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TEAM Conditioning (Thiotepa, Etoposide, Cytarabine, Melphalan) Prior to Autologous Hematopoietic Stem Cell Transplantation for Hodgkin and Non-Hodgkin Lymphoma: Final Results from a Prospective Multicenter Study
Abstract
Introduction
Although a large variety of conditioning regimens are used in autologous hematopoietic stem cell transplantation (autoSCT), including the widely used BEAM (carmustine, etoposide, cytarabine, melphalan), there is no consensus regarding a standard approach. In the context of a carmustine shortage, we replaced it with thiotepa. However, clinical data on the TEAM (thiotepa, etoposide, cytarabine, melphalan) conditioning regimen are sparse and only retrospective. Thus, we designed a multicenter prospective study (NCT02504190) to assess the efficacy and toxicity of a TEAM conditioning regimen.
Patients and methods
The TEAM regimen consisted of a total dose of thiotepa of 8 mg/kg on day -6; etoposide 100 mg/m2/12h and cytarabine 200 mg/m2/12h (day -5 to -2); melphalan 200 mg/m2 on day-1. Inclusion criteria were the following: age between 18 and 65 years, biopsy-proven Hodgkin or non-Hodgkin lymphoma, HIV seronegative, and first autoSCT.
Results
Seventy-four male and eighteen female patients with a median age of 53 years (range, 19-65) were included. Karnofsky score was <90% in 17 patients (18%). Lymphoma diagnoses comprised diffuse large B cell (n=48), mantle cell (n=8), follicular (n=12), Hodgkin (n=14), peripheral T-cell (n=9) and miscellaneous (n=4). Advanced stage disease (Ann Arbor stage III-IV) was noted in 83 patients (90%). Disease status at time of autoSCT was complete response (CR) in 69 patients (75%), partial response in 22 (24%), including 12 patients who never reached CR, and progressive disease in 1 (1%). Median number CD34+ cells infused in the graft were 4.6x10e6/kg (range, 1.39-12.7).
Median time to neutrophil recovery was 12 days (range, 9-48) and to platelet recovery >20 G/L was 13 days (range, 7-197). The most significant regimen-related toxicities were mucositis in 100% of patients (median grade=3, range, 1-4) and diarrhea in 98% of patients (median grade=1, range, 0-3). Other non-hematologic grade 3 adverse events occurred in 17 patients (18%). Blood cultures were positive for Staphyloccocus sp. in 27% patents, other Gram- positive bacteria in 5% and Gram negative in 6%. Central line-associated bloodstream infection occurred in 22 patients (24%). Invasive fungal infection occurred in 3 patients. Four patients required transfer to the intensive care unit. The median length of stay in hospital was 27 days (range, 16-62).
At day+100, 89 patients were evaluable for response and all were in CR. Deaths directly attributed to disease progression or relapse occurred in 5 patients. After a median follow-up of 31 months (range, 15-48), the non-relapse mortality (NRM) was 3.3%. Two patients died of infection during aplasia and one patient died 67 days after autoSCT of necrotizing fasciitis. At last follow-up, 17 patients (19%) relapsed, 9 died and 83 were alive. The estimated 3-year overall survival (OS) and progression-free survival (PFS) were 90.2% and 77.2%, respectively. In patients with double expressor diffuse large B-cell lymphoma (n=15), the estimated 3-year OS and PFS were 93% and 73%, respectively. None of the 31 patients with intermediate or high-risk CNS international prognostic index experienced CNS relapse.
Conclusion
The TEAM conditioning regimen is a safe and valid platform in autoSCT for patients with high-risk or relapsed/refractory lymphoma. Although mucositis and diarrhea were frequent, the NRM was similar to that reported for BEAM conditioning. Most notably, no CNS relapse occurred in patients at intermediate or high-risk of CNS relapse.
Disclosures
Duléry: Keocyt: Honoraria. Choquet:Keocyt: Honoraria. Di Blasi:Novartis: Honoraria. Malard:Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria; Keocyte: Honoraria; Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria. Coppo:Ablynx/Sanofi: Consultancy; Shire: Consultancy; Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.
... Replacement of BCNU with thiotepa as part of TEAM (thiotepa, etoposide, cytarabine, and melphalan) was initially used in primary central nervous system lymphoma 19 but showed encouraging results in patients with Hodgkin and non-Hodgkin lymphoma as well. [20][21][22] Although impaired lung function has been proven to critically influence the outcomes of patients after conditioning with BEAM, 23 the effect of pulmonary dysfunction has not been systematically studied in patients receiving treatment with TEAM before auto-HSCT. As part of the HCT-CI score, pulmonary function, age, and comorbidities are yet regarded to be important predictive outcome factors for patients undergoing auto-HSCT. ...
... [37][38][39] BCNU replaced by thiotepa as part of TEAM conditioning regimen has promising activity. [20][21][22] However, an observational study described the BEAM protocol to be superior in terms of clinical outcomes, 40 whereas a recent study shows similar results between BEAM and TEAM. 41 We hypothesize that organ dysfunction might play a crucial role in the outcomes of patients undergoing auto-HSCT and only selected patients might profit from TEAM conditioning before auto-HSCT. ...
Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto‐HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety‐six patients undergoing auto‐HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO‐diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto‐HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT‐CI score ≥ 4, and cardiac disease before auto‐HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto‐HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non‐relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto‐HSCT.
... Studies have shown that the BEAM regimen can safely be administered in an outpatient setting in order to: reduce costs and length of hospitalization, decrease risks of severe toxicities and infectious complications, and improve patient satisfaction and quality of life [60,65]. In patients with HL, several other chemotherapeutic regimens have been employed in the conditioning therapy prior to autologous HSCT as alternatives to BEAM chemotherapy and these include: (1) a mini-BEAM regimen, (2) the addition of rituximab or anti-CD 25 radioimmunotherapy to BEAM regimen, (3) modi ication of BEAM regimen such as the use of TEAM regimen (thiotepa, etoposide, cytarabine, melphalan) and (4) replacing BEAM chemotherapy by other regimens such as BEC (BCNU, etoposide, cyclophosphamide); etoposide and melphalan; mitoxantrone and melphalan; as well as busulfan, cyclophosphamide, and etoposide [66][67][68][69][70][71][72][73][74][75][76][77]. Studies have shown that the use of HD melphalan alone given as conditioning therapy prior to autologous HSCT in patients with advanced or R/R HL has the following advantages: (1) being adequate and cost-effective with outcomes that are comparable to multiagent chemotherapeutic regimens such as BEAM, (2) less exposure to other toxic chemotherapies, and (3) allowing autologous HSCT to be performed in an outpatient setting [78][79][80][81]. ...
Background: Autologous hematopoietic stem cell transplants (HSCT) is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM) and patients with relapsed and refractory Hodgkin lymphoma (R/R-HL) who achieve chemosensitivity after salvage therapy. Although autologous HSCT is routinely performed in an inpatient setting, the procedure can safely be performed in an outpatient setting. Methods and materials: A retrospective study of patients with MM and R/R- HL who received outpatient autologous HSCT at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia between the first of April 2017 and the 31st of January 2022 was performed. Results: Over the study period of 4 years and 10 months, a total of 90 outpatient autologous HSCTs were performed for 79 patients (54 patients with MM; 4 of them received planned tandem autografts and 7 other myeloma patients received second autologous HSCTs for relapsed or progressive disease; and 25 patients with R/R-HL) at our institution. The median ages of patients with MM and those with R/R-HL at HSCT were 50.4 years and 27.8 years respectively. At the presentation of their MM, the following high-risk (HR) features were encountered: stage II and III diseases according to the revised international scoring system (RISS) in 53.7%; adverse cytogenetics in 42.6% and extensive bone involvement in 53.7% of patients. In patients with HL at presentation, 48% of patients had stage IV disease according to Ann Arbor staging classification and 84% of patients had B symptoms. Survival for 100 days post-HSCT for all patients with MM and HL who received outpatient autologous transplants was 100%. For patients with MM, the overall survival (OS) rates at 3 years and 4 years post-HSCT were 80% and 67%, while the progression-free survival (PFS) rates over 3 years and 4 years were 58% and 38% respectively. For patients with HL, the OS at 6 years post-HSCT was 95% while the PFS rates at 3 years and 6 years post-HSCT were 84% and 62% respectively. Conclusion: Outpatient autologous HSCT for patients with MM and HL is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation performed in an inpatient setting. Additional benefits of outpatient autologous include saving beds and reducing hospital costs.
One of the most widely accepted conditioning regimens for hematopoietic stem cell transplantation (HSCT) is BEAM (carmustine, etoposide, cytarabine, melphalan). However, a recent increase in the cost of carmustine has limited its use bringing our institution to replace carmustine with bendamustine. This observational retrospective single-center study aims to report the efficacy and safety of the BeEAM regimen. 55 patients with diffuse large B-cell lymphoma (47%), Hodgkin lymphoma (25%), mantle cell lymphoma (25%), or follicular lymphoma (2%) were included. Progression-free survival (PFS) at 24 months was 75% and overall survival (OS) was 83%. Treatment-related mortality was 4%. The most common adverse effects were febrile neutropenia (98%), mucositis (72%) and colitis (60%). Our study demonstrated excellent efficacy of the BeEAM regimen. However, the toxicity profile of BeEAM significantly varies from one study to another, and guidelines suggesting optimal dose of bendamustine and supportive care are currently lacking.
This work was carried out by the importance of providing insights into the nano-based drug delivery of anticancers. To this aim, a representative model of aluminum nitride (AN) nanocage scaffold and two of its boron and gallium doped forms (BAN and GAN) were investigated towards the adsorption of thiotepa (Tep) anticancer. Density functional theory (DFT) calculations were performed to evaluate the stabilized structures and their corresponding electronic features. The results indicated the contribution of N-head and S-head of Tep to interactions with each scaffold resulting six complexes; [email protected] and [email protected], [email protected] and [email protected], [email protected] and [email protected] In each complex model, the characteristic features were obtained based on the interactions details and frontier molecular orbitals related features. In this regard, the investigated scaffolds were found suitable for adsorbing the Tep substance with different strengths and frontier molecular orbitals levels yielding the possibility of assigning specified recovery time and conductance. As a consequence, the models of investigated scaffolds were found suitable to work as possible carriers of Tep anticancer for approaching the nano-based drug delivery purposes.
Despite the success of frontline anthracycline-based chemotherapy for classical Hodgkin Lymphoma (cHL), approximately 15% of patients do not achieve an adequate response and require further therapy. For transplant-eligible patients, additional treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHCT) provides a durable response in 50% of patients. The most refractory patients, including those requiring multiple lines of therapy to achieve a response or those relapsing after an autoHCT, may achieve long-term survival with allogeneic hematopoietic stem cell transplant (alloHCT). Contemporary salvage regimens used as a bridge to transplant have expanded to include not only non-cross resistant chemotherapy, but also brentuximab vedotin (BV) and checkpoint inhibitors (CPI). As the management of relapsed/refractory (R/R) cHL evolves with the introduction of novel agents, so too does the role of transplantation. The paradigm of chemosensitivity as a predictor for autoHCT efficacy is being challenged by favorable post- autoHCT outcomes in heavily pre-treated CPI-exposed patients. Contemporary supportive care measures, validated comorbidity assessments, and an increased donor pool with haploidentical donors have broadened the application of transplantation to an increasingly older and diverse patient population. Despite the introduction of increasingly effective treatment options for R/R cHL, transplantation continues to play an important role in the management of these patients. In this review, we explore the impact of salvage therapy on autoHCT, conditioning regimens, maintenance therapy and the diminishing role of alloHCT for patients with cHL.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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