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)

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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Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation during First Complete Remission Following Imatinib-Combined Chemotherapy in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v112.11.462.462 ◽

2008 ◽

Vol 112 (11) ◽

pp. 462-462 ◽

Cited By ~ 1

Author(s):

Shuichi Mizuta ◽

Masamitsu Yanada ◽

Isamu Sugiura ◽

Fumiharu Yagasaki ◽

Toshiaki Yujiri ◽

...

Keyword(s):

Stem Cell ◽

Cord Blood ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Philadelphia Chromosome ◽

Combined Chemotherapy ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Donor Type

Abstract The treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has been changed dramatically since the introduction of imatinib. We previously reported a 96% complete remission (CR) rate in newly diagnosed patients treated with imatinib-combined chemotherapy (Yanada et al. J Clin Oncol2006;24:460–466), and showed that the combination therapy is useful in terms of providing patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation (HSCT) in first CR. However, little is known about the outcome after allogeneic HSCT in such patients. To address this issue, we analyzed detailed data from 60 patients who underwent allogeneic HSCT in first CR following a uniform treatment protocol consisting of imatinib and chemotherapy. The median age of the studied patients was 37 years (range, 15–64 years), with 32 males and 28 females. Donors were HLA-matched related (n=24), matched unrelated (n=21), mismatched cord blood (n=9), and mismatched related (n=6). All 52 patients aged less than 55 years received a myeloablative conditioning regimen, whereas 6 of 8 patients aged 55 years or older received a reduced intensity conditioning (RIC) regimen. Grade 2–4 acute graft-versus-host disease (GVHD) was recorded in 20 patients, and chronic GVHD was recorded in 32 patients, 17 of whom had the extensive form. During a median follow-up of 2.6 years (maximum, 4.6 years) after transplantation, relapse and death in first CR occurred in 9 and 15 patients. The probabilities for overall survival (OS) and relapse-free survival (RFS) were 64% and 53%, respectively, at 3 years. Patients younger than 40 years had a trend toward better RFS than those at 40 to 54 years (60% vs. 38% at 3 years, p=0.16). Unexpectedly, all of the 8 patients aged 55 years or older remained alive in first CR. In relation to the donor type, RFS did not differ among patients allografted from a matched related donor, a matched unrelated donor, and mismatched cord blood (52% vs. 59% vs. 56% at 3 years, p=0.92). For risk factor analysis, the following variables were examined: donor type (sibling vs. unrelated vs. cord blood), age group (<40 years vs. 40–54 years vs. ≥55 years), minimal residual disease status at time of HSCT (quantitative real-time PCR negative vs. positive), type of conditioning regimen (RIC vs. myeloablative conditioning), performance status at time of HSCT, and bcr/abl isotype (major vs. minor). Multivariate analysis revealed that only the presence of major bcr/abl was significantly associated with inferior RFS (HR, 3.70; 95% CI, 1.34–10.2; p=0.012). Conclusion: In patients with Ph+ ALL who were initially treated with imatinibcombined chemotherapy, the outcome after allogeneic HSCT in first CR was favorable irrespective of the donor type. Cord blood transplantation and RIC transplantation might be attractive options for those without a suitable donor and for those unfit for conventional myeloablative conditioning, respectively. Prospective studies are warranted to confirm the roles of these forms of transplantation, especially RIC for patients between 40 and 54 years of age.

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Polyoma (BK) Viruria Prior to Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) from Donors Other Than Matched Siblings: A Prospective Evaluation of Hemorrhagic Cystitis (HC) Incidence

Blood ◽

10.1182/blood.v112.11.50.50 ◽

2008 ◽

Vol 112 (11) ◽

pp. 50-50

Author(s):

Leandro de Padua silva ◽

Poliana Patah ◽

Rima M. Saliba ◽

Nicholas A. Szewczyk ◽

Lisa Gilman ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Univariate Analysis ◽

Bk Virus ◽

Time Dependent ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Donor Type

Abstract Background: BK virus infection has been associated with development of HC after HSCT, but most studies detected the virus at the time of bleeding, therefore not allowing estimation of the risk imposed by asymptomatic infection. We hypothesized that viruria prior to HSCT increased the risk of HC, and sought to investigate this hypothesis in a cohort of consecutive patients receiving HSCT from donors other than HLA-identical siblings in our institution from 09/2005 and 08/2007. Patients and Methods: We prospectively performed a quantitative PCR on urine samples collected before admission to transplant and on day 30 after transplant. The quantitative BK virus assay was performed at Focus Diagnostics, Inc., Cyprus, CA with a commercially available kit. A set of quantitative standards are run in parallel and assay is linear through 39 million copies/mL. Risk factors for the development of HC were evaluated on univariate and multivariate analysis using Cox’s regression model. The cumulative incidence (CI) of HC was estimated considering death without HC as a competing event. Results: 209 pts were studied (132 males). Median age was 49 years (range, 19–71). Diagnoses included leukemias (n=161, 77%), lymphoma and myeloma (n=46, 22%) and others (n=2, 1%). Donors were unrelated (n=178), haploidentical (n=8) and unrelated cord blood (CB) (n=23). Stem cell source was bone marrow (BM, n=78), peripheral blood (PB; n=108), and CB (n=23). . Conditioning regimen was myeloablative in 110 pts and reduced intensity (RIC) in 99 pts; 38 pts (18%) received cyclophosphamide-containing regimens. GVHD prophylaxis was tacrolimus and mini-methotrexate. Median time to platelet engraftment was 20 days (range, 0–164). Pre transplant BK viruria was detected in 96 patients (46%). The number of viral copies ranged from 300 to > 200 million copies. Twenty five patients (11%) developed HC within one year after HSCT at a median of 59 days (range, 8–225). In 6 pts, HC was diagnosed before platelet engraftment. The severity of HC was grade 1 in 3 pts, grade 2 in 11, grade 3 in 8, an grade 4 in 3. On univariate analysis, donor type was the most significant predictor of the incidence of HC within a year of HSCT, with recipients of haploidentical or CB transplant having the highest incidence rate (HR=3.1, p=0.009). There was also a trend for higher HC incidence in patients who received a myeloablative conditioning (HR=2.3, p=0.06), and in those who had a positive PCR before transplant (HR=2, p =0.095). Because of the small number of HC cases in pts who received a RIC (n=7/99, CI of HC 7%) we could not perform a multivariate analysis adjusting for the type of conditioning. In patients who received a myeloablative conditioning multivariate analysis showed a significantly higher incidence of HC in pts who received a haploidentical or CB transplant (HR=3.8, p=0.006); and in pts with a positive PCR before transplant (HR=2.9, p=0.03). The cumulative incidence of HC in pts who had both adverse factors was 58%, compared with 11% and 13% in those who had either one or none of these factors, respectively. There was no significant association between the incidence of HC and grade II-IV acute GVHD, considered as a time dependent variable, patient age, stem cell type (BM vs. PB), use of cyclophosphamide in conditioning, BK viral load, or PCR positivity on day 30 post HSCT. With a median follow-up among survivors of 11 months (range 4–32), HC, considered as time dependent variable, did not have a significant impact on survival. Conclusion: BK viruria pre-HSCT may be a predict factor for development of HC, especially for those receiving haploidentical or CB transplants using a myeloablative regimen. Cumulative incidence of HC as a function of preparative regimen intensity and BK virus PCR status pre transplant Figure Figure Incidence of HC Variable (n) No patients with HC (%) Total (209) 25 (12%) Age ≤ 50 years (99) 12 (12%) > 50 years (110) 13 (12%) Sex M/F 132/77 16(12%)/9(12%) Diagnosis Leukemia (161) 18 (11%) Lymphoma (40) 7 (17.5%) Conditioning Ablative (110) 18 (16%) Non-ablative (99) 7 (7%) Donor Type MUD(169) 17 (10%) Haplo/cords (31) 8 (25%) acute GVHD I – II (88) 10 (12%) III – IV (26) 4 (15%) Pre SCT PCR Positive (96) 16 (17%) Negative (111) 9 (8%)

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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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Long-Term Outcome of Preemptive Immunotherapy Based on Post-Transplant Chimerism and MRD Monitoring after Allogeneic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia: A Single Center Experience

Blood ◽

10.1182/blood.v124.21.3953.3953 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3953-3953

Author(s):

Eva Rettinger ◽

Michael Merker ◽

Hermann Kreyenberg ◽

Thomas Krenn ◽

Matthias Dürken ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Stem Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Post Transplant ◽

Remission Status ◽

High Level

Abstract Introduction: Mixed chimerism (MC) and minimal residual disease (MRD) strongly predict risk for relapse in children with acute lymphoblastic leukemia (ALL) following allogeneic stem cell transplantation (allo-SCT). Preemptive immunotherapy (IT), e.g. withdrawal of immunosuppression (WD-IS) or donor lymphocyte infusion (DLI) guided by chimerism and MRD monitoring can prevent impending relapse in allo-SCT recipients. In this study we retrospectively analyzed chimerism and MRD monitoring and the effect of preemptive IT in all pts undergoing allo-SCT for ALL in our institution. Patients: Between January 2005 and July 2014, a total of 89 children and adolescents (median age 11.5; range 2.2-26.0 years) with ALL (pB-ALL, n=63; T-ALL, n=20; biphenotypic/bilinear ALL, n=6) were transplanted in our center after remission induction treatment. 47 pts were in first, 26 pts were in second, 15 pts were in third, and 1 pt was in fourth complete remission (CR) at time of transplant. 18 pts received grafts from matched sibling donors (MSD), 61 pts from matched unrelated donors (MUD), and 10 pts were grafted from a haploidentical parent. Pts who received their graft from a matched donor (n=79) all underwent a fully myeloablative conditioning regimen consisting of TBI (12 Gy) and etoposide. Pts who were grafted from a haploidentical donor were prepared with fludarabine, thiotepa and melphalane. Methods: Serial and semi quantitative analyses of post-transplant hematopoietic chimerism in peripheral blood were performed weekly until day 200 and monthly thereafter. Bone marrow analyses were done at days +30, +60, +90, +180 and +365 post-transplant. Thereby, MRD was assessed in 56 pts, whereas no diagnostic material was available in 33 pts. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD-Group. All patients should receive preemptive IT if they develop MC after day +28. Results: 64/89 pts (72%) showed complete chimerism (CC) in all follow-up analyses, and 25/89 pts (28%) developed MC although all pts received a fully myeloablative conditioning regimen. From 56 pts in whom MRD could be assessed, 40 pts remained MRD negative and 16 developed MRD positivity after transplantation. IT (WD-IS, n=12; DLI, n=14) was initiated based on chimerism analysis in 22/25 pts with MC, and was guided by MRD detection in 4 pts. For the total cohort of pts, probability of event free (pEFS) and overall survival (pOS) were 0.67 and 0.77, respectively. Furthermore, cumulative incidence of treatment related mortality (CI-TRM) and relapse (CI-relapse) were 0.11 and 0.24 for all pts. Chimerism: pEFS was 0.74 in CC-pts and 0.51 in MC-pts (p<0.032). 22/25 MC-pts received pre-emptive IT resulting in a pEFS of 0.58. Due to rapid progression of their disease IT was not initiated in 3/25 MC-pts. All MC-pts without IT relapsed, and in part received further treatment. While CI-TRM remained low (0.10 for CC resp. 0.12 for MC, p>0.68) in both groups, CI-relapse was 0.17 in CC- and 0.41 in MC-pts (p<0.021). MRD: Besides MC, MRD level post-transplant emerged as poor prognostic factor. Pts were grouped according to their highest MRD value post-transplant in MRD negative, low positive (<10E-4), and high positive (>10E-4) pts. pEFS and pOS were 0.82 and 0.95 in MRD negative (n=40), 0.56 and 0.88 in low level MRD (n=8), and 0.25 and 0.25 in high level MRD (n=8) positive pts (p<0.001). CI-relapse was 0.14 in MRD negative, 0.36 in MRD low, and 0.75 in MRD high positive pts (p<0.001), while CI-TRM between these groups remained low (0.05 for MRD negative, 0.13 for MRD low and 0.00 for MRD high, p>0.55). Other risk factors: Furthermore, remission status at the time of transplant influenced relapse rate. CI-relapse was 0.16 in CR1, 0.26 in CR2, and 0.45 in CR>2 pts (p<0.025). Differences in pEFS, pOS and CI-TRM among CR1, CR2, and CR>2 pts were not statistically significant. Multivariate analysis: Multivariate analysis for pEFS also indicated that MC and high level MRD were independent poor prognostic factors (MC, p<0.049, RR 3.16 and high level MRD, p<0.022, RR 3.99), while remission status before transplantation, ALL lineage, donor type, graft source, T cell depletion or sex showed no significant influence. Conclusion: Our results show that analysis of chimerism and MRD allow the prediction of impending relapse in virtually all children and adolescents transplanted for ALL and that preemptive IT can improve outcome in these high-risk pts. Disclosures No relevant conflicts of interest to declare.

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