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Modified Conditioning Regimen with Idarubicin Followed by Autologous www.nature.com/scientificreports OPEN Modifed conditioning regimen with idarubicin followed by autologous hematopoietic stem cell transplantation for invasive B‑cell non‑Hodgkin’s lymphoma patients Chen Tian*, Yueyang Li, Su Liu, Zehui Chen, Yizhuo Zhang, Yong Yu, Hongliang Yang, Haifeng Zhao, Zhigang Zhao, Tian Yuan & Yafei Wang* High‑dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory B‑cell non‑Hodgkin’s lymphoma (NHL) patients and some aggressive B‑cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin‑substituted BEAC (IEAC) conditioning regimen. We retrospectively compared the outcomes of 72 aggressive B‑cell NHL patients treated with IEAC or BEAC regimens followed by ASCT as upfront consolidative treatment. The median time to neutrophil and platelet reconstitution showed no diference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant‑related mortality didn’t occur. The overall survival (OS) and progression‑free survival (PFS) of IEAC group (33 and 23 months) were a little longer than that of BEAC group (30 and 18 months). However, due to the small sample numbers, there’s no signifcant diference in OS and PFS between IEAC and BEAC group with DLBCL or MCL. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase level, remission of disease, modifed regimen were related with PFS and OS. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could be an alternative when carmustine was not available. Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy1. High-dose chemotherapy (HDC) has been a standard front-line therapy for patients with aggressive NHL for decades. Autologous hemat- opoietic stem cell transplantation (ASCT) is standard of care (SOC) for relapsed/refractory DLBCL2–4, which can eliminate the residual tumor cells, thereby decrease the probability of disease recurrence and prolong the survival5. BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, cyclophosphamide) and CBV (carmustine, cyclophosphamide, and etoposide) are the most commonly used conditioning regimens for NHL 6,7. With the aim of obtaining a higher anti-lymphoma activity and/or reducing the toxic efects, a number of studies suggested the possibility of improving the outcomes of NHL patients through modifying the condition- ing regimens8–10. BuCyE (busulfan, cyclophosphamide, and etoposide)11,12 and Benda-EAM (bendamustine, etoposide, cytarabine, and melphalan)13,14 were approved to be efective and safe for NHL patients 15,16. However, idarubicin, which was a widely used anthracycline drug for NHL patients, was rarely reported to be added in conditioning regimen. In 1997, Engert et al. found that IIVP (ifosfamide, idarubicin, and etoposide) was a sal- vage regimen with acceptable toxicity and highly efective for patients with R/R NHL 17. Due to the shortage of carmustine, bendamustine and nimustine in China, we aimed to examine conditioning with idarubicin and to compare the efcacy and toxicity between BEAC and idarubicin-substituted BEAC (IEAC). Key Laboratory of Cancer Prevention and Therapy, Department of Hematology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. *email: tcgirl2001@ sina.com; [email protected] Scientifc Reports | (2021) 11:4273 | https://doi.org/10.1038/s41598-021-81944-8 1 Vol.:(0123456789) www.nature.com/scientificreports/ Figure 1. Study design. Methods Patients. Tis study was subject to approval by the Research Ethics Committee of Tianjin Medical Univer- sity Cancer Institute and Hospital. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects. A retrospective study of 72 invasive B-cell NHL patients (18–65 years old) who received either IEAC (n = 40) or BEAC (n = 32) between 01/2015 and 06/2018 were enrolled, as shown in Fig. 1. All patients received 4–6 cycles of standard chemotherapy such as R-CHOP (doxorubicin 50 mg/m2) or R-DA-EPOCH (doxorubicin 10 mg/m2/day infusion × 96 h, days 1–4) regimen and performed 18-fuorodeoxyglucose positron emission tomography/computed tomography (PET–CT) to evaluate remission state before and afer ASCT (Fig. 1). Te invasive B cell NHL patients included difuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients in frst CR with high-risk factors and patients in PR afer 6 cycles of standard induction therapy. High-risk factors included central nervous system infltra- tion (primary and secondary), high grade B cell lymphoma (exclude Burkitt and double/triple hit lymphoma), international prognostic index (IPI) score > 3. Treatment protocols. At transplantation, patients were expected to have a Karnofsky performance sta- tus > 80, together with adequate cardiac (EJF > or equal to 50%), liver, and lung function, and no infectious pro- cess. Patients were treated with either BEAC regimen consisting of Carmustine (BCNU, 300 mg/m2 on day − 6), Etoposide (100 mg/m2 every 12 h on days − 5 to − 2), Cytarabine (200 mg/m2 every 12 h on days − 5 to − 2), and Cyclophosphamide (1.5 g/m2 on days − 5 to − 2) or IEAC conditioning regimen [substitution of BCNU with ida- rubicin (8 mg/m2 on days − 9 to − 7)]. More than 2 × 106/kg of CD34 + cells were infused into the patients afer conditioning regimen. Tere’s no signifcant diference of the number of CD34 + cells infused between the two groups. We used ursodiol, acyclovir, SMZ, fuconazole and moxifoxacin as supportive care. No patients received consolidation radiation therapy afer transplantation. Rituximab (375 mg/m2, every three months) was given to all DLBCL and MCL patients as maintenance therapy for two years. Study endpoints. Te follow-up deadline was 01 October 2019. Te primary endpoint of this analysis was overall survival (OS) among the diferent conditioning regimens. Secondary endpoints included transplant- related mortality (TRM), relapse or progression, and progression-free survival (PFS). According to WHO cri- teria, the therapeutic evaluation was divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD)18. Neutrophil and platelet engrafment were defned as the frst 3 consecutive days with absolute neutrophil count > 0.5 × 109/L and untransfused platelet count > 20 × 109/L, respectively. Tox- icity was assessed using the National Cancer Institute Common Terminology Criteria, version 4.0. Statistical analysis. Statistical analysis was performed using SPSS. OS was calculated from the date of diagnosis until death, or until the last follow up date the patient was known to be alive. PFS was determined for responders from the time of diagnosis until disease progression, relapse, death, or until last follow up. PFS was only determined in those complete responders post transplantation. TRM was defned as any death without recurrent lymphoma. Te signifcance of diference between survival curves was calculated by the log-rank test. Groupwise comparisons of the distributions of variables were performed with the generalized Wilcoxon test. A multivariate Cox proportional hazard model with hierarchical forward entering was constructed to assess prog- Scientifc Reports | (2021) 11:4273 | https://doi.org/10.1038/s41598-021-81944-8 2 Vol:.(1234567890) www.nature.com/scientificreports/ IEAC (n = 40) BEAC (n = 32) P value Gender Male 19 (48%) 22 (69%) 0.10 Female 21 (52%) 10 (31%) Age < 40 22 (55%) 18 (56%) 0.64 ≥ 40 18 (45%) 14 (44%) IPI score 0–2 27 (67%) 23 (72%) 0.80 3–5 13 (33%) 9 (28%) Ann Arbor stage I–II 20 (50%) 13 (41%) 0.48 III–IV 20 (50%) 19 (59%) LDH level ≤ 250 32 (80%) 23 (72%) 0.58 > 250 8 (20%) 9 (28%) Status before ASCT CR 27 (67%) 19 (59%) 0.62 PR 13 (33%) 13 (41%) Pathological type DLBCL 35 (87.5%) 30 (93.75%) 0.42 MCL 5 (12.5%) 2 (6.25%) Table 1. Patients’ baseline demographics and clinical characteristics. IPI international prognostic index, LDH lactate dehydrogenase, CR complete remission, PR partial remission, ASCT autologous stem cell transplantation. nostic factors. Survival and hazard ratio (HR) probabilities were presented with 95% confdence intervals (CI). A P value < 0.05 was considered signifcant diferent. Ethics approval and consent to participate. Tis study was subject to approval by the Research Ethics Committee of Tianjin Medical University Cancer Institute and Hospital. Results Clinical characteristics. Patients’ clinical characteristics were shown in Table 1. Of the 72 patients’ retro- spective cohort, the median age was 39.5 years old (from 28 to 60 years old), the male to female ratio was 1.32:1. Based on the IPI score, patients were divided into the 0 –2 points group (n = 50, 69.4%) and the 3–5 points group (n = 22, 30.6%). According to Ann Arbor staging system, 33 (45.8%) patients were stage I–II and 39 (54.2%) patients were stage III–IV. Tere were no signifcant diferences in patient characteristics between IEAC and BEAC groups (Table 1). Te pathological type of the 72 newly diagnosed patients was 65 DLBCL cases including nine cases transformed from follicular lymphoma (FL), and 7 MCL cases. All of the patients were primary high- risk lymphoma achieved CR or PR afer 4 or 6 cycles of chemotherapy, excluding relapsed disease. Afer 4 cycles, patients who reached CR (n = 44 for DLBCL, n = 2 for MCL) entered autologous transplantation, while patients who did not reach CR (n = 21 for DLBCL, n = 5 for MCL) continued treatment for 2 cycles, and then entered autologous transplantation. Tirty-fve DLBCL patients including 24 in CR and 11 in PR before transplantation were given IEAC conditioning regimen and 30 DLBCL patients (17 in CR and 13 in PR) received BEAC regimen. A total of 5 MCL cases including 3 cases in CR and 2 cases in PR before transplantation were given IEAC regi- men.
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