Nutritional aspects in autoimmune diseases undergoing hematopoietic stem cell transplantation: overview and recommendations on behalf of the EBMT ADWP and Nurses Group.

Autoimmune diseases (ADs) represent a heterogeneous group of conditions affecting 5-10% of the global population. In recent decades, hematopoietic stem cell transplant (HSCT), mainly autologous, has been successfully adopted to treat patients affected by severe/refractory ADs. In this context malnutrition has a detrimental impact on relapse, mortality, infection rate, engraftment, long-term survival, and prolongation of hospitalization. However, in this population, the management of nutrition should be improved since nutritional assessment is partially performed in routine clinical practice. A panel of nurses and physicians from the European Society for Blood and Marrow Transplantation (EBMT) reviewed all available evidence based on current literature and expert practices from centers with extensive experience in HSCT for ADs, on the nutritional management of ADs patients during HSCT procedure. In this context, adequate nutritional status predicts a better response to treatment and improves quality of life. Herein, a systematic and comprehensive monitoring of nutritional status before, during and after HSCT, with adequate nutritional support in the case of ADs patients, in addition to assessing the dietary requirements associated with HSCT has been covered. Moreover, given the singularity of each AD, the underlying disease should be considered for an appropriate approach. The management and evaluation of nutritional status must be carried out by a multidisciplinary team to assess the needs, monitor the effectiveness of each intervention, and prevent complications, especially in complex situations as patients affected by ADs.

Intrabone Transplantation of a Single Unwashed Umbilical Cord Blood Unit with Antithymocyte Globulin-Free and Sirolimus-Based Graft-versus-Host Disease Prophylaxis: Fast Immune Reconstitution and Long-Term Disease Control in Patients with High-Risk Diseases.

Several strategies have been explored with the attempt of improving the safety and feasibility of umbilical cord blood transplantation (UCBT) in adults. The aim of this retrospective analysis was to examine the safety and efficacy of intrabone transplantation of a single unwashed cord blood unit in an antithymocyte globulin-free, sirolimus-based graft-versus-host disease prophylaxis platform. We collected data for all consecutive UCBTs infused intrabone (IB) and unwashed at San Raffaele Hospital in Milan between 2012 and 2021. Thirty-one consecutive UCBTs were identified. All but 3 UCB units had a high-resolution HLA typing on 8 loci at the time of selection. At the time of cryopreservation, the median CD34+ cell count was 1 × 105/kg (range, .6 to 12.0 × 105/kg) and the median total nucleated cell (TNC) count was 2.8 × 107/kg (range, 1.48 to 5.6 × 107/kg). Eighty-seven percent of patients received myeloablative conditioning, and 77% underwent transplantation for acute myeloid leukemia. The median duration of follow-up among survivors was 38.2 months (range, 10.4 to 123.6 months). No adverse events were related to the IB infusion at bedside under short-conscious periprocedural sedation or to the no wash technique. After thawing, median CD34+ cell and TNC counts were .8 × 105/kg (range, .1 to 2.3 × 105/kg) and 1.42 × 107/kg (range, .69 to 3.2 × 107/kg). The median time to engraftment was 27 days for neutrophils and 53 days for platelets. One patient experienced graft rejection and was subsequently rescued with a salvage transplantation. The median time to a CD3+ cell count >100/µL was 30 days. The 100-day cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 12.9% (95% confidence interval [CI], 4% to 27.3%), and the 2-year cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was 11.8% (95% CI, 2.7% to 28.3%). At 2 years, overall survival (OS) was 52.7% (95% CI, 33% to 69%), relapse incidence was 30.7% (95% CI, 13.7% to 49.6%), and transplantation-related mortality was 29% (95% CI, 14.3% to 45.6%). In univariate analysis, infused CD34+ cell count did not impact transplantation outcomes. In patients who underwent transplantation in first complete remission, relapse rate was 13%, with a 2-year OS >90%. In our cohort, IB infusion of a single cord blood unit was feasible, with no adverse reactions related to the no wash/IB infusion, low rates of cGVHD and disease relapse, and rapid immune reconstitution.

Defibrotide Prophylaxis of Sinusoidal Obstruction Syndrome in Adults Treated With Inotuzumab Ozogamicin Prior to Hematopoietic Stem Cell Transplantation.

Sinusoidal Obstruction Syndrome (SOS) is a life threatening HSCT complication and it can rapidly evolve in Multiple Organ Dysfunction Syndrome, with a mortality exceeding 80%. Early treatment with defibrotide is the leading factor for efficacy. Its prophylactic use is recommended in the pediatric setting, but its value isn't validated for adults, although factors for individual risk assessment are debated. We here present a real-world experience of Defibrotide prophylaxis in adults at very high risk of SOS. We treated with prophylactic Defibrotide and Ursodeoxycholic Acid seven patients receiving allogeneic HSCT for high risk B-ALL, previously treated with single agent Inotuzomab-Ozogamicin. They all had other high risk factors for SOS such as previous hepatotoxicity, previous allo-HSCT, double alkylating conditioning. All patients received Treosulfan-Fludarabine conditioning, Thiotepa was added in 4 patients and 4GyTBI in 2 patients. GvHD prophylaxis included post-transplant cyclophosphamide, rapamycin and mycophenolate. Donor source was PBSC. Five patients received family MMRD transplant, 1 patient a MRD transplant and 1 patient a MUD transplant. Non-severe gastrointestinal bleeding occurred in two patients requiring defibrotide temporarily discontinuation. SOS occurred in 3/7 cases within 21 days after HSCT and no late-onset SOS were diagnosed. SOS caused death in all cases. All three patients were characterized by a common pattern of very high risk factors by prior HSCT, they all received a myeloablative conditioning with Treosulfan-Thiotepa and a MMRD transplant. Defibrotide prophylaxis apparently failed to protect against the development of SOS in those patients treated with a double alkylator-based conditioning regimen, while a possible efficacy for the other high-risk patients is debatable.

Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia.

Post-transplant cyclophosphamide (PTCy) has emerged as a promising graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no studies have reported the efficacy of a GvHD prophylaxis based on PTCy with sirolimus (Sir-PTCy) in patients with acute myeloid leukemia (AML). In this retrospective study, we analyze the use of sirolimus in combination with PTCy, with or without mycophenolate mofetil (MMF), on 242 consecutive adult patients with AML undergoing a myeloablative first allo-HSCT from different donor types, in three European centers between January 2017 and December 2020. Seventy-seven (32%) patients received allo-HSCT from HLA-matched sibling donor, 101 (42%) from HLA-matched and mismatched unrelated donor, and 64 (26%) from haploidentical donor. Except for neutrophil and platelet engraftment, which was slower in the haploidentical cohort, no significant differences were observed in major transplant outcomes according to donor type in univariate and multivariate analysis. GvHD prophylaxis with Sir-PTCy, with or without MMF, is safe and effective in patients with AML undergoing myeloablative allo-HSCT, resulting in low rates of transplant-related mortality, relapse/progression, and acute and chronic GvHD in all donor settings.

Case report: Ponatinib as a bridge to CAR-T cells and subsequent maintenance in a patient with relapsed/refractory Philadelphia-like acute lymphoblastic leukemia.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) constitutes a heterogeneous subset of ALL with a uniformly unfavorable prognosis. The identification of mutations amenable to treatment with tyrosine kinase-inhibitors (TKIs) represents a promising field of investigation. We report the case of a young patient affected by relapsed/refractory Ph-like ALL treated with chimeric antigen receptor T (CAR-T) cells after successful bridging with compassionate-use ponatinib and low-dose prednisone. We restarted low-dose ponatinib maintenance three months later. Twenty months later, measurable residual disease negativity and B-cell aplasia persist. To the best of our knowledge, this is the first case reporting the use of ponatinib in Ph-like ALL as a bridge to and maintenance after CAR-T cell therapy.

Complicated and persistent severe COVID-19 pneumonia in a recipient of allogeneic haematopoietic stem cell transplant.

We describe the case of a 45-year-old man affected by T-cell acute lymphoblastic leukaemia and diagnosed with COVID-19 early after an allogeneic haematopoietic stem cell transplant. The infectious disease was characterised by a severe and prolonged course, further complicated by a spontaneous pneumomediastinum and pneumopericardium. We successfully treated this patient with the antiviral drug remdesivir associated with two courses of COVID-19 convalescent plasma. This case report represents a good example of the typical clinical course of COVID-19 in severely immunosuppressed patients and gives evidence that in this population only a prompt treatment directed towards viral clearance can face the absence of a valid immune reactivity.

Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial.

INTRODUCTION: Reducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated. METHODS: The aim of "AlloTreo" prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m2) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who received a first allo-HCT between June 2005 and January 2011, inside the frame of this trial at our center. Median age at allo-HCT was 49 (21-69) years. Disease Risk Index was low in 14 (13%) patients, intermediate in 73 (67.7%), high in 17 (15.7%), and very high in 4 (3.7%). Donors were human leukocyte antigen (HLA)-matched related in 50 cases, 10/10-matched unrelated in 36, and 9/10-mismatched unrelated in 22. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine-A and methotrexate. Anti-T-lymphocyte globulin (ATLG) was administered in patients receiving unrelated allo-HCT. Stem cell source was mainly peripheral blood stem cells (95%). RESULTS: Conditioning regimen was well tolerated. Full donor chimerism was documented for most patients (88%) at day +30. At 12 years, overall survival (OS) was 41.7% (32.2%-50.9%), progression-free survival (PFS) was 31.7% (23%-40.7%), GvHD-free/relapse-free survival was 20.9% (13.7%-29.1%), cumulative incidence (CI) of relapse was 44.5% (34.9%-53.6%), and transplant-related mortality (TRM) was 22.5% (15.1%-30.9%). CI of acute GvHD grades II-IV was 27.8% (19.7%-36.5%) at 100 days; 12-year CI of chronic GvHD was 40.7% (31.3%-49.9%). Relevant long-term adverse effects were 10 secondary malignancy, 3 fatal cardiovascular events, and 1 late-onset transplant-associated thrombotic microangiopathy. Ten successful pregnancies were reported after allo-HCT. In multivariate analysis, older age (≥60 years) at transplant [hazard ratio (HR), 2.157; p = 0.004] and a high/very high disease risk index (HR, 1.913; p = 0.026) were significantly associated with a lower OS. CONCLUSIONS: Overall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m2) especially for the younger population.

Posttransplantation Cyclophosphamide- and Sirolimus-Based Graft-Versus-Host-Disease Prophylaxis in Allogeneic Stem Cell Transplant.

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising graft-versus-host-disease (GVHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) from haploidentical donors and more recently in matched donor transplants. Herein, we describe our real-life experience on 249 adult patients undergoing allogeneic HSCT, from HLA-matched related (MRD), HLA-matched unrelated (MUD), or mismatched related donors (MMRD). Patients received unmanipulated peripheral blood stem cells (PBSCs), using a GVHD prophylaxis with PTCy and sirolimus. Mycophenolate mofetil was added in MUD or MMRD. In the HLA-matched donor group (MRD, n = 48, MUD, n = 50), the cumulative incidence of grades II-IV and III-IV acute GvHD was 23% and 9% at 100 days, respectively. The cumulative incidence of chronic GvHD was 25% at 2 years, severe only for 5% of the patients. The cumulative incidences of relapse and transplant-related mortality (TRM) were 31% and 9% at 2 years, respectively. The 2-year overall survival (OS) was 72% and progression-free survival (PFS) 60%; the composite endpoint of GvHD/relapse-free survival (GRFS) was 52% at 2 years. In the haploidentical donor group (n = 151), we documented a cumulative incidence of grades II-IV and III-IV acute GVHD of 35% and 20% at 100 days, respectively, and a cumulative incidence of chronic GvHD of 39% at 2 years. We observed severe chronic GVHD in 15% of the patients. The cumulative incidence of relapse and TRM was 32% and 25% at 2 years, respectively. The 2-year OS was 48%, whereas PFS was 43%; GRFS was 28% at 2 years. However, more patients in the haploidentical group presented high/very high disease risk index (DRI) and higher HCT-comorbidity index. In patients classified in the low-intermediate DRI, 2-year GRFS was 53% in MRD, 65% in MUD, and 46% in haploidentical HSCT (P = .33). Sirolimus-PTCy platform deserves further investigation as an alternative to calcineurin-inhibitor-based GVHD prophylaxis for all donor sources. In patients presenting a low-intermediate DRI, this strategy translates in relevant survival independently from the transplant source.

Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide.

Background: Although the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically improved in the past decade, it is still compromised by transplant-related mortality (TRM), mainly caused by Graft-vs. -Host Disease (GvHD). Methods: We conducted a prospective observational study to ascertain the potential of serum interleukin-6 (IL6) levels, measured before conditioning and 7 days after allo-HSCT, in predicting acute GvHD, TRM and survival after allo-HSCT with Post-Transplant Cyclophosphamide (PT-Cy) based GvHD prophylaxis. Results: Between April 2014 and June 2017, we collected samples from 166 consecutive allo-HSCT patients. By ROC analysis, we identified a threshold of 2.5 pg/ml for pre-transplant IL6 and 16.5 pg/ml for post-transplant IL6. Both univariate and multivariate analyses confirmed the ability of high baseline IL6 levels to predict worse OS (HR 4.3; p < 0.01) and grade II-IV acute GvHD (HR 1.8; p = 0.04), and of high post-transplant IL6 to identify patients with worse OS (HR 3.3; p < 0.01) and higher risk of grade II-IV (HR 5; p < 0.01) and grade III-IV acute GvHD (HR 10.2; p < 0.01). In multivariate analysis, both baseline (HR 6.7; p < 0.01) and post-transplant high IL6 levels (HR 3.5; p = 0.02) predicted higher TRM. Conclusions: IL6 may contribute to the risk stratification of patients at major risk for aGvHD and TRM, potentially providing a window for additional prophylactic or preemptive strategies to improve the quality of life in the early post-transplant phase and the outcome of allo-HSCT.

Lung Ultrasound to Evaluate Invasive Fungal Diseases after Allogeneic Hematopoietic Stem Cell Transplantation / 감염과화학요법

Invasive fungal diseases (IFDs) are a leading cause of infection-related-mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In this prospective pilot study, we investigated the use of bedside lung ultrasound (US) in IFD management. Ten consecutive hematological patients, who developed pulmonary IFD after HSCT, were included in the study. Standard computed tomography scan and lung US were performed at IFD diagnosis and 10 days after antifungal treatment. The lung US demonstrated a high sensitivity in the detection of lung lesions at IFD diagnosis and in the follow-up examinations. It is of potential clinical relevance for IFD management in hematological patients.