High-dose Chemotherapy And Autologous Stem Cell Transplantation Research Articles

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma

BackgroundApproximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to...

Cardiovascular diseases after high-dose chemotherapy and autologous stem cell transplant for lymphoma: A Danish population-based study.

Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m2 ) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 [1.8-3.8]) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients – the randomized phase III PRIMA-CNS trial

BackgroundOlder primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed.MethodsThis open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT.DiscussionThe best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach.Trial registrationGerman clinical trials registry DRKS00024085 registered March 29, 2023.

Treatment Strategies and Prognostic Factors in Secondary Central Nervous System Lymphoma: A Multicenter Study of 124 Patients.

Secondary central nervous system lymphoma (SCNSL) is a rare and difficult to treat type of Non-Hodgkin lymphoma characterized by systemic and central nervous system (CNS) disease manifestations. In this study, 124 patients with SCNSL intensively treated and with clinical long-term follow-up were included. Initial histopathology, as divided in low-grade, other aggressive, and diffuse large B-cell lymphoma (DLBCL), was of prognostic significance. Overall response to induction treatment was a prognostic factor with early responding DLBCL-SCNSL in comparison to those non-responding experiencing a significantly better progression-free survival (PFS) and overall survival (OS). However, the type of induction regime was not prognostic for survival. Following consolidating high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), DLBCL-SCNSL patients had better median PFS and OS. The important role of HDT-ASCT was further highlighted by favorable responses and survival of patients not responding to induction therapy and by excellent results in patients with de novo DLBCL-SCNSL (65% long-term survival). SCNSL identified as a progression of disease within 6 months of initial systemic lymphoma presentation represented a previously not appreciated subgroup with particularly dismal outcome. This temporal stratification model of SCNSL diagnosis revealed CNS progression of disease within 6 months as a promising candidate prognosticator for future studies.

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.

High-Dose Chemotherapy and Autologous Stem Cell Transplant in Elderly and Fit Primary CNS Lymphoma Patients - a Multicenter Study By the Cooperative PCNSL Study Group (MARTA study)

Introduction: High-dose methotrexate (HD-MTX) based induction chemo-immunotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) has been shown to be feasible and effective in younger and in selected elderly PCNSL patients. We aimed to investigate this treatment approach in patients > 65 years with newly diagnosed PCNSL in a multicentre study. Methods: This open-label, multicentre, single arm phase II study was conducted at 15 German centres (DRKS 00011932). Main eligibility criteria included newly diagnosed PCNSL, immunocompetence, age > 65 years, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2, and adequate organ function. Induction treatment consisted of two 21-day cycles of HD-MTX 3.5 g/m² (day 1), cytarabine 2 g/m² twice daily (days 2, 3) and rituximab 375 mg/m² before and after each chemotherapy with stem cell harvest after the 1st cycle. Patients not suffering disease progression subsequently received consolidation treatment with HCT-ASCT with rituximab 375 mg/m² (day -8), busulfan 3.2 mg/kg (days -7, -6), thiotepa 5 mg/kg/d (days -5, -4) and reinfusion of stem cells (day 0). Primary endpoint was progression-free survival (PFS) at 1 year by intention-to-treat (ITT). Secondary endpoints included overall survival (OS), treatment response and toxicities. Results: Between Nov 2017 and Sept 2020, we registered 57 patients. Five patients were excluded because of systemic lymphoma manifestation, absence of measurable radiologic lesion(s), inadequate renal function, ECOG PS >2 and deterioration before the start of study treatment. Finally, 52 eligible patients were included in the ITT population. Mean age was 72 years (range 65-80 years), 27/52 (51.9%) patients initially presented with an ECOG PS > 1. All patients started induction chemo-immunotherapy, 45 of 52 (86.5%) patients completed induction treatment. Thirty-seven of 52 (71.2%) patients proceeded to HCT-ASCT. Most common serious adverse events were infections, renal failure and (cerebro)vascular events, which mainly occurred during induction treatment. Overall, 22 (42.3%) patients died, 12 of whom (23.1%) without evidence of disease progression or relapse. Three (5.8%) patients died because of treatment-related complications, all of them during induction treatment. An additional patient died within 30 days after HCT-ASCT due to fatal viral pneumonia, main other non treatment-related causes of deaths were late infections and (cerebro)vascular events. Forty-one of 52 (78.8%) patients responded to induction treatment; 23 (44.2%) patients achieved a (unconfirmed) complete response and 11 (21.2%) patients a partial response 30 days after HCT-ASCT. After an estimated median follow-up of 23 months, PFS at 12 and 24 months was 57.7% (95% CI 43.2-69.7%) and 54.8% (40-67.4%), respectively; median PFS was 41.1 months (95% CI 6.7 to not calculable). Overall survival at 12 and 24 months was 63.1% (95% CI 48.4-74.7%) and 60.5% (95% CI 45.5-72.5%), respectively; median OS was 41.1 months (95% CI 10.3 to not calculable). Of those 37 patients undergoing HCT-ASCT, 2-year PFS and OS rates were 71.7% (95% CI 53.4-83.8%) and 80.8% (95% CI 63.8-90.3%), respectively. Conclusions: Feasibility and efficacy of HCT-ASCT in selected elderly patients with newly diagnosed PCNSL are confirmed in a multicenter setting with survival rates comparable to those of younger cohorts. Nevertheless, non-relapse mortality remains a major challenge in this vulnerable patient population emphasizing that standardized assessment of eligibility for intensive treatment is of utmost importance. This will be addressed in the upcoming randomized phase III PRIMA-CNS trial (DRKS00022768). Final data analysis is currently ongoing and will be presented in detail at the meeting.

Reduced-Intensity Conditioning Prior Autologous Stem Cell Transplantion in Elderly DLBCL Patients

Introduction High-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is widely used in diffuse-large B-cell lymphoma (DLBCL) patients. Since HDCT/ASCT in elderly patients is associated with increased morbidity, the clinical impact is not well defined. In addition, only very few data for HDCT/ASCT with reduced intensity conditioning in elderly DLBCL patients exists. Methods We performed a single center retrospective analysis of 146 DLBCL patients aged 60 years and older who received HDCT/ASCT between 2005 and 2019. Statistical analyses were conducted with GraphPad Prism 5® and SAS V9.4. Results Patients were analyzed according conditioning regimens: 86 patients received standard intensity high-dose conditioning (SI-group) with BEAM (BCNU, etoposide, cytarabine, melphalan) or TEAM (Thiotepa, etoposide, cytarabine, melphalan) and 60 patients received reduced intensity high-dose conditioning (RI-group) with BM (BCNU, melphalan, 43.3%), TM (Thiotepa, melphalan, 16.7%), BCNU/or Busulfan-Thiotepa (38.4%) or Bendamustin-melphalan (1.7%). Comparing patients characteristics in the SI and RI-group, we found a difference for age (median age 65.5 vs. 71.8, p<0.001) and ECOG 0 vs ≥1 p=0.006, whereas we found no difference for other prognostic factors like disease stage, elevated LDH, extra-nodal disease or bulky disease. We found no statistical difference for remission status before ASCT (SI-group: PR/CR1 58.1%, PR/CR>1 25.6% and refractory disease (14%); RI-group: PR/CR1 41,7%, PR/CR>1 35% and refractory disease in 21.7% of patients), or lines of prior therapy (SI-group: 1 in 60.5% and ≥2 in 39.5% of patients, RI-group: 1 in 50% and ≥2 in 50% of patients). We observed no significant difference in frequency or severity of relevant toxicities like febrile neutropenia, enterocolitis, sepsis, lung infections, mucositis or atrial fibrillation. Median time of hospitalization did not differ between both groups (15 vs. 17 days). We found no difference for remission status after HDCT/ASCT between both groups. Cumulative incidence of relapse was higher in the RI-group: 30.8% (RI-group) and 23.4% (SI-group) at three years, p=0.034. We observed no difference in non-relapse mortality (NRM) 14.4% vs. 12.8% at three years. With a median follow-up of 62.4 month, we observed a 3-year overall survival (OS) of 67.1% and a 3-year PFS of 59.3%. Univariate analysis revealed several factors associated with inferior PFS and/or OS Table 1. Reduced intensity conditioning was associated with an inferior PFS, but not an inferior OS. Of note, in a multivariate Cox Regression analysis, we observed no difference in PFS (HR 0.74 (0.40 - 1.38) p=0.345), but a trend for better OS with reduced intensity conditioning (HR 0.45 (0.22 - 0.94) p=0.032) Table 2. Conclusion: Reduced-intensity conditioning with two alkylating agents and omission of etoposide and cytarabine is feasible in elderly patients. Our retrospective analysis indicates a comparable outcome of SI and RI conditioning, when corrected for multiple significant confounders. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Activity of Combining CNCT19 with HDT/ASCT in Refractory Large B-Cell Lymphoma: Two-Year Follow-up of a Prospective Phase 1/2 Clinical Trial

Background: We have previously reported the preliminary results of a phase 1/2 clinical trial of administrating CNCT19 (a second-generation anti-CD19 CAR T-cell) following high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) in large B-cell lymphoma (LBCL) patients with diseases refractory to first-line and/or subsequent lines of chemotherapy. Eight of 10 (80%) patients achieved complete response (CR), and the estimated proportion of progression-free survival (PFS) and overall survival (OS) at 12 months was 66.7% and 77.1%, respectively (Wei liu et al. ASH 2019, 2020). Here we reported this study's updated enrollment, efficacy, and follow-up. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with LBCL with a history of refractory to first-line rituximab-containing anthracycline-based chemotherapy and/or subsequent salvage chemotherapy were eligible for this study. Conditioning regimen of GBC/M (Gemcitabine 600 mg/m2/h, infused for 3 hours with loading bolus of 75 mg/m2, day -7, -3, busulfan 105 mg/m2, day -7 until -5, cyclophosphamide 45mg/kg or melphalan 60 mg/m2, day -3, -2) was administered once the CNCT19 product was available. Autologous stem cells were infused on day 0, and CNCT19 cells were infused on day +3 (±1 day). Cytokine release syndrome (CRS) and CAR-T-cell-related encephalopathy syndrome (CRES) were graded according to the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group criteria. Results: From December 2017 through May 2021, 21 subjects were consecutively enrolled in this study. CNCT19 cells were successfully manufactured for 20 subjects and administered to 18 subjects. The median age was 44 (range 23 to 64), and 56% were male. Patients included 11 (67%) with diffuse large B-cell lymphoma (not otherwise specified), 4 (22%) with high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement, 2 (11%) with primary mediastinal large B-cell lymphoma and 1 (6%) with transformed follicular lymphoma. The median number of lines of prior therapy was 3 (range, 2 to 5). Eighty-nine percent of patients had a history of refractory to first-line immunochemotherapy of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) or R-DA-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin), and 72% were refractory to subsequent platinum-based salvage therapy. TP53 deletion and/or mutation were detected in 7 of 11 (64%) patients. The median dose of infused stem cells was 2.6×106 (range, 1.8~8.7×106) per kilogram of body weight and the median dose of infused CNCT19 cells was 2×106 (range, 1.6~4.0×106) per kilogram of body weight. The CRS occurred in 16 patients (89%), and all were low grades (grade 1, 83%; grade 2, 6%). CRES occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved completely after glucocorticoids treatment. We did not observe any unexpected toxicity or treatment-related death throughout the therapy. The median times to neutrophil and platelet recovery were ten days (range, 8 to 30 days) and 16.5 days (range, 8 to 265 days) after stem cells reinfusion, respectively. As of July 26, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 28.2 (95% CI 16.9-39.1) months. The best overall response rate was 94.4%, with a best CR rate of 72.2%. The median PFS, duration of response (DOR), disease-free survival (DFS) and OS were not reached, and the probability of 2-year PFS, DOR, DFS and OS were 59.3% (95% CI 32.5%-78.4%), 63.5% (95% CI 35.9%-81.8%), 74.1% (95% CI 39.1%-90.9%) and 64.2% (95% CI 36.2%-82.4%), respectively. Of the patients who were in durable response at three months or six months post CNCT19 infusion, 66.7% and 83.3% were in ongoing response at the date of data cutoff, respectively. Conclusions: CNCT19 could be safely administered following HDT/ASCT in patients with relapsed or refractory LBCL. The strategy of combining CAR T-cell therapy with HDT/ASCT might improve response rate and prolong survival compared to CAR T-cell therapy alone.

Optimizing MATRix as remission induction in PCNSL: de-escalated induction treatment in newly diagnosed primary CNS lymphoma

BackgroundPrimary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) supporting this approach to be considered a standard therapy in newly diagnosed PCNSL patients ≤ 70 years. However, early treatment-related toxicities (predominantly infectious complications), occurring in up to 28% per MATRix cycle, diminish its therapeutic success. Furthermore, sensitivity to first-line treatment is an independent prognostic factor for improved overall survival (OS) in PCNSL. Thus, patients achieving early partial remission (PR) after 2 cycles of MATRix might be over-treated with 4 cycles, in the context of consolidation HCT-ASCT.MethodsThis is an open-label, multicentre, randomized phase III trial with two parallel arms. 326 immunocompetent patients with newly diagnosed PCNSL will be recruited from 37 German, 1 Austrian and 12 UK sites. Additional IELSG (International Extranodal Lymphoma Study Group) sites are planned. The objective is to demonstrate superiority of a de-escalated and optimised remission induction treatment strategy, followed by HCT-ASCT. Randomization (1:1) will be performed after completion of all screening procedures. Patients in Arm A (control treatment) will receive 4 cycles of MATRix. Patients in Arm B (experimental treatment) will receive a pre-phase (R/HD-MTX), followed by 2 cycles of MATRix. Patients in both arms achieving PR or better will proceed to HCT-ASCT (BCNU, thiotepa). The primary endpoint of the study is event-free-survival (EFS), defined as time from randomization to premature end of treatment due to any reason, lymphoma progression or death whichever occurs first. Secondary endpoints include OS, progression free survival (PFS), toxicity, neurocognitive impairment and quality of life. Minimal follow-up is 24 months.DiscussionCurrent treatment options for PCNSL in patients ≤ 70 years have improved remarkably over recent years. However, the potential efficacy benefits are offset by an increased incidence of short-term toxicities which can impact on treatment delivery and hence on survival outcomes. In patients ≤ 70 years with newly diagnosed PCNSL addressing the need to reduce treatment-related toxicity by de-escalating and optimising the induction phase of treatment, is a potentially attractive treatment strategy.Trial registrationGerman clinical trials registry DRKS00022768 registered June 10th, 2021.

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.

Durable remission for four pediatric patients with high-risk relapsed classical Hodgkin lymphoma treated with brentuximab vedotin plus gemcitabine but without autologous stem cell transplantation: A report from the Children's Oncology Group.

Patients with therapy-refractory or high-risk relapsed classical Hodgkin lymphoma are typically treated with the high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients.

PK and PD Assessment of BET Inhibitor Pelabresib (CPI-0610) in Patients with Relapsed or Refractory Lymphoma: Findings from a Phase 1 Study

PK and PD Assessment of BET Inhibitor Pelabresib (CPI-0610) in Patients with Relapsed or Refractory Lymphoma: Findings from a Phase 1 Study

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma.

Simple SummaryHigh-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a standard treatment in patients with newly diagnosed multiple myeloma (MM). At relapse, salvage HDCT/ASCT is a treatment option in patients with sufficient benefit from frontline HDCT/ASCT, but no evidence is currently available regarding its role in the era of triplet regimens combining the most active drug classes for relapsed MM. To evaluate the outcome after salvage HDCT/ASCT following re-induction treatment with carfilzomib/lenalidomide/dexamethasone (KRD) and to identify prognostic factors, we conducted a retrospective analysis of patients that had previously undergone frontline HDCT/ASCT. We found that deep remissions achieved with KRd followed by salvage autologous transplantation were associated with favorable PFS and were enhanced by maintenance treatment. Salvage autologous transplantation after state-of-the-art triplet re-induction was a safe and effective strategy for RRMM patients that may offer the chance to avoid refractoriness to multiple novel agents at the next relapse.Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ 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). 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.

Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice

Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted ‘standard-of-care’ approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients.

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.

Clinicopathological analysis of primary refractory diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone chemoimmunotherapy.

BackgroundApproximately 15% of patients with diffuse large B‐cell lymphoma (DLBCL) experience refractory or early relapsed disease after initial rituximab‐containing chemoimmunotherapy is regarded as a primary refractory disease. Although the standard treatment for relapsed DLBCL is high‐dose chemotherapy and autologous stem cell transplantation (HDC‐ASCT), the efficacy of this approach for primary refractory DLBCL is not well understood. We aimed to investigate the clinicopathological characteristics and outcomes of patients with primary refractory DLBCL.MethodsSixty‐nine consecutive patients with primary refractory DLBCL who were treated at our institution were categorized as partial responders (partial response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone [R‐CHOP] or relapse within 6 months of R‐CHOP) (n = 41) or primary progressors (no response to R‐CHOP) (n = 28). Survival curves were constructed using the Kaplan–Meier method and compared using the log‐rank test.ResultsAt initial diagnosis, 70% of patients had Ann Arbor stage III/IV disease, 56% had non‐germinal center B‐cell‐like type DLBCL, and 42% had double‐expressor lymphoma (MYC and BCL2 expression). The 3‐year overall survival rate was significantly poorer in the primary progressors group than in the partial responders’ group (15% vs. 48%, p < 0.001). Four of 17 patients treated with HDC‐ASCT were primary progressors; only one patient survived without relapse. Although double‐expressor lymphoma status did not significantly impact overall survival among all patients (p = 0.794), it was identified as an independent poor prognostic factor in HDC‐ASCT‐treated patients (p = 0.002).ConclusionsWe identified a subgroup of patients with primary refractory DLBCL who may not benefit from current treatment strategies. Further treatment development is needed to improve the outcomes of these patients.

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine (Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016-2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.

Anti-CD19 CAR T-Cell (CNCT19) Infusion Following HDT/ASCT Is Safe and Effective in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell is a promising therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma. 29~37% of patients can achieve sustained complete remission (CR) after anti-CD19 CAR T-cell infusion, which means that approximately two-thirds of patients will eventually progress and have extremely poor survival. We conducted a pilot study to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell) cellular immunotherapy in conjunction with high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT). The preliminary results of the first 6 patients had been reported at the 61st ASH Meeting (Liu et al., 784a). Here we reported the updated enrollment, safety, efficacy, and follow-up of this study. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with large B-cell lymphoma refractory to primary or salvage therapy were eligible for this study. All patients must have received rituximab and anthracycline-containing treatment during their prior therapy. Conditioning regimen included GBC/M (gemcitabine, busulfan, and cyclophosphamide/melphalan) and BEAM (carmustine, etoposide, cytarabine, and melphalan, administered in one patient), and CNCT19 was infused on day +2, +3 or +4 following autologous stem-cell infusion. Results: Between January 2018 and May 2020, 13 patients were enrolled. The median age was 48 years (range, 29~ 64 years), and there were 7 males. Diagnosis of lymphoma subtypes included diffuse large B-cell lymphoma (n=10), high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangement (n=1), primary mediastinal large B-cell lymphoma (n=1) and transformed follicular lymphoma (n=1). The patients received a median of 3 (range, 2~4) lines of prior therapy and 76.9% had disease that was resistant to last-line therapy. The median dose of infused stem cells was 2.54×106 per kilogram of body weight (range, 1.77~8.7×106) and the median dose of infused CNCT19 cells was 2×106 per kilogram of body weight (range, 1.7~4×106). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT criteria. After CNCT19 infusion, 92.3% of patients experienced grade 1 CRS, and no one experienced grade 2 or higher CRS. The median time after CNCT19 infusion until the onset of CRS was 1.5 days (range, 0~3), and the median time until resolution was 8 days (range, 6~10). Seven patients (53.8%) received tocilizumab and two patients (15.3%) received glucocorticoids for the management of CRS. ICANS occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved after glucocorticoids treatment. The median times to neutrophil and platelet engraftment were 11 days (range, 8~32) and 17 days (range, 8~265), respectively. Ten patients were followed up for 3 or more months and evaluable for response. Eight of 10 patients achieved complete remission (CR), and the best overall response rate (ORR) and CR rate were both 80%. With a median follow-up of 11 months (range, 3~31) after CNCT19 infusion, the CR rate at 3 months and 6 months were 70% and 62.5%, respectively. Median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated proportion of PFS and OS at 12 months was 66.7% and 77.1%, respectively. Conclusion: CNCT19 infusion following HDT/ASCT could be safely administered in R/R large B-cell lymphoma patients. More patients achieved sustained remission compared with those who received anti-CD19 CAR T-cell therapy alone. The preliminary results of this pilot study support further investigation of the combination of CAR T cellular immunotherapy with HDT/ASCT. Disclosures Lv: Juventas Cell Therapy Ltd.: Current Employment.

MM-235: Outcomes of Daratumumab, Pomalidomide, and Dexamethasone (DPd) Followed by High-Dose Chemotherapy and Autologous Stem Cell Transplantation (HDCT/ASCT) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

<h3>Context:</h3> At this time, there is no rationale to favor a specific therapeutic class (e.g., immunomodulatory agents (IMiD), proteasome inhibitors (PI), or monoclonal antibody) over another for the treatment of relapsed/refractory myeloma (RRMM). Our institute treated a series of patients with induction therapy consisting of daratumumab, pomalidomide, and dexamethasone (DPd) followed by high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) in patients with RRMM. <h3>Objective:</h3> To present longer-term efficacy and safety outcomes with DPd followed by HDCT/ASCT in patients with RRMM. <h3>Methods:</h3> We treated 18 patients with RRMM at the University of Kansas Health System between May 2016 and April 2020 with DPd as induction therapy followed by HDCT/ASCT. DPd was administered as daratumumab 16 mg/kg weekly for cycles 1 and 2, every 2 weeks for cycles 3–6, and then every 4 weeks; pomalidomide was dosed at 4 mg orally on days 1–21 of a 28-day cycle; and dexamethasone 20 or 40 mg weekly. Responses were evaluated using the 2016 International Myeloma Working Group (IMWG) criteria. <h3>Results:</h3> Patients received a median of two lines (1–4). Out of the 18 patients, 72% received ASCT in the past prior to this treatment. In addition, 78%, 78%, and 72% were refractory to PI and IMiDs and double refractory to IMiDs and PI, respectively. The median time from diagnosis to treatment was 12 months. The median number of DPd cycles received was 4 (2–7) cycles. A median follow-up of 27 months (range: 12–39), the overall response rate (ORR) after induction treatment with DPd was 100%. ORR on day 100-post ASCT was 100%, 67% achieved ≥CR, and 78% achieved ≥VGPR. There was no treatment-related mortality on day 100. Median progression-free survival was 34 months (95%, CI=NA); median overall survival was not reached. The most common grade ≥3 adverse events were thrombocytopenia (53%), anemia (40%), neutropenia (53%). <h3>Conclusions:</h3> DPd as induction therapy followed by HDCT/ASCT demonstrated deep, durable, and clinically meaningful responses with a manageable safety profile in patients with RRMM.