Outcome of Hematopoietic Stem Cell Transplantation in the Patients with Pediatric Acute Lymphoblastic Leukemia Enrolled in the Japan Association of Childhood Leukemia Study (JACLS) ALL-02

Background: Though the outcome of patients with acute lymphoblastic leukemia (ALL) has been greatly improved, some high-risk patients still need hematopoietic stem cell transplantation (HSCT). In this study, we evaluated clinical characteristics of children with ALL who were treated according to Japan Association of Childhood Leukemia Study (JACLS) ALL-02 trial and received HSCT to determine prognostic factors for the outcome of HSCT. Methods: Between April 1, 2002 and March 31, 2008, 1,252 patients aged 1-18 years with newly diagnosed ALL were enrolled in JACLS ALL-02 trial. Ph+ALL, mature B-ALL, and NK-leukemia were excluded. Of all the 1,252 patients, 211 (16.8%) patients were reported to receive HSCT, of which 206 patients with adequate information of 1st HSCT were subjected to further analysis. In this study, HSCT in 1st complete remission (CR) in JACLS ALL-02 trial was indicated for the patients with extremely high risk (ER: BCP-ALL with PPR and/or evidence of t(4;11) (or KMT2A-AFF1 positive), hypodiploidy (≤ 44) and/or acute mixed lineage leukemia/ acute unclassified leukemia). As a precaution, in ER patients, the timing of HSCT differs depending on whether they have a matched related donor. Results: Of all the 206 patients, 83 patients received HSCT in first CR (CR1), 68 patients in CR2, 54 patients in non-CR and 1 patient in induction failure (IF). 5-year overall survival (5y-OS) for 206 patients was 50% (95% CI 42.7-56.8). In detail, 73.8% (95% CI 62.6-82.1) for CR1 patients, 49.4% (95% CI 35.9-61.5) for CR2 patients, and 14.8% (95% CI 6.9-25.5) for non-CR patients, respectively. In univariate analysis, JACLS risk classification, disease status at HSCT (CR or non-CR or IF), stem cell source were significant prognostic factors. In multivariate analysis, only disease status retained as prognostic factor (p<0.01, HR=1.77). For CR1 patients, stem cell source was significant prognostic factor on multivariate analysis (5y-OS = 41.7%, 66.7%, and 79.3% for peripheral blood, cord blood, bone marrow; p = 0.023). When we focused on immunophenotype, stem cell source retained their effect only for patients with T-ALL. For CR2 patients, central nerves system involvement at diagnosis (p=0.02, HR=7.2), S classification (p=0.03, HR=1.2), and NCI risk (p=0.04, HR=2.5) were significant prognostic factors on multivariate analysis. S classification retained its prognostic impact only for patients with BCP-ALL (p=0.01, HR=1.5). For non-CR patients, NCI or JACLS risk classification at first diagnosis, S classification, frequency of relapse before HSCT, stem cell source, and conditioning for HSCT did not affect treatment outcome. Interestingly, non-CR patients with high-hyperdiploid (HHD) (n=5) had a significantly better 5y-OS (80%) than the other subtypes. In multivariate analysis, age at diagnosis (<10 years, p=0.04, HR=2.0)) and HHD (p=0.006, HR=1.74) contribute to the better outcome of HSCT in non-CR. Conclusion: The current study showed that the prognostic factors for HSCT varied according to the disease status or disease immunophenotype. Also, it is noteworthy that HHD patients may be rescued even in non-CR status by HSCT. Disclosures No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Treatment of Acute Lymphocytic Leukemia (ALL) in 126 Adults: Impact of Donor Source on Leukemia Free Survival (LFS).

Blood ◽

10.1182/blood.v106.11.2064.2064 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2064-2064 ◽

Cited By ~ 3

Author(s):

Priya Kumar ◽

Todd E. Defor ◽

Claudio Brunstein ◽

Juliet Barker ◽

John E. Wagner ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Growth Factor ◽

Disease Status ◽

Lymphocytic Leukemia ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Cell Source ◽

Donor Source

Abstract White blood cell (WBC) count and specific cytogenetic abnormalities at diagnosis, patient age and disease status at HSCT have previously been identified as risk factors associated with LFS in patients with ALL. As the use of umbilical cord blood (UCB) is relatively new, particularly for adults, we sought to evaluate the relative impact of donor source. In this single center study, 126 adults aged 18–61 (median 31) years (yrs) underwent myeloablative conditioning (cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy based regimen in 92%) followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 85, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14 and HLA 0–2 (A, B, DRB1) mismatched UCB in 12. At the time of HSCT, 64 patients were in CR1, 51 in CR2, and 11 patients in ≥ CR3; 20 pts had T-lineage disease; 38 pts (30%) had either t(9;22)(n=28), t(4;11) or t(1,19) (n=10) with the remainder (70%) having normal cytogenetics. WBC ≥ 30 x 109/l at diagnosis was documented in 50%. Demographics, disease characteristics at initial diagnosis and transplant variables were similar in all 4 groups except: year of transplant after 1996 and use of growth factor for all UCB recipients. Outcomes by donor source: MRD URD:M URD:MM UCB P N 85 15 14 12 Median follow up in yrs 9.3 3.5 7.2 1.2 OS 1 yr % (95% CI) 41 (31–52) 33 (9–57) 14 (0–33) 75 (51–100) 0.02 LFS 1 yr % (95% CI) 35 (25–45) 27 (4–49) 14 (0–33) 67 (40–93) 0.03 Relapse 1 yr % (95% CI) 21 (12–30) 20 (0–40) 0 8 (0–23) 0.22 TRM 1 yr % (95% CI) 44 (33–55) 53 (27–79) 86 (57–100) 25 (1–49) <0.01 As a consequence of low TRM, OS and LFS were superior after UCB transplants. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS: use of URD:M (RR 3.8, 95% CI 1.1–13.8, p= 0.04) and URD:MM (RR 4.9, 95% CI, 1.3–19.1, p= 0.02), ≥ CR3 at HSCT (RR 3.0, 95% CI, 1.1–8.8, p= 0.04), WBC >30 x 109/l (RR 2.4, 95% CI, 1.4–4.1, p<0.01), cytomegalovirus (CMV) seropositive recipient and donor (RR 4.0, 95% CI, 2.0–7.9, p<0.01), and ≥ 2 induction regimens to achieve initial CR (RR 2.7, 95% CI, 1.2–5.9, p= 0.01). Patients who developed grade II–IV acute graft versus host disease (GVHD) had significantly lower mortality rates (RR 0.4, 95% CI, 0.2–0.7, p<0.01). There was no impact on OS by year of transplant or use of growth factor. Variables associated with poor LFS were identical to those for OS, and GVHD was again associated with improved LFS. These results support the use of UCB as an alternative stem cell source for adults with ALL with results comparable to outcomes observed with MRDs. In addition, GVHD is associated with improved LFS suggesting a significant graft versus leukemia effect with all donor graft sources.

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Reduced-Intensity Versus Myeloablative Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 45 Years with Acute Lymphoblastic Leukemia (ALL) in Remission: A Study From the ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT).

Blood ◽

10.1182/blood.v120.21.3027.3027 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3027-3027

Author(s):

Junji Tanaka ◽

Kanamori Heiwa ◽

Nishiwaki Satoshi ◽

Ohashi Kazuteru ◽

Taniguchi Shuichi ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Stem Cell Transplantation ◽

Total Dose ◽

Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity

Abstract Abstract 3027 Background: Non-relapse mortality (NMR) may turn for the worse overall outcome of conventional myeloablative conditioning (MAC) allo-stem cell transplantation (SCT) for elderly patients and patients with comorbidities. Therefore, allo-SCT using reduced intensity conditioning (RIC) may provide opportunities to obtain a significant clinical effect without the adverse effects of intense myeloablative preparative regimens. Aims: In this Japanese nationwide survey we reported the outcome of 575 adult acute lymphoblastic leukemia (ALL) patients age at the first transplantation 45 years or more who underwent allo-SCT in CR and analyzed according to the type of conditioning regimen (MAC vs RIC) before allo-SCT registered in the JSHCT database between 2000 and 2009. Patients and Methods: The preparative regimen was classed as fludarabine-based RIC if it included non-myeloablative chemotherapy (total dose of busulfan ≤ 9 mg/kg or melphalan ≤ 140 mg/m2) with or without total body irradiation (TBI) ≤ 8 Gy (206 patients). Also, MAC included (total dose of busulfan > 9 mg/kg, melphalan > 140 mg/m2 or cyclophosphamide 120mg/kg) with or without TBI > 8 Gy (369 patients). Their median age was 51 years for MAC and 58 years for RIC (range: 45–70 years), with 280 males (180 vs 100) and 295 females (189 vs 106). There were 310 patients in the first complete remission (CR1) and 55 patients in the second CR (CR2) for MAC and 160 patients and 40 patients for RIC. Bone marrow from related or unrelated donors was transplanted in 343 patients (234 vs 109), as well as peripheral blood stem cell from related donors in 96 (47 vs 49) patients and cord blood in 127 (80 vs 47) patients. Results: Patients in the RIC group were older (median age, 58 vs 51 years, p<0.0001). The incidence of grade II-IV acute graft-versus-host (GVHD) was 44% of MAC group and 42% of RIC group. There were no statistically differences in one- and three-year overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM): 51% vs 53%, 47% vs 39% and 38% vs 36%, respectively. Relapse rate in the RIC conditioning group at 3 years was higher than that in the MAC group (26% vs 15%, p= 0.008). Multivariate analysis showed that CR2 and HLA mismatching were associated with poor OS (p=0.002 and p=0.019, respectively). HLA mismatching was associated with lower rate of relapse (p=0.016) but was associated with higher rate of NRM (p=0.001). RIC was associated with good OS and DFS in patients who received HLA-mismatch transplantation and were aged 55 years or more compared with MAC by multivariate analysis for each event with interaction (HR and 95% CI: 0.35 and 0.15–0.81, p=0.014 for OS and 0.36 and 0.16–0.81, p=0.013 for DFS). Conversely, MAC showed good OS and DFS in patients with HLA matching and aged less than 50 years (HR and 95% CI: 3.88 and 1.60–9.43, p=0.003 for OS and 3.51 and 1.52–8.09, p=0.003 for DFS) (Fig. 1). Conclusions: This retrospective survey showed that conditioning intensity did not affect OS or DFS for adult ALL patients aged 45–70 years at transplantation. However, patients aged 55 years or more with HLA mismatch transplantation would be candidates for RIC rather than MAC. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors — a Retrospective Study By the EBMT Chronic Malignancies Working Party

Blood ◽

10.1182/blood-2018-99-114592 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3465-3465

Author(s):

Aleksandar Radujkovic ◽

Henric-Jan Blok ◽

Arnon Nagler ◽

Francis Ayuketang Ayuk ◽

Jürgen Finke ◽

...

Keyword(s):

Stem Cell ◽

Prognostic Factors ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Blast Crisis ◽

Disease Status ◽

Advisory Committees ◽

Stem Cell Source ◽

Cell Source

Abstract Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis. Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1). Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. Disclosures Finke: Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

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Single-Institute Analysis of Allogeneic Stem Cell Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v106.11.5445.5445 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5445-5445

Author(s):

Takeshi Kobayashi ◽

Takuya Yamashita ◽

Miwa Sakai ◽

Yoshiki Okuyama ◽

Kazuteru Ohashi ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Stem Cell Source ◽

Cell Source

Abstract Purpose We report the outcomes of allogeneic stem cell transplantation (SCT) for the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in a single center. Patients and Methods Between August 1993 and March 2005, 36 patients with Ph+ALL received SCT at Tokyo Metropolitan Komagome Hospital. The median age was 41 years (range; 17 to 60 years). All patients received myeloablative conditioning regimen (cytosine arabinoside, cyclophosphamide and fractionated 12Gy total-body irradiation). Stem cell source of SCT was 14 related donors (bone marrow [n=9] and peripheral blood stem cell [n=5]) and 22 unrelated donors (bone marrow [n=13] and cord blood [n=9]). Results Seventeen (47%) of 36 patients are alive at a median of 2.16 years (range; 1.0 to 3.3 years) after transplantation. Three years overall survival (OS) and disease free survival (DFS) for all patients are 42.3% and 35.4%, respectively. Three years OS and DFS are 55.4% and 46.4% for the 24 patients in complete remission (CR) at transplantation, while 36.4% (p<0.001) and 16.7% (p<0.01) for the 12 patients in non-CR, respectively. Stem cell source and patients age do not affect the outcomes. The higher white blood cell counts at diagnosis are associated with poor OS (p=0.003). The median duration from diagnosis to SCT is 7 months (range; 3 to 29 months). Three years OS of the patients who received SCT within 7 months from diagnosis is better than that of the others (59.3% vs. 31.1%, p=0.019). Conclusion This analysis suggests that shorter duration between diagnosis and transplantation improve the clinical outcomes of SCT for Ph+ALL, especially performed in CR.

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The Comparison Between Matched Related Donor and Alternative Donor for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acquired Aplastic Anemia: KSBMT2007-02 Study

Blood ◽

10.1182/blood.v112.11.2997.2997 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2997-2997

Author(s):

Hawk Kim ◽

Hong Hoe Koo ◽

Hoon Kook ◽

Byung Soo Kim ◽

Sung Hyun Kim ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Platelet Transfusion ◽

Disease Duration ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Cell Source ◽

Donor Type ◽

Alternative Donor ◽

Related Donor

Abstract Backgound; Although allogeneic hematopoietic stem cell transplantation (alloSCT) from matched related donor (MRD) is a standard therapy for severe acquired aplastic anemia (AA), alternative donor (AD) alloSCT is increasing and the survival of alloSCT from AD improves nowadays. Aims: We planned this study to review the recent result of alloSCT survival and to compare AD with MRD. Methods: A retrospective study comparing MRD and AD for alloSCT in patients with AA was conducted by Korean Society of Blood and Marrow Transplantation (KSBMT2007-02 study). Results: The patient population was AA, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, and they underwent alloHSCT from 1997 and 2007. Total 336 patients were enrolled in 24 Korean alloSCT centers. Survival analysis was done in 331 patients because data were not available in 5 patients. Two hundred five adult patients with AA were also analyzed to define the characteristics of adult AA patients. AA was 97.3% and median age at alloSCT was 20.4 (1–62) years old. Median time from diagnosis to alloSCT was 6.2 (0.2–248.4) months. Male was 48.9%. Seventy nine percent patients received bone marrow (BM) as a stem cell source. AD had longer time from diagnosis to alloSCT (p=0.049) and received more peripheral blood (PB) or cord blood (CB) as a stem cell source (16.3% vs. 31.7%, p=0.004). Univeriate analysis showed MSD (p<0.001), age less than 15 years (p=0.010), BM as stem cell source (p=0.036) and disease duration less than 12 months (p=0.007) were significant predictor for better survival. However, multivariate analysis revealed that donor type was not significant factor (p=0.087) whereas age and BM was predictors for better survival. When 205 adult AA patients were analyzed, AD had more graft failure (p=0.005), delayed neutrophil engraftment (p=0.035), more acute graft versus host disease (GvHD; p=0.009). However, there were no different between AD and MRD in terms of platelet engraftment (p=0.618), incidence of SOS (p=0.735) and relapse rate (p=0.360). MRD (p=0.011), age less than 30Y (p=0.001), disease duration less than 12M (p=0.003), no prior immune suppression therapy, (p=0.007) and platelet transfusion less than 90U (p=0.010) significantly affected survival. Only age and platelet transfusion were significant factor for better survival in multivariate analysis. Summary: In conclusion, our study showed that donor type was not a significant factor for survival. Therefore, AD should be considered earlier when there is no MRD in patients with AA.

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Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Adult Patients with T-Cell Acute Lymphoblastic Leukemia: A Survey From the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v120.21.356.356 ◽

2012 ◽

Vol 120 (21) ◽

pp. 356-356

Author(s):

Xavier Cahu ◽

Myriam Labopin ◽

Sebastian Giebel ◽

Gerard Socie ◽

Dietrich Beelen ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Donor Type ◽

Cell Acute Lymphoblastic Leukemia

Abstract Abstract 356 Background: T-cell acute lymphoblastic leukemia (T-ALL) comprises about 25% of all adult ALL. Although allogeneic hematopoietic stem cell transplantation (allo-SCT) exerts a graft versus leukemia effect, very few large series exist on the outcome of adult T-ALL patients allografted with a myeloablative conditioning regimen. Patients and methods: adult cases of T-ALL patients who underwent related or unrelated (6/6) allo-SCT with a myeloablative regimen between 2000 and 2010 were extracted from the EBMT registry. Patients with a prior autologous or allogeneic SCT and those who received cord blood allo-SCT were excluded from analysis. Primary goal of the study was to evaluate overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM) and relapse incidence (RI) for T-ALL patients in first (CR1), second or subsequent remission (CR2+) and in relapse or refractory disease (advanced). Results: 886 patients were included in this study. The median follow-up was 43 months. The median age was 29 (range: 18–63) and 649 patients (73%) were males. Allo-SCT characteristics are described in table 1. Among patients (n=561) allografted in CR1, 25% had a white blood cell count (WBC) ≥100 G/L, and a complex karyotype was identified in 43 cases (16%, available data = 268). 4-year OS and 4-year LFS were 58% (standard deviation (SD) 2%) and 55% (SD 2%), respectively, whereas 4-year NRM and RI were 19% (SD 2%) and 26% (SD 2%), respectively. In univariate analysis, age < median age (60% versus 50%, p = 0.02) and use of total-body-irradiation (TBI) (57% versus 42%, p = 0.04) were associated with an improved 4-year LFS. In a multivariate analysis including age, use of TBI, donor type and donor sex, age <median age (Hazard Ratio (HR)= 0.71 [95% CI: 0.55–0.92], p=0.01) and use of TBI (HR = 0.67 [0.48–0.93], p=0.02) were associated with an improved LFS. In the CR2+ T-ALL group (n=151), 4-year OS and 4-year LFS were 25% (SD 4%) and 24% (SD 4%), respectively. 4-year NRM was 27% (SD 4%) whereas 4-year RI was 49% (SD 4%). In univariate analysis, use of TBI was associated with an improved 4-year LFS (29% versus 8%, p = 0.02). In a multivariate analysis including age, patient sex, use of TBI and donor type, use of TBI was associated with an improved LFS (HR = 0.57 [0.37–0.88], p=0.01). Finally, in the advanced T-ALL group (n=174), 4-year OS and 4-year LFS were 15% (SD 3%) and 12% (SD 3%), respectively. 4-year NRM was 30% (SD 4%), whereas 4-year RI was 58% (SD 4%). In univariate analysis, use of TBI was associated with an improved 4-year LFS (16% versus 3%, p= 0.002). In a multivariate analysis including age, use of TBI and donor type, use of TBI was again associated with an improved LFS (HR=0.56 [0.38–0.82], p=0.003). Conclusion: This large series demonstrates that myeloablative conditioning allo-SCT is followed by a relatively favorable outcome in patients with T-ALL transplanted in CR1, and might be an option for subgroups of patients in more advanced phase of the disease. Of note, use of TBI as part of the conditioning regimen is associated with an improved LFS in all disease stages. Disclosures: No relevant conflicts of interest to declare.

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Permissive HLA-DPB1 Mismatch and Survival after Unrelated Donor Allogeneic Stem Cell Transplantation for Hematological Malignancies: A Comparative Analysis of Different Immunogenetic Models on 422 Patients from GITMO and IBMDR

Blood ◽

10.1182/blood-2018-99-115216 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 482-482

Author(s):

Francesca Lorentino ◽

Nicoletta Sacchi ◽

Elena Oldani ◽

Valeria Miotti ◽

Alessandra Picardi ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Research Funding ◽

Disease Status ◽

Hla Matching ◽

Graft Versus Host ◽

Stem Cell Source ◽

Functional Distance ◽

Cell Source ◽

Advisory Role

Abstract Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. HLA matching plays a major role in determining HSCT outcome but the relative role of incompatibilities at the different HLA loci is still debated. In particular, over 80% of UD-HSCT are performed across HLA-DPB1 mismatches (mm): a number of previous studies have devised immunogenetic models to elucidate the impact of HLA-DPB1 mm on HSCT outcome, but a comparative analysis of these models in a recent and well-characterized cohort is lacking. Methods: We selected 422 adult patients (pts) who received an 8/8 (HLA-A, B, -C and -DRB1) allele level-matched UD-HSCT from 2012 to 2015: of them, 382 (90%) had a mm at one or both HLA-DPB1 alleles. We classified functional HLA-DPB1 matching by four models, on the basis of: I) differential immunogenicity of alleles belonging to 3 groups of T-cell epitopes (TCE), as defined by functional studies (Zino, Blood, 2004) and refined by in silico prediction (Crivello, BBMT 2015); II) a similar model subdividing allelles in 4 TCE groups (TCE4, Crocchiolo, Blood 2009); III) differences in "delta functional distance" scores between the alleles of donor and pt, based on 12 polymorphic AA in HLA-DPB1 exon 2 (Crivello, Blood 2016); IV) mismatches in the rs9277534 single-nucleotide polymorphism in the HLA-DPB1 3′ UTR region, predicted on the basis of the DPB1 genotype (Schöne, Hum Immunol 2018), and previously shown to be associated to the expression levels of HLA-DPB1 molecules (HLAexp, Petersdorf, NEJM 2015). Indication for HSCT was acute leukemia (55%), lymphoma and multiple myeloma (29%), myelodysplastic and myeloproliferative syndromes (16%). According to EBMT score definition, 45% of pts were in early, 26% in intermediate, and 29% in advanced disease status. Conditioning regimens were myeloablative (64%) or reduced intensity (36%). Peripheral blood was the preferred stem cell source (81%). Graft-versus-host disease (GvHD) prophylaxis was based on anti-thymocyte globulin (ATG) in 91% of pts, mostly associated with cyclosporine and methotrexate (81%). Median follow-up was 3.2 y. Results: Among the four models adopted to classify functional HLA-DPB1 matching, the TCE4 provided the best results in predicting mm that were permissive (P) or non permissive (NP) for HSCT outcomes. By this model, P mismatched pairs (N=135) had a significantly superior 3-y overall survival (OS) and Graft-versus host disease and Relapse-Free Survival (GRFS) compared to NP pairs (N=247) (60±8% vs 49±7%, p .05; and 36±8% vs 29±5%, p .04). This was associated with a higher transplant-related mortality (TRM), 30±6% in NP mm and 21±6% in P mm, p .09 and a higher 3-y CI of extensive cGvHD in NP mm (12±4%) compared to P (4±2%), p .01 (Figure 1). No effect was found for relapse incidence. Cox multivariate analysis (adjusted for pt age, donor/host gender and CMV, disease status, Sorror score, conditioning intensity, stem cell source, ATG use, HLA matching on 5 loci, center effect), showed that a NP mm compared to P mm was associated with higher hazards for OS (HR 1.6, p .01), GRFS (HR 1.4, p .02), TRM (HR 1.9, p .01), cGvHD (HR 1.6, p .03) and extensive cGvHD (HR 3.6, p <.01). No interaction was found between HLA matching on 5 loci and HLA-DPB1 permissivity predicted by TCE4. Directionality of NP mm did not impact on clinical risk stratification. Of the 382 transplants with HLA-DPB1 mismatches, 229 had unidirectional mismatches in GvH direction and thus could be classified by the HLAexp model. The predicted expression level of the mismatched allele in the patient was associated with 100-d CI of grade≥2 aGvHD: 32±10% in high expression (N=76) versus 16±6% in low expression (N=153) mismatched alleles, p <.01. This was also confirmed in adjusted Cox multivariate analysis for grade≥2 aGvHD (HR 2.2, p <.01). However, this did not have a significant impact on severe aGvHD, TRM and OS. No significant associations with clinical outcomes were found for the "delta functional distance" or the TCE3 model, respectively. Conclusions: Our study provides further proof that functional HLA-DPB1 matching is crucially associated to UD-HSCT outcome also in recent transplants, and suggest that, at least in the cohort under analysis, mainly composed of Italian pts transplanted using an ATG-based prophylaxis, the TCE4 model appears superior to other models in stratifying risk groups and predicting survival. Figure. Figure. Disclosures Patriarca: Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Rambaldi:Italfarmaco: Consultancy; Roche: Consultancy; Omeros: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy. Fleischhauer:GENDX: Research Funding. Vago:GENDX: Research Funding; Moderna TX: Research Funding.

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Impact of Disease Status on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation with Refractory and Relapsed Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v128.22.5862.5862 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5862-5862

Author(s):

Jing Cao ◽

Xiaoming Zhu ◽

Aining Sun ◽

Huiying Qiu ◽

Zhengming Jin ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Lymphoblastic Leukemia ◽

Disease Status ◽

Hematopoietic Stem ◽

The Impact

Abstract Objective: To evaluate the impact of disease status on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of patients with refractory and relapsed acute lymphoblastic leukemia(ALL). Methods: 52 patients with refractory and relapsed ALL, including 19 cases in advanced stage (nonremission, NR) and 33 cases in more than or equal to second complete remission(≥CR2), received allo-HSCT after myeloablative conditioning regimen in our department. Results: 51 patients engrafted successfully. The transplantation-related mortality (TRM) rate of NR and ≥CR2 was 10.5% vs 12.1% (P=0.815). The incidence of aGVHD was 52.6% vs 57.6% (P=0.730), including 42.1% vs 33.3% (P=0.527) with mild (grade I-II) and 10.5% vs 24.3% (P=0.399) with severe (grade III-IV) aGVHD. The incidence of cGVHD was similar also(41.6% vs 57.9% ,P=0.660). With a median follow-up of 12(1.8-44.5) months, the cumulative relapse rate of NR and ≥CR2 was 47% vs 34.3% (P=0.425) respectively. The estimated 2 year overall survival (OS) and 2 year leukemia-free survival (LFS) rate were 42.6% vs 45.7% (P=0.487) and 46.3% vs 46.2% (P=0.571) respectively. Multivariate Analysis results showed that cGVHD was independent favorable risk factor for OS and LFS of R/R ALL. For relapsed patients, OS was significantly better with first CR duration>6 month and time to transplant≤2 months. Conclusion: AlIo-HSCT is an effective salvage treatment option for patients with refractory and relapsed ALL. Our retrospective analysis showed that R/R ALL with different status prior transplant had similar outcome post transplantation. Disclosures No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Stem Cell Transplantation for Treatment of Philadephia Chromosome Negative Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v114.22.4338.4338 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4338-4338

Author(s):

Shiqiang Qu ◽

Chengcheng Fu ◽

Wu Depei

Keyword(s):

Risk Factor ◽

Stem Cell ◽

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Lymphoblastic Leukemia ◽

Hematopoietic Stem

Abstract Abstract 4338 Objective To explore the optimum donor selection of allogeneic hematopoietic stem cell transplantation (allo-HSCT) applied in patients with Philadephia chromosome-negative acute lymphoblastic leukemia(Ph- ALL) and investigate its relevant prognostic factors. Methods A total of 48 adult patients with Ph- ALL who had admitted to our hospital and been treated by allo-HSCT from February 2002 to May 2008 were followed up until July 2008. They were divided into match related donor(MRD -HSCT) group, match unrelated donor(MUD-HSCT) and Haploidentical (Haplo-HSCT) group. Clinical characteristics of these groups were retrospectively analyzed. Survival data were analyzed by the Kaplan-Meier method and the prognostic factors were analyzed with the COX regression model. Results Of all the 48 cases, 5-year overall survival(OS) was 45.4±8.1%, disease free survival(DFS) was 40.7±7.9%.The 5-year OS and DFS of MRD –HSCT subgroup, MUD-HSCT subgroup and Haplo-HSCT subgroup were 50%±14.4%,53.2%±13.2%, 31.3%±13.6%(p=0.048) and 44.7%±13.3%,41.4%±13.6%,32.1±14.2%(p=0.167), respectively. Haplo-HSCT subgroup 5-year OS lower than other two subgroups, which showed statistical significance. GradeIIto‡W acute graft versus host disease(aGVHD) [p=0.001,RR=6.980] and white blood cell at diagnosis higher than 30×109 /L[p=0.028, RR=2.679]were the risk factor of OS in multiple covariate analysis model. The HSCT type was not independent risk factor of OS. Conclusion MUD-HSCT and MRD-HSCT have similar efficacy in adult Ph- ALL. Haplo-HSCT can be a distinct option in High-risk adult Ph- ALL patients without a MRD and MUD. Disclosures: No relevant conflicts of interest to declare.

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