Regimen For Autologous Stem Cell Transplantation Research Articles

Efficacy and Safety of Chidamide Combined with BEAM Conditioning Regimen in Autologous Transplantation for T-Cell Lymphoma

Background: T cell lymphoma (TCL) is a group of highly heterogeneous aggressive non-Hodgkin lymphomas with different pathogenesis and clinical prognosis. Despite the survival benefits of anthracycline-based chemotherapy bridging autologous stem cell transplantation (ASCT), 40% to 50% of TCL patients fail to respond to treatment and relapse or die within a short period of time. Chidamide is an oral selective histone deacetylase inhibitor (HDACi), interferes with epigenetic regulation by deacetylating nuclear transcription factors, affects proliferation and differentiation of tumor cells, and regulates cytokines in the tumor microenvironment. Chidamide combined with chemotherapy has promising clinical applications in ASCT. Aims: This prospective Phase II trial aims to evaluate the efficacy and safety of chidamide in combination with carmustine, etoposide, cytarabine, and melphalan (Chi-BEAM) conditioning regimen in ASCT of TCL patients received CR/PR to first-line chemotherapy. Method: In this study, eligible patients with TCL (except IPI 0-1 ALK+ anaplastic large cell lymphoma) aged 18-65 years were enrolled. All patients received Chi-BEAM conditioning regimen before ASCT. 30mg of chidamide was administered twice a week for at least 2 years after ASCT.The primary end point was 2-year progression-free survival (PFS) rate, and the secondary end points were 2-year overall survival (OS) rate and safety evaluation. Results: At the time of data cut off, a total of 18 patients were enrolled, with a median age of 48 (15-65) years. The 1-year PFS rate and OS rate after ASCT were 90.0% and 100.0%, respectively. The median implantation time of neutrophils was 10 days (9-13 days), and the median implantation time of platelets was 17 days (11-25 days). Most of the adverse reactions (AEs) were tolerable, including controlled grain deficiency with fever, electrolyte disturbance, and abnormal liver function. Conclusion: Chidamide combined with BEAM as a conditioning regimen for ASCT can significantly improve PFS and OS in TCL patients, and the AEs are controllable. The study is ongoing and further results will be continuously released.

BendaEAM versus BEAM as conditioning regimen for ASCT in patients with relapsed lymphoma (BEB): a multicentre, randomised, phase 2 trial

Replacement of carmustine (BCNU) in the BEAM regimen (BCNU, etoposide, cytarabine, melphalan) with bendamustine (BendaEAM) before autologous stem cell transplantation (ASCT) is feasible in lymphoma. However, randomised trials are lacking. Here, we present the first trial addressing this topic. This multicentre, randomised, phase 2 study (BEB-trial) conducted at four haematological centres in Austria and Switzerland compares BEAM with BendaEAM in patients with relapsed lymphoma. Both regimens were administered intravenously before ASCT, in BEAM according to the standard protocol (300mg/m2 BCNU on day-6), in BendaEAM, BCNU was replaced by 200mg/m2 bendamustine given on days-7 and-6. Eligible patients were aged 18-75 years and had mantle cell lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma in first or second remission or chemosensitive relapse. The primary endpoint of the study was to evaluate whether replacement of BCNU by bendamustine reduces lung toxicity, defined as a decrease of the diffusion capacity of the lung for carbon monoxide by at least 20% at three months after ASCT. Data analyses were performed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02278796, and is complete. Between April 20, 2015, and November 28, 2018, 108 patients were enrolled; of whom 53 were randomly assigned to receive BendaEAM (36 male, 17 female) and 55 to receive BEAM (39 male, 16 female). All patients engrafted rapidly. Lung toxicity did not differ between groups (BendaEAM: n=8, 19.5%; BEAM: n=11, 25.6%; risk difference=-6.1%: 95% confidence interval:-23.9% to 11.7%). Acute toxicities of at least grade 3 were comparable in both groups (BendaEAM: 35.8%, BEAM: 30.9%). Overall survival (BendaEAM: 92.5%, BEAM: 89.1%) and complete remission (BendaEAM: 76.7%, BEAM: 74.3%) after 1 year (median follow-up: 369 days) were similar. No difference in quality of life was observed. Results were similar for both regimens in terms of survival and response rates. A phase 3 non-inferiority study is required to investigate whether BendaEAM can be considered as an alternative to BEAM. Mundipharma.

CEAC (oral semustine, etoposide, cytarabine and cyclophosphamide) vs BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimen of autologous stem cell transplantation for diffuse large B-cell lymphoma: a post-hoc, propensity score-matched, cohort study in Chinese patients.

Autologous stem cell transplantation (ASCT) is a salvage therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We have developed a novel conditioning regimen called CEAC (oral semustine 250mg/m2 d-6, etoposide 300mg/m2 d-5 ~ d-2, cytarabine 500mg/m2 d-5 ~ d-2, and cyclophosphamide 1200mg/m2 d-5 ~ d-2) In lymphoma patients in China. Here, we conducted a study to compare the conventional BEAM regimen with the CEAC regimen in 110 DLBCL patients. Propensity-score matching was performed in a 1:4 ratio (22 patients received BEAM and 88 received CEAC). Our results showed no significant difference in the overall response rate (95% vs 97%, P = 1.000) and complete response rate (66% vs 73%, P = 0.580) between the two cohorts. The 5-year progression-free survival (PFS), 5-year overall survival (OS), and 5-year cumulative incidence of relapse (CIR) for all patients were 72% (95% CI 62%-82%), 92% (95% CI 86%-97%), and 29% (95% CI 17%-38%), respectively. There was no significant difference in the 5-year PFS (80% vs 70%, P = 0.637), 5-year OS (95% vs 91%, P = 0.496), and 5-year CIR (20% vs 30%, P = 0.733) between cohorts. In terms of safety, the CEAC cohort had a lower incidence rate of grade 1-2 gastrointestinal hemorrhage (P = 0.023) and severe nausea (P = 0.007) compared with the BEAM cohort. In conclusion, the CEAC regimen seems to be a suitable alternative to the BEAM regimen for ASCT in DLBCL patients.

A NOVEL CONDITIONING REGIMEN OF CHIDAMIDE, CLADRIBINE, GEMCITABINE, AND BUSULFAN (CHICGB) IN THE AUTOLOGOUS STEM CELL TRANSPLANTATION OF AGGRESSIVE T‐CELL LYMPHOMA

Background: The prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT). Methods: Patients with PTCL or T-LBL were enrolled to receiviing ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess patient outcome, and adverse events were used to assess the safety of the regimen. The survival curve was estimated via the Kaplan-Meier method. Results: Twenty-five PTCL and 11 T-LBL patients were recruited. The median time to white blood cell (WBC) and platelet engraftments were 10 days (8–13 days) and 13 days (9–31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR), but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable. Conclusions: ChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to further assess ChiCGB as conditioning regimen for ASCT. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Stem Cell Transplant No conflicts of interests pertinent to the abstract.

Long-Term Results with Thiotepa-Containing Conditioning Regimens for Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of both Hodgkin lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most frequently used conditioning regimen; however, owing due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results in ASCT with a TECAM (thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan) conditioning regimen from 2000 to 2013. We aimed to update our experience with the TECAM regimen by adding our experience from 2013 to 2020 to the previously reported cohort. Moreover, we aimed to use the detailed data for the 2 transplant cohorts to identify improvements in ASCT outcomes in the recent era. We retrospectively analyzed all lymphoma patients who underwent ASCT at our center between January 2000 and December 2020. A total of 353 lymphoma patients were included (142 in the newer cohort added to 211 previously reported patients), all of whom were treated with our standard TECAM conditioning regimen. The cohort included 127 patients with HL, 107 with DLBCL, and 119 with other NHL subtypes. The newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) prior to ASCT (45.7% versus 19.3% with ECOG-PS ≥1; P < .01), whereas a higher proportion of patients entered transplantation in complete response (CR) (71.9% versus 47.8%; P < .01). The median follow-up after ASCT was 136.4 months (95% confidence interval [CI], 91.4 to 181.4 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates post-ASCT for the entire cohort were 59.8% and 79.3%, respectively. Evaluating the 303 of 353 patients (86.4%) who entered ASCT with a responsive disease-a population that represents today's approach to the selection of patients for ASCT-the 3-year PFS and OS rates were 61.5% and 81.9%, respectively. In this population, the 3-year PFS rate was 62.2% for HL, 62.6% for DLBCL, 64.3% for primary central nervous system lymphoma (PCNSL), and the 3-year OS rate were 90.1%, 75.2%, and 78.6%, respectively. OS was significantly better in the newer cohort (P < .01), but not when evaluating only patients who entered ASCT with responsive disease. Dose reductions, poor disease status, and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. In accordance with our previous report, patients entering transplantation for DLBCL with a partial response achieved similar outcomes as those with a CR. Eighteen patients died within the first 100 days, 8 due to disease progression and 10 due to transplantation-related complications (2.8%). There were no cases of interstitial pneumonitis syndrome. Twenty-two cases (6.2%) of secondary malignancies were documented. Our results confirm that TECAM is an effective and safe conditioning regimen for ASCT in patients with HL and various NHLs, including favorable results in PCNSL. Despite a higher proportion of frail patients, the newer cohort's outcomes were favorable, driven by better lymphoma control pretransplantation. In the DLBCL cohort, ECOG-PS had more prognostic value than achieving a CR pre-ASCT, a finding relevant to the optimal allocation of patients to different treatment options in the era of chimeric antigen receptor T cell availability.

A novel conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan in the autologous stem cell transplantation of aggressive T-cell lymphoma.

The prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT). Patients with PTCL or T-LBL were enrolled to receive ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess the patient outcome, and adverse events were used to assess the regimen's safety. The survival curve was estimated via the Kaplan-Meier method. Twenty-five PTCL and 11 T-LBL patients were recruited. The median time to neutrophile and platelet engraftments was 10 days (8-13 days) and 13 days (9-31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR) but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable. ChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to assess ChiCGB as a conditioning regimen for ASCT.

Fotemustine, etoposide, cytarabine, and cyclophosphamide (FEAC) conditioning regimen for autologous stem cell transplantation in lymphoma

To investigate the efficacy and safety of the FEAC (fotemustine, etoposide, cytarabine, and cyclophosphamide) conditioning regimen for the treatment of lymphoma, we retrospectively analyzed the records of 76 Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients who underwent autologous stem cell transplantation (ASCT) after the FEAC conditioning regimen. Their survival, as well as the clinical efficacy, hematopoietic engraftment time, and toxicity, were analyzed. One patient died of severe pulmonary infection, and the transplant-related mortality (TRM) was 1.3% (1/76). Hematopoietic engraftment was achieved successfully in the remaining 75 patients. The median times of neutrophil and platelet engraftment were 11 d (6–21 d) and 13 d (8–24 d), respectively. The 2-year progression-free survival (PFS) rate was 69.1%, and the 2-year overall survival (OS) rate was 84.2%. FEAC conditioning regimen has acceptable toxicity, and the prognosis of patients is good, making it a feasible alternative to the BEAM regimen for ASCT.

Comparative Efficacy and Safety of Beam and Team Conditioning Regimens for Autologous Stem Cell Transplantation in Lymphoma Patients

Conditioning regimens with high-dose chemotherapy and autologous stem cell transplantation (ASCT) are the mainstays of treatment in lymphoma patients. Although the most frequently used conditioning regimen is the BEAM regimen (Carmustine, Etoposide, Cytarabine, and Melphalan), and alternatives are also used in certain circumstances. The TEAM regimen (carmustine is substituted by the alkylating agent thiotepa) is one of these alternatives; however, data regarding the comparisons of efficacy and safety profiles of these 2 regimens is scarce. This study compared the outcomes of patients who received conditioning regimens with BEAM and TEAM and underwent an ASCT. This study was conducted as a retrospective assessment of 294 patient outcomes in terms of efficacy and safety. Adult patients with lymphoma diagnosis who received BEAM or TEAM conditioning regimens and underwent an ASCT between January 1, 2016 and December 31, 2019 were included in the analyses. A total of 294 patients (median age at ASCT: 50 years, males: 60.5%, diffuse large B-cell lymphoma: 35%) were included. Eighty patients (27.2%) received the TEAM regimen, and 214 (72.8%) received the BEAM regimen. Regarding safety profiles, the thrombocyte engraftment time was significantly higher in the TEAM group (P=.003) and fever of unknown etiology was significantly higher in the BEAM group (P=.042). Also, nausea was more in the TEAM group (P=.031). The complete remission rate was 57.5% and 70.3% in the TEAM and BEAM regimens, respectively. The overall mortality rate was 37.3% and not significantly different between the groups (43% and 35% in the TEAM and BEAM groups, P=.22) over a similar median follow-up of 1667 days (P=.28). The 3-year survival rate was 66% and 67% and the 5-year survival rate was 52% and 58% in the TEAM and BEAM regimens, respectively, without significant difference. To the best of our knowledge, this is one of the few studies in the literature that compared the TEAM and BEAM as conditioning regimens for ASCT in lymphoma patients. The 2 regimens may provide similar overall survival outcomes and have a comparable safety profile. Although the BEAM regimen may be associated with longer progression-free survival times, the difference may be covered by the similar survival after ASCT.

Tecam (Thiotepa, Etoposide, cyclophosphamide, Cytarabine and Melphalan) Is an Effective and Safe Conditioning Regimen for Autologous Transplant in Lymphoma

Background: Autologous stem cell transplant (ASCT) is still a cornerstone in the treatment armamentarium of both Hodgkin's lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, cytarabine, etoposide and melphalan) is the most commonly used conditioning regimen; however, due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results with TECAM conditioning regimen (thiotepa, etoposide, cyclophosphamide, cytarabine and melphalan). Objectives: We aimed to update our experience with TECAM as the conditioning regimen for ASCT in all lymphomas, by adding our experience from Oct 2013 to 2020 to the previously reported cohort of Jan 2000 - Sep 2013 (Grisariu et al 2018). Moreover, we aimed to utilize the detailed data on the two transplant cohorts, from different eras, to appreciate possible improvement in ASCT outcome in the recent era. Furthermore, we aimed to evaluate our ASCT results in different NHL subgroups. Methods: We retrospectively analyzed all lymphoma patients who underwent ASCT in our center between 2000 and 2020. Results: Three hundred and fifty-three patients were included (141 in the newer cohort added to the 212 in the cohort of 2000-2013 previously reported), all of whom were treated with TECAM, which is our standard conditioning regimen for lymphoma patients undergoing ASCT. The cohort included 126 HL patients, 108 diffuse large B-cell lymphoma (DLBCL) patients and 119 patients of other subtypes (among them 14 diagnosed with primary central nervous system lymphoma (PCNSL)). The median number of treatment lines before ASCT was 2 (range 1-7). Compared to the older cohort, the newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group performance status (ECOG-PS) prior to ASCT (45.6% vs 19.3% with ECOG-PS ≥1, p<0.001), while A Higher proportion of patients in the newer cohort were in complete remission (CR) status at transplantation (71.9% vs. 47.8%, p<0.001). The median follow-up from ASCT was 38.8 months (range: 0.03-251.6). The 3-years progression-free survival (PFS) and overall survival (OS) rates post-ASCT were 59.8% and 79.3% respectively. For HL, the 3-years PFS and OS rates were 61.1% and 89% respectively; for DLBCL 59.4% and 67.9% respectively and for PCNSL 64.3% and 78.6% respectively. Outcomes of the newer cohort were significantly favorable (3-years OS of 87.3% vs. 73.8%, p=0.015, 5-year OS of 86.6% vs 69%, p=0.008, Figure 1). Poor disease status and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. Dose reduction was associated with a shorter PFS but did not affect OS. Similar to our previous report, patients entering transplantation for DLBCL with a partial response (PR) achieved similar outcomes as those with CR. Eighteen patients died within the first 100 days, eight due to disease progression, and 10 due to transplant related causes (2.8%). There were no cases of interstitial pneumonitis syndrome (IPS). Twenty cases (5.7%) of secondary malignancies were documented. Discussion: Our results confirms that TECAM is an effective and safe conditioning regimen for ASCT in patients with HL and various NHL's, including favorable results in PCNSL. Though outcomes were compared to published experience with BEAM, we have shown similar efficacy with a favorable toxicity profile. Despite a higher proportion of frail patients, the newer cohort's outcomes were favorable, probably due to better lymphoma control at transplant entry, which can be explained by more efficacious therapies pre- and post-transplant. In the DLBCL cohort, ECOG performance status was more prognostic than achieving a CR before ASCT, a finding that is relevant to the optimal selection of patients to different second-line options in the era of chimeric antigen receptor (CAR-T) availability. Conclusion: TECAM is a safe, effective, CNS-penetrating conditioning regimen for ASCT, in HL and various NHL's. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Retrospective, Matched Paired Analysis Comparing GBM/GBC Versus BEAM/Beac Conditioning Regimen for Autologous Stem Cell Transplantation in Non-Hodgkin's Lymphoma

Objective: Since BCNU was in short supply across China, we explored alternative conditioning regimens gemcitabine, busulfan combined with melphalan/cyclophosphamide (GBM/GBC) followed by ASCT in lymphoma patients (Bone Marrow Transplant. 2022; 57(6):1017-1020). Herein, we compared the safety and efficacy of GBM/GBC versus carmustine, etoposide, cytarabine combined with melphalan/cyclophosphamide (BEAM/BEAC) conditioning regimen for autologous stem cell transplantation (ASCT) in non-Hodgkin's lymphoma (NHL). Methods: A comparative analysis of matching cohorts was performed to compare the side effects, hematopoiesis recovery time, treatment response, and long-term survival of GBM/GBC versus BEAM/BEAC conditioning regimen followed by ASCT in NHL. From October 2010 to October 2021, a total of 204 patients at the lymphoma and myeloma center of Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College were identified: 92 patients were in the BEAM/BEAC group and 112 in the GBM/GBC group. Results: There was no statistical difference in baseline characteristics between the two groups, and first-line treatment patients accounted for 69.6% and 72.3% in the GBM/GBC and BEAM/BEAC groups, respectively. The incidence of grade 3/4 hematological toxicity showed no statistical difference between the two groups. Also, there was no statistical difference in the incidence of grade 3/4 non-hematologic side effects, including fever/infection, nausea, vomiting, diarrhea, oral mucositis, cardiotoxicity, renal toxicity and neurotoxicity. However, the incidence of grade 3/4 rashes (28.6% vs 0%, p< 0.001) and hepatopathy (28.2% vs 3.3%, p<0.001) was higher in the GBM/GBC group versus the BEAM/BEAC group, which could be recovered after appropriate treatment. VOD and treatment-related death did not occur during the study. No patients experienced graft failure. The median time to neutrophil engraftment was 10 days in both groups and platelet engraftment was 12 days (GBM/GBC group) versus 11 days (BEAM/BEAC group) (p=0.130), respectively. The complete response (CR) rates in the GBM/GBC group and the BEAM/BEAC group at 3 months after transplantation were 93.5% and 91.1%, respectively (p=0.537), and there was no difference in the estimated 3-year PFS (80.4% vs 83.5%; p=0.771) and the estimated 3-year OS (88.5% vs 92.3%; p=0.620). Conclusion: In this retrospective, matched paired analysis, our results demonstrate that GBM/GBC conditioning regimens with ASCT are feasible with tolerable toxicity, which appears be an alternative to the classical BEAM/BEAC conditioning regimens for ASCT in the treatment of NHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR Tcells.

Unlimited generation of chimeric antigen receptor (CAR) Tcells from human-induced pluripotent stem cells (iPSCs) is an attractive approach for "off-the-shelf" CAR Tcell immunotherapy. Approaches to efficiently differentiate iPSCs into canonical αβ Tcell lineages, while maintaining CAR expression and functionality, however, have been challenging. We report that iPSCs reprogramed from CD62L+ naive and memory Tcells followed by CD19-CAR engineering and 3D-organoid system differentiation confers products with conventional CD8αβ-positive CAR Tcell characteristics. Expanded iPSC CD19-CAR Tcells showed comparable antigen-specific activation, degranulation, cytotoxicity, and cytokine secretion compared with conventional CD19-CAR Tcells and maintained homogeneous expression of the TCR derived from the initial clone. iPSC CD19-CAR Tcells also mediated potent antitumor activity invivo, prolonging survival of mice with CD19+ human tumor xenografts. Our study establishes feasible methodologies to generate highly functional CAR Tcells from iPSCs to support the development of "off-the-shelf" manufacturing strategies.

Autologous Stem Cell Transplantation after Conditioning with Chidamide Plus Carmustine, Etoposide, Cytarabine, and Cyclophosphamide (Chi-BEAC) for Treatment of High-Risk and Relapsed/Refractory Aggressive Lymphoma: Multi-Center, Single-Arm, Open-Label Phase II Clinical Trial

Background:Chidamide, as a novel subtype-selective histone deacetylase inhibitors (HDACi), can directly inhibit tumor cell cycle progression and induce tumor cell apoptosis, inhibit phenotypic transformation of tumor cells and pro-drug resistance/pro-metastasis activity of the microenvironment, induce differentiation of tumor stem cells, and reverse epithelial-mesenchymal transformation of tumor cells, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and enhancing the effect of chemotherapy agents through loosening chromatin and exposing DNA. The efficacy and safety of chidamide-BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide, Chi-BEAC) conditioning regimen combined with autologous stem cell transplantation (ASCT) were evaluated in a current phase II clinical trial for the treatment of high-risk and relapsed/refractory aggressive lymphoma.Methods: A total of 70 patients with high-risk diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), or mantle cell lymphoma (MCL) who had achieved complete remission (CR) or partial remission (PR) after first-line therapy or second-/third-line therapy were recruited from January 2018 to June 2021. Three of the patients were not evaluated after ASCT and two patients withdrew from the study; 65 patients were then evaluated for the effectiveness of Chi-BEAC treatment.Results: DLBCL and MCL are referred as B-cell non-Hodgkin lymphoma (B-NHL) and PTCL is referred as T and NK-cell non-Hodgkin lymphoma (T&NK-NHL) in the study. The median neutrophil engraftment time was 10 d (7-13 d) and median platelet engraftment time was 11 d (8-13 d).The CR rate at 3-6 months after transplantation was 75.4% in the 65 evaluable patients. The median progression free survival (PFS) and overall survival (OS) had not reached at the end of the follow-up period (median 18.1 month; range 1.8-42.0 months). The estimated PFS and OS at 24 months was 78.5% and 84.2%, respectively. Stratified analyses showed that in patients with B-NHL who previously received first-line treatment, the CR rate at 3-6 months after transplantation was 77.8%, and 2-year PFS was 74.8%. The survival rate might be better than previously reported for SWOG9704 (Stiff et al., 2013; PMID 24171516)-a 2-year PFS of 69%-and for DLCL04 (Chiappella et al., 2017; PMID 28668386)-a 2-year failure-free survival of 71%. In our patients with B-NHL who previously received second-/third-line treatments, the CR rate at 3-6 months after transplantation was 71.4%, and 2-year PFS was 77.1%. The survival rate might also be higher than previously reported for the CORAL trial (Gisselbrecht et al., 2010; PMID: 20660832), which showed a 2-year PFS of approximately 65%. In our patients with T&NK-NHL the CR rate at 3-6 months after transplantation was 73.3%, and 2-year PFS was 93.3%, The survival rate might be higher than previously reported for the NLG-T-01 trial (Francesco d'Amore et al., 2012; PMID: 22851556), which showed a 2-year PFS of approximately 55%. PFS stratification analysis showed that previous treatment outcomes affected the PFS: patients who had achieved CR before transplantation demonstrated better PFS than patients who had achieved PR (P = 0.199), while there was no significant difference between patients with different pathological subtypes (B or T&NK-NHL) or different risk groups.Most non-hematological adverse events (AEs) were of grade 1/2. Grade 4 AE only occurred in one patient, i.e., γ-glutamyl transpeptidase (GGT) elevation. Grade 3 AEs that occurred in ≥ 5% of the patients included febrile agranulocytosis (37.7%), hypokalemia (24.7%), hyponatremia (23.4%), GGT elevation (9.1%), and diarrhea (5.2%), which were well tolerated.Conclusions: This study showed that inclusion of the HDACi chidamide in conditioning regimen for ASCT greatly increased the PFS and OS, especially in patients with T&NK-NHL, and revealed an acceptable safety profile for refractory and relapsed lymphoma patients. Therefore, chidamide-containing conditioning regimen may be a great choice for patients with refractory and relapsed lymphoma, and awaits further confirmation by additional large-scale multi-center investigations. DisclosuresNo relevant conflicts of interest to declare.

Application of the Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Backgroud Busulfan isthe most commonly used drug in conditioning regimens for hematopoietic stem cell transplantation, and high-dose melphalan (HDM)is the standard conditioning regimen in autologous stem cell transplantation(ASCT)for multiple myeloma. Studies have shown that in ASCT for multiple myeloma, conditioning regimens containing busulfan is equally effective as HDM.Aims Evaluate the safety and efficacy of BUCY(busulfan and cyclophosphamide ) conditioning regimen for autologous hematopoietic stem cell transplantation(ASCT)in patients with multiple myeloma(MM).Methods We retrospectively analyzed the clinical data of 72 MM patients who received transplantation in the Hematology Department of the First People's Hospital of Soochow University from May 2012 to June 2015. Among them, 36 patients underwent BUCY regimen, while the others received HDM regimen. Those were compared between the two groups including the complication, the hematopoietic reconstitution and the post-transplantation efficacy.Results There were no significant differences in age, stage, induction therapy, mobilization method between the two groups. The transplantation-related adverse events were similar in both groups but the incidence of pulmonary infection and bloodstream infection were slightly higher in BUCY group .The median time to neutrophil engraftment in the BUCY and HDM groups were 10(8-17)days versus 10(9-13)days, taking the same time on average(P=0.046). On the other hand, the median time to platelet engraftment was 10(8-18)versus 11(9-47)days accordingly (P=0.017). The TRM in both group was 2.7%. The SCR/CR rates after ASCT (47.2% and 50.0%) were higher than those before it (38.9% and 26.6%) in both groups. In the BUCY group, the median follow-up was 12.5(0-26) months. Six patients (16.7%) underwent disease progression. The 2-year progression-free survival(PFS) rate was 68%. Correspondingly, in the HDM group, the median follow-up time was 23 (0-38) months. Fifteen patients (41.7%) developed disease progression and the 2-year PFS rate was 55%.Conclusion The BUCY regimen is a safe and effective therapy for ASCT in patients with multiple myeloma. Besides, BUCY regimen is not inferior to HDM regimen. In conclusion, BUCY regimen may replace HDM regimen as a standard conditioning regimen for ASCT in multiple myeloma. DisclosuresNo relevant conflicts of interest to declare.

Thiotepa, Busulfan, and Cyclophosphamide and Busulfan, Cyclophosphamide, Etoposide As Autologous Stem Cell Transplantation Conditioning Regimen in Primary Central Nervous System Lymphoma

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma and standard treatment is yet to be established. Induction therapy with methotrexate-based chemotherapy regimen and consolidation with high-dose chemotherapy followed-by autologous stem cell transplantation (ASCT) is a good treatment option with promising outcomes, but only few studies are available. Asan Medical Center had previously used busulfan, cyclophosphamide, and etoposide regimen (BuCyE) as standard high-dose chemotherapy in consolidation therapy until thiotepa, busulfan, and cyclophosphamide regimen (TBC) was introduced in December, 2012. The purpose of this study is to compare outcomes and toxicity profile of BuCyE and TBC as conditioning regimens for ASCT in consolidation therapy of PCNSL patients.MethodsThe registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients who had BuCyE or TBC as conditioning regimens were enrolled in analyses. BuCyE group had busulfan with dose of 3.2 mg/kg IV in day-7 to day-5, etoposide 200 mg/ IV in day-5 to day-4 and cyclophosphamide 50 mg/kg IV in day-3 to day-2. TBC group had thiotepa with dose of 250 mg/ IV in day-9 to day-7, busulfan 3.2 mg/kg IV in day-6 to day-4 and cyclophosphamide 60 mg/kg IV in day-3 to day-2. OS was defined as from beginning of high-dose chemotherapy conditioning to any cause of death, and PFS as from beginning of ASCT to disease progression or any cause of death. Analyses with chi-square test or Fisher's exact test were done to compare variables between two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analyses were done with known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.ResultsTotal 241 patients with diagnosis of PCNSL were identified and 73 patients who had ASCT as frontline or salvage setting with conditioning regimens of either TBC (45 patients) or BuCyE (28 patients) were enrolled in analyses. Median follow-up duration was 3.7 years [IQR 0.01-10.3], median OS was 6.1 years [95% CI 3.7-8.5], and median PFS was 6.5 [95% CI 1.4-11.7]. Median age was 54 years (range, 17-65), 27.4% of patients were 60 years or older and 54.8% of patients was male. Fifty three patients (72.6%) had upfront ASCT after induction therapy and 27.4% of patients had relapsed or refractory disease. ECOG performance status and infused dose of CD34 positive cells showed no statistical difference between two groups. Proportion of patient with refractory or relapsed disease was significantly higher in TBC group [TBC 37.8%, BuCyE 10.7%, p = 0.012]. Median OS of TBC group was not reached and median OS of BuCyE group was 4.5 years [95% CI 1.8-7.2] and TBC group showed better OS with log-rank test (p = 0.048). Median PFS of TBC group was not reached and median PFS of BuCyE group was 1.3 years [95% CI 0.00-2.7] and TBC group showed better PFS with log-rank test (p = 0.007). In multivariate analyses with age, ECOG performance status, CSF protein level, serum LD level, TBC group showed significantly better OS with HR of 0.20 [95% CI 0.04-0.97, p = 0.046] and better PFS with HR of 0.24 [95% CI 0.09-0.66, p = 0.006] compared to BuCyE group. Severe oral mucositis, nausea, vomiting (NCI CTC grade 3 or 4) was higher in TBC group. Median days to engraftment were 8 days (range, 3-19) in TBC group, and 9 days (range, 3-15) in BuCyE group. Median admission duration was 17 days (range, 4-42) in TBC group, and 18.5 days (range, 14-36) in BuCyE group. One case of treatment-related mortality was reported in TBC group due to septic shock.ConclusionTBC regimen showed better outcomes in both OS, PFS compared to BuCyE. Although TBC group showed more oral mucositis, nausea, vomiting, and diarrhea, it maybe tolerable regimen compared with BuCyE considering the fact that admission duration and days to engraftment was not inferior. Further long-term follow-up results with TBC regimen are warranted. DisclosuresNo relevant conflicts of interest to declare.

Preliminary Safety and Efficacy Data for Combined Checkpoint Inhibition with Ipilimumab (I) and Nivolumab (N) As Consolidation Following Autologous Stem Cell Transplantation (ASCT) for High-Risk Hematologic Malignancies - Cpit-001 Trial

Preliminary Safety and Efficacy Data for Combined Checkpoint Inhibition with Ipilimumab (I) and Nivolumab (N) As Consolidation Following Autologous Stem Cell Transplantation (ASCT) for High-Risk Hematologic Malignancies - Cpit-001 Trial

A Phase II Study of a Novel Conditioning Regimen of Bendamustine and Melphalan Followed By Autologous Stem Cell Transplant for Patients with Multiple Myeloma

IntroductionHigh dose melphalan 200mg/m2 (MEL200) followed by autologous stem cell transplantation (ASCT) is the standard of care for fit patients with Multiple Myeloma (MM). Bendamustine has been shown to induce responses in MM resistant to other alkylating agents. Our prior Phase I trial, adding bendamustine to MEL200, demonstrated no additional toxicity above that expected with MEL200 alone (Mark et. al. BBMT 2013). A phase 2 trial of bendamustine/MEL200 conditioning was conducted to evaluate treatment efficacy.Objective and MethodsThis single arm, open-label, phase II study was designed to establish the efficacy of Bendamustine (225 mg/m2) in combination with MEL200 in patients undergoing first ASCT for MM. Patients 18 to 75 years with confirmed MM, prior induction therapy, adequate mobilization (at least 2x106 of CD34+ hematopoietic stem cells), Karnofsky performance status >70% and life expectancy >12 weeks were eligible for screening. Major exclusion criteria included serious/uncontrolled medical conditions, or previous ASCT. Responses were determined according to the IMWG response criteria and adverse events (AEs) were reported per CTCAEv4.0. The primary endpoint was to evaluate the overall response rate (ORR) and CR or better at 6 months.ResultsA total of 35 patients were enrolled (Table 1). Median age was 61 (range 41 - 75). Intermediate or high-risk disease was present in 44.8% by R-ISS. All patients engrafted. Median time to neutrophil and platelet engraftment was 11 days (range 10-14) and 21 days (range 15 to 29) respectively. At day +180, the ORR was 91.4% and 51.4% of patients achieved a CR or sCR (Table 2). Only 1 patient progressed before day +100 (R-ISS 1 double-refractory to lenalidomide + bortezomib, achieved VGPR with second line therapy with VDT-PACE prior to transplant), and one additional patient progressed before Day +180 (R-ISS 2, with prior 4 lines of therapy, SD prior to transplant). Maintenance was initiated in 20 patients out of 32 patients (62.5%). Choice of maintenance was at the discretion of the treating physician and patient.After a median 33 months (range 3-73) of follow up post ASCT, 20 patients had progressed (57.1%), 4 of whom died from complications of MM progression (11.4%). Median progression free survival (PFS) was 40 months (14 months vs 48 months depending on maintenance therapy, p=0.024). The 3 year PFS was 64.5% (95%CI 44.7-78.8). The median overall survival (OS) was not reached. The 3 year OS was 91.2% (95%CI 75.1-97.1) (Figure 1). Baseline response, categorized as CR or better, VGPR, PR and SD or PD prior to transplant, was statistically significant for PFS (p=0.019). In a multivariable Cox proportional hazards model controlling for baseline response prior to transplant, maintenance therapy continued to be associated with improved PFS (HR 0.16, p=0.004). No variable had a statistically significant impact on OS. There was no transplant related mortality (TRM). The most common overall AEs were hypocalcemia (100%), nausea (94.3%), fatigue (94.3%), anorexia (91.4%), mucositis (57.1%), abdominal pain (51.4%), peripheral edema (48.6%) and constipation (34.7%). The most frequently observed grade 3 AEs were febrile neutropenia in 45.7% of patients, hypocalcaemia in 34.3%, hypokalemia in 20%, and hypophosphatemia in 14.3%. There was only one grade 4 AE, hyperbilirubinemia associated with a reaction to antibiotics.ConclusionWe confirmed that Bendamustine can safely be combined with standard dose MEL200 as a conditioning regimen for ASCT. This regimen shows promising efficacy, with median PFS of 48 months for patients who received maintenance. Further evaluation of this conditioning regimen in a Phase III comparison trial with single agent MEL200 is warranted in conjunction with newer induction approaches and standard maintenance therapies. (NCT00916058). [Display omitted] DisclosuresNiesvizky:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Rossi:Celgene: Consultancy; Thrassos: Consultancy.

A Single Autologous Stem Cell Transplant (ASCT) Followed By Two Years of Post-Transplant Therapy Is Safe in Older Recently Diagnosed Multiple Myeloma (MM) Patients. Preliminary Results from the Prospective Phase II Trial (NCT01849783)

Introduction: The median age at diagnosis of MM patients is around 70. The current standard of treatment for younger eligible MM patients is ASCT after initial induction chemotherapy. Multiple studies have shown that age by itself is not necessarily an exclusion criterion for transplant and that elderly eligible patients derive benefits from ASCT. While melphalan 200mg/m2 has been the standard preparative regimen for ASCT, more studies are currently evaluating the role of including novel agents along with melphalan to improve outcomes. We previously reported the safety and efficacy of VDT-Mel in patients mostly younger than 65 years. Here we report the tolerability of the same regimen in elderly patients.Methods and patients: A total of 41 eligible patients above the age 65 were prospectively enrolled in the IRB approved phase II trial beginning in June 2013. After an induction chemotherapy and stem cell collection, ASCT was performed with a preparative chemotherapy consisting of VDT-Melphalan 200mg/m2. Early after engraftment, patients were started on maintenance for 2 years with triple agent therapy. Primary end points include PFS, frequency of severe toxicities, ICU admissions, and percentage of patients able to complete the full course of maintenance.Results: Of the 41 patients enrolled, 37 patients had at least day 100 follow up post-transplantation and were included in this analysis. Six have been removed from study due to relapse (N=2), development of acute leukemia (N=1), failure to collect stem cells (N=1) or failure to comply with therapy (N=2). Toxicity and best response were assessed at day 100. Median age was 68 (range: 65 to 75). Median follow up was 21 months (3.5 months - 3.7 years). Major non-hematologic toxicities ≥ grade 3 were related to infections (25%), diarrhea (16%) and mucositis (11%). Median time to ANC and platelet engraftment was 11 and 17 days, respectively. 18 patients achieved a stringent CR (sCR) by day 100 restaging (50%). There was one death within day 100 related to candida sepsis. Only 2 patients were re-hospitalized within 100 days. Thirty-five patients started maintenance therapy. Median time to start post-transplant therapy was 66 days (range: 42 to 174 days).Conclusion: This is the first trial to prospectively evaluate the feasibility of combined intensified preparative regimen with two years of maintenance using triple agent therapy in elderly MM patients. Toxicity and mortality were not increased compared to the younger patients (median age 59) receiving a similar regimen. It is too early to comment on the efficacy of this approach, but we are encouraged by the high frequency of sCR, early after transplantation. DisclosuresNo relevant conflicts of interest to declare.

High-dose lenalidomide and melphalan as conditioning for autologous stem cell transplantation in relapsed or refractory multiple myeloma.

8021 Background: Autologous stem cell transplantation (ASCT) remains a standard of care of eligible patients with multiple myeloma, despite the many novel therapies introduced over the past decade. High dose melphalan (HDM) is the only approved regimen to date. Lenalidomide (LEN) is an oral immunomodulatory drug which has become the backbone of myeloma therapy from induction through salvage and maintenance. Early studies noted a dose response relationship, and found myelosuppression to be the dose limiting toxicity. We previously reported on our phase 1 study of high dose lenalidomide (HDLEN) with HDM in conditioning for ASCT, where no DLT was noted up to 350mg PO daily of LEN. Here we report the phase 2 data of patients undergoing ASCT with combination conditioning regimen. Methods: 50 patients with relapsed/refractory multiple myeloma (RRMM) underwent ASCT using HDLEN+HDM conditioning. HDLEN was dosed at 350mg PO daily from day -5 to day -1 and HDM was dosed 100mg/m2 on days -2 and -1. TPatients were heavily pre-treated: 32% had prior HDM-ASCT, 96% had received prior lenalidomide, and 42% prior pomalidomide; 40% prior anti-CD38 mAB. Of note, 68% entered the study with progressive disease at time of enrollment. Results: Overall response rate was 96%, with 80% being ≥VGPR. Median progression free survival (PFS) was noted at 14.3 months, while overall survival (OS) was 68.2 months. PFS was similar when patients were stratified by prior ASCT, depth of response at enrollment, or presence of high risk FISH. Toxicities were mostly hematologic (100% neutropenia and thrombocytopenia, 90% anemia), GI (88% diarrhea, 72% nausea, 42% vomiting) and metabolic (30-96% derangement in electrolytes), and similar to historical controls receiving HDM alone. Second malignancies were noted in 2 patients. Conclusions: HDLEN/HDM is a well tolerated and effective conditioning regimen for ASCT in patients with RRMM. This regimen merits further investigation as ASCT is likely to remain an integral part of the treatment of RRMM patients, yet few advancements have been made to this modality. HDLEN may be particularly useful in patients with high risk disease and those progressing after multiple lines of therapy. HDLEN added little toxicity to HDM and SPMs were not more frequent than expected per SEER database for patients in this age range. Clinical trial information: NCT01054196. [Table: see text]

Excellent Outcomes in Patients with Primary and Secondary Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using a Rituximab, Busulfan, Melphalan, Thiotepa Conditioning Regimen

Introduction: Historically, CNS lymphomas have been associated with a very poor prognosis High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) with promising results in small recent small prospective phase 1/2 results and retrospective series. We hypothesized that the use of R-BuMelTt (rituximab, busulfan, melphalan, thiotepa) conditioning regimen with ASCT regimen will be effective for both patients with PCNSL and SCNSL as used in previously reported promising data by Oh et al 2016 for patients with SCNSL with higher remission and survival rates. Patients and Methods: A retrospective analysis was performed of 6 consecutive patients who had undergone R-BuMelTt conditioning regimen with ASCT for 3 patients with PCNSL and 3 patients with SCNSL from December 2017 to March 2020. The median age of this patient population was 62 years at the time of ASCT. The induction chemotherapy regimen used for patients with SCNSL was R-CHOMP except one patient who received DHAP, and for patients with PCNSL MATRix regimen was used. The median duration of chemotherapy cycles was 4, and all of them had achieved remission prior to transplant based on PET/CT scan/MRI scan. All patients were planned to undergo ASCT using the Conditioning Regimen of Rituximab 375 mg/m2 on Day-7, Thiotepa 250 mg/m2 on Day-6,-5, Busulfan 3.2 mg/kg on Day-4,-3,-2 and Melphalan 100 mg/m2 on Day-1. Supportive cares measures were given at treating physician's discretion. Results: Patients received a median cell dose of 4.4x106 CD34+cells/kg (range: 2.5-5.7), had neutrophil engraftment at 11.5 days (range:9-13), platelet recovery was achieved on days 11,15 and 16 for three patients but was delayed at 27, 46, 89 days for 3 patients. Infectious complications were common with documented bacteremia in in 3 out of 6 patients, 2 patients with c. difficile infection and with significant platelet support due to thrombocytopenia. At a median follow up of 24.5 months (range: 6-30 months), 5 out of 6 patients had complete metabolic response on radiological imaging with PET/CT in conjunction with MRI head. One of the patients with SCNSL died after transplant due to CNS relapse 223 days post ASCT giving an overall survival of 66.6%. Amongst the 2 patients with SCNSL that survived there was no relapse after 30 month follow-up. None of the patients with PCNSL died or relapsed during or after transplant therefore having a 100% overall survival. Although this is a small retrospective study, our results are comparable to current literature. Toxicities included nausea/vomiting, diarrhea, mucositis with 5/6 patients requiring TPN. Also busulfan PK levels were not done. Conclusions: R-BuMelTt regimen can be used successfully as conditioning regimen for ASCT for patients with PCNSL and SCNSL, however with increased hematological toxicity, most notably delayed platelet engraftment. The rate of progression free and overall survival is promising with short median follow up of 24 months. Disclosures Lam: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau.

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

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