High-dose Chemotherapy Followed By Autologous Stem Cell Transplantation Research Articles

Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma.

About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL. We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes. Highly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay. We identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.

Patients with Relapsed Large B-Cell Lymphoma after 12 Months Have a Similarly Poor Prognosis As Patients with a Relapse before 12 Months

Recently, ZUMA-7 study patients with early relapsed LBCL (<12 months after first-line immunochemotherapy) who were treated directly with CAR T-cell therapy in second-line instead of third-line, had a significantly better overall survival (OS) compared to patients who were treated with standard salvage treatment consisting of high-dose chemotherapy followed by autologous stem-cell transplantation (HDT-ASCT). Despite non-protocolled cross-over to CAR T-cell therapy in third-line for 57% of patients in the HDT-ASCT arm, a significant difference in OS of 9% remained, suggesting that patients benefit if the most effective therapy is applied at an early stage. On the basis of these results, the paradigm of HDT-ASCT shifted to CAR T-cell therapy as second-line therapy for patients who have refractory or early relapsed disease <12 months. However, patients with a late relapse (>12 months) are still unable to receive CAR T-cell therapy until the third-line. A main argument is that late relapsed LBCL is considered to be still chemo sensitive and therefore these patients would have a better OS following HDT-ASCT salvage. The aim of this study was to compare the responses of LBCL patients with an early (<12 months) versus a late (>12 months) relapse onset, to see whether this argument is justified in real world. All patients diagnosed with LBCL between 2005 and 2020 in the province Friesland, The Netherlands, were included (n=877). Detailed patient characteristics and outcomes of patients in first-line, relapsed setting and beyond were analyzed. OS was calculated from relapse onset. Median follow-up was 7.0 years from diagnosis (range 0.01-15.6). In the first line, 729 patients (83.1%) were treated with curative intent. Early relapse (refractory and <12 months after first-line therapy) and late relapse (>12 months) occurred in 120 (16.4%) and 70 patients (9.6%), respectively. Patients with an early relapse show a 2-year and 5-year OS of 21.5% and 18.3%. Compared to early relapse, patients with a late relapse show a slightly favorable OS of 36.1% at 2 years, yet an almost similar OS at 5 years of 19.6%. Main cause of death for both groups were lymphoma, including treatment related complications (93.9% in early and 82.6% in late relapse). Second-line salvage therapy, consisting of HDT was initiated in 53 patients (44.2%) with early and 22 patients (31.4%) with late relapsed disease. Of these, only 16 patients (30.1%) with an early relapse and 11 patients (50%) with a late relapse obtained a sufficient response and maintained an acceptable clinical performance to undergo ASCT. Patients who completed ASCT, had a 5-year OS of 73.3% (early relapse) versus 49.2% (late relapse). In contrast, early and late relapsed patients who initiated salvage HDT but did not reach ASCT showed a 5-year OS of only 8.3% and 18.2%, respectively. This OS was comparable to the 67 patients (55.8%) with an early relapse who were upfront ineligible to start salvage HDT (5-year OS 10.2%). For HDT-ineligible patients with a late relapse (n=48, 68.6%) OS was similarly disappointing with a 5-year OS of 14.6% In conclusion, these real-world data contradict the argument that LBCL patients with a late relapse (>12 months) have an advantage over patients with early relapse (<12 months) in their potential to reach a long-term remission and survival with HDT-ASCT. This supports the evaluation of early application of CAR T-cell therapy in second-line, also for DLBCL patients who relapse beyond 12 months.

535 - High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDT/ASCT) As Compared to Standard-Dose Chemotherapy (SDT) for Newly Diagnosed Multiple Myeloma: An Updated Systematic Review and Meta-Analysis

535 - High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDT/ASCT) As Compared to Standard-Dose Chemotherapy (SDT) for Newly Diagnosed Multiple Myeloma: An Updated Systematic Review and Meta-Analysis

Patient Reported and Clinical Outcomes after High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSL) are rare and associated with an adverse prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) improves progression free (PFS) and overall survival (OS) but neurocognition, performance status and quality of life (QoL) in patient-reported outcome (PRO) after HDC/ASCT remains underexplored. Especially elderly patients may insufficiently recover from this demanding therapy. Therefore, this single-center analysis investigated all PCNSL patients who received HDC/ASCT at the University Hospital Tübingen from 2006-2021 (n = 40, median age 60.5 years) in a retrospective manner. The 2-year PFS/OS was 78.7%/77.3%, respectively, without significant differences between the tested age-groups (≤60 vs. >60 years, p = 0.531/p = 0.334). Higher Thiotepa dosage was an independent predictor for better OS (p = 0.018). Additionally, a one-time prospective, cross-sectional analysis after HDC/ASCT in the same cohort was performed (n = 31; median follow-up 45 months). Here, the median ECOG improved by HDC/ASCT from 1 to 0 and mini-mental state examinations revealed unimpaired neurocognitive functioning (median 28 pts.). PRO data collected by EORTC QLQ-C30 showed a good QoL in both age groups with an average global health status (GHS) of 68.82% (≤60y: 64.72%, >60y: 74.14%). Together, our data indicate that HDC/ASCT is an effective therapy with respect to disease control, overall health status and quality of life, irrespective of patient age.

Effects on Survival of Non-Myeloablative Chemoimmunotherapy Compared to High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDC-ASCT) As Consolidation Therapy in Patients with Primary CNS Lymphoma - Results of an International Randomized Phase III Trial (MATRix/IELSG43)

BACKGROUND: Patients with primary central nervous system lymphoma (PCNSL) eligible for intensive treatment approaches are currently treated with high-dose methotrexate (HD-MTX) based induction immuno-chemotherapy followed by consolidative high-dose chemotherapy and ASCT (HDC-ASCT). However, it is unclear whether overcoming chemo-resistance and subsequently eliminating minimal residual disease may also be achieved by conventional-dose non-myeloablative immuno-chemotherapy, comprising non-cross resistant cytotoxic agents able to cross the brain-blood-barrier. We thus conducted an international randomized phase III trial comparing HDC-ASCT with non-myeloablative consolidation in patients with newly diagnosed PCNSL (MATRix/IELSG43 trial, NCT02531841). This is the first report on its primary endpoint. METHODS: This open label, randomized phase III trial was conducted in 56 centers of 5 countries (Germany, Italy, Denmark, Norway, Switzerland). Main eligibility criteria included newly diagnosed PCNSL, HIV-negative, age 18-65 years irrespective of ECOG PS or 66-70 years with ECOG PS ≤ 2, and adequate organ function. Induction consisted of 4 cycles of MATRix regimen (rituximab 375 mg/m2/d days 0 & 5; methotrexate 3.5 g/m2 day 1; cytarabine 2 × 2 g/m2/d days 2 & 3; thiotepa 30 mg/m2 day 4, every 21 days). Stem cell harvest was conducted after the 2nd cycle. Pts achieving at least partial response (PR) after completion of induction were randomly allocated to either arm A with two courses of R-DeVIC regimen (375 mg/m2 day 0; dexamethasone 40 mg/d days 1 to 3; etoposide 100 mg/m2/d days 1 to 3; ifosfamide 1500 mg/m2/d days 1 to 3; carboplatin 300 mg/m2 day 1); or arm B, consisting of HDC with BCNU 400 mg/m2 (day -6) and thiotepa 2 x 5 mg/kg/d days -5 & -4) followed by ASCT. The primary endpoint progression-free survival (PFS) was analyzed with a Cox proportional hazards model, containing the randomized treatment as hypothesis variable and the stratification variable response status as a covariate. RESULTS: Between July 2014 and August 2019, 368 pts were registered; 346 started treatment, 260 (75%) completed the induction therapy, and 115 and 114 pts were randomly assigned to arm A and arm B, respectively. Main reasons for not reaching randomization were toxicities (n= 87; 25%) and disease progression (n= 36; 10%). Median age of the randomized pts was 59 years (range 21 - 70) with 22.3% of pts being 65 years or older. Distribution of patient characteristics were well balanced between arms. Median follow-up of all registered patients is 44 months (range 0,2-86). 239 of 346 (69%) pts responded to induction treatment, 27% achieved a complete remission (CR) and 52% a partial remission (PR). Both consolidation strategies were well tolerated: R-DeVIC and HDC-ASCT were completed in 100 (87%) and 111 (97%) pts, respectively. 13 (3.8%) pts died of treatment-related complications during induction treatment, 11 of them due to neutropenic infectious complications. Consolidation treatment with R-DEVIC or HDC-ASCT resulted in a substantial increase of pts with CR (65% in arm A and 68% in arm B, respectively; p= 0.71). To date, there were 79 PFS events: 67 pts experienced progressive disease after randomization (47 for arm A and 20 for arm B). 6 pts died of toxicity during consolidation treatment (2 arm A and 4 arm B), and 6 pts died of unrelated causes while relapse-free (5 arm A and 1 arm B). The 3-year PFS (primary endpoint) differed significantly between the two arms: 79% (95% CI 71-86) after HDC-ASCT and 53% (95% CI 43-62%) after R-DeVIC (HR 0.42; p=0.0003). The 3-year OS was 86% (95% CI 78-91) for HDC-ASCT arm and 71% (95% CI 61-78) for R-DeVIC arm (HR 0.47; p=0.01). The evaluation of neurocognitive functions showed no difference between arms. CONCLUSION: This international randomized phase III trial demonstrates that consolidation with HDC-ASCT results in significantly better outcome than non-myeloablative chemoimmunotherapy. This comes along without any measurable negative effect on neurocognitive functions and with an excellent risk-to-benefit ratio. HDC-ASCT is the standard consolidation therapy for fit PCNSL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Spatial Tumor Microenvironment Characterization and Outcome of Relapsed/Refractory Classic Hodgkin Lymphoma

INTRODUCTION: Despite recent treatment advances, about half of relapsed or refractory classic Hodgkin lymphoma (r/r CHL) patients succumb to their disease after high dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT). Our group has previously developed a gene expression based prognostic assay (RHL30) that identifies high-risk r/r CHL patients treated with HDT/ASCT (J Clin Oncol 2017). However, RHL30 does not incorporate important information about cellular interactions, specific expression features of Hodgkin and Reed-Sternberg (HRS) cells and the spatial architecture of the tumor-microenvironment (TME). Here, we aimed to determine spatially resolved TME ecosystems and establish novel biomarkers associated with treatment failure in r/r CHL. METHODS: Using a customized marker panel specific for CHL biology, we performed imaging mass cytometry (IMC) using a tissue microarray containing formalin-fixed paraffin-embedded tissues from 169 CHL tumors, including 73 patients with paired primary and relapse samples, as well as 23 pretreatment diagnostic samples from patients in long-term remission. Segmentation was performed by the Ilastik machine learning package following the Bodenmiller IMC segmentation pipeline to obtain single cell level data. We used the Phenograph clustering algorithm to identify major cell types and functional subsets. For each cell, we calculated a spatial cell enrichment score, called 'spatial score', of a given cell type as the distance to the five nearest neighbor cells, capped at the spatial interaction range (50um). Patients were classified as having early relapse disease if their CHL progressed within 12 months after initial diagnosis. For prognostic model development, we used an empirical Bayesian approach based on LPS (linear prediction score). RESULTS: We obtained highly multiplexed images for a total of 7,146,042 cells that could be broadly clustered into T cell, macrophage, B cell as well as HRS cells using the phenograph tool. We also identified subsets within the HRS cell cluster, such as GATA3-high HRS cells and CXCR5-high HRS cells. We, then, investigated the difference of TME characteristics according to the disease status. Overall, CHL biopsies from early relapse demonstrated shared TME patterns between diagnostic and relapse samples, and were characterized by a lesser extent of CD8+ cells (P < 0.01) as well as enrichment of a myeloid cell population (P < 0.05). In contrast, late relapse samples often demonstrated significant TME changes between diagnostic and relapse biopsies (P < 0.01). Considering the previous finding of the superiority of relapse biopsies for outcome prediction in comparison to pretreatment diagnostic samples in r/r CHL, we again focused our prognostic model development on relapse biopsies. Using LASSO based analyses, four variables, CXCR5+ HRS cells (Hazard Ratio [HR]: 2.86), PD1+ CD4+ T cells (HR: 2.80), macrophage (HR: 1.99), and CXCR5+ B cells (HR: 0.19) were identified as factors that were significantly associated with post-ASCT failure free survival (FFS). Using these 4 variables, we developed a spatial score-based prognostic model (RHL-4S) and compared performance with a classical protein%-based model. The RHL-4S produced a high-risk group of patients with significantly inferior post-ASCT FFS compared with the low-risk group (5-year post-ASCT FFS: high risk, 38% vs low risk, 96%; P < 0.0001, Figure A) as well as inferior post-ASCT overall survival (OS) (5-year post-ASCT OS: high risk, 45% vs low risk, 95%; P < 0.0025). IMC analyses furthermore identified unique spatial architecture defined by CXCR5+ HRS cells. In particular, CXCR5+ HRS cells were spatially arranged together with other HRS cells forming cell clusters as an architectural feature (P < 0.05, Figure B). CXCR5+ HRS cells in these clusters were also characterized by a lower abundance of neighboring non-malignant immune cells, including CD4+ T cells and CD20+ B cells when compared to CXCR5- HRS cells. CONCLUSION We developed a novel prognostic model, RHL-4S, applicable to relapse biopsies of r/r CHL patients who were treated with ASCT. In particular, we have shown the interaction between CXCR5 on HRS cells with ligand-expressing CXCL13+ follicular T helper cells (Aoki et al, PNAS 2021) and macrophages as a prominent crosstalk axis in relapsed disease. This insight opens new avenues to predictive biomarker development. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in Czech Republic

Introduction: Although highly effective agents and novel therapeutic strategies are being developed, high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has not been overcome in the first-line treatment for fit patients (pts) with multiple myeloma. The objective of this work is to retrospectively analyze the use of this procedure in newly diagnosed Czech patients.Methods: Data were derived using the Czech Myeloma Group Registry of Monoclonal Gammopathies. By February 2 nd 2021, a total of 2154 newly diagnosed multiple myeloma patients who underwent HDT/ASCT were identified.Results: At the time of multiple myeloma diagnosis, the median age was 59 years; 24%/56%/14%/5%/1% pts were ECOG 0/1/2/3/4; 44%/32%/24% pts were ISS stage I/II/III; 14.5%/17.5%/68% and 84%/16% pts were Durie-Salmon stage I/II/III and subclassification A/B, respectively. The combinations of agents used in the induction regimen were proteasome inhibitor (PI), immunomodulatory drug (IMiD) and glucocorticoid (GC) in 28.5% (613/2154) pts; PI, GC and chemotherapy (CHT) in 24.8% (534/2154) pts; GC and CHT in 22,5% and IMiD, GC and CHT in 16.1% (346/2154). Other combination of drugs was used in 8.2% (177/2154) pts. It was registered that 3.7% (79/2154) induction regimens were switched to a different combination because of toxicity, patient's choice, poor peripheral venous access or other reasons. Single HDT/ASCT was performed in 77.3% (1665/2154) cases whereas tandem HDT/ASCT was given to 11.8% (254/2154) patients. In 10% (215/2154) cases, the transplantation technique was not specified. Nine percent (193/2154) patients were treated within a clinical study. The median progression free survival (mPFS) and the median overall survival (mOS) of the whole cohort was 28.9 and 92.1 months, respectively. Information about response to treatment before and after the high-dose therapy were available for 75.7% (1627/2154) and 92.2% (1987/2154) patients, respectively. Disease status at the time of HDT/ASCT was defined as stringent complete response (sCR) at 2.2% (36/1627), complete response (CR) at 11.9% (194/1627), very good partial response (VGPR) at 38.2% (621/1627), partial response (PR) at 40.9% (666/1627), minimal response (MR) at 3.6%, (58/1627), stable disease (SD) at 2.2% (36/1627), progressive disease (PD) at 1% (16/1627) patients. The overall response rate (ORR) on day 100 was 92.8% (sCR: 10.5% [209/1987], CR: 22.4% [446/1987], VGPR: 35% [696/1987], PR: 24.8% [493/1987], MR: 2.7% [54/1987], SD: 1.4% [27/1987], PD: 3.1% [62/1987]). We also performed a survival analysis of patients progressing up to 18 months after HDT/ASCT (n=1219) versus patients progressing in more than 18 months (n=935). The median OS was 41.5 versus 124.9 months, respectively. An analysis of the role of tandem HDT/ASCT in this real-world cohort will be presented at the conference.Conclusion: Globally as well as in the Czech Republic, HDT/ASCT is an important therapeutic approach in the first-line treatment of multiple myeloma. Our analysis of 2154 newly diagnosed transplant-eligible patients confirms high effectiveness - ORR of 92.8%, mPFS of 28.9 months, and long-term survival reaching mOS of 92.1 months. DisclosuresMinarik: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

P-188: Carfilzomib, lenalidomide, and dexamethasone followed by salvage autologous stem cell transplant with or without maintenance for relapsed or refractory multiple myeloma

<h3>Background</h3> Salvage high dose chemotherapy followed by autologous stem cell transplantation (HDCT/ASCT) is a treatment option in patients with relapsed and/or refractory multiple myeloma (RRMM) after prolonged remissions with frontline transplantation. The role of salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens has not been defined. The present analysis therefore aims to investigate the efficacy and toxicity of salvage HDCT/ASCT after carfilzomib (CFZ)/lenalidomide (LEN)/dexamethasone (KRd) re-induction with or without post-transplant maintenance treatment. <h3>Methods</h3> We retrospectively assessed efficacy and toxicity in 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients had received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2-13.5) years, allowing for paired comparison of frontline and salvage HDCT/ASCT. Median age at time of re-induction was 58.9 years (range 40-71) and n=38/44 patients (86%) had only 1 prior line of therapy (range 1-3). Sixteen of 44 patients (36%) were LEN pretreated and all patients were CFZ-naive. Maintenance treatment was administered in n=22/44 patients (50%) after frontline HDCT/ASCT and in n=17/44 patients (39%) after salvage HDCT/ASCT. <h3>Results</h3> After a median of 3 re-induction cycles (range 3-9), 25/44 patients (57%) attained at least very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Patients achieving deep remissions during frontline treatment were more likely to re-achieve deep remissions in the salvage setting at each individual timepoint: after (re-)induction (≥VGPR: odds ratio [OR] 6.22; 95% confidence interval [95%-CI] 1.33-29.01; p=0.02), after (salvage) HDCT/ASCT (≥nCR: OR 5.71; 95%-CI 1.44-22.62; p=0.01) and at best response (≥nCR: OR 4.50; 95%-CI 1.12-18.13; p=0.03). After a median follow up of 23.9 months, median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients at least in VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio [HR] 0.19, p=0.001 and HR 0.20, p=0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p=0.3). <h3>Conclusion</h3> Despite higher comorbidity scores at salvage HDCT/ASCT, no significant increase in relevant toxicity parameters including infections and intensive care unit admission was observed and no transplant-related mortality occurred after salvage HDCT/ASCT. This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.

Prognostic Role of Serum Albumin Level in Patients with Lymphoma Undergoing Autologous Stem Cell Transplantation.

BackgroundHigh-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) plays a crucial role in the therapy of patients with lymphoma. This retrospective study aimed to analyze prognostic factors in patients undergoing HDT/ASCT for lymphoma.Material/MethodsWe included patients with lymphoma who underwent HDT/ASCT at our center. Time-to-event outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed with the Kaplan-Meier method and log-rank test. Receiver operating characteristic (ROC) curve analysis and Cox proportional hazard regression analysis were performed to explore the prognostic value of different factors.ResultsA total of 113 patients with lymphoma were included. Patients with low serum albumin levels (<37 g/L) before transplantation had significantly lower PFS and OS (P<0.01). Albumin levels before transplantation significantly predicted early progression (progressed within 1 year) after transplantation (AUC=0.706, P=0.003). Multivariate Cox analysis indicated that low albumin level (hazard ratio [HR] 3.19, 95% confidence interval [CI] 1.54–6.63; P=0.002) and age >60 years (HR 2.92, 95% CI 1.27–6.71; P=0.012) were independent risk factors for PFS. Total protein <60 g/L was an independent risk factor for OS (HR 3.57, 95% CI 1.45–8.78; P=0.006).ConclusionsLow albumin level before transplantation was an independent risk factor in patients with lymphoma undergoing HDT/ASCT. Intense care and effective maintenance therapy after transplantation are required for patients with low albumin levels.

CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas

High-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) is the standard of care for chemosensitive relapsed or refractory (R/R) aggressive B cell lymphoma. Patients with a positive positron emission tomography (PET) scan before ASCT have a poor prognosis, and those who fail to achieve a therapeutic response better than partial remission after salvage treatment are ineligible candidates for ASCT. We conducted this open-label single-arm prospective clinical study to evaluate the safety and efficacy of sequential infusion of CD19/22 chimeric antigen receptor (CAR) T cells following HDT-ASCT. Eligibility for this study included patients with R/R aggressive B cell non-Hodgkin lymphoma (B-NHL) with 18F-fluorodeoxyglucose-PET positivity and patients with stable or progressive disease after salvage chemotherapy. Between November 14, 2016, and August 15, 2019, 42 patients underwent HDT-ASCT followed by CD19/22 CAR T cell infusion. Grade 3 cytokine release syndrome (CRS) occurred in only 2 patients. Twenty-one percent of patients experienced any grade of neurotoxicity, 5% with severe grade 3. All cases of CRS and neurotoxicity were reversible. The overall response rate was 90.5% (95% confidence interval [CI], 77.4% to 97.3%). At a median follow-up of 24.3 months, the median progression-free survival (PFS) and overall survival were not reached. The 2-year PFS rate was 83.3 % (95% CI, 68.2% to 91.7%). No patients were found to be CD19- and CD22-negative at the time of progression; 97.1% and 68.6% of patients with ongoing complete remission (CR) had consistently detectable levels of CD19 and CD22 CAR transgene, respectively, at 3 months. The median time to onset of sustained B cell recovery was 8.2 months. The high durable CR rates and favorable safety profiles support the strong potential of the HDT-ASCT plus CD19/CD22 CAR T cell cocktail therapy for the suboptimal group of patients with R/R aggressive B-NHL who are less sensitive or fail salvage chemotherapy. These early data are encouraging and informative for future trials to further test the efficacy and safety of HDT-ASCT plus CAR T cell therapy in a larger population. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Is Autologous Stem Cell Transplantation a Safe and Effective Alternative to Whole Brain Radiation as Consolidation Therapy in Patients With Primary Central Nervous System Lymphoma?: A Critically Appraised Topic.

High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

Salvage Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma. This unique disease shows unsatisfactory outcomes comparing to other types of non-Hodgkin lymphoma and limited treatment options are available with relapsed or refractory disease. The purpose of this study is to evaluate outcomes of relapsed or refractory PCNSL patients treated with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT).MethodsThe registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients with refractory disease to first-line therapy and who relapsed were sorted. Among selected patients, patients who showed complete response (CR) or partial response (PR) to salvage therapy were enrolled in analyses and divided into two groups with whether high-dose chemotherapy followed-by ASCT was done or not as consolidation therapy. Overall survival (OS) was defined as the time from the day response was evaluated after salvage therapy to any cause of death, and progression free survival (PFS) was defined as the time from the day response was evaluated after salvage therapy to disease progression or any cause of death. Chi square test and Fisher's exact test was done to compare variables in two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analysis with Cox-proportional hazards regression analyses was done to evaluate potential confounding effects of known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.ResultsTotal 241 patients with diagnosis of PCNSL were identified and 83 patients who had relapsed or refractory to induction chemotherapy were sorted. Among these patients, 39 patients who had CR or PR to salvage chemotherapy were enrolled in analyses. Median follow-up duration was 2.1 years (IQR 0.1-15.49), median OS was 1.5 years (95% CI 0.3-2.7), and median PFS was 1.4 years (95% CI 0.2-2.7). Median age was 63 years (range, 29-77), 69.2% of patients were 60 years or older and 59.0% of patients was male. Thirty patients (76.9%) had high-dose methotrexate based chemotherapy as first-line therapy and 71.8% had overall response (CR or PR). Twenty patients (48.7%) had ICE (ifosfamide, carboplatin, etoposide) + dexamethasone regimen, 22.9% had high-dose methotrexate based regimen. Thirty-one patients (79.5%) showed good performance (ECOG performance status < 2). Among these patients, 16 patients had high-dose chemotherapy followed-by ASCT as consolidation therapy and 23 patients did not. Proportion of patients with good performance status, salvage chemotherapy regimen, response to salvage therapy showed no statistically significant difference between two groups who had salvage ASCT or not. The median age was 55 years old (range 29-64) in salvage ASCT group, and 68 years old (range, 36-77) in non-ASCT. Median OS was 2.5 years [95% CI 0.3-4.6] in salvage ASCT group, and 1.0 years [95% CI 0.4-1.7] in group without salvage ASCT (p = 0.032). Median PFS was 1.5 years in salvage ASCT group, and 0.4 years [95% CI 0.4-0.5] in non-ASCT group (p = 0.027). In multivariate analyses with age, ECOG performance status, CSF protein level, and serum LD level, salvage ASCT revealed its independent prognostic impact for OS with HR of 0.11 [95% CI 0.01-0.96, p = 0.046], and for PFS with HR of 0.13 [95% CI 0.02-0.78, p = 0.025].ConclusionConsolidation therapy with high-dose chemotherapy followed-by ASCT could be a good treatment option in relapsed or refractory PCNSL patients who had response to salvage therapy. Prospective studies are needed to validate our results. DisclosuresNo relevant conflicts of interest to declare.

Autologous bone marrow transplantation for diffuse large B-cell lymphoma in Egypt: a two-center experience

ObjectiveThe aim of this work was to study the outcome of autologous bone marrow transplantation in diffuse large B-cell lymphoma (DLBCL) according to the experience of two centers, Naser Institute and Sheikh Zayed centers.BackgroundTreatment for patients with DLBCL is based on the international prognostic index score and age. Autologous stem-cell transplantation (ASCT) is actually recommended in young patients who did not achieve complete remission after first-line chemotherapy.Patients and methodsThis retrospective case series study included the files of 191 patients who were diagnosed as having DLBCL according to the 2008 WHO classification of lymphoma in Naser Institute and Sheikh Zayed hematology units in the period from 2012 to 2018. The patients were classified into two groups. Group I: patients with DLBCL and received chemotherapy only, Group II: patients with DLBCL and received chemotherapy and then high-dose chemotherapy followed by ASCT (HDC).ResultsThe data we had shown that there is no significant statistical difference between the studied groups as regards age and sex. The mean age was 40.34 years (±11.620) in patients with DLBCL and received chemotherapy only while in patients with DLBCL and received chemotherapy then HDC/ASCT was 42.66 years (±11.554). The 5-year overall survival in patients with chemotherapy only is not statistically significant compared with patients with chemotherapy and then HDC/ASCT (P = 0.202).ConclusionOn the basis of our results, we can conclude that the outcome of HDC/ASCT in patients with DLBCL is nearly equal to the outcome of chemotherapy alone.

CD19/CD22 CAR-T Cell Cocktail Therapy Following Autologous Transplantation in Patients with Relapsed/Refractory B-Cell Lymphomas

High-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or refractory(R/R) B-cell lymphoma. Eligibility for HDT-ASCT is based upon the presence of chemo-sensitive disease to salvage therapy. Patients with a positive PET scan prior to ASCT have a substantially inferior suvival. Furthermore, the outcomes of patients who have progressive disease after salvage treatment is extremely dismal. We hypothesized that, following HSCT, the immunosuppressive microenvironment would be diminished as a result of myeloablative conditioning and that administering CAR-T cell therapy during the hematopoietic reconstitution could eradicate posttransplant residual disease, leading to lower relapse rates after HSCT. Based on our previous work that a dual-targeting CAR T cell cocktail of sequential cell infusions targeting CD19 and CD22 may help overcome antigen escape relapse in B-cell malignancies, we therefore conducted an open-label, single-center, and single-arm pilot study of a treatment comprising the sequential infusion of CD22 and CD19 CAR-T cells following autologous hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the safety and efficacy of the treatment in R/R B cell lymphoma patients with residual or progression disease after salvage treatment. Between November 14, 2016 and August 15, 2019, 42 patients underwent BEAM conditioned HDT-ASCT and followed by CAR 19 /22 T cells infusion. The overall response rate was 90.5% (95% CI, 77.4-97.3). At a median follow-up of 13.8 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 85.7 % (95% CI, 70.9 to 93.3). Grade 3 cytokine release syndrome (CRS) occurred in only 2 (5%) patients. 21% patients experienced any grade of neurotoxicity, 5% was severe Grade 3. All CRS and neurotoxicity were reversible. Beyond its extremely high complete response rates, the durability of remission and low toxicity of the autologous HSCT plus CD19/CD22 CAR-T cell cocktail therapy examined in this study emphasize strong potential of such myeloablative conditioning and dual-targeting approaches for R/R B-cell lymphomas. Disclosures No relevant conflicts of interest to declare.

Treatment Strategies and Outcomes for Patients with Peripheral T-Cell Lymphoma and Its Subtypes

Introduction Peripheral T-cell lymphoma (PTCL) is diverse group of an uncommon and aggressive type of non-Hodgkin lymphoma (NHL). It generally affects people aged 60 years and above and is diagnosed slightly more often in men than in women. However, younger adults and children are also diagnosed with PTCL. Being a rare entity, the best treatment regimen has not been established for newly diagnosed patients or for relapsed/refractory patients with PTCL. In general, treatment outcomes have been poor with conventional chemotherapy regimens. Methods We performed a retrospective cohort study of patients with newly diagnosed and relapsed PTCL, and its subtypes, who are seen in the hematology-oncology clinic at the University of Arkansas for Medical Sciences from July 2014 to December 2019. The demographics of the study population, the frontline and second-line treatment strategies for all the subtypes and the response to the treatment were studied. Also, the role of high dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) in the overall survival (OS) and progression-free survival (PFS) is analyzed. Results Out of the 48 patients, 45.8% (n=22) patients had PTCL not otherwise specified (PTCL NOS) type, 29% (n=14) had Anaplastic large cell lymphoma ALK-negative subtype, 4.2 % (n=2) had Anaplastic large cell lymphoma ALK-positive subtype, Angioimmunoblastic T-cell lymphoma, Extra nodal NK/T cell lymphoma, Enteropathy associated T- cell lymphoma each. The mean age of diagnosis was 58 ± 2. Males were affected more when compared to females (66.6% vs 33.3%). Also, Caucasians were more affected than African Americans (73% vs 25%). The mortality of PTCL was found to be 40%. After frontline treatment, complete response (CR) was observed in 43.7% (n= 21) patients, partial response (PR) was observed in 18.7% (n= 9) patients, stable disease (SD) was seen in 4% (n=2), progression of disease (PD) was observed in 12.5% (n= 6) patients. Stem cell transplant (HDT-ASCT) was done for 28% (n=13) of patients who achieved CR after frontline chemotherapy (CR1). Relapse was observed in 60% of patients. Patients with stage III and IV on the initial diagnosis had a higher chance of relapse or refractory disease. After the second-line treatment, out of 20 patients, 9 patients had CR, 5 had PR, 5 patients had PD, 1 patient had SD. CR was observed in 7 patients with either brentuximab vedotin alone or brentuximab vedotin with combination chemotherapy as second-line treatment. The OS and PFS were found to be higher in patients who received HDT-ASCT after CR1. Conclusion PTCL has a high risk of relapse and there are no uniform guidelines for the treatment of PTCL in relapsed or refractory setting. The currently available second line treatment options have shown modest response rates. Our study has shown that brentuximab vedotin, when used alone or in combination, showed better response rate in the relapsed setting. Also, stem cell transplant improved the overall survival and progression-free survival in patients with PTCL after frontline chemotherapy. Disclosures No relevant conflicts of interest to declare.

Complete response to pixantrone as a salvage therapy in a relapsed/refractory diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma (NHL). It is one of the most common form of the disease. A combination of chemotherapy with anthracycline and a monoclonal antibody targeting CD20 is used as a I line therapy. About two out of three people with DLBCL achieve and maintain complete remission after this treatment. In case of relapse or refractory disease a salvage high-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is the standard of care. Patientrs who relapse after HD-ASCT have a very poor prognosis. Pixantrone is a new anthracycline derivative registered to treat relapsed/refractory DLBCL in adult patients. It is a cytostatic agent with a reduced cardiotoxicity comparing to classic anthracyclines. Herein, we report two cases of relapsed/refractory DLBCL treated with pixantrone as a salvage therapy. The first case concernes a 58-year-old female patient with a diagnose of DLBCL, who relapsed after four prior lines of therapy (R-CHOP, ICE, HD-Mtx, CSN radiation) and achieved complete remission after pixantrone therapy, but died of acute myeloid leukemia 3 months after the end of treatment. Second case is a story of a 75-year-old female patient treated with two prior lines of treatment (R-CHOP, R-IVE), who achieved complete remission after a III line of therapy with pixantrone. Pixantrone monotherapy proves to be effective in relapsed/refractory DLBCL. This treatment is well tolerated in a group of elderly patients and can be also used in a group of patients with a limited cardiac function.

Clinical outcomes and prognostic factors in patients with multiple myeloma in South Tyrol: a retrospective single-center analysis.

High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) as well as the introduction of novel agents (NA) significantly improved survival for patients with multiple myeloma (MM). A total of 150 unselected newly diagnosed MM patients treated at our institution from 1998 to 2017 were retrospectively analyzed. Median age at diagnosis was 69years (range 33-93years) with a median follow-up of 48.6months. The median overall survival (OS) for the entire cohort was 60.7months (range 0.3-280.1). Patients who received frontline HD-ASCT (p < 0.01) or NA-based first-line treatment (p = 0.043) had a significantly better OS. According to the revised Myeloma Comorbidity Index (R-MCI), patients were defined as fit (36.5%), intermediate-fit (44.5%), or frail (19%) with a significant difference in OS between these categories (p < 0.01). Multivariate analysis revealed R-MCI as an independent prognostic factor for OS (p < 0.01). Presence of subclinical amyloid deposits (A+) was detected in 18 out of 66 patients (27.3%) and significantly correlated with a serum free light chain (sFLC) ratio ≥ 100 (p = 0.01) and bone marrow plasma cell infiltration > 60% (p = 0.04). Furthermore, patients with A+ had significantly worse OS compared with their counterparts (p = 0.048). Our results corroborate the efficacy of both early HD-ASCT and the use of new agents as initial therapy of MM patients in "real-world" daily clinical practice. The R-MCI is an easily applicable tool to stratify MM patients and may support treatment decisions. The prognostic value of subclinical amyloid deposition should be validated within prospective studies.

Brain glucose metabolism in patients with newly diagnosed multiple myeloma significantly decreases after high-dose chemotherapy followed by autologous stem cell transplantation.

The aim of this study was to compare the effect of intensive therapy [consisting of high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT)] and conventional standard-dose chemotherapy (CDC) on brain FDG uptake, as an indicator of glucose metabolism, in multiple myeloma patients. Twenty-four patients with newly diagnosed multiple myeloma were included. Sixteen patients received HDC/ASCT, including bortezomib-based induction therapy, and eight patients received CDC. F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) was performed 1 and 3 hours following tracer administration before and after the treatment. The manual segmentation of supratentorial and cerebellum of each patient was performed by two independent observers. The data were expressed as global mean standardized uptake values (GSUVmean). Wilcoxon signed-rank test was used to compare changes from before to after treatment. A significant decrease in the GSUVmean of supratentorial brain and cerebellum was observed after treatment in the patients who received HDC/ASCT (1 hour scans: 7.03 ± 1.18 vs. 6.56 ± 0.94; P = 0.03 and 7.01 ± 1.08 vs. 6.34 ± 0.93; P = 0.01, respectively). GSUVmean changes in the patients who received CDC were not significantly different after treatment (1 hour scans: 6.47 ± 1.16 vs. 6.21 ± 0.91; P = 0.40 and 6.30 ± 1.21 vs. 6.09 ± 0.86; P = 0.62, respectively). The same findings were observed for 3 hours scans. A high level of agreement was observed between two operators. Multiple myeloma patients who received HDC/ASCT demonstrated a significant decrease in FDG uptake in the supratentorial brain and cerebellum, while patients who received CDC did not demonstrate significant changes in the brain FDG uptake.

A Real-Life Study of Autologous Stem-Cell Transplantation in Patients with Multiple Myeloma Older Than 65 Years in a Latin American Country

Introduction: The majority of patients with Multiple Myeloma (MM) are elderly (≥ 65 years). High dose chemotherapy followed by autologous stem cell transplantation (HDCT-ASCT) is the standard of care in patients younger than 65 years. This treatment option should be individualized in elderly patients, mainly due to increased toxicity. Goals: To assess the safety and outcome of HDCT-ASCT in real life in patients ≥ 65 years of age with a diagnosis of MM. Material and methods: Retrospective cohort study of consecutive patients with a diagnosis of MM according to the IMWG 2014 criteria from a single academic center in Argentina, undergoing their first HDTC-ASCT during the period 2008- 2018. Patients with plasma cell leukemia or light chain amyloidosis were excluded. Data was extracted from medical records and collected in an standardized case report form. Consolidation treatment and maintenance were used according to the standard of institutional care at the time of the ASCT. The patients ≥ 65 years old at HDCT-ASCT were compared with those below &lt; 65 years treated in the same period. Response were categorized as: complete remission (CR), very good partial remission plus partial remission (VGPR/PR) and stable disease plus progression disease (EE/PD). Overall response rate (ORR) included CR, VGPR and PR. Overall survival (OS) and progression free survival (PFS) were calculated using the Kaplan and Meier method and compared using log-rank test. For survival, the risk ratio (HR) was calculated according to the multivariate Cox regression model. Transplant-related mortality (TRM) was analyzed with cumulative incidence curves of competitive risks. Values of p &lt;0.05 were considered statistically significant. Results: A total of 221 patients were included in the analysis: 50 patients ≥65 years (7 out of 50 &gt; 70 years) and 171 patients &lt;65 years. Patient's demographics and disease characteristics by age group are summarized in Table 1. Reduced conditioning regimen (melphalan 140 mg/m2) was used in 5% of younger patients and 24% of older patients, p &lt;0.001. In the safety analysis, no significant differences were found between the two groups in the median days of hospitalization, duration of days of neutropenia or thrombocytopenia and life support measures during the period of hospitalization for the transplant (Table 2). The TRM was 2.7% at 100 days (95% CI 1.1-5.5); there was no difference between patients ≥ 65 years and &lt;65 years (2% vs. 2.9%, respectively; p = 0.928). CR before transplant was 22% and 24% and at day 100 after ASCT 44% and 37% in patients ≥65 years and &lt;65 years, respectively. For VGPR, corresponding rate were 64% and 67% before transplant and 79% and 77% at day 100 after ASCT in patients ≥65 years and &lt;65 years, respectively. ASCT increased CR rate in both groups (p=0.050 and p=0.024, respectively). After a median follow-up of 42.5 months (IQR 21-71.5), 3-year PFS was 56.2% (95% CI 39.8-70%) in ≥65 years and 58.2% (95% CI 49.6-65.9) in &lt;65 years; (p = 0.86). The OS at 3 years was 78.3% (95% CI 62.1-88, 2) in ≥65 years and 79.3% (95% CI 71.6-85.1) in &lt;65 years; (p = 0.94). In the multivariate analysis including age at transplant, the quality of pre-transplant response (HR 0.08 for CR, p &lt;0.001; HR 0.16 for VGPR/PR, p = 0.003) and the use of IP (HR 0.51; p = 0.047) were associated with better OS; while the age at transplant had no impact (HR 1.06; p=0.865) (Figure 1). For PFS , including age at transplant, only the quality of pre-transplant response demonstrated statistical significance (HR 0.06 for CR, p &lt;0.001; HR 0.14 for VGPR/PR, p &lt;0.001). Additionally, post-transplant maintenance, was independently associated with better OS (HR 0.34; p=0.016) and PFS (HR 0.47; p &lt;0.001). Conclusions: Our data shows that it is feasible and safe to perform HDCT-ASCT in fit patients with multiple myeloma older than 65 years, and even in patients &gt;70 years old. Patient selection should be based on frailty and comorbidities rather than chronological age alone. This group of patients experiences survival benefits similar to young patients. Disclosures No relevant conflicts of interest to declare.

The role of immuno-checkpoint inhibitors in Hodgkin lymphoma

Abstract Although Hodgkin lymphoma has become one of the most curable lymphomas, 20-30% of patients still relapse after first-line treatment. In relapsed patients, high dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) is a standard treatment approach, however transplant-ineligible patients or patients who relapse after HDC/ASCT still have a rather poor prognosis. Immuno-checkpoint inhibitors are one of the most promising cancer immunotherapies in various advanced cancers including hematologic malignancies. PD-1-blocking antibodies have been used to enhance immunity in several malignancies and obtain durable responses, especially in the patients with heavily treated relapsed/refractory Hodgkin lymphoma. Nowadays, several clinical trials including single agent or combination therapies for Hodgkin lymphoma have been developed or are currently under investigation. The results of ongoing and future clinical trials may establish new treatment paradigm in Hodgkin lymphoma.