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Busulfan‐containing conditioning regimens in allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia: A Taiwan observational study

Busulfan‐containing conditioning regimens in allogeneic hematopoietic stem cell transplantation... INTRODUCTIONAdvances in the treatment of adult acute lymphoblastic leukemia (ALL) by small molecular agents and chimeric antigen receptor T‐cell therapy have greatly improved patient survival in the last decade.1‐7 Meanwhile, recurrence is common in the post‐therapy course, which poses a challenge to long‐term remission.8‐11 Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is thus still considered the ultimate cure for ALL.12‐14 An essential component of allo‐HSCT is the conditioning regimen, which eradicates the cancer cells and provides stem cell niches in the host bone marrow for the new stem cells. Total body irradiation (TBI) is effective against a variety of malignancies without sanctuary sites, such as the central nervous system, and therefore has been the gold standard conditioning regimen.15,16 Complications of TBI include delayed growth and development in children, interstitial pneumonitis and secondary malignancies.15,17,18 TBI has been widely used in the Western world, while reports of its treatment effectiveness in the Chinese population have been rare. Busulfan (Bu) is an alkylating agent that has a potent effect on leukemia and can also serve as a common conditioning agent along with cyclophosphamide.19,20 Nevertheless, the absorption of Bu in the gastrointestinal tract is quite variable among patients.21,22 Some adverse effects, such as sinusoidal obstruction syndrome (SOS; previously known as veno‐occlusive disease [VOD]), restrict patients' and physicians' choices.23‐25 Previous studies have confirmed the safety and efficacy of targeted‐dose Bu, which reduces patients' risks of SOS, treatment‐related mortality (TRM), and relapse.26‐29 The comparison of the treatment efficacies of TBI/cyclophosphamide (Cy) and busulfan (Bu)/Cy as conditioning regimens, both of which are major options for conditioning regimens for ALL, has long been unclear. Patients receiving different regimens might have moderately different outcomes from the perspective of relapse‐free survival (RFS), TRM, and the cumulative incidence of acute or chronic graft‐versus‐host disease (GvHD). However, no single regimen has clear benefits in terms of overall survival (OS).30‐34 This real‐world observational study was performed to compare the outcomes of Chinese ALL patients receiving a Bu‐based or a TBI‐based regimen, and pre‐treatment parameters and therapy modalities were analyzed for risk stratification and survival analyses.METHODSPatientsWe enrolled 224 ALL patients who received their 1st allo‐HSCT at National Taiwan University Hospital (NTUH) from January 1997 to December 2016. We retrospectively reviewed the medical records and obtained the clinical information. This study, along with the policy to waive informed consent, was approved by the Research Ethics Committee of NTUH (Project number: 201810058RIND).Conditioning regimen before allogeneic hematopoietic stem cell transplantationIn this study, the conditioning regimens were categorized as follows: myeloablative TBI (MA‐TBI); MA‐Bu; and reduced intensity stem cell transplantation Bu (RIST‐Bu). The MA‐TBI protocol was administered as follows: TBI 150 centi‐gray (cGy) twice daily from Day −7 to Day −4 (total dose 1200 cGy) and cyclophosphamide IV 60 mg/kg/day on Day −3 and Day −2. The MA‐Bu regimen was administered as follows: busulfan IV 3.2 mg/kg/day or oral 4 mg/kg/day from Day −8 through Day −5 consecutively and cyclophosphamide IV 60 mg/kg/day on Day −3 and Day −2. RIST‐Bu protocol was administered as follows: fludarabine 30 mg/m2/day from Day −8 to Day −4 consecutively, busulfan IV 3.2 mg/kg/day or oral 4 mg/kg/day on Day −5 and Day −4, and cyclophosphamide IV 60 mg/kg/day on Day −2. Notably, the IV form of busulfan was introduced to our institute in 2009. The criteria used to use MA‐TBI, MA‐Bu or RIST‐Bu conditioning regimens are based on the patients' age, comorbidities, presence of high‐risk features (e.g., hyperleukocytosis, poor‐risk karyotypes, extramedullary disease, and disease status before transplant), and patients' willing after explanation of risks of adverse events of each regimen. The worth of mention is that the equipment for TBI had been in malfunction from August 2013 to August 2017; thus, patients who underwent HSCT during this period all received busulfan‐based conditioning regimens.Prophylaxis of graft‐versus‐host diseaseWe used cyclosporin and methotrexate for GvHD prophylaxis in patients receiving MA‐TBI and MA‐Bu conditioning; cyclosporin and mycophenolate mofetil were used in the RIST‐Bu conditioning group. Rabbit anti‐thymoglobulin (ATG) was given to the patients who received Hematopoietic stem cells from the human leukocyte antigen (HLA)‐mismatched donors or the unrelated donor. A total dose of 5 mg/kg of body weight was given to the patients who received stem cells from the matched unrelated donors, and a total dose of 6 mg/kg of body weight was given to the patients who received stem cells from the haploidentical donors or mismatched unrelated donors. The ATG was divided into 2–3 days and given before the infusion of Hematopoietic stem cells.DefinitionsThe transplant data, including demographics, underlying disease characteristics, transplantation procedures, and post‐HSCT complications, were collected according to the European Society for Blood and Marrow Transplantation Registry data collection forms and manuals (https://www.ebmt.org/registry/data-collection). The first infusion day of hematopoietic stem cells was defined as Day 0. OS was defined as the duration from Day 0 to the date of last follow‐up or death. RFS was the duration from Day 0 to the date of relapse, last follow‐up or death, whichever occurred first. TRM was defined as a death resulted from any cause other than relapse.Statistical analysisWe used the Mann–Whitney U test to compare the medians of continuous variables with normal distributions. Fisher's exact test or the χ2 test were performed to examine the differences among discrete variables, including sex, responses, and recurrence in different treatment subgroups. Kaplan–Meier method was used to plot the survival curves and the log‐rank test was used to calculate the statistical significance. The Cox proportional hazards model was used in univariate and multivariable regression analyses. A p values less than .05 were considered statistically significant. All statistical analyses were performed with IBM SPSS Statistics 23 for Windows.RESULTSPatient characteristicsThe patient characteristics are shown in Table 1. The median age at allo‐HSCT was 33 years, and 119 males and 105 females were included in our study. We stratified the adult ALL patients into three groups according to the types of conditioning chemotherapies (MA‐TBI, MA‐Bu, and RIST Bu; Table 1). Patients in MA‐TBI and MA‐Bu groups were younger than in those in the RIST‐Bu group (p < .001) and more male patients received myeloablative chemotherapy (MA‐TBI or MA‐Bu) rather than a reduced‐intensity regimen. There was no difference between the three groups in the distribution of WBC at diagnosis, presence of extramedullary disease, cytogenetic changes, disease status before allo‐HSCT, source of stem cell, and the dose of stem cells infusion. Although the majority of the patients received stem cells from the peripheral blood stem cell harvest, some patients in the MA‐TBI and MA‐Bu groups also received stem cells from bone marrow harvest (p < .001; Table 1). Moreover, in the MA‐Bu group, 46 (48.4%) patients received oral busulfan whereas only two (4.3%) patients in the RIST‐Bu group received oral busulfan (p < .001; Table 1).1TABLEClinical and laboratory features of patients receiving different conditioning regimensClinical characteristicsTotal(n = 224)MA‐TBI(n = 83)MA‐Bu(n = 95)RIST‐Bu(n = 46)p valueAgea33.3 (15.5–65.5)28.1 (16.4–56.3)30.9 (15.5–52.3)51.8 (20.4–65.5)<.001Sex (n, %).001Male119 (53.1%)56 (67.5%)48 (50.5%)15 (32.6%)Female105 (46.9%)27 (32.5%)47 (49.5%)31 (67.4%)Initial WBC (×103/μl)a23.6 (0.7–858.0)30.0 (0.7–530.7)22.6 (0.8–791.7)15.5 (1.8–858.0).237Extramedullary disease (n, %)45 (20.1%)18 (21.7%)19 (20%)8 (17.4%).843Immunophenotype (n, %).461B cell137 (67.8%)52 (70.3%)53 (63.1%)32 (72.7%)Pro‐B188 (44.5%)6 (33.3%)4 (22.2%)Early Pre‐B4014 (35.0%)15 (37.5%)11 (27.5%)Pre‐B3413 (38.2%)13 (38.2%)8 (23.6%)Mature B124 (33.3%)5 (41.7%)3 (25%)Unclassified B3313 (39.4%)14 (42.4%)6 (18.2)T cell65 (32.2%)22 (29.7%)31 (36.9%)12 (27.3%)Unknown229112Cytogenetics (n, %)t(9;22)41 (22.7%)13 (19.1%)16 (22.2%)12 (29.3%).468Standard risk101 (55.8%)38 (55.9%)41 (56.9%)22 (53.7%).944Poor risk, without t(9;22)39 (21.5%)17 (25.0%)15 (20.8%)7 (17.1%).611Unknown4215225Pre‐HSCT disease status (n, %).626Relapse/refractory54 (24.1%)23 (27.7%)21 (22.1%)10 (21.7%)Complete remission170 (75.9%)60 (72.3%)74 (77.9%)36 (78.3%)CR1114 (50.9%)36 (60%)55 (74.3%)23 (63.9%)Late CR56 (25.0)24 (40%)19 (25.7%)13 (36.1%)Cell source (n, %)<.001BM50 (22.3%)28 (33.7%)22 (23.2%)0 (0%)PBSC159 (71.0%)54 (65.1%)66 (69.5%)39 (84.8%)BM + PBSC15 (6.7%)1 (1.2%)7 (7.4%)7 (15.2%)Donor (n, %).275Sibling matched123 (56.2%)48 (60%)53 (57%)22 (47.8%)Relative, haplotype17 (7.8%)4 (5%)6 (6.5%)7 (15.2%)Unrelated donor79 (36%)28 (35%)34 (36.5%)17 (37.0%)Unknown5Busulfan (n, %)<.001Oral46 (48.4%)2 (4.3%)Intravenous49 (51.6%)44 (95.7%)CD34+ cells (×106/kg)a4.81 (0.7–12.6)4.75 (1.1–12.3)4.79 (0.7–12.6)4.69 (1.5–10.73).873Abbreviations: BM, bone marrow; CR, complete remission; MA, myeloablative; PBSC, peripheral blood stem cell; RIST, reduced‐intensity stem cell transplantation; TBI, total body irradiation.aMedian (range), at diagnosis.Survival analysisWith a median follow‐up duration of 19.2 (range: 0.4–294.4) months, the RFS and OS of all patients were 11.7 months and 26.7 months, respectively. At the end of follow up, 32 (39%) patients in the MA‐TBI group, 48 (51%) patients in the MA‐Bu group, and 22 (48%) patients in the RIST‐Bu group remained alive. The relapse of disease was the main cause of death, accounting for more than 50% in all groups. In the MA‐Bu group, no patient died of GVHD while 13 (28%) patients succumbed to infection. In the subgroup analysis, the MA‐Bu group had significantly longer RFS than the TBI‐based group (median, 24.1 vs. 6.7 months, p = .044, Figure 1A). However, there was no significant difference in OS among patients receiving different conditioning regimens (median, MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276, Figure 1B). By stratifying patients receiving busulfan‐based regimen on whether they were taking the oral or IV form, we found no differences in RFS and OS (median RFS, 8.5 vs. 26.3 months, p = .436; and median OS, 17 vs. 39.4 months, p = .236, respectively, Figure S1A,B). Besides, since the recruitment of patients spanned a long period, we further analyzed patients receiving busulfan orally or intravenously transplanted in different eras to exam possible chronologic effect. Patients were separated by the median calendar year of transplantation, in 2004 for patients receiving busulfan orally and in 2014 for patients receiving busulfan intravenously, respectively. The survival of patients receiving transplantation more contemporarily did not overwhelm their counterparts (Figure S2), notwithstanding that this should be interpreted cautiously given that there was discrepancy of post‐transplant follow‐up period and the bi‐modal distribution.1FIGUREKaplan–Meier plots of survival and cumulative incidence of graft‐versus‐host disease stratified by different conditioning regimens. (A) RFS, (B) OS, and (C) TRM of the 224 ALL patients receiving different conditioning regimens; cumulative incidence of (D) grade 3–4 acute GvHD at day+100, (E) all grade chronic GvHD, and (F) grade 2–4 chronic GvHD of the 224 ALL patients receiving different conditioning regimensTreatment‐related mortalityThere was no difference in cumulative TRM (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 17% vs. 21.7% vs. 10.9%, p = .308, Figure 1C) among all regimen groups. However, patients who took oral busulfan had a higher risk of TRM than those who received IV busulfan (25% vs. 9.8%, p = .016, Figure S1C).Graft‐versus‐host diseaseThe cumulative incidences of grade 3–4 acute GvHD at day +100 were not significantly different among the three groups (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 15.8% vs. 10.8% vs. 15.2%, p = .445, Figure 1D), whereas the cumulative incidence of all‐grade chronic GvHD in the RIST‐Bu group was significantly higher than those in the other two groups (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 41.1% vs. 27.7% vs. 56.5%, p = .001, Figure 1E). The majority (80.8%) of chronic GvHD in the RIST and Bu‐based groups were grade 2–4, and the incidence of grade 2–4 chronic GvHD was consistently higher than those in the other two groups (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 24.2% vs. 18.1% vs. 45.7%, p < .001, Figure 1F). We next performed subgroup analysis to dissect the potential impact of different prophylactic measures. Interestingly, in MA‐Bu and RIST‐Bu groups, patients receiving ATG prophylaxis (and HSCs from nonsibling‐matched donors) had a higher incidence of grade 3–4 acute GvHD at day +100 than their counter partners (Figure S3A,B, p = .073 and p = .005, respectively) while there was no such difference in the MA‐TBI group (Figure S3C, p = .802). On the other hand, among patients receiving identical prophylactic regimens, there was no difference between MA‐Bu and MA‐TBI groups regarding the incidence of grade 3–4 acute GvHD, grade 2–4, and all‐grade chronic GvHD (Figure S4A–F).Extramedullary diseaseIn this cohort, patients with extramedullary disease at diagnosis did not have significantly shorter OS than those without (median, with extramedullary disease vs. without, 28.1 vs. 25.8 months, p = .898, Figure 2A). This might imply that allo‐HSCT can overcome the expected poor prognosis of extramedullary disease. The MA‐Bu group outperformed the other two regimens in regard to RFS (median, MA‐Bu vs. RIST‐Bu, 39.4 vs. 3.8 months, p = .018; MA‐Bu vs. MA‐TBI, 39.4 vs. 5.2 months, p = .034, Figure 2B) and OS (median, MA‐Bu vs. RIST‐Bu, 109.9 vs. 51.2 months, p = .091; MA‐Bu vs. MA‐TBI, 109.9 vs. 60.4 months, p = .078, Figure 2C).2FIGUREKaplan–Meier plots in extramedullary disease subgroup analysis. (A) OS of the 224 ALL patients stratified by extramedullary disease. (B) RFS and (C) OS of the 45 ALL patients with extramedullary disease receiving different conditioning regimensMultivariable analysisFor multivariable analysis, we included parameters with a p value <.15 in univariate Cox regression analysis (Table 2) and biologically relevant parameters as covariates, including age, WBC count at diagnosis, karyotype, presence of extramedullary disease, disease status before HSCT, and the conditioning regimen. In multivariable analysis, disease status before HSCT and MA‐Bu conditioning were factors that affected RFS, while disease status before HSCT was the only risk factor for OS. In the subgroup analysis of patients with extramedullary diseases, MA‐Bu conditioning was found to have protective effects compared to TBI‐based conditioning, while status before transplant remained an independent risk factor for OS (Table 3).2TABLEUnivariate and multivariable analyses of RFS and OS of the 224 patients with acute lymphoblastic leukemiaVariableUnivariateMultivariateHR95% CIp valueHR95% CIp valueRFSAge (≥ vs. < 40 y/o)0.930.64–1.36.7101.210.68–2.14.513Initial WBC (≥10 vs. < 10K/μl)1.130.76–1.68.5481.290.78–2.15.314Cytogenetics (Standard vs. High riska)0.940.64–1.38.7501.100.70–1.72.678Extramedullary (Yes vs. No)1.160.78–1.74.4601.230.74–2.05.420Immunophenotype (T vs. B)1.180.82–1.71.368Pre‐HSCT disease status (vs. CR1)Late CR1.611.07–2.42.0231.671.01–2.75.047Relapse/refractory2.861.91–4.27<.0012.611.51–4.49.001Cell source (PBSC vs. BM/BM + PBSC)1.150.79–1.67.462Donor (Unrelated donor vs. Sibling)1.010.90–1.14.816Conditioning (vs. MA, TBI‐based)MA‐Bu basedf0.680.47–0.99.0460.610.38–0.97.035RIST‐Bu basedf0.790.51–1.24.3040.650.34–1.23.186Busulfan (intravenous vs. oral)0.840.53–1.32.437CD34+ cells (×106)0.990.91–1.08.876OSAge (≥ vs. < 40 y/o)0.980.66–1.46.9271.410.77–2.56.263Initial WBC(≥10 vs. < 10K/μl)0.990.66–1.49.9791.210.71–2.05.490Cytogenetics (Standard vs. High riska)0.910.61–1.37.6651.090.68–1.75.719Extramedullary (Yes vs. No)1.460.84–2.55.1841.080.63–1.84.792Immunophenotype (T vs. B)1.130.77–1.67.529Pre‐HSCT disease statusLate CR vs. CR11.771.16–2.72.0091.831.08–3.10.024Relapse/refractory vs. CR12.851.87–4.34<.0012.771.56–4.93.001Cell source (PBSC vs. BM/BM + PBSC)1.060.72–1.55.782Donor (Unrelated donor vs. Sibling)1.050.92–1.18.491ConditioningMA‐Bu based vs. MA, TBI‐based0.730.49–1.09.1200.650.39–1.06.083RIST‐Bu based vs. MA, TBI‐based0.790.49–1.27.3310.620.31–1.24.176Busulfan (intravenous vs. oral)0.750.47–1.21.238CD34+ cells (×106)0.990.92–1.09.970Note: Statistically significant if p < .05.Abbreviations: BM, bone marrow; CI, confidence interval; CR, complete remission; HSCT, hematopoietic stem cell transplantation; HR, hazard ratios; MA, myeloablative; PBSC, peripheral blood stem cell; RIST, reduced‐intensity stem cell transplantation; TBI, total body irradiation.aHigh risk: t(9;22)/BCR‐ABL1, t(v;11q23)/KMT2A (MLL) rearrangements, or hypodiploidy (<44 chromosomes).3TABLEMultivariable analysis for RFS and OS of the 45 ALL patients with extramedullary diseasesVariableRFSOSHR95%CIpHR95%CIpAge (≥ vs. < 40 y/o)0.740.19–2.82.6630.660.17–2.55.547Initial WBC (≥10 vs. < 10K/μl)0.510.14–1.90.3120.540.14–2.06.365Cytogenetics (Standard vs. High riska)3.931.37–11.23.0112.490.80–7.73.115Pre‐HSCT disease statusLate CR vs. CR12.070.64–6.72.2264.321.31–14.27.016Relapse/refractory vs. CR112.271.90–79.12.00820.883.04–143.3.002ConditioningMA‐Bu based vs. MA, TBI‐based0.370.12–1.16.0880.560.16–1.98.369RIST‐Bu based vs. MA, TBI‐based0.930.24–3.62.9191.630.42–6.28.478Note: Statistically significant if p < .05.Abbreviations: CI, confidence interval; CR, complete remission; HSCT, hematopoietic stem cell transplantation; HR, hazard ratios; MA, myeloablative; RIST, reduced‐intensity stem cell transplantation; TBI, total body irradiation.aHigh risk: t(9;22)/BCR‐ABL1, t(v;11q23)/KMT2A (MLL) rearrangements, or hypodiploidy (<44 chromosomes).DISCUSSIONThis is the first study comparing transplant outcomes in Chinese ALL patients receiving TBI‐ and Bu‐based conditioning therapy to the extent of our knowledge. A higher proportion of patients (63.4%) in our study received Bu‐based conditioning compared with patients in Western cohorts (4.2%–52.6%, Table 4).30‐38 Long‐term TBI toxicities, including delayed growth and secondary malignancy, might be the main reason preventing our patients from receiving irradiation therapy. Additionally, we explored patient outcomes based on the form of busulfan administered (IV or oral form). Patients receiving IV busulfan had comparable RFS and OS to the oral group and a lower TRM rate, which could result from more stable pharmacokinetics; however, drug level monitoring was not routinely performed in our institute. This cohort could provide some directive for the real‐world practice where TBI or therapeutic drug monitoring of Bu are not available.4TABLESelected studies comparing the outcomes of patients with acute lymphoblastic leukemia receiving busulfan‐based or total body irradiation‐based conditioning regimensCohortPatient numberOSRFS/DFS/PFSNRM/TRMRIaGVHD (II‐IV)cGVHDSummary/notesMitsuhashi, 2016aTBI = 202859%RFS 55.0%NRM 20.8%22.8%40.4%37.6% at 2 yrTBI over PO BU for OSPO BU = 6048.2%RFS 44.6%NRM 26.1%28.5%36.8%31.5% at 2 yrIV BU = 4237.4%RFS 34.2%NRM 27.0%32.6%33.3%40.1% at 2 yrKebriaei, 2018aTBI = 81949%DFS 45%TRM 27%29%40.0%55% at 3 yrSimilar OS and DFSBU = 29946%DFS 37%TRM 22%42%47.0%49% at 3 yrCandoni, 2019bTBI = 221HR: 0.86, 95% CI:PFS HR: 0.72, 95% CI: 0.55–0.94NRM HR: 1.16, 95% CI:HR: 0.56, 95% CI:Not reportedHR: 1.45, 95% CI: 0.93–2.26Favor TBI for PFS and RICT = 2200.65–1.140.78–1.720.39–0.79Eroglu, 2013cTBI = 4553.2%EFS 27.2%TRM 9.0%51%22.2%31.1%Favor TBI for OS, EFS and RIBU = 5030.9%EFS 18.8%TRM 16.0%76%26.0%24.0%Granados, 2000c, dTBI = 114Not reportedEFS 43%TRM 17% at 18 mo47%30.3%7.9% extensiveFavor TBI for EFS and RIBU = 42EFS 22%TRM 22% at 18 mo71%23.8%0% extensiveSakellari, 2018aTBI = 8446.7%; 57.6%eDFS 46.1%TRM 27.7%Not reportedNot reported48%eFavor TBI in patients younger than 40 yearsBU = 6735.8%; 39.7%eDFS 35.4%TRM 24.1%27.4%Giebel, 2017TBI = 50469.5%LFS 61.6%NRM 17.3%21.1%Not reportedNot reportedFavor TBI for LFS and RICT = 5864.0%LFS 49.7%NRM 17.6%32.7%Nishiwaki, 2016f, gTBI = 310HR 1.3, 95% CI: 0.65–2.57LFS HR: 1.42, 95% CI: 0.79–2.57NRM HR 1.51, 95% CI: 0.64–HR 1.18, 95% CI:Not reportedNot reportedSimilar outcomes in patients under age of 55CT = 143.520.51–2.72Abdelaty, 2020TBI = 7842% at 2 yrDFS 80% at 2 yrNRM 38.5%11.5%33.3%h30.8%Favor TBI for EFS and RI; no significant difference in OS, DFS, and NRMBU = 4144% at 2 yrDFS 55% at 2 yrNRM 48.8%26.8%36.6%17.1%NTUH (this study)TBI = 8328.2 moRFS 6.7 moTRM 21.7%44.6%10.8%h27.7%Favor MA, BU‐based group for RFSMA, BU = 9539.4 moRFS 24.1 moTRM 17.0%33.7%15.8%41.1%RIC, BU = 4613.1 moRFS 18.3 moTRM 10.9%47.8%15.2%56.5%Abbreviations: BU: busulfan‐based regimen; CI, confidence interval; CT: chemotherapy; IV: intravenous form; PO: oral form; RI, relapse incidence; TBI: total body irradiation.aFollowed up at 5 years post‐transplant.bTBI‐based vs. Bu‐based, Bu as reference.cFollow‐up at 3 years post‐transplant.dNinety patients received allogenic transplant, and 66 patients received autologous transplant.eIn patients younger than 40 years.fBu‐based vs. TBI‐based, TBI as reference.gSubanalyses of 324 patients under the age of 55 within the whole cohort treated with a myeloablative conditioning regimen.hAll grades included.While there is currently no firm consensus on the best conditioning therapy for allo‐SCT in adult patients with ALL, the results from previous studies provided evidence in modest favor of TBI (Table 4). Kebriaei et al. analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR), revealing that patients using Bu had lower TRM (Bu 19% vs. TBI 25%, p = .04) but a higher relapse rate (Bu 37% vs. TBI 28%, p = .007) than patients using TBI.33 Compared with TBI‐based conditioning, Bu‐based conditioning led to similar disease‐free survival (DFS) and OS following allo‐SCT for ALL. Meanwhile, Mitsuhashi and colleagues conducted an analysis to compare TBI/Cy, oral Bu/Cy, and IV Bu/Cy in a cohort of 2130 Japanese patients, most of whom received TBI/Cy. The oral Bu/Cy group had a shorter OS than the TBI/Cy group, while the IV Bu/Cy group had comparable OS to the TBI/Cy group.34 No between‐group differences were seen in the incidence of non‐relapse mortality (NRM), relapse, acute GvHD, or chronic GvHD.Herein, we present our transplant experience with ALL patients in Taiwan. The survival outcome of our cohort is comparable to those in other recently published studies (Table 4). The TRM of our patients seemed to be acceptable, yet the incidence of relapse (33.7%–47.8%) remained alarming. While the studies by Kebriaei et al. and Abdelaty et al. revealed a markedly increased relapse incidence in the busulfan group,33,38 the relapse rates among three groups in our study were not that different. Interestingly, in a recent study, Speziali and colleagues analyzed outcomes of 146 ALL patients receiving TBI/Cy (1200 cGy) or fludarabine, busulfan, and low‐dose TBI (400 cGy) as conditioning regimens. The Flu/Bu/TBI group had a significantly lower incidence of relapse than the TBI/Cy group (18.5% vs. 31.5% at 2‐year, p = .05), while there was no difference in OS, PFS, and NRM, implicating an alternative combination of low‐dose TBI and Bu.39Regarding survival, our patients in the MA‐Bu group had a better RFS than those in the MA‐TBI group. Nevertheless, the survival benefit of RFS conferred by Bu was not extended to long‐term OS. One explanation might be higher mortality rates resulted from late relapse and infection (Table 5). The overall relapse incidence was higher in the TBI group (44.6%) than in the MA‐Bu group (33.7%), but the MA‐Bu group caught up in terms of relapse‐related mortality. The MA‐Bu group had a higher rate (1.76‐fold) of death due to infection. Improvements in the management of disease relapse and infection after transplant might particularly help improve patient survival. In patients with extramedullary diseases, the MA‐Bu group consistently had longer RFS than the other two groups. There was also a trend towards longer OS, lower relapse incidence and TRM in the MA‐Bu group. This could be contrary to our impression of the anti‐leukemic effect of TBI on the sanctuary sites. As intrathecal chemotherapy was routinely performed for adult ALL patients in our institute, this could remunerate the suboptimal penetration of busulfan into the central nervous system. Another possible confounding factor is the timing of the transplant. More patients with extramedullary disease in the MA‐Bu group received allo‐SCT in their first complete remission (CR, MA‐Bu vs. MA‐TBI: 94.7% vs 66.7%, p = .042) rather than in latent CR. Excluding patients in the RIST‐Bu group and those not in remission, the difference in RFS and OS would become trivial (p = .97 and p = .841, respectively). Furthermore, the rate of TRM was higher in the MA‐TBI group than in the MA‐Bu group (22.2% vs 3.7%). Lastly, the dose of TBI (12 Gy) is inferior to higher doses (≥13 Gy), which was promoted by Marks et al.16 For patients receiving allo‐SCT, not in first CR, the risks of relapse and mortality might be diminished with TBI doses >13 Gy.5TABLECauses of death by treatment groupClinical CharacteristicsMA‐TBIDeath (n = 51)MA‐BuDeath (n = 47)RIST‐BuDeath (n = 24)p valueRelapse29 (56.9%)28 (59.6%)17 (70.8%).504Graft failure01 (2.1%)0.447GVHD6 (11.8%)04 (16.7%).025*Infection8 (15.7%)13 (27.7%)1 (4.2%).044*Interstitial pneumonitis or ARDS3 (5.9%)1 (2.1%)0.350Secondary malignancy1 (2.1%)2 (4.3%)1 (4.2).786Other2 (3.9%)00.243Unknown2 (3.9%)2 (4.3%)1 (4.2%).996Note: *Indicating statisticallysignificant with P < 0.05.Abbreviations: ARDS, acute respiratory distress syndrome; GVHD, graft‐versus‐host disease.There are several limitations to our study. First, its retrospective nature imposed diverse sources of biases and temporal confounding factors that were difficult to assess. Although prospective and randomized trials for allogenic transplantation in ALL are challenging in clinical practice due to the complexity of the disease nature and treatment course, they are warranted and will be appreciated. Second, targeted drug monitoring was not routinely implemented in our institute. Regardless of the lack of pharmacokinetic data in patients receiving oral Bu, this subgroup had a higher TRM than those receiving IV busulfan, which was consistent with previous studies that showed that a more stable Bu pharmacokinetic level with IV dosing and the reductions in toxicities. Moreover, some bias may be recondite since the recruitment of patients spanned a long period. Although we confirmed that the survival of patients receiving transplantation more contemporarily did not overwhelm their counterparts, potential underlying confounding factors could not be all excluded. Despite these limitations, multivariable analysis in our study confirmed that there were no significant differences between the Bu‐based and TBI‐based groups in terms of OS, and MA‐Bu conditioning might improve RFS in eligible patients. These results imply that the Bu‐based regimen might improve patient outcomes in adult patients with ALL by reducing treatment toxicity and mortality. In the meantime, strategies for the prevention and salvage of disease relapse, which accounted for more than 50% of the deaths, should also be further investigated and improved.In summary, this study provided a risk stratification and survival analysis of ALL patients undergoing allo‐SCT and demonstrated that a Bu‐based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Larger‐scale, prospective and randomized controlled trials are challenging but warranted to compare and validate the long‐term outcome of patients receiving Bu‐based and TBI‐based conditioning before transplant.ACKNOWLEDGMENTSWe would like to acknowledge the service provided by Department of Laboratory Medicine, and Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital; and Tai‐Cheng Cell Therapy Centre, National Taiwan University, Taipei, Taiwan.This study was supported by the YongLin Healthcare Foundation, which is a non‐profit organization, and the Ministry of Science and Technology (MOST) of Taiwan (grant number MOST 108‐2823‐8‐002‐003).CONFLICT OF INTERESTThe authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this study.AUTHOR CONTRIBUTIONSYu‐Hung Wang: Formal analysis; visualization; writing‐original draft. Feng‐Ming Tien: Data curation; resources. ChengHong Tsai: Data curation; resources. Huai‐Hsuan Huang: Data curation; resources. Jia‐Hau Liu: Data curation; resources. Xiu‐Wen Liao: Data curation; project administration; resources. Jih‐Luh Tang: Data curation; project administration; resources. Ming Yao: Data curation; project administration; resources. Bor‐Sheng Ko: Conceptualization; funding acquisition; investigation; resources; supervision; writing‐original draft.ETHICS STATEMENTThis study, along with the policy to waive informed consent, was approved by the Research Ethics Committee of NTUH (Project number: 201810058RIND). This article does not use any samples from human or animal subjects.DATA AVAILABILITY STATEMENTThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.REFERENCESKantarjian HM, DeAngelo DJ, Stelljes M, et al. 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CD19‐targeted CAR T‐cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016;127(26):3312‐3320.Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19‐negative myeloid phenotype allows immune escape of MLL‐rearranged B‐ALL from CD19 CAR‐T‐cell therapy. Blood. 2016;127(20):2406‐2410.Brown CE, Mackall CL. CAR T cell therapy: inroads to response and resistance. Nat Rev Immunol. 2019;19(2):73‐74.Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. 2019;16(6):372‐385.Orlando EJ, Han X, Tribouley C, et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med. 2018;24(10):1504‐1506.Chiaretti S, Foa R. Management of adult Ph‐positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015:406‐413.Giebel S, Labopin M, Potter M, et al. Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia‐positive acute lymphoblastic leukaemia in first complete molecular remission: an analysis by the acute leukemia working party of the EBMT. Eur J Cancer. 2018;96:73‐81.Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre‐imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009;113(19):4489‐4496.Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard‐risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111(4):1827‐1833.Marks DI, Forman SJ, Blume KG, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006;12(4):438‐453.Sutton L, Kuentz M, Cordonnier C, et al. Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia in first complete remission: factors predictive of transplant‐related mortality and influence of total body irradiation modalities. Bone Marrow Transplant. 1993;12(6):583‐589.Oliansky DM, Camitta B, Gaynon P, et al. Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence‐based review. Biol Blood Marrow Transplant. 2012;18(4):505‐522.Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983;309(22):1347‐1353.Ciurea SO, Andersson BS. Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15(5):523‐536.Schuler US, Ehrsam M, Schneider A, Schmidt H, Deeg J, Ehninger G. Pharmacokinetics of intravenous busulfan and evaluation of the bioavailability of the oral formulation in conditioning for haematopoietic stem cell transplantation. Bone Marrow Transplant. 1998;22(3):241‐244.Andersson BS, Madden T, Tran HT, et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant. 2000;6(5a):548‐554.Lee JL, Gooley T, Bensinger W, Schiffman K, McDonald GB. Veno‐occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome. Biol Blood Marrow Transplant. 1999;5(5):306‐315.Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno‐occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157‐168.Ho VT, Revta C, Richardson PG. Hepatic veno‐occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. Bone Marrow Transplant. 2008;41(3):229‐237.Kashyap A, Wingard J, Cagnoni P, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD‐related mortality, and overall 100‐day mortality. Biol Blood Marrow Transplant. 2002;8(9):493‐500.Russell JA, Tran HT, Quinlan D, et al. Once‐daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8(9):468‐476.Geddes M, Kangarloo SB, Naveed F, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14(2):220‐228.Andersson BS, Thall PF, Madden T, et al. Busulfan systemic exposure relative to regimen‐related toxicity and acute graft‐versus‐host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8(9):477‐485.Nishiwaki S, Imai K, Mizuta S, et al. Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT. Bone Marrow Transplant. 2016;51(1):43‐50.Giebel S, Labopin M, Socie G, et al. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the acute leukemia working Party of the European Society for blood and marrow transplantation. Haematologica. 2017;102(1):139‐149.Candoni A, Rambaldi A, Fanin R, et al. Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia in the era of tyrosine kinase inhibitors: a registry‐based study of the Italian blood and marrow transplantation society (GITMO). Biol Blood Marrow Transplant. 2019;25(12):2388‐2397.Kebriaei P, Anasetti C, Zhang MJ, et al. Intravenous busulfan compared with total body irradiation pretransplant conditioning for adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018;24(4):726‐733.Mitsuhashi K, Kako S, Shigematsu A, et al. Comparison of cyclophosphamide combined with total body irradiation, oral busulfan, or intravenous busulfan for allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2016;22(12):2194‐2200.Eroglu C, Pala C, Kaynar L, et al. Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant. Leuk Lymphoma. 2013;54(11):2474‐2479.Granados E, de La Camara R, Madero L, et al. 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Leuk Lymphoma. 2019;60(3):639‐648. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Reports Wiley

Busulfan‐containing conditioning regimens in allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia: A Taiwan observational study

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Abstract

INTRODUCTIONAdvances in the treatment of adult acute lymphoblastic leukemia (ALL) by small molecular agents and chimeric antigen receptor T‐cell therapy have greatly improved patient survival in the last decade.1‐7 Meanwhile, recurrence is common in the post‐therapy course, which poses a challenge to long‐term remission.8‐11 Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is thus still considered the ultimate cure for ALL.12‐14 An essential component of allo‐HSCT is the conditioning regimen, which eradicates the cancer cells and provides stem cell niches in the host bone marrow for the new stem cells. Total body irradiation (TBI) is effective against a variety of malignancies without sanctuary sites, such as the central nervous system, and therefore has been the gold standard conditioning regimen.15,16 Complications of TBI include delayed growth and development in children, interstitial pneumonitis and secondary malignancies.15,17,18 TBI has been widely used in the Western world, while reports of its treatment effectiveness in the Chinese population have been rare. Busulfan (Bu) is an alkylating agent that has a potent effect on leukemia and can also serve as a common conditioning agent along with cyclophosphamide.19,20 Nevertheless, the absorption of Bu in the gastrointestinal tract is quite variable among patients.21,22 Some adverse effects, such as sinusoidal obstruction syndrome (SOS; previously known as veno‐occlusive disease [VOD]), restrict patients' and physicians' choices.23‐25 Previous studies have confirmed the safety and efficacy of targeted‐dose Bu, which reduces patients' risks of SOS, treatment‐related mortality (TRM), and relapse.26‐29 The comparison of the treatment efficacies of TBI/cyclophosphamide (Cy) and busulfan (Bu)/Cy as conditioning regimens, both of which are major options for conditioning regimens for ALL, has long been unclear. Patients receiving different regimens might have moderately different outcomes from the perspective of relapse‐free survival (RFS), TRM, and the cumulative incidence of acute or chronic graft‐versus‐host disease (GvHD). However, no single regimen has clear benefits in terms of overall survival (OS).30‐34 This real‐world observational study was performed to compare the outcomes of Chinese ALL patients receiving a Bu‐based or a TBI‐based regimen, and pre‐treatment parameters and therapy modalities were analyzed for risk stratification and survival analyses.METHODSPatientsWe enrolled 224 ALL patients who received their 1st allo‐HSCT at National Taiwan University Hospital (NTUH) from January 1997 to December 2016. We retrospectively reviewed the medical records and obtained the clinical information. This study, along with the policy to waive informed consent, was approved by the Research Ethics Committee of NTUH (Project number: 201810058RIND).Conditioning regimen before allogeneic hematopoietic stem cell transplantationIn this study, the conditioning regimens were categorized as follows: myeloablative TBI (MA‐TBI); MA‐Bu; and reduced intensity stem cell transplantation Bu (RIST‐Bu). The MA‐TBI protocol was administered as follows: TBI 150 centi‐gray (cGy) twice daily from Day −7 to Day −4 (total dose 1200 cGy) and cyclophosphamide IV 60 mg/kg/day on Day −3 and Day −2. The MA‐Bu regimen was administered as follows: busulfan IV 3.2 mg/kg/day or oral 4 mg/kg/day from Day −8 through Day −5 consecutively and cyclophosphamide IV 60 mg/kg/day on Day −3 and Day −2. RIST‐Bu protocol was administered as follows: fludarabine 30 mg/m2/day from Day −8 to Day −4 consecutively, busulfan IV 3.2 mg/kg/day or oral 4 mg/kg/day on Day −5 and Day −4, and cyclophosphamide IV 60 mg/kg/day on Day −2. Notably, the IV form of busulfan was introduced to our institute in 2009. The criteria used to use MA‐TBI, MA‐Bu or RIST‐Bu conditioning regimens are based on the patients' age, comorbidities, presence of high‐risk features (e.g., hyperleukocytosis, poor‐risk karyotypes, extramedullary disease, and disease status before transplant), and patients' willing after explanation of risks of adverse events of each regimen. The worth of mention is that the equipment for TBI had been in malfunction from August 2013 to August 2017; thus, patients who underwent HSCT during this period all received busulfan‐based conditioning regimens.Prophylaxis of graft‐versus‐host diseaseWe used cyclosporin and methotrexate for GvHD prophylaxis in patients receiving MA‐TBI and MA‐Bu conditioning; cyclosporin and mycophenolate mofetil were used in the RIST‐Bu conditioning group. Rabbit anti‐thymoglobulin (ATG) was given to the patients who received Hematopoietic stem cells from the human leukocyte antigen (HLA)‐mismatched donors or the unrelated donor. A total dose of 5 mg/kg of body weight was given to the patients who received stem cells from the matched unrelated donors, and a total dose of 6 mg/kg of body weight was given to the patients who received stem cells from the haploidentical donors or mismatched unrelated donors. The ATG was divided into 2–3 days and given before the infusion of Hematopoietic stem cells.DefinitionsThe transplant data, including demographics, underlying disease characteristics, transplantation procedures, and post‐HSCT complications, were collected according to the European Society for Blood and Marrow Transplantation Registry data collection forms and manuals (https://www.ebmt.org/registry/data-collection). The first infusion day of hematopoietic stem cells was defined as Day 0. OS was defined as the duration from Day 0 to the date of last follow‐up or death. RFS was the duration from Day 0 to the date of relapse, last follow‐up or death, whichever occurred first. TRM was defined as a death resulted from any cause other than relapse.Statistical analysisWe used the Mann–Whitney U test to compare the medians of continuous variables with normal distributions. Fisher's exact test or the χ2 test were performed to examine the differences among discrete variables, including sex, responses, and recurrence in different treatment subgroups. Kaplan–Meier method was used to plot the survival curves and the log‐rank test was used to calculate the statistical significance. The Cox proportional hazards model was used in univariate and multivariable regression analyses. A p values less than .05 were considered statistically significant. All statistical analyses were performed with IBM SPSS Statistics 23 for Windows.RESULTSPatient characteristicsThe patient characteristics are shown in Table 1. The median age at allo‐HSCT was 33 years, and 119 males and 105 females were included in our study. We stratified the adult ALL patients into three groups according to the types of conditioning chemotherapies (MA‐TBI, MA‐Bu, and RIST Bu; Table 1). Patients in MA‐TBI and MA‐Bu groups were younger than in those in the RIST‐Bu group (p < .001) and more male patients received myeloablative chemotherapy (MA‐TBI or MA‐Bu) rather than a reduced‐intensity regimen. There was no difference between the three groups in the distribution of WBC at diagnosis, presence of extramedullary disease, cytogenetic changes, disease status before allo‐HSCT, source of stem cell, and the dose of stem cells infusion. Although the majority of the patients received stem cells from the peripheral blood stem cell harvest, some patients in the MA‐TBI and MA‐Bu groups also received stem cells from bone marrow harvest (p < .001; Table 1). Moreover, in the MA‐Bu group, 46 (48.4%) patients received oral busulfan whereas only two (4.3%) patients in the RIST‐Bu group received oral busulfan (p < .001; Table 1).1TABLEClinical and laboratory features of patients receiving different conditioning regimensClinical characteristicsTotal(n = 224)MA‐TBI(n = 83)MA‐Bu(n = 95)RIST‐Bu(n = 46)p valueAgea33.3 (15.5–65.5)28.1 (16.4–56.3)30.9 (15.5–52.3)51.8 (20.4–65.5)<.001Sex (n, %).001Male119 (53.1%)56 (67.5%)48 (50.5%)15 (32.6%)Female105 (46.9%)27 (32.5%)47 (49.5%)31 (67.4%)Initial WBC (×103/μl)a23.6 (0.7–858.0)30.0 (0.7–530.7)22.6 (0.8–791.7)15.5 (1.8–858.0).237Extramedullary disease (n, %)45 (20.1%)18 (21.7%)19 (20%)8 (17.4%).843Immunophenotype (n, %).461B cell137 (67.8%)52 (70.3%)53 (63.1%)32 (72.7%)Pro‐B188 (44.5%)6 (33.3%)4 (22.2%)Early Pre‐B4014 (35.0%)15 (37.5%)11 (27.5%)Pre‐B3413 (38.2%)13 (38.2%)8 (23.6%)Mature B124 (33.3%)5 (41.7%)3 (25%)Unclassified B3313 (39.4%)14 (42.4%)6 (18.2)T cell65 (32.2%)22 (29.7%)31 (36.9%)12 (27.3%)Unknown229112Cytogenetics (n, %)t(9;22)41 (22.7%)13 (19.1%)16 (22.2%)12 (29.3%).468Standard risk101 (55.8%)38 (55.9%)41 (56.9%)22 (53.7%).944Poor risk, without t(9;22)39 (21.5%)17 (25.0%)15 (20.8%)7 (17.1%).611Unknown4215225Pre‐HSCT disease status (n, %).626Relapse/refractory54 (24.1%)23 (27.7%)21 (22.1%)10 (21.7%)Complete remission170 (75.9%)60 (72.3%)74 (77.9%)36 (78.3%)CR1114 (50.9%)36 (60%)55 (74.3%)23 (63.9%)Late CR56 (25.0)24 (40%)19 (25.7%)13 (36.1%)Cell source (n, %)<.001BM50 (22.3%)28 (33.7%)22 (23.2%)0 (0%)PBSC159 (71.0%)54 (65.1%)66 (69.5%)39 (84.8%)BM + PBSC15 (6.7%)1 (1.2%)7 (7.4%)7 (15.2%)Donor (n, %).275Sibling matched123 (56.2%)48 (60%)53 (57%)22 (47.8%)Relative, haplotype17 (7.8%)4 (5%)6 (6.5%)7 (15.2%)Unrelated donor79 (36%)28 (35%)34 (36.5%)17 (37.0%)Unknown5Busulfan (n, %)<.001Oral46 (48.4%)2 (4.3%)Intravenous49 (51.6%)44 (95.7%)CD34+ cells (×106/kg)a4.81 (0.7–12.6)4.75 (1.1–12.3)4.79 (0.7–12.6)4.69 (1.5–10.73).873Abbreviations: BM, bone marrow; CR, complete remission; MA, myeloablative; PBSC, peripheral blood stem cell; RIST, reduced‐intensity stem cell transplantation; TBI, total body irradiation.aMedian (range), at diagnosis.Survival analysisWith a median follow‐up duration of 19.2 (range: 0.4–294.4) months, the RFS and OS of all patients were 11.7 months and 26.7 months, respectively. At the end of follow up, 32 (39%) patients in the MA‐TBI group, 48 (51%) patients in the MA‐Bu group, and 22 (48%) patients in the RIST‐Bu group remained alive. The relapse of disease was the main cause of death, accounting for more than 50% in all groups. In the MA‐Bu group, no patient died of GVHD while 13 (28%) patients succumbed to infection. In the subgroup analysis, the MA‐Bu group had significantly longer RFS than the TBI‐based group (median, 24.1 vs. 6.7 months, p = .044, Figure 1A). However, there was no significant difference in OS among patients receiving different conditioning regimens (median, MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276, Figure 1B). By stratifying patients receiving busulfan‐based regimen on whether they were taking the oral or IV form, we found no differences in RFS and OS (median RFS, 8.5 vs. 26.3 months, p = .436; and median OS, 17 vs. 39.4 months, p = .236, respectively, Figure S1A,B). Besides, since the recruitment of patients spanned a long period, we further analyzed patients receiving busulfan orally or intravenously transplanted in different eras to exam possible chronologic effect. Patients were separated by the median calendar year of transplantation, in 2004 for patients receiving busulfan orally and in 2014 for patients receiving busulfan intravenously, respectively. The survival of patients receiving transplantation more contemporarily did not overwhelm their counterparts (Figure S2), notwithstanding that this should be interpreted cautiously given that there was discrepancy of post‐transplant follow‐up period and the bi‐modal distribution.1FIGUREKaplan–Meier plots of survival and cumulative incidence of graft‐versus‐host disease stratified by different conditioning regimens. (A) RFS, (B) OS, and (C) TRM of the 224 ALL patients receiving different conditioning regimens; cumulative incidence of (D) grade 3–4 acute GvHD at day+100, (E) all grade chronic GvHD, and (F) grade 2–4 chronic GvHD of the 224 ALL patients receiving different conditioning regimensTreatment‐related mortalityThere was no difference in cumulative TRM (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 17% vs. 21.7% vs. 10.9%, p = .308, Figure 1C) among all regimen groups. However, patients who took oral busulfan had a higher risk of TRM than those who received IV busulfan (25% vs. 9.8%, p = .016, Figure S1C).Graft‐versus‐host diseaseThe cumulative incidences of grade 3–4 acute GvHD at day +100 were not significantly different among the three groups (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 15.8% vs. 10.8% vs. 15.2%, p = .445, Figure 1D), whereas the cumulative incidence of all‐grade chronic GvHD in the RIST‐Bu group was significantly higher than those in the other two groups (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 41.1% vs. 27.7% vs. 56.5%, p = .001, Figure 1E). The majority (80.8%) of chronic GvHD in the RIST and Bu‐based groups were grade 2–4, and the incidence of grade 2–4 chronic GvHD was consistently higher than those in the other two groups (MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 24.2% vs. 18.1% vs. 45.7%, p < .001, Figure 1F). We next performed subgroup analysis to dissect the potential impact of different prophylactic measures. Interestingly, in MA‐Bu and RIST‐Bu groups, patients receiving ATG prophylaxis (and HSCs from nonsibling‐matched donors) had a higher incidence of grade 3–4 acute GvHD at day +100 than their counter partners (Figure S3A,B, p = .073 and p = .005, respectively) while there was no such difference in the MA‐TBI group (Figure S3C, p = .802). On the other hand, among patients receiving identical prophylactic regimens, there was no difference between MA‐Bu and MA‐TBI groups regarding the incidence of grade 3–4 acute GvHD, grade 2–4, and all‐grade chronic GvHD (Figure S4A–F).Extramedullary diseaseIn this cohort, patients with extramedullary disease at diagnosis did not have significantly shorter OS than those without (median, with extramedullary disease vs. without, 28.1 vs. 25.8 months, p = .898, Figure 2A). This might imply that allo‐HSCT can overcome the expected poor prognosis of extramedullary disease. The MA‐Bu group outperformed the other two regimens in regard to RFS (median, MA‐Bu vs. RIST‐Bu, 39.4 vs. 3.8 months, p = .018; MA‐Bu vs. MA‐TBI, 39.4 vs. 5.2 months, p = .034, Figure 2B) and OS (median, MA‐Bu vs. RIST‐Bu, 109.9 vs. 51.2 months, p = .091; MA‐Bu vs. MA‐TBI, 109.9 vs. 60.4 months, p = .078, Figure 2C).2FIGUREKaplan–Meier plots in extramedullary disease subgroup analysis. (A) OS of the 224 ALL patients stratified by extramedullary disease. (B) RFS and (C) OS of the 45 ALL patients with extramedullary disease receiving different conditioning regimensMultivariable analysisFor multivariable analysis, we included parameters with a p value <.15 in univariate Cox regression analysis (Table 2) and biologically relevant parameters as covariates, including age, WBC count at diagnosis, karyotype, presence of extramedullary disease, disease status before HSCT, and the conditioning regimen. In multivariable analysis, disease status before HSCT and MA‐Bu conditioning were factors that affected RFS, while disease status before HSCT was the only risk factor for OS. In the subgroup analysis of patients with extramedullary diseases, MA‐Bu conditioning was found to have protective effects compared to TBI‐based conditioning, while status before transplant remained an independent risk factor for OS (Table 3).2TABLEUnivariate and multivariable analyses of RFS and OS of the 224 patients with acute lymphoblastic leukemiaVariableUnivariateMultivariateHR95% CIp valueHR95% CIp valueRFSAge (≥ vs. < 40 y/o)0.930.64–1.36.7101.210.68–2.14.513Initial WBC (≥10 vs. < 10K/μl)1.130.76–1.68.5481.290.78–2.15.314Cytogenetics (Standard vs. High riska)0.940.64–1.38.7501.100.70–1.72.678Extramedullary (Yes vs. No)1.160.78–1.74.4601.230.74–2.05.420Immunophenotype (T vs. B)1.180.82–1.71.368Pre‐HSCT disease status (vs. CR1)Late CR1.611.07–2.42.0231.671.01–2.75.047Relapse/refractory2.861.91–4.27<.0012.611.51–4.49.001Cell source (PBSC vs. BM/BM + PBSC)1.150.79–1.67.462Donor (Unrelated donor vs. Sibling)1.010.90–1.14.816Conditioning (vs. MA, TBI‐based)MA‐Bu basedf0.680.47–0.99.0460.610.38–0.97.035RIST‐Bu basedf0.790.51–1.24.3040.650.34–1.23.186Busulfan (intravenous vs. oral)0.840.53–1.32.437CD34+ cells (×106)0.990.91–1.08.876OSAge (≥ vs. < 40 y/o)0.980.66–1.46.9271.410.77–2.56.263Initial WBC(≥10 vs. < 10K/μl)0.990.66–1.49.9791.210.71–2.05.490Cytogenetics (Standard vs. High riska)0.910.61–1.37.6651.090.68–1.75.719Extramedullary (Yes vs. No)1.460.84–2.55.1841.080.63–1.84.792Immunophenotype (T vs. B)1.130.77–1.67.529Pre‐HSCT disease statusLate CR vs. CR11.771.16–2.72.0091.831.08–3.10.024Relapse/refractory vs. CR12.851.87–4.34<.0012.771.56–4.93.001Cell source (PBSC vs. BM/BM + PBSC)1.060.72–1.55.782Donor (Unrelated donor vs. Sibling)1.050.92–1.18.491ConditioningMA‐Bu based vs. MA, TBI‐based0.730.49–1.09.1200.650.39–1.06.083RIST‐Bu based vs. MA, TBI‐based0.790.49–1.27.3310.620.31–1.24.176Busulfan (intravenous vs. oral)0.750.47–1.21.238CD34+ cells (×106)0.990.92–1.09.970Note: Statistically significant if p < .05.Abbreviations: BM, bone marrow; CI, confidence interval; CR, complete remission; HSCT, hematopoietic stem cell transplantation; HR, hazard ratios; MA, myeloablative; PBSC, peripheral blood stem cell; RIST, reduced‐intensity stem cell transplantation; TBI, total body irradiation.aHigh risk: t(9;22)/BCR‐ABL1, t(v;11q23)/KMT2A (MLL) rearrangements, or hypodiploidy (<44 chromosomes).3TABLEMultivariable analysis for RFS and OS of the 45 ALL patients with extramedullary diseasesVariableRFSOSHR95%CIpHR95%CIpAge (≥ vs. < 40 y/o)0.740.19–2.82.6630.660.17–2.55.547Initial WBC (≥10 vs. < 10K/μl)0.510.14–1.90.3120.540.14–2.06.365Cytogenetics (Standard vs. High riska)3.931.37–11.23.0112.490.80–7.73.115Pre‐HSCT disease statusLate CR vs. CR12.070.64–6.72.2264.321.31–14.27.016Relapse/refractory vs. CR112.271.90–79.12.00820.883.04–143.3.002ConditioningMA‐Bu based vs. MA, TBI‐based0.370.12–1.16.0880.560.16–1.98.369RIST‐Bu based vs. MA, TBI‐based0.930.24–3.62.9191.630.42–6.28.478Note: Statistically significant if p < .05.Abbreviations: CI, confidence interval; CR, complete remission; HSCT, hematopoietic stem cell transplantation; HR, hazard ratios; MA, myeloablative; RIST, reduced‐intensity stem cell transplantation; TBI, total body irradiation.aHigh risk: t(9;22)/BCR‐ABL1, t(v;11q23)/KMT2A (MLL) rearrangements, or hypodiploidy (<44 chromosomes).DISCUSSIONThis is the first study comparing transplant outcomes in Chinese ALL patients receiving TBI‐ and Bu‐based conditioning therapy to the extent of our knowledge. A higher proportion of patients (63.4%) in our study received Bu‐based conditioning compared with patients in Western cohorts (4.2%–52.6%, Table 4).30‐38 Long‐term TBI toxicities, including delayed growth and secondary malignancy, might be the main reason preventing our patients from receiving irradiation therapy. Additionally, we explored patient outcomes based on the form of busulfan administered (IV or oral form). Patients receiving IV busulfan had comparable RFS and OS to the oral group and a lower TRM rate, which could result from more stable pharmacokinetics; however, drug level monitoring was not routinely performed in our institute. This cohort could provide some directive for the real‐world practice where TBI or therapeutic drug monitoring of Bu are not available.4TABLESelected studies comparing the outcomes of patients with acute lymphoblastic leukemia receiving busulfan‐based or total body irradiation‐based conditioning regimensCohortPatient numberOSRFS/DFS/PFSNRM/TRMRIaGVHD (II‐IV)cGVHDSummary/notesMitsuhashi, 2016aTBI = 202859%RFS 55.0%NRM 20.8%22.8%40.4%37.6% at 2 yrTBI over PO BU for OSPO BU = 6048.2%RFS 44.6%NRM 26.1%28.5%36.8%31.5% at 2 yrIV BU = 4237.4%RFS 34.2%NRM 27.0%32.6%33.3%40.1% at 2 yrKebriaei, 2018aTBI = 81949%DFS 45%TRM 27%29%40.0%55% at 3 yrSimilar OS and DFSBU = 29946%DFS 37%TRM 22%42%47.0%49% at 3 yrCandoni, 2019bTBI = 221HR: 0.86, 95% CI:PFS HR: 0.72, 95% CI: 0.55–0.94NRM HR: 1.16, 95% CI:HR: 0.56, 95% CI:Not reportedHR: 1.45, 95% CI: 0.93–2.26Favor TBI for PFS and RICT = 2200.65–1.140.78–1.720.39–0.79Eroglu, 2013cTBI = 4553.2%EFS 27.2%TRM 9.0%51%22.2%31.1%Favor TBI for OS, EFS and RIBU = 5030.9%EFS 18.8%TRM 16.0%76%26.0%24.0%Granados, 2000c, dTBI = 114Not reportedEFS 43%TRM 17% at 18 mo47%30.3%7.9% extensiveFavor TBI for EFS and RIBU = 42EFS 22%TRM 22% at 18 mo71%23.8%0% extensiveSakellari, 2018aTBI = 8446.7%; 57.6%eDFS 46.1%TRM 27.7%Not reportedNot reported48%eFavor TBI in patients younger than 40 yearsBU = 6735.8%; 39.7%eDFS 35.4%TRM 24.1%27.4%Giebel, 2017TBI = 50469.5%LFS 61.6%NRM 17.3%21.1%Not reportedNot reportedFavor TBI for LFS and RICT = 5864.0%LFS 49.7%NRM 17.6%32.7%Nishiwaki, 2016f, gTBI = 310HR 1.3, 95% CI: 0.65–2.57LFS HR: 1.42, 95% CI: 0.79–2.57NRM HR 1.51, 95% CI: 0.64–HR 1.18, 95% CI:Not reportedNot reportedSimilar outcomes in patients under age of 55CT = 143.520.51–2.72Abdelaty, 2020TBI = 7842% at 2 yrDFS 80% at 2 yrNRM 38.5%11.5%33.3%h30.8%Favor TBI for EFS and RI; no significant difference in OS, DFS, and NRMBU = 4144% at 2 yrDFS 55% at 2 yrNRM 48.8%26.8%36.6%17.1%NTUH (this study)TBI = 8328.2 moRFS 6.7 moTRM 21.7%44.6%10.8%h27.7%Favor MA, BU‐based group for RFSMA, BU = 9539.4 moRFS 24.1 moTRM 17.0%33.7%15.8%41.1%RIC, BU = 4613.1 moRFS 18.3 moTRM 10.9%47.8%15.2%56.5%Abbreviations: BU: busulfan‐based regimen; CI, confidence interval; CT: chemotherapy; IV: intravenous form; PO: oral form; RI, relapse incidence; TBI: total body irradiation.aFollowed up at 5 years post‐transplant.bTBI‐based vs. Bu‐based, Bu as reference.cFollow‐up at 3 years post‐transplant.dNinety patients received allogenic transplant, and 66 patients received autologous transplant.eIn patients younger than 40 years.fBu‐based vs. TBI‐based, TBI as reference.gSubanalyses of 324 patients under the age of 55 within the whole cohort treated with a myeloablative conditioning regimen.hAll grades included.While there is currently no firm consensus on the best conditioning therapy for allo‐SCT in adult patients with ALL, the results from previous studies provided evidence in modest favor of TBI (Table 4). Kebriaei et al. analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR), revealing that patients using Bu had lower TRM (Bu 19% vs. TBI 25%, p = .04) but a higher relapse rate (Bu 37% vs. TBI 28%, p = .007) than patients using TBI.33 Compared with TBI‐based conditioning, Bu‐based conditioning led to similar disease‐free survival (DFS) and OS following allo‐SCT for ALL. Meanwhile, Mitsuhashi and colleagues conducted an analysis to compare TBI/Cy, oral Bu/Cy, and IV Bu/Cy in a cohort of 2130 Japanese patients, most of whom received TBI/Cy. The oral Bu/Cy group had a shorter OS than the TBI/Cy group, while the IV Bu/Cy group had comparable OS to the TBI/Cy group.34 No between‐group differences were seen in the incidence of non‐relapse mortality (NRM), relapse, acute GvHD, or chronic GvHD.Herein, we present our transplant experience with ALL patients in Taiwan. The survival outcome of our cohort is comparable to those in other recently published studies (Table 4). The TRM of our patients seemed to be acceptable, yet the incidence of relapse (33.7%–47.8%) remained alarming. While the studies by Kebriaei et al. and Abdelaty et al. revealed a markedly increased relapse incidence in the busulfan group,33,38 the relapse rates among three groups in our study were not that different. Interestingly, in a recent study, Speziali and colleagues analyzed outcomes of 146 ALL patients receiving TBI/Cy (1200 cGy) or fludarabine, busulfan, and low‐dose TBI (400 cGy) as conditioning regimens. The Flu/Bu/TBI group had a significantly lower incidence of relapse than the TBI/Cy group (18.5% vs. 31.5% at 2‐year, p = .05), while there was no difference in OS, PFS, and NRM, implicating an alternative combination of low‐dose TBI and Bu.39Regarding survival, our patients in the MA‐Bu group had a better RFS than those in the MA‐TBI group. Nevertheless, the survival benefit of RFS conferred by Bu was not extended to long‐term OS. One explanation might be higher mortality rates resulted from late relapse and infection (Table 5). The overall relapse incidence was higher in the TBI group (44.6%) than in the MA‐Bu group (33.7%), but the MA‐Bu group caught up in terms of relapse‐related mortality. The MA‐Bu group had a higher rate (1.76‐fold) of death due to infection. Improvements in the management of disease relapse and infection after transplant might particularly help improve patient survival. In patients with extramedullary diseases, the MA‐Bu group consistently had longer RFS than the other two groups. There was also a trend towards longer OS, lower relapse incidence and TRM in the MA‐Bu group. This could be contrary to our impression of the anti‐leukemic effect of TBI on the sanctuary sites. As intrathecal chemotherapy was routinely performed for adult ALL patients in our institute, this could remunerate the suboptimal penetration of busulfan into the central nervous system. Another possible confounding factor is the timing of the transplant. More patients with extramedullary disease in the MA‐Bu group received allo‐SCT in their first complete remission (CR, MA‐Bu vs. MA‐TBI: 94.7% vs 66.7%, p = .042) rather than in latent CR. Excluding patients in the RIST‐Bu group and those not in remission, the difference in RFS and OS would become trivial (p = .97 and p = .841, respectively). Furthermore, the rate of TRM was higher in the MA‐TBI group than in the MA‐Bu group (22.2% vs 3.7%). Lastly, the dose of TBI (12 Gy) is inferior to higher doses (≥13 Gy), which was promoted by Marks et al.16 For patients receiving allo‐SCT, not in first CR, the risks of relapse and mortality might be diminished with TBI doses >13 Gy.5TABLECauses of death by treatment groupClinical CharacteristicsMA‐TBIDeath (n = 51)MA‐BuDeath (n = 47)RIST‐BuDeath (n = 24)p valueRelapse29 (56.9%)28 (59.6%)17 (70.8%).504Graft failure01 (2.1%)0.447GVHD6 (11.8%)04 (16.7%).025*Infection8 (15.7%)13 (27.7%)1 (4.2%).044*Interstitial pneumonitis or ARDS3 (5.9%)1 (2.1%)0.350Secondary malignancy1 (2.1%)2 (4.3%)1 (4.2).786Other2 (3.9%)00.243Unknown2 (3.9%)2 (4.3%)1 (4.2%).996Note: *Indicating statisticallysignificant with P < 0.05.Abbreviations: ARDS, acute respiratory distress syndrome; GVHD, graft‐versus‐host disease.There are several limitations to our study. First, its retrospective nature imposed diverse sources of biases and temporal confounding factors that were difficult to assess. Although prospective and randomized trials for allogenic transplantation in ALL are challenging in clinical practice due to the complexity of the disease nature and treatment course, they are warranted and will be appreciated. Second, targeted drug monitoring was not routinely implemented in our institute. Regardless of the lack of pharmacokinetic data in patients receiving oral Bu, this subgroup had a higher TRM than those receiving IV busulfan, which was consistent with previous studies that showed that a more stable Bu pharmacokinetic level with IV dosing and the reductions in toxicities. Moreover, some bias may be recondite since the recruitment of patients spanned a long period. Although we confirmed that the survival of patients receiving transplantation more contemporarily did not overwhelm their counterparts, potential underlying confounding factors could not be all excluded. Despite these limitations, multivariable analysis in our study confirmed that there were no significant differences between the Bu‐based and TBI‐based groups in terms of OS, and MA‐Bu conditioning might improve RFS in eligible patients. These results imply that the Bu‐based regimen might improve patient outcomes in adult patients with ALL by reducing treatment toxicity and mortality. In the meantime, strategies for the prevention and salvage of disease relapse, which accounted for more than 50% of the deaths, should also be further investigated and improved.In summary, this study provided a risk stratification and survival analysis of ALL patients undergoing allo‐SCT and demonstrated that a Bu‐based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Larger‐scale, prospective and randomized controlled trials are challenging but warranted to compare and validate the long‐term outcome of patients receiving Bu‐based and TBI‐based conditioning before transplant.ACKNOWLEDGMENTSWe would like to acknowledge the service provided by Department of Laboratory Medicine, and Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital; and Tai‐Cheng Cell Therapy Centre, National Taiwan University, Taipei, Taiwan.This study was supported by the YongLin Healthcare Foundation, which is a non‐profit organization, and the Ministry of Science and Technology (MOST) of Taiwan (grant number MOST 108‐2823‐8‐002‐003).CONFLICT OF INTERESTThe authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this study.AUTHOR CONTRIBUTIONSYu‐Hung Wang: Formal analysis; visualization; writing‐original draft. Feng‐Ming Tien: Data curation; resources. ChengHong Tsai: Data curation; resources. Huai‐Hsuan Huang: Data curation; resources. Jia‐Hau Liu: Data curation; resources. Xiu‐Wen Liao: Data curation; project administration; resources. Jih‐Luh Tang: Data curation; project administration; resources. Ming Yao: Data curation; project administration; resources. Bor‐Sheng Ko: Conceptualization; funding acquisition; investigation; resources; supervision; writing‐original draft.ETHICS STATEMENTThis study, along with the policy to waive informed consent, was approved by the Research Ethics Committee of NTUH (Project number: 201810058RIND). This article does not use any samples from human or animal subjects.DATA AVAILABILITY STATEMENTThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.REFERENCESKantarjian HM, DeAngelo DJ, Stelljes M, et al. 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Leuk Lymphoma. 2019;60(3):639‐648.

Journal

Cancer Reports – Wiley

Published: Mar 1, 2022

Keywords: acute lymphoblastic leukemia; allogeneic transplantation; busulfan; conditioning chemotherapy; Taiwan

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