Allogeneic Hematopoietic Transplantation Research Articles

Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.

BCL-2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax-based regimens under compassionate use forr/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy.

Transplant Eligible and Ineligible Elderly Patients with AML-A Genomic Approach and Next Generation Questions.

The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized.

Neuropsychological and biopsychosocial evolution, therapeutic adherence and unmet care needs during paediatric transplantation: study protocol of a mixed-methods design (observational cohort study and focus groups) - the TransplantKIDS mental health project.

The present article describes the protocol of a mixed-methods study (an observational cohort design and focus groups), aimed to examine neuropsychological functioning and other biopsychosocial outcomes, therapeutic adherence and unmet care needs in paediatric population undergoing solid organ or allogeneic hematopoietic transplant during the pre- and post-transplant phases. Following a multi-method/multi-source approach, neuropsychological domains will be comprehensively measured with objective tests (SDMT, K-CPT 2/CPT 3, TAVECI/TAVEC, WISC-V/WAIS-IV Vocabulary and Digit Span subtests, Verbal Fluency tests, Stroop, ROCF, and TONI-4); ecological executive functioning, affective and behavioral domains, pain intensity/interference, sleep quality and therapeutic adherence will be assessed through questionnaires (parent/legal guardians-reported: BRIEF-2 and BASC-3; and self-reported: BASC-3, BPI, PROMIS, AIQ and SMAQ); and blood levels of prescribed drugs will be taken from each patient's medical history. These outcomes will be measured at pre-transplant and at 4-weeks and 6-months post-transplant phases. The estimated sample size was 60 patients (any type of transplant, solid organ, or hematopoietic) from La Paz University Hospital (Madrid, Spain). Finally, three focus group sessions will be organized with patients, parents/guardians, and transplant clinicians (n = 15, with 5 participants per group), in order to qualitatively identify unmet care needs during the pre-, and post-transplant stages of the process. The study protocol was registered at ClinicalTrials.gov (NCT05441436).

The effect of glucose-6-phosphate dehydrogenase deficiency on allogeneic hematopoietic stem cell transplantation in patients with hematological disorders

Objectives: To determine the effect of glucose-6-phosphate-dehydrogenase (G6PD) deficiency on patients' complications and prognosis following allogeneic stem cell hematopoietic transplantation (allo-HSCT) . Methods: 7 patients with G6PD deficiency (study group) who underwent allo-HSCT at Peking University People's Hospital from March 2015 to January 2021 were selected as the study group, and thirty-five patients who underwent allo-HSCT during the same period but did not have G6PD deficiency were randomly selected as the control group in a 1∶5 ratio. Gender, age, underlying diseases, and donors were balanced between the two groups. Collect clinical data from two patient groups and perform a retrospective nested case-control study. Results: The study group consisted of six male patients and one female patient, with a median age of 37 (range, 2-45) years old. The underlying hematologic diseases included acute myeloid leukemia (n=3), acute lymphocytic leukemia (n=2), and severe aplastic anemia (n=2). All 7 G6PD deficiency patients achieved engraftment of neutrophils within 28 days of allo-HSCT, while the engraftment rate of neutrophils was 94.5% in the control group. The median days of platelet engraftment were 21 (6-64) d and 14 (7-70) d (P=0.113). The incidence rates of secondary poor graft function in the study group and control group were 42.9% (3/7) and 8.6% (3/35), respectively (P=0.036). The CMV infection rates were 71.4% (5/7) and 31.4% (11/35), respectively (P=0.049). The incidence rates of hemorrhagic cystitis were 57.1% (4/7) and 8.6% (3/35), respectively (P=0.005), while the bacterial infection rates were 100% (7/7) and 77.1% (27/35), respectively (P=0.070). The infection rates of EBV were 14.3% (1/7) and 14.3% (5/35), respectively (P=1.000), while the incidence of fungal infection was 14.3% (1/7) and 25.7% (9/35), respectively (P=0.497). The rates of post-transplant lymphoproliferative disease (PTLD) were 0% and 5.7%, respectively (P=0.387) . Conclusions: The findings of this study indicate that blood disease patients with G6PD deficiency can tolerate conventional allo-HSCT pretreatment regimens, and granulocytes and platelets can be implanted successfully. However, after transplantation, patients should exercise caution to avoid viral infection, complications of hemorrhagic cystitis, and secondary poor graft function.

Alternative Versus Matched Donor Allogeneic Hematopoietic Transplantation for Afro-Caribbean and Latin American HTLV1-Associated Adult T Cell Leukemia/Lymphoma

Alternative Versus Matched Donor Allogeneic Hematopoietic Transplantation for Afro-Caribbean and Latin American HTLV1-Associated Adult T Cell Leukemia/Lymphoma

How adoptive transfer of components of the donor immune system boosts GvL and prevents GvHD in HLA-haploidentical hematopoietic transplantation for acute leukemia.

Why a new Perspective in allogeneic hematopoietic transplantation? A summary. Nowadays, for high-risk acute leukemia patients without an HLA-matched donor (sibling or volunteer), hematopoietic transplants that use HLA-haploidentical grafts combined with enhanced post transplant immune suppression (i.e., high-dose cyclophosphamide) are widely used. They are associated with low TRM rates. However, they are also associated with significant chronic GvHD while they only partially abrogate leukemia relapse rates. One may speculate that post-transplant immune suppression, required for GvHD prophylaxis, weakens the anti-leukemic potential of the graft. Historically, haploidentical transplants became feasible for the first time through transplantation of T cell-depleted peripheral blood hematopoietic progenitor cells. Lack of post-transplant immune suppression allowed the emergence of donor-versus-recipient NK-cell alloreactions that eradicated AML. In an attempt to improve these results we recently combined an age-adapted, irradiation-based conditioning regimen with transplant of T-cell-depleted grafts and infusion of regulatory and conventional T cells, without any post transplant immune suppression. With the obvious limitations of a single center experience, this protocol resulted in extremely low relapse and chronic GvHD rates and, consequently, in a remarkable 75% chronic GvHD/relapse-free survival in over 50 AML patients up to the age of 65 many of whom at high risk of relapse.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia

AbstractThe curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT. Therefore, we conducted a phase 1 study to determine the dose and safety in this setting. Patients were eligible if they were aged 16 to 75 years, had undergone allo-HCT for CD22+ ALL, were in complete remission (CR) after allo-HCT, had high risk of recurrence, were between day 40 and 100 after allo-HCT with adequate graft function, and did not have a history of sinusoidal obstruction syndrome (SOS). The objectives of this trial were to define INO maximum tolerated dose (MTD), to determine post–allo-HCT INO safety, and to measure 1-year progression-free survival (PFS). The trial design followed a “3+3” model. The treatment consisted of INO given on day 1 of 28-day cycles. Dose levels were 0.3 mg/m2, 0.4 mg/m2, 0.5 mg/m2, and 0.6 mg/m2. Median age was 44 years (range, 17-66 years; n = 18). Disease status at transplantation was first CR (n = 14) or second CR or beyond (n = 4). Preparative regimen was of reduced intensity in 72% of patients who received transplantation. Most common toxicity was thrombocytopenia. There were no instances of SOS; the MTD was 0.6 mg/m2. One-year nonrelapse mortality was 5.6%. With a median follow-up of 18.1 months (range, 8.6-59 months) 1-year post–allo-HCT PFS and overall survival is 89% and 94%, respectively. Low-dose INO has a favorable safety profile and was associated with high rates of 1-year PFS. This trial was registered at www.clinicaltrials.gov as #NCT03104491.

Efficacy of off-the-shelf bone marrow mesenchymal stem cells for pediatric steroid-refractory acute graft-versus-host disease.

Temcell is a mesenchymal stem cell (MSC) product approved for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in Japan. However, reports regarding Temcell's efficacy in pediatric patients have been scarce, and the appropriate use of MSC therapy against pediatric SR-aGVHD also remains to be determined. We retrospectively assessed a cohort of pediatric patients treated with Temcell for SR-aGVHD following allogeneic hematopoietic transplantation. MSCs were infused intravenously at a dose of 2 × 106 cells/kg according to the manufacturer's instructions. Twelve patients received eighteen cycles of MSC therapy (median age, 10.3 [1.7-17.8] years), with four receiving additional cycles (one cycle: n = 3, three cycles: n = 1). The severity of aGVHD before MSC therapy was grade I-II in three patients and grade III-IV in nine patients (gut stage 3-4, n= 7; liver stage 3-4; n =2). The median number of immunosuppressive therapy regimens received prior to MSC administration was two (range: 1-5). The first MSC cycle displayed the best overall response rate of 83%, including six patients with a complete response (CR) and with a 49% reduction in the mean daily dose of prednisone after eight weeks. The median time to first response was 3.5 days (range: 2-15 days). Two of the four patients who were re-administered MSCs for recurrent or persistent GVHD achieved a CR. The three-year overall survival rate was 69.4%, while the three-year failure free survival (FFS) rate was 22.2%, with a median FFS of 4.9 months. There were no observable side effects of MSC therapy. MSC therapy appears to be an effective and safe treatment for pediatric SR-aGVHD, with a steroid-sparing effect and satisfactory efficacy upon re-administration. Further studies are needed to determine its appropriate combination with additional treatments and the optimal use of re-administration of MSCs.

Recurrence of HBV Reactivation after Allogeneic Hematopoietic Transplantation in Recipients with Resolved HBV Infection: A Nation-Wide Multicenter Retrospective Study

Introduction Reactivation of hepatitis B virus (HBV) is known to cause fulminant hepatitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in recipients with resolved HBV infection. Monitoring of HBV-DNA and HBV-DNA-guided preemptive therapy using nucleotide analogue (NA) is recommended to prevent developing hepatitis due to HBV reactivation after allo-HSCT. However, little is known about the adequate duration of NA treatment and the frequency of the recurrence of HBV reactivation (2nd HBV reactivation) after discontinuation of NA. We conducted a nationwide retrospective study of HBV reactivation after allo- HSCT. Patients and Methods We retrospectively reviewed the clinical information of recipients with resolved HBV infection (HBsAg-negative, anti-HBc-positive) before allo-HSCT and were diagnosed as HBV reactivation (HBsAg and/or HBV-DNA positive) after allo-HSCT from January 2010 to December 2020. Patients who received prophylactic NA before HBV reactivation were excluded. This study was approved by the Hokkaido University Hospital institutional review boards and registered as UMIN 000046803. Results A total of 72 patients were enrolled (median age of 60 years, range, 27-73 years; 42 males and 30 females) from 16 institutions. Initial hematological diseases were acute myeloid leukemia 21, myelodysplastic syndrome 14, chronic myeloid leukemia 4, acute lymphoblastic leukemia 12, non-Hodgkin lymphoma 8, adult T cell leukemia-lymphoma 6, mixed phenotype acute leukemia 4, and others 3. HSCT details were as follows: donor source, unrelated bone marrow 33, cord blood 24, related peripheral blood 11, unrelated peripheral blood 4; acute graft versus host disease (GVHD) 48 (66.7%); chronic GVHD 44 (61.1%); systemic steroid usage 41 (56.9%). Initial HBV reactivation after allo-HSCT was observed on day 10-3034 (median 512.5). Immunosuppressants and systemic steroids were administered in 35 (48.6%) and 28 (38.9%) patients respectively at the time of HBV reactivation. The patients who showed anti-HBs below protection levels (<10mIL/mL) were 18 (25%) of 72 patients at pre-HSCT, however, the number increased to 35 (81.4%) of 43 patients who were analyzed at the point of HBV reactivation after allo-HSCT. All patients received preemptive NA (entecavir 65, tenofovir alafenamide 6, tenofovir 1). Elevated aspartate transaminase of more than 200 U/L was observed in 7 cases at HBV reactivation, and all of them showed HBV-DNA more than 4 Log IU/mL. No one developed fulminant hepatitis but 5 patients resulted in continuous HBV carriers. Twenty-four of 72 patients were discontinued NA by each physician's decision. Of 24 patients who discontinued NA, 11 (45.8%) patients developed 2 nd HBV reactivation. The median duration from discontinuation of NA to 2 nd HBV reactivation was 113 days (range, 15 to 434). Duration of initial NA administration was not significantly different between patients with 2 ndHBV reactivation and those without 2 nd HBV reactivation (90-1968 days, median 553 vs 145-3734 days, median 861; p=0.11). In those who analyzed anti-HBs at discontinuation of NA, 4 of 8 cases (50.0%) with anti-HBs <10 mIU/mL developed 2 nd HBV reactivation, whereas only 1 of 6 cases (16.7%) with anti-HBs >10 mIU/mL developed 2 nd HBV reactivation. Four of the 11 cases with 2 nd HBV reactivation were attempted rechallenge of NA discontinuation, however, all 4 cases developed 3 rd HBV reactivation on day 28-127 after discontinuation of NA. These 4 cases further developed 4 th HBV reactivation after the rechallenge of discontinuation of NA. One patient developed protective anti-HBs titer after 2 courses of HB vaccination, and finally successfully discontinue the NA after 4 th HBV reactivation. The patient did not develop further reactivation for more than 3 years. Conclusion 2 nd reactivation of HBV after NA discontinuation was common in patients with HBV reactivation who received allo-HSCT despite the long duration of NA. Acquisition of anti-HBs by HBV reactivation itself or HB vaccine would be necessary to suppress further HBV reactivation. Careful monitoring of HBV-DNA is important even after the discontinuation of NA in the case with HBV reactivation after allo-HSCT because multiple reactivations could occur. A prospective randomized trial of the HB vaccine after allo-HSCT for preventing HBV reactivation is now ongoing (UMIN000034113).

Use of a Tissue-Targeting Recombinant Human Interleukin-22 Fusion Molecule (F-652) for the Treatment of Advanced Refractory Lower GI Acute Gvhd

Background: Steroid-refractory (SR) gastrointestinal acute GVHD (GI aGVHD) is a serious complication after allogeneic hematopoietic transplantation (allo-HCT), and subsequent lines of treatment following steroid failure are often ineffective. The JAK 1/2 inhibitor ruxolitinib is the only FDA-approved treatment for SR aGVHD, and patients for whom ruxolitinib is not effective or not tolerated have limited therapeutic options and high mortality. Interleukin-22 (IL-22) is a tissue-protective IL-10-family cytokine that has been shown to support intestinal mucosa after damage, directly signaling to the intestinal epithelium and promoting its survival, regeneration, and production of innate antimicrobial molecules. F-652, a recombinant human (rh)IL-22 fusion protein composed of an IL-22 dimer and IgG2 Fc fragment, has recently been studied in a phase 2 trial for patients with newly diagnosed lower GI aGVHD, demonstrating a promising day 28 treatment response rate and improved gut microbial health. Given this, we examined F-652 administration in 3 patients with severe SR GI aGVHD. Methods: Three patients with hematologic malignancies underwent MUD allo-HCT with tacrolimus and methotrexate GVHD prophylaxis ( Table). The patients were initially treated for GI aGVHD with methylprednisolone at a dose of 2 mg/kg/day without response. All patients presented with or progressed to stage 4 gut aGVHD and failed several lines of therapy, including ruxolitinib. All patients also had multiple episodes of bacteremia and at least some degree of GVHD-associated GI bleeding. F-652 treatment was initiated under single-patient-use authorization as the 5 th-7 th line of therapy and was administered at a dose of 45 mcg/kg IV weekly. In vitro cultures suggested that rho kinase inhibition did not interfere with trophic effects of IL-22 on intestinal epithelium, so patients were permitted to continue belumosidil upon F-652 initiation. While there was concern that JAK inhibition could compromise the activity of IL-22, continuation of ruxolitinib was considered on a case-by-case basis. C-reactive protein (CRP) is an acute phase reactant induced by IL-22, and circulating CRP levels served as a pharmacodynamic marker of in vivo biologic activity of F-652. Results: Consistent CRP elevations were observed 3 days after F-652 dosing in patients A and C, both of whom demonstrated a reduction in GVHD symptoms following F-652 treatment. These CRP elevations occurred despite concurrent use of belumosidil in Patient A and ruxolitinib in Patient C. CRP levels increased in Patient B after the first two doses, but not the third ( Figure). By day 28 following F-652 initiation, 2-of-3 patients (A and C) achieved a partial response, with decreased stool output and resolution of GI bleeding. Patient A had experienced 21 episodes of bacteremia prior to initiating rhIL-22 therapy but continued to demonstrate a partial response at day 56 and resolutiuon of bacteremias. Further improvement during the continued treatment (12 total doses) allowed for hospital discharge after 14 months of hospitalization. Patient B received 4 failed lines of therapy beyond ruxolitinib and was experiencing GI bleeding necessitating frequent transfusions prior to F-652 initiation. The symptoms persisted following F-652 treatment, and the patient passed at day 149 post-HCT. Patient C continues on active F-652 treatment and remains in a partial response as of this submission (> 50 days after treatment initiation). Overall, F-652 treatment has been well tolerated, and no significant adverse events attributable to the drug were observed. Conclusions: This is the first report of IL-22 therapy in SR aGVHD. Treatment was well tolerated, and 2-of-3 patients achieved a response following rhIL-22 administration after failing multiple previous therapies. Whereas most treatments for GVHD target immune cells and deepen immunosuppression, IL-22 is understood to act directly upon epithelial cells where it can support tissue recovery, improve barrier function, and promote innate antimicrobial immunity. CRP elevations post-treatment suggest that IL-22 administration may be able to exert these effects even with concurrent use of a JAK inhibitor. Our findings support further development of this approach and provide proof-of-concept for the use of tissue-supportive strategies to enhance the recovery of damaged gastrointestinal mucosa in advanced lower GI aGVHD.

Safety and Preliminary Efficacy of DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

Background and Significance: Patients (pts) with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have a high unmet medical need, with limited standard-of-care therapeutic approaches, particularly after failure of response to first-line agents, and with allogeneic hematopoietic transplant as the only potential curative option. Through the production of interleukin (IL)-1β and IL-18, the NLRP3 inflammasome has been implicated as a major driver of inflammation associated with acute and chronic inflammatory diseases. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms such as MDS and CMML contributing to ineffective hematopoiesis and clonal progression (Hamarsheh 2020; Basiorka 2016). DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals, both in vitro and in vivo. Therefore, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to pts by improving hematopoiesis. Study Design and Methods: This is an open-label, phase 1b, multicenter study with a randomized dose-optimization part and a dose-expansion part consisting of two groups evaluating DFV890 in pts with very low, low, or intermediate risk MDS (LR-MDS) per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML (LR-CMML) per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). Eligible pts must be 18 years of age, with an Eastern Cooperative Oncology Group performance status ≤2, candidates for serial bone marrow assessments who are willing to undergo a bone marrow aspirate/biopsy during the trial, and meet one of the following: (a) IPSS-R-defined LR-MDS who failed to respond to or did not tolerate erythropoiesis-stimulating agents (ESAs) or luspatercept or hypomethylating agents (HMAs) and pts with del 5q who failed to respond to or did not tolerate lenalidomide; (b) CPSS-defined LR-CMML who failed to respond to or did not tolerate hydroxyurea or HMAs. Key exclusion criteria include treatment with systemic antineoplastic or any experimental therapies within 28 days (or 5 half-lives, whichever longer); unresolved treatment-related toxicities prior to the first dose of study treatment; previous treatment with agents targeting the NLRP3 inflammasome and the IL-1 pathways; prior use (≤1 week or 5 half-lives, whichever is longer) of hematopoietic colony-stimulating growth factors, thrombopoietin mimetics or ESAs; and concomitant medications, known to modulate cytochrome P450 enzymes. DFV890 is administered orally twice daily (bid) for a minimum of 24 weeks (6 cycles of treatment [1 cycle=28 days]) until treatment discontinuation. In the dose-optimization part, pts are randomized to receive either low dose or high dose bid and stratified by indications. The recommended dose (RD) determined from this part is further explored in the dose-expansion part to confirm safety and tolerability of DFV890 and explore preliminary efficacy. The primary objective is to assess safety (incidence and severity of adverse events, and dose-limiting toxicities) and tolerability to then determine the optimal RD for DFV980. Secondary objectives include assessment of DFV890 pharmacokinetics, evaluation of the preliminary efficacy of DFV890 on transfusion burden, and hematologic improvement: time to onset of transfusion independence; duration of response, best overall response, overall response rate, progression-free survival, and time to progression; and reduction in spleen volume (for CMML). Key exploratory objectives include patient perceptions of tolerability as measured by patient-reported outcomes; and determination of genetic characteristics and potential predictive markers of efficacy and/or resistance. The study is currently enrolling in Singapore, Hong Kong, and the USA with plans to treat approximately 80 pts. The first patient first visit was achieved on May 8, 2023.

Efficacy and Safety of Processed Amniotic Fluid (pAF) Drops for the Treatment of Ocular Chronic Graft-Versus-Host Disease

Background: Ocular graft-versus-host disease (GVHD) affects more than 50% of patients with chronic GVHD and can lead to debilitating dry or painful eyes, impaired activities of daily living and poor quality of life. Management is mainly supportive, through control of surface inflammation, lubrication, and control of drainage and evaporation. Amniotic fluid (AF) is a rich source of nutrients, cytokines, and growth factors that has antimicrobial and immunomodulatory activities and may have reparative and regenerative roles in human disease. Investigators at the University of Utah developed protocols to collect AF from full-term pregnant women, process and sterile filter AF to separate cytokines and growth factors from residual cells and debris contained in the no-cellular fraction of AF, and treat patients with different conditions. We report the treatment effects and safety of processed AF (pAF) for the treatment of ocular GVHD. Methods: In this randomized, double-blinded, placebo-controlled phase II trial (NCT# 03298815), patients age ≥ 18 years diagnosed within 5 years after allogeneic hematopoietic transplant with ocular GVHD causing dry eye symptoms requiring lubricant drops >3x/day, punctal plugs, thermally cauterized puncta or special eyewear to relieve pain; or inability to work because of ocular symptoms; or loss of vision due to keratoconjunctivitis sicca were enrolled. Patients with any other chronic GVHD treated with >3 lines of therapy beyond corticosteroids with or without calcineurin inhibitors or sirolimus; or had a difference in dryness between both eyes of >2 points by the International Dry Eye WorkShop (DEWS) 2007 report; or were not willing to discontinue the use of medicated lubricant eye drops prior to randomization were excluded. Randomization was performed within participants, with one eye receiving one drop of pAF and the other eye saline treatment (placebo) twice daily for 30 days. In patients wearing scleral lenses, the eye drops were applied prior to lens insertion in the morning and after removal at night. Patients were allowed to resume their medicated eye drops after the 30-day treatment period. The primary objectives were to determine the day 30 overall response (complete and partial response) and safety of pAF. Response type to treatment is defined in Table 1. Key secondary objectives included longitudinal changes in visual acuity and the corneal surface, and patient-reported outcomes. Results: All fifteen patients' eyes were randomized to either pAF or saline treatment. The median age was 61 years (range, 35-72). At enrollment, six patients wore scleral lenses. The median baseline FACT-G score was 88 (range, 58-104). Baseline eye characteristics by treatment are shown in Table 2. Baseline NIH CC eye scores were similar between pAF and saline-treated eyes. The saline-treated group had more eyes with DEWS score 3 (n=7) compared to the pAF group (n=2). All 15 patients completed treatment. The overall response at day 30 in the pAF and saline-treated groups was 25% and 50%, respectively, p=0.38. All responding eyes had a partial response. No treatment-related serious ocular adverse events were observed. Two minor events occurred in the pAF treated eye group, including a change in eyelid position (n=1) and stinging after study drop application (n=1). There was no significant change in visual acuity and corneal surface staining between treatment groups at 30, 60, and 100 days. There was no significant change in the FACT-G score at 30, 60, and 100 days, and there was no significant difference in patient reported eye pain between pAF vs. saline-treated eyes over time (p=0.21). Conclusion: In this study, the primary endpoint of safety was met as there were few adverse events. One quarter of pAF-treated eyes responded. These findings justify evaluating pAF for ocular GVHD in a larger study. Limitations of this study included restricting patients to pAF application to twice a day and the study design of randomizing eyes within each subject as several patients had mild asymmetric disease between the two eyes. Other challenges included having delayed ocular assessments and/or altered perceptions of quality of life due to the COVID19 pandemic.

Immune Profiling of Respiratory Syncytial Virus (RSV) for the Development of Targeted Immunotherapy

Introduction: RSV-associated respiratory viral infections are a major public health problem affecting the immunologically naïve/compromised population. For example, RSV-induced bronchiolitis and pneumonia are the leading cause of hospitalization in infants and young children worldwide, while in adult allogeneic hematopoietic transplant (HCT) recipients the incidence of progression from upper to lower respiratory tract infection (LRTI) is 40-60%, with mortality rates as high as 80%. At the national level, the Fall 2022-Spring 2023 RSV surge translated into a sharp rise in hospitalization rates surpassing last season's respective rate by almost 5-fold (https://www.cdc.gov/rsv/research/rsv-net). Our group has previously demonstrated the feasibility, safety and clinical efficacy of administering allogeneic ex vivo expanded multivirus-specific T cells (multi-VSTs) as a banked, off-the-shelf product for the treatment of EBV, CMV, BKV, HHV6, AdV and SARS-CoV-2 infections/disease in immunocompromised individuals. Given the RSV-associated morbidity and the paucity of therapeutic agents, we sought to characterize the cellular immune responses to RSV with a view to developing a targeted T-cell therapy product for those at highest risk of severe disease (i.e. HCT recipients, elderly/immunocompromised patients). Methods: To first identify immunogenic and protective RSV antigens we exposed PBMCs from healthy adult donors to pepmixes (overlapping peptide libraries) spanning the 11 RSV-encoded antigens and found that 7 induced highly reactive T cells. However, Nucleoprotein (N) and Fusion Protein (F) proved to be immunogenic in all donors and were thus advanced for VST manufacturing. We subsequently utilized our optimized VST manufacturing process and culture in a G-Rex device in medium supplemented with activating cytokines to generate RSV-specific VSTs (RSV-STs) with activity against this combination of immunodominant targets. Results: We achieved a mean 5.2±1-fold expansion (mean±SEM; n=13) of cells that were comprised almost exclusively of CD3+ T cells (94.08±1.15%), with a mixture of cytotoxic (CD8+; 28.91±5.16%) and helper (CD4+; 71.09±5.15%) T cells. These cells had a phenotype consistent with effector function and memory potential, as evidenced by upregulation of the activation markers CD25, CD69, and CD28 and expression of central (CD45RO+/CD62L+) and effector memory markers (CD45RO+/CD62L-) with minimal expression of exhaustion-related markers such as PD1, Tim3 and LAG3. The anti-viral activity of the expanded cells was confirmed in an IFNγ ELISpot using both stimulating antigens as an immunogen and all lines proved to be reactive against the target antigens (N: 3587±939 SFC/2x10 5; F: 3526±743). As demonstrated by surface and intracellular flow cytometry, the immune response was mediated by both CD4+ and CD8+ T cell subsets through IFNγ/TNFα production and upregulation of activation/costimulatory markers. Reactive cells were polyfunctional and primarily Th1-polarized as evidenced by IFNγ, Granzyme-B, IL-2 and GM-CSF production measured by FluoroSpot and Luminex array. Finally, the expanded cells were able to kill viral pepmix-loaded autologous PHA blasts with minimal/no activity against non-antigen-expressing autologous and allogeneic targets. Conclusion: Healthy donor-derived RSV-STs are Th1-polarized, polyfunctional and selectively able to kill viral antigen-expressing targets with no auto- or alloreactivity, indicative of their safety for clinical use. A clinical trial evaluating their safety and activity in HCT recipients as part of an off-the-shelf multi-respiratory virus-directed product is currently underway (NCT04933968, https://clinicaltrials.gov).

An Acute Gvhd Classification Based on the Dynamic of Gvhd Skin Involvement from Its Appearance to Start of Systemic Treatment

The currently used classifications of acute GVHD are based on signs and symptoms in the skin, gut and liver, graded at the start of first-line therapy. However, they do not consider the rate at which these symptoms developed. Since skin aGVHD is the most frequent initial sign, we conducted a prospective observational study aimed at investigating the prognostic value of the dynamic of skin involvement such as the rate at which aGVHD progresses from cutaneous involvement to visceral involvement. One hundred and eight consecutive patients who underwent allogeneic hematopoietic transplantation in our centre were registered for this observational study, their aGVHD episodes were classified according to both the modified Glucksberg classification and according to a “GHVD skin dynamic” proposed by us. Our classification “GVHD skin dynamic” classified acute GVHD based on the time interval between rash initial appearance to time when treatment using corticosteroids (CS) was started. In patients left untreated, we considered the change in skin rash extension shown during the first week without treatment. Median age of treated patients was 49 years, 69% were affected by Acute Leukemia, 64% had an alternative donor type (MUD, HAPLO). Primary aGVHD treatment was started in all patients in the case of progression to Glucksberg Overall Grade 2 or a persisting Overall Grade 1, no local corticosteroids were used on the skin. Eighty-two presented a skin rash as a first sign of a-GVHD (80.3%) and were classified according both to Glucksberg classification and our scheme; 18/82 started CS within 48 hours (Group 1); 13/82 started CS within days 3-7 (Group 2). Fifty-one patients (62.2%) were left untreated for 7 days (Group 3) and subclassified 3a and 3b. Group 3a (n 31) was defined when Skin GVHD Overall Grade 1, left untreated for 1 week, showed an absolute increase in involved body surface area <5 %. Group 3b (n 20), was defined when Skin GVHD Overall Grade 1, left untreated at 1 week, had an absolute increase in involved body surface area >5% (Fig 1). Demographic, disease-related and transplant features (Age, Donor type, Disease status, HSC Source, ATG use, Conditioning RIC, Diagnosis) in the four groups were not significantly different. The four groups, identified by “GVHD skin dynamic”, had distinctive 2-y OS, (Fig 2). In Group 1 (patients who were started on CS within 48 h) the OS at 2y was 50.1% and TRM 41.6%. In Group 2 (patients who started on CS after 2 days and within 7 days) the OS at 2 y was 64.8% and TRM 16.8%. In Group 3a (patients who were started on CS after 7 days and had no increase of skin rash during days 1-7) the OS was 75.1% and TRM 10.4%. In Group 3b (patients who were started on CS after 7 days and had an increase of skin rash during days 1-7) the OS was 39.8% and TRM 39.2%. Patients were then grouped based on “GVHD skin dynamic” into “Dynamic type poor risk” (Group 1 and Group 3b) and “Dynamic type good risk” (Group 2 and Group 3a). Such grouping was found statistically important using Cox proportional hazard univariate analysis for OS (p=0.04). Such grouping “Dynamic type poor risk” and “Dynamic type good risk” retained importance for OS when evaluated in Cox proportional hazard multivariate analysis (HR 2.222 ; 95% CL 1.017-4.875; p=0.04) together with age, status of the disease and conditioning. Patients who were left untreated because of skin-only acute GVHD and who during a week had a worsening skin extension (Group 3b) were compared to those who when left untreated for one week showed a stable skin-only involvement (Group 3a). Overall Survival at 2 y in Group 3b was significantly inferior compared to Group 3a: 39.8% vs 75.1% (log-rank: p= 0.03). Group 3b had also increased Treatment-Related Mortality: 39.2% versus 10.4% vs (Gray test: p=0.05) and increased rate in need of secondary anti-GVHD treatment: 76.4% vs 46.6% (chi-test p=0.002). The dynamic of skin aGVHD during the first week from appearance may be used to classify acute GVHD and this proposed acute GVHD classification has good prognostic value. Further, patients who have a skin-only acute GVHD and who, when left untreated for one week show an increase in skin involvement, have inferior prognosis and should start systemic CS promptly.

Evaluation of Atrial Fibrillation Risk and Outcome after Allogeneic Transplantation Using an Artificial Intelligence ECG Algorithm and Echocardiographic Parameters in an MDS Cohort

Introduction Atrial fibrillation/flutter (Afib) contributes independently to the hematopoietic cell transplant comorbidity index (HCTCI) and is a known complication of allogeneic hematopoietic transplantation (AlloHCT) which has been linked to inferior outcomes, particularly in older patients. An electrocardiogram (ECG)-based artificial intelligence (AI) algorithm to predict Afib and cardiac contractile dysfunction risk has been validated (Lancet 394:861, 2019). We hypothesized that assessment of pre-transplant Afib risk using the AI algorithm may predict future development of Afib and help identify patients at higher risk for this complication. Methods 191 consecutive MDS patients undergoing AlloHCT with curative intent using myeloablative (28.3%) or reduced intensity conditioning (62.3%) in the Mayo Clinic Comprehensive Cancer Center (Rochester, Jacksonville, Phoenix) between November 2015 and January 2022 were included in this retrospective analysis. Primary outcome was Afib within 100 days and 365 days of transplantation, and we also assessed the outcomes of Death and Relapse. Revised IPSS (IPSS-R) and HCTCI scores were included for all patients. Elevated Afib risk score using the AI algorithm was calculated from pre-transplant ECG, performed during vital organ testing at AlloHCT clearance. In addition to left ventricular (LV) ejection fraction (EF) we evaluated detailed echocardiographic (Echo) parameters including LV volume and mass indices, left atrial volume index (LAVI), maximum trans mitral flow velocities during LV filling (E velocity) and during the diastolic phase due to atrial contraction (A velocity), the velocity of the annulus away from the apex during the protodiastolic phase (e' velocity), E/A and E/e' ratios, the presence of valvular disease, and right ventricular systolic pressure (RVSP). We performed an analysis using a Cox proportional hazards regression models (adjusting for age and sex) to evaluate associations with Afib risk, Relapse, and Overall Survival. Results The median age was 64 years (18-75), 58.6% were male, 6.9% non-white race, and 3.7% Hispanic/Latino ethnicity. Most patients had an HCTCI score of 0-3 (76.3%). GVHD prophylaxis was predominantly with calcineurin inhibitor-based regimes plus/minus methotrexate or mycophenolate mofetil (83.8%). 5.2% of patients had a history of Afib before transplant. Non-relapse mortality was 7.9% at 100 days, and 18.3% at 365 days. N=25 patients (13.1%) developed Afib within 100 days, and n=28 (14.7%) within 1-year after AlloHCT. On multivariable analysis, Age [Hazard Ratio (HR) 2.83, 95% Confidence Interval (CI) 1.36-5.89, p=0.0055] and Echo parameters [including LAVI (HR 2.10, CI 1.23-3.58, p=0.0067), E velocity (HR 3.28, CI 1.29-8.80, p=0.013), E/A ratio (HR 3.74, CI 1.75-7.97, p=0.0006), E/e ' ratio (HR 1.81, CI 1.07-3.07, p=0.026) and RVSP (HR 1.68, CI 1.04-2.70, p=0.032)] were significantly associated with Afib risk; elevated AI risk score was significant in the univariate model (HR 2.74, CI 1.15-6.53, p=0.023) but was borderline in the multivariate model (HR 2.34, CI 0.98-5.60, p=0.056) ( Table 1). Based on previous observations we evaluated the association of AI and Echo parameters with Relapse and Death after AlloHCT ( Table 1). Age (HR 1.32, CI 1.01-1.71, p=0.041) and IPSS-R (HR 1.20, CI 1.08-1.33, p=0.0009) were significantly associated with Death after AlloHCT, while HCTCI (HR 1.10, CI 1.00-1.22, p=0.052) and higher LV EF (HR 0.63, CI 0.38-1.06, p=0.084) were borderline. For Relapse, only IPSS-R (HR 1.52, CI 1.31-1.75, p=1.22E-08) was significant, while increase Echo E velocity was of borderline significance (HR 0.45, CI 0.20-1.02, p=0.057). Conclusions Afib is a common post-AlloHCT complication and is more frequent with increasing Age. Echo parameters (specifically E/A ratio) predict significantly higher Afib risk, while the baseline ECG AI algorithm was of borderline significance. The selection of patients with lower HCTCI scores, and the low background prevalence of Afib in this cohort (i.e., selection of patients with lower baseline cardiac morbidity) are possible explanations for non-significance of the AI algorithm. As anticipated Age and IPSS-R are the greatest predictors of Death after AlloHCT, although the suggestion of an association with baseline Echo parameters highlights the importance of identifying those who may benefit from preemptive Cardiology intervention.

Impact of Therapy Sequence on Survival Outcomes Among Patients with Relapsed or Refractory Mature T and NK Cell Neoplasms: A Global Retrospective Cohort Study

Despite evolution of therapeutic strategies, there is no universal standard of care for relapsed or refractory (RR) mature T and NK-cell neoplasms (TNKL). Most patients receive multiple lines of therapy and cycle through many available options. 1-3 There is no data to inform optimal therapy sequence, however emerging data suggest that exposure to epigenetic modifiers (EM) can sensitize tumors to other therapies. 4-6 Here we report results of comparative analyses assessing survival outcomes based on therapy sequence using a global RR TNKL patient cohort with data from 15 centers across 6 continents. We conducted a retrospective target-trial 7,8 cohort study using an updated global patient cohort. 9 Patients were excluded from analyses if they had anaplastic large cell lymphoma (as EM is infrequently used 10,11), did not receive first line cytotoxic chemotherapy (CC), or no documented second line (2L) start date. Cohort assignment was based on 2L therapy received: EM (e.g. histone deacetylase or DNA methyltransferase inhibitors), small molecule inhibitors (SI; broad or selective), or CC. Antibody-drug conjugates were included in CC. Outcomes were overall survival (OS; time from 2L start to death) and real-world progression-free-survival-2 (rwPFS2; time from 2L start to fourth line start or death 12 to assess if 2L modifies the effect of third line [3L]). Planned subgroups included histologic subtype and those who received allogeneic hematopoietic transplant (HSCT) after 2L. For sequence analyses, included patients must have received 3L. Outcomes were assessed between all prespecified 2L to 3L sequences using a single comparator, and pairwise. Kaplan Meier curves were used, and adjusted hazard ratios (aHR) were estimated using Cox regression with previously described a priori covariates. 9 Maximal, minimal, and no covariate Cox models were compared using likelihood ratio tests and Akaike's information criterion. Of the 925 RR patients in the global cohort, 472 were included who received EM (n=89), SI (n=46), or CC (n=337) at 2L. The most common SI included immunomodulatory imide drug (26.1%), PI3K inhibitor (21.7%), investigational pathway inhibitor (19.6%) and JAK inhibitor (17.4%). Within EM, SI, and CC, 42.7%, 37%, and 47.2% of patients were primary refractory to first line, respectively. The most common histologies were PTCL-NOS (51.7%, 41.3%, and 57.3%) and AITL (43.8%, 54.3%, and 26.4%) in EM, SI, and CC, respectively. Most patients had a Prognostic Index for T-cell Lymphoma (PIT) score at diagnosis of 1 (27%, 34.8%, and 27%) or 2 (28.1%, 26.1%, and 25.8%) in EM, SI, and CC, respectively. In EM, 34.8% received first-line autologous HSCT, versus 28.2% in SI, and 15.4% in CC. Following 2L, 12.4%, 17.4%, and 9.8% received allogeneic HSCT in EM, SI, and CC, respectively. The Cox model containing histology, PIT, and primary refractory status was used as the final model (vs maximal model: p=0.88). Compared to CC at 2L, EM did not affect OS (aHR 0.88, 95% CI 0.63-1.24; p=0.46) or rwPFS2 (aHR 0.84, 95% CI 0.61-1.16; p=0.28), however SI improved OS (aHR 0.61, 95% CI 0.37-0.97; p=0.038) and rwPFS2 (aHR 0.61, 95% CI 0.38-0.90; p=0.038). In the allogeneic HSCT subgroup, there was no difference in OS (EM vs CC: aHR 0.32, 95% CI 0.04-2.40; p=0.27; SI vs CC: aHR 0.51, 95% CI 0.06-4.69; p=0.55) or rwPFS2 (EM vs CC: aHR 0.30, 95% CI 0.05-1.96; p=0.21; SI vs CC: aHR 0.64, 95% CI 0.05-3.90; p=0.46). There were no differences in PTCL-NOS patients in OS (EM vs CC aHR 0.80, 95% CI 0.51-1.25; p=0.33; SI vs CC: aHR 1.00, 95% CI 0.54-1.84; p=0.99) or rwPFS2 (EM vs CC: aHR 0.91, 95% CI 0.61-1.38; p=0.66; SI vs CC: aHR 0.90, 95% CI 0.49-0.97; p=0.16). In AITL, SI improved OS (aHR 0.34, 95% CI 0.16-0.76; p=0.009) and rwPFS2 (aHR 0.36, 95% CI 0.17-0.77; p=0.008) versus CC, but EM showed no difference in OS (aHR 0.80, 95% CI 0.43-1.46; p=0.46) or rwPFS2 (aHR 0.56, 95% CI 0.31-1.02; p=0.059). There was no difference in rwPFS2 or OS across sequences overall (Figure 1) or between pairwise sequence comparisons (Figure 2). Compared to CC, SI at 2L improved OS and rwPFS2 in AITL patients. Therapy sequence did not affect OS or rwPFS2. Advanced approaches such as machine learning and dynamic treatment regimes have been initiated to fully elucidate the effect of therapy sequence. Our study highlights several equally effective therapy sequences to treat RR TNKL allowing therapy to be individualized based on patient and disease characteristics, and drug access at a given time.

Nutritional intervention with TGF-beta enriched food for special medical purposes (TGF-FSMP) is associated with a reduction of malnutrition, acute GVHD, pneumonia and may improve overall survival in patients undergoing allogeneic hematopoietic stem transplantation

Malnutrition in allogeneic stem cell transplant (allo-SCT) is associated with poor outcomes. Supplementation with Foods for Special Medical Purposes may be a valid alternative to enteral nutrition or total parental nutrition to reduce malnutrition in allo-SCT. In this study, 133 patients consecutively allo-transplanted were assessed for nutritional status by Patient- Generated Subjective Global Assessment (PG-SGA) and supplemented with TGF-beta enriched Food for Special Medical Purposes (TGF-FSMP).PG-SGA, gold standard for nutritional assessment in oncologic patients, was assessed at admission and on day 0, +7, +14, +21, and + 28 from transplant and categorized as follows: A = good nutritional status; B = moderate malnutrition; C = severe malnutrition. TGF-FSMP (Modulen-IBD) is currently used in Inflammatory Bowel Diseases (IBD) as primary nutritional support and in this study the dose was calculated according to BMI and total daily energy expenditure (TDEE). The patients assuming ≥50% of the prescribed TGF-FSMP dose were classified in Group A; the patients who received < 50% were included in Group B per protocol. The primary endpoint of the study was the assessment of the malnourished patients in Group A and B at day+28 after transplantation, according to the criteria of PG-SGA C categorization. At day +28 after transplant: i) patients in Group A were significantly less severely malnourished than patients in the Group B (21/76,28% vs 42/53, 79% respectively, OR 2.86 - CI 1.94–4.23 -, p = 0.000); ii) the incidence of severe (MAGIC II-IV) aGVHD and of any grade gastrointestinal (GI) aGVHD was higher in Group B than in Group A, (43% vs 21% p = 0.003) and (34.5% vs 9.2% p = 0.001); iii) Pneumonia was more frequent in the malnourished patients of Group B than in well/moderate nourished patients of Group A (52.7% vs 27.6% p = 0.002). In group A parenteral nutrition was avoided more frequently than in group B (67.5% vs 33.3% p = 0.000) and a median hospital stay of 27 days in comparison to 32 was reported (p = 0.006). The estimated median overall survival (OS) of the population was 33 months in Group A and 25.1 months in group B (p = 0.03). By multivariate and ANN analysis, TGF-FSMP TR < 50% assumption was significantly correlated with malnutrition, severe and GI aGVHD, pneumonia and reduced OS.

Abatacept-Prophylaxis Based Haploidentical Transplantation May Allow Sustained Engraftment and Offset Gvhd in Non-Malignant Disorders

Introduction: Non-malignant disorders (NMD) derive no benefit from graft-versus-host disease (GVHD) after allogeneic hematopoietic transplantation (HCT). Transplantation designed to optimize engraftment and immune reconstitution while minimizing GVHD and organ toxicities is desirable. Post-transplant cyclophosphamide (PTCy) decreases severe chronic GVHD risk in radiation-containing regimens for NMD when combined with serotherapy (anti-thymocyte globulin) (PMID: 22955919; PMID: 30500440). Abatacept effectively offsets GVHD following unrelated donor (URD) HCT (PMID: 33449816; PMID: 32813873). Based on these reports, NCT03128996 was developed for haploidentical transplantation in NMD after radiation-free reduced intensity conditioning (RIC) combining PTCy + Abatacept for GVHD prophylaxis. Serotherapy does not contribute to GVHD prophylaxis in this RIC approach. Outcomes focused on safety and GVHD- free donor engraftment in children with NMD and no better donor options. Method: Conditioning included alemtuzumab (day -22 to -19), fludarabine (day -8 to -4), melphalan (day -3) and thiotepa (day -4) as previously published (hydroxyurea prior to RIC was used in proliferative marrow disorders) (PMID: 32813873). Stem cell source was bone marrow (BM) or CD34-selected peripheral blood cells with a fixed CD3 cell dose of 1x10^6/kg recipient weight. GVHD prophylaxis included tacrolimus (day -1, with wean beginning 6-9 months post-HCT), PTCy on days +3 and +4, mycophenolate mofetil until day +28, and monthly abatacept doses until 13 months post-HCT. Survival, safety, donor chimerism, GVHD incidence, and incidence of post HCT infection were primary outcome measures. Results: Eleven patients 6 to 24 years old (median 9 years) underwent HCT for adrenoleukodystrophy ( 2), sickle cell disease (SCD) ( 6), aplastic anemia ( 1), second transplant for severe combined immunodeficiency ( 1) and STAT 5B gain-of-function mutation ( 1). Eight were trial participants and 3 treated according to trial guidelines. All patients tolerated abatacept infusions and engrafted with neutrophil recovery (&amp;gt;500/cu mm) at a median of 17 days (range 15-24 days). As of 7/31/2023, median follow up is 411 days (range 83-1979 days). The mean myeloid and T-cell chimerisms at D100 (n=10) and 1 year (n=6) were 97.8%+/- 5.3 and 96.3% +/- 6.4 and 98.6% +/- 3.3 and 95% +/-8.7, respectively. One patient with SCD has low myeloid engraftment (24%) at 7 months post-HCT (lymphoid 91%); a stem cell boost is planned after immune suppression with fludarabine/Cytoxan/ATG (PMID: 35798858). Viral reactivation was noted in 4 patients, none developed CMV disease or EBV post-transplant lymphoproliferation. One patient developed grade 1 acute GVHD. Of 6 evaluable patients, one developed localized chronic skin GVHD. This patient remains on systemic immune suppression beyond 13 months (ruxolitinib). The overall and GVHD-free survival at 1-year post HCT in evaluable patients (N=6) is 100 % and 83%, respectively. Conclusion: Promising preliminary results in this cohort support continuation of the trial with longer term follow-up. The effective suppression of GVHD without serious infectious complications in the first year post-HCT is encouraging. Virus reactivation was however noted early post-HCT and requires monitoring and prophylaxis. Incorporating abatacept into GVHD prophylaxis was successful in achieving desired outcomes; the phase 1 portion of the study is completed and the phase 2 trial and follow-up are ongoing.

Acute Myeloid Leukemia Patients Who Stopped Venetoclax or/and Azacytidine for Other Reasons Than Progression Have a Prolonged Treatment Free Remission and Overall Survival. a Filo Study

Background Recent update of the VIALE-A study showed a long-term survival for approximately 30% of acute myeloid leukemia (AML) patients treated with venetoclax and azacitidine (VEN-AZA) for a newly-diagnosed AML (ND-AML) (Pratz K.W et al., ASH 2022). A recent report of a small cohort of responding patients who interrupted VEN-AZA displayed a sustained treatment-free remission (TFR) period suggesting that treatment interruptions might be considered (Chua CC. et al., Blood Adv. 2022). To evaluate the impact of VEN-AZA discontinuation on survival and time without treatment, we retrospectively analyzed the characteristics and outcomes of patients who stopped VEN and/or AZA for reasons other than progression (e.g. hematological or other toxicities). We presented the first 51 patients from our cohort last year at ASH meeting (Garciaz S. et al, ASH 2022). In this abstract, we analyzed separately ND-AML and relapsed/refractory (R/R) AML. Methods Eligible patients 1) have been treated with VEN-AZA for a ND or R/R AML, 2) have stopped AZA and/or VEN for more than 3 months, 3) are in remission (CR, CRi or Morphologic leukemia-free state, [MLFS]) at the time of treatment interruption, 4) are ≥ 18-year-old. Main endpoints were overall survival (OS) and treatment-free remission (TFR) calculated from the time between the last day of VEN to relapse, retreatment, or death. We measured the impact of prognostic factors on OS by a Cox regression taking disease status (ND vs R/R), the discontinued treatment (VEN vs VEN-AZA), the cytogenetics and NPM1 or IDH mutations. Results We included 83 patients from French Innovative Leukemia Organization (FILO) centers and Moffit Cancer Center (US) treated with VEN-AZA for a ND-AML or a R/R AML between 11/18 and 07/23. Regarding the ND-AML patients (n=60; 32 males and 28 females), the median age was 76 (range, 26-86.5), median platelet count, WBC, ANC and bone marrow blast involvement was 52 G/L (range, 9-296), 2.8 G/L (range, 0.6-200), 0.6 G/L (range, 0.02-31.6) and 40% (range, 10-99), respectively. Cytogenetics was intermediate (int.) in 48 cases (80%) and unfavorable (unfav.) in 12 patients (20%). Eleven AML (18.3%) had NPM1 mutations, and 19 (31.6%), IDH alterations including 7 IDH1, 8 IDH2R140 and 4 IDH2R172. Six (10%) and 5 (8.3%) patients had FLT3 or TP53 mutations, respectively. The median number of VEN-AZA cycle was 4 (1-17). The best response was CR (n=44, 73.3%), CRi (n=13, 18.3%) and MLFS (n=3, 5%). Twenty-one patients out of 25 (78%) reached MRD negativity assessed by molecular (n=11) or flow cytometry (n=10) techniques. Twenty-six patients (43.3%) stopped VEN-AZA and 34 (56.7%) stopped VEN and continued AZA monotherapy for a median number of 7 AZA cycles (1-41). Reasons for treatment discontinuation were prolonged cytopenia, non-hematological toxicities, patient choice or unknown in 35 (58%), 6 (10%), 8 (13.3%), and 11 (18.3%) patients, respectively. We registered 27 relapses and 24 deaths. Fourteen patients were retreated including 11 patients who were rechallenged with VEN-AZA. Second CR/CRi rate with VEN-AZA was 3/11 (27.7%). With a median follow of 23 months, median TFR was 15 months (ranges, 3-47) and median OS was 44 months (ranges, 7-50). We also analyzed a smaller cohort of 23 R/R responding patients who stopped AZA and/or VEN. The median age was 73, median number of previous lines was 1 (1-3). Twenty-one patients (91.3%) received prior intensive chemotherapy and 4 (17.4%) prior allogeneic hematopoietic transplantation. Cytogenetic risk was int. in 17 (73.9%) and unfav. in 5 patients (21.7%) and missing in one patient. NPM1 and IDH genes were mutated in 6 (26%) and 10 (43.4%) cases, respectively. Sixteen patients (69.6%) stopped VEN-AZA and 7 (30.4%) interrupted VEN only. Nine patients resumed a treatment including 6 patients rechallenged with VEN-AZA. Among them, 3/6 (50%) obtained a second CR/CRi. Median TFR and OS were 10 (ranges, 3-23) and 19 (ranges, 7-32), respectively. Factor impacting OS in multivariate analysis were R/R AML disease status (Hazard Ratio [HR] =0.47, ranges, 0.23-0.87), and IDH mutations (HR= 2.1, ranges, 1.05-4.34), but not unfav. cytogenetics, NPM1 mutations, or the discontinued treatment (VEN vs VEN-AZA). Conclusion: Discontinuation of VEN and/or AZA in responding patients was associated with sustained responses and long-term survival rates. Resuming treatment may induce a second remission in some patients.

Characteristics and Outcomes of Patients With Multiple Myeloma Who Developed Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome After Autologous Cell Transplantation

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing the therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1/1/2000 and 12/31/2018, and later developed t-MDS/AML. Among the 2982 patients that underwent at least one Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n=52; AML, n=3). The median age at t-MDS/AML diagnosis was 66 years (range, 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis was 58.5 months (range, 6-206 months). At diagnosis, all 3 patients with tAML and 65% of those with tMDS had high-risk disease, per ELN2022 and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed t-MDS/AML were older at MM diagnosis (median: 61 vs. 59 years; p=0.06), more often were male (73% vs. 58%; p=0.029), received more than 2 years of lenalidomide maintenance (57% vs. 39%; p=0.014) and experienced complete remission more frequently following Auto-HCT compared to those who did not develop t-MDS/AML (56% vs. 40%; p=0.012). In a multivariable model, male gender, advanced age at MM diagnosis, experiencing complete remission after Auto-HCT, and lenalidomide maintenance were independent predictors of developing t-MDS/AML. Among the patients who developed t-MDS/AML, 14 (25%) underwent allogeneic hematopoietic stem transplant (Allo-HCT). After a median follow-up of 9.9 months from t-MDS/AML diagnosis, the median overall survival (OS) after t-MDS/AML diagnosis was 11.8 months for all patients, and 18.2 months vs. 11.1 months for Allo-HCT recipients vs. nonrecipients, respectively (P=0.25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% CI]: 2.9 [1.3-6.3]; P=0.009), age > 60 years (3.1 [1.2-8.2]; P=0.025), and higher risk R-IPSS (2.7 [1.3-6.0]; P=0.011) predicted worse OS after t-MDS/AML diagnosis. None of these retained significance in the multivariable analysis. T-MDS/AML following an Auto-HCT for MM is associated with aggressive disease characteristics, including high risk cytogenetics and TP53 mutations. The outcomes of patients remain poor, even with Allo-HCT. A better understanding of disease biology and novel therapeutic approaches is warranted.