Personalized Timing for Allogeneic Stem-Cell Transplantation in Hematologic Neoplasms: A Target Trial Emulation Approach Using Multistate Modeling and Microsimulation.

PURPOSE: Decision about the optimal timing of a treatment procedure in patients with hematologic neoplasms is critical, especially for cellular therapies (most including allogeneic hematopoietic stem-cell transplantation [HSCT]). In the absence of evidence from randomized trials, real-world observational data become beneficial to study the effect of the treatment timing. In this study, a framework to estimate the expected outcome after an intervention in a time-to-event scenario is developed, with the aim of optimizing the timing in a personalized manner. METHODS: Retrospective real-world data are leveraged to emulate a target trial for treatment timing using multistate modeling and microsimulation. This case study focuses on myelodysplastic syndromes, serving as a prototype for rare cancers characterized by a heterogeneous clinical course and complex genomic background. A cohort of 7,118 patients treated according to conventional available treatments/evidence across Europe and United States is analyzed. The primary clinical objective is to determine the ideal timing for HSCT, the only curative option for these patients. RESULTS: This analysis enabled us to identify the most appropriate time frames for HSCT on the basis of each patient's unique profile, defined by a combination relevant patients' characteristics. CONCLUSION: The developed methodology offers a structured framework to address a relevant clinical issue in the field of hematology. It makes several valuable contributions: (1) novel insights into how to develop decision models to identify the most favorable HSCT timing, (2) evidence to inform clinical decisions in a real-world context, and (3) the incorporation of complex information into decision making. This framework can be applied to provide medical insights for clinical issues that cannot be adequately addressed through randomized clinical trials.

Allogeneic haematopoietic cell transplantation for chronic myeloid leukaemia in Switzerland in the face of rapid development of effective drugs.

AIM: Until the year 2000, allogeneic haematopoietic cell transplantation (HCT) was the standard treatment for young and fit chronic myeloid leukaemia (CML) patients. CML was the main indication for allogeneic HCT. The introduction of tyrosine kinase inhibitors changed the treatment of CML patients dramatically. Allogeneic HCT was rapidly replaced by tyrosine kinase inhibitors as first-line treatment for CML, and the indication shifted to the treatment of non-responders, patients intolerant to tyrosine kinase inhibitors and patients whose CML is transforming to the accelerated phase and blast crisis. This paper describes changes in the use of transplantation technology for CML patients in the face of rapid drug development. METHODS: All patients receiving a transplant for CML between 1997 and 2021 in Switzerland were included in the study. For the purpose of this analysis, time periods were analysed in quinquennia, 1997-2001 (Q1), 2002-2006 (Q2), 2007-2011 (Q3), 2012-2016 (Q4) and 2017-2021 (Q5), as the observation period spanned 25 years. RESULTS: Overall, 239 patients received a transplant. These included 96 in Q1, 56 in Q2, 25 in Q3, 34 in Q4 and 28 in Q5. Patient characteristics changed over time: recent patients were older and had a longer interval from diagnosis to transplantation because of tyrosine kinase inhibitor treatment. However, the proportions of patients receiving transplants during an early versus advanced disease stage differed little. Transplant technology changed, as well. Patients received intensive conditioning regimens less often due to higher age and more commonly had peripheral blood as opposed to bone marrow transplants. However, the type of stem cell donor selected did not differ. In a univariable analysis, there were no significant differences in survival, progression-free survival, non-relapse mortality, relapse incidence or incidences of acute and chronic graft-versus-host disease among the five quinquennia. In a multivariable analysis, older age, donors other than HLA-identical siblings and more advanced disease stage, but not the quinquennium, were associated with higher risk of death. CONCLUSION: Since the introduction of tyrosine kinase inhibitors haematopoietic cell transplantation has been used less frequently to treat CML. Patients in recent cohorts received transplants at an older age and later in the disease course; despite these higher risks, the outcome of allogeneic HCT has not worsened over time but has not improved, either. As the outcome is worse in advanced phases, it is important to conduct transplants before disease progression. Therefore, patients with advanced disease should be monitored closely and receive transplants in time.

A phase I/II clinical trial of ex-vivo expanded human bone marrow derived allogeneic mesenchymal stromal cells in adult patients with perianal fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulas (PF) affect one-third patients with Crohn's disease (CD) with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells (BMSCs) in this population. METHODS: An open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn's disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically until week 104 , and MRI at week 24 and 104. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with < 2 cm perianal collection on MRI, and fistula response was decrease in drainage by ≥ 50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model. RESULTS: Ten patients (male:8, mean age:27.4 ± 12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index (P = 0.008), Van Assche Index (P = 0.008) and improvement in quality-of-life (P = 0.001) were observed over time. CONCLUSIONS: Allogeneic BMSCs are safe and effective for the treatment of perianal fistulizing CD with significant improvement in clinical severity and radiological healing. TRIAL REGISTRATION: The study was prospectively registered on Clinical trials registry - India (CTRI), CTRI/2020/01/022743 on 14 January 2020, http://ctri.nic.in .

Leveraging machine learning for predicting acute graft-versus-host disease grades in allogeneic hematopoietic cell transplantation for T-cell prolymphocytic leukaemia.

Orphan diseases, exemplified by T-cell prolymphocytic leukemia, present inherent challenges due to limited data availability and complexities in effective care. This study delves into harnessing the potential of machine learning to enhance care strategies for orphan diseases, specifically focusing on allogeneic hematopoietic cell transplantation (allo-HCT) in T-cell prolymphocytic leukemia. The investigation evaluates how varying numbers of variables impact model performance, considering the rarity of the disease. Utilizing data from the Center for International Blood and Marrow Transplant Research, the study scrutinizes outcomes following allo-HCT for T-cell prolymphocytic leukemia. Diverse machine learning models were developed to forecast acute graft-versus-host disease (aGvHD) occurrence and its distinct grades post-allo-HCT. Assessment of model performance relied on balanced accuracy, F1 score, and ROC AUC metrics. The findings highlight the Linear Discriminant Analysis (LDA) classifier achieving the highest testing balanced accuracy of 0.58 in predicting aGvHD. However, challenges arose in its performance during multi-class classification tasks. While affirming the potential of machine learning in enhancing care for orphan diseases, the study underscores the impact of limited data and disease rarity on model performance.

Successful allogeneic fecal microbiota transplantation for severe diversion colitis: a case report.

Ileostomy diverts the flow of feces, which can result in malnutrition in the distal part of the intestine. The diversity of the gut microbiota consequently decreases, ultimately leading to intestinal dysbiosis and dysfunction. This condition can readily result in diversion colitis (DC). Potential treatment strategies include interventions targeting the gut microbiota. In this case study, we effectively treated a patient with severe DC by ileostomy and allogeneic fecal microbiota transplantation (FMT). A 69-year-old man presented with a perforated malignant tumor in the descending colon and an iliac abscess. He underwent laparoscopic radical sigmoid colon tumor resection and prophylactic ileostomy. Follow-up colonoscopy 3 months postoperatively revealed diffuse intestinal mucosal congestion and edema along with granular inflammatory follicular hyperplasia, leading to a diagnosis of severe DC. After two rounds of allogeneic FMT, both the intestinal mucosal bleeding and edema significantly improved, as did the diversity of the gut microbiota. The positive outcome of allogeneic FMT in this case highlights the potential advantages that this procedure can offer patients with DC. However, few studies have focused on allogeneic FMT, and more in-depth research is needed to gain a better understanding.

Epstein-Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada.

Epstein-Barr virus-related post-transplantation lymphoproliferative disorder (EBV-PTLD) is a serious complication following hematopoietic stem cell transplantation (HSCT). A pre-emptive strategy using rituximab, which aims to manage patients early at the time of EBV reactivation to avoid PTLD, has been recommended by the most recent ECIL-6 guidelines in 2016. However, there is still a great heterogeneity of viral-load monitoring protocols, targeted patient populations, and pre-emptive treatment characteristics between centers, making precise EBV monitoring recommendations difficult. We conducted a literature review from the most recent publications between 1 January 2015 and 1 August 2023, to summarize the emerging data on EBV-PTLD prevention strategies in HSCT recipients, including the EBV-DNA threshold and use of rituximab. We also present the results of a survey of current practices carried out in 12 of the main HSCT centers across Canada. We confirm that pre-emptive rituximab remains an efficient strategy for EBV-PTLD prevention. However, there is an urgent need to perform prospective, randomized, multicentric trials with larger numbers of patients reflecting current practices to determine the best clinical conduct with regards to rituximab dosing, timing of treatment, and criteria to initiate treatments. Longer follow-ups will also be necessary to assess patients' long-term outcomes.

Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Peracetic acid sterilized tendon and ligament allografts for knee reconstruction : For anterior cruciate ligament (ACL), posterior cruciate ligament (PCL) and complex knee surgery.

BACKGROUND: The use of allografts and autografts has been met with mixed views on whether allografts are a suitable alternative to autografts. QUESTION: We aimed to investigate if chemically sterilized allografts show similar rerupture rates to those reported in the literature for allografts and autografts in anterior (ACL) and posterior cruciate ligaments (PCL) and complex knee surgery. MATERIALS AND METHODS: Retrospective data on knee reconstructions performed between 2011 and 2015 with tendon/ligamnet allografts sterilized with peracetic acid were collected in the form of a questionnaire. The inclusion criteria of 2 years for each patient were met by 38 patients, representing 22 ACL reconstructions, 5 PCL reconstructions, 3 OTHER surgeries, including the Larson technique and medial patellofemoral ligament (MPFL) reconstruction and 8 COMPLEX surgeries. The main endpoints were rerupture and complication rate. Secondary endpoints included stability of the knee (Lachman test, Pivot shift test) and the range of motion. RESULTS: The rerupture rate was 7.9% (3 grafts). Reruptures only occurred in the ACL group. No reruptures were observed in the PCL, OTHER and COMPLEX surgery groups. Stability improved significantly after surgery and the range of motion returned to values similar to that of healthy knees. CONCLUSIONS: Tendon allografts sterilized with peracetic acid show promising low rerupture rates and good clinical scores and the results are comparable to the literature on autografts and other allografts.

Two novel assays demonstrate persistent daratumumab exposure in a pediatric patient with delayed engraftment following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism. METHODS: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment. RESULTS: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted. CONCLUSIONS: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.

Comparing between HLA-matched sibling donor allogenic HSCT and non-sibling matched related donor allogenic HSCT outcome in pediatric patients; single center retrospective study.

BACKGROUND: Extended family donor search other than siblings may yield an HLA matched donor in communities with high rate of consanguinity. The outcome of patients who are transplanted from non-sibling matched related donors (NS-MRD) including engraftment and graft versus host disease (GVHD) are scarce in comparison with matched sibling donor (MSD). METHODS: We retrospectively reviewed the outcome of all our pediatric hematopoietic stem cell transplantation (HSCT) patients who had non-sibling matched related donor and controlled them with matched sibling donor HSCT (based on age, indication of HSCT, conditioning regimen, GVHD prophylaxis, serotherapy, stem cell source and cytomegalovirus status). RESULTS: A total of 76 patients were reviewed during study period. Thirty patients (39.5%) in NS-MRD arm and 46 patients in MSD (60.5%) were identified after matching in age, disease, and conditioning regimens. All patients had similar approach including stem cell source and GVHD prophylaxis (CNI + 2nd agent). Out of the NS-MRD group, 18 patients (59%) had one of their parents as a donor and the rest as second degree relatives. Both groups were equally distributed and were homogeneous. Both groups had no statistically significant difference in outcome including engraftment, GVHD and Chimerism tests results. GVHD was seen in (13%) NS-MRD patients compared to (11%) in MSD patients. All patients remain alive with median follow up of 1249 days (431-3525). CONCLUSIONS: This study showed no significant difference in allogenic HSCT outcomes between matched sibling donors and non-sibling matched related donors and support using the same management approach in terms of conditioning therapy, GVHD prophylaxis, and serotherapy only if indicated.

Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model.

Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.

Impact of early cyclosporine A levels on acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation using in vivo T-cell depletion.

BACKGROUND AIMS: Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS: To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS: CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS: Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.

Second line extracorporeal photopheresis for cortico-resistant acute and chronic GVHD after allogeneic hematopoietic cell transplantation for hematological malignancies: Long-term results from a real-life study.

BACKGROUND & OBJECTIVES: The primary objective of this observational study was to perform an exhaustive description concerning patients receiving extracorporeal photopheresis (ECP) as second line treatment after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes. STUDY DESIGN: A total of 106 patients were included, 65 (61%) males and 41 (39%) females with a median age at transplantation of 52 years (range: 20-67). ECP was initiated after transplantation either for acute GVHD [N = 25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N = 5), gut alone (N = 12), gut and liver (N = 8), or chronic GVHD [N = 81 (76%), 15 (14%) limited and 66 (62%) extensive]. RESULTS: Among the 25 patients treated for acute GHVD, 67% were responders and among the 81 patients with chronic GVHD, 78% were responders. Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14-56]. Patients with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56-78]. There was a significant difference in terms of survival for patients responding to ECP compared to non-responders in both acute and chronic GVHD forms. Acute GVHD grade III-IV, negatively impacted on OS (HR=7.77, 95%CI: 1.7-34), p = 0.007 and on disease relapse HR= 5.88, 95%CI: 1.7-20, p = 0.005. CONCLUSION: We demonstrated that ECP is an effective treatment for GVHD in a good proportion of patients with high overall response rate.

The effectiveness of acellular nerve allografts compared to autografts in animal models: A systematic review and meta-analysis.

BACKGROUND: Treatment of nerve injuries proves to be a worldwide clinical challenge. Acellular nerve allografts are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous nerve graft. OBJECTIVE: To systematically review the efficacy of the acellular nerve allograft, its difference from the gold standard (the nerve autograft) and to discuss its possible indications. MATERIAL AND METHODS: PubMed, Embase and Web of Science were systematically searched until the 4th of January 2022. Original peer reviewed paper that presented 1) distinctive data; 2) a clear comparison between not immunologically processed acellular allografts and autologous nerve transfers; 3) was performed in laboratory animals of all species and sex. Meta analyses and subgroup analyses (for graft length and species) were conducted for muscle weight, sciatic function index, ankle angle, nerve conduction velocity, axon count diameter, tetanic contraction and amplitude using a Random effects model. Subgroup analyses were conducted on graft length and species. RESULTS: Fifty articles were included in this review and all were included in the meta-analyses. An acellular allograft resulted in a significantly lower muscle weight, sciatic function index, ankle angle, nerve conduction velocity, axon count and smaller diameter, tetanic contraction compared to an autologous nerve graft. No difference was found in amplitude between acellular allografts and autologous nerve transfers. Post hoc subgroup analyses of graft length showed a significant reduced muscle weight in long grafts versus small and medium length grafts. All included studies showed a large variance in methodological design. CONCLUSION: Our review shows that the included studies, investigating the use of acellular allografts, showed a large variance in methodological design and are as a consequence difficult to compare. Nevertheless, our results indicate that treating a nerve gap with an allograft results in an inferior nerve recovery compared to an autograft in seven out of eight outcomes assessed in experimental animals. In addition, based on our preliminary post hoc subgroup analyses we suggest that when an allograft is being used an allograft in short and medium (0-1cm, > 1-2cm) nerve gaps is preferred over an allograft in long (> 2cm) nerve gaps.

The indirect effects of CMV reactivation on patients following allogeneic hematopoietic stem cell transplantation: an evidence mapping.

Cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a challenging problem, and the impact on the risk of overall mortality (OM) and non-relapse mortality (NRM) in patients following allo-HSCT is still controversial. Utilizing the evidence mapping method, we aimed to assess the effect of CMV infection on outcomes of patients post-transplantation and identify research gaps through systematic reviews (SRs) and clinical studies. PubMed, EMBASE, Web of Science, and Cochrane library databases were searched from inception until 5 July 2022 to identify relevant literature. After systematic literature screening and data extraction, evidence mapping of the effects of CMV reactivation on patients post-allo-HSCT was conducted. Three SRs and 22 clinical studies were included. In one SR, CMV reactivation was associated with an increased risk of mortality (HR 1.46; 95% CI, 1.24-1.72; P ≤ 0.001). In two SRs, CMV reactivation was associated with NRM. One SR reported CMV reactivation was potentially associated with significant protection against relapse in patients with acute myelocytic leukemia (AML), but no significant correlation with graft-versus-host disease (GVHD) was found. Lastly, in one SR CMV reactivation significantly increased the risk of invasive fungal disease (IFD). Most clinical articles reported that CMV reactivation increased the risk of renal dysfunction, poor graft function, re-hospitalization, and bacterial infections. CMV reactivation following allo-HSCT is associated with an increased risk of OM, NRM, IFD, and renal dysfunction, as well as a reduced risk of relapse in patients with AML.

Short-Term Outcomes After Bipolar Osteochondral Allograft Transplantation (OCAT) in the Ankle.

Treatment options for symptomatic cartilage loss in the ankle are not consistently effective. This study documents initial outcomes for patients undergoing bipolar OCAT in the ankle after advances in tissue preservation, transplantation techniques, and patient management strategies were implemented. Patients were prospectively enrolled into a registry designed to follow outcomes after OCAT in the ankle. Fourteen patients were included for analyses (12 primary OCAT, 2 revision OCAT). Four patients underwent Bipolar OCAT (tibia, talus) and 10 Bipolar+ OCAT (tibia, talus, fibula). Short-term (median follow-up 43, range 13-73 months) success was documented for 13 patients. Radiographic assessments indicated OCA integration and maintenance of joint space in 12 patients. Statistically significant (p < .030) and clinically meaningful improvements in AAOS and VAS pain scores were noted at 3 months, 6 months, 1 year, and 2 years following OCA transplantation when compared to preoperative measures. For patients that were nonadherent to postoperative restriction and rehabilitation protocols, all 1-year postoperative PROs were significantly lower (p < .050) than for patients who were adherent. The successful outcomes documented in 13 of 14 patients in conjunction with significant and clinically meaningful improvements in patient-reported measures of pain and function support OCA transplantation as an appropriate treatment option in indicated patients. These improvements in outcomes were associated with advances in OCA preservation, preimplantation treatment, transplantation techniques, and patient management strategies, suggesting this shift in practice be considered for OCA transplantation in the ankle.

Utilization Trends of Nerve Autograft Alternatives for the Reconstruction of Peripheral Nerve Defects.

BACKGROUND: Autologous nerve grafting is the time-honored reconstruction method for peripheral nerve gaps. However, it is associated with donor-site morbidities. A growing number of studies have demonstrated the effective use of decellularized nerve allograft and synthetic conduits, which are convenient options with no donor deficit. The specific aim of this study was to characterize changes in practice trends for peripheral nerve defect reconstruction. METHODS: The authors queried the 2015 to 2020 Merative MarketScan Databases for patients who underwent nerve autograft, allograft, synthetic conduit, and/or vein graft reconstruction. Patient demographic data (ie, location, indication) and hospital characteristics (ie, facility, provider type) were recorded. Regression analysis identified changes in trends over the study period. RESULTS: A total of 4331 patients underwent one or more nerve gap reconstructive procedures over the study period. Since the introduction of allograft CPT code in 2018, segmented mixed effect longitudinal modeling revealed that allograft utilization significantly increased from 21.5% to 29.6% after 2018 ( P < 0.001), whereas nerve autograft use decreased from 18.6% to 15.8% and conduit use decreased from 60% to 54.7% ( P = 0.09 and P = 0.03, respectively). When stratifying autograft by size, use of autograft less than or equal to 4 cm significantly decreased from 10.6% to 7.7% after 2018 ( P = 0.03), and autograft greater than 4 cm did not. When stratifying by state, there is heterogeneity in utilization rates of each product. CONCLUSION: After creation of a designated allograft CPT code in 2018, there was an increase in allograft use with concomitant decrease in conduit and short length autograft use, suggesting that allograft replaced a portion of procedures used in short nerve gap reconstruction.

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

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