Reduced Intensity Conditioning Group Research Articles

Conditioning Intensity in Patients Aged > 50 Years Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrom: A Study on Behalf of the Chronic Malignancies Working Party of the EBMT

Introduction Myelodysplastic syndromes (MDS) affect mainly older individuals, with a median age > 70 years. Reduced intensity conditioning (RIC) is usually used for MDS patients undergoing allo-HCT to balance the toxicity of myeloablative conditioning (MAC), particularly in the more elderly or those with multiple comorbidities. In addition, the clinicians subjective opinion/ experience remains a major guide in choosing the intensity of conditioning. The majority of studies comparing RIC and MAC reported a higher cumulative incidence (CI) of relapse (RP) and lower non-relapse mortality (NRM) in the RIC groups. However, the impact of conditioning intensity on outcome after allo-HCT remains controversial. To gain more insight into the impact of conditioning on outcomes following allo-HCT for MDS, we evaluated RIC versus MAC in MDS patients aged > 50 years in a large EBMT cohort. Patients and methods This was a registry-based retrospective multicenter study that included MDS patients above 50 years, who received a first allo-HCT following RIC or MAC conditioning between 2014 - 2018 and had data on IPSS-R at allo-HCT and RIC/MAC conditioning available. Data collected included disease features, patient, donor and transplantation characteristics. Patients with ex vivo T-cell depletion were excluded. Variables with missing values ≤35% were handled with multiple imputation. OS, DFS, RP and NRM were compared using the Log-rank and Gray's test for CI, and (cause-specific) Cox proportional hazard models for multivariable analyses (MVA). A conditional logistic regression after propensity score matching (PSM) was also performed for potential risk confounders. Results Among the 1393 included patients (from 121 centres), 922 (66%) were men and the median age at allo-HCT was 62.8 (IQR:58.2-66.9) years. The majority of patients (n=884; 64.3%) had RAEB. The IPSS-R was recorded as very low/low (n=598, 43%), intermediate (n=352, 25%) and high/very high (n=443, 32%). Cytogenetic risk score was very good/good (n=932, 66.9%), intermediate (n=250, 17.9%) and poor/very poor (n=211, 15.1%). Karnofsky index was ≥ 90 in 916 pts (69.3%) and HCT-CI ≥ 3 in 292 pts (27.3%). Disease status at transplant was recorded as complete remission (n=486, 34.9%), untreated/stable disease (n=544, 39.0%), and progressive disease (n=310, 22.3%). Donor was HLA-matched (related/unrelated) (n=989, 71.1%), unrelated HLA-mismatched (n=286, 20.5%) or familial HLA haplo-identical donor (n=153, 10.9%). Source of SC was BM (n=112, 8.0%) and PB (n=1255, 90.0%). A RIC regimen was used in 1053 (75.5%) patients. In vivo T-cell depletion with anti-thymocyte globulin (ATG) was used in 941 pts (67.5%). Median time of follow up was 27.9 months (IQR: 26.4-30.6). Median rate of OS in RIC vs MAC group was 54.2(95% CI: 33.5-NA) vs 46.2(95% CI: 32.6-69.4), p=0.84; median rate of DFS was 28.4(95% CI: 19.4-58) vs 28.0 (95% CI: 22.5-39.1), respectively, p=0.64. Cumulative incidence rate of RP and NRM for RIC vs MAC regimen at 36 months were 31.2% vs 29.7% and 29.9% vs 30.4%, respectively (Figure 1). Both in univariable and MVA we did not observe a significant (> 0.05) association between the conditioning regimen on the outcomes. Similar results were obtained using PSM to control potential confounders (such as age, source of SC, stage of disease, HCT-CI, cytogentic risk score, neutrophile and platelet counts and sAML) and conditional logistic regression analysis (Table1). Conclusion To our knowledge, this is the largest retrospective cohort study that highlights a lack of association between RIC/MAC regimen and outcomes in MDS patients undergoing allo-HCT. Our results are in line with the recent published systematic review and metanalysis where evidence for using a one conditioning regimen over another remains weak [1,2]. 1) Rashidi et al. Biology of Blood and Marrow Transplantation. 2020; 26:138-141. 2) Akbar et al. Blood.2020; 136:40-41.

Impact of Conditioning Intensity and Regimen on Outcomes after Unrelated Cord Blood Transplantation for Patients with Myelodysplastic Syndrome

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). Unrelated cord blood transplantation (CBT) is an alternative donor option in MDS patients who lack an HLA-matched donor, and the increased availability of CBT expand indications for allo-HSCT in MDS patients. Because concerns have been expressed regarding decreased hematopoietic recovery and increased relapse after CBT, many studies have been conducted to develop the conditioning regimen in CBT. The optimal intensity of conditioning regimen needs to be addressed based on patient- and disease-related factors. However, the optimal intensity of conditioning regimen in CBT for MDS remains unclear. We here conducted a nationwide retrospective study to clarify the optimal conditioning intensity for MDS in CBT. Methods This study included patients diagnosed with de novo MDS according to the WHO classification. The clinical data of 856 de novo MDS patients (i) who were 16-69 years old and (ii) who underwent their initial single-unit CBT between 2001 and 2020 were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In this study, 501 and 355 patients received myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), respectively. The median age at CBT was 53 (range,17-69) and 62 years (range,18-69) in MAC and RIC groups, respectively. The most frequently used MAC regimen consisted of total body irradiation >8 Gy-based regimen (n=209, 41.7%), followed by fludarabine (Flu) with myeloablative doses of busulfan (Bu 9.6 to 12.8 mg/kg)-based regimen (n=93, 18.6%). The most frequently used RIC regimen consisted of Flu with reduced doses (80 to 120 mg/m 2) of melphalan-based regimen (n=245, 96.1%), followed by Flu with reduced doses of Bu (6.4 mg/kg)-based regimen (n=63, 17.7%). The 3-year OS were 44.3 % and 48.8 % in MAC and RIC groups, respectively; the 3-year CRFS were 33.8 and 37.2%; the 3-year GRFS were 19.2 % and 26.9%; the 3-year CIR were 27.1% and 30.0%; and the 3-year NRM were 18.6% and 18.2 %. The univariate analysis revealed that RIC group tended to correlate with higher GRFS than MAC group (Hazard ratio (HR) 0.86 [95% confidential interval 0.74-1.00]; P=0.057), but there was no significant difference of OS (HR 0.95 [0.79-1.13]; P=0.552), CRFS (HR 0.95 [0.80-1.12]; P=0.522), CIR (HR 1.11 [0.87-1.41]; P=0.401) and NRM (HR 0.96 [0.77-1.20]; P=0.735) between MAC and RIC groups. The multivariate analyses confirmed the better GRFS in RIC group than MAC group (HR, 0.73 [0.61-0.89]; P=0.001). Apart from the conditioning intensity, the following six factors were associated with worse overall mortality: patient's age (40-60 years; P=0.039 and >60 years; P<0.001), patient's sex (male; P=0.038), performance status (PS) at CBT (PS 2-4; P=0.033), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (HCT-CI ≥3; P=0.035), high number of platelet transfusion before HSCT (≥20 times; P<0.001) , and cytogenetic risk group (poor risk; P=0.001). We next performed the subgroup analysis stratified by the patient's characteristic affecting OS, such as age, sex, PS, HCT-CI, the number of platelet transfusion, and cytogenetic risks. The subgroup analysis showed the better OS (HR, 0.74 [0.59-0.92]; P<0.007), CRFS (HR 0.74, [0.60-0.94]; P=0.012), and GRFS (HR 0.62, [0.50-0.78]; P<0.001) of RIC group than MAC group among patients with patients aged >60 years, but no significant impact on CIR and NRM. Conclusion This study showed no significant difference of OS, CRFS, CIR and NRM between MAC and RIC groups, but RIC group correlated with better GRFS in the entire population. Furthermore, the subgroup analysis showed that RIC regimen may be preferable for patient aged >60 years. These findings would improve the management for CBT candidates with MDS.

Prognostic Impact of Conditioning Intensity on Outcomes after Allogeneic Transplantation for MDS with Low Blasts

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). The blast percentage in MDS is one of the important factors to utilize allo-HSCT, and the other disease-related factors, such as transfusion dependency and chromosomal risk, are crucial to consider whether patients harboring MDS with less than 5% of marrow blasts (MDS-Lo) undergo to allo-HSCT. However, the prognostic impacts of conditioning intensity in MDS-Lo patients are still unclear. We here conducted a nationwide retrospective study to clarify the prognostic factor and investigate the optimal conditioning intensity for MDS-Lo. Methods In this study, patients diagnosed as the other than refractory anemia with excess blasts (RAEB)-1 and -2 according to the WHO classification (marrow blasts <5% and peripheral blood blasts <1%) were considered to be MDS-Lo. The clinical data of 1,229 de novo MDS-Lo patients (i) who had stayed MDS-Lo from diagnosis to transplantation and (ii) who underwent their initial allo-HSCT between January 2001 and December 2020 were collected from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In a total of 1,229 patients, 651, 397, and 181 patients received myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), and non-myeloablative conditioning (NMAC) groups, respectively. The estimated 3-year OS rates were 63.3%, 61.0%, and 69.7% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CRFS rates were 41.1%, 43.9%, and 47.2% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year GRFS rates were 27.5%, 33.4%, and 35.4% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CIR were 11.9%, 14.2%, and 16.0% in MAC, RIC, and NMAC groups, respectively; and the estimated 3-year NRM were 29.8%, 31.0%, and 24.7% in MAC, RIC, and NMAC groups, respectively. The multivariate analyses revealed four factors affecting lower OS: older recipient's age (Hazard ratio (HR) [95% confidential interval], 1.70 [1.28-2.24]; P<0.001 for 40-59 years)(HR, 2.32 [1.71-3.15]; P<0.001 for 60 years or older), performance status 2-4 at HSCT (HR, 1.84 [1.32-2.57]; P<0.001), the history of infection before HSCT (HR, 2.12 [1.55-2.89]; P<0.001), and high number of red blood cell (RBC) transfusion before HSCT (HR, 1.65 [1.35-2.02]; P<0.001). These factors also negatively affected CRFS, GRFS, and NRM. In addition, poor cytogenetic risk group was associated with worse OS (HR, 1.66 [1.32-2.09]; P<0.001), CRFS (HR, 1.48 [1.22-1.80]; P<0.001), and GRFS (HR, 1.36 [1.14-1.64]; P=0.001) but not CIR. There was no significant difference of OS, CRFS, GRFS, CIR, and NRM in either RIC or NMAC group compared to MAC group. We next performed the subgroups analysis based on the prognostic factors. The subgroup analysis for the comparison between MAC and RIC regimens showed the better OS of MAC regimen among patients with low number of RBC transfusion (HR, 1.33 [1.01-1,75]; P=0.039). The subgroup analysis for the comparison between RIC and NMAC regimens revealed the better OS of NAMC regimen among patients aged <40 years (HR, 0.43 [0.19-0.96]; P=0.038), no history of infection (HR, 0.67 [0.50-0.91]; P=0.009), and good cytogenetic risk (HR, 0.54 [0.38-0.83]; P=0.004). Conclusion This study showed the prognostic factors on the post-transplant outcomes among MDS-Lo patients, and no significant difference of conditioning intensity in the entire population. Furthermore, we found the factors (the number of RBC transfusion, patient's age, the history of infection, and cytogenetic risk) potentially affecting the selection of conditioning intensity. These findings would improve the management for transplant candidates with MDS-Lo.

Early cessation of calcineurin inhibitors is feasible post–haploidentical blood stem cell transplant: the ANZHIT 1 study

AbstractHaploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.

Association between conditioning intensity and height growth after allogeneic hematopoietic stem cell transplantation in children.

The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We reviewed the clinical records of 89 children with malignant diseases who underwent initial allo-HSCT between 2003 and 2021. Height measurements were standardized using standard height charts prepared by the Japanese Society for Pediatric Endocrinology to calculate standard deviation score (SDS). We defined short stature as a height SDS less than -2.0 in that reference. Myeloablative conditioning (MAC) comprised total-body irradiation at more than 8 Gy and busulfan administration at more than 8 mg/kg (more than 280 mg/m2 ). Other conditioning regimens were defined as reduced intensity conditioning (RIC). A total of 58 patients underwent allo-HSCT with MAC, and 31 patients received allo-HSCT with RIC. There were significant differences in the height SDS at 2 and 3 years after allo-HSCT between MAC and RIC group (-1.33 ± 1.20 vs. -0.76 ± 1.12, p = 0.047, -1.55 ± 1.28 vs. -0.75 ± 1.11, p = 0.022, respectively). Multivariate logistic regression analysis with the adjustments for potential confounding factors of patients less than 10 years of age at allo-HSCT and chronic graft-versus host disease demonstrated that MAC regimen was associated with a markedly increased risk of a short stature at 3 years after allo-HSCT (adjusted odds ratio, 5.61; 95% confidence interval, 1.07-29.4; p = 0.041). The intensity of conditioning regimen may be associated with short statures after allo-HSCT.

Allogeneic Hematopoietic Stem Cell Transplantation for Primary Myelofibrosis: A 20-year Experience in a Single Center

Allogeneic hematopoietic stem cell transplantation is a well-established approach for patients diagnosed with primary myelofibrosis and remains the only potentially curative treatment. To present the overall outcome of patients with myelofibrosis treated with allogeneic hematopoietic stem cell transplantation. A retrospective cross-sectional study. This study is a retrospective analysis of 26 consecutive patients with primary myelofibrosis who underwent transplantation at our center between January 2002 and January 2022. Disease and transplant variables contributing to outcomes were analyzed. The median age at the time of transplantation was 52.5 (range, 32-63) years and the median time from diagnosis to allogeneic hematopoietic stem cell transplantation was 25 (range, 3.1-156.8) months. Myeloablative conditioning and reduced-intensity conditioning regimens were used in 8 (30.8%) and 18 (69.2%) transplantations, respectively. Neutrophil and platelet engraftment was achieved in 23 patients at a median follow-up of 21.2 months (range, 12 days to 234.8 months). Primary graft failure occurred in 1 of 23 patients (4.3%). Neutrophil and platelet engraftment occurred at a median of 16 (range, 12-39) days and 20 (range, 11-78) days, respectively. Acute graft-versus-host disease was seen in 11 of 22 patients engrafted allografts, of which 7 (31.8%) were grade 3-4 acute graft-versus-host disease. Eight patients (36.4%) developed chronic graft-versus-host disease, and three cases were extensive. Four patients (19%) relapsed after a median of 5.5 months, and three patients received donor lymphocyte infusion. The 3-year overall survival rate of the entire study population was 46.2%. The median overall survival was not reached in the myeloablative conditioning group; however, it was 11.9 months in the reduced-intensity conditioning group (p =0.3). According to the donor graft source, the median overall survival was 0.73 months in mismatched unrelated graft recipients, 12 months in matched sibling donors, and not reached in matched unrelated graft recipients (p = 0.03). The 3-year progression-free survival rate of patients who survived > 100 days was 74.7%. The effect of JAK-2 status, graft source, conditioning regimen or dynamic international prognostic scoring system on progression-free survival was not statistically significant. Given the poor prognosis of non-transplant recipients and the lack of non-transplant curative approaches, our results support the consideration of allogeneic hematopoietic stem cell transplantation for eligible patients with primary myelofibrosis.

Reduced-intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for patients with myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is the sole curative option for myelofibrosis (MF). However, it is unknown as to which of the two, myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), is a better preconditioning regimen. Twenty-five patients with MF were treated with alloSCT, 12 of whom underwent RIC. Baseline characteristics, response to alloSCT, adverse events, including graft-versus-host disease (GVHD), and survival outcomes were reviewed. There was no difference in the neutrophil engraftment rate and time to engraftment between MAC vs. RIC. The time to platelet engraftment was significantly longer in the MAC group (median, 112.8 vs. 28.8 days for MAC vs. RIC, respectively, P=0.049). RIC was more advantageous in terms of achieving complete chimerism (38.5% vs. 83.3%, P=0.041). The incidence of acute GVHD was 84.6% (11 of 13) and 58.3% (7 of 12) in the MAC and RIC groups, respectively. The cumulative incidence of grade III‒IV acute GVHD was significantly higher in the MAC group than in the RIC group (P=0.03). No significant differences were observed in progression-free and overall survival. The 17-month probability of progression-free survival was 38.4% [95% confidence interval (CI), 19.3‒76.5] vs. 47.6% (95% CI, 25.7‒88.2) (P=0.21), and that of overall survival was 53.8% (95% CI, 32.5‒89.1) vs. 48.6% (95% CI, 26.8‒88.3) (P=0.85) for MAC vs. RIC, respectively. RIC offers a significant advantage over MAC, even in younger patients with MF undergoing alloSCT, in terms of cell engraftment, rate of complete chimerism achievement, and incidence of acute GVHD.

Myeloablative Vs Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation in Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia

Background: Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has historically been associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is recommended in first complete remission (CR1). Strategies to decrease non-relapse mortality (NRM) and to increase the number of patients eligible to receive HCT have led to the utilization of reduced intensity conditioning (RIC) for patients unfit or too old for myeloablative conditioning (MAC), at the cost of a higher risk of relapse. Limited data exist comparing MAC vs. RIC HCT in Ph+ ALL. Here, we compared the outcomes of MAC- and RIC-HCT in Ph+ ALL. Methods: This was a single-center retrospective study examining patients with Ph+ ALL who underwent HCT from 2000-2019. The primary endpoint was progression free survival (PFS), while secondary endpoints include overall survival (OS), graft versus host disease free survival (GRFS), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR), and GVHD. Survival estimates were calculated using the Kaplan-Meier method and differences were examined by the log-rank test. CIR and NRM were calculated using a competing risk analysis and differences were examined by Gray's test. Results: 185 patients were included, of whom, 131 (70.8%) underwent MAC, 128 (97.7%) of whom received total body irradiation (TBI)-based treatment, while 54 (29.2%) underwent RIC, 45 (83.3%) of whom received fludarabine plus melphalan (Flu/Mel). The median age (range) of the patients receiving MAC and RIC were 40 years (19-59) and 57 years (23-73), respectively. 66 (50.3%) vs 7 (13.0%) were ≤40 years in the MAC vs RIC groups (P<0.001). 66 (50.4%) vs 38 (70.4%) in the MAC vs RIC groups underwent HCT ≥2010. 115 (87.8%) vs 47 (87.0%) were in CR1 at the time of HCT in the MAC vs RIC groups (P=1.0), and 41 (31.3%) vs 16 (29.6) had measurable residual disease (MRD) by PCR at the time of HCT, although 34 (26.0%) vs 9 (16.7%) did not have a MRD pre-HCT report available (P=0.31), respectively. 110 (59.5%) received tyrosine kinase inhibitor (TKI) maintenance post-HCT, 73 (55.7%) in the MAC group vs 37 (68.5%) in the RIC group (P=0.14). The rest of their baseline characteristics are described in Table 1. In a sub-analysis of patients in MRD-negative CR1 at HCT, there was no statistically significant difference in 4-year PFS between MAC vs RIC, 71.1% vs 55.7% (P=0.12). PFS was similar in patients receiving TKI maintenance regardless of whether they received MAC vs RIC, hazard ratio 1.73 (95% confidence interval, 0.93-3.22; P=0.08). The 4-year NRM, CIR, and GVHD with MAC vs RIC were 25.6% vs 26.8% (P=0.50), 14.5% vs 21.4% (P=0.27), and 48.4% vs 46.3% (P=0.75), respectively. Conclusions: Patients with Ph+ ALL had similar PFS, OS, and GRFS when treated with MAC vs RIC. RIC-HCT is appropriate in those who would not be expected to tolerate MAC and may also be an acceptable strategy for younger patients when TKI maintenance post-HCT is administered. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many pediatric malignant and nonmalignant conditions. Gonadal insufficiency or infertility is present in almost all HSCT survivors who received a myeloablative conditioning (MAC) regimen. Reduced-intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with nonmalignant diagnoses to limit the toxicities associated with HSCT; however, the short-term and long-term gonadal toxicity of RIC regimens in pediatric and young adult survivors remains unknown. In this study, we compared the prevalence of gonadal insufficiency and infertility among pubertal and postpubertal pediatric and young adult survivors of HSCT who received a RIC regimen versus those who received a MAC regimen. Twenty-three females (RIC, n=8; MAC, n=15) and 35 males (RIC, n=19; MAC, n=16) were included in this single-center, retrospective cross-sectional study. Eligible patients were those with available laboratory results who were ≥1 year post-HSCT, age <40 years, and pubertal or postpubertal as assessed by an endocrinologist. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels were measured in females, and FSH, LH, total testosterone, and inhibin B (InhB) levels were measured in males. Twenty-one males (RIC, n=11; MAC, n=10) underwent semen analysis through a separate consent. Parametric and nonparametric analyses were undertaken to compare the RIC and MAC groups. Female patients who received RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P=.02) and low estradiol (P=.01) or elevated LH (P=.09). Most females in the RIC (75%) and MAC (93%) groups had low AMH levels, indicating low or absent ovarian reserve, with no significant difference between the groups (P=.53). In males, there were no significant differences between the 2 groups in the prevalence of abnormal FSH, LH, testosterone, or InhB levels. Ten of 11 RIC males (91%) and 10 of 10 MAC males (100%) had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range, 1.3 to 12.2 years). RIC may pose less risk than MAC for primary ovarian insufficiency among female survivors of HSCT; however, both female and male recipients of either RIC or MAC regimens are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling about the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.

The effect of intensity of conditioning regimen on the outcome of HSCT in children with sickle cell disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for patients with sickle cell disease (SCD). This study describes the effect of conditioning regimen intensity on HSCT outcomes among children younger than 14 years with SCD. Transplants from HLA-matched related donors (MRD) and unrelated donors (MUD) using either myeloablative conditioning (MAC) regimens or reduced intensity conditioning (RIC) regimens were considered. Event-free survival (EFS) was the primary endpoint. Secondary endpoints included overall survival (OS) and occurrence of GVHD. 48 SCD patients underwent HSCT, 45 (93.8%) patients had MRD, 1 (2.1%) had 9/10 related donor, and 2 (4.1%) had MUD. The median age at transplant was 8.6 years (range, 3.1-13.8). Conditioning regimens were myeloablative (MAC) in 41 (85.4%) patients and of reduced intensity in 7 (14.6%) patients. EFS at 2 years was 100% among MAC group compared to 29% in the RIC group (p<.001). The median follow-up was 43.4 months (range 26.8-134). All events in the RIC group were secondary graft failure. However, OS was 100% in both groups at 2 years. Acute GVHD II-IV was diagnosed in 2 (4.1%) patients. Chronic GVHD occurred in 2 (4.1%) patients. GVHD did not occur in patients who underwent MUD HSCT. MAC in children with SCD is well tolerated and associated with an excellent outcome for HLA-matched HSCT in SCD. There was a high rate of secondary graft failure with the use of RIC. Future studies are needed to optimize RIC regimens in HSCT of children with SCD.

Analysis of Hematopoietic Niche Components Post Allogeneic Transplantation

Timely and effective reconstitution of the hematopoietic niche is imperative post-allogeneic stem cell transplantation (alloHCT) for prevention of life-threatening opportunistic infections and relapses. Efficient engraftment is dependent on the ability of donor hematopoietic stem cells (HSCs) to expand and provide long-term multi-lineage progenitors in the recipient. Mesenchymal stem cells (MSCs) are essential in providing a conducive environment for HSC reconstitution and maintenance. Conditioning chemotherapy with or without total body irradiation is required to confer a competitive advantage to donor HSCs. However, myeloablative conditioning (MA) regimens also destroy the specialized stromal niches which support HSC self-renewal and maintenance (Acar et al., 2015), providing a plausible explanation for the long term cytopenias observed post allogeneic transplantation (Domenech et al., 1995). Previous studies in humans showed CD146-expressing stromal cells support the establishment of the hematopoietic cell microenvironment (Sacchetti et al., 2007). Expression of markers of stromal/progenitor cells (CD146, CD31 and CD34) was evaluated pre and post alloHCT at day 30 in bone marrow biopsies obtained from patients treated with either MA or reduced intensity conditioning (RIC) approaches. CD146 and CD31 expression was evaluated by immunohistochemistry performed on formalin-fixed, paraffin-embedded bone marrow core biopsies. Whole slide imaging (Aperio) was used to digitize the histology and positive cells were scored using image analysis software (strong positive pixel count; ST PPC). In bone marrow, CD146 is expressed on vascular endothelial cells, pericytes on sinusoids, adipose and bone marrow stromal cells. CD31 positive cells include vascular endothelial cells, sinusoidal cells, megakaryocytes, and myeloid cells (Fig. 1). The percent of CD34 positive stem cells was determined by flow cytometry in concurrent bone marrow aspirate cells.The indications for an alloHCT were AML (5/10), ALL (2/10) or MDS (3/10). Median age was 62 (59-69) years in the RIC group and 34 (25-46) years in the MA group. Average HCT CI score was higher in the RIC group (2.5 versus 1.2) (Table 1). 3/10 patients received total body irradiation (TBI) based conditioning. All patients received peripheral blood stem cell alloHCT and 7/10 were MUDs. Chronic GVHD was present (grade 2 or 3) in 3/10 patients in the RIC groups and 1 patient (grade 1) in the MA cohort. Chimerism studies showed optimum engraftment of donor cells in 2 patients in the RIC group and 1 patient in the MA (Table 1).On average, pretransplant bone marrow cellularity was lower in the RIC group. The average overall cellularity on D30 was similar in the two groups (Fig.2). The average percent of CD34 positive cells was similar pretransplant and lower at D30 in the RIC cohort compared to the MA group (0.96% CD34 pre alloHCT versus 0.30% D30 post alloHCT RIC; pre alloHCT 0.96% CD34 versus D30 post alloHCT 0.92% MA). The mean number of CD31 positive cells was higher in the RIC group compared to the MA cohort both pre-transplant and at D30 (Fig 3). On average, an increase in CD146 positive cells on D30 was noted in the alloHCT RIC group compared to the MA cohort (Fig. 4).In conclusion, the RIC cohort showed a pre-post-transplant increase in average overall bone marrow cellularity, more numerous CD31 and CD146 positive cells on average and an increase in CD146 positive cells at D30 post alloHCT compared to the MA group. Despite the modest number of patients, this is the first study to date comparing pre and post alloHCT niche components which may provide important insights in the reconstitution process and impact of conditioning. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of conditioning intensity and regimen on transplant outcomes in patients with adult T-cell leukemia-lymphoma.

In allogeneic hematopoietic cell transplantation (allo-HCT) for adult T-cell leukemia-lymphoma (ATL), the optimal conditioning regimens have not yet been determined. We conducted a Japanese nationwide, retrospective study to investigate this issue. This study included 914 ATL patients who underwent allo-HCT between 1995 and 2015. In patients aged 55 years or younger, there was no statistically significant difference between reduced-intensity conditioning (RIC) regimens and myeloablative conditioning (MAC) regimens regarding risk of relapse (vs. RIC group: MAC group, hazard ratio (HR) 0.76, P = 0.071), non-relapse mortality (vs. RIC group: MAC group, HR 1.38, P = 0.115), or overall mortality (vs. RIC group: MAC group, HR 1.17, P = 0.255). Among RIC regimens, fludarabine plus melphalan-based (Flu/Mel) regimens were associated with a lower risk of relapse (Flu/Mel140 group, HR 0.59, P < 0.001; Flu/Mel80 group, HR 0.79, P = 0.021) than the Flu plus busulfan-based regimen (Flu/Bu2 group). Meanwhile, Flu/Mel140 group had a significantly higher risk of non-relapse mortality (vs. Flu/Bu2 group: HR 1.53, P = 0.025). In conclusion, it is acceptable to select a RIC regimen for younger patients. Moreover, it might be beneficial to select a Flu/Mel-based regimen for patients at high risk of relapse.

The Risk Of BK Virus Haemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation Is Increased With Myeloablative Conditioning, CMV Viremia and Acute Gvhd

IntroductionBK virus associated hemorrhagic cystitis (HC) is a common complication post allogeneic hematopoietic cell transplantation (HSCT). A number of retrospective studies have suggested a variety of risk factors for HC following HSCT including busulfan-containing myeloablative conditioning regimens, unrelated donors, and the occurrence of graft versus host disease (GVHD). However, these risk factors were not observed consistently and have led us to review the incidence and risk factors for BK-HC confirmed by microbiologic test at our institution. Methods and patientsWe retrospectively reviewed 339 patients who received HSCT between 2009 and 2012 at the Princess Margaret Cancer Centre, Toronto Canada. The diagnosis of BK-HC was based on clinical features, urinalysis and detection of BK virus by urine PCR. The cumulative incidence of BK-HC was calculated considering competing risks and Gray's method was used for univariable analysis. To confirm the results of the univariable analysis, we conducted a multivariable analysis using the Fine-Gray method and EZR software. ResultsOut of 339 patients, 79 patients (23.3%) developed BK-HC. The median onset was 47 days (range 16-749) after HSCT. The median time to resolution of symptoms was 21 days (range 4-260). The clinical grades were as follows: grade 1 (n=14, 17.9%), 2 (n=34, 43.0%), 3 (n=22, 27.8%) and 4 (n=8, 10.1%). Sixty-two patients (83.7%) out of 74 had urine BK virus PCR testing which showed a high titer of BK virus PCR (mean 2.56x1010 (SD 7.41x1010) and median 6.19x109). The cumulative incidence of BK-HC at 2 years was 24.0% (95% CI, 19.4-28.9). There was no difference in transplant characteristics between the HC and non-HC groups, in terms of age, gender, gender match, diagnosis, HLA match and donor type, stem cell source, T-cell depletion, GVHD prophylaxis and CMV serostatus. However there was a higher incidence of BK-HC in the group of patients receiving myeloablative conditioning (62/208, 29.8%) vs (17/132, 12.9%, p<0.001) in the reduced intensity conditioning group. In the univariable model three risk factors for BK-HC were identified: myeloablative conditioning (31.2% in myeloablative vs 12.4% in reduced intensity; p<0.001), HLA mismatch (34.9% in mismatched vs 22.0% in matched, p=0.027), CMV viremia (28.6% in CMV+ vs 19.1% in CMV-; p=0.023) and acute GVHD (30.2% in aGVHD vs 12.0% in without aGVHD; p<0.001). Unrelated donor or T-cell depletion did not increase the risk of HC in univariable analysis. Multivariable analysis confirmed that these 3 factors were independent risk factors for BK-HC: myeloablative conditioning (p<0.001; HR 2.38, 95% CI, 1.35-4.17), CMV viremia (p=0.012; HR 1.77, 95% CI, 1.10-2.83) and aGVHD (p<0.001; HR 2.26, 95% CI, 1.23-4.13). HLA mismatch was not an independent risk factor. The 2-year overall survival (OS) of the study cohort was 51.6%. The development of BK-HC did not affect transplant outcomes with respect to OS (p=0.446). We observed a higher incidence of 1-year non-relapse mortality (NRM) in the BK-HC group 39.7% vs 24.2% in the non HC group, but this was not confirmed in the multivariable analysis. ConclusionSymptomatic BK-HC is a frequent complications following HSCT with a 2-year cumulative incidence of 24.0%. Three risk factors for BK-HC were identified including myeloablative conditioning, CMV viremia and aGVHD. While this infection did not adversely impact survival, it is associated with significant morbidity and constitutes an unmet need given the lack of effective therapy. Disclosures:No relevant conflicts of interest to declare.

Myeloablative Hematopoietic Cell Transplantation (HCT) for Low and Intermediate Disease Risk Index Myeloid Malignancies Results in Better Outcomes Compared to Reduced Intensity HCT

The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) remains an unsettled question. The recent Blood and Marrow Transplant Clinical Trial Network BMTCTN 0901 randomized phase III study showed that Myeloablative conditioning (MA) results in better relapse-free survival and a trend towards better overall survival compared to reduced intensity conditioning (RIC). The findings of BMTCTN 0901 though contradicts several prior studies addressing the same question, was limited by the fact that most patients in the RIC received fludarabine/low dose Busulfan and the study was not designed to assess the effect of intensity on patients with different disease risk index (DRI) groups. Acute myeloid leukemia and myelodysplastic syndrome patients with low/intermediate DRI tend to respond well to chemotherapy and can potentially be cured with chemotherapy regimens alone. On the other hand, high and very high risk DRI myeloid malignancies have a high relapse rate and very low rates of success with chemotherapy only approach. We hypothesize that conditioning intensity benefit is limited to patients with low/intermediate risk DRI and no such benefit is seen in the high/very high risk DRI myeloid malignancy patients. To answer this question, we retrospectively analyzed AML/MDS HCT recipients with low/intermediate DRI to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and non-relapse mortality (NRM). Survival was calculated using the Kaplan-Meier estimator. Univariate analysis with Gray test and log-rank test will be used for cumulative incidence and survival respectively. Cox regression models were built to study the effect of conditioning intensity adjusted for other significant factors on OS, NRM, DFS, relapse and graft-versus-host disease (GVHD). Conditioning intensity was retained in the cox models and other variables were selected to be included if the P-value was less than 0.05.A total of 232 consecutive allogeneic HCT recipients with low/intermediate DRI myeloid malignancy (AML 170, MDS 60) were included in the analysis with a median follow up of 37 months. Median age was 55 years (18, 75) and 83% were of white race. Patient and transplant related characteristics were as follows: 42% RIC, 11% Myeloablative high dose TBI, 47% non-TBI Myeloablative conditioning; 21% bone marrow graft; 31% matched related donor transplant MRDT, 47% matched unrelated donor transplant MUDT, 22% haploidentical donor HIDT; 49% had hematopoietic cell transplant comorbidity index HCT-CI ≥3 ; donor/recipient female to male 21%; and donor/recipient CMV +/+ 42%, -/- 19%, other 39%. Both MA and RIC groups had similar patient, disease and transplant related characteristics except for a higher percentage of MA recipients received methotrexate as part of their GVHD prophylaxis compared to RIC (78% vs 55%, p<0.001). Recipients of Myeloablative conditioning had better overall survival estimate (3-year 69% vs 57%, p=0.001), DFS (3-year 65% vs 51%, p=0.003) and lower relapse cumulative incidence (3-year 17% vs 32%, p=0.01) but similar NRM (3-year 19% vs 17%, p=0.04) to RIC recipients (figure 1). There was no difference in the cumulative incidence of grade 2-4 acute and moderate-severe GVHD between Myeloablative and RIC groups. Multivariate analysis revealed MA conditioning to be associated with better DFS (HR 0.58, 95% CI 0.39-0.88, p=0.01), lower relapse (HR 0.56, 95% CI 0.32-0.97, p=0.038) and similar NRM (HR1.11, 95% CI 0.54-2.26, p=0.781) compared to RIC. When same analysis was performed for high/very high DRI myeloid malignancy patients (N=247), conditioning intensity had no effect on OS, DFS, Relapse and NRM (P value>0.10 for all).Myeloablative conditioning results in better overall survival and disease control when compared to RIC among AML/MDS patients with low/intermediate DRI risk group. This benefit is not shown among high/very high DRI risk patients. [Display omitted] DisclosuresSolh:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding; Amgen: Speakers Bureau.

Myeloablative Versus Reduced Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Analysis.

The conditioning regimens used for the allo-HSCT include either myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimens based on the age, performance status and co-morbidities. Studies comparing the survival outcomes of RIC and MAC allo-HSCT in AML and MDS patients have reported contradictory results. We therefore retrospectively analyzed our data of AML and MDS patients who received MAC and RIC allo-HSCT at our center and compared the long term outcome of the two conditioning regimens. One hundred twenty six consecutive patients were evaluated, 32 (25.4%) underwent MAC allo-HSCT and 94 (74.6%) underwent RIC allo-HSCT. The most common MAC regimen used was busulfan plus cyclophosphamide and the most common RIC regimen used was fludarabine plus melphalan. The median age was higher in RIC group (44years, range 4-75years) compared to MAC group (31 yrs, range 6-51 yrs, p = 0.001). There was no significant difference in terms of overall survival (p = 0.498), relapse-free survival (p = 0.791) and non-relapse mortality (p = 0.366) between the two groups. In multivariate analysis, only chronic graft-versus-host disease resulted in decreased risk of relapse and improved overall survival irrespective of the conditioning regimens used.

Don't Let the HCT-CI Fool You: Similar Outcomes with Myeloablative CD34+ Selected Allo-HCT Compared to Unmodified RIC Allo-HCT in Patients with AML or MDS and High Comorbidity Scores.

Introduction The BMT CTN 0901 phase 3 trial showed improved relapse-free survival (RFS) in patients with AML or MDS with myeloablative-conditioning (MAC) vs. Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). However, overall survival (OS) increase was not statistically significant because of higher non-relapse mortality (NRM) compared to RIC allo-HCT. HCT-CI ≥ 3 also predicts for poor OS related to high NRM in patients undergoing MAC CD34+ selected allo-HCT. Objectives We aimed to evaluate impact on OS, NRM and RFS of MAC CD34+ selected vs. RIC allo-HCT in patients with high comorbidity burden. Methods We retrospectively compared the outcomes of 221 patients with AML or MDS with HCT-CI ≥ 3 who underwent MAC CD34+ selected (n=157) vs. RIC allo-HCT (n=64) at our institution from 2009 to 2017. The indication for MAC CD34+ vs. RIC allo-HCT was based on multidisciplinary consensus and primary physician's choice. Results Patients in the RIC group were older, had a higher proportion of high disease risk index (DRI), and higher use of matched unrelated donors compared to the MAC CD34+ group. HCTCI grades were balanced between the two cohorts, but the RIC group had a higher though non-significant proportion of patients with HCTCI > 5 (Figure 1). When comparing the MAC CD34+ vs. unmodified RIC cohorts, respectively, no difference was seen in OS [43% (95% CI 32-59) vs. 53% (95% CI 46-52), p=0.37], NRM [31% (95% CI 19-44) vs. 30% (95% CI 23-38), p=0.74], and relapse-free survival (RFS) [34% (95% CI 23-49) vs. 48% (95% CI 41-57) p=0.1], even when adjusting for age, DRI, and donor differences (Figure 2). However, incidence of acute and chronic graft versus host disease (GVHD) was lower for MAC CD34+ allo-HCT. When evaluating outcomes by HCT-CI subgroups (3, 4-5 and >5), MAC CD34+ allo-HCT resulted in higher 3-year estimated RFS [54% (95% CI 44-68) vs. 28% (95% CI 14-58), p=0.03] in patients with HCT-CI = 3, though this did not translate into an OS advantage [44% (95% CI 27-73) vs 59% (95% CI 48-72), p=0.26], possibly related to higher though non-significant NRM [16% (95% CI 4-35) vs. 28% (95% CI 18-39), p=0.26] (figure 3). When adjusting for differences in age, DRI, and donor, the difference in RFS was no longer statistically significant (p=0.13). Conclusions Though limited by their retrospective nature, our data suggest that CD34+ selected allografts after myeloablative conditioning can be feasible in selected patients with comorbidity scores over 3 with low rates of acute and chronic GVHD. However, further prospective studies are needed to reduce NRM and optimize this treatment platform in older patients with comorbidities.

Comparison of Fixed Dose, Reduced-Intensity Conditioning with Busulfan and Fludarabine to Reduced PK-Guided Busulfan AUC Conditioning in Patients Undergoing Hematopoietic Stem Cell Transplant for AML/MDS

<h3>Introduction</h3> The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to receive allogeneic hematopoietic stem cell transplant (HSCT) by reducing toxicities associated with myeloablative conditioning (MAC). Key in reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). Prior studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day × 4 days in a subset of patients to balance toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. <h3>Objectives</h3> The objectives of this study were to assess differences in safety and efficacy in patients receiving different busulfan dosing strategies. <h3>Methods</h3> To compare regimens, a retrospective cohort study was conducted of patients undergoing HSCT for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to count recovery; incidence of acute and chronic graft vs host disease (GVHD); key adverse effects. <h3>Results</h3> Seventy-four patients were eligible. There were no differences in disease risk status, rate of AML with myelodysplastic changes, or therapy-related AML/MDS. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different (p=0.37) (A). Eighteen-month overall survival was also not significantly different (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not also significantly different (p=0.82, p=0.18, respectively). There was a significant difference in the 18-month cumulative incidence of relapse in favor of AUC 4,000 (hazard ratio 4.08, 95% CI 1.15-14.5) (C). Grade 2-4 mucositis was more common in the AUC 4,000 group (p<0.01), but there were no significant differences in other adverse effects. <h3>Conclusion</h3> Though no difference existed in disease risk between groups, regimen choice was driven by physician judgement, perceived fitness, and ability to tolerate toxicity. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower incidence of relapse. Toxicities other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed.

Myeloablative Vs Reduced-Intensity Conditioning for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Among Patients over 50 Years Old Who Achieved Negative Minimal Residual Disease

Reduced-intensity conditioning (RIC) regimen for allogeneic hematopoietic cell transplantation (HCT) has widely used in elderly patients to reduce the risk of treatment-related toxicities. Previous studies showed that RIC lead to lower non-relapse mortality (NRM), but higher relapse rate compared to myeloablative conditioning (MAC). Over the last decade, tyrosine kinase inhibitor (TKI) has dramatically improved the long-term outcomes for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) and many patients achieved negative results of minimal residual disease (MRD) at HCT. However, available data regarding the impact of conditioning intensity in patients with negative-MRD are limited. In this nationwide retrospective cohort study, we included patients over 50 years old with Ph-positive ALL who received TKI before HCT, achieved negative-MRD at HCT, and underwent their first allogeneic HCT between 2008 and 2017. Patients who received in vivo T-cell depletion or post-transplant cyclophosphamide were excluded. In this study, 90 and 136 patients received MAC and RIC regimen, respectively. MAC consisted of the vast majority of cyclophosphamide and total-body irradiation. Fludarabine and melphalan with or without low dose total-body irradiation (less than 4 Gy) were the majority of RIC regimen. The median age of patients with MAC and RIC was 54 and 60, respectively. Patient characteristics were not significantly different except for patient age and donor source between MAC and RIC groups. There were no significant differences on overall mortality, hematological relapse, and NRM, respectively (Figure). Even in multivariate analyses, RIC was not significantly associated with overall mortality (hazard ratio [HR], 1.09; 95% confidential interval [CI], 0.67-1.77; P = 0.724), hematological relapse (HR, 1.97; 95% CI, 0.75-5.15; P = 0.170), and NRM (HR, 0.84; 95% CI, 0.49-1.45; P = 0.540), respectively. Post-hoc analyses suggested that RIC resulted in the superior overall survival due to lower incidence of NRM in patients with poor performance status or high HCT comorbidity index. In conclusion, RIC is a reasonable option for patients over 50 years with negative-MRD at HCT.

Reduced-intensity versus Myeloablative Conditioning Regimens for Younger Adults with Acute Myeloid Leukemia and Myelodysplastic Syndrome: A systematic review and meta-analysis.

Background: Historically, reduced-intensity conditioning (RIC) was recommended to be performed for older patients who were considered ineligible for myeloablative conditioning (MAC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the evidence regarding the optimal conditioning intensity in younger patients with AML or MDS is weak and contradictory.Methods: PubMed, Medline, Embase, and other online sources were searched from the initial period to February 25, 2020. Odds ratios and 95% confidence intervals were calculated to estimate pooling effects.Results: Four randomized controlled trials (RCTs) about conditioning intensity involving 633 patients were included. There were no significant differences of 1/2/4/5 years progression-free survival (PFS) and relapse incidence (RI) between two conditioning intensities. Overall survival (OS) was similar at 1/2/4 years, but patients receiving RIC had a higher OS at 5 years. Additionally, RIC were associated with lower non-relapse mortality, less grade II-IV and grade III-IV acute graft-versus-host disease (GVHD), and lower incidence of chronic GVHD compared with MAC regimens. Subgroup analysis showed similar OS and RI for AML patients, and there was a trend towards lower NRM and grade II-IV aGVHD in RIC group. Available data for MDS indicated that OS, PFS, and RI were comparable. For intermediate-risk patients, there was no evidence that RIC is inferior to MAC. However, for high-risk patients, MAC tends to perform better.Conclusions: Based on the above results, it might be concluded that RIC is a feasible treatment option for adults with AML or MDS younger than 66 years, particularly those with intermediate-risk disease. Future RCTs incorporating of risk stratifications are warranted to guide the optimal decision under certain conditions.

Comparison of Fixed Dose, Reduced-Intensity Conditioning with Busulfan and Fludarabine to Reduced PK-Guided Busulfan AUC Conditioning in Patients Undergoing Hematopoietic Stem Cell Transplant for AML/MDS

Background: Consolidation therapy with allogeneic hematopoietic stem cell transplant (HSCT) is recommended to prevent relapse and improve survival in patients with intermediate and poor risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Due to toxicity, older patients with comorbidities were historically not candidates for HSCT. The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to proceed to HSCT by reducing toxicities associated with myeloablative conditioning (MAC).The cornerstone of reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). This can be achieved by the use of patient-specific pharmacokinetic targets. Previous studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day x 4 days in a subset of patients to balance reduced toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. Methods: To compare the two regimens, a retrospective, IRB-approved cohort study was conducted. The inclusion criteria were as follows: age 18-89 years, HSCT for a diagnosis of AML or MDS, and fludarabine + busulfan conditioning regimen ± antithymocyte globulin. In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to neutrophil recovery; time to platelet recovery; incidence of acute and chronic graft vs host disease (GVHD); sinusoidal obstructive syndrome; febrile neutropenia; graft failure; and grade 3-5 mucositis, acute kidney injury, or hepatic dysfunction. The log-rank test was used to compare RFS and OS, and Cox proportional hazard regression model was used to estimate the hazard ratio. Gray's test was used for competing risks analysis of relapse, acute GVHD, and chronic GVHD. Fine and Gray regression models were used to estimate the hazard ratio. Results: Seventy-four patients who received conditioning from 2015-2018 with either AUC 4,000 or RIC were identified. Disease type was similar between groups with 61.8% AML in the AUC 4,000 group and 52.5% in the RIC group. There were no significant differences in disease risk status. In the AUC 4,000 group, 17.6% had either AML with myelodysplastic changes or therapy-related AML/MDS, compared to 17.5% in the RIC group. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different, at 66.9% with AUC 4,000 compared to 57.5% with RIC (p=0.37) (A). Eighteen-month overall survival was also not significantly different with 66.9% alive in the AUC 4,000 group and 60% in the RIC group (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not significantly different (p=0.82, p=0.18, respectively) (C,D). There was, however, a statistically significant difference in the cumulative incidence of relapse over 18 months in favor of the AUC 4,000 regimen (hazard ratio 4.08, 95% confidence interval 1.15-14.5) (E). Grade 2-4 mucositis was more common in the AUC 4,000 group (85.3% vs 30%, p&lt;0.01), but there were no significant differences in transaminitis, kidney injury, neutropenic fever, sinusoidal obstructive syndrome, or graft failure. Discussion: Though no significant difference existed in disease risk between the groups, choice of regimen was driven by physician judgement, perceived fitness, and ability to tolerate potential adverse effects. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower cumulative incidence of relapse. Adverse effects other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed. Figure Disclosures Brammer: Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. William:Guidepoint Global: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.