Matched Sibling Donor Research Articles

Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies. With a median follow-up of 41.6months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II-IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

Hematopoietic Stem Cell Transplantation Activity in China 2020–2021 During the SARS-CoV-2 Pandemic: A Report From the Chinese Blood and Marrow Transplantation Registry Group

Between 2020 and 2021, 31,525 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group throughout mainland China. In this report, we describe the activity and current trends for HSCT in China during the SARS-CoV-2 pandemic. In 2020, a total of 13,415 cases of HSCT were reported from 166 transplantation teams, and 75% (10,042 cases) were allogeneic HSCTs. In 2021, a total of 18,110 cases of HSCT were reported from 174 transplantation teams, and 70% (12,744 cases) were allogeneic HSCTs. Haploidentical donor (HID) transplantation accounted for 63% (7977 cases) of allogeneic HSCTs in 2021. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (37%) and acute lymphoblastic leukemia (23%), and the largest proportion of nonmalignant disease comprised aplastic anemia (13%). The peripheral blood stem cell source accounted for 41% of HIDs and 75% of matched sibling donors. The BuCy-based regimen (57%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu-based regimen (28%) and total body irradiation-based regimen (11%). This survey provides comprehensive information about the current activities and might benefit clinical physicians' decision planning for HSCT.

Cytomegalovirus infection is associated with rapid NK differentiation and reduced incidence of relapse in HLA matched sibling donor transplant patients.

The effect of cytomegalovirus (CMV) infection on leukemia relapse and the potential mechanism remains controversial. In this retrospective study, we evaluated the association among CMV infection, NK reconstitution and clinical outcomes in consecutive patients with hematologic malignancy who underwent HLA matched sibling donor transplantation (MST). In total, 228 patients were enrolled in the study between January 2010 and December 2011. The cumulative incidence of CMV infection on day 100 post-HSCT was 13.6 ± 4.9%. The probabilities of OS and DFS were 45.4% vs. 71.7% (P = 0.004) and 43.9% vs. 64.2% (P = 0.050) in the patients with CMV infection and without CMV infection, respectively. The cumulative incidence of treatment-related mortality (TRM) and relapse at 5 years was 48.6 ± 9.6% vs. 11.5 ± 2.9% (P < 0.001) and 6.2 ± 4.3% vs. 29.2 ± 3.9% (P = 0.024) in the patients with CMV infection and without CMV infection, respectively. In the multivariate analysis, CMV infection was associated with higher TRM, lower OS, and lower DFS. In addition, we found that CMV infection may promote the recovery of the absolute number of NK cells and promote the differentiation of NK cells post-MST. In conclusion, CMV infection may promote the recovery and differentiation of NK cells and was correlated with a lower relapse rate post-MST.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from Different Donor Types in Primary Refractory Acute Myeloid Leukemia: A Report from the ALWP of the EBMT

Background Primary refractory acute myeloid leukemia (prAML) is a poor prognosis disease for which allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option currently available. We aimed to estimate outcomes in the recent period, to analyze how different donor types may have impacted survival outcomes and to identify the most relevant predictive factors for allo-HSCT in prAML. Methods We conducted a retrospective multicenter study of adult patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who received an allo-HSCT between 2015 and 2020 for prAML. We considered HSCT performed from matched sibling donors (MSD), 10/10 unrelated donors (UD 10/10), 9/10 unrelated donors (UD 9/10) and haploidentical donors. Primary endpoint was leukemia-free survival (LFS), secondary endpoints were overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM). A Cox proportional hazards model was used for multivariate analysis. Results We included 1574 patients. Median age was 56.9 years (range 18.1-77.9). Cytogenetic risk was intermediate in 855 (54.3%), adverse in 679 (43.2%) and favorable in 40 (2.5%) patients. Donor type was distributed as follows: MSD n = 521 (33.1%), UD 10/10 n = 540 (34.3%), UD 9/10 n = 153 (9.7%), haploidentical n = 360 (22.9%). Table 1 summarizes patient and transplant characteristics. Patients allografted from an MSD were younger, allografted faster after diagnosis, more often received myeloablative conditioning (MAC) (details in Table 1) and had less secondary AML. Use of post-transplant cyclophosphamide, and bone marrow as a stem cell source were more frequent in haploidentical transplants. LFS at 2 years was significantly lower in haploidentical transplants (27% [95%CI: 22-32.2]) compared to MSD (35.2% [95%CI: 30.6-39.9]), to UD 10/10 (37.6% [95%CI: 33.2-42.1]) and to UD 9/10 (35.2% [95%CI: 27.1-43.5]) (p=0.003). Haploidentical transplants also showed inferior OS at 2 years: 31.2% (95%CI: 25.8-36.8) compared to 40.9% (95%CI: 35.9-45.8) in MSD, to 45.7% (95%CI: 41.1-50.2) in UD 10/10 and to 43% (95%CI: 34.5-51.3) in UD 9/10 (p=0.001). In the UD 9/10 group we observed the lowest RI (33.5% [95%CI: 25.6-41.6], 46.7% [95%CI: 41.8-51.4] in MSD, 42.7% [95%CI: 38.2-47.1] in UD 10/10, 46.8% [95%CI: 41.1-52.3] in haploidentical) (p=0.013), and the highest NRM (31.2% [95%CI: 23.6-39.2], 18.1% [95%CI: 14.6-21.9] in MSD, 19.7% [95%CI: 16.3-23.3] in UD 10/10, 26.2% [95%CI: 21.6-31.1] in haploidentical) (p=0.001). Of note, LFS at 2 years was reduced for adverse cytogenetic risk (26.1% for adverse, 39.8% for intermediate and 51.9% for favorable risk) (p=0.001) and significantly differed between reduced intensity conditioning (RIC) and MAC (37.4% and 29.8%, respectively) (p=0.033). In multivariate analysis, factors predicting poor LFS were haploidentical donor (hazard ratio [HR] 1.22 [95%CI: 1.01-1.48], p=0.043), adverse cytogenetic risk (HR 1.73 [95%CI: 1.51-1.99], p<0.0001) and time from diagnosis to HSCT (HR 1.03 [95%CI: 1.01-1.06], p=0.009), whereas factors associated with a better LFS were RIC conditioning (HR 0.85 [95%CI: 0.73-0.98], p=0.025) and good Karnofsky performance status (KPS) ≥ 80 (HR 0.74 [95%CI: 0.62-0.88], p=0.0009). Haploidentical transplant correlated with lower OS (HR 1.3 [95%CI: 1.06-1.61], p=0.014) and higher NRM (HR 1.69 [95%CI: 1.18-2.41], p=0.004) and adverse cytogenetic risk was associated with higher RI (HR 1.9 [95%CI: 1.6-2.24], p<0.0001), higher NRM (HR 1.47 [95%CI: 1.15-1.87], p=0.002) and lower OS (HR 1.82 [95%CI: 1.57-2.11], p<0.0001). Moreover, increased age predicted higher NRM (HR 1.31 [95%CI: 1.17-1.47], p<0.0001) and lower OS (HR 1.09 [95%CI: 1.02-1.16], p=0.006). Conclusions Our study identified risk factors for survival outcomes in the challenging setting of allo-HSCT for prAML. The most relevant factors are adverse cytogenetic risk and haploidentical donor, both associated with worse outcomes. Of note, the group of haploidentical transplants presented the highest rate of bone marrow used as a stem cell source, with a possible impact on survival outcomes. Longer time from diagnosis to HSCT negatively impacted LFS, whereas use of RIC and KPS ≥ 80 showed a higher LFS. As concerns secondary endpoints, unrelated donors achieved better OS compared to other donors, and UD 9/10 showed the lowest RI at the expense of the highest NRM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Conditioning Regimen Intensity and Donor Choice Do Not Impact Outcomes of Patients (pts) with Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) in First Complete Remission (CR1): An EBMT Analysis

Allo-HCT is a curative treatment for fit pts with intermediate and adverse risk AML who achieve CR1. The presence of minimal residual disease (MRD) before allo-HCT has been shown to increase risk of relapse and decrease survival. Here, we describe outcomes of pts with AML who received allo-HCT in CR1 and the impact of MRD before allo-HCT on outcomes. We identified 1032 pts with AML who received allo-HCT in CR1 between 2015 and 2020 from the EBMT registry. The median age was 53.6 (range, 18.1-82.5) years and 526 (51%) were male. Most (94%) pts had de novo AML. FLT3-ITD and NPM1 mutations were detected in 46% and 44% of pts, respectively and high-risk cytogenetics were present in 20%. >1 course of induction therapy was required by 18% of pts to achieve CR1 and 39% were MRD positive at time of allo-HCT. The median time from diagnosis to allo-HCT was 4.9 months. Of pts with FTL3-wild type (FLT3-wt) disease, 33% were MRD negative and 22% were MRD positive at time of allo-HCT. In pts with FTL3-ITD mutation, 29% were MRD negative and 17% were MRD positive at time of allo-HCT. Donor type was matched sibling donor (MSD) in 29% of pts (n=297), matched unrelated donor (MUD) in 47% (n=481), mismatched unrelated donor (MMUD 9/10) in 8% (n=88), or haploidentical donor (haplo) in 16% (n=166). HCT-specific comorbidity index (HCT-CI) was >3 in 22% of pts (n=190). Myeloablative conditioning (MAC) was administered to 45% of pts (n=470), while reduced intensity conditioning (RIC) was used in 55% (n=562). The most common conditioning regimen was fludarabine/busulfan in MSD (n=148, 50%), MUD (n=272, 57%) and MMUD (n=38, 43%) recipients, while thiotepa/fludarabine/busulfan was the most used in haplo-HCT (n=99, 60%). Total body irradiation (TBI) was given to only 8% of pts (n=84), mainly in haplo-HCT (n=29). Most (n=1002, 98%) pts received calcineurin inhibitors (CNI), tacrolimus or cyclosporine A, for graft-versus-host disease (GVHD) prophylaxis in addition to mycophenolate mofetil (43%) or methotrexate (38%). Post-transplant cyclophosphamide was used in 18% (n=191) of pts, with 71% (n=136) having received haplo-HCT, and anti-thymocyte globulin was given to 67% (n=689). The median follow-up was 24 months. At day 60, the cumulative incidence of neutrophil engraftment was 99%. The cumulative incidence of grade III-IV acute GVHD (aGVHD) was 9% at day 180. At 2 years, the cumulative incidence of extensive chronic GVHD (cGVHD) was 17%. At 2 years, relapse incidence (RI), NRM, overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) were 26%, 13%, 69%, 61%, and 48%, respectively. The main cause of death was primary disease in 55% of pts (n=157). Other causes of NRM were infections in 16% (n=45), and GVHD in 17% (n=47). In the multivariate analysis, compared to MSD, the use of MUD increased NRM (hazard ratio (HR) 1.86, p=0.02), GRFS (HR 1.28, p=0.039), aGVHD (HR 2.17, p<0.0001), and cGVHD (HR 1.36, p=0.044). The use of MMUD was associated with worse OS (HR 1.6, p=0.042) and higher risk of aGVHD (HR 2.11, p=0.003). Haplo-HCT was associated with higher incidence of aGVHD (HR 1.69, p=0.021) but lower risk of cGHVD (HR 0.63, p=0.033). Older age, lower performance status (PS), requiring >1 induction to achieve CR1, and FLT3-MRD positivity before allo-HCT were associated with worse LFS. Factors associated with lower OS were MMUD 9/10, older age, poor PS, >1 induction to achieve CR1, adverse cytogenetics, and FLT3-MRD positivity before transplant. In vivo TCD was associated with improved GRFS and lower risk of acute and cGVHD without increase of relapse. The use of RIC compared with MAC did not affect relapse, NRM or any other outcome. In conclusion, in pts with AML transplanted in CR1, those requiring >1 induction or with persistent FLT3-MRD positivity at time of allo-HCT had lower OS. Strategies to improve induction therapy, possibly through the addition of targeted agents, aiming to improve CR rates and deepening responses could potentially improve OS after allo-HCT. The use of RIC was associated with similar outcomes compared to MAC. This finding is particularly important for older pts or those with high HCT-CI scores unlikely to tolerate MAC. Survival after MSD allo-HCT is comparable to MUD and haplo, a finding that is in accordance with previous results for haplo and MUD as valid alternative donors in the absence of MSD. The use of MMUD was associated with lower OS compared to MSD and should be used as a last resort donor in this setting.

Comparison of Allogeneic Hematopoietic Cell Transplantation Outcomes from Younger Matched Unrelated Donor Versus Older Sibling Donor for Acute Myeloid Leukemia

Background: Aging population has resulted in an increase in the incidence of acute myeloid leukemia (AML). The median age of diagnosis for AML is 68 years. Allogeneic hematopoietic cell transplant (alloHCT) is a curative modality for patients with AML, however, disease relapse remains a major issue. Human leukocyte antigen (HLA)-matched sibling donors (MSD) are considered the preferred donor type in clinical practice. However, with increasing median age of patients, sibling donors for these patients are likely to be older as well, often with higher comorbidities. Prior registry studies demonstrated that older donor age is associated with inferior survival. A recent study in older MDS patients demonstrated reduced relapse risk with improved disease-free survival (DFS) with younger matched unrelated donors (MUD). However, the impact of donor age and type on alloHCT outcomes in AML patients remains unknown. Methods: This retrospective cohort study accessed data from the Center for International Blood and Marrow Transplant Research database (CIBMTR) in AML patients 50 years or older undergoing alloHCT from older (>50) MSDs or younger (<35) MUDs between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host-disease (GVHD) prophylaxis strategies. Other exclusion criteria were recipients of ex vivo T-cell depleted grafts, mismatched unrelated donor, cord blood or identical twin transplants. The primary outcome, compared between the 2 donor age groups, was relapse risk, and secondary outcomes included non-relapse mortality (NRM), DFS, and overall survival (OS). Cumulative incidence estimates were calculated for competing risks outcomes. To evaluate potential risk factors, multivariable cox regression was used, and relevant transplant-related covariates were considered. Interactions between the main effect (donor age group) and significant risk factors were tested. Fine and gray model was used for NRM and relapse. Results: Among 4684 eligible patients in the study cohort, 1736 underwent alloHCT with an older MSD (median age, 61 [range: 50-80]) whereas 2948 received transplant from a younger MUD (median age, 63 [range: 50-84]). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (HR 0.86; 95% CI, 0.77-0.96; p=.005) as compared to older MSDs (Table 1; Figure 1). The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs (35%; 95% CI, 33-37%) versus older MSDs (41%; 95% CI, 38%-43%) (p=.003) (Table 2). NRM was reported in 2 subgroups of transplant years (2011-2015 and 2016-2018) as there was significant interaction between the main effect (MUD vs MSD) and alloHCT year (p=.003). Younger MUDs conferred an increased NRM (HR 1.24; 95% CI, 1.04-1.49; p=.016) compared to older MSDs in the earlier period of 2011-2015, whereas the NRM was lower with younger MUDs in the latter period of 2016-2018 (HR, 0.78, 95% CI, 0.64-0.96; p=.017) (Table1; Figure 1). While there was no difference in the adjusted cumulative incidence of NRM at 5 years in the latter period (17% vs 20%; p=.147), NRM was significantly higher in AML patients who underwent alloHCT between 2011 and 2015 from a younger MUD (28%; 95% CI, 25-30%) compared to older MSDs (24%; 95% CI, 20%-27%; p=.045) (Table2). There was no difference in OS or DFS rates of alloHCT with younger MUDs vs older MSDs (OS: HR 1.02; 95% CI, 0.94-1.12; p=.607; DFS: HR 0.92; 95% CI, 0.85-1.01; p=.073) (Table 1; Figure 1). While the adjusted 5-year OS probability was 47% in each of the 2 cohorts (p=0.95), the adjusted 5-year DFS probability was 44% with younger MUDs (95% CI, 42%-46%) as compared to 41% with older MSDs (95% CI, 38%-43%; p=.04) (Table2). Conclusions: This large study from a prospectively collected registry data found significant relapse reduction in AML patients who underwent alloHCT with younger MUDs as compared to older MSDs and highlights that a younger MUD donor type exerts a stronger GVL effect and should be preferred when available. The higher NRM associated with younger MUDs has decreased in recent years, likely due to enhanced GVHD prophylaxis, infection preemption and preventative strategies, and supportive cares measures translating into improved leukemia-free survival. The results aid in donor selection and younger MUDs should be preferred in AML patients at a higher risk for post-alloHCT relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Prospective Study of Short-Term Chemotherapy Bridging Allogeneic-SCT in High Risk Peripheral T-Cell Lymphoma

Background: Results of conventional therapy in patients with peripheral T-cell lymphoma (PTCL) are dismal. Current guidelines recommend consolidation with autoSCT after 6 course of induction for most PTCL patients, but one third of new diagnosed patients progressed before autoSCT. Allogeneic hematopoietic stem cell transplantation (alloSCT) can cure relapsed/refractory patients, even those failured to HDT/ASCT. We hypothesized that AlloSCT as first-line consolidation post short course of induction could improve outcome in high-risk PTCL patients. Patients and Methods: A prospective study was conducted in high-risk PTCL patients (except ALK+ ALCL, and stage 1 with aaIPI 0) who were scheduled to undergo upfront allo-SCT after 3 x CHOEP(or -like) induction chemotherapy (registered in Clinical Trials, NCT03672084). Matched sibling donor(MSD) was the first choice, an unrelated donor or haploidentical family donor(Haplo-donor) search was performed in patients without MSD. From Jan.2018 to June 2022, 23 newly diagnosed patients enrolled, 8 PTCL-NOS, 1 ALK-negative ALCL, 6 AITL and 9 HSTL. After 1st line induction, 12 proceeded upfront alloSCT(10 in CR,1 in PR and 1 in SD), 9 of 11 with progressive disease received transplant after 2nd line chemotherapy (salvage alloSCT), the other 2 (diagnosed with PTCL-NOS) did not undergo transplantation because of PD. All patients received myeloablative conditioning and antithymocyte globulin was administered for Haplo-SCT (with 2.5mg/kg daily on days -5 to -2). All patients received cyclosporineA, MMF and short-term MTX as GVHD prophylaxis (Patients characters were in Table 1). Results: Untill July 30,2022，we had an interim results with the median follow up of 367(38-1237)d. For all transplanted patients, the median age was 38(4-63) years old, five had a MSD and the other 16 had a haplo-donor. Before alloSCT, 11 patients (52.4%) were in CR and 6 (28.6%) in PR, 1 (4.7%) in SD, and 3(14.3%) in PD. All but one patients had CR post alloSCT, 1 in PR received donor lymphocyte infusion(DLI) on D30 then had got CR on D60. One patient received a second alloSCT from another haplo-donor because of secondary graft failure. Acute GVHD of grade II-IV occurred in 9 of 21 patients (42.9%) (6 of grade III-IV). Thirteen of 20 (65%) evaluable patients developed chronic GVHD, which was extensive in 4 cases(20%). Four patients, all diagnosed with HSTL, experienced with post-SCT relapse on day 60,75, 180 and 455 respectively. Two had response to salvage chemotherapy with DLI, and stay in CR at last follow-up. Three patients died, 2 of lymphoma and 1 of pneumonia on day 280. The estimated 1- and 2-year event-free survival (EFS) in all transplanted cases were 78% and 67%, and those of overall survival(OS) were all 83%. The D100 and 1-y toxicity-related mortality(TRM) were 0% and 6.4%, respectively. There were no differences in PFS and OS between upfront and salvage alloSCT. The patients who diagnosed with HSTL had a significant poor PFS compared to other types of PTCL, with the 1y PFS of 56% vs 92% (p=.017), and had a comparable 1-y OS ,78% vs 92% (p=.337). This result may due to the higher relapsed rate of HSTL (44% vs 0%, p=0.003). So we involved a prophylaxis DLI in HSTL patients recently. Conclusions: Upfront AlloSCT in high-risk PTCLs was feasible with low TRM, and it could provide long-term disease control. And the strategy of haplo-donor SCT can bring more patients to AlloSCT. However, half of patients had progressed disease after 1st line induction, due to the strong anti-lymphoma effect of allograft, salvage alloSCT had been shown increased response rate in this group of refractory patients. The treatment strategy of short-term induction followed by alloSCT may improve the outcome for high-risk PTCL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Younger Matched Unrelated Donors Confer a Decreased Relapse Risk As Compared to Older Sibling Donors for Adult B-Cell ALL Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: The incidence of acute lymphoblastic leukemia (ALL) has increased due to aging population and the median age at diagnosis is 56 years among adults. Allogeneic hematopoietic cell transplant (alloHCT) offers cure for ALL patients, however, disease relapse remains a major issue. Human leukocyte antigen (HLA)-matched sibling donors (MSD) are considered the ideal donor type, mainly due to lower incidence and severity of graft-versus-host-disease (GVHD) and improved disease-free survival (DFS) in ALL. However, siblings are also likely to be older, often with higher comorbidities, and adult ALL patients typically undergo reduced-intensity conditioning and need novel strategies to reduce the post-alloHCT relapse risk. While recent data have suggested relapse reduction and survival benefit with younger matched unrelated donors (MUD) in AML and MDS, the impact of donor age on alloHCT outcomes in adult ALL patients remain unknown. Methods: This retrospective cohort study from the Center for International Blood and Marrow Transplant Research database (CIBMTR) data in B-cell ALL patients 50 years or older, undergoing alloHCT from older (>50) MSDs or younger (<35) MUDs between 2011 and 2018, included common allograft types (PB vs BM), conditioning regimens (RIC/NMA vs MAC), and graft-versus-host-disease (GVHD) prophylaxis strategies (FK-based vs CSA-based vs. others). Other exclusion criteria were recipients of ex vivo T-cell depleted grafts, recipients of mismatched unrelated donors, cord blood or identical twin transplants. The primary outcome, compared between the 2 donor age groups, was relapse risk whereas secondary outcomes included non-relapse mortality (NRM), DFS, and overall survival (OS). Cumulative incidence estimates were calculated for competing risks outcomes, including NRM and relapse. The Kaplan-Meier method was used to estimate the probabilities for survival. To evaluate potential risk factors, multivariable cox regression was used, and relevant transplant-related covariates were considered. Interactions between the main effect (donor age group) and significant risk factors were tested. Fine and Gray model was used for NRM and relapse. Given the multicenter nature of the database, center effect was tested for OS by fitting a gamma frailty model. Results: Among 925 eligible patients in the study cohort, 386 underwent alloHCT with an older MSD (median age, 59 [range: 50-75]) whereas 539 received transplant from a younger MUD (median age, 60 [range: 50-77]). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (HR 0.68; 95% CI, 0.53-0.87; p=.002) versus older MSDs (Table 1; Figure 1). The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs compared to older MSDs (26% vs 37%; p=.001) (Table 2). Younger MUDs conferred an increased NRM compared to older MSDs (HR 1.38; 95% CI, 1.05-1.82; p=.02) (Table1; Figure 1). The adjusted cumulative incidence of NRM at 5 years was also significantly higher in B-ALL patients who underwent alloHCT from younger MUDs compared to older MSDs (31% vs 22%; p=.006) (Table2). There were no differences in OS or DFS rates of alloHCT with younger MUDs vs older MSDs (OS: HR 1.09; 95% CI, 0.90-1.32; p=.37; DFS: HR 0.95; 95% CI, 0.79-1.14; p=.57) (Table 1; Figure 1). The adjusted 5-year OS probability was 48% in younger MUDs (95% CI, 43%-52%) and 51% among older MSDs (95% CI, 45%-56%; p=0.37). The adjusted 5-year DFS probability was 44% with younger MUDs (95% CI, 40%-49%) compared to 42% with older MSDs (95% CI, 37%-47%; p=.59) (Table2). Conclusions: This is the largest study to date performed in a mature, prospectively collected registry cohort that aids in donor selection and found significant relapse reduction in adult B-ALL patients who underwent alloHCT with younger MUDs as compared to older MSDs. The results highlight that younger MUD donor type exerts a stronger GVL effect and should be preferred in patients at a higher risk for post-alloHCT relapse. The higher NRM associated with younger MUDs will need enhanced GVHD prophylaxis, infection preemption and preventative strategies, and supportive cares measures to consolidate the leukemia-free survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Second Haploidentical Stem Cell Transplantation (HAPLO-SCT2) after Relapse from First Haplo-SCT Is Feasible and Produces Results That Are Comparable to Data Reported after Second SCT in an HLA-Matched Setting - a Study on Behalf of the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Introduction For patients with high-risk acute leukemia (AL) lacking a matched sibling donor (MSD) or matched unrelated donor (MUD), an allogeneic stem cell transplant (alloSCT) from a haploidentical (HAPLO) donor is an increasingly used alternative. However, available data on the treatment of relapse after HAPLO-SCT is scarce. After a first transplant from MSD/MUD, a second allogeneic SCT (alloSCT2) using either MSD or MUD achieved 2-year overall survival (OS) in 20-30% of patients, independently of donor type for alloSCT2 and donor change. In contrast, there is little information supporting the feasibility and efficacy of a second HAPLO-SCT (HAPLO-SCT2) in patients with AL transplanted from a HAPLO donor at alloSCT1. On behalf of the Acute Leukaemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT), we report here on the outcome of 82 patients with AL that underwent HAPLO-SCT2 after relapse from a first HAPLO- SCT in Europe. Methods This was a registry-based analysis of adults with acute myeloid leukemia and acute lymphoblastic leukemia (AML/ALL). All consecutive patients that had received a HAPLO-SCT2 without ex-vivo manipulation after hematologic relapse from HAPLO-SCT1 between 2007 and 2021 were included. Outcomes of interest were engraftment, OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse incidence (RI), graft-versus-host disease (GvHD), and GvHD-free, relapse-free survival (GFRS) rates after HAPLO-SCT2. Results Eighty-two patients (AML, n=63, 77%; ALL, n=19, 23%) were identified. The median age at HAPLO-SCT2 was 47.2 years (range, 18.3-69.3) for AML and 33.5 (range, 19.7-58.2) for ALL (p=0.002), median interval from HAPLO-SCT1 to relapse was 7.5 months. A donor change between HAPLO-SCT1 and 2 was chosen in 35 (62.5%) of AML and 17 (89.5%) of ALL patients (p=0.042). Cell source was peripheral blood/bone marrow (PB/BM) in 15/67 (18%/82%), respectively. At HAPLO-SCT2, 21 (33.3%) AML patients had a complete remission (CR) and 49 (59.8%) an active disease, whereas 12 (63.2%) ALL patients were in CR (p=0.02). Reduced intensity conditioning (RIC) was used for HAPLO-SCT2 in 57% of patients, and post-transplant cyclophosphamide (PTCy) was the most frequent GvHD prophylaxis (82%). Following HAPLO-SCT2, median follow-up was 38/19 months for AML/ALL patients, respectively. In the entire cohort, 87% of patients engrafted. Cumulative incidences (CI) at day 180 of acute GvHD grade 2-4 and 3-4 were 23.9% and 15.3%, respectively. The CI of chronic GvHD and extensive chronic GvHD at 2 years was 22.6% and 11.2%, respectively. Overall, 2-year OS and LFS from HAPLO-SCT2 were 34.3% and 25.4%; 2-year NRM, RI, and GRFS rates were 17.6%, 57% 15.1%, respectively (Figure 1). When analysed separately by diagnose, 2-year OS/LFS were 28.7%/22.3% for AML and 55.3%/38.4% for ALL, respectively. NRM was relatively low (16.2%/23.5% in AML/ALL), while RI was considerable, reaching 61.6%/38.2% for AML/ALL, respectively. Consequently, leukemia was the most frequent cause of death. Among the 63 patients with AML, an analysis of risk factors for OS/LFS from HAPLO-SCT2 identified disease status at HAPLO-SCT1 (p=0.008/p=0.026), and at Haplo-SCT2 (p=0.047/p=0.043) as well as the interval from HAPLO-SCT1 to relapse (p=0.001/p=0.001) as most important variables. In contrast, conditioning intensity and change of donor did not make a significant difference. No clear risk factor was identified for NRM. Conclusion This is the largest cohort of patients undergoing double HAPLO-SCT analysed so far. Within the limits of a registry-based analysis, the data show the feasibility of a second HAPLO-SCT after relapse from HAPLO-SCT1 with high engraftment rates and acceptable NRM. Outcome data as well as risk factors are comparable to results reported after alloSCT2 in a matched donor setting. Results were encouraging among patients with ALL (n=19, only 2 with Philadelphia chromosome positive [Ph+] disease), who were younger and more often received HAPLO-SCT2 in CR and from a new donor. HAPLO-SCT2 is a viable option for AL patients relapsing after a HAPLO-SCT1. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Significance of Measurable Residual Disease for Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission and Beyond

Introduction: For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HCT) in first complete remission (CR1), measurable residual disease (MRD) prior to HCT is strongly associated with post-HCT relapse rates and overall survival (OS). However, for a growing number of patients with ALL, HCT is deferred until the second remission (CR2) or beyond. It is unclear whether pre-transplant MRD assessment is also prognostic in the setting of HCT beyond CR1. Methods: We performed a single center retrospective study to test the hypothesis that pre-transplant MRD positivity is associated with outcomes in patients receiving HCT in CR2 or beyond for ALL. MRD was measured by 6-color flow cytometry with a sensitivity of 0.01%. Consecutive pediatric and adult patients who underwent first allogeneic HCT between the years 2004-2021 for ALL in CR2 or beyond were included. Results: We identified 162 patients (Table 1), 123 (76%) with B-ALL and the remainder with T-ALL. The majority (80%, n=129) of patients were in CR2 at the time of HCT, the remainder in third CR or beyond (CR3+). One hundred and five (65%) patients were male and median age at transplant was 31 (range 4-69) years. Graft source was either matched unrelated donor (MUD) (43%, n=69), matched sibling donor (MSD) (24%, n=39), haploidentical (18%, n=29) or cord blood transplantation (CBT) (15%, n=25). Pre-HCT MRD status was determined for 150 (93%) of patients and of those was positive in 43 (26%). Subsequent analyses were limited to the subset of patients with known MRD status. There was no statistical difference in characteristics according to MRD status except for higher proportion of CR3+ patients (33% vs. 16%, p=0.02) and comorbidity index >2 (70% vs. 40%, p=0.001) in MRD positive vs. negative patients. The median follow-up in surviving patients was 62 (range 20-104) and 47 (range: 2-171) months in MRD positive and negative patients, respectively. In multivariate analysis (MVA) evaluating transplantation outcomes at 3 years, pre-HCT MRD positivity was associated with a higher rate of disease relapse (HR 1.9, 95% CI 1.1-3.6; p=0.02); but it had no impact on non-relapse mortality (NRM) (HR 0.8, 95% CI 0.4-1.8; p=0.6). Subset analyses showed that these trends were consistent for patients receiving HCT in CR2 or CR3+; however the impact on disease relapse was more pronounced for patients in CR2 at HCT. MRD positivity was also associated with less favorable overall (HR 1.96, 95% CI 1.2-3.3; p=0.01) and progression-free survival (PFS) (HR 2.5, 95% CI 1.5-4.2; p<0.001) for patients receiving HCT in CR2. MRD was not associated with OS (HR 0.9, 95% CI 0.4-2, p=0.8) or PFS (HR 0.8, 95% CI 0.3-1.7, p=0.5) for patients receiving HCT in CR3+. As shown in Figure 1 A-B, OS and PFS were significantly superior for MRD negative patients receiving HCT in CR2. OS and PFS for MRD positive patients in CR2 were comparable to patients receiving HCT in CR3+. Conclusions: Pre-transplant MRD positivity is predictive of disease relapse in patients undergoing HCT for ALL in CR2 or beyond; however, the survival advantage associated with MRD negativity maybe limited to patients undergoing HCT in CR2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Data Confirm the Superiority of Total Body Irradiation-Containing Conditioning Regimen in Comparison to a Chemotherapy-Based Preparation in Children with Acute Lymphoblastic Leukemia Above the Age of 4 Years Given an Unmanipulated Allograft. Results of the Forum Randomized Clinical Trial

Background Conditioning regimen plays a crucial role in determining the outcomes of patients with hematological malignancy treated with allogeneic hematopoietic stem cell transplantation (HSCT). In a multicenter, international, randomized, phase 3 clinical Trial (FORUM study), we documented (Peters C, et al. J Clin Oncol 2021) that children with acute lymphoblastic leukemia (ALL) given total body irradiation (TBI) in combination with etoposide had a superior probability of 2-year overall (OS) and event-free survival (EFS) in comparison to patients given either one of two myeloablative chemo-conditioning regimens. In this report, we assessed whether the benefit deriving from the use of TBI was sustained over time. Patients and methods Patients <18 years at diagnosis, 4-21 years at HSCT, in complete morphological remission (CR) pre-HSCT, and with an HLA-compatible related or unrelated donor (UD) were randomly assigned 1:1 to a myeloablative conditioning regimen with fractionated TBI and etoposide or fludarabine, thiotepa, and either busulfan (BU) or treosulfan (TREO). Children transplanted from a matched sibling donor (MSD) received cyclosporine A only as graft-versus-host disease (GvHD) prophylaxis, whereas recipients of UD HSCT also received short-term methotrexate and anti-thymocyte globulin (ATG). Further details on transplant procedure have been described elsewhere (Peters C, et al. J Clin Oncol 2021). Results Between 04/2013 and 12/2018, 413 patients were randomly assigned to receive either TBI (212) or a chemotherapy-based conditioning (201). Compliance with random assignment was 92%. Sixty-five percent of patients were male, 72% had B-cell precursor ALL, 73% were transplanted from a UD, and in 82% of patients bone marrow was the stem cell source employed. Fifty-four percent of patients were in CR1 at time of allograft, while 40% and 4% were transplanted in CR2 and CR3, respectively. Patient's outcomes were updated on February 1st, 2022. With a median follow-up of 3.7 years (range, 0.3-7.9), the 3-year probability of OS of patients allocated to TBI/etoposide or to the chemotherapy-based conditioning regimens was 90±2% and 71±3% (p<0.001), respectively, while that of 3-year EFS was 81±3% and 59±4% (p<0.001). OS and EFS remain comparable in patients receiving BU or TREO in combination with fludarabine and thiotepa. In detail, OS and EFS of the 102 patients given BU, fludarabine and thiotepa were 73±5% and 69±5% respectively, while those of the 99 patients treated with TREO, fludarabine and thiotepa were 62±5% and 61±5%. Multivariate analysis confirmed that the use of chemotherapy-based regimens correlated with worse OS [Hazard Ratio, HR, 2.63, 95% confidence interval, CI, (1.61- 4.31), p<0.001] and EFS [HR 2.30, 95%CI (1.58- 3.35) p<0.001]. Transplantation in >CR1 predicted a worse EFS in multivariate analysis, as well [HR 1.67, 95% CI (1.14- 2.45) p=0.009]. Patients given TBI benefited from a lower cumulative incidence of relapse (Figure 1A), as well as from a lower 3-year cumulative incidence of non-relapse mortality (2+1% vs. 10+2% in the chemo arm, p=0.007). The 3-year cumulative incidence of chronic GvHD was comparable between the 2 arms (15+3% vs. 12+2% in the TBI and chemo arm, respectively, p=n.s.). We also analyzed the probability of GvHD/relapse-free survival (GRFS) considering both relapse and chronic GvHD as events; children prepared with TBI had a better 3-year GRFS probability (Figure 1B) as compared to chemo-prepared patients. Five patients (all transplanted from an UD) developed secondary malignancies: 4 of them had received TBI. Conclusions With a significantly longer follow-up, we confirm that the use of TBI during the conditioning regimen is associated with better outcomes in children and adolescents with ALL above the age of 4 years transplanted in CR, mainly due to a lower risk of leukemia recurrence. The number of cases of secondary malignancies, particularly in patients offered radiotherapy, deserves particular attention and underlines the importance of continuous safety monitoring over time to comprehensively evaluate the long-term sequels observed in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Easix Application in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Prophylaxis

INTRODUCTION The Endothelial Activation and Stress Index (EASIX) is a biomarker-based laboratory formula applicable in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) which has been proposed to predict non-relapse mortality (NRM), overall survival (OS), and thrombotic microangiopathy (TMA) incidence when measured during the pre-transplant evaluation, and sinusoidal obstruction syndrome (SOS), when measured on day 0. The use of post-transplant cyclophosphamide (PTCY) for graft vs. host disease (GVHD) prevention has become a standard in haploidentical hematopoietic cell transplantation (HCT) and it is increasingly used for allo-HCT performed with unrelated (UD) and matched sibling donors. PTCY-based prophylaxis was incorporated at our Institution between 2014 and 2018. Since then, lower rates of endothelial complications including acute GVHD (aGHVD) have been documented. The predictive ability of EASIX has been validated mainly in patients receiving GVHD prophylaxis that did not contain PTCY. Considering that fewer endothelial complications have been diagnosed at our Institution since the use of PTCY-based prophylaxis, and that EASIX is considered a surrogate parameter of endothelial activation, this study investigates whether the dynamics of EASIX differ between patients receiving PTCY vs. other prophylaxis, and if the predictive ability of EASIX persists in PTCY-based allo-HCT. METHODS Between 2014 and 2020, 328 consecutive adults underwent first allo-HCT at our Institution and were included in the study. EASIX [(creatinine*LDH)/platelets] was calculated based on the information provided at the bloodwork collected at the pre-transplant assessment, on days 0, +7, +21, +28, +100, and +180. EASIX was transformed to a base-2 logarithm to perform the statistical analysis. The ability of EASIX to predict outcomes (OS and NRM) and post-transplant complications (SOS, TMA, and grade 2-4 aGVHD) was explored using landmark and regression analyses. Patients who died or who were diagnosed with the study time-dependent adverse event before each landmark point were excluded from the next time point. RESULTS The study cohort was divided into two groups according to the GVHD prophylaxis (PTCY n=201 vs. others n=127). Median age was 52 years and 81 patients (40.4%) received myeloablative conditioning regimens. One hundred and nine patients (65.2%) received transplants from mismatched donors [68 (44.8%) from mismatched UD and 41 (20.4%) haploidentical]. The dynamics of EASIX, in conjunction to creatinine, LDH, and platelets counts consecutively recorded from day 0 to +180 are depicted in Figure 1. As reported, the values of EASIX differed significantly from day 0 to day +28 between the two groups. These differences were attributed to lower LDH levels from day 0 to day +180, a lower platelet count documented between days +14 and +180 in patients receiving PTCY. The ability of EASIX to predict outcomes and complications was explored in patients receiving PTCY. The cumulative incidence functions of SOS, TMA, and grade 2-4 aGVHD day +100 were 2.0%, 3.5%, and 21.4%, respectively. The 2-years OS and NRM were 69.0% and 16.4%, respectively. As reported in Table 1, higher values of EASIX , measured at the pre-transplant assessment, days 0, +7, +14, +28, and +180 were associated with a higher probability of NRM and lower OS. Moreover, increased values of EASIX, measured at the pre-transplant assessment, days 0, +7, and +14 were predictors for TMA, and higher values of EASIX, measured before allo-HCT, on days +21 and +28 were predictors for grade 2-4 aGVHD. No association was observed between EASIX and SOS prediction. CONCLUSIONS The dynamic of EASIX differs between patients receiving PTCY and those that did not. However, despite this difference, the ability of pre-transplant EASIX to predict NRM and OS persists in patients receiving PTCY. Higher values of EASIX, measured not only at the pre-transplant evaluation, but also on days 0, +7, +21, +28 and +180 were associated with higher NRM and lower OS in patients receiving PTCY. In addition, pre-transplant EASIX was found to be a useful predictor for TMA and grade 2-4 aGVHD in these patients. This analysis validates the predictive ability of EASIX in patients receiving PTCY for GVHD prevention, and enhances the relevance of the assessment of endothelial dysfunction markers for the prognosis of PTCY-based allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome and Molecular Measurable Residual Disease Monitoring in Adult B-Cell Acute Lymphoblastic Leukemia Patients with MEF2D Fusions

Oncogenic gene fusions caused by chromosomal rearrangements are the major hallmarks of B-cell acute lymphoblastic leukemia (B-ALL). With the application of next-generation sequencing technologies, several non-scarce recurrent fusion genes have been identified in B-ALL, and MEF2D fusions is the one. More clinical data is needed to clarify the incidence and prognosis. Furthermore, the prognostic significance of measurable residual disease (MRD) monitored by the quantitative detection of MEF2D fusions remains absent to date. A total of 357 adult Ph-negative B-ALL cases who were consecutively diagnosed and received treatment in our institute from 2009 to 2021, and have available bone marrow cDNA samples at diagnosis were retrospectively screened MEF2D fusions. All patients have been tested common fusion transcripts at the time of diagnosis. MEF2D fusions were tested by the multiplex TaqMan-based real time quantitative polymerase chain reaction technology. A total of 7 fusion partners were included. The split-out real time PCR was performed to identify the partner. Totally 16 patients were identified MEF2D fusions with the incidence of 4.5% in Ph-negative BCP-ALL. The distributions were as follows: 7 MEF2D-BCL9, 7 MEF2D-HNRNPUL1, 1 MEF2D-DAZAP1 and 1 MEF2D-FOXJ2. Their median transcript levels were 65.0% (range, 20.9%-335.5%) at diagnosis. The median age of these 16 patients were 30 (range, 17-60) years and 10 of them were male (63%). The median follow-up time of 16 patients with MEF2D fusions was 26 months (range, 8-156 months). 9 (61.1%) patients were alive at the last follow-up. 14 and 2 patients individually achieved complete remission (CR) after 1 and 2 courses of CODP ± L regimen for induction. Thereafter, 8 patients received hyper-CVAD-based chemotherapy alone and all of them relapsed after 1-6 cycles of consolidation, then 2 relapsed patients received allogeneic hematologic stem cell transplantation (allo-HSCT) as salvage treatment after achieving the 2nd CR (CR2); the remaining 8 patients received chemotherapy followed by allo-HSCT (matched sibling donor, n = 3; haploidentical related donor, n = 5) in CR1. The median follow-up time after HSCT was 19 (6-148) months, and 5 patients (4 CR1, 1 CR2) relapsed at a median of 9 (range 6-15) months post-HSCT. The 3-year relapse free survival [RFS] and overall survival (OS) rates of all 16 patients were 30.0% (95% confidence interval [CI]: 10.2%-53.0%) and 54.6% (95% CI: 23.9%-77.5%) (Fig 1). Bone marrow samples serially collected after treatment were retrospectively tested MEF2D fusion transcript for MRD monitoring. 58.3% (7/12) and 50.0% (6/12) of patients were PCR-negative at the time of achieving CR1 and after one cycle of consolidation, respectively. PCR-negative at the above both time-points was not related to relapse (P=1.0 and 0.45). For patients receiving allo-HSCT, the scheduled monitoring time-points were 0, 1, 2, 3, 4.5, 6, 9, 12, 18, 24 months post-HSCT then every 12 months thereafter. There was a tendency that PCR-negative at the time of receiving HSCT was related to a lower relapse rate (post-HSCT 2-year RFS rate, 75.0% [95% CI, 12.8%-96.1%] vs 20.0% [95% CI, 0.8%-58.2%], P=0.13). 5 patients who were in continuous CR were tested MEF2D fusion transcript at a median of 9 (range, 3-11) time-points after HSCT, 38 (97.4%) samples were PCR-negative. 5 patients who relapsed post-HSCT were tested MEF2D fusions at a median of 5 (range, 4-7) time-points before relapse, they all were in continuous PCR-negative from 1 to 2-6 months post-HSCT, then all became PCR-positive before the occurrence of relapse. Their intervals between the 1st PCR-positive and relapse were 1.5-6 months. As a result, occurrence of PCR-positive post-HSCT was significantly related to relapse (post-HSCT 2-year RFS rate, 100.0% (95% CI, 100%-100%) vs 33.0% (95% CI, 4.3%-67.2%), P=0.039, Fig 2). In conclusion, MEF2D fusions confer adverse prognostic significance to adult B-ALL, and relapse is a treatment challenge. PCR-negative of MEF2D fusion transcript at the time of achieving CR and after the 1st consolidation could not predict long-term CR, whereas PCR-positive after HSCT predict relapse. The benefit of urgent allo-HSCT after achieving CR and MEF2D fusion transcript levels directed intervention post-HSCT remains to be investigated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Long-Term Romiplostim Use for Refractory Aplastic Anemia

Introduction: Aplastic anemia (AA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow caused by the destruction of hematopoietic stem cells by lymphocytes. About one-third of patients with severe AA who cannot undergo allogeneic hematopoietic stem cell transplantation from a matched sibling donor are refractory to single or repeated immunosuppressive therapy courses. Romiplostim (ROMI), a thrombopoietin receptor agonist, signals and activates intracellular transcriptional pathways via the thrombopoietin receptor, resulting in stimulation of hematopoietic stem and progenitor cells. Our previous research, a phase II/III, multicenter, open-label interventional study, showed that ROMI induced the recovery of at least one lineage of blood cells in >80% of patients with refractory AA. However, data on the long-term efficacy and safety of ROMI in refractory AA beyond 52 weeks are scarce. Additionally, the pretreatment baseline factors of patients who achieve hematological response during treatment and maintain response after discontinuing ROMI are unclear. To address these issues, we report the results at the end of the extension phase (June 2020) of the aforementioned phase II/III study. Methods: We conducted a long-term follow-up analysis of the efficacy and safety of ROMI 10 μg/kg administered subcutaneously once weekly for 4 weeks (Weeks 1-4), followed by 1-step titration to 5, 10, 15, and 20 μg/kg once weekly up to 52 weeks (Weeks 5-52) depending on platelet response. The extension study was started from Week 56 after a 4-week suspension period. The patients continued to receive the same dose of ROMI they received on Week 52 until its commercially available date for the treatment of AA in the study country or the end of June 2020 (end of the extension phase), whichever occurred first. Results: Of the 31 patients enrolled in the phase II/III study, 27 completed the 53-week assessment. Twenty-five hematological responders (any cell lineage) and 2 non-responders entered the extension phase. ROMI was administered for 2 years in 23 patients, 3 years in 7 patients, and 3.5 years in 6 patients in this extension study. The median dose of ROMI was 20 μg/kg at Week 53, which was reduced to 15 μg/kg at 2 years, and 7.5 μg/kg at 3.5 years (Figure 1). Of the 2 non-responders, 1 patient showed platelet response at 2 years, which was sustained thereafter, while the other failed to respond by the end of the extension study at 103 weeks. Of the patients who failed to achieve the platelet (n=7) and erythrocyte (n=6) responses at 1 year, 3 (43%) and 1 (17%) showed responses at 2 years; the mean platelet count increased from 38.3 to 76.7 ×109/L in the 3 platelet responders, and the hemoglobin level increased from 8.0 to 9.2 g/dL in the erythrocyte responder (Figure 2). Of the 23 patients who needed blood transfusions at baseline, 4 and 2 of them still required erythrocyte and platelet transfusions at 1 year, and 4 and 5 of them did so at 2 years, respectively. Five patients remained in response after discontinuing ROMI lasting 29-111 weeks even after discontinuing treatment. These 5 patients had relatively high baseline reticulocyte counts (45.8-93.8 ×109/L, median 57.5 ×109/L) compared with the remaining 22 patients (2.7-114.7 ×109/L, median 46.5 ×109/L). The most common adverse drug reactions included headache (3 cases, 9.7%) and muscle spasms (2 cases, 6.5%); cytogenetic abnormality (-7) led to discontinuation of the study drug in 1 case. Two patients presented with chromosomal abnormalities of unknown significance, including 46,XX,t(11;17) at Week 108 and 46,XX,add(10) at Week 134. No transformation to acute myeloid leukemia or myelodysplastic syndromes occurred. Conclusions: The up to 3.5-year follow-up study of ROMI administration in adult patients with refractory AA demonstrated its safety and efficacy during the extension period. The dose of ROMI was on a downward trend during the long-term follow-up. Nearly half the patients who did not achieve platelet or erythrocyte responses to ROMI at Week 52 eventually achieved responses by continuing the administration until the end of the study, demonstrating the efficacy of prolonged ROMI administration. High reticulocyte counts at ROMI initiation may predict achievement of response after discontinuing ROMI. Further studies with larger sample sizes should confirm these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic but Not Autologous Stem Cell Transplantation Improves Outcome in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare mature T-cell malignancy driven by the human T-cell lymphotropic virus type I (HTLV-1) that remains challenging to treat and is associated with a dismal prognosis. While some reports have shown encouraging results with allogeneic stem-cell transplantation (allo-SCT), data remains scarce and mostly limited to Japanese patients. Patients and Methods: This is a retrospective single center analysis with 100 HTLV-1-associated North American ATLL patients. Variables collected included age, sex, ethnicity, CMV/HTLV1 serologies, karnofsky performance score (KPS), diagnosis date, disease subtype, number of prior therapy lines, transplant type, status at transplant, transplant date, prior SCT, donor sex, CMV/HTLV1 serologies, stem cell source, donor type, in-vivo T-cell depletion, engraftment, conditioning regimen, GVHD prophylaxis, maximum acute and chronic GVHD grade, relapse date when applicable, and main cause of death. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Cumulative incidence functions were used to estimate relapse incidence (RI) and non-relapse mortality (NRM) in a competing risk setting. Death and relapse were considered as competing events for acute and chronic GVHD. Univariate analyses were done using the Gray's test for cumulative incidence functions and the log rank test for OS and PFS. A Cox proportional hazards model was used for multivariate regression, results were expressed as hazard ratio (HR) with a 95% confidence interval (CI). All tests were two-sided, type-1 error was fixed at 5%. Results: One hundred patients met eligibility criteria, 18-87 years old, 69 of which were Black, 27 Hispanic, and 2 of Asian descent. Sixty-seven patients had acute ATLL and 22 lymphomatous. In total, 22 patients underwent SCT with 17 allo-SCT and 5 autologous SCT (ASCT) between 2005-2020 with a median follow-up of 62 months. Ten patients (45%) were transplanted in first complete remission (CR1), and 15 (68%) had KPS ≥90. Among patients undergoing allo-SCT, 41% had matched sibling donors (MSD), 18% matched unrelated (MUD), and 35% haploidentical. The 1-year and 3-years rates of overall survival from diagnosis of the cohort were 42% and 21%, respectively. Acute ATLL subtype was a strong predictor of worse outcome (Figure 1) with 1-year and 3-years OS of 32% vs 71% (p=0.004) and 11% vs 46% (p=0.002), respectively, compared to lymphomatous disease. To account for immortal time bias, 37 non-transplanted patients with early mortality within 4 months of diagnosis that were not able to make it to transplant were excluded from the Kaplan-Meier survival analysis. Patients undergoing transplant had improved outcomes compared to non-transplanted patients (Figure 1, Table 1), with allo-SCT reaching statistical significance in multivariate analysis compared to the non-transplant group with OS HR of 0.3 (p=0.004) compared to 0.7 (p=0.6) in ASCT vs non-transplant. In transplanted patients, the 3-year RI and NRM were 51% and 37%, respectively, and 3-year PFS and OS were 31% and 39%, respectively. Four of five patients who received ASCT rapidly relapsed with 3 dying from disease progression and one lost to follow-up, with 1-year RI of 80% vs 30% in allo-SCT (p=0.03). In exploratory multivariate analysis, patients achieving CR1 and with good baseline performance scores (KPS >90) had significantly better outcomes compared to their counterparts regardless of transplant type, and surprisingly, race was a strong and significant predictor of outcomes affecting PFS and OS with Hispanic vs Black PFS and OS HRs of 6 (p=0.04) and 10 (p=0.04), respectively. Thirteen patients died within 2 years, eight from relapse/progression including 3 ASCT patients, and 4 from transplant-related toxicities. Conclusion: Our data suggest that allo-SCT, but not ASCT, is a valid option in select ATLL patients. It also appears that patients of Hispanic descent have worse outcome post-transplant but not overall, which could be explained by lack of compatible donors or barriers to early transplant. Although this is the largest NA-ATLL transplant cohort presented to date outside of Japan and Europe, further studies are necessary to fully explain these discrepancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved T-Cell Chimerism and Successful Withdrawal of Immunosuppression after Non-Myeloablative Stem Cell Transplantation for Sickle Cell Disease with Azathioprine/Hydroxyurea Preconditioning Added to Alemtuzumab/TBI Conditioning

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adult SCD patients, myeloablative conditioning is associated with significant toxicity, primarily because of cumulative organ damage. Recently, matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) showed promising outcomes in adult SCD patients. This chemotherapy-free regimen, typically resulting in mixed chimerism, is associated with mild toxicity with no reports of graft-versus-host disease (GvHD). Despite mixed chimerism, the red blood cell (RBC) phenotype is completely donor-derived. However, in a large series, 13% of patients experienced graft failure. Another 8.2% of patients could not stop their immunosuppression (sirolimus) after one year, because of low donor T-cell chimerism (<50%). Reported mean donor T-cell chimerism at 12-months post-transplantation was 48% (Br J Haematol. 2021 Feb;192(4): 761-768). We hypothesized, that the addition of azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI conditioning regimen will reduce the risk of graft failure and improve donor T-cell chimerism, enabling successful withdrawal of sirolimus in all patients. Aim: To investigate the effects of adding azathioprine/hydroxyurea preconditioning to alemtuzumab/TBI conditioning on donor chimerism levels and the occurrence of graft failure in adult SCD patients receiving non-myeloablative MSD-HSCT. Methods: Adult SCD patients with an available HLA-identical sibling donor were eligible for this treatment. All patients received three months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd preconditioning. After exchange transfusion (target HbS <30%), conditioning with alemtuzumab 1mg/kg total dose and 3Gy TBI started on day -7, followed by unmanipulated peripheral hematopoietic stem cell infusion on day 0. Sirolimus as GvHD and rejection prophylaxis started on day -1. Results: Twenty SCD patients (median age 26 (range 19-49) years) were transplanted with a median follow-up of 24.5 months (range 1-52 months). Patient and transplant characteristics are shown in Table 1. Median donor myeloid and T-cell chimerism of engrafted patients was 100% (range 87-100%) and 68.5% (range 37-89%) at 12-months post-transplantation and 94% (range 86-100%) and 78.5% (range 68-88%) at 18-months post-transplantation, respectively (Figure 1). These donor T-cell chimerism percentages are higher than previously reported with alemtuzumab/TBI conditioning only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Importantly, all patients with a follow-up of ≥ 12 months (n=12) could successfully taper and stop sirolimus without decreases in donor chimerism. One year estimated disease-free survival and overall survival were 94.7%. and 93.3%, respectively. One patient (5%) experienced graft failure without autologous regeneration and subsequently died after a series of complications, including EBV reactivation, post-transplantation lymphoproliferative disease, and systemic aspergillosis. Acute gastrointestinal GvHD grade 2 occurred in one patient (5%) and resolved quickly after treatment with prednisolone. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI resulted in improved donor T-cell chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T-cell chimerism >50% and were able to stop immunosuppressives as scheduled. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sustained Engraftment in Fanconi Anemia (FA) Mice Using in Utero Hematopoietic Cell Transplantation (IUHCT)

Introduction FA is the most common inherited bone marrow failure syndrome caused by a mutation in one of 23 genes involved in DNA repair; the disease manifests as hematologic abnormalities by age seven with near uniform bone marrow failure in adult patients. The gold standard therapy is bone marrow transplantation (BMT), which portends best outcomes when performed at a young age from Human Leukocyte Antigen (HLA)-matched sibling donors. However, due to the underlying pathophysiology of the disease, FA patients are especially sensitive to the chemoradiation conditioning regimens used with BMT, leading to high short-term morbidity and an increased long-term cancer risk. Due to these challenges of conventional BMT in FA, IUHCT is an attractive non-myeloablative and non-immunosuppressive option capable of inducing donor-specific tolerance when in utero testing has identified pathogenic FA mutations. Here we analyzed whether non-conditioned IUHCT confers fetal engraftment as a potential therapy in the FA mouse disease model. Methods Fanconi anemia type C homozygous mice (Fancc-/-) underwent IUHCT on gestation day 14 (E14) via vitelline vein injections of 1x107 T-cell depleted bone marrow cells from green fluorescent protein (GFP)-expressing congenic donor mice. Littermate wild-type mice served as controls. Donor cell engraftment in peripheral blood and bone marrow was assessed by flow cytometry. To confirm long-term donor HSC engraftment, we performed primary and secondary transplantation of an equivalent number of BM mononuclear cells from either Fancc -/- or wild-type mice that had undergone IUHCT. Statistical analysis was performed via Welch's t-test. P values <0.05 were considered statistically significant; for graphical purposes ***p<0.001; **p<0.002; *p<0.033; nonsignificant, ns. Results Fancc-/- homozygous mice had significantly higher donor GFP+ cell engraftment than wild-type controls at one, three, and six months post-transplantation (Figure 1). This higher engraftment was maintained across cell types in peripheral blood including CD3+ T cells (0.7% vs 3.4%), B220+ B cells (1.2% vs 6.9%), GR1+ granulocytes (1.7% vs 10.6%), and CD11B+ myeloid cells (1.9% vs 11.5%). Analysis of the bone marrow of these mice at 6 months post-transplant similarly showed a trend toward increased donor cell engraftment of progenitor cell populations including LSK, HSPC, LTHSC, STHSC, MPP2, MPP3, MPP4, CLP, CMP, GMP, and MEP cells in Fancc -/- recipients compared to wild-type mice. At all timepoints after primary and secondary transplants, recipient mice engrafted with BM mononuclear cells from prenatally transplanted Fancc -/- mice had higher peripheral blood GFP+ chimerism than those engrafted with BM mononuclear cells from prenatally transplanted wild-type mice (Figure 2). Conclusion Fancc-/- homozygous mice have higher sustained donor cell engraftment compared with wild-type littermates, indicating successful engraftment and possible early selection for wild-type donor cells in this preclinical model. These initial studies support the potential of IUHCT as a therapy for FA and highlight the need for additional studies to identify approaches to enhance donor cell engraftment to more clinically relevant levels. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Amsa/ARA-C Followed By TBI 4 Gy or High Dose Chemotherapy Conditioning Regimens in Primary Refractory AML - Significantly Worse Outcomes in Younger Patients Conditioned with 4 Gy TBI

Background: Allogeneic stem cell transplantation (allo-SCT) plays a fundamental role in the management of acute myeloid leukemia (AML) and is generally recommended for patients with primary induction failure. The optimal conditioning regimen in preparation for SCT in this specific difficult contex has been the subject of continued controversy. Specifically, the role of total body irradiation (TBI) or chemotherapy (CT) as part of sequential conditioning, continues to be central to this debate. With improvement in CT delivery and the introduction of intravenous (IV) busulfan, the utilization of TBI has decreased in popularity. This is a retrospective, multi-center, registry-based, European Society of Blood and Marrow Transplantation (EBMT) study which aimed to compare the outcomes of allo-SCT with amsacrine (AMSA) /cytarabine (ARA-C) followed by TBI conditioning to CT-based conditioning and thus determine certain prognostic factors that could potentially aid in the decision to implement TBI into a patient's conditioning regimen in preparation for allo-SCT. Patients and Methods: For this analysis, we identified 466 adult patients (58.8% male, median age: 55 years, range: 18-75) with primary refractory AML (73.6% de novo) transplanted between the years 2001 and 2021 (median: 2013) from matched sibling donors (MSD) or matched unrelated donors (MUD: 59.2%), who had received AMSA and ARA-C conditioning followed by CT or TBI sequential conditioning. In patients with available cytogenetic data, 50% had intermediate cytogenetics and 50% had poor cytogenetics. Karnofsky score at the time of transplant was >90 in 57.8% of the patients. The majority (73.1%) received a combination cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis and 92.7% underwent in vivo T-cell depletion. Results: Of the 466 eligible patients identified, 237 (50.8%) received sequential CT-based conditioning following high-dose AMSA/ARA-C with busulfan-fludarabine (BuFlu) or busulfan-cyclophosphamide-fludarabine (BuCyFlu) and 229 received sequential TBI-based conditioning following high-dose AMSA/ARA-C with a total of 4 Gy and cyclophosphamide-fludarabine (CyFlu). In univariate analysis, there was a significant difference in age between the two groups whereby patients receiving CT-based sequential conditioning were older (59.9 years vs 49.7 years, p<0.0001). Moreover, there was a significant difference in the proportions of MSD/MUD between the two groups with 67.9% being allografted from MUD in the CT group compared to 50.2% in the TBI group (p=0.0001). Given the significant interaction between age and conditioning (sequential TBI vs. CT), we stratified our sample by median age (<55 vs >= 55). In patients younger than 55 years, 2-year leukemia-free survival (LFS) was significantly higher in the CT group (51.9% vs 25.1%, p=0.002), as was overall survival (OS) (57.5% vs 38.3%, p=0.021). CT-based sequential conditioning was also associated with higher rates of grades II-IV and III-IV acute GVHD (38.1% vs 24.7%, p=0.02 and 19.8% vs 8.9%, p=0.022). In multivariate analysis, the use of TBI- vs CT-based sequential conditioning significantly influenced relapse (hazard ratio [HR] 1.98, p=0.018), non-relapse mortality (NRM: HR 2.7, p=0.038), LFS (HR 2.03, p=0.004), OS (HR 1.86 p=0.016) and acute GVHD II-IV (HR 0.45, p=0.014). Moreover, age (per 10 years) significantly impacted NRM (HR 2.42, p=0.0005), female to male donor impacted NRM (HR 2.41, p=0.032) and chronic GVHD incidence (HR 2.21, p=0.033) and in vivo T-cell depletion (TCD) impacted chronic GVHD (HR 0.32, p=0.03). In patients 55 years or older, there was no significant difference in post-allo-SCT outcome between patients who received TBI-based vs CT-based sequential conditioning. Conclusion: The above results highlight a significant difference in outcomes in AML patients receiving sequential TBI-based vs CT-based conditioning in preparation for allo-SCT according to age, whereby patients younger than 55 years had significantly worse outcomes after receiving TBI. This was not reflected in patients aged 55 years or more. Although only 4 Gy, these results emphasize the importance of age in the transplant physician's decision to incorporate TBI into conditioning regimens to optimize outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Brentuximab in Children, Adolescent and Young Adults with Relapsed/Refractory Anaplastic Large Cell Lymphoma

Background: Anaplastic Large Cell Lymphoma (ALCL) is an aggressive malignancy characterized by strong expression of CD30. Multi-agent chemotherapy cures 65-90% of newly diagnosed patients, the rate of relapse approaching 30%. Targeted agents eventually followed by allogeneic stem cell transplantation (SCT) may represent a valuable salvage therapy in patients with relapsed/refractory ALCL. Brentuximab vedotin is a CD30-directed monoclonal antibody-drug conjugate (ADC) that comprises a monoclonal human/murine antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Design and methods: We retrospectively analyzed monocentric data of 20 patients with ALCL treated with Brentuximab from 2.10.2014 to 22.05.2022. Treatment was characterized by the intravenous infusion of 1.8 mg/kg Brentuximab in monotherapy or as part of a polychemotherapy regimen, in children with either relapsed disease or not fully responding to first-line treatment. More in detail, chemotherapy regimens administered in combination with the immunotherapy were: bendamustine, AM and BM blocks (ALCL99 Trial), or AA, BB and CC blocks (LNH97 Trial). Objective response rate (ORR) was assessed through computed tomography (CT)/FDG-PET scans. Results: Eight patients received Brentuximab for incomplete response to first-line treatment (2 of them had haemophagocytic lymphohistiocytosis at diagnosis, and underwent genetic testing that revealed the heterozygous variant c.1336C>T (p.Arg446Trp) in IKBKB gene and the hemizygous variant c.622T>C (p.Ala91Val) in IL2RG gene, respectively). In these patients, Brentuximab was mostly used in combination with the ALCL99 regimen. Three of these 8 patients experienced a subsequent relapse and were re-exposed to the drug after disease recurrence. Fifteen patients received Brentuximab at relapse. Median time between diagnosis and relapse was 10.3 months (range 3.4-34 months). The median number of Brentuximab infusions was 7 (range 2-25). The combination of Brentuximab 1.8 mg/kg/dose on Day 1 and Bendamustine 120 mg/m2/dose on Day 2 and 3, was the principal reinduction regimen in the relapsed cohort, having been infused in 9 patients with a median of 4 cycles (range 2 to 5). This drug combination was very well tolerated and showed a 100% complete response (CR) assessed by CT and FDG-PET scans, allowing to perform allogeneic SCT in all of them. Allogeneic SCT was performed in 15 patients (one of them was the child with haemophagocytic lymphohistiocytosis at diagnosis given Brentuximab during the first-line treatment because of incomplete response), while the remaining child, who had relapsed 34 months after the diagnosis, was treated with Brentuximab monotherapy and remains in CR. Nine patients received HLA-haploidentical SCT, while the remaining 6 were transplanted using either a matched sibling donor (3 patient) or an unrelated volunteer (3 patients) respectively. Sixteen out of the 20 patients (80%) are alive and disease free with a median follow-up of 28.6 months (range 3-78.7). Three patients died due to transplant related causes and 1 patient due to disease progression. Conclusions: Despite the limitations of a limited number of patients analyzed and the retrospective nature of the study, our data suggest that Brentuximab administered either in monotherapy or in combination with chemotherapy is a valuable salvage option and may represent a suitable bridge to allogeneic SCT.

Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation

Introduction: Since non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) is influenced by the conditioning regimen, it is essential to precisely calculate its intensity for any patient. Therefore, the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) registry previously developed the Transplant Conditioning Intensity (TCI) score to define conditioning regimens based on the sum of the doses (weight scores) for every component of the pre-transplantation regimen. HCT patients (pts) were stratified by a 3-index scheme with a low [1-2], intermediate [2.5-3.5] or high [4-6] TCI-score. (Bone Marrow Transplantation 2020; 55:1114) When tested in a large registry dataset of acute myeloid leukemia (AML) pts >45 years of age, TCI grouping was highly predictive for early and 2-year NRM, and better compared with the classical 2-index reduced intensity conditioning/ myeloablative conditioning (RIC/MAC) classification. The aim of the current study was to validate using a distinct dataset, the ability of the original TCI classification scheme to predict post-HCT NRM. Methods: TCI score was applied to a timely distinct cohort reported to the EBMT as the one used to establish the TCI classification scheme. We tested the impact of TCI in predicting early (day 180) NRM (defined as any death without previous relapse) in 55-75 years of age AML first complete remission (CR-1) pts who were transplanted between 2018 and 2021. Included pts were allografted with peripheral blood stem cells (PBSC, 96.4%) or bone marrow (BM, 3.6%) from a matched sibling donor (MSD, 25%) or unrelated donor (UD, 75%). NRM at 2 years was a secondary endpoint. Results: 4,312 AML pts (median age 63.4, interquartile range 59.5-67.2) were assigned to a TCI category, as previously described. 49% of the pts received a low [1-2], 47% an intermediate [2.5-3.5] but only 4% of the pts received a high [4-6] TCI-score regimen. As expected, there was an inverse relationship between age, Karnofsky status and hematopoietic cell transplant-specific comorbidity index (HCT-CI) and TCI group (p<0.0001). Besides a higher prevalence of MSD transplantations in the high (40%) as compared to low (21.6%) and intermediate (26.4%) TCI-groups (p<0.0001), pts were well balanced within TCI groups regarding other transplant and patient characteristics. The day (d)100, d180 and 2-year NRM ranged from 4.8-12.5%, 8.9-17%, and 17.4-23.9% between low, intemediate and high TCI scores, respectively. In univariate analysis, TCI provided a highly significant risk stratification for early and 2-year NRM (p<0.0001 for all pairwise comparisons between groups) (Figure 1). In the multivariate Cox regression analysis adjusted for age, Karnofsky status, HCT-CI and other variables, there was a significant increase in risk of early NRM with each TCI group (Table 1). Compared to low TCI, pts receiving intermediate and high score TCI regimens had a significantly increased risk for d180 NRM (hazard ratio [HR] 1.34, 95% CI, 1.03-1.74, p=0.029 and HR 2.37, 1.39-4.06, p<0.002, respectively). The HRs for d180 NRM pts receiving a high TCI [4-6] score regimen was 1.77 (1.06-2.97, p=0.029) when compared to the intermediate TCI [2.5-3.5] group. As expected, early NRM was also significantly influenced by incremental age, Karnofsky status score <90 and HCT-CI >=3. TCI grouping was also significantly associated with overall NRM. Similar results were found when the analysis was restricted to pts aged between 55 and 65 years (N=2,640). There was good concordance between RIC/MAC and low/high TCI score grouping, whereas 49% of the MAC pts and 51% of the RIC pts were re-classified as having received a reduced toxicity conditioning regimen with a TCI score of 2.5-3.5. Conclusion: Here, we validated in an independent patient cohort, the recently proposed 3-group TCI score for its ability to predict early NRM in AML pts >55 years of age. TCI predicts early NRM independently of other known prognostic factors such as age, Karnofsky, or HCT-CI. Compared to the current RIC/MAC classification model, the TCI provides a finer and more precise tool which may be easily calculated for any patient to offer safer transplantation especially in older and unfit pts. TCI may be used as a new, well-defined, and standard terminology for conditioning intensity in registry databases, in the literature and in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal