Severe Graft-versus-host Disease Research Articles

Pembrolizumab for the treatment of disease relapse after allogeneic hematopoietic stem cell transplantation.

A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Although targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. Therefore, we developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8patients with acute myeloid leukemia, 1 patient with myelodysplastic syndrome, 1 patient with classical Hodgkin lymphoma, and 2 patients with diffuse large B-cell lymphoma [DLBCL]). All participants received reduced-intensity preparative regimens with invivo T-cell depletion. The median time from alloHCT to enrollment was 587 days (range, 101-4211). Three participants (25%) experienced grade 3 to 4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1 to 2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. irAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response (CR) rates were 22% (2/9). Both patients achieving CRs hadPD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pretreatment biopsies. An acquired EZH2 mutation was identified at relapse in a patient with DLBCL who achieved an initial CR to pembrolizumab, which was associated with downregulated HLAexpression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism after PD-1-blockade therapy. In conclusion, after alloHCT, treatment with pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies but can induce severe irAEs, requiring vigilant monitoring. Thistrial was registered at www.clinicaltrials.gov as #NCT02981914.

A Successful Bridge Therapy Combining Hypomethylating Agents with Venetoclax for Adult Patients with Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia

Recently, the combination of VEN-HMA has been shown to achieve durable responses in patients with both newly diagnosed (ND) and R/R-AML. We retrospectively evaluated the post-allo-HCT outcomes of 50 patients who received VEN-HMA therapy. In total, 10 were ND and 40 were R/R and, at the time of HCT, the median age was 53 years. In the ND- and R/R-AML groups, the percentage of patients who achieved CR/CRi or MLFS was 90% and 92.5%, respectively. In all, after a median follow-up of 13.7 months, the probabilities of overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) at 1 year were 63.7%, 59.3%, 28.5%, and 12.2%, respectively. In addition, the cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and moderate-severe chronic GVHD at 1 year were 28.4% and 37.4%, respectively. In multivariate analysis, the factors associated with a statistically significant impact on OS were VEN-HMA cycle (p = 0.021), ELN risk group (p = 0.041), and the response to VEN-HMA therapy before allo-HCT (p = 0.003). Although 80% of our patients had R/R-AML and 30% underwent a second allo-HCT, our data still suggest that allo-HCT following VEN-HMA therapy is a safe and effective treatment option.

Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis.

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

Anti-E. coli Immunoglobulin Yolk (IgY): Reduction of pathogen receptors and inflammation factors could be caused by decrease in E. coli load

Graft versus host disease (GVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation, especially for intestinal GVHD, as steroid resistant GVHD results in high mortality. For this reason, new treatments of GVHD are needed. One approach is the reduction of pathogenic bacteria using anti-E. coli Immunoglobulin Yolk (IgY). In a haploidentical murine model, B6D2F1 mice conditioned with total body irradiation (TBI), received bone marrow cells (BM) and splenocytes (SC) from either syngeneic (Syn = B6D2F1) or allogeneic (Allo = C57BL/6) donors. Following this, animals received from day −2 until day +28 chow contained IgY or control chow. Thereafter the incidence and severity of aGVHD, the cytokines, chemokines, IDO1 and different pathogen-recognition receptors (PRR) were analyzed and compared to control animals (received chow without IgY). We found that animals receiving chow with IgY antibody showed reduced GVHD severity compared to control animals. On day28 after alloBMT, IDO, NOD2, TLR2, TLR4 and the inflammatory chemokine CCL3, were reduced in the colon and correlated with a significant decrease in E. coli bacteria. In summary chow containing chicken antibodies (IgY) improved GVHD via decrease in bacterial load of E coli conducting to reduction of pathogen receptors (NOD2, TLR2 and 4), IDO, chemokines and cytokines.

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.

There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P= .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P= .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

Degradation of band3 and PRDX2 in erythrocytes during severe acute GVHD.

We investigated the proteins of erythrocytes from stem cell transplantation patients and found decreased expression of band3 and C-terminal-truncated peroxiredoxin 2 (PRDX2) only during severe graft-versus-host disease (GVHD), using time-of-flight mass spectrometry (TOF-MS) analysis and Western blotting. During the same period, PRDX2 dimerization and calpain-1 activation were observed, indicating severe oxidative stress. We also found a putative cleavage site for calpain-1 in the C-terminal-truncated site of PRDX2. Decreased band3 expression impairs the plasticity and stability of erythrocytes, and C-terminal-truncated PRDX2 induces irreversible dysfunction of antioxidant activity. These effects may exacerbate microcirculation disorders and the progression of organ dysfunction.

Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation

The severity of Tcell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic Tcells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in a host intestinal HIF-1α- and a microbiome-dependent manner. Regulation of intestinal ambient oxygen levels with oral iron chelation mitigated dysbiosis and reduced the severity of the GI GVHD. Thus, targeting ambient intestinal oxygen levels may represent a novel, non-immunosuppressive strategy to mitigate Tcell-driven intestinal diseases.

Comparison of the effect of DLI according to cell sources in relapsed AML after allogeneic stem cell transplantation

For relapsed acute myeloid leukemia (AML) patients who received allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion (DLI) is an effective therapy. However, the cell source of DLI remains a topic of debate. In this study, we aimed to compare the efficacy and safety of G-CSF mobilized cells (G-DLI) with conventionally collected DLI (C-DLI). A total of 81 patients (50 C-DLI vs. 31 G-DLI) were assessed for clinical outcomes. There were no statistically significant differences in the baseline characteristics between the two groups including AML risk, donor types, interval from relapse to DLI, and infused CD3+ cell count. Although not statistically significant, complete remission (CR) and chimerism conversion rates were higher in G-DLI than in C-DLI: 51.6% vs. 28.0%, P = 0.057 and 42.3% vs. 28.2%, P = 0.363, respectively. There was no difference in acute graft-versus-host disease (GVHD) incidence and severity of acute GVHD between the two groups. The median overall survival (OS) of the G-DLI and C-DLI groups was 139 days and 106 days, respectively (P = 0.58). In conclusion, G-DLI appears to be a safe and an equally efficacious substitute for C-DLI, which is more readily available.

Impact of Post-Transplantation Cyclophosphamide on Transfusion Requirements in HLA-Matched Sibling Peripheral Blood Stem Cell Transplantation

Post-transplant cyclophosphamide (PT-Cy)-based graft-versus-host disease (GVHD) prophylaxis is progressively being used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donors (MRD). However, information regarding the transfusion needs in this setting is lacking. to compare red blood cell (RBC) and platelet units transfused and time to transfusion independence according to the GVHD prophylaxis in MRD HSCT. We performed a matched-pair analysis comparing the transfusion requirements and the clinical outcomes of patients who received a MRD peripheral blood HSCT using PT-Cy from January 2017 until June 2021 (n = 100) with historical MRD transplants using standard cyclosporine A-based prophylaxis (n = 100). Neutrophil engraftment was significantly delayed in the PT-Cy group as compared with the CsA group (16 days vs. 13 days; P = 0.003). PT-Cy was associated with increased RBC (median, 5 units vs. 4; P = 0.04) and platelet transfusion requirements (median, 6 units vs. 3; P = 0.01) during the first 30 days after transplant. The proportion of patients requiring platelet transfusion during days 31 to 90 after transplant was also higher in the PT-Cy cohort (55% vs. 25%; P < 0.0001). In multivariate analysis, PT-Cy was associated with delayed RBC and platelet transfusion independence ([Hazard ratio [HR] = 0.61; P = 0.007 and HR = 0.51; P < 0.0001, respectively). Cumulative incidence at 100 days of BK polyomavirus (BKPyV)-associated haemorrhagic cystitis grade ≥ 2 was higher in the PT-Cy cohort (34% vs. 12%; P < 0.0001). However, PT-Cy resulted in lower rates of acute GVHD grade II-IV (100-days cumulative incidence 57% vs. 23%; P < 0.0001) and moderate to severe chronic GVHD (1-year cumulative incidence 49% vs. 28%; P = 0.003), as well as improved 2-year overall survival (74% vs. 56%; P = 0.01). Our study shows that PT-Cy increases transfusion burden in MRD HSCT. However, it results in a low incidence of severe GVHD, with encouraging survival outcomes.

Selection strategy for graft source in 2023

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) grafts have expanded from related human leukocyte antigens (HLA)-matched donors to unrelated HLA-matched donors and umbilical cord blood. Either one of these grafts is now available for almost all patients who need allo-HSCT. Furthermore, an allo-HSCT from an HLA one haplo-mismatched donor can be safely performed with cyclophosphamide administration after transplantation. Graft-versus-host disease (GVHD) and graft-versus-leukemia effects are inextricably linked in allo-HSCT, and a transplant with more GVHD-associated complications is not necessarily a worse transplant as a graft selection indicator. Transplants with severe GVHD have fewer relapses, which offset the negative effects. This study presents data to guide graft selection by comparing transplant outcomes from different donor sources. The current position of post-transplant cyclophosphamide haplo from HLA-one haplo mismatched donor is also discussed based on data presented to date.

Utility of eGVHD App for bedside GVHD assessment in a high-volume BMT center.

Assessing acute and chronic graft-versus-host disease (GVHD) is challenging because there are several classification systems. The European Society for Blood and Marrow Transplantation and the Center for International Bone Marrow Transplantation Registry task force recommends using the eGVHD application (App) to score acute GVHD according to the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria and chronic GVHD according to the National Institutes of Health 2014 criteria. We prospectively used the eGVHD App at each follow-up visit in a large-volume bone-marrow transplant center in India from 2017 to 2021. We retrospectively evaluated the discrepancy in scoring GVHD severity by physicians not using the App from the same patient charts. The App user satisfaction and experience were recorded using the technology acceptance model (TAM) and the Post-Study System Usability Questionnaire (PSSUQ). In 100 consecutive allogeneic hematopoietic cell transplantation recipients, there was more discrepancy in scoring the severity of chronic GVHD (38%) than acute GVHD (9%) without using the App. The median TAM and PSSUQ scores were six (IQR:1) and two (IQR:1), respectively, indicating high perceived usefulness and user satisfaction. The eGVHD App is an excellent learning tool for hematology/BMT fellows and helps manage GVHD in high-volume BMT centers.

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., &amp;lt;7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (&amp;lt;6/8) HCT recipients (75% vs. 76%, respectively; P &amp;gt;0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = &amp;gt;0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

Role of abatacept in the prevention of graft-versus-host disease: current perspectives.

Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. Equivalent results are being reported in recent studies using alternative donors, in reduced-intensity conditioning HSCT and nonmalignant disorders. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD. This review summarized all the limited reports of this novels approach in the HSCT setting.

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective.

Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.

Antithymocyte Globulin Plus Post-Transplant Cyclophosphamide Combination as an Effective Strategy for Graft-versus-Host Disease Prevention in Haploidentical Peripheral Blood Stem Cell Transplantation for Children with High-Risk Malignancies.

Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this setting. The addition of antithymocyte globulin (ATG) in PTCy-based regimens for GVHD reduction in haploidentical hematopoietic stem cell transplantation is rational and was reported in adult series. However, its feasibility is unknown in pediatric patients. Here, we firstly describe our experience of 15 consecutive children with high-risk malignancies receiving haploidentical peripheral blood stem cell transplantation using ATG plus PTCy for GVHD prophylaxis. Only three patients developed grade 1-2 acute GVHD, limited to skin. No grade 3-4 acute GVHD and chronic GVHD were observed. Viral reactivations were frequently seen but manageable. Six patients relapsed, as the main cause of death in our series. None died from events related to GVHD. Our data suggest that ATG plus PTCy is an effective strategy for GVHD prevention in haploidentical peripheral blood stem cell transplantation and is feasible in children with high-risk malignancies.

Patient-reported symptom burden and impact on daily activities in chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) treatment for hematologic malignancies. There are limited patient-reported data concerning symptom burden and effects on activities of daily living (ADL). The cross-sectional Living With Chronic GVHD Patient Survey was administered online in the United States (May-August 2020) to participants aged ≥18 years who underwent allogeneic HSCT, were diagnosed with chronic GVHD by a healthcare provider, and self-reported active chronic GVHD (within past 5 years). Information on patient demographics, disease characteristics, symptom burden, and ability to perform ADL was collected. Symptom burden was assessed using the validated Lee Symptom Scale (range from 0-100 with higher scores indicating greater burden). All data were summarized using descriptive statistics; no formal statistical comparisons were conducted. Out of 580 participants who entered the survey screener, 165 participants (28.4%) across 33 states fulfilled all study eligibility criteria, completed the entire survey, and were included (age: mean [SD], 53.7 (13.8) years; median [range], 57.0 [18-78] years; female, n= 105 [63.6%]; White, n= 137 [83.0%]). Respondents described their chronic GVHD severity primarily as moderate (n= 54 [32.7%]) or severe (n= 102 [61.8%]) at the time when symptoms were at their worst. One-third of respondents (33.9%) indicated that their chronic GVHD symptoms were at their worst for ≥1year in duration. Mean (SD; range) Lee Symptom Scale score was 44.8 (19.4; 2-100); 44% of respondents considered "dry eye" the most burdensome symptom. Almost half of respondents (n= 73 [44.2%]) rated their overall quality of life (QoL) as poor. Participants reported a detrimental impact of symptoms on ADL, including basic activities (eg, eating, personal hygiene, dressing). Survey respondents self-reported high chronic GVHD symptom burden and felt that their symptoms severely interfered with physical function and ADL. Effective strategies to mitigate chronic GVHD symptoms are needed to improve QoL among HSCT survivors.

Allogeneic Hematopoietic Stem Cell Transplant Outcomes in Adults with Inherited Myeloid Malignancies

Recognition of hereditary hematopoietic malignancies (HHMs) has accelerated in recent years, with deleterious germline variants in more than 20 genes recognized as drivers of myeloid malignancies. Individuals with HHMs generally receive similar treatment plans as those with de novo disease. Hematopoietic stem cell transplantation (HSCT) is often employed as a curative approach for myeloid malignancies, and in those with germline pathogenic (P)/likely pathogenic (LP) predisposition variants, there is a preference for use of related donors who lack the familial variant. However, there are limited data on the outcomes of patients with HHMs who are treated in this manner. In this study, we used comprehensive clinical and genomic data to investigate the allogeneic transplant-related outcomes in the largest international myeloid HHM cohort reported to date. We performed a retrospective analysis of all patients with myeloid malignancies who underwent germline predisposition testing at The University of Chicago (UofC) or the Central Adelaide Health Network between 2010 and 2021; or were known to have deleterious germline DDX41 variants from the University of Pennsylvania and Moffitt Cancer Center. We studied 472 patients, of whom 28% (80/289) in the UofC cohort and 20% (35/175) in the Adelaide cohort had a deleterious germline variant causative of HHMs. In the UofC cohort, P/LP CHEK2 variants were the most common, whereas P/LP DDX41 variants were most common in the Adelaide cohort (Fig. 1). A total of 161 patients (34% of the entire cohort) underwent allogeneic HSCT for their myeloid neoplasm (Table 1). There were no differences in the distribution of diagnoses, donor types, disease status at the time of HSCT (remission vs active disease), conditioning regimens, or conditioning intensity. All donor cells were mobilized from peripheral blood. Almost all donors lacked the deleterious germline causative variant, with one donor sharing a deleterious familial DDX41 variant with the relative/HSCT recipient. The median time to engraftment was similar between those who had vs lacked germline HHM variants. Patients with P/LP germline DDX41 variants had higher rates of severe (stage 3-4) acute graft versus host disease (GVHD) when compared to patients with P/LP CHEK2, those with other germline variants, or those without P/LP germline variants (38% vs 0, 12%, and 9%, respectively; p=0.002). Notably, severe gastrointestinal GVHD was seen in a third of patients with P/LP germline DDX41 variants as opposed to <10% incidence in other groups (p<0.001, Table 1). Similarly, 33% of patients with P/LP germline DDX41 variants experienced moderate to severe chronic GVHD, whereas this incidence was 29% for patients with P/LP germline CHEK2 variants, 4% for patients with other P/LP germline variants, and 10% for patients without a P/LP inherited variant (p=0.008). Patients with P/LP germline DDX41 variants who received post-HSCT cyclophosphamide had lower rates of severe acute GVHD compared to those who received other forms of GVHD prophylaxis (0% vs 53%, p=0.03). To adjust for the effects of known GVHD risk factors, we performed a multivariable logistic regression analysis. Germline DDX41 status remained an independent predictor of both acute GVHD (OR: 4.76, range 1.27-17.9; p=0.01) and chronic GVHD (OR: 3.39, range 1.09-10.5; p=0.03). Importantly, post-HSCT cyclophosphamide use was associated with a reduced risk of acute GHVD when adjusted for other variables (OR: 0.10, range 0.01-0.71; p=0.008). Our data establish severe GVHD as a clinically relevant post-transplant phenomenon in germline DDX41-associated HHMs and suggest that donor-derived wild-type T-cells may become activated by a pro-inflammatory milieu conferred by P/LP germline DDX41 variants. Moreover, our observations suggest that post-HSCT cyclophosphamide is an effective strategy for GVHD prevention in these individuals. Broader confirmation of our results in other heterogeneous patient cohorts will serve to expand the spectrum of known pathogenic variants implicated in HHMs and support the development of targeted interventions for those with deleterious germline HHM alleles. Finally, these results argue for germline genetic testing in patients prior to allogeneic HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Advanced Machine Learning Techniques to Predict Gvhd Occurrence and Severity with High Accuracy

Introduction Graft versus host disease (GVHD) after allo-HSCT is dependent on conditioning regimen, GVHD prophylaxis, HLA matching, as well as recipient-donor discrepancies in sex, age, and CMV status. GVHD is a leading cause of transplant-related mortality with incidence varying between 30% to 70%. Few machine learning (ML) models have been implemented to accurately quantify a patient's risk for aGVHD development and subsequent severity with mixed results, utilizing various ML methodologies of analyzing clinical data, genetic differences, and biomarkers. Comparing across four different ML algorithms, we demonstrate exceptionally high accuracy for prediction of acute GVHD occurrence, severity (Grade I-II vs III-IV), disease relapse, and survival. Materials and Methods Data on 868 adult patients (age 18-76) that received either MA or RIC for any transplant indication between January 2004 and July 2018 at The Ohio State University James Cancer Center was analyzed. Predictive models were developed utilizing four different machine learning algorithms: logistic regression, k-nearest neighbors (KNN), decision tree with hyperparameter tuning, and multilayer perceptron (MLP) neural networks. Models were trained and tuned using K-fold cross validation, and prediction performance was quantified by the receiving operating characteristic area-under-the-curve (ROC AUC) and accuracy. Features included patient demographics (age, gender, KPS/ECOG, race, disease type, disease status, donor type, graft type, sex match, HLA match, conditioning regimens groups, use of (ATG), use of alemtuzumab, GVHD prophylaxis type, date of engraftment, date of aGVHD diagnosis, organ involvement of aGVHD, steroid treatment, specific steroid therapy, date of chronic GVHD diagnosis, relapse date, date of death, and cause of death was collected. The dataset was preprocessed through the standardization of numerical features and encoding of categorical features. This dataset was separated pre-analysis into cohorts - 70% exploratory and 30% validation. Results All 868 patients were included, verified, and data cleaned. The algorithms predicted with high accuracy - >80% for GVHD occurrence and >90% for Grade I-II and Grade III-IV acute GVHD, relapse, and survival. MLP provided the most accurate predictions when compared to decision tree, KNN and logistic regression algorithms. SHapley Additive exPlanations (SHAP) analysis was used to demonstrate the top 20 features contributing to the overall output. SHAP analysis for acute GVHD occurrence is shown for MLP algorithm with age and HLA match as the most critical features. Conclusions We demonstrate the results of utilizing advanced ML algorithms for highly accurate prediction of acute GVHD occurrence, severity (Grade I-II vs III-IV), disease relapse, and survival. The difference between the models' performances may be due to the disproportionate sizes of cohorts in Grade III-IV acute GVHD as opposed to relapse and survival analyses. The risk factors identified as being most influential in affecting outcomes by our ML algorithms are consistent with those historically reported. While the importance of these features are similar to prior models, the ability of the models used to generate highly accurate results is novel contribution. The improved accuracy of our methods compared to previous reports may be due to several factors. MLP algorithm with one or two layers have ample hidden neurons to find patterns to achieve superior and robust classification for GVHD. Such deep learning models have not been used in prior classification. Decision trees also provide higher accuracy compared to KNN and regression due to the deterministic nature of the model which automates feature selection. Our single center data may also present a more homogeneous population with decreased variability of practice and GVHD prophylaxis approaches. Further studies to validate these algorithms in a more recent cohort are planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in Gvhd Risk without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate

Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning (MAC) is currently the standard of care for young and fit patients; however, graft-versus host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one that combines strategies to reduce the incidence and severity of GVHD, without compromising graft versus-tumor effect. We hypothesized that the GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of chronic GVHD in patients receiving a standard MAC HCT without an increase in risk of malignant relapse. Methods This is an analysis of a phase II study at the University of Minnesota using a MAC regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 μmol/min/L) plus fludarabine 160mg/m2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. We compared those results to our previous MAC protocol which utilized a regimen of either cyclophosphamide (60mg/kg days -6 and -5)/TBI (1320 cGy administered twice a day from days -4 to -1) or busulfan (0.8 mg/kg/dose IV in 4 daily doses days -9 to -6 [total 12.8 mg/kg])/ cyclophosphamide (50 mg/kg days -5 to -2) and GVHD prophylaxis consisted of cyclosporine and methotrexate. Results Through June 2022, we treated 125 patients with a median follow up of 472 days post-transplant. Of those, 48% were female and 22 (17.6%) were ≤ 18 years old with median age at HCT of 38 years (range, 1-59 yrs; Interquartile range [IQR], 22-50 yrs). Donor source was 8/8 MRD in 69 patients (55.2%), 8/8 MUD in 44 (35.2%), and 7/8 MUD in 12 (9.6%). Graft source was bone marrow in 43 patients (34.4%) and PB in 82 (65.6%). Preparative regimen was TBI in 89.6% of patients. 124 of 125 patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-30). 119 of 125 achieved platelet engraftment by 6 months, median 25.5 days (range, 14-98). 91 patients (72.8%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by day +100 was 16% (95% confidence interval (CI): 9-23%); Grade III-IV acute GVHD was 4% (CI: 0-8%). No patients experienced grade IV GVHD and there were no deaths due to GVHD. At 1 year, only 3 of 105 patients developed chronic GVHD requiring immune suppression, for a cumulative incidence of 4% (CI: 0-8%). Two-year cumulative incidence of relapse was 25% (CI: 15-36%). Two-year overall survival was 80% (CI: 69-87%) and two-year GVHD-free relapse free survival (GRFS) was 57% (CI: 45-67%). Kaplan-Meier curves comparing overall survival and GRFS between this cohort and our previous MAC protocol without PTCy are shown in Figure 1. Figure 2 shows the comparison between these two consecutive cohorts in incidence of acute and chronic GVHD, transplant-related mortality (TRM) and relapse. Discussion Myeloablative HCT with a TBI or Busulfan/Fludarabine-based preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in extremely low incidence of chronic GVHD, the primary objective of this clinical trial. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes could potentially be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ruxolitinib in Acute and Chronic Graft-Versus-Host Disease: Real Life Experience in a Multi-Centre Study

Introduction The JAK1/2 inhibitor ruxolitinib has been approved for the treatment of adults and paediatric patient ≥12 years with steroid refractory graft-versus-host disease (GvHD) based on the REACH-2 and 3 studies. However, real-life studies are needed to validate the results of clinical trials and assess its efficacy in specific organs, particular population groups such as paediatric patients, and possibility to reduce immunosuppression. Moreover, these pivotal studies focused on ruxolitinib after failure to corticosteroids and showed no data about its efficacy after more than one previous line of treatment. Methods A descriptive, retrospective, multi-centre study of adult and paediatric patients (<14 years) treated with ruxolitinib for steroid-refractory acute or chronic GvHD from 16 Spanish hospitals belonging to the Spanish Transplantation Group (GETH) between October 2015 and June 2022. The severity of GvHD was evaluated according to the Glucksberg/Magic/Harris criteria for acute GvHD and according to the international consensus of National Institutes of Health (NIH) for chronic GvHD. Results A total of 366 patients were analysed: 324 adults and 42 paediatric patients. Their baseline characteristics and response and toxicity data are described in Tables 1 and 2. Adult patient group. In acute GvHD, overall response (OR) was observed in 57.6% of patients after a median of 2 weeks of treatment, and 30.7% achieved complete remission (CR). Dose of corticosteroids was reduced in 63.5% of patients. Cytopenias grades ≥3 were observed in 11.3% of patients. Infections included CMV replication (51%), fungal infection (19.2%) and herpes zoster (6.7%). Twelve patients relapsed of their underlying disease. Sixty-six patients died due to: GvHD 17 (25.7%), relapse 4 (6%), infection 36 (54.5%) and other 9 (13.6%). The median overall survival (OS) was 4.1 months, and at 2 years the OS was 28.8% (95%CI: 19.1-39.2). Median follow-up was 2.8 months (range: 0.1-71.6). In chronic GvHD, the OR was 65.6% and was obtained after a median of 4 weeks of treatment; 18% achieved CR. OR in patients with scleroderma, gastrointestinal tract (GI) or lung involvement was 66.6%, 76% and 42%, respectively. The dose of corticosteroids was reduced in 68.3% and ruxolitinib was tapered in 37.9% of patients. Cytopenias grades ≥3 were observed in 5% of patients. Infections included CMV replication (14%), fungal infection (11.3%) and herpes zoster (5%). Seventeen patients relapsed of their underlying disease. Fifty-three patients died due to: GvHD 13 (24.5%), relapse 4 (7.5%), infection 23 (43.3%) and other 12 (22.6%). The median OS was not reached, and at 2 years the OS was 78.9% (95%CI: 72.5-84). Median follow-up was 26.8 months (range: 0.4-77). Paediatric patients. In acute GvHD, 82.7% of patients with aGvHD responded after a median of 2 weeks of treatment and 51.7% achieved CR. Corticosteroids were reduced in 79.3% and ruxolitinib in 34.4% of patients. Cytopenias occurred in 3.4% of patients. Infections included CMV replication (34.5%), fungal infection (10.3%) and herpes zoster (17.2%). Four patients relapsed of their underlying disease. Eleven patients died due to: GvHD 3 (27.2%), relapse 2 (18.8%), infection 3 (27.2%) and other 3 (27.2%). The median OS was not reached, and at 2 years the OS was 59.2% (95%CI: 38.2-75.1). Median follow-up was 8.9 months (range: 0.4-59.5). In chronic GvHD, OR was 100% after a median of 4 weeks of treatment and 23% achieved CR. Corticosteroids and ruxolitinib were reduced in 69.2% and 23% of patients, respectively. Cytopenias occurred in 7.7%. Infections included CMV replication (23.1%), fungal infection (15.4%) and herpes zoster (7.7%). Only 1 patient died due to relapse of the underlying disease; there were 2 relapses in total. The median OS was not reached, and at 2 years the OS was 100%. Median follow-up was 43.1 months (range: 0.9-59.6). Conclusions 1. Ruxolitinib in the real world setting, showed similar results in terms of responses to clinical trials. In the paediatric population, the data are more favourable: Acute GvHD: 7%; chronic GvHD: 100%. 2. Results seems not be influenced by line of treatment (≥3). 3. By organ, main benetifs in cGvHD were seen in scleroderma (66.6%) and GI (76%) of the affected patients. 4. 5% of adult patients and 79.3% of children with acute GVHD were able to reduce the dose of corticosteroids, while these figures were 68.3% and 69.2% for chronic GvHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal