Letermovir profilaxis allogén vérképző-őssejt transzplantációban: egy hazai centrum gyakorlati tapasztalatai

Összefoglaló. Bevezetés: A humán cytomegalovírus infekció direkt és indirekt szövődményei napjainkban is veszélyeztetik az allogén őssejt-transzplantációval kezelt betegeket. A széles körben alkalmazott preemptív stratégia mellett előnyös lehet a kórokozó reaktivációjának megelőzése profilaktikusan adagolt vírusellenes vegyülettel. A letermovir innovatív hatásmechanizmusú, szűk spektrumú antivirális szer, mely allogén őssejt-transzplantáltak körében végzett, placebo kontrollált klinikai vizsgálatban csökkentette a cytomegalovírus infekciók gyakoriságát és javította a túlélést. A szerzők 23, allogén őssejt-transzplantált beteg retrospektív módon gyűjtött adatait ismertetik, akik a beavatkozás kapcsán letermovir profilaxisban részesültek. A betegek több mint fele akut leukémiában szenvedett, harmaduk aktív betegséggel került transzplantációra, kétharmaduk donora haploidentikus egyezést mutatott. A letermovir adagolása során 2, azt követően további 3 személyben lépett fel cytomegalovírus infekció. Szervi érintettséggel járó cytomegalovírus betegség egyetlen esetben sem alakult ki. A megfigyelési időszak során 2 fő hunyt el, cytomegalovírustól független okok miatt. Az alkalmazhatóságot korlátozó mellékhatást nem észleltek. A letermovir a mindennapi klinikai gyakorlatban is hatékonynak és biztonságosnak bizonyult az őssejt-transzplantáltak cytomegalovírus fertőzésének megelőzésére. Summary. Introduction: Direct and indirect effects of cytomegalovirus infection remain an ongoing threat to patients treated with allogeneic stem cell transplantation. In addition to the widely used preemptive approach, prevention of viral replication with a prophylactically administered antiviral drug seems to be feasible. Letermovir, a narrow-spectrum antiviral compound with an innovative mechanism of action, has been shown to decrease the incidence of cytomegalovirus infection and to improve survival in a placebo-controlled clinical trial recruiting allogeneic stem cell transplant patients. Authors present retrospectively collected data from 23 patients receiving letermovir prophylaxis as a part of their allogeneic stem cell transplantation procedure. More than half of prophylaxed individuals had acute leukemia, a third of them underwent transplantation with an active disease and two third of the cohort had a haploidentical donor. During prophylaxis 2, subsequently further 3 patients developed a cytomegalovirus infection. No organ-specific disease could be detected. Through the observational period 2 patients have died due to causes unrelated to cytomegalovirus. No side effect interfering with drug use could be revealed. In this real-life case series letermovir has been shown to be effective and safe for the prevention of cytomegalovirus infection in allogeneic stem cell transplant patients.

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Introduction: Acute myeloid leukemia (AML) is heterogenous disease with a range of cytogenetic and molecular changes. Several molecular mutations identified in AML patients at diagnosis have prognostic implications and play important roles in guiding induction and consolidative treatment decisions. The prognostic impact of mutations peri allogeneic stem cell transplant are less well characterized. In this study, we examine the significance of pre and by D100 Post-transplant mutation status in AML patients underwent Fludarabine/Melphalan conditioned reduced intensity allogeneic stem cell transplant (SCT). Methods: AML patients who are in morphologic complete remission (CR1 or greater) with available molecular mutation at diagnosis, within 6 weeks prior to allogeneic SCT, and by 100 days post-transplant were included. Variables analyzed included baseline demographics, clinical variables (CIBMTR disease risk index (DRI), type of transplant, ELN risk, performance status) and 23 recurring molecular mutations. Analysis was also performed by grouping mutations into six pre-defined gene groups based on gene function (Table 2). Multivariable cox regression analysis was adjusted for age, gender, DRI and molecular mutation. Backward selection method was used to select the best combination of genes that is associated with overall survival (OS) and relapse-free survival (RFS). Results : A total of 142 AML patients with molecular genetic data available from 2014 to June, 2020 at Weill Cornell Medicine/New York Presbyterian Hospital were analyzed. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (range 20 -78). Total of 261 mutations were detectable at diagnosis (Table 3). Prior to allo SCT and by D100, the detectable mutations were 87 and 40 respectively, which represent 56 and 26 patients. High-dose chemotherapy was less effective on clearing DNMT3A, ASXL1, TET2 (DAT) or IDH mutations, resulting in over-representation of DAT and IDH mutations prior to transplant. With a median follow-up time of 25 months, the median overall survival for the group was 40.8 months. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced OS and RFS, and Age >60 at diagnosis was associated with worse OS (HR 1.7 CI 1.04-3, p 0.03). Presence of any molecular mutation prior to transplant did not impact OS or RFS. For patients with any persistent mutations by D100 post-transplant, both OS ( HR 2.04, p 0.027, CI 1.08-3.8) and RFS (HR 1.99, p 0.025, CI 1.09-3.6,) were reduced in the univariate analysis, but not on multivariate analysis (HR 1.88, p 0.5, CI 0.99-3.49). Analysis based on six mutational groups (table 2) did not show any difference in their OS or RFS. However, worse RFS was independently associated with persistent IDH1 (HR 3.8, p 0.004, CI 1.07-56,), TET2 (HR 3.9, P 0.04, CI 1.04-14.1), and FLT3-ITD (HR 4.5, p 0.01, CI 1.7-52). Worse OS was independently associated with persistent TET2 (HR 3.9, p 0.013, CI 1.04-14.1), with a trend towards worse OS for IDH1, FLT3-ITD, with a trend towards worsening OS and RFS for ASXL1 (OS HR 7.4, p 0.06, CI 0.86 -63; RFS HR 4.9, p 0.06, CI 0.9-26) and DNMT3A (OS HR 2.3, p 0.12, CI 0.86-6.9; RFS 2.9, p 0.08, CI 0.98-8). Association with worse clinical outcomes remained significant after multivariate analysis for TET2 (both OS HR 3.98 p 0.041, CI1.07- 32 and RFS HR 5.8, p 0.032, CI 1.1- 29), IDH1 (RFS HR 8.02, p 0.049, CI 1.02 - 65) and FLT3-ITD (RFS HR 11.4, p0.010, CI 2.2- 80). Conclusions: Presence of TP53 mutations was associated with worse OS. Presence of pre-transplant mutation did not impact RFS or OS. Persistent presence of mutations in TET2, IDH1 and FLT3-ITD after Fludarabine/melphalan conditioning regimen allogeneic SCT were associated with shorter RFS and OS (in the case of TET2) independent of CIBMTR DRI. This analysis supports association of adverse outcomes in AML patients with selected persistent mutations by D100 post-transplant in reduced intensity transplant setting. Post-transplant strategies that can further eliminate persistent mutations should be investigated in prospective studies. Figure 1 Figure 1. Disclosures Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Desai: Kura Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Takeda: Consultancy; Janssen R&D: Research Funding; Astex: Research Funding. Ritchie: Protaganist: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; NS Pharma: Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Roboz: MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

Real-World Outcomes in Adolescents and Young Adults with Acute Lymphoblastic Leukemia without Access to Allogeneic Stem Cell Transplant

Introduction: Adolescents and young adult (AYA) patients (ages 15-39) with acute lymphoblastic leukemia (ALL) have inferior outcomes and increased treatment-related toxicity when compared to children. The use of pediatric-inspired protocols has resulted in improved outcomes in the AYA population but outcomes remain inferior to their pediatric counterparts. Hispanic patients with ALL also have inferior outcomes compared to non-Hispanic White patients. Real-world outcomes in AYA ALL patients without access to allogeneic transplant are not known, especially in Hispanic/Latino populations. Thus, in order to understand treatment outcomes with modern chemotherapy regimens in this high-risk population, we conducted a retrospective cohort analysis of all AYA ALL patients without access to allogeneic stem cell transplant at a large safety-net hospital. Methods: We conducted a retrospective single-center cohort analysis of ALL patients ages 18 to 39 treated at a large safety-net hospital in Dallas, TX between January 2010 and May 2021. All patients who received induction and consolidation at Parkland Health and Hospital System and did not receive an allogeneic stem cell transplant were included. We interrogated the database for demographic, laboratory, cytogenetic, and next-generation sequencing (using the Foundation Medicine platform) information as well as treatment outcomes and post-relapse therapy. Chemotherapy consisted of either Hyper-CVAD (+/- TKI) or the CALGB 10403 protocol. Data were stored in the RedCap database and SPSS analytical software was used to generate survival analysis and Kaplan-Meier plots. Results: We identified 54 AYA ALL patients during the designated time period, consisting of 36 males and 18 females. The median age of the cohort was 28 years, and 81% of patients were Hispanic. Twelve patients were Ph(+) and 42 patients were Ph(-); 11/12 Ph(+) patients received a TKI with induction and one patient received a TKI beginning with consolidation. Cytogenetic/FISH testing and next-generation sequencing (NGS) were performed in 42 (78%) and 13 (24%) patients respectively, with the most common aberrations noted in Table 1. Of note, NGS was not routinely performed before 2017 at our institution. Six of the 13 patients with NGS results available had Ph-like mutation signatures. The most common induction regimens used were CALGB 10403 (65%), Hyper-CVAD (15%), and Hyper-CVAD + TKI (20%). Forty-one of 49 patients (84%) with a documented day 30 bone marrow biopsy achieved a CR or CR with incomplete count recovery after induction which included 11/12 (92%) Ph(+) patients, 24/31 (77%) Ph(-) patients, and 6/6 (100%) Ph-like patients. Of the patients in CR or CRi at day 30, 27 (50%) were negative for minimal residual disease (MRD) by flow cytometry. Overall survival at 3 years for the entire cohort was 69%, and there was no statistical difference between Ph(+) and Ph(-) patients. Three-year OS was improved in patients who received Hyper-CVAD + TKI (78%) or CALGB 10403 (65%) compared to those who received Hyper-CVAD alone (59%) though this did not reach statistical significance (p=0.72). Conclusions: Our results underscore the ongoing outcomes disparities in the AYA and Hispanic populations, even with the use of modern pediatric-inspired and TKI-containing regimens. The 69% 3-year OS in our population is similar to that in the transplant-eligible AYA population and suggests a diminishing role for allogeneic transplant with current protocols. The high rate of Ph-like signatures on NGS in our population is consistent with the increased prevalence of these mutations in Hispanic ALL patients. Our study is limited as it is a retrospective analysis with a small sample size and represents the results of a single institution. Prospective studies are needed to determine the role of allogeneic transplant in Ph(+) and Ph-like AYA with ALL, and concerted efforts should be made to enroll Hispanic patients in these clinical trials given their high-risk biology and inferior outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Outcomes for Allogeneic Stem Cell Transplantation in Secondary AML Are Inferior to De Novo AML and Are Independent of the Disease Risk Index

Background Patients with secondary acute myeloid leukaemia (sAML), defined as AML that follows a diagnosis of myelodysplastic syndrome or myeloproliferative neoplasm, are known to have a poor prognosis with conventional chemotherapy alone, when compared to de novo AML (dnAML). Allogeneic stem cell transplant offers the best chance of cure due to the often chemo-resistant nature of sAML, although there are limited studies assessing the outcome of allografting in this patient population. The Disease Risk Index (DRI) is a clinical decision tool which assists in determining the balance of transplant risk versus benefit, however validation studies to date have not evaluated the DRI in patients with sAML. Methods A retrospective analysis of 211 patients with dnAML or sAML who underwent allogeneic stem cell transplant between 1 st January 1998 and 31 st July 2015 at St Vincent's Hospital or Royal North Shore Hospital in Sydney Australia, was undertaken. Cases were identified from the Australasian Bone Marrow Transplant Recipient Registry, with additional data collected by medical record review. Overall survival (OS) probability was calculated by the Kaplan-Meier method. Non-relapse mortality (NRM) and relapse incidence (RI) were estimated by cumulative incidence with "death without relapse" and "relapse" as competing risks. A Cox proportional hazards model was used for multivariate regression, with results expressed as hazard ratio (HR) with 95% confidence intervals. Results Of the 211 eligible patients, 63 (30%) had a diagnosis of sAML, compared to 148 with dnAML. Of those with sAML, 74% had antecedent MDS and 26% an MPN. Patients with sAML had an older median age (55 vs 44 years, p<0.001), more often had HCT-CI >3 (p=0.003), and more commonly had at least one cytogenetic abnormality (p=0.026). A myeloablative conditioning regimen was used in 35.3% and 66.0% of s- and dn- AML respectively. Grade II or greater acute graft-versus-host disease (GVHD) occurred in 39.7% of sAML and 29% of dnAML, with chronic GVHD reported in 60.3% and 64.5% respectively. OS at 1 year was 48.5% in sAML and 71.6% in dnAML (HR 1.93 [95%CI 1.32-2.97, p=0.0001]). Multivariate analysis accounting for disease risk index (DRI) as a co-factor identified sAML as an independent adverse risk factor for OS (HR 2.13 [95%CI 1.31-3.45], p=0.002). Compared to dnAML, sAML was associated with higher rates of disease relapse (HR 2.21 [95%CI 1.20-4.05], p=-0.011). Figure 1: Transplant outcomes (A) Overall survival dnAML vs sAML (B) Cumulative incidence of relapse at 1 year dnAML vs sAML Conclusions Patients with sAML experience poorer outcomes following allogeneic stem cell transplant than those with dnAML. Whilst the DRI stratifies AML based on cytogenetic risk and stage, our study identifies sAML as a prognostic marker independent of risk ascribed by the DRI. This has not been reported previously and if replicated, suggests the need for development of an independent prognostic model to capture the adverse risk in the sAML patient cohort. Importantly, despite poor outcomes, the lack of alternate management strategies still makes allogeneic stem cell transplant the only potential curative therapy. Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Single Center Retrospective Analysis of Letermovir for Cytomegalovirus Prophylaxis after Allogeneic Stem Cell Transplant in Cytomegalovirus Seropositive Recipients or Donors

Background: Up to 70% of allogeneic stem cell transplant (alloSCT) recipients who are cytomegalovirus (CMV) seropositive experience CMV reactivation and up to a third are complicated by end-organ disease. Letermovir, an antiviral agent targeting CMV, is FDA-approved for prophylaxis of CMV reactivation in CMV seropositive recipients of alloSCT. 1-4 In CMV seropositive recipients, letermovir use up to week 14 after alloSCT has demonstrated a significantly lower incidence of clinically significant CMV infection (csCMVi) and an overall mortality benefit as far as 24 weeks after transplant. 5-8 However, data on csCMVi beyond 24 weeks is lacking. Additionally, more information is needed on letermovir use in patients who had prior alloSCT, are CMV seronegative, have a detectable CMV viral load but without csCMVi, and/or are high risk*. Methods: This is a single-center, retrospective, comparative cohort analysis of 524 patients who received alloSCT at Barnes-Jewish Hospital from January 2016 to June 2019. Of those, 191 patients were excluded because both the recipient and donor were seronegative for CMV. Patient information was obtained from the electronic medical record systems after IRB approval of the protocol. Gray's sub-distribution methods (while account for death as competing risk) were used to calculate the incidence of csCMVi and to assess the effect of letermovir on csCMVi. Univariate and multivariate Cox proportional hazards models were fitted for the effect of letermovir on overall survival (OS), and time-dependent Cox model was used to determine the effect of csCMVi on OS. Results: Out of 333 patients, 149 received letermovir. The median follow-up period was 13.38 months (0.033 to 63.8 months). A univariate analysis demonstrated that csCMVi was associated with worse OS (HR 2.173, 95% CI 1.602-2.948). Among those who received letermovir, there were reductions in csCMVi for the overall cohort and for high-risk patients at 100 days, 180 days, and 365 days after alloSCT. In seropositive recipients receiving seropositive alloSCT (CMV +/+), there were reductions in csCMVi at days 100, 180, and 365 after transplant. In seropositive recipients receiving seronegative alloSCT (CMV +/-), there was a reduction in csCMVi at 100 days after transplant. There was a reduction in CMV-related mortality at day 180 post-transplant (p=0.03) but not at day 365 (p=0.46). Additionally, for the overall cohort, the letermovir group showed worse OS from days 180-365 (HR 1.938, 95% CI 1.143-3.285). In CMV seronegative patients receiving seropositive SCT (CMV -/+), no difference in csCMVi was detected at days 100, 180, and 365. A landmark analysis of Day 100 IgG level effect on csCMVi incidence demonstrated that lower IgG level (<485) is associated with higher csCMVi rates after Day 100 (p=0.004). Day 100 CD4 level was not found to be predictive of csCMVi (p=0.744). Conclusion: Letermovir prophylaxis reduces csCMVi overall and in high risk and CMV seropositive patients. We observed a reduction in CMV-related mortality at 180 days after transplant with letermovir prophylaxis. A worsening of OS after day 180 and a trend towards worse non-relapse mortality was surprising and may be related to a higher degree of immunosuppression associated with post-transplant cyclophosphamide (PTCy) use, haploidentical SCT, thymoglobulin use, prior SCTs, and CMV high-risk* patients. Additionally, letermovir was stopped at day 100 at which point survival worsens and the incidence of csCMVi precipitously increases. Our results suggest that there may be additional benefit to extending letermovir therapy past day 100 in the high-risk groups, haploidentical SCT group, patients with low IgG levels at day 100, and subclinical CMV viremia. *High risk patients were defined as those receiving haploidentical, mismatched related, mismatched unrelated, umbilical cord blood, T-cell depleted graft stem cell transplants or immunosuppression with methylprednisolone > 1 mg/kg or 2 or more immunosuppressants. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.