Myeloablative Conditioning Group Research Articles

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.

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.

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.

Allogeneic stem cell transplant outcomes between TBI-containing reduced intensity and myeloablative conditioning regimens for ALL in complete remission

Total-body irradiation (TBI)-based conditioning regimen is preferred in acute lymphoblastic leukemia (ALL). We retrospectively evaluated allogeneic stem cell transplant (alloSCT) outcomes of 86 adult ALL patients in complete remission (CR) who received TBI-containing reduced intensity (RIC) (Flu/Mel/TBI = 31) and myeloablative conditioning (MAC) (VP16/TBI = 47; CY/TBI = 8) between January 2005 and December 2019. All patients received peripheral blood allografts. Patients in the RIC group were older than the MAC group (61 years old versus 36 years, p < .001). Donor was 8/8 HLA-matched in 83% and unrelated in 65% of patients. Three-year survival was 56.04% for RIC and 69.9% for MAC (HR 0.64; p = .19). Propensity score-based multivariable Cox analyses (PSCA) did not demonstrate any difference in grade III–IV acute graft versus host disease (GVHD) (SHR 1.23, p = .91), chronic GVHD (SHR 0.92, p = .88), survival (HR 0.94, p = .92), and relapse-free survival (HR 0.66, p = .47) between both groups, while relapse rate was lower (SHR 0.21, p = .02) for MAC compared to RIC. Our study did not demonstrate any difference in survival for TBI-containing RIC and MAC alloSCT for adult ALL in CR.

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.

Pulmonary function is a strong predictor of 2-year overall survival and non-relapse mortality after allogenic hematopoietic cell transplantation.

The purpose of the study was to assess the validity of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and of pulmonary comorbidity prior to HCT in terms of predicting non-relapse mortality (NRM) and overall survival (OS). In this retrospective single-center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low-risk, intermediate-risk, and high-risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT-CI. In univariate analysis, the HCT-CI and the PCS were associated with OS after transplantation when comparing patients in high-risk groups with patients in low-risk groups. Using the PCS, the hazard ratios (HRs) of the 2-year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (p< .001) and 3.27 (p< .001), respectively, whereas the HRs using the HCT-CI were 1.83 (p< .001) and 2.57 (p= .002). The 2-year NRM incidence in the three risk-groups in the entire population was significant using both indexes. In the MAC group, the 2-year NRM was significant using the PCS (p= .003), but not using the HCT-CI (p= .23). Our study suggest that pulmonary function alone is a strong predictor of 2-year OS and NRM after HCT.

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.

HLA-Matched Related Hematopoietic Stem Cell Transplantation in Adolescents and Adults with Sickle Cell Disease: Comparison of Myeloablative Versus Non Myeloablative Approaches. Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) allowing a SCD-free survival over 95% among children with matched HLA-identical donor (Gluckman E. Blood, 2017; Bernaudin F. Haematologica, 2020). In adults, myeloablative HSCT is associated with more graft-versus host disease (GVHD) and higher toxicity (Cappelli B. Haematologica, 2019). More recent approaches using non myeloablative (NMA) conditioning regimen (3 gray (Gy) total body irradiation (TBI) plus alemtuzumab) followed by HLA-identical peripheral blood stem cells (PBSC) and post-transplant sirolimus appear safe in adults (Hsieh MM. JAMA, 2014), but incidence of graft failure might be higher than the one reported after myeloablative conditioning (MAC) (Alzahrani M. Br J Haematol, 2021). Here, we compare outcomes after MAC or NMA conditioning regimens in patients over 15 years old transplanted from a matched related donor (MRD).Patients and methodsAll consecutive patients transplanted for SCD from a MRD from January 2015 to October 2020 were eligible if they were over 15 years old and received a busulfan-based MAC conditioning regimen or a NMA conditioning regimen.Chimerism was studied by analyzing various polymorphisms after polymerase chain reaction (PCR) amplification of DNA obtained from whole blood cells. Rejection was defined as donor chimerism <5%. Event-free survival (EFS) was defined as the probability to be alive with blood donor chimerism over 20%.ResultsThirty-four patients were included: 20 in the MAC and 14 in the NMA groups. Median age at transplant was 17 years (range 15-46) without difference between groups. Forty four percent of patients had a history of cerebral vasculopathy, 79% of recurrent vaso-occlusive crises and 76% of acute chest syndrome. ABO major incompatibility was present in 15% of patients. There was no difference in patient characteristics according to the conditioning regimen group except for pre-transplant cerebral vasculopathy, more frequently reported in the MAC group: 70% versus 6% in the NMA group (p<0.001).In the MAC group, conditioning regimen associated busulfan (12.8 mg/kg IV), cyclophosphamide (N=17) or fludarabine (N= 3) and anti-thymoglobulin (ATG, mostly 20mg/kg). Stem cell source was bone marrow and post-transplant immunosuppression combined cyclosporine and mycophenolate or methotrexate. In the NMA group, conditioning regimen associated 3Gy TBI and alemtuzumab (1mg/kg), followed by PBSC and post-transplant sirolimus.All patients engrafted and no secondary graft failure was observed. One MAC group patient died from GVHD. The 2-year overall and EFS were 95% (CI 95%: 85.9-100) in the MAC group (median follow-up of 39 months (range 8-63)) and 100% (CI 95%: 100-100) in the NMA group (median follow-up of 17 months (range 9-39)). Incidence of grade II-IV acute GVHD was 0% in the NMA group versus 20% in the MAC group (p=0.12). Incidence of chronic GVHD was 0% in the NMA group versus 25% in the MAC group (p=0.06). From the 27 patients with follow-up>12 months, 17/17 discontinued immunosuppressive therapy in the MAC group versus 8/10 in the NMA group. Hematopoietic recovery was faster in the NMA group with less platelet and red blood cell units transfused (Table). Throughout the follow-up, median donor chimerism was higher after MAC transplantation than after NMA transplantation: 98% (range 69-100) and 86 % (range 50-97) respectively at 1 year (p=0.017). Donor chimerism remained above 50% throughout the follow-up in all patients except 1 of the NMA group who displayed stable chimerism between 40 and 50%. All patients achieved HbS level close to the one of their donors. There was no difference between the 2 groups regarding occurrence of infections. MAC transplant was more often associated with hypertension, neurological complications, severe mucositis and need of enteral or parenteral nutrition. Moreover, duration of hospitalization was longer in MAC group: 54 days (range 39-192) versus 35 days in the NMA group (range 21-52) (p<0.001) (table).ConclusionIn this series of adolescents and adults transplanted for SCD, the survival without SCD was excellent with a faster hematological recovery and a lower toxicity after NMA HSCT. Longer follow-up is required to confirm stable mixed donor chimerism and the cure of SCD after NMA approach. [Display omitted] DisclosuresJoseph: bluebird bio: Consultancy. Boissel: Servier: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Pondarré: ADDMEDICA: Honoraria.

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.

Hematopoietic Stem Cell Transplantation in 65 Patients with Leukocyte Adhesion Deficiency Type I and Type III — A Retrospective Multi-Center Study

Leukocyte adhesion deficiency (LAD) is an autosomal recessive, primary immunodeficiency disorder, characterized by lethal deep tissue infections, leukocytosis with impaired pus-formation, delayed wound healing and hyper-inflammation. Life expectancy of affected patients is severely shortened. LAD-I is caused by defective expression of beta-2 integrin on immune cells, resulting in impaired leukocyte adhesion and migration. LAD-II is a metabolic disease with syndromal features. LAD-III is caused by mutations in the FERMT3 gene resulting in activation defect of all beta-integrins. LAD-III is characterized by leukocyte adhesion/migration deficiency and an additional Glanzmann's thrombasthenia-like syndrome.In this retrospective multi-center study, data were collected from the European Group for Blood and Marrow Transplantation (EBMT) registry. This study included 65 children from 14 European and Asian centers with either LAD-I (n=60) or LAD-III (n=5), all receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT) from 2008 to 2015.Median age at diagnosis was 0.3 years (yrs); interval from diagnosis to alloHSCT was 8.1 months (median; range 0.6 to 134.5 months). An HLA-identical sibling or matched non-sibling family donor was available for 35 (54%) patients; 28 (43%) received the allograft from a matched unrelated donor and 2 (3%) patients were transplanted from an HLA-haplo-identical family donor. Stem cell source was bone marrow in 37 (58%) patients, peripheral blood in 17 (26%) and cord blood in 10 (16%) of the cohort. Reduced intensity conditioning (RIC) was used in 19 (29%) and myeloablative conditioning (MAC) in 46 (71%) patients. Half of the cohort (n=33) received a busulfan-based conditioning regimen; treosulfan was used in 18 (28%) patients. Serotherapy was applied to 71% of the cohort and consisted primarily of ATG (85%).The overall survival of the cohort was 80% (95%CI: 70-91%) at 24 months, and 77% (95%CI: 65-89%) at 60 months post alloHSCT. In total 12 patients died. The cause of death was GVHD (n=6) and infections (n=6).Primary or secondary graft failure occurred in 9 patients. The incidence of graft failure at 24 months was 11% (95% CI: 7-24%) in RIC and 14% (95% CI: 3-24%) in MAC group. A second alloHSCT was performed in 8 patients; it was successful in 7 cases.At 100 days, 10% (95% CI: 2-17%) and 16% (95% CI: 7-25%) of patients developed grade I-II and grade III+IV aGVHD, respectively . Extensive chronic GVHD was reported in 2 cases.AlloHSCT restored leukocyte function in LAD-I and both leukocyte and thrombocyte function in LAD-III leading to complete remission of symptoms with hematological and immunological reconstitution. Transplantation should be performed early in the course of the disease and prior to the occurrence of life-threatening infectious complications. DisclosuresBader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

Comparison of Myeloablative versus Reduced-Intensity Conditioning Regimens in Allogeneic Stem Cell Transplantation Recipients with Acute Myelogenous Leukemia with Measurable Residual Disease-Negative Disease at the Time of Transplantation: A Retrospective Cohort Study

The ideal conditioning intensity in allogeneic hematopoietic stem cell transplantation (HSCT) is evolving. Previous prospective studies comparing myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) regimens in adults with acute myelogenous leukemia (AML) have shown mixed results. In many of these studies, patients were not stratified based on measurable residual disease (MRD). We evaluated the effect of conditioning intensity on the outcomes of AML patients in complete remission (CR) with flow cytometry evidence of MRD negativity. A total of 135 patients age 20 to 75 years with AML in CR1 or CR2 and flow cytometry evidence of MRD negativity who underwent allogeneic HSCT at our center between 2011 and 2019 were evaluated. We compared overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD) in recipients of MAC (n=89) and RIC (n=46). Although the patients receiving RIC were older (62 versus 51 years; P < .0001), there were no statistically significant differences between the groups in terms of Eastern Cooperative Oncology Group and European Leukemia Network risk criteria and disease status (CR1 or CR2) at the time of transplantation. At a median follow-up of 24.6 months, no statistically significant differences in OS (hazard ratio [HR], 0.78; 95% confidence interval [CI] 0.42 to 1.42, P=.411) or RFS (HR, 1.004; 95% CI, 0.48 to 2.09, P=.99) were identified. The cumulative incidence of NRM (HR, 0.595; 95% CI, 0.24 to 1.48; P=.2644) and relapse (HR, 1.007; 95% CI, 0.45 to 2.23; P=.9872) was not different between the 2 groups. Grade II-IV and grade III-IV acute GVHD were more frequent in the MAC group (39.3% verses 19.9% [P=.018] and 19.3% versus 2.3% [P < .001], respectively), as was moderate/severe chronic GVHD (23.6% versus 15.8%; P=.038). Our data indicate that conditioning intensity did not appear to affect OS, RFS, NRM, and relapse risk in patients with MRD-negative AML as measured by flow cytometry. RIC resulted in less severe acute and chronic GVHD.

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.

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.

Conditioning‐based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991‐2012) on behalf of EBMT CMWP

The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative(NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. A retrospective analysis of the EBMT database (1991-2012) was performed. A total of 344 patients aged between 40 and 60years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54months, the probabilities of overall survival (OS) at 5years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P=.004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR=4.1, P<.001) but not after 2002 (HR=1.2, P=.276). From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

Allogeneic Stem Cell Transplantation Has Limited Benefit in Older Patients with Mixed Phenotype Acute Leukemia

Allogeneic Stem Cell Transplantation Has Limited Benefit in Older Patients with Mixed Phenotype Acute Leukemia