Nutritional interventions in patients with graft-versus-host disease.

PURPOSE OF REVIEW: This review aims to highlight the benefits of nutrition before and during graft-versus-host disease (GvHD) and the promising precision medicine approach that should be offered to prevent and mitigate GvHD. RECENT FINDINGS: The intestinal damage induced by preconditioning/conditioning chemotherapies is the main trigger of GvHD. Impaired nutritional status and decreased plasma citrulline level, which is the most sensitive biomarker of intestinal barrier health, predict the occurrence of acute GvHD after allogeneic hematopoietic cell transplantation (allo-HCT). Optimal oral and/or enteral nutrition and a lack of vitamin D deficiency limit this intestinal damage. As intestinal dysbiosis plays an important role in GvHD, probiotics and prebiotics supplementation could be a promising therapy. Diverting enterostomy combined with parenteral nutrition saves the lives of patients with severe steroid-refractory gastrointestinal GvHD. SUMMARY: Regardless of age, healthy nutritional status and a healthy gut barrier are protective factors against GvHD in patients undergoing allo-HCT, and above all, these are closely dependent on adequate oral and/or enteral intake. Therefore, maintaining gut barrier integrity through adequate oral nutrition before allo-SCT and early first-line enteral nutrition after allo-HCT are of critical importance, not forgetting vitamin D supplementation. In the future, probiotics and prebiotics are expected to play a growing role for replenishing the commensal microbiota given the impact of gut dysbiosis on GvHD. Parenteral nutrition remains the only nutritional support that can be used in the event of severe gastrointestinal GvHD.

Upfront Alternative Donor Transplant versus Immunosuppressive Therapy in Patients with Severe Aplastic Anemia Who Lack a Fully HLA-Matched Related Donor: Systematic Review and Meta-Analysis of Retrospective Studies, on Behalf of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation.

Idiopathic aplastic anemia is a rare and life-threatening disorder, and hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the standard treatment strategy for young patients. Alternative donor transplantation (ADT) from a matched unrelated donor or an HLA haploidentical donor is not commonly used in the frontline setting. This systematic review/meta-analysis was conducted to compare ADT as an upfront, rather than delayed, treatment strategy in the absence of an MSD to immunosuppressive therapy (IST) in severe aplastic anemia (SAA). We searched PubMed/MEDLINE and Embase (1998 to 2019) for studies that compared the outcomes of ADT with IST as upfront therapy in patients with SAA. We included studies with 5 patients or more in each arm. Studies that included patients with inherited forms of bone marrow failure syndromes were excluded. The primary outcome was the 5-year overall survival (OS) rate. Five studies met the inclusion criteria and were included in this meta-analysis. The pooled 5-year odds ratio (OR) for OS was statistically significant at 0.44 (95% confidence interval [CI], 0.23 to 0.85) in favor of upfront ADT. In addition, survival was compared between upfront ADT versus salvage ADT in 6 studies. The pooled 5-year OR for OS was statistically significant at 0.31 (95% CI, 0.15 to 0.64) in favor of upfront ADT. Although this analysis has some limitations, including the retrospective nature of the included studies, the lack of ethnic diversity, the predominantly pediatric population, and the relatively suboptimal IST regimen used in some of the studies, it indicates that upfront ADT is a potential alternative treatment option in young and pediatric SAA patients who lack an HLA identical sibling donor, particularly when optimal IST is not available. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Epidemiology and clinical profiles of cutaneous graft versus host disease in allogeneic peripheral blood stem cell transplantation.

INTRODUCTION: The epidemiology of cutaneous graft versus host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (PBSCT) in Malaysia has not been described. MATERIALS AND METHODS: We retrospectively analysed 691 allogeneic PBSCT patients between 2010-2017 in two centers. RESULTS: The prevalence of cutaneous GVHD was 31.4% (217/691). No associations were detected with race, age or gender of donor and recipients. Cutaneous GVHD was associated with host cytomegalovirus (CMV) seropositivity (p<0.01), conditioning (p<0.01), GVHD prophylaxis (p=0.046) and survival (p<0.01). Majority developed the acute form (58.1%;126/217). Biopsies in 20.7% (45/217) showed 55.6% positivity for GVHD. Overall, involvement was non-severe. A majority demonstrated complete response (CR) to first-line corticosteroids (70.0%;152/217). Secondline therapies (extracorporeal phototherapy (ECP), psolaren ultraviolet A (PUVA), mycophenolate, tumour necrosis factor (TNF) inhibitors, interleukins inhibitors, or CD20 monoclonal antibodies) were required in 65/217, with 38.5% CR. Second-line therapy was associated with gender (p=0.042), extra-cutaneous GVHD (p=0.021), treatment outcomes (p=0.026) and survival (p=0.048). Mortality in cutaneous GVHD was 24.0% with severe sepsis being the leading cause at Day 100 (7.8%) and 5-years (7.8%), and relapsed disease at 2-years (32.7%). In steroid refractoriness, severe GVHD caused 30.8% mortality. In cutaneous GVHD, survival at Day 100 was 95.4%; 80.2% at 2-years and 73.1% at 5-years. The median survival in cutaneous GVHD was significantly shorter at 55 months, compared to those without GVHD at 69 months (p=0.001). CONCLUSION: Cutaneous involvement is the commonest clinical manifestation of GVHD. A larger national study is warranted to further analyse severity and outcome of multiorgan GVHD, and factors associated with steroid refractoriness.

Impact of anti-thymocyte globulin dose for graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation from matched unrelated donors: a multicenter experience.

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6-7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.

Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donors.

BACKGROUND: Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD. METHODS: Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis RESULTS: No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis. CONCLUSION: These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.

Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Using Tacrolimus/Sirolimus-based GvHD Prophylaxis: Impact of HLA Mismatch.

BACKGROUND: While tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS: Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor HCT (2005-2013) with T/S-based GvHD prophylaxis. RESULTS: With a median follow-up of 6.2 years (range = 2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95% confidence interval [CI]: 43.0-52.0) and 43.6% (95% CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of nonrelapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% versus 50.7% at 5 y; P = 0.034), primarily due to greater risk of NRM (33.5% versus 21.7%; P = 0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% versus 12.8%; P = 0.022) and infection (33.0% versus 18.1%; P < 0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (hazard ratio [HR] = 2.21, 95% CI: 1.16-4.23; P < 0.01) and mMUD (HR = 1.55, 95% CI: 1.15-2.08; P = 0.004) were independent predictive factors for OS. CONCLUSIONS: T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.

Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms.

PURPOSE: The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D. PATIENTS AND METHODS: Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day -5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays. RESULTS: We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, P interaction < 0.001). CONCLUSIONS: Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.

Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure.

BACKGROUND: Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated. METHODS: This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM). RESULTS: Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P < .0001). CONCLUSIONS: Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018;124:2541-51. © 2018 American Cancer Society.

Epidemiology and Outcomes of Hematopoietic Stem Cell Transplantation in Human Immunodeficiency Virus-Positive Patients From 1998 to 2012: A Nationwide Analysis.

Background: Prior studies have shown that outcomes of hematopoietic stem cell transplantation (HSCT) in human immunodeficiency virus (HIV)-positive patients have been similar to outcomes in HIV-negative patients since effective implementation of highly active antiretroviral therapy by 1998, but they are limited by small sample size or noninclusion of recent data. Methods: We queried National Inpatient Sample, a large inpatient data set in the United States, from 1998 to 2012 for HSCT, using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure code 41.0. HIV-positive patients were identified by the presence of ICD-9-CM diagnostic codes 042, 043, 044, V08, and 079.53. The primary outcome was in-hospital mortality rate, and the secondary outcome the in-hospital complication rate of HSCT. Outcomes were assessed by means of univariate, multivariate regression and matched-pair analysis. Results: A total of 39517 patients who underwent HSCT were identified. Among these, 108 patients had HIV infection. There were no differences in in-hospital mortality rates or rates of intubation, sepsis, bacteremia, or graft-vs-host disease between HIV-positive and HIV-negative patients after allogeneic or autologous HSCT. In allogeneic HSCT, HIV-positive patients had a significantly higher incidence of nontuberculous mycobacterial and cytomegalovirus infection than HIV-negative patients. Conclusion: Although HIV-positive patients may have a higher risk of certain opportunistic infections, they are not at higher risk of serious in-hospital complications of HSCT. Allogeneic and autologous HSCT can be safely performed in HIV-positive patients.

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.

BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. METHODS: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. FINDINGS: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37). INTERPRETATION: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications. FUNDING: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.

Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation.

The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT.

Pretransplantation use of the second-generation tyrosine kinase inhibitors has no negative impact on the HCT outcome.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) was a standard therapy in chronic phase (CP) chronic myeloid leukemia (CML). As a result of the effective therapy with tyrosine kinase inhibitors (TKI), HCT was shifted to defined clinical situations. We present the results of observational prospective analysis of 28 CML patients undergoing HCT after exposure to, at least, two lines of TKI (including dasatinib and/or nilotinib), with respect to response, overall survival (OS), treatment toxicity, graft versus host disease (GVHD), and progression/relapse incidence. RESULTS: All the patients but one engrafted with median time 19 days. OS for patients in CP1 and CP2/accelerated phase (AcP) were 92.9 and 85.7 %, respectively. Six patients allotransplanted in blast crisis (BC) CML died early after HCT. Eighteen patients achieved deep molecular remission (MR(4.5) or MR(4.0)). Relapse incidence was 29.6 %. Median time to progression (TTP) differs significantly depending on the CML phase prior to HCT, the best response achieved after HCT and development of chronic GvHD. NRM yielded the values 7.1, 12.5, and 50 % in CP1, CP2/AcP, and BC, respectively. Fatal outcome, due to veno-occlusive disease (VOD), was observed in two (7 %) patients. In five (17.9 %) patients, mild or moderate VOD was observed with no negative impact of preceding therapy with TKI2. Acute GvHD was diagnosed in 25.9 % of patients, while chronic GvHD developed in 42.9 % of individuals. CONCLUSION: Pretransplantation therapy with TKI2 in CP CML is safe and reasonable. In BC, the optimal approach before HCT is to reduce the leukemic burden and achieve subsequent CP.

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation.

Vitamin D has emerged as a central player in the immune system, with its deficiency being implicated in the pathogenesis of several autoimmune diseases, including chronic GvHD. This is a retrospective cohort analysis of 166 patients, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Karolinska University Hospital, evaluating GvHD, graft failure, infectious complications and survival after HSCT in relation to pre-transplantation vitamin D levels. Most of the patients were deficient in vitamin D before HSCT (median 42 nmol/L). In multivariate analysis, vitamin D level before HSCT was identified as a significant independent risk factor for development of cGvHD. The increased incidence of cGvHD was not coupled to better disease-free survival; instead there was a trend towards lower overall survival in the vitamin D-deficient patients. In addition, we found a significant correlation between vitamin D deficiency and incidence of CMV disease, with no case of CMV disease occurring in patients with sufficient levels of vitamin D before HSCT. Our results support a role of vitamin D in immune tolerance following HSCT. These findings could be highly relevant for the care of HSCT patients, and prospective, randomized studies on the effect of vitamin D supplementation are therefore needed.

Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.

Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted. (clinicaltrials.gov: NCT01385124).

[Use of glutamine in total parenteral nutrition of bone marrow transplant patients]. / Uso de la glutamina en la nutricion parenteral total de pacientes sometidos a trasplante de médula ósea.

UNLABELLED: Glutamine is an essential amino acid for nucleotide synthesis and an important energy resource for cellular division. There is contradictory evidence about its benefits as part of parenteral nutrition. More than 75% of bone marrow transplant patients (BMTP) have, during their evolution, digestive tract complications limiting enteral nutrition, for this reason, sometimes total parenteral nutrition (TPN) is required. OBJECTIVE: Our aim was to analyze the relation between the use of glutamine in TPN of BMTP, and the evolution of clinical acute complications as mucositis, graft versus host disease (GVHD) and infections days of stay and days of TPN. MATERIALS AND METHODS: observational retrospective study. All BMTP with total parenteral nutrition during the period 2007-2013 were included. We analyzed days of stay, days of nutrition, glutamine use and acute complications. Results were analyzed in SPSS 15.0. RESULTS: 73 BMTP were divided in two comparable groups depending on glutamine use. The mean age was 36,96 ± 12,89 years. 47,9% of patients received glutamine in TPN. Patients who received glutamine had a mean stay of 31,49±7,41 days with 14,11±5,87 days of TPN compared with the non-glutamine group with 32,16±7,99 and 15,50±7,71 days respectively (p=0,71 y 0,39). Mucositis lasted 12,23±5,66 days in the glutamine group, and 15,50±7,71 days in the non-glutamine group (p=0,042). Severe grades of GVHD (II,III) was observed in 20,6% of the non glutamine group compared with the 13,7% of the other group (p=0,636). In patients with glutamine suplementation, mucositis last 12,23±5,66 days compared with 15,50±7,71 days in the non-glutamine group (p=0,042).13,7% of all patients suffered infections while receiving TPN with glutamine compared with 16,4% in patients who did not receive glutamine (p=0,700). CONCLUSION: In our group, a statistically significant reduction in the duration of mucositis was observed in patients who received parenteral glutamine.

La glutamina es un amioácido esencial para la síntesis de nucleótidos y una fuente de energía para la replicación celular, existe evidencia contradictoria respecto a los beneficios de su administración como parte de la nutrición parenteral en pacientes sometidos a trasplante de médula ósea (TMO). Más del 75% de los pacientes sometidos a trasplante de precursores hematopoyéticos, presentan durante su evolución complicaciones que comprometen el tracto digestivo, principalmente mucositis, limitando la ingesta oral, de allí la necesidad del uso de nutrición parenteral total (NPT) en estos casos. Objetivo: Analizar la relación entre uso de glutamina en la NPT de TMO y la evolución de complicaciones agudas como mucositis, EICH e infecciones, así como la estancia hospitalaria y los días de nutrición parenteral total. Material y métodos: Estudio observacional retrospectivo. Se incluyeron la totalidad de TMO con NPT entre 2007 y 2013 en nuestro hospital. Se analizaron días de hospitalización, días de soporte nutricional, uso de glutamina y complicaciones agudas. Los resultados se analizaron con el programa SPSS 15.0. Resultados: Se incluyeron 73 pacientes trasplantados, se dividieron en dos grupos según el aporte de glutamina siendo ambos grupos comparables entre sí. La edad media fue de 36,96±12,89 años. El 47,9% de los pacientes estudiados recibió suplemento de glutamina en la NPT. Los pacientes que recibieron glutamina tuvieron una estancia media de 31,49±7,41 días con 14,11±5,87 días de NPT en comparación a los que no recibieron glutamina con 32,16±7,99 y 15,50±7,71 días respectivamente (p=0,71 y 0,39). La duración de la mucositis en los pacientes que recibieron glutamina fue de 12,23±5,66 días comparado con 15,50±7,71 días en los que no recibieron glutamina (p=0,042).Se observaron grados severos de EICH (II, III) en un 20,6% de los pacientes sin glutamina en comparación al 13,7% en los que la recibieron (p=0,636). . Del total de los pacientes estudiados, el 13,7% sufrieron complicaciones infecciosas mientras recibían NPT con glutamina, comparado con 16,4% en pacientes que no recibieron (p=0,700).Conclusiones: En nuestra serie, se observó una reducción estadísticamente significativa en la duración de la mucositis en pacientes que recibieron NPT con glutamina.

A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor.

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.

Intravenous BU plus Mel: an effective, chemotherapy-only transplant conditioning regimen in patients with ALL.

We investigated the administration of i.v. BU combined with melphalan (Mel) in patients with ALL undergoing allogeneic hematopoietic SCT. Forty-seven patients with a median age of 33 years (range 20-61) received a matched sibling (n=27) or matched unrelated donor transplant (n=20) for ALL in first CR (n=26), second CR (n=13), or with more advanced disease (n=8). BU was infused daily for 4 days, either at a fixed dose of 130 mg/m² (5 patients) or using pharmacokinetic (PK) dose adjustment (42 patients), to target an average daily area-under-the-curve (AUC) of 5000 µmol/min, determined by a test dose of i.v. BU at 32 mg/m². This was followed by a rest day, then two daily doses of Mel at 70 mg/m². Stem cells were infused on the following day. The 2-year OS, PFS and non-relapse mortality (NRM) rates were 35% (95% confidence interval (CI), 23-51%), 31% (95% CI, 21-48%) and 37% (95% CI, 23-50%), respectively. Acute NRM at 100 days was favorable at 12% (95% CI, 5-24%); however, the 2-year NRM was significantly higher for patients older than 40 years, 58% vs 20%, mainly due to GVHD.

Vitamin D level after allogeneic hematopoietic stem cell transplant.

Vitamin D (VD) deficiency can cause osteomalacia, bone pain, muscle weakness, fatigue, and increased risk of fracture, and may precipitate or exacerbate osteopenia and osteoporosis. Patients receiving treatment for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) may have limited exposure to sunlight and often experience gastrointestinal side effects that may decrease their ability to maintain an adequate VD level. We hypothesized that patients with AML and ALL would have a low VD level after allogeneic hematopoietic cell transplant (HCT), and that these patients would have a high incidence of osteoporosis/osteopenia. We therefore studied the incidence of low VD level and low bone mineral density after HCT. Of 289 patients with AML or ALL undergoing HCT between January 1, 2000, and January 31, 2009, at the Cleveland Clinic, 58 (20.1%) patients had VD testing after HCT. Of these, 52 (89.7%) patients had a low VD level, and 6 (10.3%) had a normal level. Most patients with VD testing had graft-versus-host disease (GVHD) and were taking corticosteroids (94.8% and 98.3%, respectively). Of the 49 patients with VD testing who also had bone mineral density testing, 65% had abnormal (low bone density) results. Only 21% of patients with VD testing were taking VD supplements prior to testing, and 65% had an elevated parathyroid hormone level. We found that most patients did not have VD testing after HCT, but those that did were very likely to have a low level and have low bone mineral density. Those with a low VD level were likely to have received corticosteroids, have GVHD, and have an elevated parathyroid hormone (PTH) level. Given the potential morbidity of low VD level, VD deficiency should be considered after HCT. Prospective study of VD level and its impact on morbidity and mortality after HCT is warranted.

25-hydroxy vitamin D deficiency following pediatric hematopoietic stem cell transplant.

Children may be at increased risk for vitamin D deficiency following HSCT because of lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, malabsorption, and the use of certain medications. We prospectively assessed the prevalence of and risk factors for 25-hydroxy (25-OH) vitamin D deficiency in 67 patients transplanted at our institution. 25-OH vitamin D levels were checked during 3 separate 4-week periods in the spring, autumn, and winter. Subjects were <2 years following transplant and/or being treated for chronic graft-versus-host disease (cGVHD). Levels less than 20 ng/mL were considered deficient, and those less than 30 ng/mL were considered insufficient. The mean 25-OH vitamin D level was 22.8 ng/mL (range: 7-46.2). A total of 80.6% (confidence interval [CI] 69.1%-89.3%) of patients had a level less than the lower limit of the institutional normal range. The deficiency rate was 37.3% (CI 25.8%-50%). The mean parathyroid hormone (PTH) level was 77.5 (SD = 80.5). There was no correlation between 25-OH vitamin D and PTH levels. We evaluated potential risk factors for 25-OH vitamin D deficiency including age, season of testing, sun exposure, sunscreen use, use of steroid or calcineurin inhibitor, race, and dairy intake. In multivariate logistic regression, only older age was found to be a risk factor for deficiency (P = .004). Patients with deficient levels were treated with 50,000 IU of ergocalciferol once weekly for 6 weeks. A postrepletion 25-OH level was available for 22 patients. The majority of repleted patients had a normal posttreatment level (63.6%). The postsupplementation level corrected into the insufficient range for 31.8% of patients and 4.6% remained deficient. Vitamin D insufficiency and deficiency are common following HSCT. Further investigation into potential risk factors and the appropriate supplementation for these patients is warranted.

Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire.

This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.