Primary Disease Relapse Research Articles

Evaluation of Novel Endpoints As Treatment Outcome in Allogeneic Hematopoietic Stem Cell Transplantation: A Comparison of “Classical” and “Refined” Definition of Graft-Versus Host Disease Free and Relapse Free Survival for Registry-Based Studies

Allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Holtan et al. (Blood 2015) proposed GVHD free/relapse free survival (GRFS), as a composite endpoint to analyse transplant associated morbidity. This endpoint considers as events grades III-IV acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse, or death for any cause. Although it could be a good indicator in prospective trials, since it seems to characterize the survival without mortality or ongoing morbidity, it might be difficult to use in retrospective setting. A “refined” GRFS (considering grade III-IV acute GVHD, extended/severe chronic GVHD, relapse and death for any cause) was proposed by Ruggeri et al (BMT 2016) to adapt this endpoint also to registry-based studies.To compare definitions of this composite endpoint we retrospectively analyzed “classical” and “refined” GRFS on 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital in Paris (n=840) between 2007 and 2014. Data collection is based on the European Group of Blood and Marrow Transplantation (EBMT) registry via the central data processing system “Project Manager Internet Server” (ProMISe), considering the MED-A and MED-B forms for patients registered in those two centers. A MED-C form was built for all patients who developed chronic GVHD.Median age of patients at transplant was 41 (range 4-64 years) whereas median duration of follow-up for survivors after HSCT was 38 months (range: 0-97.7 months). Characteristics of patients were reported in table 1. Cumulative incidence (CI) at day 100 of grade II-IV and grade III-IV acute GVHD were 41.1% (95%CI 37.9-44.3%) and 15.6% (95%CI 13.4-18), respectively. CI of chronic GVHD requiring systemic treatment and diagnosed according to NIH criteria was 22.3% (95%CI 20.7 -26.3) at 1 year and 32.6 % (95%CI 29.5-36.0) at 3 years. CI of severe/extended chronic GVHD (as reported in ProMise registry) was estimated at 16.6% (95%CI 14.1-19.5) at 1 year and 22.5% (95%CI 19.4-26.0) at 3 years. CI of relapse was 18.7% (95%CI 16.3-21.5%) at 1 year, 25.1% (95%CI 22.3-28.2%) at 3 years and 26.7 (95%CI 23.7-30.0) at 5-years. Probability of survival (OS) of the whole population at 1, 3 and 5 years was respectively: 75% (95%CI 73.0-76.9), 62% (95%CI 58.0-65.8), and 57% (95%CI 55.0-58.9). Event free survival (EFS) was 64% (95%CI 48.0-56.9) at 1 year, 53% at 3 years (95%CI 49.1-56.9) and 50% at 5 years (95%CI 48.0-52.0). Global classical GRFS was 71% (95%CI, 69.0-72.9) at 1 years, 52% (95%CI 48.1-55.9) at 3 years and 35% (95%CI 31.2-39.0) at 5 years, whereas refined GRFS was 71% (95%CI, 69.0-72.9), 53% (95%CI 49.1-56.9) and 38% (95%CI 34.2-42.0) at 1, 3, and 5 years respectively. Six hundred twenty-eight subjects were censored by classical GRFS whereas 546 patients have been identified as reporting at last one event according to refined GRFS. Chronic GVHD and relapse represented the major components of classical GRFS (35.7 and 35.2% respectively) whereas relapse (40.5%) and III-IV acute GVHD (25.6%) were major constituents of refined GRFS (Figure 2). According both definitions several risk factors were identified in univariate and multivariate analysis. Particularly, transplants performed after 2010, diagnosis of acute leukemia and RIC regimens had a significant impact on survival without GVHD and relapse (both in classical and in refined GRFS) whereas age, stem cell source, disease risk group (identified as influencing factors in univariate analysis) did not impacted on GRFS in multivariate model. Transplants from non-matched unrelated donors showed a significant impact only on classical GRFS in COX regression. The multivariable c-statistics were 0.609 for classical and 0.614 for refined GRFS.Our data support the use of both composite endpoints to describe HSCT outcomes. Classical GRFS could represent the ideal endpoint following HSCT in prospective setting, whereas refined GRFS could be used as good surrogate of GRFS in retrospective studies. However, attention need to be paid concerning the use of refined indicator because of the risk of underestimation of censored events, since it may not reflect the real impact of chronic GVHD on population in study. [Display omitted] DisclosuresPeffault De Latour:Amgen: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Socié:Alexion Pharmaceuticals, Inc.: Consultancy.

AML SCT-BFM 2007: Results of the Prospective Hematopoietic Stem Cell Transplantation (HCT) Trial of the Berlin-Frankfurt-Münster (BFM) Study Group for Children with Very High Risk Acute Myeloid Leukemia

BACKGROUNDPediatric AML represents a rare and heterogeneous disease. Within the BFM study group, HCT for this patient cohort was performed with considerable inter-center variability. AML SCT-BFM 2007 was based on a transplantation consensus and aimed to prospectively generate a reliable body of data on which further transplantation technologies could be based. METHODSAML SCT-BFM 2007 was conducted according to current legislation as an international multicenter clinical trial (EudraCT: 2007-004517-34, NCT00606723), data were collected via a specifically developed remote data entry (RDE)-based data bank, and verified against source data by an on-site monitoring program. Children with cytogentic and molecular high-risk features achieving a complete first remission (CR1) and those in CR2 after a first relapse qualified for HCT from a matched donor (MD). A MD was defined to be identical when at least 9/10 alleles on the HLA-A, B, C, DRB1 and DQ loci did match. A myeloablative conditioning regimen consisting of Busulfan (age adjusted i.v. dosing: 3.2 - 4,8 mg/kg BW on days -7 through -4), Cyclophosphamide (60mg/kg iv on days -3 and -2), and Melphalan (140 mg/m2 on day -1) termed BuCyMel was used. For GVHD prophylaxis CSA and short term MTX were given, for unrelated donors anti-thymocyte globulin (ATG Neovii) was added. Children with refractory primary disease or refractory relapse were eligible for early transplantation. A cytoreductive regimen containing Fludarabine (30mg/m2/d i.v.), Amsacrine (100 mg/m2/d i.v.) and Cytarabine (2g/m2/d i.v.) all on days -12 through -9 (FLAMSA) was immediately followed by a reduced intensity conditioning (RIC) consisting of 4 Gy TBI and Cyclophosphamide (60 (unrelated)/40 (related) mg/kg/d i.v.) on days -4 and -3. After early taper of immunosuppression (MMF halted by day 40 and CSA after taper by day 90) increasing doses of prophylactic donor lymphocyte infusions (DLI) were given on days 120, 150, and 180. Standard statistical methods were used for the analysis of event-free survival (EFS, events: relapse, death from any cause), overall survival (OS), cumulative incidence of treatment related mortality (TRM) and relapse (CIR) after HCT. RESULTSRecruitment was conducted between 5/2010 and 2/2016. 97 children underwent HCT after conditioning with BuCyMel. Median neutrophil engraftment was achieved after 21 days (range 9-38). 3-year EFS and OS were 62%, standard error (SE) 5%, and 73%, SE 5%. CIR was 22%, SE 4%. Median time to relapse was 8 months (range 1-66) after HCT. TRM was 15%, SE 4%, with 8/15 patients dying before day 100. TRM correlated with age with a rate of 9% in children younger than 12 years (n = 68) and 31% in older children and adolescents (Fig. A). This resulted in a stop of using BuCyMel for older children and adolescents in 6/2014. The rate of acute graft versus host disease (aGVHD) grade II-IV was 22%, chronic GVHD developed in 11%. Median neutrophil engraftment for children transplanted for refractory disease (n= 35) was 23 days (range 10-34). 3-year EFS and OS were 46%, SE 8%, and 51%, SE 9%. EFS for primarily refractory disease was 53%, SE 11%, whereas EFS for refractory relapses (n = 7) was 29%. Relapse rate was 43%, SE 9%, and TRM reached 11%, SE 5% (Fig. B). Acute and chronic GVHD rates were at 26% and 17%. CONCLUSIONWithin a well-defined trial concept HCT from a matched donor using BuCyMel for conditioning results in an EFS of 60% with a low TRM rate in younger children. The identical approach is associated with a high TRM rate of 31% in older children and adolescents. Whether the use of alternative conditioning strategies in this population can reduce mortality while maintaining the relapse-free survival rates remains to be determined. In high-risk patients with refractory disease, early use of RIC HCT followed by the infusion of prophylactically given DLI can induce long-term remissions in more than 50% of children without increasing the risk for GVHD. [Display omitted] DisclosuresSauer:Neovii: Research Funding. Lang:Miltenyi Biotec GmbH: Patents & Royalties, Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Handgretinger:Miltenyibiotec GmbH: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation

Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplantation (alloHSCT), defined as those living ≥5 years post-transplantation, is significantly lower compared with that of the age-matched general population despite a relatively low primary disease relapse rate at >2 years post-transplantation. Among several factors, patient sex is increasingly recognized as a prognostic indicator of long-term survival. We examined the influence of patient sex and donor-recipient sex matching on overall survival (OS) in a landmark analysis of long-term survivors. Using our institutional database supplemented with individual patient record review, we retrospectively investigated the relative influence of recipient sex and donor-recipient sex matching on outcomes of long-term survivors of alloHSCT between 1994 and 2014. Over this 20-year period, 247 met inclusion criteria for analysis; males and females had similar demographic and treatment characteristics. However, significantly more deaths after the 5-year landmark occurred in male recipients. Interestingly, donor sex did not have a significant impact on OS in multivariate analysis, and differences in OS of donor-recipient sex pairs was driven by recipient sex. In addition to recipient sex, only chronic graft-versus-host disease (cGVHD) retained significance as a covariate with an impact on OS in multivariate analysis. Men experienced slightly higher, but statistically nonsignificant, rates and increased severity of cGVHD, and had higher cGVHD-related mortality compared with females. In this long-term survival analysis of adult alloHSCT recipients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplantation. This outcome is independent of other common pretransplantation prognostic indicators, such as donor sex or performance status at transplantation. The inferior survival in males is consistent with survival outcomes described in the transplantation literature. Increasing evidence suggests a biological basis for long-term sex-determined outcomes, possibly owing to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Larger studies are warranted to validate these retrospective clinical results.

Salvage therapies in transplant-eligible relapsed classic Hodgkin lymphoma, are novel regimens better?

7530 Background: Clinical trials of novel salvage therapies (ST) have encouraging outcomes for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) eligible for autologous stem cell transplant (ASCT). In this observational study, we report efficacies and outcomes of different ST in ASCT-eligible R/R cHL. Methods: Consecutive ASCT-eligible R/R cHL pts at 3 Mayo Clinic sites were included. Demographics and clinical variables at relapse were recorded by medical records review. Time to event endpoints were defined from relapse. Univariate associations were confirmed in multivariate models of age, sex, B symptoms, stage, bulky disease (BD, single mass > 6 cm) extra nodal disease (END), primary refractory disease (PRD) and early relapse (ER, within 1 year). Results: From Jan 2008 to May 2020, 207 ASCT-eligible pts with R/R cHL were included. Median age was 33 (24-43) years, 53% were male, 52% had advanced stage, 24% had BD, 36% had B symptoms, 41% had END, 11% had PRD and 43% had ER. All patients received ST and underwent ASCT; 43 (21%) received 2 ST, 14 (7%) 3 ST and 4 (0.5%) received 4 ST. 6 groups of ST were identified: ifosfamide, carboplatin and etoposide (ICE), bendamustine/brentuximab (BBV), brentuximab vedotin (BV), gemcitabine-based therapy (Gem), checkpoint inhibitor (CPI), and others. Table lists response to first line ST. BBV had significantly higher overall response rate (ORR) and complete response (CR) as first ST in univariate and multivariate models. 114 (79%) after ICE, 30 (97%) after BBV, 15 (56%) after BV, 25 (76%) after Gem, 8 (73%) after CPI and 15 (79%) after other ST underwent ASCT. Higher number of pts were bridged to ASCT after BBV than ICE (p<0.01). 110 (53%) went to ASCT in CR, 74 (36%) in partial response (PR) and 11% in progressive disease (PD). 43 received BV maintenance (BVm) after ASCT. Pts going to ASCT in PR or PD had significantly lower progression free survival (PFS) compared to pts in CR (2 yr PFS: 62%, 18% vs 77%, respectively, p<0.0001) in univariate and multivariate models. There was no difference in PFS and overall survival (OS) by type of ST. BVm was associated with higher PFS (HR 0.3 (CI95 0.2-0.8)) and higher number of ST was associated with lower OS (HR 2 (CI95 1.4-3)) in multivariate model (p<0.001). For pts transplanted in CR, there was no significant difference in PFS and OS by type of ST but higher number of ST predicted lower OS (HR 2.4 (CI95 1.2-3.5), p<0.01). Conclusions: Type of ST did not predict survival, response to and number of ST did. For pts with CR, number of ST not type of ST predicted survival. BBV had higher response rates, higher rates of bridge to ASCT, and may be a preferable ST than ICE. Large, randomized trials are needed to evaluate efficacy of BBV compared to ICE.[Table: see text]

Relapse Protection Following Early Cytomegalovirus Reactivation after Hematopoietic Stem Cell Transplantation Is Limited to HLA-C Killer Cell Immunoglobulin-Like Receptor Ligand Homozygous Recipients

Although the risk for nonrelapse mortality (NRM) associated with early cytomegalovirus (CMV) reactivation (CMVR) after allogeneic hematopoietic stem cell transplantation (HSCT) is well established, debate is ongoing on whether CMVR may reduce the risk of primary disease relapse. The aim of this study was to evaluate relapse protection following early CMV reactivation after HSCT in the context of the recipient HLA-C killer cell immunoglobulin-like receptor ligands (KIRLs). In this retrospective bicentric study, 406 matched related or unrelated donor transplantations for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were stratified by HLA-C KIRL group (homozygous versus heterozygous) and analyzed separately for the impact of early CMVR on the cumulative incidences of relapse, NRM, and acute and chronic graft-versus-host-disease (GVHD) using landmark and multistate analyses. By landmark analysis of patients alive and relapse-free at 45 days post-HSCT, HLA-C KIRL homozygous recipients (C1/1 or C2/2) had a lower risk of subsequent relapse if CMVR occurred before this landmark (subhazard ratio [sHR], 0.36; P=.002). In contrast, in HLA-C KIRL heterozygous (C1/2) recipients, early CMVR had no impact on subsequent relapse (sHR, 0.88; P=.63). NRM (sHR, 3.31; P < .001) and grade III-IV acute GVHD (sHR, 2.60; P=.04) were significantly increased after early CMVR in the homozygous cohort, but not in the heterozygous cohort (NRM: sHR, 1.23; P=.53; grade III-IV acute GVHD: sHR, 1.40; P=.50). Multivariable landmark analyses and a multistate model confirmed the limitation of the relapse-protective effect of early CMVR to the homozygous cohort. Chronic GVHD and overall survival were not influenced in neither cohort. An antileukemic effect of early CMVR after HSCT for AML/MDS was significant but strictly limited to recipients homozygous for HLA-C KIRL. However, particularly in this cohort, CMVR had an adverse impact on aGVHD and NRM.

Cannabidiol Enhances Intestinal Cannabinoid Receptor Type 2 Receptor Expression and Activation Increasing Regulatory T Cells and Reduces Murine Acute Graft-versus-Host Disease without Interfering with the Graft-versus-Leukemia Response.

Cannabidiol (CBD) is a highly lipidic phytocannabinoid with remarkable anti-inflammatory effects. The aim of this study was to evaluate CBD's effects and mechanisms of action in the treatment of mice subjected to acute graft-versus-host disease (aGVHD). aGVHD was induced by the transplantation of bone marrow cells and splenocytes from C57BL-6j to Balb-c mice. The recipient mice were treated daily with CBD, and the treatment reduced mouse mortality by decreasing inflammation and injury and promoting immune regulation in the jejunum, ileum, and liver. Analysis of the jejunum and ileum showed that CBD treatment reduced the levels of C-C motif chemokine ligand (CCL) 2, CCL3, CCL5, tumor necrosis factor α, and interferon γ (IFNγ). CCL3 and IFNγ levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB2) receptors on CD4+ and forkhead box P3+ cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB2 receptor reduced the survival rates of CBD-treated mice, suggesting the participation of this receptor in the effects of CBD. Furthermore, treatment with CBD did not interfere with the graft-versus-leukemia response. CBD treatment appears to protect aGVHD mice by anti-inflammatory and immunomodulatory effects partially mediated by CB2 receptor interaction. Altogether, our study suggests that CBD represents an interesting approach in the treatment of aGVHD, with potential therapeutic applications in patients undergoing bone marrow transplantation. SIGNIFICANCE STATEMENT: This study provides for the first time a mechanism by which cannabidiol, a phytocannabinoid with no psychoactive effect, induces immunomodulation in the graft-versus-host disease. Enhancing intestinal cannabinoid receptor type 2 (CB2) receptor expression on CD4+ and forkhead box P3+ cells and increasing the number of these regulatory cells, cannabidiol decreases proinflammatory cytokines and increases graft-versus-host disease mice survival. This effect is dependent of CB2 receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.

Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy.

Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%–40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM.

Distinct Clinical and Genetic Factors Predict Early Versus Late Mortality in AML Patients Undergoing Induction Chemotherapy

Background: Long-term survival after intensive induction chemotherapy in acute myeloid leukemia (AML) is limited by both early mortality and disease resistance. A central clinical challenge is predicting which patients will experience early toxicity during induction or resistant disease. Limitations of prior analyses include a specific focus on either early treatment-related mortality or overall survival (OS), an absence of genetic annotation in early mortality studies, and reliance on clinical trial cohorts which may not be broadly representative. Here, we perform a detailed analysis of pretreatment clinical and disease characteristics in a cohort of real-world AML patients to elucidate factors associated with early mortality and with OS after induction. Methods: We identified 290 consecutive adult patients treated with standard induction chemotherapy ("7+3" with cytarabine and an anthracycline, or CPX-351) for newly diagnosed AML (2014-2019). We collected pretreatment clinical, pathology, and laboratory data, and annotated clinical outcomes. Gene mutations were determined at the time of diagnosis using targeted next-generation sequencing of recurrently mutated genes. The median age at diagnosis was 61 years (range 19-76), with 56% of patients aged 60 or older. Most patients (71%) had de novo AML; 15% had clinically defined secondary AML and 14% had therapy-related AML. Median follow-up for survivors landmarked at 60 days was 26.1 months, with a minimum follow up of at least 60 days for all patients. Median OS and relapse-free survival (RFS), both landmarked at day 60, were 33.9 months and 28.0 months, respectively. Results: In total, 24 of 290 (8%) patients died within the first 60 days of receiving induction chemotherapy, with shock being the most common cause of death (42%), followed by respiratory failure (21%) (Figure 1A). In a multivariable logistic regression model, we found that pretreatment albumin &amp;lt; 3 mg/dL, pretreatment LDH &amp;gt;= 600 U/L, and mutations in TET2 or RUNX1 were independently associated with death within 60 days (Figure 1B). Factors not independently associated with early mortality included older age (&amp;lt;60 versus 60 or older), clinical ontogeny (secondary or treatment-related AML), complex karyotype, and pretreatment blood counts. To identify factors associated with outcomes among patients surviving past 60 days, we generated a multivariable model with allogeneic stem cell transplantation as a time-varying covariate. In this model, age &amp;gt;= 60, secondary AML, pretreatment LDH &amp;gt;= 600 U/L, and the presence of TP53 mutation, U2AF1 mutation, or 11q23 rearrangement were independently associated with inferior OS after day 60, whereas the presence of CBF rearrangement was independently associated with superior OS after day 60 (Figure 1C). To determine the contribution of resistant disease to OS landmarked at day 60, we developed multivariable models for failure to achieve remission by day 60 and for RFS landmarked at day 60, and then applied them to the OS model. All variables remained significant, indicating that disease resistance is a main driver of OS after 60 days. Conclusions: Early treatment-related mortality is most commonly the result of shock and respiratory failure, irrespective of disease status, and is associated with specific pretreatment lab values (elevated LDH, low albumin) and disease-specific mutations (TET2 and RUNX1). Among patients surviving induction, survival is driven primarily by resistant disease (primary refractoriness and disease relapse) and is associated with factors previously correlated with outcome in AML, including age, clinical ontogeny, and disease genetics. Overall, we show that early and late outcomes in AML are associated with distinct sets of pretreatment clinical, genetic, and laboratory characteristics and for the first time show that disease-specific mutations are associated specifically with induction toxicity. Improved ability to identify patients likely to experience toxicity after receiving anthracycline-based AML induction may help develop mitigation strategies for these patients. Figure 1: Predictors of early mortality and overall survival in AML patients undergoing induction. A. Clinical and genetic characteristics of early mortality patients. B-C. Forest plots of multivariate analysis of pretreatment risk factors associated with early mortality (B) and with OS landmarked at 60 days (C). Disclosures Lindsley: Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding; Bluebird Bio: Consultancy.

Factors Associated with the Improvement of Outcomes of High-Risk Relapsed Hodgkin Lymphoma (HL) Patients Receiving High-Dose Chemotherapy (HDC) and Autologous Stem-Cell Transplantation (ASCT): The MD Anderson Cancer Center Experience

Factors Associated with the Improvement of Outcomes of High-Risk Relapsed Hodgkin Lymphoma (HL) Patients Receiving High-Dose Chemotherapy (HDC) and Autologous Stem-Cell Transplantation (ASCT): The MD Anderson Cancer Center Experience

Amahrelis : Adcetris Maintenance after Autologous Stem Cell Transplantation in Hodgkin Lymphoma : A Real Life Study from Sfgmtc and Lysa Groups

Background : AETHERA randomized controlled study (Moskowitz, Lancet 2015) showed that the administration of Brentuximab Vedotin (BV) maintenance after autologous stem cell transplantation (ASCT) improved progression free survival (PFS) in BV-naive refractory/relapsed (R/R) Hodgkin lymphoma (HL) patients. However, since BV approval for R/R HL in 2012, many patients are receiving salvage BV before ASCT, alone or combined with chemotherapy. In the AMAHRELIS retrospective nationwide French study, we investigated the real-life outcome of patients with R/R HL mostly treated with BV-based salvage therapies and who received post-ASCT BV maintenance. Objectives : As primary 0objective, we assessed 2 years-PFS of patients treated with post-ASCT BV maintenance from 2012 to 2017 in France. As secondary objectives, we correlated variables (such as use of salvage BV before ASCT, centrally reviewed TEP-assessed response) with survival, and evaluated reported tolerance of BV using the CTCAE v4.0 criteria. Methods : We conducted this observational retrospective study in 58 national centers. Inclusion criteria were R/R HL patients who received at least two infusions of BV after ASCT, at the exclusion of patients in progression after transplant. Among 1134 patients who underwent ASCT for R/R HL between 2012 and 2017 in France based on the French society of bone marrow transplantation database, 835 (74%) patients were screened and data were available for 794 (70%) patients. FDG-PET scan at relapse and before transplantation were recorded and centrally reviewed (still ongoing). FDG-PET scan were reported using the Deauville score (DS), and complete remission was defined by a DS &amp;lt; 4. Post-transplant status was evaluated based on CT-scan or on FDG-PET scan results. This study was approved by the SFGMTC and the LYSA. Results : Fifteen percent (115/794) of patients met eligibility criteria, and were enrolled in this study. Among them, 95% met inclusion criteria for BV maintenance according to the AETHERA study as primary refractory disease (43%), early relapse (27%) or extranodal disease (49%). The mean number of BV injections after ASCT was 11 (3-18). Patients characteristics were : mean age was 34 y (range between 16-70y), 54% were male, and 57% of patients were stage III or IV at relapse. Notably, 70% of patients received BV as salvage therapy and 81% achieved a complete remission before ASCT. The median follow-up period was 35 months. The 2 years survival for the whole cohort was 75,3% for PFS (95% CI : 68,4-84,3) and 96,4% for overall survival (95% CI : 94,2-100) (Figure 1). The use of BV as part of salvage therapy before transplant had no impact on PFS. We observed a trend to an increased occurrence of neuropathy in patients receiving BV before transplant without impact on early treatment discontinuation. We tested several variables for correlation with survival using a univariate Cox model including high risk patients defined as primary refractory disease or early relapse and disseminated disease, extranodal relapse, use of BV before transplant, number of salvage lines, remission status before and after transplant (complete response versus partial response or stable disease), time between ASCT and BV onset and number of BV cycles after transplant. Among these variables, high risk status, less than 10 post transplant BV cycles and absence of post transplant complete remission significantly correlated with a reduced survival probability, and remained significant after analysis using a multivariate Cox model (Table 1). Conclusion : From the real-life AMAHRELIS study, we confirmed the very good outcome of R/R HL patients in the era of post-transplant BV maintenance, with a 2y-PFS of 75% similar to the results of the AETHERA landmark study (2y-PFS of 63%). The results of current strategies with pre- and post-transplant BV outperformed historical series based on high dose therapies, including those of tandem transplant for high risk patients. Future studies incorporating BV strategies with immune checkpoint inhibitors might improve outcome in R/R HL patients. Disclosures Meignan: ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Fornecker:Takeda: Consultancy; Roche: Consultancy. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cartron:Gilead: Honoraria; Jansen: Honoraria; Abbvie: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Ghesquieres:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. Brice:Takeda: Consultancy; Roche: Consultancy. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents &amp; Royalties, Research Funding; Celgene BMS: Consultancy, Research Funding; Roche: Consultancy; Novartis: Research Funding; Alexion: Research Funding. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding. Deau Fischer:Takeda: Consultancy; Roche: Consultancy.

Female Gender Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplant

Introduction: Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplant (allo-HCT) is significantly lower compared to that of the age-matched general population, despite a relatively low primary disease relapse rate &amp;gt;2 years post-transplant. Long-term transplant-related complications instead account for most mortality in this patient population. These include chronic graft-versus-host disease (cGVHD), infection, organ failure, and secondary cancers. In addition, gender is emerging as a critical determinant of outcome in the immediate post-transplant setting. However, less is known regarding gender effects on outcomes of long-term survivors. We retrospectively investigated the impact of recipient gender and donor-recipient gender mismatch on outcomes of long-term survivors of allo-HCT. Methods: We performed a retrospective analysis using Duke University's Adult Blood and Marrow Transplant database, supplemented by individual patient chart review. Inclusion criteria consisted of long-term survivors of first allo-HCT, excluding syngeneic, between 1995 - 2015 for a hematologic malignancy. A long-term survivor is defined as having been alive with documented follow-up to at least five years following allo-HCT. Patient characteristics were summarized as count (%) for categorical variables and median (interquartile range) for continuous variables. Fisher's exact tests or t-tests were used to compare difference between groups. Overall survival was estimated using the Kaplan-Meier method and multivariable Cox proportional hazard model. Patients who had received cord blood allograft were excluded from donor-recipient gender survival analyses. SAS version 9.4 (SAS Institute, Cary, NC) and R 3.5.0 were used to perform statistical analyses. Results: Over this 20-year period, 1103 patients underwent allo-HCT, with 247 (22%) meeting inclusion criteria. Of these 247, males and females had similar demographic and treatment characteristics (Table 1). However, significantly more deaths after the 5-year landmark occurred in male recipients (Figure 1, p value=0.003). To estimate whether this was due to the general population-wide shorter life expectancy for males, we performed Kaplan-Meier estimates of survival for patients aged &amp;lt; 50 years at transplant and aged ≥ 50 years at transplant, with similar results for both groups (Figure 2, p value=0.006). Interestingly, donor gender did not have a significant impact on overall survival in multivariate analysis (Table 2), and differences in overall survival of donor-recipient gender pairs was driven by patient gender (Figure 3, p value =0.007). A separate multivariate analysis of interaction between donor-recipient gender pairs further demonstrated that significant differences in overall survival were due to patient gender (Table 3). In addition to patient gender, only cGVHD retained significance as a covariate with impact on overall survival in multivariate analysis (Table 2, Table 3). Men experienced slightly higher rates and increased severity of cGVHD, and a greater percentage of cGVHD-related mortality as compared to females, though these findings were not statistically significant (Table 1). Conclusion: In this long-term survival analysis of allo-HCT adult patients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplant. This outcome is independent of other common pre-transplant prognostic indicators such as donor gender or performance status at transplant. Inferior survival for males is consistent with survival outcomes described in another large and fully risk annotated HCT cohort, and in solid organ transplants such as lung and kidney. Gathering evidence suggests a biologic basis for long-term gender-determined outcomes, possibly due to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Male patients should be counseled on their possible increased long-term risk. Prospective and larger studies are warranted to validate these retrospective clinical results. Disclosures Rizzieri: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees.

Ocular neuromyotonia of the right third cranial nerve

Ocular neuromyotonia is a rare disorder of the oculomotor nerves caused by chronic damage to the nerve, usually secondary to previous irradiation or longstanding compression. We present the case of a 40-year-old man who had received proton beam therapyfor a right cavernous sinus chondrosarcoma 15 years earlier. He developed intermittent episodes of self-limited horizontal diplopia, which occurred over the course of 1 year. At its peak, the deviation reached 20Δ in primary gaze and 25Δ in right gaze. Signs included right upper lid retraction and right medial rectus muscle absence of relaxation after sustained left gaze, with mild deficit of elevation and depression but no pupillary involvement. Full recovery occurred after he closed his eyes. Ocular neuromyotonia of the right oculomotor nerve was diagnosed after recurrence of primary disease relapse was ruled out. Symptoms remitted completely under oxcarbazepine.

The complex intensive therapy regimen as curative therapy in patients with primary-resistant and relapsed neuroblastoma: R.M. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation experience

About 20% of initially high-risk patients with neuroblastoma (NB) develop primary resistant to chemotherapy and more than 50% of them subsequently have a relapse. There is currently no uniform approach to therapy in this group and long-term outcomes are dismal. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. A total of 78 patients with a median age of 5 (1–20) years with primary resistant (n = 33) or (n = 45) relapsed NB receiving treatment in R.M. Gorbacheva Memorial Center were included in this study. In 20 cases the 2nd-line therapy including topotecan (n = 10) or irinotecan (n = 10) was used, 58 patients received combined chemo- and targeted therapy (RIST regimen: rapamycin, irinotecan, sirolimus, temozolomide). Nineteen patients with primary resistant disease (n = 4) or systemic relapse (n = 15) subsequently underwent an allogeneic hemopoietic stem cell transplantation from haploidentical donor (haplo-HSCT). In all cases fludarabin-based reduced intensity conditioning (RIC) regimens were used. Ten patents received modified graft (immunomagnetic selection or depletion), in 9 unmodified graft with subsequent post-transplant cyclophosphamide (PTCM) was used. Also, 16 of 19 haplo-HSCT recipients had post-transplant therapy. The clinical effect was seen in 79% of patients. The median event-free survival (EFS) in 2nd-line therapy and RIST recipients was 2.5 (1–11) and 8 (1–76) months, accordingly. The complete of good partial response in 2nd-line therapy or RIST recipients was seen in 5% and 15%, 14% and 31% of cases accordingly. The therapy toxicity was comparable in both groups. The median EFS for haplo-HSCT recipients was 15 months with 2-year OS and EFS in this group bring 44% and 21% accordingly. Seven of 19 (37%) patients are currently alive and 4 (21%) of 19 maintain response. All long-term responders have history of posttransplant therapy. There was no statistically significant difference based on graft-versus-host disease prophylaxis used (graft modification or PTCM) or KIR compatibility. Combined chemo- and targeted therapy (RIST) is characterized by acceptable toxicity and effective even in some previously resistant cases. In 20% of responders a long-term effect may be achieved by subsequent haplo-HSCT and post-transplant therapy.

Cytokine and Chemokine Profile in Patients with Multiple Myeloma Treated with Bortezomib.

The aim of the study was to determine the levels of selected cytokines and chemokines in the serum of multiple myeloma (MM) patients treated with bortezomib-based regimens. A total of 71 MM patients were examined: 41 with primary refractory disease (17) or early relapse (28), and 30 who were bortezomib sensitive with no progression for at least six months. Patients who demonstrated CR or PR after bortezomib-based therapies longer than six months after treatment discontinuation were designated bortezomib sensitive. Serum cytokine levels were assayed with Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad). Higher levels of MIP-1α and lower levels of MIP-1β and IL-9 were associated with better responses to bortezomib-based treatment, and higher levels of IL-1ra and IL-8 were associated with bone involvement. MCP-1 was elevated in patients with hemoglobin < 10 g/dl compared to those without anemia. The levels of IL-8, MIP-1α, and TNF-α were significantly higher in patients with renal insufficiency. Only MIP-1α was elevated in patients with hypercalcemia compared to patients with normal calcium levels. In conclusion, distinct cytokines are involved in the pathogenesis of MM and may play a prominent role in the prediction of treatment response. However, a single measurement of serum cytokines should be interpreted with caution and further studies are needed.

Research Advances on Clinical Application of Umbilical Cord Blood Transplantation in the Treatment of Hematological Diseases--Review

Abstract Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells (HSCs) for patients who were lack of HLA match related or unrelated donors. Compared with bone marrow and mobilized peripheral blood, UCB has the advantages of easy availability, safety for donors, and low requirement for HLA match between donors and recipients. However, the cell amount in UCB is relatively less, which was associated with increased graft failure, delayed hematologic recovery, immune reconstitution, and higher transplant related mortality after UCB transplantation (UCBT). Double-unit UCB is a straightforward method to augment cell amount in UCB. Compared with single-unit UCBT, double-unit CBT associated with less risk of primary disease relapse and increased incidence rate of graft-versus-host disease (GVHD), but the hematologic recovery and overall survival of recipients were no significantly difference between single and double-unit UCBT. Novel strategies for UCB expansion significantly increased the cell amount in UCB, single-unit expanded UCBT not only increased the sources of UCB, but also decreased the high cost of double-unit UCB. ATG can decrease the risk of graft failure and GVHD rate, but the role of ATG in UCBT is still controversial. Herein, the recent clinical advances on UCBT in the treatment of hematologic diseases are systematically reviewed.

Phase III randomized study of adjuvant treatment with the ANTI-PD-L1 antibody avelumab for high-risk triple negative breast cancer patients: The A-BRAVE trial.

TPS598 Background: Chemotherapy represents, today, the only treatment option for triple negative breast cancer (TNBC) and still a considerable proportion of pts with primary TNBC experience disease relapse. The risk is particularly high in the presence of poor prognostic features, such as more advanced stage and, for pts treated with neoadjuvant chemotherapy, failure to achieve a pCR. Recent evidence suggest that immunotherapy can play a major role in TNBC pts. Methods: The A-BRAVE trial is an investigator-driven trial sponsored by the University of Padova (Dept. of Surgery, Oncology and Gastroenterology). This is a phase III, multicentric, randomized adjuvant study that compares 1 year of treatment with the anti PD-L1 avelumab vs observation for pts who completed treatment with radical intent for primary TNBC including surgery and chemotherapy. The study enrolls pts in two strata: -Stratum A: primary TNBC pts who completed surgery followed by adjuvant, defined according to one of the following stage categories: if pN2, any pT; if pN1, pT &gt; 2 cm; if pN0, pT &gt; 5 cm. -Stratum B: primary TNBC pts who completed neoadjuvant chemotherapy followed by surgery who did not achieve pCR. Pts who also received additional adjuvant chemotherapy for no more than 6 months are eligible in Stratum B, after the completion of the adjuvant chemotherapy. Pts are randomized (1:1, balanced for strata A and B) to receive Avelumab 10 mg/kg I.V. q2w for 1 year or to observation. The first and second co-primary endpoints are disease-free survival (DFS) in all pts and DFS in Stratum B pts. With a planned sample size of n = 474 pts the trial has 90% power to detect a HR = 0.60 for the first co-primary endpoint (n = 172 events required). Taking into account that the percentage of patients enrolled in the stratum B could range from 70 to 80%, there will be 70-79% power to detect a HR = 0.60 at alpha allocated in this patient subgroup (second co-primary endpoint). Secondary objectives include: DFS in PD-L1 positive pts, overall survival, safety, biomarkers. Tumor tissue, plasma samples and fecal samples are collected for biomarker analysis. The study is currently recruiting across 73 sites in Italy and UK. As of February 2020, n = 349 pts have been enrolled. EUDRACT 2016‐000189‐45. The authors present the A-BRAVE trial in progress on behalf of Italian and UK investigators. Clinical trial information: NCT02926196 .

Expression of Lefty predicts Merkel cell carcinoma-specific death.

Lefty and Nodal are transforming growth factor β-related proteins, which, beside their role in determination of laterality during embryogenesis, have also been linked with cancer progression. Prompted by the observed significant left-sided laterality of Merkel cell carcinoma (MCC), we addressed whether Lefty and Nodal are expressed in MCC and correlated expression patterns with clinical parameters such as MCC laterality and patient outcome. Expression of Lefty and Nodal in primary MCC was assessed in 29 patients by immunohistochemistry. The histology (H-)score was calculated and correlated with clinical parameters. The median (range) H-score of Lefty and Nodal was 17.6 (0-291) and 74.9 (0.7-272), respectively. There was a significant correlation between Lefty expression and Nodal expression (correlation coefficient of 0.60, P=0.0006). There was no significant correlation between Lefty expression and Nodal expression with either tumour laterality, gender, age, Merkel cell polyomavirus status, disease stage, anatomical localization of primary tumours or disease relapse. On univariate analysis, low Lefty expression and Nodal expression were significantly associated with MCC-specific death (P=0.010 and P=0.019, respectively). On univariate analysis, low Lefty expression was the only significant independent predictor for MCC-specific death (P=0.025) as indicated by an odds ratio of 14 (95% CI: 1.43-137.33). Lefty and Nodal are frequently expressed in MCC, but not correlated with tumour laterality. Importantly, our data suggest that a low level of Lefty expression in primary MCC is a strong predictor of MCC-specific death.

Fatty acid synthase and adenosine monophosphate-activated protein kinase regulate cell survival and drug sensitivity in diffuse large B-cell lymphoma

Fatty acid synthesis is crucial in supporting the survival and proliferation of multiple forms of cancer. The high metabolic demands of fatty acid synthesis are regulated by the AMP-activated kinase and activity of the fatty acid synthase enzyme. In this study, the roles of these enzymes in diffuse large B-cell lymphoma (DLBCL) were investigated by genetic knock-down and pharmacological activation of AMP-activated kinase by metformin, and selective inhibition of fatty acid synthase using the novel drug Fasnall. We observed distinct heterogeneity and adaptive plasticity of lipid metabolism in a panel of DLBCL cell lines and demonstrate the therapeutic potential of inhibiting fatty acid synthesis in a subset of DLBCL cells. The translational relevance of these in vitro data is supported by the strong correlation between AMP-activated protein kinase expression in primary DLBCL samples and disease relapse. Inhibition of fatty acid synthase with Fasnall may represent a therapeutic option for DLBCL that preferentially subverts to de novo fatty acid synthesis.

High proportions of CD3+ T cells in grafts delayed lymphocyte recovery and reduced overall survival in haploidentical peripheral blood stem cell transplantation.

T cells in grafts serve an important role in the pathogenesis of graft versus host disease (GVHD) and immune recovery during HLA matched allogeneic stem cell transplantation. However, the role of T cells in the haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is yet to be determined. In the present study, the role of CD3+ T cells in grafts and impact on hematopoietic and immune recovery, cytomegalovirus (CMV) reactivation, GVHD, relapse, progress free survival and overall survival (OS) were evaluated and analyzed. A total of 30 patients who underwent haplo-PBSCT were included in the present study. CD3+ T cells accounted for a median of 23.1% (range 8-47.4%) with a median dose of 299.7x106/kg (range 104-623.4). Patients were divided into two groups according to the CD3+ T cell count: Above the median (high T cell group) and below the median CD3+ T cell (low T cell group). No significant difference was identified between neutrophil and platelet recovery time between two groups (P>0.05). The mean lymphocyte recovery time of high T cell group and low T cell group were 107.07 days (95% CI 79.88-134.25), and 50.4 days (95% CI 41.42-59.38), respectively. The lymphocyte recovery time of high T cell group was higher that of low T cell group (P<0.05). No significant difference between CMV reactivation, chronic GVHD and primary disease relapse rates was observed between two groups (P>0.05). The cumulative incidence of grade II or above acute GVHD was higher in the high T groups compared with low T groups (P<0.05). The overall survival and progress free survival rates were higher in the low T cell group compared with the high T cell group (P<0.05). In conclusion, high levels of CD3+ T cells in the grafts were associated with delayed lymphocyte recovery and an increased risk of acute GVHD and decreased overall survival.

Prophylactic donor lymphocyte infusion for relapse prevention: a meta-analysis.

Primary disease relapse (PDR) of malignant hematologic conditions after standard hematopoietic stem cell transplant (HSCT) is one of the most challenging diseases; therefore ongoing researches are aiming at relapse prevention and minimizing the transplant-related side effects. Prophylactic donor lymphocytes (pDLI) had been proposed as a valuable strategy for PDR prevention, but early studies had been discouraging due to the limited benefit and possible association with acute graft-versus-host disease (aGVHD). Therefore, we conducted a meta-analysis to evaluate the association between pDLI use, PDR, aGVHD and OS. We performed a comprehensive literature search in MEDLINE, Cochrane library and Embase database from inception to May 2019 for studies that evaluated the association between pDLI and PDR. We conducted a random effect meta-analysis of 9 studies involving a total of 748 participants (pDLI=398, non-pDLI=350) and reported the pooled odd ratio (OR) for association of pDLI use, PDR, aGVHD and OS. We found a significant decreased odd of PDR in the pDLI group (pooled OR=0.42, 95% CI 0.30-0.58, I2=0%), but there was no significant increased odd of aGVHD (pooled OR of 0.98, 95% CI 0.56-1.72, I2=0.8%). We also found that there was an increased odd of overall survival (OS) (pooled OR 3.17, 95% CI 1.85-5.45, I2=50.2%). There are significantly decreased odd of PDR and increased odd of OS in the pDLI group compared to the control group, but there is no statistically significant increased odd of aGVHD as suggested by previous studies. We concluded that pDLI is a potentially valuable method for post-transplant PDR prevention.