Allogeneic HCT Research Articles

Impact of muscle mass loss assessed by computed tomography on the outcome of allogeneic stem cell transplantation

The definition of sarcopenia assessed by computed tomography (CT) varies among different reports, and few studies have examined the effect of muscle mass loss on the prognosis of post-hematopoietic cell transplantation (HCT). We retrospectively evaluated 172 patients who underwent an initial allogeneic HCT for acute leukemia at our institution. They were divided into 3 groups according to muscle mass measured at the third lumbar vertebra as assessed by CT. Patients with low muscle mass had a worse performance status, higher comorbidity index and higher disease risk. There was a significant difference in 2-year overall survival between the 3 groups, and worse overall survival (OS) was associated with lower muscle mass (p = 0.005). Muscle mass loss did not affect non-relapse mortality (p = 0.238) but was significantly associated with relapse (p = 0.067). Pre-transplant muscle mass loss may therefore reflect a poor prognosis for the primary disease.

Acute GVHD, BK virus hemorrhagic cystitis and age are risk factors for transplant-associated thrombotic microangiopathy in adults

AbstractHematopoietic cell transplantation–associated thrombotic microangiopathy (TMA) is a complication associated with higher nonrelapse mortality (NRM) in patients who undergo allogeneic transplant (HCT). Current classification criteria are not generally agreed on or validated, and the presence of confounding factors after transplant contribute to underdiagnosis or delayed diagnosis of TMA. We studied risk factors, incidence, and biomarkers of TMA in 119 adult allogeneic HCT recipients. Twenty-seven patients developed a clinically actionable phenotype of TMA (CA-TMA) and the incidence of CA-TMA was 22% by day 180. Among the 27 patients who developed CA-TMA, 10 developed it before the onset of acute graft-versus-host disease (aGVHD), and 17 patients developed it after the onset of aGVHD. We report for the first time that age >50 years, BK hemorrhagic cystitis, and other viral infections (CMV, HHV-6, or adenovirus) are risk factors for adult CA-TMA. Even after adjustment for aGVHD, CA-TMA was independently associated with significantly higher NRM. These data illustrate relationships between CA-TMA and aGVHD, describe new risk factors for CA-TMA and emphasizes the need to develop validated set of criteria for timely diagnosis.

1384. Practice Variations in Pre-Hematopoietic Stem Cell Transplantation Infectious Disease Evaluation

BackgroundHematopoietic stem cell transplantation (HCT), and other forms of cellular therapies such as chimeric antigen receptor T cell therapy (CAR-T), while of critical therapeutic value, confers significant, long-term risk of infectious complications. Recipients would benefit from evaluation by infectious disease (ID) specialists. However, amidst many existing guidelines from ID and oncology societies, pre-transplant ID evaluation and management practices vary across US institutions. To better understand these variations and identify targets for standardization, we conducted a survey of ID and oncology providers at transplant centers in the US.MethodsA 38-question, anonymous, voluntary, online survey was distributed via Google Forms to a professional organization e-mail list of ID providers as well as to followers of relevant Twitter accounts. Responses were collected and analyzed.ResultsA total of 51 responses were received, the majority of which (68.6%) came from ID providers. 60.8% of respondents worked at healthcare facilities with over 500 beds. 43 respondents (84.3%) reported that their center performed autologous and allogeneic HCT as well as CAR-T. 56.8% of CAR-T centers use a standardized template, compared to 70.8% of those providing HCT. For allogeneic HCT centers, 8% reported that no ID evaluation is offered; 34% reported that it is offered “sometimes.” Practices varied for treatment of latent tuberculosis infection prior to HCT: 26.5% treat “All the time;” 10.2% treat “Very rarely.” In assessing risk factors, only 63% and 54% identified HIV infection and healthcare occupation, respectively, as epidemiologic risk factors for tuberculosis infection. 59.2% answered that < 10% of patients are screened for Strongyloides. Only 5 respondents reported universal Strongyloides screening prior to transplant. COVID-19 vaccination for family is recommended “Always” by 95.5% of respondents. 25% have offered influenza vaccination to family through the transplant clinic.Table 1 Differences in ID evaluation practices by type of cellular therapy candidate.Table 2 Characteristics of survey respondents.ConclusionPractices around pre-HCT infectious disease evaluation and management are heterogenous among the centers surveyed. The adoption of standardized screening for and management of infectious diseases in this patient population would likely be beneficial.Disclosures All Authors: No reported disclosures

20. Risk Factors for Breakthrough Cytomegalovirus (CMV) Infection and De Novo Resistance in Hematopoietic Cell Transplantation (HCT) Recipients Receiving Letermovir Prophylaxis

BackgroundSubclinical CMV reactivation on letermovir prophylaxis may be important for CMV-specific immune reconstitution after HCT (Zamora et al. Blood 2021) but concerns remain regarding the development of antiviral resistance. Here we analyze risk factors associated with breakthrough CMV infection on letermovir and describe the incidence of de novo letermovir resistance.MethodsAll CMV-seropositive, allogeneic HCT recipients who received letermovir prophylaxis from 10/2018-2020 were analyzed. Weekly proportions and cumulative incidences of CMV reactivation in the first 100 days post-HCT were calculated at different levels. Clinically significant CMV infection was treated preemptively with (val)ganciclovir or foscarnet. Univariable/multivariable Cox regression models for breakthrough CMV reactivation at each viral threshold were performed. Patients with CMV reactivation ≥ 200 IU/mL were tested by UL56 sequencing to identify de novo letermovir resistance.ResultsTwo hundred thirty HCT recipients who received letermovir prophylaxis were identified. Weekly proportions and cumulative incidences of CMV reactivation are shown in Figure 1. Nine of 15 patients with CMV reactivation had sufficient serum for letermovir resistance testing. One C325Y mutation was identified in an umbilical cord blood transplant recipient who developed 4 weeks of CMV DNAemia with a peak of 2512 IU/mL. The patient received 56 days of letermovir prior to reactivation and responded to treatment initially with foscarnet (due to cytopenias) followed by ganciclovir. Greater cumulative steroid exposure was associated with increased risk of CMV reactivation and the association remained statistically significant at any level (adjusted Hazard Ratio [aHR] 10.8 mg/kg*days, 95% confidence interval [CI] 5.18-22.7) and ≥ 150 IU/mL (aHR 15.9 mg/kg*days, 95% CI 7.07-35.6) after adjusting for underlying disease and GVHD prophylaxis (Figure 2). ConclusionLetermovir prophylaxis was effective at preventing clinically significant CMV infection but subclinical reactivation continued to occur. Cumulative steroid exposure was the strongest risk factor for reactivation while on letermovir. Development of de novo letermovir resistance on prophylaxis occurred infrequently.Disclosures Michael Boeckh, MD PhD, AlloVir (Consultant)Ansun Biopharma (Grant/Research Support)Astellas (Grant/Research Support)EvrysBio (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Gilead Sciences (Consultant, Grant/Research Support)GlaxoSmithKline (Consultant)Helocyte (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Janssen (Grant/Research Support)Kyorin (Consultant)Merck (Consultant, Grant/Research Support)Moderna (Consultant)Symbio (Consultant)Takeda (formerly known as Shire) (Consultant, Grant/Research Support)VirBio (Consultant, Grant/Research Support) Alexander L. Greninger, MD, PhD, Abbott (Grant/Research Support)Gilead (Grant/Research Support)Merck (Grant/Research Support)

Post-Transplantation Cyclophosphamide for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Higher-Risk Myelodysplastic Syndrome

Introduction: Allogeneic hematopoietic cell transplantation is an only potentially curative option for patients with higher-risk myelodysplastic syndrome (MDS). Owing to the advances in treatment strategies including reduced intensity conditioning, graft-versus-host disease (GVHD) prevention and supportive care, more elderly patients or those with comorbidities can proceed to allogeneic HCT. However, the long-term survival rate following allogeneic HCT is reported to be less than 50%, and non-relapse mortality (NRM) rate is still high reaching upto 30%. In this study, we aimed to evaluate the feasibility of using post-transplantation cyclophosphamide (PTCy) as a GVHD prophylaxis in allogeneic HCT for higher-risk MDS patients. We also compared the post-transplantation outcomes of PTCy group and those of historical control who received HCT using anti-thymocyte globulin (ATG).Methods: Patients with higher-risk MDS or MDS/myeloproliferative neoplasm (MPN) with bone marrow blast ≥ 5% were included in this study. Higher-risk MDS was defined by MDS with International Prognostic Scoring System >1.0 or bone marrow blast ≥ 5% at any time points before HCT. Conditioning regimen consists of busulfan (4-days for patients aged <55 years, 2-days for 55 years), fludarabine. For GVHD prophylaxis, PTCy (50 mg/kg on days 3 and 4), cyclosporine, and mycophenolate mofetil were administered. In historical group, patients received 2- or 4-days of busulfan, fludarabine, and ATG with short course of methotrexate and cyclosporine.Results: Ninety-two and 144 patients received allogeneic HCT using PTCy and ATG, respectively. The median overall survival were 47.9 and 44.0 months, respectively (P=.383). Cumulative incidence of total and grade II-IV acute GVHD in PTCy and ATG group were 19.6% vs. 37.5% (P=.002), and 2.6% vs. 21.7% (P<.001), respectively. Incidence of total and extensive chronic GVHD (50.0% vs. 49.1%, P=.567; 32.5% vs. 33.4%, P=.581), 1-year NRM (20.8% vs. 22.9%, P=.702), and 2-year relapse (16.0% vs. 18.1%, P=.605) were not different between two groups. Neutrophil and platelet engraftment was significantly faster with ATG than PTCy (median 12 vs. 15 for neutrophil; median 15 vs. 24 days for platelet).Conclusion: Allogeneic HCT using PTCy as GVHD prophylaxis in higher-risk MDS seems feasible in terms of low rate of acute GVHD and relapse incidence. DisclosuresChoi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board.

Gvhd Targets Organoid-Forming Biliary Epithelial Stem Cells Via a TGF-β-Dependent Manner

[Introduction] Graft-versus-host disease (GVHD) is a potentially life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that GVHD targets adult tissue stem cells in the gut and skin, while a role of liver tissue stem cells in hepatic GVHD remains to be clarified. Biliary epithelial cells (BECs) are primary targets in hepatic GVHD and a single BEC stem cell gives rise to multipotent liver organoids (Cao W: Gastroenterology 2017). We studied the fate and role of BEC stem cells in experimental hepatic GVHD. [Methods] B6D2F1 recipients were lethally irradiated and transplanted with 5 x 10 6 splenocytes plus 5 x 10 6 bone marrow cells from allogeneic (B6) or syngeneic (B6D2F1) donors on day 0. Liver organoids were generated from the bile ducts isolated from the liver right lobe. [Results] Flowcytometric analyses of the liver demonstrated donor T cell infiltration in the liver within the first week after allo-HCT, followed by massive infiltration of monocytes and macrophages. Hepatic GVHD was characterized by apoptosis of BEC (Figure 1A), elevated expression of Mmp7, a biomarker of biliary injury (Figure 1B), and elevation of plasma levels of total bilirubin (Figure 1C). To evaluate fate of BEC stem cells in hepatic GVHD, we enumerated BEC-derived organoids generated from the right lobe of the liver isolated after allo-HCT. The organoid-forming BEC stem cells were profoundly reduced at later time point after allo-HCT (Figure 1D), while they persisted in syngeneic controls, indicating that GVHD targets BEC stem cells. Next, we explored the mechanism of BEC stem cell injury. Among the cytokines elevated in the liver after allo-HCT, we found that TGF-β, not IFN-γ or TNF-α, inhibited generation of liver organoids (Figure 1E). Furthermore, we found that liver infiltrating mononuclear cells isolated from the allogeneic livers, not from syngeneic livers, suppressed growth of liver organoids. This effect was abrogated by the addition of a TGF-β inhibitor, SB-431542 in culture. Among these cells, monocyte-derived macrophages, not Kupffer cells, demonstrated enhanced production of TGF-β after allo-HCT (Figure 1F), suggesting that TGF-β from inflammatory macrophages damaged BEC stem cells. Based on these findings, we next tested if TGF-β inhibition could protect BEC stem cells and ameliorate hepatic GVHD after allo-HCT. Admnistration of SB-431542 from day +14 to day +28 after allo-HCT significantly increased organoid-forming BEC stem cells, suppressed BEC apoptosis and Mmp7 expression, and mitigated jaundice on day +28 after allogeneic HCT, indicating that TGF-β inhibition is a novel therapeutic strategy against hepatic GVHD (Figure 1, G-J). [Conclusion] Our results for the first time demonstrated that hepatic GVHD targets BEC stem cells via a TGF-β-dependent manner. Mmp7 and organoid-forming capacity could be the biomarkers for hepatic GVHD. BEC stem-cell protection by TGF-β inhibition is a promising novel therapeutic strategy against hepatic GVHD.Figures1: (A) Proportion of cleaved caspase 3 (cCaspase3) + cells among the biliary epithelial cells (BECs) on day +28. (B) Total RNA extracted from the liver on day +28 was subjected to Q-PCR targeting Mmp7. (C) Plasma levels of total bilirubin at indicated time points. (D) The numbers of organoid derived from the right lobe of the liver at indicated time point are shown. (E) Absolute numbers of TGF-β producing Kupffer cells and macrophages (Mφ) in the liver on day +28 are shown. (F) Liver organoids were enumerated after incubation in the presence or absence of TGF-β for 4 days. (G-J) Allogeneic recipients were intraperitoneally injected with 5 mg/kg SB-431542 daily from day +14 to day +28 after allogeneic HCT, and recipient mice were sacrificed on day +28. Numbers of organoids derived from the right lobe of the livers (G), the proportion of cCaspase3 + BECs (H), relative expression of Mmp7 in the liver (I), and plasma levels of total bilirubin (J) are shown. *; p < .05, **; p < .01, ***; p < .005. [Display omitted] DisclosuresTeshima: CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Honoraria; Sanofi S.A.: Research Funding; TEIJIN PHARMA Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fuji pharma CO.,Ltd: Research Funding; Pfizer Inc.: Honoraria; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Janssen Pharmaceutical K.K.: Other.

MAIT and Vδ2 Unconventional T Cells Predict Favorable Outcome after Allogeneic HCT and Are Supported By a Diverse Intestinal Microbiome

MAIT and Vδ2 Unconventional T Cells Predict Favorable Outcome after Allogeneic HCT and Are Supported By a Diverse Intestinal Microbiome

Health-Related Quality of Life in a Biologic Assignment Trial of Reduced Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome

Health-Related Quality of Life in a Biologic Assignment Trial of Reduced Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome

Single-Cell Transcriptomics for Residual Disease Detection in Acute Myelogenous Leukemia Post Allogeneic Hematopoietic Cell Transplantation

Detection of residual disease is a critical component of modern, risk-adapted therapy for Acute Myeloid Leukemia (AML). However, the genetic and phenotypic diversity of AML has made the development of a universal assay for disease assessment particularly challenging. While purely mutation-based tests promise high sensitivity, they are not broadly applicable given molecular heterogeneity and complex clonal evolution. Single-cell approaches, such as multiparameter flow cytometry (MFC), are more broadly applicable and increasingly accepted as the standard in clinical care. However, the limited number of leukemia-specific cell-surface markers and high numbers of shared markers between malignant myeloid blasts and healthy progenitors make MFC data extremely challenging to interpret. Motivated to develop a broadly applicable assay that can provide a more confident assessment of residual disease, we developed a platform using droplet-partitioned single-cell RNA sequencing accompanied by a computational pipeline specifically tailored to quantify residual disease after allogeneic HCT (alloHCT).With bone marrow samples from an 11-year-old patient with suspected post-alloHCT relapse of AML, we interrogated three methods of sample processing, 1) RBC lysis, 2) Ficoll-centrifugation, and 3) Ficoll-centrifugation combined with CD34+ immunomagnetic selection. The samples were further split to separately capture the 3' or 5' end of polyadenylated transcripts. The six resulting libraries were sequenced using standard short-read sequencing, and reads were demultiplexed and counted using common workflows. Data from the samples were combined, and sub-populations were visualized using UMAP (see Figure).This study demonstrated the feasibility of real-time single-cell sequencing for clinical utility. It is possible to process, capture, and sequence a patient's sample in approximately three working days (A). By integrating our data with single-cell expression profiles from an atlas of healthy human bone marrow, we were able to identify cells with gene-expression programs distinct from those of normal hematopoietic cells (B). With these integrated data, we could clearly identify populations of cells that embed away from healthy atlas cells (yellow circle, B), defining a different than normal single-cell profile. This “malignant” profile also included several genes whose expression is usually restricted to healthy hematopoietic progenitors (Panel C), suggesting these cells had a severely dysregulated transcriptome. As this patient was post-alloHCT, we interrogated the abundance of single-nucleotide-polymorphisms (SNPs) in the sequence data. We quantified these SNPs in single cells to distinguish each cell as either of donor or recipient origin using a method we have previously validated for genotyping RNA sequence in single cells. We clearly demonstrate that those cells identified as “different than normal” have a distinct SNP profile suggesting they are of recipient origin. Further analysis revealed that this malignant population was highly enriched for a population of cells expressing a previously described set of “AML-restricted genes” (Huang, B. et al., ASH 2021). (Panel E). Finally, from the Ficoll-processed sample, we quantified a level of 9.8% residual disease (243 malignant cells from a total of 2487). Notably, the number of abnormal myeloid progenitors determined by MFC was 2.0% which increased to 13% on a subsequent marrow sample drawn one week later. Incidentally, we observed only minimal differences across the two single-cell sequencing chemistries (3' vs. 5').Taken together, our data strongly argue that droplet-based, single-cell RNA sequencing is a feasible and powerful tool for the ascertainment of residual disease in AML. Given the robust nature of the platform and the ability to incorporate SNP integration into the analytic pipeline, it allows confident detection of residual disease in the post-alloHCT setting. By combining genomic quantification of transcripts with the power of SNP-based genotyping all at the level of the single cells, we believe this technology can substantially improve our diagnosis of post-alloHCT AML relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Phase 1/2 Study of Nexi-001 Donor-Derived Multi-Antigen Specific CD8+ T Cells for the Treatment of Relapsed Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Transplantation

Phase 1/2 Study of Nexi-001 Donor-Derived Multi-Antigen Specific CD8+ T Cells for the Treatment of Relapsed Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Transplantation

First Reported Case Series of Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD)

Background: Graft-versus-Host Disease (GVHD) is a complication that occurs in 30-70% of hematologic malignancy patients post-hematopoietic stem cell transplant (HCT) (Flowers, February 2021). Steroid refractory GVHD has led to studies approving ruxolitinib and ibrutinib as the first FDA approved therapies for steroid refractory GVHD. Ruxolitinib is approved to treat acute GVHD (aGVHD) and inhibits Janus associated kinase (JAK). Ibrutinib is approved to treat chronic GVHD (cGVHD) and functions by inhibiting Bruton's tyrosine kinase (BTK). Here we describe 2 cases of patients who received both drugs for their GVHD.Patient #1 was a 4-year-old female who had a diagnosis of NK cell dysfunction. The patient underwent a conditioning regimen with melphalan 140 mg/m2, fludarabine 30 mg/m2 X5, and alemtuzumab for 5 days. The allogeneic HCT was performed with cells from a 9/10 NMDP donor and received a CD34+ enrichment with T cell addback of 2.1 x10^5 CD3/kg. Tacrolimus was given for GVHD prophylaxis. The patient developed aGVHD stage 2, grade 3 of the gut on day +148. Patient received steroids, extracorporeal photopheresis (ECP), and cellcept, and the GVHD resolved. The patient then developed skin GVHD on day +189 (stage 1, grade 3) that resolved. Approximately 15 months post-transplant there was concern the patient was developing cGVHD of the skin and gut (chronic though stable diarrhea), and therefore ibrutinib was initiated day +490 at 140 mg daily. The cGVHD persisted despite ibrutinib, ECP, tacrolimus, and sirolimus. Ruxolitinib was then initiated 2.5 mg bid on day +883. Patient demonstrated stable to slightly improved GVHD and tapered ibrutinib to 110 mg between days +951 and +980. The patient remained on ruxolitnib and ibrutinib as of day +1172.Patient #2 was a 1-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother, receiving a CD34+ enrichment with T cell addback of 2x10^5 CD3/kg. The conditioning regimen was busulfan 2 mg/kg, fludarabine 30 mg/m2, cyclophosphamide 50 mg/kg, and thymoglobulin 2 mg/kg with tacrolimus as GVHD prophylaxis. Patient was experiencing fevers, dyspnea and CT was concerning for an infiltrative process. Broad spectrum antibiotics did not improve symptoms. A lung biopsy was performed and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed on day +217 (pathology confirmed GVHD). The pathology report was reviewed at an outside institution, raising the question of thrombotic microangiopathy (TMA) in context of hemolysis markers (high LDH and low platelets). Patient was placed on Fluticasone, Azithromycin, and Montelukast (FAM). Due to persisting BOOP confirmed on lung biopsy on day +407, the patient started ibrutinib 140 mg daily on day +411 and was started on ruxolitinib 2.5 mg bid on day +412. ECP commenced on day +414. Within 1 month, symptoms improved. Lung CT imaging appeared stable since initiation of these modalities. Patient continued with ruxolitinib, ibrutinib and ECP (twice per week) for GVHD, though the ruxolitinib dose was tapered in half starting day +477. Symptoms have improved.Discussion: To our knowledge this is the first reported case series of concomitant use of ruxolitinib and ibrutinib. A literature search (PubMed and abstracts in society meetings) was conducted that found 1 paper focused on ruxolitinib for cGVHD with 3 patients on concomitant ibrutinib, but without further details (Ferreira et al., June 2021). Our cases represent a proof-of-concept approach to GVHD management and demonstrate the feasibility of administrating both agents. The combination was well-tolerated with no significant adverse events noted. Neither patient had to discontinue due to poor tolerance or interactions. We expect this dual-drug therapy will become more common going forward given FDA approvals for both ruxolitinib and ibrutinib. Recently, ruxolitinib underwent a successful trial for glucocorticoid-refractory cGVHD when compared to best available therapies, including ibrutinib, though the drugs were not tested in combination (Zeiser et al., July 2021). These findings may open the door for further concomitant use, especially if ruxolitinib is approved by the FDA for cGVHD. We propose further investigation into dual therapy of these drugs in cGVHD either compared to steroids or as a second line option. DisclosuresCairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:Ruxolitinib is being used here for chronic GVHD, while it is FDA approved for acute GVHD.

Potential Benefits of a 6-Week Exercise and Mindfulness-Based Telehealth Training for HCT Survivors to Meet the Challenges of the COVID-19 Pandemic - a Feasibility Study

Background: Impairment of quality of life (QOL) such as reduced physical fitness and psycho-social dysfunction, is a recognized late effect of HCT, a life-saving procedure. Guided exercise and mindfulness-based stress management (MBSM) programs, delivered alone or in combination, have shown promise in improving patient's QOL mainly in the inpatient setting. Delivery of equitable and effective interventions in outpatient settings is challenging but may be addressed via telecommunication technology, reducing clinic visits and infection transmission. The aim of this study is to examine the feasibility and efficacy of a virtual and home-based program of combined exercise and MBSM via videoconference.Methods: Patients attending our post-HCT outpatient clinic were invited to participate (SVH HREC approval 12/175). Eligibility criteria included aged 18-75 years, >6 months post allogeneic HCT and the basic skills to access the online training and assessment packages. Patients with severe medical and psychological problems were excluded by their clinicians. Consented participants attended an initial in-person introductory session and were provided materials including booklet and audio recordings for skill practice. This was followed by once weekly exercise and MBSM training for 6 weeks via videoconferencing. Assessments were performed pre, and then virtually post training, and at 3, 6 and 12 months. Assessment session included: 6-minute walk test (6-MWT), Modified Bruce Test (MBT), sit-to-stand (STS), hand grip strength (HGS). Subjective measures were Goal Attainment Scale, Karnofsky Score, FACT-BMT, Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Godin-Shephard Leisure Time Index. Linear mixed-effects model was used for outcome comparisons. This maximum likelihood approach utilizes all acquired data points and manages missing data points by missing at random (MAR) assumption. P values were adjusted using Holm-Sidak method for multiple comparisons.Results: Twenty-four eligible patients responded to the invitation and completed the program (54% male, median age 53 years (33 - 73), median time post-HCT of 37 months (13 - 68), 38% rural/remote). Based on participant feedback surveys at 6 months, this combined modality telehealth program was found to be well-accepted and safe.The 6-MWT scores were significantly higher at 3 and 12 months (M=646.5m, SD=53.34 and M=615.33m, SD= 94.95, respectively; both p < 0.01) compared to baseline (M=566.94, SD=145.22). The MBT, the only test that required participants to attend the clinic was ceased after 3 months as changes in 6-MWT paralleled changes in MBT. STS Test was significantly higher at 3 and 12 months (M=19.53, SD=6.93, p<0.01 and M=19.07 SD= 8.0; both p < 0.05) compared to baseline (M=15.14, SD=6.44). For the upper limb assessment, dominant hand grip was significantly stronger at 3, and 12 months (M=35.09, SD=9.83; p< 0.01) compared to baseline (M=29.07, SD=9.79). A significantly higher FACT-BMT total and FACT-G scores were found at 3 months (M=123.37, SD=15.12 and M=91.23, SD=11.76; p< 0.01) compared to baseline (M=116.44, SD=14.16 and M=88.25, SD=12.52 respectively), and a trend non-significant at 12 months.Conclusion: A 6-week internet and home-based exercise and MBSM programme was an acceptable, safe, and potentially effective intervention for sustained improvement of some QOL outcomes in HCT survivors. The positive findings of this feasibility study provided valuable data for the design of a multicentre RCT that is underway . DisclosuresNo relevant conflicts of interest to declare.

Non-Relapse Mortality in TP53-Mutated MDS/AML - a Multi-Center Collaborative Study

Non-Relapse Mortality in TP53-Mutated MDS/AML - a Multi-Center Collaborative Study

Post-Transplantation Cyclophosphamide for Gvhd Prophylaxis in Related and Unrelated Allogeneic Hematopoietic Cell Transplantation: Study from the SFGM-TC Registry

Rational: The significant increase in haplo-identical allogeneic cell transplantation (Allo-HCT) has led to the more frequent use of cyclophosphamide (Cy) after transplantation for graft-versus-host disease (GVHD) prophylaxis (PT-Cy). This strategy has subsequently been used in related and unrelated allogeneic HCT settings as well with some controversial results.Patients and Methods: We analyzed all consecutive Allo-HCTs from matched related (MR) and unrelated donors (HLA matched and mismatched: MUD and MMUD) reported to the SFGM-TC registry from January 2014 to December 2019 and who have received PT-Cy alone or in combination with other immunosuppressive molecules (IS). We therefore performed a pair-matched analysis (1/2) with transplantations using classic GVHD prophylaxis with (w) or without (wo) anti-thymocyte globulins (ATG). The primary objective was to evaluate the incidence and severity of acute and chronic GVHD in PT-Cy compared to other strategies. Secondary objectives included: modalities of PT-Cy and IS, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), overall survival (OS), GVHD and relapse free-survival (GRFS), infection rates.Results: We analyzed a total of 1190 patients (pts), 386 (32%) received PT-Cy and matched with 804 (68%) pts who received classic GVHD prophylaxis (no PT-Cy). Among PT-Cy patients, 59% were males with a median age of 55.3 years (3.4-75.5), 49% were AML, 14% ALL, 20% MDS and MPS, 12.5% NHL and HL, and 4.5% Multiple Myeloma. Before transplantation, 61% of pts were in complete remission (CR), 34% not in CR, 2% in stable disease and 3% were not treated. Conditioning regimen was myeloablative in 35% of patients, 86% received peripheral blood stem cells, 31% were CMV negative pairs, 58% were sex-matched and 51% were ABO compatible. There was no significant difference between the PT-Cy and no PT-Cy groups regarding all the variables. We identified four groups: group 1: PT-Cy + IS (n=259), group 2: PT-Cy + ATG + IS (n=120), group 3: ATG w or wo IS (n=651) and group 4: other IS (n=160). We observed significant differences between the 4 groups for age (p<0.001), type of disease (p<0.001), disease status (p=0.016), conditioning intensity (p=0.002), HC source (p<0.001), HLA matching (p<0.001) and ABO compatibility (p<0.001).The cumulative incidence of acute GVHD grades II, III/IV, chronic GVHD, relapse and NRM, the probability of OS and GRFS are shown in Table 1. The results of multivariate analysis (Table 2) showed a significant lower incidence of acute GVHD gr II, III, IV and chronic GVHD after PT-Cy + IS and a significant higher TRM after ATG ± IS. In addition, other well-known parameters were found to have a significant impact as age on OS and GRFS, use of unrelated donor on OS and CIR and PBSC on chronic GVHD. Regarding severe infections after HCT, there was no difference between PT-cy and pair-matched patients except for pneumonia (12.5% vs. 8% respectively, p=0.08) and septicemia (12% vs. 1.7% respectively, p<0.001).In conclusion, there was a significant lower incidence and severity of acute and chronic GVHD in the PT-Cy group after related, HLA matched and mismatched unrelated Allo-HCT compared to matched patients with other GVHD prophylaxis with a higher NRM when patients received ATG. We did not observe significant translation into GRFS improvement probably due to the higher toxicity of PT-Cy. [Display omitted] DisclosuresYakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huynh: Jazz Pharmaceuticals: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

Differential Prognostic Impact of IDH1 and IDH2 Mutations in Chronic Myelomonocytic Leukemia

Introduction: Mutations involving isocitrate dehydrogenase 1/2 (IDH) are known oncogenic drivers in hematological malignancies, conferring neomorphic enzymatic activity to IDH 1/2, resulting in the oncometabolite, 2-hydroxyglutarae (2-HG). 2-HG in turn suppresses TET activity, making IDH and TET2 mutations synthetically lethal and almost mutually exclusive. The frequency of IDH mutations in CMML is <10% and their prognostic impact remains unclear. We carried out this study in a large database of molecularly annotated CMML patients to better define the clinical profile and prognostic impact of these mutations.Methods: After IRB approval, CMML patients from the Mayo Clinic, Minnesota and the Moffitt Cancer Center (MCC), Tampa, Florida, were included in the study. All patients had bone marrow (BM) biopsies with cytogenetics and molecular genetics done either at diagnosis, or at first referral. Clinical and mutational data were abstracted and retrospectively analyzed. Overall survival (OS) was calculated from date of CMML diagnosis to date of death/last follow, while AML-free survival (AML-FS) was calculated from date of CMML diagnosis to date of leukemic transformation (LT). Patients that had undergone allogeneic HCT were excluded from the study (n=3). Statistical analysis was carried out using the Blue Sky software.Results: Six hundred and forty four patients were included in the study (Mayo Clinic-357, MCC- 287), median age 71 years (range, 20-95 years), 67.8% being male. Forty-three (6.7%) patients had IDH mutations, 35 (82%) IDH2 and 8 (18%) IDH1; of which, 34 (97%) involved the IDH2R140 hotspot and 5 (62.5%) involved the IDH1R132 hotspot, respectively. The median variant allele fractions (VAF) for IDH1 mutations was 41% (range, 8-46%) and for IDH2 mutations was 46% (range, 7-70%). There were no significant demographic or clinical differences between IDH mutant and wild type CMML patients, with the exception that IDH mutant CMML patients were less likely to be thrombocytopenic (p=0.006), were less likely to have TET2 co-mutations (14% vs 53.2%; p<0.001) and were more likely to have SRSF2 co-mutations (69.8% VS 40.3%; p<0.001). Importantly there were no differences in proliferative or dysplastic subtypes (p=0.3), cytogenetic (p=0.12) and molecular risk stratifications (p=045). There were also no significant demographic or clinical differences between IDH1 vs IDH2 mutant CMML patients. Six (14%) IDH mutant CMML patients had TET2 co-mutations; 5 (83%) with IDH2R140Q (median VAF-28%;all male) and 1 (17%) with IDH1R132H (VAF-44%;female) (Figure 1). Five (11%) IDH2 mutant patients were treated with enasidenib (IDH2 inhibitor), none with a durable response, while none of the IDH1 mutant patients received targeted therapy.At last follow up (median 18 months), 337 (52%) deaths and 119 (18.5%) LT have been documented, with IDH mutant patients having a higher LT rate (30.2% vs 17.6%, p=0.04) compared to wildtype patients. The median OS of the entire cohort was 35 months, with no difference in OS between IDH mutant and wild type patients (34.5 vs 35 months, p=0.12), with IDH1 mutant patients having a shorter OS in comparison to IDH2 mutant patients (31 vs 37 months; p=0.005- Figure 1). IDH mutant CMML patients also had a shorter AML-FS in comparison to wild type patients (36.6 vs 210 months, p=0.005), with there being no differential impact on AML-FS of IDH1 vs IDH2 mutations (p=0.26, Figure 1).Conclusions: IDH mutations are infrequent in CMML (7%), with IDH2 mutations being more common than IDH1 mutations (80 vs 20%). IDH mutations co-occur very infrequently with TET2 mutations (14%), with IDH mutant patients being less likely to have thrombocytopenia and more likely to have SRSF2 co-mutations. IDH mutations negatively impacting AML-FS without a significant impact on OS. Prospective clinical trials testing the safety and efficacy of IDH1/2 inhibitors in CMML are much needed. [Display omitted] DisclosuresKomrokji: AbbVie: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Acceleron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Padron: BMS: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

Peri-Transplant Alemtuzumab Levels Predict Risk of Secondary Graft Failure and Inversely Impact CXCL9 Levels after RIC HCT (A Correlative Biology Study to BMT-CTN 1204 RICHI)

Peri-Transplant Alemtuzumab Levels Predict Risk of Secondary Graft Failure and Inversely Impact CXCL9 Levels after RIC HCT (A Correlative Biology Study to BMT-CTN 1204 RICHI)

Ruxolitinib Plus Nivolumab in Patients with R/R Hodgkin Lymphoma after Failure of Check-Point Inhibitors: Preliminary Report on Safety and Efficacy

Background: Recent studies demonstrated that classical Hodgkin lymphoma (cHL) is characterized by chromosome 9p24.1 amplification with associated overexpression of PD-1 ligands as well as JAK2 tyrosine kinase activation. Immune evasion mediated by the PD-1/PD-1 ligand axis can be inhibited with IgG4 agonist antibody specific for human PD-1 nivolumab which has shown excellent overall response rate (ORR) of over 60% in relapsed cHL. JAK2 induces PD-1 ligand expression and augments tumor cell proliferation. JAK2 signaling can be inhibited with clinical grade small molecules (i.e. ruxolitinib). Given this biology, we designed a Phase I/II study to target both pathways in cHL patients who had failed PD-1 blocking agents.Methods: This is a Phase I/II, multicenter, open-label, dose escalation/dose-expansion study to evaluate the safety and tolerability of ruxolitinib when combined with nivolumab (fixed dose 3mg/kg IV every 2 weeks) in patients with relapsed or refractory (R/R) cHL (NCT03681561). Eligible patients had to fail prior check-point inhibitor (CPI; nivolumab or pembrolizumab). Three dose levels of ruxolitinib were tested: 10 mg orally twice a day (bid), 15 mg bid, and 20 mg bid. Planned duration of therapy was 2 years. The primary objective was to find the maximum tolerated dose (MTD) of ruxolitinib when given with nivolumab and characterize the safety and tolerability of this combination. The phase 2 objective was to evaluate the overall response rate (ORR).Results: We enrolled 19 patients. Median age was 38 years (range 22-76); 68% were males. Patients were a median of 3.4 years from the initial diagnosis (range 0.9-16.7 years), 89% had stage III-IV disease and all had experienced progressive disease following CPI. 17 (89%) had prior autologous HCT and 1 had prior allogeneic HCT. All patients received nivolumab combined with ruxolitinib, and the highest ruxolitinib dose 20mg BID (MTD) was reached without DLTs. The combination was well tolerated; most AEs were grade 1 and 2. Only 3 patients required hospitalization (2 had pneumonia, one for disease progression). Three patients experienced immune mediated adverse events (LFT elevation: 1 Gr 1 and 1 Gr 2; 1 Gr 3 pneumonitis) and all were reversible. Three subjects were not evaluable for response (2 patients who received < 1 month of therapy due to rapid disease progression and Gr 2 immune hepatitis and 1 patient with short follow-up is not yet evaluable for response). Median follow-up was 13 months (range 3-27 months).In 16 patients evaluable for response, best ORR was 75% (12 of 16); including 3 CRs (19%), 2 PRs (13%), 6 patients had stable disease (SD, 44%) with tumor bulk reduction ranging from 10-45%. One patient had indeterminate response (negative biopsy of new PET-avid site). Duration of responses were 12.5 months (ranged from 3.7 to 20.4 months); 5 responders continue study therapy and 2 completed 2 years; 1 went on to autologous HCT in PR, and 3 progressed while on therapy after 6, 6 and 23 months. One patient died after later experimental therapy. Progression-free survival at 1 year was 64% (95%CI 34-84%).Conclusions: Inhibition of JAK2 combined blockade of the PD-1 pathway represent complementary rational therapeutic targets in cHL. Therapy combining ruxolitinib with nivolumab is well tolerated and yield encouragingly high remission rates and durable responses in patients who had all failed previous CPI. Pharmacodynamic and correlative analyses on the mechanism of synergism are underway. DisclosuresBachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Janakiram: ADC Therapeutics: Research Funding; FATE Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Kyowa Kirin Therapeutics: Honoraria. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Farooq: Kite, a Gilead Company: Honoraria. OffLabel Disclosure:ruxolitinib for Hodgkin lymphoma

Healthcare utilization and cost of cancer-related care prior to allogeneic hematopoietic cell transplantation for hematologic malignancies in the US: a retrospective real-world analysis

BackgroundHematopoietic cell transplantation (HCT) is a potentially curative therapy as well as a costly procedure. Published studies have examined the cost of HCT in the US and the complications that follow but little is known about the cancer-related healthcare costs and resource utilization prior to the procedure and none of the studies have examined the variability in cost based on the type of hematologic malignancy involved. The aim of this study was to estimate mean cancer-related costs and resources incurred before the HCT is performed from the time the hematologic malignancy first develops.MethodsThe IBM® MarketScan® Research Databases were used to identify adult patients ≥18 years of age with commercial or Medicare supplemental insurance who had undergone allogeneic HCT for hematologic malignancies from January 1, 2008 to December 31, 2017. Healthcare utilization and costs were assessed during the 6 months prior to diagnosis (pre-diagnostic period) and the follow-up period from diagnosis just prior to the HCT (pre-HCT period). Multivariable regression models were constructed to estimate total all-cause costs and cancer-related costs as well as healthcare utilization by type in each time period.ResultsA total of 2663 commercially insured patients and 266 with Medicare supplemental insurance were included in the study population. The mean-adjusted incremental cancer-related costs for commercially insured patients was $399,011 in the overall observation period including the pre-diagnostic and pre-HCT periods combined, 9% of which was incurred in the pre-diagnostic period. The corresponding mean-adjusted incremental cancer-related costs for Medicare supplemental patients was $195,575 for the same time period but the patterns of healthcare utilization were similar to the commercially insured population. Inpatient care accounted for approximately one-half the cost in both patient populations. By type of hematologic malignancy, costs were lowest for myeloproliferative disorders ($211,561) and highest for acute lymphocytic leukemia ($462,072) in the commercially insured population.ConclusionThis study demonstrates that overall patients with hematologic malignancies requiring HCT have considerable cancer-related healthcare resource utilization and costs leading up to HCT compared to the period of time prior to developing cancer.

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after HCT for malignant disease. Graft versus tumor (GVT) is a major component of the overall beneficial effects of allogeneic HCT in the treatment of hematological malignancies. Better understanding of GVHD pathogenesis is important to identify new therapeutic targets for GVHD prevention and therapy. Emerging data suggest opposing roles for different T cell subsets, e.g., IFN-γ producing CD4+ and CD8+ T cells (Th1 and Tc1), IL-4 producing T cells (Th2 and Tc2), IL-17 producing T cells (Th17 and Tc17), IL-9 producing T cells (Th9 and Tc9), IL-22 producing T cells (Th22), T follicular helper cells (Tfh), regulatory T-cells (Treg) and tissue resident memory T cells (Trm) in GVHD and GVT etiology. In this review, we first summarize the general description of the cytokine signals that promote the differentiation of T cell subsets and the roles of these T cell subsets in the pathogenesis of GVHD. Next, we extensively explore preclinical findings of T cell subsets in both GVHD/GVT animal models and humans. Finally, we address recent findings about the roles of T-cell subsets in clinical GVHD and current strategies to modulate T-cell differentiation for treating and preventing GVHD in patients. Further exploring and outlining the immune biology of T-cell differentiation in GVHD that will provide more therapeutic options for maintaining success of allo-HCT.

Hidden blood loss in adolescent idiopathic scoliosis patients undergoing posterior spinal fusion surgery: a retrospective study of 765 cases at a single centre

BackgroundIn scoliosis corrective surgery, total blood loss is composed of visible blood loss, including intraoperative haemorrhage and drainage, and hidden blood loss in which blood extravasates into the tissues and accumulates in the surgical field. The purpose of this study was to investigate hidden blood loss (HBL) and its potential risk factors in adolescent idiopathic scoliosis patients undergoing posterior spinal fusion surgery and elucidate the influence of HBL on the necessity for postoperative blood transfusion.MethodsWe retrospectively studied adolescent idiopathic scoliosis patients undergoing posterior spine fusion for adolescent idiopathic scoliosis from January 2014 to December 2018 at our hospital. The patients’ demographics, blood loss-related parameters, surgeries and blood loss data were extracted. The association between patient characteristics and HBL was analyzed by Pearson or Spearman correlation analyses. Multivariate linear regression analysis was used to determine independent risk factors associated with HBL. Binary logistic regression analysis was used to analyze the influence of HBL on the necessity for postoperative blood transfusion.ResultsA total of 765 patients, of whom 128 were male and 637 were female (age range 10–18 years), were included in this study. The mean volume of HBL was 693.5 ± 473.4 ml, accounting for 53.9 % of the total blood loss. The multivariate linear regression analysis revealed that preoperative Hct (p = 0.003) and allogeneic blood transfusion (p < 0.001) were independent risk factors for HBL, while tranexamic acid (p = 0.003) was negatively correlated with HBL. Binary logistic regression analysis showed that HBL > 850 ml (P < 0.001, OR: 8.845, 95 % CI: 5.806–13.290) was an independent risk factor for the necessity for postoperative blood transfusion.ConclusionsSubstantial HBL occurred in adolescent idiopathic scoliosis patients undergoing posterior spinal fusion surgeries. Allogeneic blood transfusion and preoperative Hct were independent risk factors for HBL, while tranexamic acid was negatively related to HBL. HBL and its influencing factors should be considered when planning perioperative transfusion management. Patients with HBL greater than 850 ml should be closely monitored in cases of postoperative anaemia.Level of evidenceLevel III.