Alternative Conditioning Regimen Research Articles

Early Toxicity and Efficacy of Four Different Conditioning Regimens for Autologous Hematopoietic Cell Transplantation in Patients With Lymphoma: Impact of Drug Shortages in a Resource-Constrained Country

High-dose therapy followed by autologous hematopoietic cell transplant (AHCT) remains a viable consolidation strategy for a subset of patients with relapsed or refractory (R/R) lymphomas. BEAM (carmustine, etoposide, cytarabine, and melphalan) is widely recognized as the predominant conditioning regimen due to its satisfactory efficacy and tolerability. Nevertheless, shortages of carmustine and melphalan have compelled clinicians to explore alternative conditioning regimens. The aim of this study was to compare the toxicity and transplant outcomes following BEAM, CBV (carmustine, etoposide, cyclophosphamide), BuMel (busulfan, melphalan), and BendaEAM (bendamustine, etoposide, cytarabine, melphalan). We retrospectively analyzed data from 213 patients (CBV 65, BuMel 42, BEAM 68, BendaEAM 38) with R/R lymphomas undergoing AHCT between 2014 and 2020. Multivariate models were employed to evaluate toxicity and transplant outcomes based on conditioning type. Among grade III to IV toxicities, oral mucositis was more frequently observed with BuMel (45%) and BendaEAM (24%) compared to BEAM (15%) and CVB (6%, P ≤ .001). Diarrhea was more common with BendaEAM (42%) and less frequent with BuMel (7%, P = .01). Acute kidney injury was only found after BendaEAM (11%). Febrile neutropenia and infectious complications were more frequent following BendaEAM. Frequencies of other treatment-related toxicities did not significantly differ according to conditioning type. BendaEAM (odds ratio [OR] 3.07, P = .014) and BuMel (OR 4.27, P = .002) were independently associated with higher grade III to IV toxicity up to D+100. However, there were no significant differences in relapse/progression, nonrelapse mortality, progression-free survival, or overall survival among the four regimens. BuMel and BendaEAM were associated with a higher rate of grade III to IV toxicity. Carmustine-based regimens appeared to be less toxic and safer; however, there were no significant differences in transplant outcomes. The utilization of alternative preparative regimens due to drug shortages may potentially lead to increased toxicity after AHCT for lymphoma.

Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma

Background aimsThe combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. MethodsIn total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. ResultsThe objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93–51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). ConclusionsFor patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

The Efficacy and Safety of Decitabine Combined with Fludarabine and Cyclophosphamide As Conditioning Regimen in Second CD19 CAR-T Infusion

Background Chimeric antigen receptor (CAR) T therapy is widely accept for the first line treatment of refractory/relapsed diffuse large B cell lymphoma(DLBCL). However, insufficient remission and short duration of response are the barrier of current CART therapy. More and more patients meet the failure of CD19 CART therapy. Pre-CART condition treatment is an important factor in durable responses. Decitabine, the hypomethylating agent, has been found that it can reduce T cell exhaustion, enhance T cell cytotoxicity and overcome tumor immune escape in the tumor microenvironment. We initiated this study to evaluate the efficacy and safety of decitabine combined with fludarabine and cyclophosphamide as conditioning regimen in 2nd CD19 CART therapy. Methods Patients are enrolled in the clinical trail (NCT02537977), inclusion and exclusion criteria are described. Pre-CART conditioning regimen is decitabine 10mg/m2 D-7~-3, fludarabine 25mg/m2 D-5~-3 and cyclophosphamide 300mg/m2 D-5~-3. The dose of second CD19 CART infusion is 5*10^6/kg. Primary outcome is the safety and secondary outcome is the efficacy. Results 6 patients are enrolled in this trail and all patients are failure of CD19 CART. The media age is 57 year old and median line of treatment is 4. 4 patients(67%) are female. 5 patients(83%) have TP53 mutation/deletion and double expression, 4 patients(67%) have IPI ≥3.4 patients(67%) got complete remission(CR) after the first CD19 CART therapy and 2 patients(33%) got partial remission(PR). The median time of relapse/progression after first CD19 CART is 9 months. The objective response rate is 50%, 2 patients(33%) got CR and 1 patient(17%) got PR. With median 13 months followup, the 3 patients(50%) maintain remission more than 1 year and are still under follow up. 2 patients(33%) got stable disease for 3 months and undergo salvage therapy. 1 patient(17%) had no response in 1 month and died due to disease progression. Of all 6 patients, only 1 patient(17%) received 2nd CART infusion in 3 months after 1st infusion and had detecable CART cell in peripheral blood. 2 patients(33%) got grade 1-2 cytokines release syndrome(CRS). No sever CRS and Immune effector cell-associated neurotoxicity syndrome(ICANS) were observed. Grade 3-4 adverse events are hematologic toxicity. Conclusion Decitabine combined with fludarabine and cyclophosphamide maybe an alternative conditioning regimen in CD19 CART therapy in high risk DLBCL patients. More patients are needed for further study and the trail is undergoing.

Current Results of Intensive Therapy in Younger Adults with Acute Myeloid Leukemia (AML): The Large Randomized French Backbone Intergroup (BIG)-1 Study on Behalf of the Filo, ALFA, and SFGM-TC Study Groups

Introduction. This multicenter study randomly explored various standard intensive chemotherapy (ICT) strategies in adults with AML, namely higher-dose idarubicin (IDA) vs high-dose daunorubicin (DNR) and intermediate-dose (IDAC) vs high-dose (HDAC) cytarabine. The study was planned large enough to allow patient subgroup analysis. Treatments. Eligible patients (pts) were randomized (R1) to receive an induction course with either DNR at 90 mg/m 2/d for 3 days or IDA at 9 mg/m 2/d for 5 days combined with cytarabine at 200 mg/m 2/d CIV for 7 days. Since 09/2018, FLT3-mutated AML pts may also receive midostaurin 100 mg/d d8-21. Then, all pts alive without contra-indication for further ICT were randomized (R2) to receive a first consolidation (C1, if in CR/CRp/CRi) or salvage (if induction failure) with either HDAC (3g/m 2/12h) or IDAC (1.5g/m 2/12h) cytarabine at day 1, 3 and 5. Pts in CR/CRp/CRi after C1/salvage received two additional HDAC/IDAC cycles (C2, C3), according to R2 arm. In intermediate (int) or adverse (adv) risk AML pts as defined in the protocol, allogeneic HSCT from sibling or 10/10 (or even 9/10 if adv-risk) matched donors was offered after C1 (adv-risk) or C2 (int-risk). Conditioning regimens were myeloablative (MAC; Bu-Cy ± ATG) if age<45y or reduced-intensity (RIC; Bu-Flu-ATG) if age≥ 45y or HCTCI> 2 in int-risk pts, and sequential FLAMSA/Bu-Cy-ATG in adv-risk pts. Fav-risk pts were also eligible for HSCT if late CR/CRp/CRi or suboptimal NPM1 MRD response. Alternative stem cells sources and conditioning regimens might also be offered to adv-risk pts. Patients & Methods. Pts aged 18-60y with de novo, post-MDS or therapy-related AML (CBF, APL, Ph+, and post-MPN excluded) were eligible if ECOG-PS ≤3, no active infection or neoplasia, no organ contra-indication, and a health insurance. Patient characteristics are shown in Table 1. Between 01/2015 and 05/2019, 1405 pts were enrolled and 1357 were evaluable. Among them, 1159 were randomized in R1 with the primary objective to increase 3-year OS from 45% in the DNR to 55% in the IDA arm. A total of 1221 pts were randomized in R2, including 198 pts after the end of the R1 inclusion period (they received DNR or IDA according to centers' preferences). Primary R2 objective was to show OS non-inferiority after IDAC vs HDAC in a per protocol (PP) set, defined as pts who received the planned HDAC/IDAC dose ± 20% during C1/salvage. The non-inferiority boundary was an upper limit of the hazard ratio [HR] CI below 1.25. Analysis of R1 and R2 effects was adjusted on ELN-2022 risk groups, the other randomization/treatment arms, and time-dependent HSCT in first remission. Median follow-up was 5.4 years. Results. Overall, 1148 (84.6%) pts achieved CR/CRp/CRi and 564 (41.6%) received HSCT in first remission ( Table 1). At 6 years, OS was estimated at 53.4% (95% CI, 50.6-56.2). In the R1 population, IDA did not prolong OS (adjusted HR, 1.04 [0.88-1.23]; p=0.67). This lack of effect was observed in the three ELN-2022 risk groups. During induction, IDA was associated with longer neutropenia and antibiotic administration durations, more RBC/platelet transfusions, more mucositis and fungal infections. Remission and induction death rates were similar in both arms. In the R2-PP set that excluded 39 R2 pts, OS was significantly non inferior in the IDAC as compared to the HDAC arm (adjusted p-value, 0.004) and this was observed in the three ELN-2022 groups ( Figure 1). During the first C1/salvage cycle, IDAC was associated with less CNS toxicity and less RBC/platelet transfusions. Only 2 pts died during this cycle. Neither responses, HSCT rates, relapse incidence, nor RFS were significantly impacted by R1 or R2. With respect to the OS endpoint, no interactions were found between induction anthracycline and R2. In pts in induction failure at R2, the salvage rate was 51.6% after HDAC vs 39.5% after IDAC (adjusted p-value, 0.081). As expected, time-dependent HSCT in first remission significantly prolonged RFS (adjusted HR, 0.41 [0.32-0.52]; p<0.0001) and OS from remission (adjusted HR, 0.65 [0.50-0.83]; p=0.001) in int/adv-risk AML pts. In these pts, no interaction was found between the effect of HSCT and the R2 arm (HDAC or IDAC). Conclusions. In younger adults with non-CBF AML, benefit/risk analysis favors high-dose DNR vs IDA for remission induction and confirms IDAC as the standard for consolidation. The high overall transplant rate may have contributed to the good results of this study.

BeEAM Conditioning including High-Dose Bendamustine before Autologous Stem Cell Transplantation Is Safe and Effective in Patients with Waldenstrom’s Macroglobulinemia

High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom's macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, problems with BCNU, including pneumotoxicity, tolerance, and availability, necessitate the search for alternatives. In this pilot study, we investigated high-dose chemotherapy with BeEAM, in which BCNU is replaced with high-dose bendamustine as an alternative conditioning regimen in six subsequent patients with WM. Bendamustine treatment was well tolerated without unexpected toxicities. The overall response rate was 6/6 patients (2 very good partial responses (VGPR) and 4 PR). After a median follow-up of 72 months, two (33%) patients relapsed. Median progression-free and overall survivals were not reached, and no severe late-onset toxicities were observed so far. In this pilot study, BeEAM conditioning before ASCT seems feasible, safe, and effective in patients with WM.

Chimeric Antigen Receptor T-Cell Therapy and Hematopoiesis.

Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment option for patients suffering from B-cell- and plasma cell-derived hematologic malignancies and is being adapted for the treatment of solid cancers. However, CAR T is associated with frequently severe toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), macrophage activation syndrome (MAS), and prolonged cytopenias-a reduction in the number of mature blood cells of one or more lineage. Although we understand some drivers of these toxicities, their mechanisms remain under investigation. Since the CAR T regimen is a complex, multi-step process with frequent adverse events, ways to improve the benefit-to-risk ratio are needed. In this review, we discuss a variety of potential solutions being investigated to address the limitations of CAR T. First, we discuss the incidence and characteristics of CAR T-related cytopenias and their association with reduced CAR T-cell efficacy. We review approaches to managing or mitigating cytopenias during the CAR T regimen-including the use of growth factors, allogeneic rescue, autologous hematopoietic stem cell infusion, and alternative conditioning regimens. Finally, we introduce novel methods to improve CAR T-cell-infusion products and the implications of CAR T and clonal hematopoiesis.

BeEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) Versus BEAM (Carmustine, Etoposide, Cytarabine, Melphalan) as Conditioning Regimen Before Autologous Haematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for selected patients with refractory/relapsed Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL), and it is also used as first-line clinical consolidation option for some aggressive NHL subtypes. Conditioning regimen prior to ASCT is one of the essential factors related with clinical outcomes post transplant. The conditioning regimen of carmustine, etoposide, cytarabine, and melphalan (BEAM) traditionally is considered the standard of care for patients with lymphoma who are eligible for transplantation. Replacement of carmustine with bendamustine (BeEAM) was described as an alternative conditioning regimen in the autograft setting for patients with lymphoma. Several studies have reported inconsistent clinical outcomes comparing BeEAM and BEAM. Therefore, in the lack of well-designed prospective comparative studies, the comparison of BeEAM versus BEAM is based on retrospective trials. To compare the clinical outcomes between BeEAM and BEAM, we performed a meta-analysis of 10 studies which compared the outcomes between BeEAM and BEAM in patients autografted for lymphoma disease (HL or NHL). We searched article titles and compared transplantation with BeEAM versus BEAM in MEDLINE (PubMed), Cochrane library, and EMBASE database. Here, we report the results of nine main endpoints in our meta-analysis comparing BeEAM and BEAM, including neutrophil engraftment (NE), platelet engraftment (PE), overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), relapse rate (RR), grade 3 mucositis, renal toxicity, and cardiotoxicity. We discovered that the BeEAM regimen was associated with a slightly better PFS [pooled odds ratio (OR) of 0.70, 95% confidence interval (CI), 0.52-0.94, P = 0.02], lower RR (0.49, 95% CI, 0.31-0.76, P = 0.002), higher mucositis (3.43, 95% CI, 2.29-5.16, P = 0.001), renal toxicity (4.49, 95% CI, 2.68-7.51, P = 0.001), and cardiotoxicity (1.88, 95% CI, 1.03-3.40, P = 0.03). We also discovered that the two groups had equivalent NE (pooled WMD -0.64, 95% CI, -1.46 to 0.18, P = 0.13), PE (pooled WMD -0.3, 95% CI, -1.68 to 2.28, P = 0.77), OS (0.73, 95% CI, 0.52-1.01, P = 0.07), and NRM (1.51, 95% CI, 0.76-2.98, P = 0.24). The results of this meta-analysis show that the BeEAM regimen is a viable alternative to BEAM. More prospective comparisons between BeEAM and BEAM are required.

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

Fludarabine/Cyclophosphamide Conditioning Regimen in Aplastic Anemia Patients Receiving Matched-Sibling Donor Transplant Is Non-inferior to ATG/Cyclophosphamide: A Single-Center Experience from Pakistan.

The successful outcome of allogeneic hematopoietic stem cell transplant (HSCT) in aplastic anemia patients is driven by suitable donor selection, appropriate conditioning regimen, early intervention, and optimal supportive care after transplant. Pakistan, being a developing country, faces grave economic challenges due to meager health care budget; therefore, cost constraints remain the foremost impediment in optimizing transplant facilities for socioeconomically deprived patients. We conducted a single-center retrospective analysis of aplastic anemia patients (N = 130), who received matched sibling donor transplants from 2011 to 2019, treated with either fludarabine/cyclophosphamide (Flu/Cy) or antithymocyte globulin/cyclophosphamide (ATG/CY) conditioning regimen. Median age was 16 years (IQR, 11-20), and it ranged from 3 to 48 years. The median time from diagnosis to transplant was 3 months (IQR, 2 to 4), and it ranged from 1 to 8 months. The estimated overall survival (OS), relapse-free survival (RFS), and GvHD-free survival (GFS) were found to be 69.0%, 66.7%, and 64.3% in the ATG/Cy group while 76.1%, 72.7%, and 62.5% in the Flu/Cy group, respectively, after a median follow-up of 30 months (IQR, 8 to 55), and it ranged from 0 to 98 months for the study groups. The Flu/Cy regimen was well tolerated and was not associated with increased risk of GvHD. Hence, it may be an appropriate alternative conditioning regimen for developing countries with limited health care resources.

Busulfan and thiotepa as a conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma: A study of the Korean Multiple Myeloma Working Party (KMMWP-1801 study).

BackgroundAutologous stem cell transplantation (ASCT) remains the standard of care for patients with newly diagnosed multiple myeloma (MM). Several attempts to improve the efficacy of conditioning regimens have been conducted in MM, but no more effective regimen than conventional high-dose melphalan has been introduced.ObjectiveIn this study, the efficacy and toxicity of busulfan and thiotepa (BuTT) and those of high-dose melphalan (HD-MEL) were compared retrospectively as a conditioning regimen for ASCT in patients with MM.Study designIncluded in the analysis were 114 patients who received BuTT and 114 patients who received HD-MEL treatment between March 2008 and May 2020. The BuTT regimen consisted of intravenous thiotepa 5 mg/kg once a day from days 7 to 6, followed by intravenous busulfan 3.2 mg/kg once a day from days 5 to 3. The HD-MEL conditioning regimen consisted of melphalan 100 mg/m2 once a day from days 3 to 2.ResultsThe overall response rate after ASCT did not differ between BuTT and HD-MEL (94.7% in BuTT vs. 97.4% in HD-MEL, p = 0.333). After a median follow-up of 47.6 months, progression-free survival (PFS) tended to be longer in the BuTT group (median PFS, 41.5 months vs. 30.3 months; hazard ratio (HR), 0.706; 95% confidence interval (CI), 0.497–1.004, p = 0.053). In the subgroup analysis of patients who did not proceed to maintenance or consolidation treatment after ASCT, the difference in PFS became more significant (median PFS, 41.5 months vs. 24.4 months; HR, 0.621; 95% CI, 0.388–0.993; p = 0.047). Additionally, the BuTT group had fewer adverse events, such as grade 3 or 4 stomatitis and diarrhea, than the HD-MEL group (stomatitis, 10.5% vs. 23.7%, p = 0.013; diarrhea, 10.5% vs. 25.4%, p = 0.005). There was no difference in the occurrence of venous-occlusive disease (2.6% in BuTT vs. 0.9% in HD-MEL, p = 0.622).ConclusionOur study results suggest that BuTT is an effective alternative conditioning regimen with reduced toxicity in patients with newly diagnosed MM.

A comparison of C+SCAV and SEAM conditioning regimens in efficacy and safety in autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma patients

Objective: This study aimed to compare the efficacy and safety of cladribine, smustine, etoposide, cyclophosphamide, and cytarabine (C+SCAV) and smustine, etoposide, cytarabine, and melphalan (SEAM) conditioning regimens in autologous stem cell transplantation (auto-HSCT) for non-Hodgkin's lymphoma (NHL) . Methods: A retrospective analysis was conducted on 61 NHL patients who received auto-HSCT in the Department of Hematology, the First Affiliated Hospital of Suzhou University, from March 2018 to May 2021. The C + SCAV group and SEAM group had 19 and 42 patients, respectively. Results: ① Among the 61 patients with NHL, 37 were male and 24 were female. The median age was 48 (21-66) years old. There were 19 cases in the C+SCAV group and 42 cases in the SEAM group. There was no significant difference in the baseline characteristics between the two groups (P>0.05) . ② The median time to neutrophil and platelet engraftment in the C+SCAV cohort were 10 (8-15) days and 13 (9-22) days, respectively, which does not differ from the SEAM group (P=0.103, P=0.403) . ③ No differences existed between the two groups in terms of survival. The 1-year progression-free survival (PFS) was (76.5±10.3) % for patients receiving C+SCAV and (78.4±6.8) % for those who received SEAM (P=0.841) . The 1-year overall survival was 100.0% for the C+SCAV group and 95.2±3.3% for the SEAM group (P=0.339) . ④The 1-year PFS of patients with complete remission in the C+SCAV group was similar to those who in the SEAM group [ (92.3±7.4) % vs (82.5±7.2) %, P=0.406]. ⑤ The incidence of non-hematological serious adverse events (≥ grade 3) in the C+SCAV group and SEAM group were 10.5% (2/19) and 40.5% (17/42) (P=0.013) , the incidence of severe mucositis was 5.3% (1/19) and 31.0% (13/42) (P=0.015) , and the incidence of severe infection (≥ grade 3) was 10.5% (2/19) and 19.0% (8/42) (P=0.389) , respectively. Conclusion: C + SCAV conditioning regimen appeared to be no different from the SEAM regimen in terms of survival. It can lower the incidence of SAE and does not increase the risk of severe infection. As a result, it can be used as an alternative conditioning regimen for lymphoma patients undergoing auto-HSCT.

Treosulfan-based conditioning vs. low-dose busulfan-based conditioning for allogeneic hematopoietic stem cell transplantation: a cost-utility analysis in Poland

Introduction: In Poland, busulfan conditioning is used for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cost-utility analyses comparing alternative conditioning regimens in patients undergoing allo-HSCT have not been conducted so far. Material and methods: A United Kingdom-based partitioned survival model was adapted to the Polish setting to compare treosulfan to low-dose busulfan conditioning regimen from the public payer’s perspective in Poland. Patient characteristics, overall survival (OS), event-free survival (EFS), and the rate of adverse events were obtained from the randomized MC-FludT.14/L trial. Parametric survival models of up to 5 years (the cure threshold), with subsequent mortality defined using survival of the general population of Poland adjusted for cancer survivors, were used to extrapolate OS and EFS beyond the trial duration. Published utilities were adjusted for age using age-dependent general population utilities. The costs of treatment, adverse events, and inpatient/outpatient care were assessed via official remuneration schemes. Results: Treosulfan-based conditioning outperformed low-dose busulfan, i.e. it was more effective with incremental quality-adjusted life years (QALY) of 0.78 and less expensive by 1,139 PLN per patient over the lifetime horizon. Deterministic sensitivity analyses revealed treosulfan was highly cost-effective (i.e. incremental cost-utility ratio was lower than the gross domestic product per capita in Poland) compared to low-dose busulfan, if most uncertain parameters are changed or alternative scenarios are implemented. The probability of treosulfan being cost-effective with a threshold of 155,514 PLN was 99.6%. Conclusions: Compared to low-dose busulfan, treosulfan is a highly cost-effective conditioning regimen for allo-HSCT patients ineligible for standard conditioning regimens.

Umbilical Cord Blood or HLA-Haploidentical Transplantation: Real-World Outcomes versus Randomized Trial Outcomes

Randomized clinical trials offer the highest-quality data for modifying clinical practice. Results of a phase III randomized trial of nonmyeloablative transplantation for adults with high-risk hematologic malignancies with 2 umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM; n=154) revealed a 2-year progression-free survival (PFS) of 41% after Haplo-BM transplantation and 35% after 2-unit UCB transplantation (P=.41), with overall survival (OS) of 57% and 46%, respectively (P=.04). We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's prespecified 2-year outcomes. All transplantations were performed between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial would be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM with those after haploidentical peripheral blood (Haplo-PB). The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select nontrial subjects. Extended follow-up of trial subjects was obtained from this data source. Three separate analyses were performed: (1) trial subjects beyond the trial's 2-year endpoint; (2) comparison of trial subjects with a contemporaneous cohort of nontrial subjects (195 2-unit UCB, 358 Haplo-BM, and 403 Haplo-PB); and (3) comparison of nontrial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. With longer follow-up of the trial cohorts, 5-year PFS (37% versus 29%; P=.08) and OS (42% versus 36%; P=.06) were not significantly different between the treatment groups. We then compared the trial results with outcomes of comparable real-world transplantations. Five-year OS did not differ between trial and nontrial 2-unit UCB transplantations (36% versus 41%; P=.48) or between trial and nontrial Haplo-BM transplantations (42% versus 47%; P=.80), confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in PFS. With substantially larger numbers of nontrial Haplo-BM transplantations, 5-year survival was higher after nontrial Haplo-BM compared with trial 2-unit UCB (47% versus 36%; P=.012). Nontrial patients who underwent Haplo-PB transplantation had higher 5-year survival (54%) compared with trial Haplo-BM (hazard ratio [HR], 0.76; P=.044) and nontrial Haplo-BM (HR, 0.78; P=.026). Similarly, survival was better after Haplo-PB compared with trial UCB (HR, 0.57; P < .0001) and nontrial UCB (HR, 0.63; P=.0002). When considering alternative donor low-intensity conditioning regimen transplantation, a haploidentical relative is preferred, and PB is the preferred graft source.

Conditioning Intensity and Probability of Live Birth after Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: The observed inter-individual variability in the probability of live birth after BMT is due to exposure to gonadotoxic agents (including total body irradiation [TBI]), age at exposure to gonadotoxic agents, sex of the BMT recipient, and post-BMT morbidity. The last decade has seen an increase in use of non-myeloablative (NMA) conditioning to reduce the risk of early post-treatment mortality. However, the impact of TBI in the context of conditioning intensity (NMA vs. myeloablative conditioning [MAC]) on the probability of post-BMT live birth remains unknown. We addressed this gap by utilizing the BMTSS - a multi-institutional collaborative designed to understand the burden of morbidity after BMT.Methods: This study included 1,607 BMT survivors who underwent BMT between 1974 and 2014 at age ≤45, had survived ≥2y, and were ≥18y of age at study. This study also included pair-matched nearest-age, same-sex biologic siblings (≥18y of age at study) to control for genetic or environmental factors that could affect fertility. Survivors and their siblings completed the BMTSS survey. Sociodemographic characteristics (race/ethnicity, annual household income, availability of health insurance, level of education), chronic health conditions, medical assistance for fertility assistance and details about all pregnancies and their outcomes were retrieved from the BMTSS survey. Clinical characteristics were obtained from the institutional BMT databases and/or participants' medical record. Within survivor analysis: Potential risk factors for not reporting a live birth after BMT were analyzed using multivariable logistic regression. Exposure to TBI and conditioning intensity were consolidated to create four distinct exposure groups: no_TBI/NMA (least intense), TBI/NMA, no_TBI/MAC, TBI/MAC (most intense). Matched-pair comparison with biologic siblings: We matched 172 survivors with their closest-age, same-sex, biological siblings and used conditional logistic regression to determine the failure to report live birth in BMT survivors when compared with their siblings.Results: In this cohort of 1,607 survivors, 599 (37.3%) were autologous BMT recipients, and 765 (47.6%) were female. Median age at BMT was 30y, and at study participation was 45y (IQR: 18-73); median length of follow-up from BMT to study was 14.4y (IQR: 2.4-41.4). The primary indications for BMT included HL/NHL (30.6%), AML/MDS (24.3%), CML (13.4%), ALL (12.2%), and other diagnoses (13.5%). Of the 1,607 survivors, 120 (7.5%) reported one or more live births after BMT. Within survivor comparison: Multivariable analysis (Figure) revealed that receipt of TBI/MAC (OR=2.9, 95%CI: 1.5-5.8; ref: no_TBI/ NMA) was associated with an increased risk of not reporting a post-BMT live birth. Of note, TBI/NMA (OR=1.5, 95%CI, 0.5-5.0), and no_TBI/ MAC (OR=0.9, 95%CI, 0.4-2.0) were at a similar risk of reporting a post-BMT live birth as no_TBI/NMA. Other factors associated with increased risk of not reporting a post-BMT live birth included older age at BMT (>35y: OR=3.5, 95%CI, 1.4-7.9; reference: <12y), lower income ($50k-100k: OR=2.0, 95%CI, 1.1-3.6; <$50k: OR=3.2, 95%CI, 1.6-6.4; reference: >$100k), no medical interventions to facilitate pregnancy (OR=2.7, 95%CI, 1.6-4.6), and history of pre-BMT live birth (OR=2.7, 95%CI, 1.6-4.6). Matched-pair comparison with biologic siblings: Multivariable conditional logistic regression revealed that BMT survivors were less likely to report live birth (OR=0.5, 95%CI: 0.3-0.8) compared to their siblings. However, once pregnant, they were also less likely to report a miscarriage (OR=0.4. 95%CI: 0.2-0.8).Conclusion: While full dose TBI in the setting of myeloablative conditioning is associated with a lower probability of live birth after BMT, lower doses of TBI in the setting of myeloablative or reduced intensity conditioning yield a similar probability of live birth as no TBI. These findings provide evidence for alternative conditioning regimens for patients who wish to have children after BMT. [Display omitted] DisclosuresWeisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

BuCyE can safely replace BEAM as a conditioning regimen for autologous stem cell transplantation in the treatment of refractory and relapsed lymphomas

IntroductionHodgkin’s (HL) and non-Hodgkin’s (NHL) lymphomas have usually high cure rates. The standard of care for chemosensitive relapsed/refractory lymphoma patients is salvage chemotherapy followed by AHSCT. Due to carmustine and melphalan shortages, alternative pre-AHSCT conditioning regimens with similar tolerance and response were needed. ObjectivesTo compare the efficacy and toxicity profile between relapsed/refractory HL and NHL lymphomas given BEAM or BuCyE. MethodsA retrospective analyses of 122 patients in a Brazilian center was made. OS and PFS were calculated by Kaplan-Meier and compared by log rank. Toxicity and engraftment data were also compared. ResultsMost clinical characteristics were similar between groups, although a higher frequency of grade ≥ 2 mucositis (p = .01) was seen in the BuCyE group. No significant difference in OS or PFS were observed between the groups. ConclusionBEAM and BuCyE are well tolerated with similar toxicity profiles and survival outcomes. Therefore, BuCyE conditioning regimen can be considered an alternative to BEAM.

FLAMSA vs BU-FLU in patients undergoing allogeneic stem cell transplantation for acute leukemia and myelodysplastic syndrome

Objective: Similar to other regimens, the specific role of fludarabine-amsacrine-cytarabine (FLAMSA) regimen before allogeneic transplantation has still unclear. We compared the results of patients who received either the FLAMSA regimen or the busulfan-fludarabine (BuFlu) regimen prior to allogeneic transplantation.&#x0D; Materials and Methods: Patients who underwent allogeneic transplantation and who administered reduced-intensity conditioning (RIC) regimens before transplantation were included in this study. Patients were divided into two groups (BuFlu and FLAMSA) according to the applied RIC regimens.&#x0D; Results: A total of 37 allogeneic transplant patients (13 FLAMSA, 24 BuFlu patients) were included in this study. The time between diagnosis and transplantation was shorter in the patients in the FLAMSA group compared to the patients in the BuFlu group (p&lt;0.001). Although platelet engraftment time was shorter in the FLAMSA group than in the busulfan-fludarabine group (p=0.048), the neutrophil engraftment time and adverse events were similar in the two groups (all p&gt;0.05). The estimated median disease-free survival of the patients in the FLAMSA group was 7.2 months, while it was 3.7 months in the busulfan-fludarabine group (p=0.778). Similarly, the estimated median overall survival of the patients in the FLAMSA group was 7.2 months, while 7 months in the BuFlu group (p=0.815).&#x0D; Conclusion: BuFlu and FLAMSA are two alternative conditioning regimen options that provide similar efficacy, toxicity profile and survival as regimens used in allogeneic transplantation. The FLAMSA regimen may be an alternative to Bu-Flu as a priming regimen for allogeneic stem cell transplantation. Meta-analyzes should be performed to evaluate with more patients.

IEAC versus CEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for lymphoma: analysis of efficacy and safety in 106 cases

ObjectiveTo evaluate the efficacy and safety of IEAC (idarubici, etoposide, cytosine arabinoside, and cyclophosphamide) and CEAC (lomustine, etoposide, cytosine arabinoside, and cyclophosphamide) high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) in the treatment of lymphoma.MethodWe retrospectively analyzed the data of 106 lymphoma patients undergoing ASCT from 2013 to 2018 using IEAC (n=43) or CEAC (n=63) regimens. The time of hematopoietic reconstruction, adverse events and the patients' survival outcomes in the two groups were compared to evaluate the efficacy and safety of the two regimens. Univariate and multivariate analyses were performed to identify the factors potentially affecting the patients' survival.ResultsIn the total of 106 patients, successful hematopoietic reconstruction was achieved in 104 patients and treatment-related deaths occurred in 2 patients. No significant differences were observed in the time to hematopoietic recovery, adverse events or survival outcomes between the patients receiving IEAC and CEAC regimens. In the 104 patients with successful hematopoietic reconstruction who were followed for a median of 27.4 months (range 4.3 to 74.3 months), the 5-year progress-free survival (PFS) and overall survival (OS) rates were 72.9% and 81.9%, respectively. The main adverse events (beyond grade 2 based on CTCAE v5.0) included infection, oral mucositis, nausea and vomiting, liver damage, cardiotoxicity, hypokalemia, and diarrhea. No significant difference was found in the survival outcomes or adverse events between the 2 regimens. T cell lymphoma and failure to achieve complete remission (CR) before ASCT were the risk factors of PFS (P=0.015 and P=0.007, respectively) and OS (P=0.038 and 0.031, respectively). The patients who achieved CR 3 months after the transplantation had higher rates of PFS (P=0.007) and OS (P=0.003).ConclusionIEAC and CEAC regimens prior to by ASCT are both safe and effective in the treatment of lymphoma and can be used as alternative conditioning regimens for lymphoma patients undergoing ASCT.

Intravenous busulfan and melphalan versus high-dose melphalan as a conditioning regimen for early autologous stem cell transplantation in patients with multiple myeloma: a propensity score-matched analysis

We compared the efficacy and toxicity of busulfan and melphalan (BUMEL) and those of high-dose melphalan (HDMEL) as conditioning regimens for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) through a propensity score-matched analysis. No significant difference in the complete response and overall response rate after ASCT was observed between BUMEL and HDMEL. After a median follow-up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, the median progression-free survival was calculated to be 32.9 months and 25.2 months (p = 0.995). With respect to non-hematologic toxicities, infections were more frequently reported in the BUMEL group (p < 0.001). Three patients who received BUMEL developed veno-occlusive disease (VOD), and all of them recovered without administration of defibrotide. In conclusion, BUMEL is an effective alternative conditioning regimen in terms of efficacy, but attention should be paid to toxicities.

Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning

Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient’s marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.