High-dose Consolidation Chemotherapy Research Articles

Busulfan, melphalan and carfilzomib high-dose chemotherapy and autologous haematopoietic stem cell transplantation in multiple myeloma.

The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high-dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression-free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR-matched controls. We now integrate the second-generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end-points were safety and tolerability. Secondary end-points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R-ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2 . Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2-year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned.

Relevance of different prognostic scores in primary CNS lymphoma in the era of intensified treatment regimens: A retrospective, multicenter analysis of 174 patients.

Treatment intensification (including consolidative high-dose chemotherapy with autologous stem cell transplantation [HDT-ASCT]) significantly improved outcome in primary central nervous system lymphoma (PCNSL) patients. We conducted a multicenter, retrospective analysis of newly diagnosed PCNSL patients, treated with intensified treatment regimens. The following scores were evaluated in terms of overall survival (OS) and progression-free survival (PFS): Memorial Sloan-Kettering Cancer Center (MSKCC), International Extranodal Lymphoma Study Group (IELSG), and three-factor (3F) prognostic score. Further, all scores were comparatively investigated for model quality and concordance. Altogether, 174 PCNSL patients were included. One hundred and five patients (60.3%) underwent HDT-ASCT. Two-year OS and 2-year PFS for the entire population were 73.3% and 48.5%, respectively. The MSKCC (p = .003) and 3F score (p < .001), but not the IELSG score (p = .06), had the discriminatory power to identify different risk groups for OS. In regard to concordance, the 3F score (C-index [0.71]) outperformed both the MSKCC (C-index [0.64]) and IELSG (C-index [0.53]) score. Moreover, the superiority of the 3F score was shown for PFS, successfully stratifying patients in three risk groups, which also resulted in the highest C-index (0.66). The comparative analysis of established PCNSL risk scores affirm the clinical utility of the 3F score stratifying the widest prognostic spectrum among PCNSL patients treated with intensified treatment approaches.

R-GemOx Plus Nivolumab Vs R-GemOx As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Interim Analysis of the Niveau Trial, an International, Randomized Phase 3 Study of the AGMT, GLA, HOVON, Lysa and PLRG

Introduction: Patients (pts) with relapsed or refractory ( R/ R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo consolidative high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Rituximab, gemcitabine and oxaliplatin (R-GemOx) is a common immuno-chemotherapy regimen used in this setting. The objective of the open-label, phase 3, NIVEAU study (NCT03366272) was to evaluate the efficacy and safety of Nivolumab added to R-GemOx in pts with R/ R LBCL after 1 prior line of therapy not eligible for HDCT/HSCT owing to age and/or comorbidities. Patients and Methods: Eligible pts were adults with R/R LBCL that were refractory to or had relapsed after first-line immuno-chemotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥65 years; age ≥18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥18 years and prior ASCT (as 1st line consolidation). Therapy consisted of 8 cycles R-GemOx (arm A) or 8 cycles of nivolumab plus R-GemOx followed by nivolumab as maintenance for up to 1 year in total or until progression or unacceptable toxicity (arm B). The primary endpoint was progression-free survival (PFS) after 1 year. Major secondary endpoints were response rates, event-free- (EFS) (time to progression, relapse, death or unplanned anti-lymphoma treatment), overall survival (OS) and toxicity. The protocol specified a pre-planned interim analysis after the first 180 pts completed up to at least 1 follow-up investigation. Results: Between Jan 2018 and May 2021, 180 pts were randomized. Two pts did not receive any treatment (one withdrawn informed consent, one death) resulting in a full analysis set of n=90 (arm A) and n=88 (arm B). Median age was 76 years (range 44-87), 52% of pts were &amp;gt;75 years of age, 37% were primary progressive after first-line therapy, 62% had IPI 3-5. Overall response (OR) and complete response (CR) rates were similar with 34% and 20% (arm A) vs. 34% and 22% (arm B), respectively. Rates of progressive disease (PD) were 53% (arm A) vs. 50% (arm B). After a median follow-up of 21 months, 1-year PFS was 28% (95%-CI: 18%-37%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.827) in arm B (Figure A). 1-year EFS was 22% (95%-CI: 13%-31%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.654) in arm B. One-year OS was 48% (95%-CI: 38%-59%) in arm A vs. 58% (95%-CI: 47%-68%), (p=0.126) in arm B. At 2 years, PFS, EFS and OS were 15% (95%-CI: 6%-24%), 13% (95%.CI: 5%-21%) and 34% (95%-CI: 22%-46%) in arm A vs. 15% (95%-CI: 7%-23%), 15% (95%-CI: 7%-23%) an 43% (95%-CI: 32%-55%) in arm B. Because of an identical PFS but a trend toward better OS for arm B, we performed an event-driven OS analysis of pts after second progression or relapse (n=70 in arm A, n= 73 in arm B). OS survival was superior in arm B vs. arm A after second progression or relapse (Log Rank p= 0.010) (Figure B). There was a small increase in number of pts with grade 3-5 AEs in arm B (arm A/arm B: thrombocytopenia 37%/39%; anemia 19%/26%; leukopenia 19%/24%; infection 15%/22%). No increase in number of pts with immune-related grade 3-5 AEs was observed except asymptomatic increase of lipase (arm A/arm B: 23%/27%), (p=0.625) and amylase (arm A/arm B: 5%/11%), (p=0.192). Most common grade 3-5 AEs during nivolumab consolidation in arm B were leukopenia 13%, peripheral neuropathy 10%, increase of lipase 8%, anemia 5% and infection 5% of pts). In total, 7 treatment-related deaths occurred (arm A/arm B: 3 (3%)/4 (5%). After this interim analysis revealed futility to demonstrate superiority for the primary endpoint, recruitment was stopped in March 2023. At that point, 270 of 310 initially intended pts had been recruited. Conclusions: In pts with R/R LBCL, the addition of nivolumab to R-GemOx followed by nivolumab maintenance is feasible without relevant additive toxicity. The addition of Nivolumab did not improve PFS of the R-GemOx regimen alone. These results demonstrate the poor prognosis of R/R transplant-ineligible pts treated with immuno-chemotherapy. However, a trend towards a better OS was observed, which allows for the hypothesis that nivolumab might enhance the efficacy of subsequent therapies. The final analysis of the study is scheduled after completion of follow-up of the last patient included as defined by the study protocol.

Economic burden of acute myeloid leukemia on patients in a resource-limited tertiary hospital in the Philippines

IntroductionThe remission induction treatment for acute myeloid leukemia (AML) has remained unchanged in the resource-limited setting in the Philippines. AML treatment consists of induction chemotherapy followed by high dose consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. In the Philippines, the Filipino household bears the burden of health care cost of hospitalization expenditure. Insights into the treatment costs becomes an essential requirement as these guides the allocation of resources to scheme health programs. MethodThis study involved a retrospective cohort analysis of AML patients who underwent treatment for AML. Review of the statements of account per admission per patient during treatment for remission induction, consolidation, relapsed and refractory disease and best supportive care from 2017 to 2019. Of the 251 eligible patients, 190 patients were included. ResultThe mean healthcare expenditure for remission induction chemotherapy (Phase 1) was US $2, 504.78 (Php 125,239.29). While 3 to 4 cycles of consolidation chemotherapy cost an average of US $3,222.72 (Php 162,103.20). For patients who had relapsed and refractory disease, an additional mean cost of US $3,163.32 (Php 159,115.28) and US $2, 914.72 (Php 146,610.55) were incurred, respectively. The average cost of palliative care was US $1,687.00 (Php 84,856.59). ConclusionThe cost of chemotherapy and other therapeutics bear most of the weight of the direct healthcare cost. The cost of AML treatment represents a significant economic burden for patients and the institution. The cost increases as patients proceed through subsequent lines of treatment for induction failure. Existing subsidy for health insurance benefits could still be improved for appropriate source allocation of resources.

Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas.

Standard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors. All consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Among 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively]. In patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes.

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

Favorable Outcomes with R-CHOP Induction and Consolidative Autologous Stem Cell Transplantation for Double-Hit Lymphoma

Double-hit lymphoma (DHL) is an aggressive large B cell lymphoma associated with a poor prognosis with R-CHOP chemotherapy. The optimal treatment is unknown, but outcomes might be improved with intensive induction regimens or consolidative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). The purpose of this study was to determine the real-world outcomes of patients with DHL treated with primarily R-CHOP induction and consolidative HDT/ASCT. This retrospective, multicenter study included consecutive patients age 18 to 70 years with newly diagnosed DHL intended for consolidative HDT/ASCT in Alberta, Canada. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. The cohort comprised 58 patients with a median age of 59.5 years (range, 30 to 69 years). High-risk features at diagnosis included International Prognostic Index score 3 to 5 in 45 patients (78%), transformed indolent lymphoma in 25 (43%), and central nervous system involvement in 3 (5%). Forty-six patients (79%) patients received R-CHOP induction, and 45 (78%) proceeded to consolidative HDT/ASCT. With a median follow-up of 4.6 years, the 4-year PFS and OS rates were 67% (95% confidence interval [CI], 53% to 78%) and 68% (95% CI, 54% to 79%), respectively, for all patients and 86% (95% CI, 72% to 93%) and 88% (95% CI, 73% to 95%) for those undergoing HDT/ASCT. R-CHOP induction and consolidative HDT/ASCT result in excellent outcomes for patients with chemosensitive DHL, whereas patients with primary refractory disease might benefit from alternative strategies, such as earlier use of chimeric antigen receptor T cell therapy.

Immunochemotherapy of refractory classical Hodgkin's lymphoma with high-dose consolidation and autologous hematopoietic stem cell transplantation complicated by a new coronavirus infection

Classical Hodgkin's lymphoma is one of the most treatable lymphoproliferative diseases with current chemotherapy regimens. The 5-year overall survival rate among patients after initial chemotherapy reaches 95 %, however, despite the significant success achieved, the problem of refractoriness/relapse remains very relevant. A standard approach to the treatment of refractory/recurrent Hodgkin's lymphoma among young patients with preserved general status and chemoresponsive to salvage therapy tumor is high-dose consolidation chemotherapy followed by transplantation of autologous hematopoietic stem cells. The intensification of chemotherapy regimens is highly difficult task for a doctor during the COVID-19 pandemic, which requires careful assessment of a risk-benefit ratio.In current conditions, new targeted and immune drugs are used to overcome resistance and reduce toxicity among pretreated patients, which allows not only to improve the results of a treatment, but also to preserve the high quality of life among patients with extremely unfavorable prognosis.We show our experience of using a checkpoint inhibitor in combination with a dose-intensive regimen of DHAP (dexamethasone, cytarabine, cisplatin) in the treatment of a refractory classical Hodgkin's lymphoma followed by high-dose consolidation chemotherapy and allogeneic hematopoietic stem cells transplantation, among patients complicated with a new coronavirus infection in the post-transplant period.

[Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives].

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton's tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.

Outcomes of Patients with Extranodal Natural Killer/T-Cell Lymphoma: Single Institution Series

BACKGROUNDExtranodal natural killer/T-cell lymphoma, nasal type, (ENKTCL) is a rare and aggressive peripheral T-cell lymphoma associated with Epstein-Barr virus infection of neoplastic cells. The current standard-of-care for patients (pts) with localized disease is combined modality with radiation and systemic chemotherapy, while advanced disease is treated with asparaginase-based combination chemotherapy or chemoradiation. To date, there is limited real-world data regarding the clinico-pathological markers, survival patterns, and long-term outcomes ENKTCL in the United States. METHODSWe conducted a retrospective study of pts with ENKTCL. We reviewed clinical variables, pathological characteristics, treatment patterns and outcomes. Patients who were treated/referred to our instituition from 2009-2020 were included in the analysis. We excluded cases with missing treatment and/or no follow up information. Fisher's exact test or Chi-square test was used to evaluate the association between two categorical variables. Kaplan-Meier method was used to estimate the time-to-event endpoints including progression free survival (PFS) and overall survival (OS). RESULTSA total of 69 patients met diagnostic criteria and were included in this retrospective analysis. Forty (60%) patients were <60 years of age at diagnosis with median age of 53 years (range 13-94); 38 (57%) were men. Thirty-five (50%) patients had early-stage, 28 (40%) advanced-stage disease among whom all but one had stage 4 disease, and 6 (10%) were unknown. Extranodal sites involved were cutaneous/ subcutaneous (n=16), CNS (n=5) and bone/ bone marrow (n=5). Of the cases with CD30 testing done, 54% (20/36) were positive. In early-stage disease, 10 pts received either radiation alone (n=4) or chemotherapy alone (n=6), while 24 received combined modality therapy. Only 15 patients with advanced-stage disease received frontline asparaginase based therapy. Five patients received CHOP based therapy all prior to 2014. Among the 53 patients evaluable for response, the overall response (OR) to first line treatment was 67.92% (95% CI: 53.68 ~ 80.08%) with complete response (CR) rate of 66.04% (95% CI: 51.73 ~ 78.48%). In those with early stage, 77% had a CR, whereas only 47 % with advanced disease had CR to frontline treatment (p=0.0327). Eight patients with advanced-stage disease underwent consolidation high dose chemotherapy and autologous stem cell transplant, with 2 relapses post-therapy.The the median PFS to frontline treatment was 12.48 months (95% CI: 7.23-38.63), for stages I/II 19.15 months, and for stages III/IV 7.23 months . The PFS rate at 2 years was 35% (95% CI: 0.24-0.51) for the entire cohort, 46% (95% CI: 0.3-0.71) for stage I/II, and 21% (95% CI: 0.09-0.47) for stage III/ IV (p=0.0264) (Figure 1A). Extranodal involvement of the skin / subcutaneous tissue was associated with worse outcomes (Figures 1B and C), with a median PFS to frontline treatment at 3.52 months versus 14.22 months (P=0.0025), and a 2-year PFS of 14% (95% CI: 0.04-0.52). The median OS (Figure 1D) for the entire cohort was 33.94 months (95%CI 14.22 - NA), with OS at 2 years (Figure 1A) of 54% (95% CI: 0.42 -0.71) for the whole cohort, 72% (95% CI: 0.56 -0.92) for stage I/II and 33% (95% CI: 0.18 - 0.6) for stage III/ IV (p=0.0055). The most common second line regimen was SMILE (n=7, 5CRs and 1PR). Novel therapies included brentuximab vedotin (n=4), pembrolizumab (n=6), and EBV-directed T cell infusion (n=5). Analysis of molecular predictive markers, clinical correlates and toxicity data is currently ongoing and will be presented at the meeting. CONCLUSIONENKTCL has poor prognosis especially in advanced stages. In this large single institution cohort, we evaluated the clinical and treatment patterns of this disease over a 12-year period. Our cohort was characterized by younger age and early stage. Higher response rates and improved survival were seen in those with early stage. In advanced stage; the presence of skin/ subcutaneous involvement was identified as a high-risk feature for worse survival. Furthermore, this trend was maintained for PFS and OS for those with advanced stages and skin/ subcutaneous involvement. A better understanding of targetable pathways and a unified treatment approach is needed to improve the outcomes for patients with high-risk features. [Display omitted] DisclosuresHuen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Steiner: BMS: Research Funding; Seattle Genetics: Research Funding; Rafael Pharmaceuticals: Research Funding. Chihara: Astrazeneca: Honoraria. Jain: Lilly: Consultancy; kite: Consultancy. Nastoupil: Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; MorphoSys: Honoraria; Genentech: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; ADC Therapeutics: Honoraria; TG Therapeutics: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Denovo Pharma: Other: DSMC. Pinnix: Merck Inc: Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Flowers: 4D: Research Funding; TG Therapeutics: Research Funding; Adaptimmune: Research Funding; Morphosys: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Kite: Research Funding; Ziopharm: Research Funding; Iovance: Research Funding; Nektar: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Celgene: Consultancy, Research Funding; Biopharma: Consultancy; Bayer: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Denovo: Consultancy; Janssen: Research Funding; Takeda: Research Funding; Burroughs Wellcome Fund: Research Funding; Genmab: Consultancy; BeiGene: Consultancy; Amgen: Research Funding; Xencor: Research Funding; Novartis: Research Funding; Genentech/Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding; EMD: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Sanofi: Research Funding; Acerta: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Allogene: Research Funding; Pfizer: Research Funding; Guardant: Research Funding; Pharmacyclics: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Wang: OMI: Honoraria; Celgene: Research Funding; BGICS: Honoraria; Moffit Cancer Center: Honoraria; Genentech: Consultancy; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Bayer Healthcare: Consultancy; Imedex: Honoraria; Juno: Consultancy, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Scripps: Honoraria; InnoCare: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Mumbai Hematology Group: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; CAHON: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Chinese Medical Association: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; VelosBio: Consultancy, Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; BioInvent: Research Funding; CStone: Consultancy; Newbridge Pharmaceuticals: Honoraria; Physicians Education Resources (PER): Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding. Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding.

Reducing length of stay for patients with acute myeloid leukemia receiving inpatient high-dose cytarabine consolidation chemotherapy.

257 Background: For patients receiving high dose cytarabine (HiDAC) at University of Virginia (UVA) Health between 10/2019 and 10/2020, median length of stay (LOS) from time of clinic appointment to hospital discharge was 119.35 hours. Standard treatment time should be 112 hours from premedication to end of chemotherapy. There are no national standards for duration of inpatient stay for planned chemotherapy, but only 50% of these patients were discharged after noon (over 3 hours post-chemotherapy completion). LOS that extends beyond the standard treatment time results in increased cost, overutilization of hospital resources, delayed admissions for future patients, and patient dissatisfaction. Methods: A multidisciplinary team comprised of licensed providers, pharmacists, and nurses was formed. The team focused on percentage of patients discharged by noon as a surrogate marker for LOS due to inconsistency of admission times; the aim was to increase patients discharged by noon to 65%. Reviewing the baseline data revealed an unstable process with a 3-sigma X-bar statistical process control chart. The team developed current and ideal process state maps, a Pareto chart, and a priority matrix to determine an action plan. The most common identified causes for delay in discharge included: lack of standardized discharge checklist, discharge order placed after 10 am, medications dispensed from the outpatient pharmacy after 11 am, licensed providers not prioritizing discharge patients, and medication reconciliation not completed prior to day of discharge. Results: From 10/2020 to 5/2021, the first PDSA cycle focused on standardizing the discharge process to correct the instability in the process. A discharge checklist was created based on the ideal process map, which allowed the providers to have a consistent process at discharge. 3-sigma Xbar chart demonstrated a now stable process and an increase of patients discharged by noon to 58%. During the second PDSA cycle starting in 6/2021, providers completed medication reconciliation the day before discharge, prioritized HiDAC discharges first during rounds, and ensured discharge orders were placed by completion of the last chemotherapy bag. Data collection is ongoing, and will be analyzed by August 2021. Future tests of change are planned to focus on the pharmacy medication delivery service. Hospital LOS has also decreased after the first PDSA cycle. Conclusions: Using quality improvement methodology, a multidisciplinary team developed an action plan for patients receiving HiDAC which to date has increased the percentage of patients discharging by noon and decreased length of stay. This outcome may lead to reduce hospitalization costs and increase bed availability for other oncology patients. Further PDSA cycles are scheduled and continuous evaluation of the process is ongoing.

Induction Chemo-Immunotherapy with the Matrix Regimen in Patients with Newly Diagnosed PCNSL - a Multicenter Retrospective Analysis on Feasibility and Effectiveness in Routine Clinical Practice

▪BackgroundThe randomized IELSG32 trial compared 3 different induction chemo(immuno)therapy combinations in patients with newly diagnosed primary CNS lymphoma (PCNSL). Results showed that the MATRix combination (methotrexate [MTX], cytarabine [AraC], thiotepa, and rituximab) followed by consolidation therapy significantly improved outcomes in patients up to the age of 70 years (Ferreri et al. Lancet Haematol 2016; Ferreri et al. ASH abstract 2016). The MATRix protocol (4 cycles repeated every 3 weeks) followed by consolidation high dose chemotherapy and autologous stem cell transplant (HDT-ASCT) or whole-brain radiotherapy (WBRT) is now widely regarded as a new treatment standard and benchmark for future randomized trials. However, treatment associated toxicity is common, and many patients encountered in routine practice are older/frailer than those treated in the IELSG32 trial. We conducted a retrospective multicenter study of clinical outcomes in newly diagnosed PCNSL patients treated with MATRix in routine clinical care.MethodsThis retrospective cohort included all consecutive patients with newly diagnosed PCNSL who received at least 1 cycle of MATRix chemotherapy in a real-world non-trial setting between 2010 and 2017 at 9 European centers. One cycle consisted of: 2 x rituximab 375 mg/m² before and/or after chemotherapy, MTX 3.5 mg/m² on day 1, AraC 2 g/m² twice daily on days 2 and 3, and thiotepa 30 mg/m² on day 4. Patients were enrolled at the discretion of the treating physician. Main endpoints were theoretical eligibility for the IELSG32 trial, rate of (serious) adverse events, feasibility, remission status after MATRix therapy, progression free survival (PFS) and overall survival (OS).Results88 patients were included, with a median age of 61 years (range 28-76). Twenty-three patients (26%) would not have met the inclusion criteria of the IELSG32 trial (age > 70 years: 10; reduced performance status [PS]: 4; HIV infection: 3; active hepatitis: 3; inadequate organ function: 3). Anticipated treatment courses were delivered in 228/352 (65%) cases. Dose modifications were performed in 35/88 patients (40%) during cycle 1, in 43/79 patients (54%) during cycle 2, in 33/70 patients (47%) during cycle 3, and in 29/57 patients (51%) during cycle 4. The most common reasons for chemotherapy modification during cycle 1 were reduced PS, co-existing comorbidities and age. Main reasons for dose reduction during subsequent chemotherapy cycles were hematological toxicities, infectious complications and reduced performance. Adverse events, mainly infections, were reported in 48/88 patients (55%) during cycle 1, in 39/79 patients (49%) during cycle 2, in 33/70 patients (47%) during cycle 3, and in 22/57 patients (39%) during cycle 4. Severe infectious complications were more common during cycle 1 (16%) compared to cycle 4 (5%). Intensive care support was required in 4/88 patients (4.5%) during cycle 1, in 1/79 patients (1%) during cycle 2, in 1/70 patients (1.5%) during cycle 3, and in no patients during cycle 4. We recorded six (7%) treatment related deaths during induction chemotherapy (4 during cycle 1, 2 during cycle 2; median patient age 65 years; range 54-75), 5 due to infectious complications and one due to sudden death. Two other patients died later (over 1 year after initiation of MATRix treatment thus not considered treatment related) whilst off therapy and without evidence of disease (one due to hepatic failure and another due to septic encephalitis). After a median of 4 MATRix cycles (range 1-4), the overall response rate was 83% (41% complete remission, 42% partial remission). Nine patients (11%) had progressive disease. Consolidation therapy was applied in 44/82 patients (54%) after MATRix induction therapy (HDT-ASCT: 35; WBRT: 8; lenalidomide: 1). After a median follow-up of 13.1 months, 2-year OS and PFS was 64% (95% CI 52% to 80%) and 57% (95% CI 45% to 72%).ConclusionsThe MATRix protocol is feasible and effective in the treatment of newly diagnosed PCNSL in routine practice, and can be delivered to patients aged >70, with reduced PS and/or co-morbidity to produce similar clinical outcomes to the IELSG32 trial. Importantly, close monitoring and consideration of dose reductions is strongly recommended, especially during cycle 1, to avoid treatment associated complications. Further details will be presented at the meeting. DisclosuresSchorb:Riemser: Honoraria. Fox:Janssen: Consultancy, Honoraria, Other: Travel Sponsorship, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding. Yallop:Jazz Pharmaceuticals: Honoraria; Pfizer: Other: Advisory board; Amgen: Honoraria. Cummin:Janssen: Other: Travel reimbursement. Illerhaus:Riemser: Honoraria. Cwynarski:Gilead, Roche: Other: Advisory board; Gilead, Janssen: Other: Conference expenses.

How should we use ibrutinib in patients with mantle cell lymphoma?

Mantle cell lymphoma (MCL) is not among the most common forms of lymphoid malignancies, representing around 6% of all lymphomas.1 Nevertheless, it may be the lymphoma subtype where management, as well as treatment outcome, has undergone the most changes during the last decades. This dynamic shift in treatment strategies is still very much ongoing. MCL is currently considered a non-curable disease, but as response duration continues to improve, this statement may soon be contradicted. The reason for optimism is the access to several novel agents that have all shown particular high activity in MCL. Arguably, MCL may be the type of lymphoma where the application of anti-CD20 antibodies as single agents has the most significant impact on outcome, as maintenance with rituximab leads to improvement not only in terms of progression-free survival (PFS), but also overall survival. This has been shown both in younger patients and in the elderly population.2, 3 During the last years, we have witnessed the development of a number of agents with impressive activity, specifically in MCL. This includes agents blocking the B-cell receptor pathway, inhibitors of BCL2 such as venetoclax,4 immunosensitizers such as lenalidomide,5 chimaeric antigen receptor T-cells (CAR-T),6 and bispecific antibodies. Among B-cell receptor blockers, one group has emerged as the most active in MCL, inhibitors of Bruton’s tyrosine kinase (BTK). The first BTK inhibitor (BTKi), ibrutinib, has consistently shown response rates around 70% in patients with relapsed MCL, and has secured its place in treatment algorithms.7, 8 How should we use this agent in the clinic? As per current standard, patients with MCL will receive chemotherapy in combination with rituximab as initial treatment. In addition, younger patients usually undergo consolidative high-dose chemotherapy with autologous stem cell support (ASCT).9 Most patients will also receive maintenance rituximab, as this has been shown to improve survival.2, 3 For non-responders, a shift to a BTKi is the treatment of choice, followed by consolidation with an allogeneic stem cell transplant in eligible patients. This is also true for patients with an early relapse (<24 months), where ibrutinib has been shown to be superior to alternative chemoimmunotherapy regimens.10 In a series of pooled data from clinical trials, it was noted that outcome with ibrutinib is superior when used as second-line treatment, compared to later lines, associated with a median PFS of 25 vs 10 months, indicating that earlier use may be of benefit.11 In a recent issue of BJHaem, McCulloch et al.,12 report a multicentre retrospective analysis of 211 MCL patients from the UK, investigating the approach of giving ibrutinib as second-line therapy. Although not all patients could be included nation-wide, these data should provide a more realistic picture of efficacy and safety outside of the clinical trial situation. Data are comforting to clinicians, confirming a high overall response rate, 69%, and a median PFS of 18 months in this situation, slightly lower than shown in the pooled trial data analysis. Only a small minority (7%) stopped ibrutinib due to adverse events, indicating that this is a safe and well-tolerated treatment. This is clinically useful information. Among the 17 patients that proceeded to an allogeneic transplant, median PFS was considerably longer, 34 months, confirming ibrutinib to be an effective bridge to allo-SCT. On the other hand, there are patients for whom treatment with ibrutinib is not efficacious. In this report, patients with blastoid histology could be identified as faring considerably worse, with a more than threefold higher risk for death in a multivariable analysis. This is a patient population clearly in need of experimental, novel treatment strategies. Two other important biological high-risk factors have been established for MCL: proliferation rate, measured by the fraction Ki67-positive cells, and aberrations of TP53. Data on TP53 abnormalities were not available in this report, as this is not yet part of the routine work-up for MCL, but interestingly, high Ki67 (>30%) did not in any way affect the efficacy of ibrutinib. Ibrutinib is not a curative treatment in relapsed MCL. This means that management of patients progressing on this treatment is an increasingly more common clinical situation, for which there is no current standard approach. In this report, the authors confirm that the combination of rituximab, bendamustine and cytarabine (R-BAC), could be the treatment of choice here, possibly as a bridge to an allo-SCT or CAR-T. Twenty-three patients received R-BAC post ibrutinib, associated with a median survival of 14 months, markedly superior to other therapies (median 3·6 months). The next step in the use of ibrutinib in MCL is its introduction as part of first-line treatment. This is being studied in several randomised phase 3 trials; the large European TRIANGLE trial for patients up to 65 years (NCT02858258), evaluates the addition of ibrutinib in the induction phase and as maintenance, as well as if ASCT may be omitted. This trial recently stopped enrolment after the inclusion of 870 patients. The second trial is the SHINE trial (NCT01776840), for elderly patients with MCL, assessing the efficacy of adding ibrutinib to a backbone of rituximab and bendamustine (RB). This trial fulfilled its enrolment several years ago, and results may be expected within the coming year. The third, and possibly most innovative, as it challenges the use of chemotherapy in MCL, is the UK ENRICH trial, comparing chemoimmunotherapy [cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (R-CHOP) or RB] to rituximab + ibrutinib. Enrolment to the latter is likely to be concluded during early 2021. The management of patients with MCL is evolving at a rapid pace. For younger patients that are eligible for intensive therapies that may include ASCT, but also allo-SCT13 and/or chimaeric antigen receptor (CAR)-T-cell products for selected populations, the aim will be to provide a cure for this disease. For elderly and frail patients, highly efficacious, but likely not curative, low-toxic combinations are being developed. In both scenarios, BTK inhibitors such as ibrutinib, are likely to play an important role in the foreseeable future.

ATRT-30. RETROSPECTIVE ANALYSIS OF CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMOR TREATED ACCORDING TO ACNS0333

Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system tumor with poor outcome. ACNS0333, a Children’s Oncology Group phase 3 trial, enrolled 65 evaluable patients who received two cycles of induction chemotherapy, three cycles of consolidative high-dose chemotherapy (HDCT), and focal radiation therapy (RT) pre- or post-consolidation. Craniospinal irradiation (CSI) was left to clinician discretion. We retrospectively analyzed medical records of 27 children treated at our institutions according to ACNS0333. Median age at diagnosis was 14 months (range 4–165); 13 (48%) were male. M-stage was M0, M2, and M3 for 18 (66%), 5 (19%), and 4 (15%), respectively. Tumor location was supratentorial (n=14, 52%), infratentorial (n=12, 44%), or both (n=1, 4%). Complete resection was achieved for 17 (63%). All but one completed induction. Of 13 (51%) with residual disease at diagnosis, 5 (36%) and 7 (50%), respectively, exhibited complete and partial response to induction. Three patients progressed on therapy, and six progressed after completion of therapy at a median of 9.7 months. In all, 18 patients completed RT (16 focal/4 CSI and 6 pre-/12 post-consolidation). Three died of therapy-related toxicity (two in primary therapy and one in relapse therapy), and 8 died of disease. Sixteen patients (59%) are alive at a median follow up of 53 months (range 9–114). Of 17 with germline testing, eight (47%) had rhabdoid predisposition syndrome of whom three are alive. At the time of presentation, data for approximately 50 patients is expected, and we will compare outcomes to soon-to-be published data from ACNS0333.

Melphalan Based Regimens for Treatment of Newly Diagnosed Amyloidosis, Lessons from Clinical Literature: A Systematic Review

Introduction: Melphalan causes cross linkage between DNA, causes cytotoxicity in both dividing and non-dividing tumor cells. Our objective is to analyze and summarize the published literature for the efficacy of melphalan based regimen used for the treatment of newly diagnosed Amyloidosis (ND-AL). Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after June 2006, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 649 articles were identified initially and after detailed screening, we finalized 10 studies involving 616 ND-AL patients. Results: Melphalan (M), Bortezomib (V) and dexamethasone (d)/prednisone (p): A retrospective study by Zhao et al., included 123 ND-AL patients (pts) were given M, V, and d. Overall hematological response (OHR) was 100% with complete response (CR) in 44% and partial response (PR) in 38.9% pts. Median overall survival (mOS) was 38 months (mo) and 3-yr survival ranged from 41-72%. Organ response (OR) was 25%. In a study by Lee et al., with 19 pts who received M, V, and p demonstrated OHR of 84% (Table 1). Melphalan (M) and dexamethasone (d): Sanchorawala et al. (n=70) reported patients treated with M and d showed OHR of 69%, with CR in 13% and PR in 25%. Similarly, a study by Lebovic et al. reported 40 pts who were given M, d. OHR was 58% and 13% pts showed CR (Table 1). High dose Melphalan/Stem Cell Transplant (HDM/SCT) with and without induction: In study by Cowan et al., (n=45) pts in group A (n=21) were given novel induction using agents like protease inhibitor (PI), cyclophosphamide, bortezomib and dexamethasone (CyBorD), Lenalidomide (L), dexamethasone (d) prior to high-dose melphalan (HDM). CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given frontline HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. In a study by Scott et. al., 31 pts were categorized in 3 groups who received HDCT either with no induction, induction with V-based regimen and induction with other regimens including lenalidomide/dexamethasone (len/dex), melphalan/dexamethasone (mel/dex) and thalidomide/dexamethasone (Thal/dex). OHR in mel/dex cohort (n=3) was 67% (Table 1). In a study by Huang, X. et al., 56 pts were divided in two groups of 28 pts each. Pts in group A received Vd+HDM/SCT demonstrated CR in 67.9%, VGPR in 7.1%, PR in 10 .7 % and no response (NR) in 7.1 % pts. In group B, pts received with HDM/SCT upfront demonstrated CR in 35.7%, VGPR in 10.7%, PR in 2.1 % and no response NR in 21.4 % pts (Table 1). Randomized Standard dose Melphalan (SDM) versus HDM: In a study by Jaccard et al., there were two groups. The OHR was 68% in group A pts who were given SDM and high-dose dexamethasone (HD-dex) with CR in 31% and PR in 36% pts. The OHR was 67% in group B pts who were given HDM+ASCT with CR in 40% and PR in 25% pts (Table 1). Melphalan with Total body irradiaton (TBI): Vesole et al., reported 107 pts who were given M and TBI. OHR was 32% with CR in 16% and PR in 16% pts. mOS was 47.2 mo (Table 1). Melphalan (M), dexamethasone (d), Lenalidomide (L): In a clinical trial (NCT00890552) involving 25 pts M, d, and lenalidomide were give. CR, VGPR and PR were observed in 8%, 16% and 33%. 37.5% pts showed no-response (Table 1). Conclusion: Despite heterogeneity in the AL patient population and various regimens used in published literature, melphalan based regimens are very effective for treatment. Induction regimens and supportive care have evolved over the years. Novel combination regimens used for induction followed by HD-Melphalan consolidation along with careful selection of patients for high dose chemotherapy consolidation and stem cell transplantation in routine clinical practice is the best approach for personalized therapy selection for AL amyloidosis. Cytopenias of three cell lines are the major side effects reported with Mel therapy. Just like melphalan use for treatment of multiple myeloma in novel combination regimens, future randomized prospective trials are needed to better understand the efficacy and safety profile of melphalan based newer combination regimens for AL amyloidosis treatment. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Can Less Intensive Chemotherapy and an Autotransplant Cure Adult T-Cell Acute Lymphoblastic Leukemia?

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease usually treated with intensive, high-dose consolidation chemotherapy followed by an allotransplant in a substantial number of patients. The data of the RALL-2009 study on 125 adult T-ALL patients suggest that similar total chemotherapy doses given less intensively over a longer interval without interruptions and with an auto- rather than an allotransplant produce outcomes like current more intensive protocols and an allotransplant: 9-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and survival were 24% (95% CI 16–33%), 70% (95% CI 59–79%) and 62% (95% CI 51–72%). In a landmark analysis, subjects achieving a complete remission and receiving an autotransplant had a lower 9-year CIR (9% [95% CI 2–22%] vs. 29% [95% CI 16–43%]; p = 0.0076) and better LFS (91% [95% CI 79–98%] vs. 58% [95% CI 41–74%]; p = 0.0009) and survival (92% [95% CI 77–99%] vs. 60% [95% CI 44–77%]; p = 0.001) compared with subjects not receiving an autotransplant. In a multivariate analysis, white blood cells ≥100 × 10⁹/L at study entry were significantly associated with worse LFS (HR = 2.842 [95% CI 1.131–7.143]; p = 0.0263) and survival (HR = 6.085 [95% CI 1.918–19.3]; p = 0.0022) because of more early deaths (HR = 2.42 [95% CI 1.04–5.67]; p = 0.041). Receiving an autotransplant correlated with a lower CIR (HR = 0.23 [95% CI 0.07–0.73]; p = 0.0136) and better LFS (HR = 0.27 [95% CI 0.08–0.85]; p = 0.0256) and survival (HR = 0.158 [95% CI 0.045–0.550]; p = 0.0037).

FRONTLINE THERAPY RESULTS IN UNSELECTED PRIMARY CNS LYMPHOMA PATIENTS WITHOUT CONSOLIDATION HD CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION

Introduction: Therapy results from large prospective clinical trials in primary CNS lymphoma (PCNSL) are influenced by restrictive inclusion and exclusion criteria. Herein we present frontline therapy results in unselected patients with PCNSL based on retrospective analysis from single center database over the past 17 years, when consolidation high-dose chemotherapy with autologous stem cell transplantation (ASCT) was not a standard therapeutic approach. Methods: Between 2000 and 2017 we register 79 patients with newly diagnosed PCNSL, median age 64 years (31 – 84). Frontline regimen for patients ≤ 70 years was 5-7x MPV +/- rituximab. Consolidation therapy conceded 2 cycles of cytarabine for selected patients in complete remission instead whole brain radiation therapy (WB RT) up to 45 Gy. None of the patients had consolidation HD chemotherapy with ASCT. Results: Chemotherapy was administered to 72 patients (91 %), in 71 % (51 pts.) MPV regimen +/- rituximab. The rest of the patients had single agent methotrexate or cytarabine or WB RT. Only 35 patients completed at least 5 cycles of MPV-based chemotherapy, the others failed to complete because of unacceptable toxicity or progressive disease. Median OS in the whole unselected cohort was 38 months, 2-year PFS was 40 % and median PFS 14 months. Response rates were evaluated only in the subgroup of 35 patients who completed at least 5 MPV-based chemotherapy. Median age was 57 years (31 - 70), ORR was 80 %, progression was seen in 5 patients (14%), 2 were unable to assess. In this subgroup of relatively fit patients 2-year PFS was 45 % and 2-year OS was 55 %. 10 patients in CR after frontline therapy did not undergo WB RT consolidation, but received 2 courses of single agent cytarabine instead. 5 of them reached durable remission and in the other 5 late relapses occured with median PFS 31 months (12-72). Keywords: autologous stem cell transplantation (ASCT); primary CNS lymphoma (PCNSL).

Toxicity and efficacy of busulfan-melphalan (BuMel) compared to treosulfan-melphalan (TreoMel) high dose chemotherapy (HDCT) consolidation in high-risk Ewing sarcoma (ES): A 12-year monoinstitutional experience.

e22507 Background: We compared toxicity and outcomes of BuMel and TreoMel HDCT consolidation with stem cell rescue in high-risk ES pts prospectively treated in 5 consecutive trials at the Istituto Ortopedico Rizzoli, Bologna, Italy. Methods: Eligible pts had histologically proven diagnosis of ES, high-risk disease defined as localized disease with poor histological/radiological response to standard chemotherapy or lung/pleural metastases or extra-pulmonary metastases or relapsed disease, were aged &lt; 40. All pts received previous standard chemotherapy (vincristine, ifosfamide, doxorubicin, etoposide, cyclophosphamide actinomycin-D) and surgery and/or radiation therapy (RT) as local treatment. From June 1, 2011, TreoMel was used instead of BuMel to avoid potential severe complications related to busulfan, as in case of previous RT on axial skeleton/pelvis. Pts with lung metastases received lung irradiation 12-15 Gy at least 2 months after HDCT. Results: Between January 1, 2007, and September 30, 2018, 98 pts received BuMel or TreoMel: 52 pts with localized disease (7 TreoMel), 26 pts with lung/pleural metastases (5 TreoMel), 10 pts with extra-pulmonary metastases (4 TreoMel) and 10 pts with relapsed disease (1 TreoMel). Median age was 18 yrs (range 3-39 yrs). 14 out of 17 TreoMel pts received previous RT on axial skeleton/pelvis. Median follow up is 4.2 yrs (range 10 mo. - 12 yrs). Pts treated with TreoMel showed a significant lower incidence of grade 3-4 stomatitis (p = &lt; 0.001) and of all grade ≥ 3 non-hematological toxicities (p = &lt; 0.001). One pt died of BuMel-related toxicity (sinusoidal obstruction syndrome/veno-occlusive disease) and none after TreoMel. For localized ES, the 5yr-EFS was 66.7% (95%CI, 47.9-78) for BuMel pts and 66.7% (95CI%, 19.5-90.4) for TreoMel pts. Conclusions: In high-risk ES, TreoMel is significantly less toxic then BuMel. Combining RT on central/axial sites and TreoMel is feasible. In localized ES, results show similar 5yr-EFS between BuMel and TreoMel. TreoMel could be used instead of BuMel when busulfan is contraindicated.

Survival outcomes in patients with good risk acute myeloid leukemia: A single-center retrospective review.

e18519 Background: Cytogenetics and gene mutations play a significant role in determining necessity of allogeneic transplant in patients with AML. Core binding cytogenetic factors (CBF) such as t(8;21), inv 16, and t(16;16) as well as molecular mutations in nucleophosmin-1 (NPM1) and bi-allelic CCAAT/enhancer binding protein alpha (CEBPA) mutations in cytogenetically normal patients have conferred improved relapse-free survival (RFS) and overall survival (OS) rates. We report outcomes of these “good-risk” patients in an Appalachian population, to evaluate differences from previous reports. Methods: A total of 79 patients with AML diagnosed between July 2007 and July 2017 at West Virginia University (WVU) who qualified for good-risk disease per ELN 2017 criteria were retrospectively analyzed for RFS and OS. Eighteen of these patients were excluded from our final analysis: 10 for primary refractory disease and 8 for proceeding to transplant in first remission. Results: A total of 61 patients were included in our analysis, with a median age of 56 (range 11-81), 32 females, and 29 males. Good-risk features included 29 patients with NPM1, no patients with CEBPA, 19 with inv 16, 9 with t(8;21), and 1 with t(16;16). All patients received cytarabine and an anthracycline induction chemotherapy, and a median of 4 cycles (range 1 -4) of high-dose cytarabine consolidation chemotherapy. The RFS and OS at 4 years was 36% and 50%, respectively. There were no occurrences of treatment-related mortality among the patients. Among the 22 patients relapsing, 12 (55%) were able to achieve a second remission and received allogeneic transplant. Conclusions: Our outcomes appear somewhat lower than previous reports, but continuing to highlight the ability to achieve long-term remissions in this subset of patients, without the need for allogeneic transplant. Continued efforts should focus on improving outcomes in these patients, to further prevent relapses.

A meta-analysis of autologous transplantation for newly diagnosed multiple myeloma in the era of novel agents

To evaluate the role of high-dose melphalan plus autologous stem-cell transplantation (ASCT) as consolidation therapy for patients with newly diagnosed multiple myeloma (NDMM) in the era of novel agents, we undertook this meta-analysis. Medline, Embase, the Cochrane controlled trials register, the SCI, ASH, EHA, and ASCO were searched for clinical trials including high-dose chemotherapy plus ASCT for patients with NDMM. Finally, we identified four RCTs of ASCT versus novel agents based consolidations, and 10 single-arm prospective trials of ASCT alone. Pooled analysis indicated that response quality improved further after ASCT in the era of novel agents (≥CR rates of 13% pre-ASCT versus 29% post-ASCT, p = .003). When compared to novel agents containing consolidation regimens, high-dose chemotherapy plus ASCT significantly improved progression-free survival (PFS) (HR =0.56, p < .001). No significant difference in overall survival (OS) was found between them (HR =0.66, p = .22). Of note, subgroup analysis indicated that ASCT could significantly improve OS (HR =0.49, p = .0004) when compared to alkylating agent-based regimens plus lenalidomide consolidation. In summary, response quality and PFS improved further over ASCT in the era of novel agents. ASCT could improve survival than alkylating agent-based regimens plus lenalidomide consolidations for patients with NDMM.