitlamp examination, Schirmer test, tear breakup time, ocular surface staining, specular microscopy of corneal endothelium, and Ocular Surface Disease Index questionnaire. RESULTS: Twenty-five patients undergoing HSCT and 25 age- and sex-matched controls were included. At baseline, hematological patients showed significantly lower values of endothelial cell density (ECD) compared with those of controls (2514.5 ± 390.2 vs. 2723.7 ± 298.0 cells/mm, P = 0.038). After HSCT, ocular surface disease index score significantly increased (P = 0.020) and tear breakup time significantly decreased (P = 0.036). Conversely, no significant changes were found in Schirmer test and corneal fluorescein staining (always P > 0.05). Eight patients (32%) developed ocular graft-versus-host disease (GVHD). ECD values significantly decreased after HSCT (from 2514.5 ± 390.2 to 2409.5 ± 330.9 cells/mm, P = 0.009). The decrease in ECD values after HSCT was more pronounced in patients with ocular GVHD compared with those without (231.1 ± 188.8 vs. 45.6 ± 156.5, P = 0.016). No significant correlations between the changes in ECD and hematological and ocular characteristics were found (always P > 0.05). CONCLUSIONS: Hematological patients showed a lower endothelial cell count already before HSCT, compared with controls. After HSCT, the endothelial cell count further significantly decreased, particularly in patients who developed ocular GVHD.

A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results.

Multiple myeloma (MM) is a genetically heterogeneous disease, in which the process of tumorigenesis begins and progresses through the appearance and accumulation of a tangle of genomic aberrations. Several are the mechanisms of DNA damage in MM, varying from single nucleotide substitutions to complex genomic events. The timing of appearance of aberrations is well studied due to the natural history of the disease, that usually progress from pre-malignant to malignant phase. Different kinds of aberrations carry different prognostic significance and have been associated with drug resistance in some studies. Certain genetic events are well known to be associated with prognosis and are incorporated in risk evaluation in MM at diagnosis in the revised International Scoring System (R-ISS). The significance of some other aberrations needs to be further explained. Since now, few phase 3 randomized trials included analysis on patient's outcomes according to genetic risk, and further studies are needed to obtain useful data to stratify the choice of initial and subsequent treatment in MM.

Diagnosis and Treatment of VOD/SOS After Allogeneic Hematopoietic Stem Cell Transplantation.

Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) is a rare complication characterized by hepatomegaly, right-upper quadrant pain, jaundice, and ascites, occurring after high-dose chemotherapy, hematopoietic stem cell transplantation (HSCT) and, less commonly, other conditions. We review pathogenesis, clinical appearance and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD occurring post-HSCT. The injury of the sinusoidal endothelial cells with loss of wall integrity and sinusoidal obstruction is the basis of development of postsinusoidal portal hypertension responsible for clinical syndrome. Risk factors associated with the onset of VOD and diagnostic tools have been recently updated both in the pediatric and adult settings and here are reported. Treatment includes supportive care, intensive management, and specific drug therapy with defibrotide. Because of its severity, particularly in VOD with associated multiorgan disease, prophylaxis approaches are under investigation. During the last years, decreased mortality associated to VOD/SOS has been reported being it attributable to a better intensive and multidisciplinary approach.

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

INTRODUCTION: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen. METHODS AND PATIENTS: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification. RESULTS: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000). CONCLUSION: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.

Longitudinal Analysis of Infrared Meibography in Patients Undergoing Hematopoietic Stem Cell Transplantation.

PURPOSE: To evaluate meibomian gland (MG) changes in patients undergoing hematopoietic stem cell transplantation (HSCT) by infrared meibography and to further investigate possible correlations with hematological characteristics. METHODS: Thirty-three patients were included: infrared meibography of the lower eyelid, Schirmer test, tear break-up time, ocular surface staining, and Ocular Surface Disease Index questionnaire were conducted before (V0) and 4 months after HSCT (V1). A paired samples t test was used to compare parameters before and after HSCT. A mixed analysis of variance was used to assess the effect of hematological characteristics on changes of MG loss (MGL) after HSCT. RESULTS: MGL and corneal staining significantly increased after HSCT (respectively, from 24.3% ± 10.1% to 32.2 ± 15.0 and from 1.2 ± 1.5 to 2.0 ± 1.7; always P < 0.011), whereas tear break-up time significantly decreased (from 6.6 ± 4.2 seconds to 3.2 ± 2.2; P < 0.001). At V1, 19 patients (57.6%) belonged to ocular graft-versus-host disease severity grade 0, 8 (24.2%) to grade I, and 6 (18.2%) to grade II. The percentage of MGL at V0 and the increase of MGL from V0 to V1 did not differ between patients who developed ocular graft-versus-host disease and those who did not (always P > 0.05). At V1, MGs' quality reduced in 16 patients (48.5%), remained unchanged in 14 (42.4%), and improved in 3 (9.1%). The increase of MGL after HSCT was higher in patients receiving myeloablative conditioning regimen (P = 0.005). CONCLUSIONS: MG function, loss, and quality significantly worsened after HSCT. Myeloablative conditioning regimen was associated with higher MGL.

Clinical utility of measuring Epstein-Barr virus-specific cell-mediated immunity after HSCT in addition to virological monitoring: results from a prospective study.

Lack of virus-specific cell-mediated immunity (CMI) is associated with worse viral infection outcome in hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the role of immunological monitoring of Epstein-Barr virus (EBV) infection in addition to virological one in 33 adult and 18 pediatric allogeneic HSCT recipients. Virological monitoring of infection was performed on whole blood samples by a quantitative real-time PCR assay. Immunological monitoring was performed by Enzyme-linked ImmunoSPOT assay, evaluating EBV-specific CMI, at fixed time-points and when EBV DNAemia was ≥ 10,000 copies/mL. Fifty-one percent of patients developed a post-transplant EBV infection and reduced-intensity conditioning regimen was the only factor associated to infection (P = 0.023). Lack of EBV-specific CMI during active EBV infection was associated with a greater severity of infection. Patients without EBV-specific CMI showed higher median peak level of EBV DNAemia than patients with EBV-specific CMI (P = 0.014), and consequently received more frequently, at EBV DNAemia peak, anti-CD20 therapy (0 versus 54.5%, P = 0.002). No patients with EBV-specific CMI versus 27.2% without EBV-specific CMI developed EBV-related complications (P = 0.063), including two lethal EBV-related post-transplant lymphoproliferative disorders. Combined immunological and virological measurements could improve EBV infection management in HSCT, anticipating the beginning of preemptive treatment from the EBV DNAemia peak to the finding of the lack of EBV-specific CMI.

Role of imaging techniques in liver veno-occlusive disease diagnosis: recent advances and literature review.

INTRODUCTION: Veno-occlusive-disease (VOD), known also as sinusoidal-obstruction-syndrome (SOS), is one of the main complications of haematopoietic stem cell transplantation and is related to the treatment with pyrrolizidine alkaloids or other toxic agents (chemotherapy for liver-metastasis). Clinical diagnosis using the recent criteria from the European Society for Blood and Marrow Transplantation, is the reference for VOD/SOS diagnosis. However, increasing evidence suggests the emerging role of several imaging methods that could help the clinician in VOD/SOS assessment. Areas covered: This review evaluates the current literature on the various imaging techniques used in VOD/SOS diagnosis in several clinical scenarios. Literature searches were performed using several keywords on MEDLINE/Ovid/In-Process/Cochrane Library/EMBASE and PubMed up to July 2018. Expert commentary: Hepatic-gradient-measurement (HVPG) and contextual transjugular-liver-biopsy are invasive and should always be considered in unclear cases. The main studies revolve around ultrasound with Doppler evaluation, identifying numerous findings suggestive of VOD/SOS. However, their accuracy and validation are still suboptimal and controversial. CT-Scan and MRI have shown encouraging data in other contexts in which VOD/SOS can develop, but studies on the post-HSCT patient are lacking. Elastography techniques measuring liver stiffness (LSM) represent the most recent and promising approach for an accurate and early diagnosis of VOD/SOS. In our view, a multidisciplinary approach to the VOD/SOS diagnosis should be highly encouraged.

Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study.

BACKGROUND: We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. METHODS: In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov. FINDINGS: In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups. INTERPRETATION: The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. FUNDING: Neovii Biotech.

Liver Stiffness Measurement Allows Early Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Adult Patients Who Undergo Hematopoietic Stem Cell Transplantation: Results from a Monocentric Prospective Study.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complication affecting patients undergoing hematopoietic stem cell transplantation (HSCT). The survival rate is higher when specific therapy is initiated early; thus, improving early, noninvasive diagnosis of VOD/SOS is an important need. In an adult population undergoing HSCT, we aimed to assess the role of liver stiffness measurement (LSM), evaluated by transient elastography (TE), for diagnosing VOD/SOS. Between April 2016 and March 2018, 78 consecutive adult patients with indications for allogeneic HSCT were prospectively included. LSM was performed before HSCT and at days +9/10, +15/17, and +22/24 post-HSCT. New European Society for Blood and Marrow Transplantation criteria were used to establish VOD/SOS diagnosis. Four patients developed VOD/SOS (5.1%) during the study period, with a median time of +17 days post-HSCT. A sudden increase in LSM compared with previously assessed values and pre-HSCT values, was seen in all patients who developed VOD/SOS. LSM increases occurred from 2 to 12 days before clinical SOS/VOD appearance. The VOD/SOS diagnostic performance of increased LSM over pre-HSCT assessment showed an area under the receiver operating characteristic curve of 0.997 (sensitivity 75%; specificity 98.7%). LSM gradually decreased following successful VOD/SOS-specific treatment. Interestingly, LSM values did not increase significantly in patients experiencing hepatobiliary complications (according to the Common Terminology Criteria) other than VOD/SOS. LSM by TE can be considered a promising method to perform an early, preclinical diagnosis and follow-up of VOD/SOS.

Eyelid metrics assessment in patients with chronic ocular graft versus-host disease.

PURPOSE: To assess eyelid metrics in the setting of chronic ocular graft versus-host disease (oGVHD), and to further correlate them with hematological and ocular characteristics. METHODS: Prospective case-control study conducted at a single tertiary-referred Center. The following eyelid tests were performed in oGVHD patients and control subjects: vertical lid pull; anterior/lower distraction; lateral/medial distraction; distance between lateral canthal angle and orbital rim; margin reflex distances (MRD) 1 and 2; duration of tarsus exposure; snap back. Correlations of eyelid metrics with hematological and ocular parameters in the oGVHD group were performed. RESULTS: Twenty-seven patients with oGVHD and 27 healthy matched subjects were finally included. Significantly higher values of vertical lid pull, anterior/lower distraction, lateral/medial distraction, and distance between lateral canthal angle and orbital rim were found in the oGVHD group compared to controls (always p < 0.02). Conversely, MRD1 was lower in oGVHD patients compared to controls (p < 0.001). Duration of tarsus exposure and snap back test were pathological in a higher percentage in oGVHD group compared to controls (respectively 66.7 and 59.3% vs 33.3 and 25.9%; p < 0.005). Vertical lid pull test was significantly higher in oGVHD patients with superior limbic keratoconjunctivitis (13.8 ±â€¯2.4 vs 10.9 ±â€¯2.4, p = 0.010). Ocular GVHD patients with subtarsal fibrosis had a higher percentage of pathological values for duration of tarsus exposure test (77.3 vs 20.0%; p = 0.014). CONCLUSIONS: The present study highlighted for the first time higher eyelid laxity in oGVHD patients. This intriguing association may add a further piece to the puzzle of clinical features occurring in the setting of oGVHD.

Comparison among different diagnostic criteria for chronic ocular graft-versus-host disease applied with and without pre-transplant ophthalmological examination.

PURPOSE: To compare the proportion and the agreement rate in the diagnosis of chronic ocular graft-versus-host disease (GVHD) among three criteria applied with and without ophthalmological examination before hematopoietic stem cell transplantation (HSCT). METHODS: National Institutes of Health (NIH), International Consensus Criteria on ocular GVHD (ICCGVHD) and TFOS Dry Eye Workshop (DEWS) II criteria were used for the diagnosis of ocular GVHD according to two protocols: ophthalmological examination after HSCT (Protocol A), or before and after HSCT (Protocol B). Proportion of GVHD diagnosis and inter-rate agreement coefficient Kappa (K) among the criteria were calculated. RESULTS: One hundred nine patients undergone HSCT were included. NIH, ICCGVHD and DEWS II criteria diagnosed ocular GVHD in 14.7%, 17.4% and 59.6% of the patients (Protocol A), whereas in 11.9%, 15.6% and 33.0% of the HSCT patients (Protocol B). The coefficient K for the proportion of patients diagnosed with ocular GVHD by NIH and ICCGVHD criteria was K = 0.626 (Protocol A) and K = 0.615 (Protocol B). The K coefficient by NIH and DEWS II criteria was K = 0.144 (Protocol A), and K = 0.233 (Protocol B). The K coefficient by ICCGVHD and DEWS II criteria was K = 0.250 (Protocol A) and K = 0.499 (Protocol B). The K coefficient for ocular GVHD diagnosis applying Protocol A and B was K = 0.881 if NIH criteria were used, K = 0.933 if ICCGVHD criteria were used and K = 0.501 if DEWS II criteria were used. CONCLUSIONS: The diagnosis of ocular GVHD varied significantly in our cohort of hematological patients according to both the diagnostic criteria used and the visit protocols applied.

Intrabone transplant provides full stemness of cord blood stem cells with fast hematopoietic recovery and low GVHD rate: results from a prospective study.

Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 109/L) and 70 ± 10% (platelet > 50 × 109/L) and correlated with CD34 + cells in the graft. NRM was 20 ± 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.

Low-Dose Anti-T Lymphoglobulin as Prophylaxis for Graft-versus-Host Disease in Unrelated Donor Transplantations for Acute Leukemias and Myelodysplastic Syndromes.

Chronic graft-versus-host disease (cGVHD) is a major complication after stem cell transplantation (HSCT). Several randomized studies already demonstrated that anti-T lymphoglobulin (ATLG) is effective in preventing GVHD after myeloablative unrelated and HLA-identical sibling transplants. However, the issue of doses and the potential increase of relapses still remain unsolved. Here we report data on 190 patients with acute leukemia and myelodysplastic syndrome who underwent an unrelated HSCT with low-dose ATLG (15 to 30 mg/kg) given at an earlier timing (days -6 to -2). HSCT was performed from HLA 10/10 (n = 62, 33%), 9/10 (n = 91, 48%), 8/10 (n = 30, 16%), and <8/10 (n = 7, 4%) identical unrelated donor. Peripheral blood was the stem cell source in 42% (n = 80). Median follow-up was 51 months. Grades II to IV and III to IV acute GVHD were 26% and 9%, respectively, and 2-year overall and moderate to severe cGVHD were 23% and 14%, respectively. The 3-year incidences of relapse and nonrelapse mortality were 26% and 18%, respectively. The rates of 3-year overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 60%, 56% and 44%, respectively. Factors such as younger donor, good performance status, and early disease were associated with better outcome in terms of OS, DFS, and GRFS. Our data indicate that doses of ATLG lower that those used in randomized clinical trials can be used for GVHD prevention, even in the adult setting, without clear increases in relapse and infections; these findings need to be further validated by a prospective randomized study.

Meibomian Gland Dropout in Hematological Patients Before Hematopoietic Stem Cell Transplantation.

PURPOSE: To perform qualitative and quantitative analysis of meibomian gland (MG) dropout in hematological patients before hematopoietic stem cell transplantation (HSCT) and to correlate it with both ocular surface and hematological characteristics. METHODS: This prospective study included 46 consecutive patients undergoing HSCT and 30 age- and sex-matched healthy controls. Noninvasive meibography of the lower eyelid, meiboscore (Pult scale), Schirmer test type I, tear film breakup time, and corneal and conjunctival staining were measured. Subjective symptoms were scored by the Ocular Surface Disease Index. The dry eye diagnosis was ascertained according to TFOS DEWS II Criteria. Hematological data included diagnosis (acute leukemias vs. other malignancies), stage of the disease, time from diagnosis to ophthalmological examination, and previous therapy (chemotherapy, radiotherapy, or autograft). RESULTS: Hematological patients presented a significantly lower tear film breakup time and a higher meiboscore compared with controls (respectively 4.8 ± 3.0 seconds vs. 11.0 ± 3.0 and 2.0 ± 1.1 vs. 0.9 ± 0.4; P < 0.001). Conversely, other parameters did not differ between both groups. Dry eye was diagnosed in 14 out 46 hematological patients (30.4%). MG loss was significantly higher in hematological patients than in controls (29.8% ± 15.0% vs. 21.2 ± 13.0; P = 0.007) and was higher in the nasal third compared with both central and temporal thirds (respectively, 39.8% ± 21.4% vs. 18.5 ± 15.6 and 25.1 ± 18.3; P < 0.0001). The diagnosis of acute leukemia (ß = 0.449; P = 0.003) and the history of previous chemotherapy (ß = 0.444; P = 0.003) were associated with lower MG loss. CONCLUSIONS: Hematological patients presented significantly reduced MG areas even before HSCT, particularly those affected by nonacute malignancies. The topographical pattern of MG dropout resembles that of conventional dry eye.

Dry Eye Disease Is Already Present in Hematological Patients Before Hematopoietic Stem Cell Transplantation.

PURPOSE: To analyze ocular surface parameters in patients before hematopoietic stem cell transplantation (HSCT) and to correlate them with hematological characteristics. METHODS: This is a retrospective analysis of prospectively collected data from 203 patients undergoing HSCT. Demographic data and hematological parameters (disorder type and stage) were collected from clinical charts. Ocular surface parameters (ocular surface disease index; Schirmer test I; tear film break-up time; corneal esthesiometry; and corneal and conjunctival staining) were analyzed the day before beginning the conditioning treatment for HSCT preparation. RESULTS: A high prevalence of dry eye (DE) was found: 116 patients (57.2%) were diagnosed as not suffering from DE, whereas 87 patients (42.8%) were diagnosed as having DE. Of these, 26 were classified as dry eye workshot (DEWS) severity score 1, 46 as DEWS score 2, and 15 as DEWS score 3. Tear film break-up time was found to be the only parameter statistically worse in the chronic lymphoproliferative disorder group compared with the stem cell malignancy group. Older age [odds ratio (OR) 1.03], female sex (OR 2.03), advanced stage of hematological disease (OR 1.4), and previous auto- or allo-HSCT (OR 1.9) showed a significant positive association in predicting DE onset before transplantation. CONCLUSIONS: DE was already present in a significant number of patients suffering from hematological disease before HSCT. Some hematological parameters seemed to influence this percentage. These results highlight the role of ocular surface examination by an ophthalmologist in hematological patients before HSCT, with the aim of diagnosing and, if necessary, treating DE patients early.

Successful management of EBV-PTLD in allogeneic bone marrow transplant recipient by virological-immunological monitoring of EBV infection, prompt diagnosis and early treatment.

Epstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is an uncommon, but frequently fatal, complication after allogeneic hematopoietic stem cell transplant. Prospective post-transplant virological and immunological monitoring allowed to successfully manage a patient who developed both polymorphic and monomorphic, "diffuse large B-cell lymphoma like", as an EBV-PTLD, 65days after allogeneic bone marrow transplant. Early detection of significant increase in EBV DNA level in patient's peripheral blood (peak of viral load equal to 119,039copies/mL whole blood, +56day after transplant) led to administration of pre-emptive anti-CD20 monoclonal antibody (rituximab) and close clinical monitoring. After one week, physical exam revealed laterocervical adenopathy. Histopathologic features, immunohistochemical characterization and in situ hybridization study allowed to establish a diagnosis of EBV-related PTLD. Immunological monitoring showed no EBV-specific T-cell responses during EBV replication, thus potentially explaining the occurrence of high EBV load with subsequent PTLD development. A total of four doses of anti-CD20 monoclonal antibody were administered and at the end of the treatment, EBV infection was cleared and imaging technique showed complete disease remission. In conclusion, the early use of anti-CD20 monoclonal antibody proved to be a safe and effective treatment strategy for EBV-PTLD. Moreover, combined virological-immunological monitoring of EBV infection may more accurately assess patients at higher risk for EBV-PTLD.