Unusual oral presentation of acyclovir-resistant herpes simplex in an allogeneic haematopoietic stem cell transplant recipient

The early engraftment phase of allogeneic haematopoietic stem cell transplantation can be associated with a number of oromucosal infective complications. While the routine use of prophylactic acyclovir has reduced the incidence of herpes simplex virus (HSV) reactivation, there is an increasing prevalence of acyclovir resistance within this cohort of patients. The authors present a case of acyclovir-resistant HSV reactivation in a 26-year-old woman 7 days post T-deplete sibling allograft on a background of combined cyclophosphamide and total body irradiation myeloablative conditioning, successfully treated with foscarnet and cidofovir therapy and discuss the differential diagnoses for early/late engraftment oral disease.

CONDITIONING REGIMEN FOR LANGERHANS HISTIOCYTOSIS

Langerhans cell histiocytosis (LCH) is a rare disease, with an estimated incidence of 0.5 per 100,000 children in the United States of America1. HCL occurs due to differentiation of myeloid precursors into CD1a+ / CD207+ cells and is characterized by constitutional activation of the MAPK2 signaling pathway, leading to a spectrum of organ involvement and dysfunction. Treatment of HCL is risk-adjusted: single lesions may respond to local treatment whereas multisystem disease requires systemic therapy. Although survival for patients without organ dysfunction is excellent3, mortality in those with compromised organs at risk (hematopoietic system, liver, and/or spleen) reaches 20%2,4. Despite the progress made in the treatment of HCL, disease reactivation rates remain above 30% and the best second-line treatment has not yet been established. Treatment failure is associated with increased morbidity and mortality, including an association with neurodegeneration2. As it is a rare disease and generally has a good prognosis, few scientific studies are evaluating the role of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of this disease. In 2015 Veys et al5 published retrospective results of 87 high-risk patients transplanted between 1990 and 2013. Myeloablative conditioning regimens (MAC) based on total body irradiation or busulfan6 were the most used until the 2000s, and reduced-intensity conditioning regimens (RIC) – predominantly a combination of Melphalan and Fludarabine – were most used between 2000 and 2013. Transplant-associated mortality rates in 3 years were similar between RIC and MAC conditioning regimens (21% versus 15%, respectively). Recurrence was higher in the RIC group compared to the MAC group (28% versus 8%, respectively), however, the 3-year overall survival (OS) was similar (77% versus 71%, respectively), since the patients who relapsed after RIC transplantation could be rescued with chemotherapy. More recently, Kudo et al7 published a retrospective study with 30 patients with refractory LCH who underwent HSCT between 1996 and 2014. Eleven patients received myeloablative conditioning regimen based on total body radiotherapy (RCT) with a dose equal to or greater than 8 Gy or busulfan, and 19 of reduced intensity based on Fludarabine and Melphalan, associated or not with low dose of RCT. There was no significant difference between the conditioning regimen modalities, with OS of 56.8% for the RIC group and 63.6% for the MAC group. Disease status was the main prognostic factor, with a 5-year OS of 100% for patients who arrived at HSCT with disease in remission or with partial remission, versus 54.5% for those who had active disease at the time of the procedure. Regarding the type of donor used and the source of stem cells, there is great variation, with greater frequency for unrelated and extensive use of bone marrow and umbilical cord, and apparently, there is no impact on survival rates.5, 6 There are few case reports and extremely restricted performance of autologous HSCT in HCL.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. Disclosures Kang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Conditioning Intensity and Probability of Live Birth after Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: The observed inter-individual variability in the probability of live birth after BMT is due to exposure to gonadotoxic agents (including total body irradiation [TBI]), age at exposure to gonadotoxic agents, sex of the BMT recipient, and post-BMT morbidity. The last decade has seen an increase in use of non-myeloablative (NMA) conditioning to reduce the risk of early post-treatment mortality. However, the impact of TBI in the context of conditioning intensity (NMA vs. myeloablative conditioning [MAC]) on the probability of post-BMT live birth remains unknown. We addressed this gap by utilizing the BMTSS - a multi-institutional collaborative designed to understand the burden of morbidity after BMT. Methods: This study included 1,607 BMT survivors who underwent BMT between 1974 and 2014 at age ≤45, had survived ≥2y, and were ≥18y of age at study. This study also included pair-matched nearest-age, same-sex biologic siblings (≥18y of age at study) to control for genetic or environmental factors that could affect fertility. Survivors and their siblings completed the BMTSS survey. Sociodemographic characteristics (race/ethnicity, annual household income, availability of health insurance, level of education), chronic health conditions, medical assistance for fertility assistance and details about all pregnancies and their outcomes were retrieved from the BMTSS survey. Clinical characteristics were obtained from the institutional BMT databases and/or participants' medical record. Within survivor analysis: Potential risk factors for not reporting a live birth after BMT were analyzed using multivariable logistic regression. Exposure to TBI and conditioning intensity were consolidated to create four distinct exposure groups: no_TBI/NMA (least intense), TBI/NMA, no_TBI/MAC, TBI/MAC (most intense). Matched-pair comparison with biologic siblings: We matched 172 survivors with their closest-age, same-sex, biological siblings and used conditional logistic regression to determine the failure to report live birth in BMT survivors when compared with their siblings. Results: In this cohort of 1,607 survivors, 599 (37.3%) were autologous BMT recipients, and 765 (47.6%) were female. Median age at BMT was 30y, and at study participation was 45y (IQR: 18-73); median length of follow-up from BMT to study was 14.4y (IQR: 2.4-41.4). The primary indications for BMT included HL/NHL (30.6%), AML/MDS (24.3%), CML (13.4%), ALL (12.2%), and other diagnoses (13.5%). Of the 1,607 survivors, 120 (7.5%) reported one or more live births after BMT. Within survivor comparison: Multivariable analysis (Figure) revealed that receipt of TBI/MAC (OR=2.9, 95%CI: 1.5-5.8; ref: no_TBI/ NMA) was associated with an increased risk of not reporting a post-BMT live birth. Of note, TBI/NMA (OR=1.5, 95%CI, 0.5-5.0), and no_TBI/ MAC (OR=0.9, 95%CI, 0.4-2.0) were at a similar risk of reporting a post-BMT live birth as no_TBI/NMA. Other factors associated with increased risk of not reporting a post-BMT live birth included older age at BMT (>35y: OR=3.5, 95%CI, 1.4-7.9; reference: <12y), lower income ($50k-100k: OR=2.0, 95%CI, 1.1-3.6; <$50k: OR=3.2, 95%CI, 1.6-6.4; reference: >$100k), no medical interventions to facilitate pregnancy (OR=2.7, 95%CI, 1.6-4.6), and history of pre-BMT live birth (OR=2.7, 95%CI, 1.6-4.6). Matched-pair comparison with biologic siblings: Multivariable conditional logistic regression revealed that BMT survivors were less likely to report live birth (OR=0.5, 95%CI: 0.3-0.8) compared to their siblings. However, once pregnant, they were also less likely to report a miscarriage (OR=0.4. 95%CI: 0.2-0.8). Conclusion: While full dose TBI in the setting of myeloablative conditioning is associated with a lower probability of live birth after BMT, lower doses of TBI in the setting of myeloablative or reduced intensity conditioning yield a similar probability of live birth as no TBI. These findings provide evidence for alternative conditioning regimens for patients who wish to have children after BMT. Figure 1 Figure 1. Disclosures Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

Comparison of haploidentical and umbilical cord blood transplantation after myeloablative conditioning

Haploidentical hematopoietic stem cell transplantation (haplo HSCT) has emerged as an important treatment modality. Most reports comparing haplo HSCT with post-transplant cyclophosphamide (PTCy) and other donor sources have focused on outcomes in older adults treated with reduced intensity conditioning. Therefore, in the current study, we evaluated outcomes in patients with hematological malignancy treated with myeloablative conditioning prior to haplo (n=375) or umbilical cord blood (UCB, n=333) HSCT. All haplo recipients received a 4 of 8 HLA matched graft while recipients of UCB were matched at 6-8/8 (n=145) or ≤5/8 (n=188) HLA antigens. Recipients of 6-8/8 UCB transplants were younger (14 years vs. 21 and 29 years) and more likely to have lower co-morbidity scores compared to recipients of ≤5/8 UCB and haplo HSCT (81% vs. 69% and 63%, respectively). UCB recipients were more likely to have acute lymphoblastic leukemia and transplanted in second complete remission (CR) whereas haplo HSCT recipients were more likely to have acute myeloid leukemia in first CR. Other characteristics, including cytogenetic risk were similar. Survival at 3 years was similar for the donor sources (66% haplo and 61% after ≤5/8 and 58% after 6-8/8 UCB). Notably, relapse at 3 years was lower in recipients of ≤5/8 UCB (21%, p=0.03) compared to haplo (36%) and 6-8/8 UCB (30%). However, non-relapse mortality was higher in ≤5/8 UCB (21%) compared to other groups (p<0.0001). These data suggest that haplo HSCT with PTCy after myeloablative conditioning provides an overall survival outcome comparable to that after UCB regardless HLA match group.