Modified BEAC conditioning regimen with idarubicin followed by autologous hematopoietic stem cell transplantation is safe and effective for invasive B-cell non-Hodgkin’s lymphoma patients

High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory (R/R) 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). We compared the outcomes of 72 B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT. The median time to neutrophil and platelet reconstitution showed no difference 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 were a little longer than that of BEAC group. 2-year OS and PFS rate were higher in IEAC group compared to BEAC group. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase (LDH) level, remission of disease, modified regimen were related with the prognosis. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could effectively prolong the survival of patients.

Modified BEAC conditioning regimen with idarubicin followed by autologous hematopoietic stem cell transplantation is safe and effective for invasive B-cell non-Hodgkin's lymphoma patients CURRENT  Introduction Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy [1]. High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) has been a standard front-line consolidation therapy for patients with aggressive NHL for decades [2][3][4], which can eliminate the residual tumor cells, thereby decrease the probability of disease recurrence and prolong the survival [5]. BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, cyclophosphamide) and CBV (carmustine, cyclophosphamide, and etoposide) are the most commonly used regimens for NHL [6][7].
With the aim of obtaining a higher anti-lymphoma activity and/or reducing the toxic effects, a number of studies suggested the possibility of improving the outcomes of NHL patients through modifing the conditioning regimens [8][9][10]. BuCyE (busulfan, cyclophosphamide, and etoposide) [11,12] and Benda-EAM (bendamustine, etoposide, cytarabine, and melphalan) [13][14] were approved to be effective 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

Study Endpoints
The follow-up deadline was 01 Oct 2019. The primary endpoint of this analysis was overall survival (OS) among the different conditioning regimens. Secondary endpoints included transplant-related mortality (TRM), relapse or progression, and progression-free survival (PFS). According to WHO criteria, the therapeutic evaluation was divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).
Neutrophil and platelet engraftment were defined as absolute neutrophil count > 0.5 × 10 9 /L and untransfused platelet count > 20 × 10 9 /L, respectively. Toxicity 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.    (Figs. 3 and 4).

Prognosis factors
The univariate and multivariate analysis showed that lactate dehydrogenase (LDH), remission status before ASCT, AnnArbor stage, IPI score and conditioning regimens were prognostic factors relating to outcomes. Patients with lower LDH, AnnArbor Stage and IPI score had better prognosis (P < 0.05), and patients achieved CR before ASCT had longer PFS (P = 0.043) and OS (P = 0.045) compared to patients with PR before ASCT. In addition, patients received IEAC conditioning regimen had longer PFS (P = 0.02) and OS (P = 0.03) than patients in BEAC group (Table 4).

Discussion
HDC followed by ASCT could make patients to achieve deeper response, as a result some of them were cured. The PARMA study was the first randomized trial to demonstrate that the use of HDC followed by ASCT resulted in better prognosis compared to standard chemotherapy in patients with relapsed NHL [18][19][20][21][22]. Several studies demonstrated that HDC followed by ASCT as consolidation therapy for patients achieved CR after induction therapy could prolong the PFS, but not the OS [23][24]. Composed of drugs usually not employed in front-line therapy and not causing high toxicities, BEAC is generally very effective and well tolerated [15][16][25][26][27][28].
Anthracyclines drug such as doxorubicin was commonly used to treat NHL patients. Some studies found that idarubicin was an important anthracyclines drug in lymphoma chemotherapy. Combination of idarubicin and other chemodrugs were utilized as the salvage treatment to achieve high response rate [18][19]. However, few reports demonstrated the efficacy and toxicities of conditioning regimen including idarubicin. Due to the shortage of carmustine, bendamustine and nimustine in China, we modified BEAC protocol by replacing BCNU with idarubicin and examine and evaluate its efficacy and side effects in our single center.
Our results showed that IEAC scheme was well tolerated. As expected, the most frequently observed hematologic toxicity was febrile neutropenia (70.8%), higher than other reports [28][29][30], however the median time of neutrophils engarftment did not differ significantly between the IEAC and the BEAC groups. No patient experienced grade IV nausea and vomiting; grade III nausea and vomiting were observed in 50% of patients, higher than other reports. But cardiac toxicity observed in our study was 6.9%, lower than other reports [31,32]. No patient showed significant liver or kidney toxicity and no patient died due to TRM.
For patients with NHL, IEAC produced longer PFS and OS to contemporary patients treated with BEAC, indicating superior outcomes for IEAC. Our results showed that AnnArbor stage, IPI score, LDH level, the remission status before ASCT and conditioning regimen were prognostic factors. Although it was a retrospective study, the case study was not large and included various histologic types of lymphoma, it was still possible to make some assessments of the efficacy of IEAC. Further prospective, randomized comparative clinical trials should be performed to confirm that IEAC is superior than BEAC.

Conclusion
In conclusion, IEAC prolonged the PFS and OS while didn't increase the incidence of toxicities. Furthermore, IEAC did not prolong the median time of hematopoietc engraftment. IEAC has been proven to be safe and effective in different histologic types of lymphoma and, therefore, it may be put forward for consideration.

Ethics approval and consent to participate
Not applicable

Consent for publication
Not applicable

Availability of data and material
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors have no conflicts of interest.

Funding
The study was funded by grants 81670104 from the National Natural Science Foundation of China (NSFC).    OS and PFS of MCL patients in IEAC group were longer than that in BEAC group.