Successful allografting for relapsing pediatric ALL: The results of two decades.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e22000-e22000
Author(s):  
O. Bulent Zulfikar ◽  
Basak Koc
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Poor Response ◽  
Response To Treatment ◽  
Laboratory Findings ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

e22000 Background: The prognosis of children and adolescents with acute lymphoblastic leukemia (ALL) has dramatically improved. This success is associated with both by multiagent chemotherapy regimens and by definition of clinical, biological and treatment response that allow the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). In treatment of relapsed and resistance ALL, allogeneic HSCT continues to play a major curative role. In the present study, we desciribed the patients who underwent HSCT in our clinic in the last 21 years. Methods: From 1999 to 2020, 147 patients who diagnosed with ALL and treated with the COG protocols at the Istanbul University Oncology Institute were retrospectively reviewed and 17 of them relapsed. HSCT was applied 7 of the relapsed cases and also 3 resistant cases who had suitable matched donors. The demographic features, laboratory findings and treatment responses of 10 patients were recorded from the patients’ medical records. Results: All 10 patients were B-ALL with median diagnosis age of 79.5 months (range: 32-195) and 5 were male. Characteristics of patients given in Table 1. HSCT was performed due to late relaps in 7 patients. Three of the 7 relaps were only bone marrow and other 4 had combined. Patient #2 had both breast, conjunctiva and bone marrow for the 1st relaps and only conjunctiva for the 2nd one and this patient had also t(9;22) in the 1st relaps. Patient #3 had bone marrow+central nervous system relaps and patient #7 had bone marrow for the 1st relaps and testis and bone marrow for the 2nd one. Other 3 had poor response to treatment and Minimal Residual Disease (MRD) was high in End of Introduction (EoI) and End of Consolidation (EoC)). All patients had allogeneic HSCT and 8 are alive. Conclusions: HSCT remains the standard-of-care treatment for ALL patients who carry high-risk features predicting leukemia recurrence and for those experiencing high-risk first relapse or multiple relapses. Additionally, defining the indications of HSCT are dynamic and it could change according to treatment options as well as new molecular and biological findings. It is important to identify the patients who have high relapse risk and HSCT should have priority in patients whom MRD is high in EoI and EoC.[Table: see text]

Results of the AIEOP-BFM ALL 2000 Study for Childhood Acute Lymphoblastic Leukemia IN AIEOP High Risk Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 319-319
Author(s):  
Valentino Conter ◽  
Maria Grazia Valsecchi ◽  
Maurizio Aricò ◽  
Carmelo Rizzari ◽  
Rosanna Parasole ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Poor Response ◽  
Cranial Radiotherapy ◽  
Hematopoietic Stem ◽  
Innovative Therapies ◽  
Risk Patients

Abstract Abstract 319 Aim: The Italian Association of Pediatric Haematology and Oncology (AIEOP) patients, diagnosed in the period September 2000-July 2006, were treated in the context of the AIEOP-BFM ALL 2000 Study. Some differences in high risk (HR) treatment and hematopoietic stem cell transplantation (HSCT) indications justify separate reporting of results obtained by AIEOP and BFM respectively. We report here the AIEOP experience. Patients and methods: Overall, 1999 AIEOP Ph negative Acute Lymphoblastic Leukemia (ALL) patients were eligible to the AIEOP-BFM ALL 2000 Study. High Risk (HR) criteria were: t(4;11) translocation, Prednisone Poor Response (PPR), no complete remission (CR) at day 33, high minimal residual disease (MRD) levels (≥10-3) at day 78 (HR-MRD). Treatment consisted of protocol I (patients were randomised to receive either dexametasone or prednisone in induction), 3 HR polychemotherapy blocks, a randomized comparison between delayed intensification based on protocol II repeated twice or protocol III repeated thrice, cranial radiotherapy (CRT), maintenance therapy for a total of 2 years of treatment. Results: 311 patients were classified as being at HR (15.6% of the total ALL population) and had an overall event-free survival (EFS) and Survival of 58.7%(standard error 2.9) and 70.1%(2.7), respectively. For the 204 patients randomized to different steroids in protocol I, we observed a 5-year EFS of 62.7%(5.0) and 62.3%(4.8) and a 5-year Survival of 72.7%(4.7) and 72.8%(4.3) for dexamethasone and prednisone arm, respectively. The 5-year EFS was 44.4%(4.5) in 132 patients at HR for MRD, 36.4%(14.5) for the 11 patients at HR for t(4;11), 41.2%(11.9) for the 17 patients at HR for no CR at day 33, 74.6%(3.7) for the 151 patients at HR only for PPR. Patients at HR with <10-3 (44/258) or negative (82/258) MRD levels at day 78 had a 5-year EFS of 63.4%(7.3) and 79.4%(4.9), respectively. Among 80 patients who underwent allogeneic HSCT at a median time of 6 months from diagnosis, 68 had HR-MRD or t(4;11) or no CR at day 33. After adjusting for waiting time to transplantation, their 5-year EFS was 51.7%(6.6) compared with a 5-year EFS of 44.6%(5.8) in patients with the same features and treated given chemotherapy only (p=0.72). Conclusions: These data show that AIEOP-BFM ALL 2000 HR therapy is very effective for patients defined at HR for PPR. These patients could thus be considered for some treatment reduction, i.e. sparing most toxic therapeutic elements such as CRT. MRD identifies patients at HR (8.7% of the analysed population, 42% of HR patients), who have a poor outcome despite receiving intensive BFM treatment, including HSCT, and who may thus be eligible for innovative therapies. Disclosures: No relevant conflicts of interest to declare.

Single Immunophenotypical Evaluation of Minimal Residual Disease before Autotransplantation of Non-Cryopreserved Bone Marrow Is Insufficient for Prediction of Outcome in High Risk Adult Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4439-4439
Author(s):  
Beata M. Stella-Holowiecka ◽  
Krystyna Jagoda ◽  
Aleksandra M. Holowiecka-Goral ◽  
Tomasz Czerw ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Long Term Results ◽  
Color Flow ◽  
Childhood All ◽  
Minimal Residual

Abstract For high-risk adult ALL patients alloHCT is a preferable option. However, a significant proportion of those not having a suitable donor may be successfully treated with autotransplantation (autoHCT). Based on our experience this treatment ensures low transplant related mortality below 3% and a reasonable overall survival and disease free survival of 60% and 45% respectively. The status of the disease before transplantation is an important factor for long term results. In childhood ALL most studies suggest that the level of minimal residual disease (MRD) after induction evaluated immunophenotypically or with bio-molecular methods is predictive for outcome after different treatments including chemotherapy, alloHCT and autoHCT. The results in adult ALL are more controversial. Patients selection. Among 1205 haematopoetic cell transplantations performed in our institution 224 (147 autologous, 77 allogeneic) were performed in 205 adults with ALL. For this study we selected an uniform group of 81 patients fulfilling following criteria’s: Ph (-) ALL, status CR1, evaluable MRD, strictly defined autoBMT procedure performed until the end of 2003. Methods. MRD was tested before autoBMT (median interval 10 days) using 2 ore 3-color flow-cytometry, as appropriate. The atypical immunophenotypes were evaluated using the “quadrans” analysis in all cases and since 2002 also the “empty spaces” technique. The sensitivity equals at least 0.0001. For all autoHSCT bone marrow was used as a source of stem cells. The CAV conditioning regimen consisted of cyclophosphamide 60mg/kg on d. -3, -2, cytarabine 2 g/m2 d. -3, -2, -1, etoposide 800 mg/m2 d. -3, -2. Bone marrow was not cryo-preserved after collection but stored in 40 C and re-transplanted after 72h. Results. In 41 patients; age med. 26 y (15–53), F/M=12/29, the MRD level was &lt;0,001: the MRD (−) group. In 40 patients; age med. 29 y (16–53), F/M=18/22, the MRD was detected at the level =/&gt; 0,001; MRD+ group. The ALL-immunophenotypes of MRD−/MRD+ groups were as follows; proB 4/7, preB 2/6, Common 18/19, B 0/1, preT 5/2, T 12/1). The interval from DGN to BMT was similar in both groups. The probability of LFS and OS at 10y calculated with median follow up time of 5y equaled; in the MRD(−) group 47% and 62% and in the MRD+ one 48% and 57% respectively (p=ns). The main reason of failure in both groups was a relapse which occurred after a median time of 277 days in the MRD(−) group and 134 days in MRD+ one (p=0.19). Conclusion and comment. Based on this observation we conclude that a single evaluation stratifying patients before autoBMT according to MRD level below or above 0.001 is not predictive for DFS and OS, because it informs only about the current amount of the disease but not about its opportunistic nature. In this respect a repeatedly confirmed MRD positivity should be more significant. Taking into consideration that the main reason of failures were relapses, this finding suggests also that in patients with chemotherapy-responsive ALL confirmed by stabile CR, the myeloablative CAV regimen is sufficiently strong to eliminate the residual disease at the level ranging 0.01–0.001. It may be speculated only that the 72h lasting incubation of bone marrow product before re-transplantation has also some kind of purging effect for leukemic blasts.

Autologous Transplantation of Non-Cryopreserved Bone Marrow for the Treatment of High-Risk Adult Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5492-5492
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Giebel ◽  
Malgorzata Krawczyk-Kulis ◽  
Maria Sadus-Wojciechowska ◽  
Lucja Kachel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Hospital Stay ◽  
Lymphoblastic Leukemia ◽  
Autologous Transplantation ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
First Complete Remission

Abstract Autologous hematopoietic stem cell transplantation (HSCT) is a recognised option of post-consolidation therapy for adults with high-risk acute lymphoblastic leukemia (ALL) not having a donor. G-CSF-stimulated peripheral blood SCT results in faster recovery compared to cryopreserved bone marrow transplantation (BMT) and is currentlly used by the majority of centres. In the current study we analyze the feasibility of a new technique of autologous BMT, which does not require cryopreservation. 115 adult patients (median age 24.5 (16–53) years) with high-risk ALL in first complete remission (CR) were treated with autologous BMT between 1991–2004 in a single center using uniform standard operating procedures. Immune phenotype was as follows: proB 17%, preB 9%, common 44%, mature B 1%, preT 9%, mature T 19%. Initial WBC was &gt;30 G/l in 30% of patients. 8% of patients were bcr/abl(+), 38% required &gt;1 course of induction to achieve CR. Bone marrow was collected in general anaesthesia and further stored for 72 hours in 4degC without any processing and reinfused 24 hours after completion of myeloablative therapy. Conditioning regimen (CAV) consisted of cytarabine 2x1000 mg/m2 d. −3, −2, −1, etoposide 800 mg/m2 d. −3, −2, cyclophosphamide 60 mg/kg d. −3, −2. Median NC dose was 2.0 (0.9–10.8)x10e8, CD34+cell dose − 1.6 (0.4–15)x10e6/kg. Median recovery of ANC&gt;0.5 G/l equaled 16(11–45) days, PLT&gt;50 G/l – 16(10–53) days (11% patients received cytokines to stimulate NC recovery). Median duration of hospital stay since the date of BMT was 19(13–51) days. The OS rate at 10 years (median follow-up 6.5 years) equaled 57% (+/−5%), LFS rate − 47% (+/−5%). Three patients died within 100 days after ABMT of septic infections (non-relapse mortality rate − 2.6%). None of the analysed factors (age, WBC at diagnosis, immonophenotype, time to achieve CR) was found to influence the long-term outcome. We conclude that autologous transplantation of non-cryopreserved bone marrow after CAV conditioning is feasible for adults with high-risk ALL. The method is characterized by fast recovery, short hospital stay and low non-relapse mortality, and may constitute good alternative to autologous PBSCT.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2321-2321
Author(s):  
Sebastian Giebel ◽  
Beata Stella-Holowiecka ◽  
Malgorzata Krawczyk-Kulis ◽  
Nicola Goekbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 2321 Poster Board II-298 The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT. Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases. With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009). CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures: No relevant conflicts of interest to declare.

Flow Cytometric Minimal Residual Disease Levels After First Inducton Can Define T-Acute Lymphoblastic Leukemia Patients with High Risk of Relapse

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4817-4817 ◽  
Author(s):  
Veselka Nikolova ◽  
Velizar Shivarov ◽  
Ricardo Morilla
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Phenotypic Expression ◽  
Time Points ◽  
Group 2 ◽  
Time Point ◽  
Group 1

Abstract Abstract 4817 T-cell acute lymphoblastic leukemia (T-ALL) patients have increased risk for treatment resistance and early relapse. The precise bone marrow evaluation for the presence of minimal residual disease (MRD) is essential for guiding treatment options. This requires techniques more sensitive than the level of sensitivity of light microscopic technique such as multicolour flow cytometry (FCM). Immunophenotypic alterations called leukemia associated immunophenotypic patterns (LAIP) (i.e.aberrant myeloid markers) and ectopic phenotypic expression (i.e. appearance of immature phenotypes such as TdT, CD1a and CD3 outside their normal site in the thymus) are of benefit to track the residual leukemic cells in T-ALL. A retrospective data analysis of MRD was done comprising T-ALL patients diagnosed and followed-up at the Institute of Cancer Research/Royal Marsden Hospital by means of 3-colour flow cytometry (3C FCM).The aim was to answer a question whether the 3C FCM can reliably split patients into two groups (positive, MRD+ and negative, MRD-) and predict a subsequent relapse and to define a right time point for performing MRD tests. Eight patients were enrolled in the study following the inclusion criteria: (i) complete remission after 1st induction phase of chemotherapy, (ii) presence of LAIP or an ectopic phenotypic expression, and (iii) monitored at defined time points after initial treatment. MRD was measured during the first year of treatment as follows: at the end of phase 1 induction (day 29–35, MRD1), before the start of consolidation (3 months, MRD2), after consolidation (MRD3), during the maintenance therapy (12 months, MRD4). Immunophenotyping was performed on lysed-washed bone marrow samples using CD45 gating strategy and originally defined blast gates at diagnosis. The phenotypes to be followed-up included: TdT+/CytCD3+, CD34+/CYTCD3+, TdT+/CD2+, CD8+/CD10+, CD2+/CD10+, CD7+/CD10+, CD7+/CD33+, CD7+CD34+. Patients were divided into 2 groups in relation to subsequent relapse. Group 1 included 6 patients without relapse. Patient characteristics of the group were: male:female 5:1, mean age 17.7 years, overall survival (OS) 59 months, relapse free survival (RFS) 85 months. Group 2, relapsed patients, included 2 men, mean age 56 years, OS 13 months, RFS 8.5 months. According to the EGIL classification system the 2 men in Group 2 were with an early T-precursor phenotype, whilst Group 1 was heterogenous but cortical-T-ALL predominated. Cytogenetics/FISH and RQ-PCR studies were performed at diagnosis and showed normal karyotype in only one of the Group 2 patients. MRD results showed a difference between the two groups as regards MRD1 and MRD2 time points. Group 1 patients had negative or low MRD levels (below 0.18%) in their MRD1 bone marrow - MRD-, n=4 and MRD+,n=2 (0.18% and 0.12% respectively, sensitivity 0.04%). Those of them who were tested at MRD2 and MRD3 were negative. Both patients in Group 2 showed higher levels of MRD positivity at MRD1 (1% of total bone marrow cells), the first one of them also being positive at MRD2 and the second one becoming MRD+ at MRD4 time point. Although turning to MRD- at MRD3 time point both Group 2 patients relapsed 2.5 and 4.5 months, respectively, after the end of consolidation treatment. Additionally, Group 1 patients had a significantly longer RFS than Group 2 (median 58 months RFS vs. 8.5 months; P <0.001). Conclusions: Reliable detection of MRD in T-ALL is possible by 3C FCM using a combination of TdT and a T cell marker (cytCD3 or mCD3) as such a combination is normally found exclusively in the thymus. The higher MRD-positive levels in Group 2 reflect the more resistant disease in this group and higher probability of early relapse and shortened overall survival. Early T-cell precursor phenotype in these patients appeared to be a subtype at very high risk for treatment failure irrespective of the lack or the presence of genetic lesions. Based on MRD positivity above 0.18% at time points MRD1 or both MRD1 and MRD2 these patients need reassessment of treatment options and more intensive therapy has to be considered for relapse prevention. Finally, the results of our retrospective study suggest the usefulness of implementation of MRD testing by FCM for taking clinical decisions in the prospective clinical trials for novel therapies for T-ALL. Acknowledgments: The study was supported by the Union for International Cancer Control, Geneva, Switzerland (Grant ICRETT-080–2011) Disclosures: No relevant conflicts of interest to declare.

CD34+CD38-CD58- leukemia-Propagating Cells at Diagnosis Could Identify Patients at High-Risk for Relapse in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3795-3795
Author(s):  
Yuan Kong ◽  
Lan-Ping Xu ◽  
Yan-Rong Liu ◽  
Ya-Zhen Qin ◽  
Yu-Qian Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Peking University

Abstract Background: Relapse of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) may result from the persistence of leukemia stem cells sometimes termed leukemia-propagating cells (LPCs). We recently found that Ph+ALL LPCs are enriched in the CD34+CD38-CD58- fraction using anti-CD122-conditioned NOD/SCID xenograft assay by intra-bone marrow injection, which translating to adverse clinical outcomes (Kong Y, et al. Leukemia 2014. accepted). Despite the widespread use of abelson tyrosine kinase inhibitors (TKIs) in Ph+ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option. However, whether the prognostic significance of the identified LPCs phenotype to identify patients at high risk for relapse could retain in Ph+ALL after allo-HSCT, if any, is unknown. Aims: To investigate the prognostic significance of the candidate CD34+CD38-CD58- LPCs in Ph+ALL subjects underwent allo-HSCT. Methods: A total of 80 consecutive adults (18-60 years) with Ph+ALL underwent allo-HSCT were eligible for the study at Peking University Institute of Hematology from January 1, 2009 to December 31, 2013. Imatinib was routinely administered in subjects pre- and post-HSCT as previously reported. A multi-parameter flow cytometry analysis of CD58-FITC/CD10-PE/CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia blasts of bone marrow was performed at diagnosis. Furthermore, minimal residual disease (MRD) was monitored by BCR/ABL transcripts in bone marrow samples at diagnosis, directly before transplantation, as well as serially at 1, 2, 3, 6, 9, 12,24,36,60 months post-HSCT and at relapse using real-time quantitative polymerase chain reaction. Cumulative incidences of relapse (CIR) and non-relapse mortality were calculated using the Kalbfleisch and Prentice method. Leukemia-free survival (LFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors at a level of P<0.1 were included as variables in the multivariate Cox regression model. The study was approved by the Ethics Committee of Peking University People’s Hospital. Results: On the basis of blasts phenotypes at diagnosis, subjects were stratified into CD34+CD38-CD58- group (N=15) and other phenotype group (N=65). The demographic and clinical characteristics showed no significant difference between the two phenotype groups. Median follow-up was 25.5 mo (range, 6-65 mo) for all subjects and 33 mo (range, 6-65 mo) for survivors. During the MRD monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in CD34+CD38-CD58- group than persons in other phenotype group especially at 3 mo post-HSCT [0.12(0-152.4)% vs. 0(0-100)%, P=0.001]. Additionally, CD34+CD38-CD58- LPCs phenotype directly correlated with higher 3-year CIR (63.2% [58.2-68.1%] vs. 5.3% [5.1-5.5%]; P<0.0001), worse LFS (30.2% [8.1-56.6%] vs. 78.7% [64.5-87.7%]; P=0.001) and OS (37.7% [12.6-63.2%] vs. 82.3% [68.5-90.4%]; P=0.0004). Multivariate analyses indicated that CD34+CD38-CD58- LPCs phenotype at diagnosis and BCR-ABL reduction at 3 mo post-HSCT were independent risk factors for relapse, LFS and OS in adults with Ph+ALL underwent allo-HSCT. Summary/Conclusion: Our data suggest that a candidate CD34+CD38-CD58- LPCs phenotype at diagnosis allows rapid identification of high-risk patients for relapse even after allo-HSCT. Risk-stratification post-HSCT therapy incorporating analysis of CD34+CD38-CD58- LPCs phenotype at diagnosis promises to benefit the adults with Ph+ALL in the future. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.

Myeloablative Chemo-Conditioning for First Hematopoietic STEM CELL Transplantation in Children with ACUTE Lymphoblastic Leukemia in First or Second Remission

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 546-546 ◽  
Author(s):  
Christina Peters ◽  
Jean-Hugues Dalle ◽  
Stelios Graphakos ◽  
Petr Sedlacek ◽  
Antonio Campos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Donor Type ◽  
Blood Stem Cells

Abstract Christina Peters, Petr Sedlacek, Jean Hugues Dalle, Stelios Graphakos, Antonio Campos, Akif Yesilipek, Jacek Wachowiak, Arjan Lankester, Andrea Pession, Amir Ali Hamidieh, Marianne Ifversen, Jochen Büchner, Gergely Krivan, Franca Fagioli, Arnaud Dalissier; Myriam Labopin; Peter Bader on behalf of the EBMT Pediatric Diseases Working Party Most children with acute lymphoblastic leukemia (ALL) with indication for allogeneic hematopoietic stem cell transplantation (HSCT) receive myeloablative conditioning with a total body irradiation (TBI)-containing regimen. To investigate the outcomes of patients (pts) who did not undergo TBI, we performed a retrospective registry based study on children below 18 years who received a myeloablative chemo-conditioning for a first allogeneic HSCT from different donors between 2000 and 2012. In this analysis, only chemotherapeutic regimens with more than 30 applications were included. In total, 732 pts were included: 313 pts who received bone marrow (BM) or peripheral blood stem cells (PBSC) in 1st CR, 247 pts with BM/PBSC transplantation in CR2, 85 pts and 52 pts who received umbilical cord blood (CB) in 1st or 2nd CR, respectively. The most commonly applied myeloablative chemo-combinations were: Busulfan (Bu)/Cyclophosphamide (Cy) (n=202), Bu/Cy/Etoposide (VP) (n=189), Bu/Cy/Melphalan (Mel) (n=93), Bu/AraC/Mel (n=80), Bu/Fludarabine (Flu)/Thiotepa (Thio) (n=62), Bu/Cy/Thio (n=53, Bu/Cy/Thio (n=53), and Bu/Flu (n=53). 313 pts received either BM or PBSC in CR1 with a median follow up of 26 months (1-156) and we compared Bu/Cy/VP vs the other chemo-conditioning regimens. The Bu/Cy/VP cohort had a longer follow up (med 37 vs. 20 months, p=0.002), pts were younger (med 3,6 vs. 6,5 years, p=0.003) and the median year of transplant was earlier (med 2009 vs. 2010, p=0.03). Donor type, CMV match, gender match, stem cell were comparable. In univariate analysis, conditioning with Bu/Cy/VP was better than all other combinations: relapse incidence (RI) 21% vs 32% (p=0.05), leukemia-free survival (LFS) 72 vs 54% (p=0.004), overall survival (OS) 79 vs 68% (p=0.03) and chronic GVHD (cGVHD) 9% vs 19% (p=0.014). Engraftment and incidence and severity of acute GVHD were similar and non- relapse mortality (NRM) was 7% vs 13% (p=0.10). Other significant influencing factors were: interval between diagnosis and transplantation below or beyond 208 days (NRM 6% vs 16%, p=0.015), donor sibling vs other (RI 35% vs 23%, p=0.01, NRM 5% vs 16%, p=0.001) and in vivo T cell depletion (TCD) vs no TCD (RI 35% vs. 19%, p=0.003; NRM 20% vs 4%, p=0.0001). In the cox model, conditioning type (Bu/CY/VP vs other), age, year of transplantation, interval from diagnosis to transplant, donor type, stem cell source and in vivo TCD were evaluated. For LFS only BU/CY/VP was associated with better outcome (p=0.004, HR .52), RI was lower after Bu/Cy/VP (HR .54, p=0.02), NRM was higher in pts older than 4,6 years (p=0.02, HR 2,48) and after TCD HSCT (p=0.01, HR 9,13) and OS was best after Bu/Cy/VP (p=0.03, HR 0.57). We conclude that omission of TBI is feasible for children who undergo first allogeneic HSCT in first or second complete remission. The combination of busulfan, cyclophosphamide and etoposide resulted in better LFS and OS with less NRM and RI for children who received bone marrow or peripheral blood stem cells in CR1. These observations should be the basis for prospective trials in homogenous patient groups. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD19-CAR-T Therapy Followed By Allogeneic Hematopoietic Stem Cell Transplantation in Refractory/Relapsed and High Risk B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2660-2660 ◽  
Author(s):  
Yanli Zhao ◽  
Jianping Zhang ◽  
Deyan Liu ◽  
Min Xiong ◽  
Zhijie Wei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Median Time ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Introduction: CD19-CAR-T cells induce high rates of initial response among patients with refractory/relapsed and MRD positive high risk B-cell acute lymphoblastic leukemia (B-ALL). Afterwards allogeneic hematopoietic stem cell transplantation (HSCT) can further reduce relapse rate. Our previous results had shown that CR obtained by CD19 CAR-T had comparable significance to CR by chemotherapy before Allogeneic HSCT in B-ALL. Patients and Methods: Between July 2015 and Mar 2018, consecutive 135 patients with refractory/relapsed or high risk B-ALL obtained CR with CD19-CART therapy followed by allogeneic HSCT were retrospective analyzed. Median follow-up of survivors was 13 months (range, 3-32 months). Results: The median age was 11 (2-49) years. The median disease course before transplant was 21(4-143) months. The median time from CART therapy to HSCT was 69 (35-312) days. Disease status was 108 cases relapsed diseases, 11 cases refractory, and 16 persistent/recurrent measurable residual diseases (MRD). MRD pre-conditioning measured by flow cytometry and QT-PCR was positive in 20(14.8%) subjects. Donor source was haploidentical donors in 107(79.3%), identical sibling in 7(5.1%), and unrelated in 21(15.6%). Most subjects (87.4%) received conventional myeloablative pretransplant conditioning with total body radiation (TBI), the rest with busulfan (Bu). Antithymocyte globulin was used in haploidentical and unrelated transplants. Cyclosporine, short-term methotrexate, and mycophenolate mofetil were employed for GVHD prophylaxis. There were no cases of graft-failure except one early death on Day 0 for septic shock. The median time to neutrophil engraftment was 14 days (10, 26 days), and median time to platelet engraftment 14 days (5, 70 days). The incidences of non-relapse mortality within 100 days were 4.4% (0.8, 7.9%) The incidence of grades II-IV acute graft-versus-host disease (GvHD) were 32.1% (24.3, 39.9%) and grades III-IV GvHD 10.5% (5.4, 15.6%). Chronic GvHD and extensive chronic GvHD were 69.7% (60.7, 78.7%) and17.6% (10.7, 24.5%). Cumulative incidence of relapses (CIRs) at 2-year was 11.1% (5.4, 16.8%). There were totally 14 subjects relapsed after HSCT, among which 8 were CD19 negative relapse, 5 CD19 positive and 1 partial CD19 positive. And among the 8 CD19 negative relapse after transplant, 4 subjects had CD19 negative MRD before conditioning. Leukemia-free survival (LFS) was 76.5% (64.2, 88.8%) and overall survival (OS) was 80.8% (72.6, 89.0%) at two years after transplant. In multivariate analysis subjects who were MRD- positive pre-transplant had a higher 2-year CIR (43.5% [18.4, 68.6%] vs. 5.9% [1.2, 10.6%]; p=0.000) and worse 2-year OS (61.5% [35.6, 87.4%] vs. 83.6% [75, 92.2%]; p=0.034). Conclusions: Our clinical results showed that CART therapy followed by allogeneic HSCT was a promising modality for refractory/relapsed B-ALL. CD19 negative relapse accounted for most relapse after allogeneic HSCT. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR HIGH-RISK ACUTE LYMPHOBLASTIC LEUKEMIA: NON-RANDOMIZED STUDY WITH A MAXIMUM FOLLOW-UP OF MORE THAN 22 YEARS

2014 ◽  
Vol 6 (1) ◽  
pp. e2014047 ◽  
Author(s):  
Grzegorz Helbig ◽  
Malgorzata Krawczyk-Kulis ◽  
Malgorzata Kopera ◽  
Krystyna Jagoda ◽  
Patrycja Rzepka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem

Objective. To evaluate the efficacy and toxicity of autologous hematopoietic stem cell transplantation (AHSCT) for high-risk acute lymphoblastic leukemia (ALL). Material and methods. Overall, 128 high-risk ALL patients at a median age of 26 years (range 18-56 years) at diagnosis received AHSCT between 1991-2008. Induction treatment was anthracycline-based in all patients. Conditioning regimen consisted of CAV (cyclophosphamide, cytarabine, etoposide) in 125 patients whereas 3 subjects received cyclophosphamide and TBI (total body irridation). Bone marrow was stored for 72 hours in 4oC and re-infused 24 hours after conditioning completion. Bone marrow was a source of stem cells in 119 patients, peripheral blood in 2 and 7 subjects received both bone marrow and peripheral blood. Results. With a median follow-up after AHSCT of 1.6 years (range 0.1-22.3 years), the probability of leukemia-free survival (LFS) for the whole group at 10 years was 27% and 23% at 20 years. Transplant-related mortality at 100 days after AHSCT was 3.2%.. There was a strong tendency for better LFS for MRD-negative patients if compared with patients who had positive or unknown MRD status at AHSCT (32% vs 23% and 25%, respectively; p=0.06). There was no difference in LFS between B- and T-lineage ALL as well as between patients transplanted in first complete remission (CR1) and CR2. LFS at 10 years for patients with detectable BCR-ABL at transplant was 20% and this was comparable with subjects with negative and missing BCR-ABL status (26% and 28%; p=0.97). Conclusions. The results of AHSCT for high-risk ALL remains unsatisfactory with low probability of long-term LFS.

Relapse in Childhood “Very High Risk” Acute Lymphoblastic Leukemia Treated with BFM Chemotherapy Has a Dismal Outcome Even When Treated with Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 915-915
Author(s):  
Adriana Balduzzi ◽  
Maria Grazia Valsecchi ◽  
André Schrauder ◽  
Daniela Silvestri ◽  
Barbara Buldini ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Poor Response ◽  
Survival After Relapse ◽  
The Central Nervous System ◽  
Induction Failure ◽  
Very High ◽  
New Strategies ◽  
Minimal Residual

Abstract The definition “very-high risk” (VHR) in the setting of childhood acute lymphoblastic leukaemia (ALL) is usually adopted to identify children eligible for transplantation in first complete remission (CR1). The endpoint of this study is to assess whether, how many, and how VHR ALL children achieving CR1 and not transplanted in CR1 can be rescued in case of relapse. Eligiblity criteria to transplantation in AIEOP-BFM ALL 2000 study slightly changed overtime and differed between the BFM (Berlin Frankfurt Muenster) and AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) Groups.. For this analysis VHR ALL was defined by one or more of the following criteria: induction failure (IF), high levels (≥ 1x10−3) of minimal residual disease at day 78 (VHR-MRD), clonal abnormality t(4;11), prednisone poor response associated (PPR+) with one or more of the followings: hyperleukocytosis, T-immunophenotype, ≥ 25% marrow blasts at day 15, pro-B immunophenotype. Patients carrying clonal abnormality t(9;22) were not included here since allocated in a specific study protocol since 2004. Out of 571 VHR patients, distributed among the four criteria (17%, 45%, 3%, 35%, as hierarchically listed), 249 (43%) were transplanted in CR1 (80%, 48%, 47%, 25% in each category) and 322 (57%) were not. Of the 322 patients treated with chemotherapy [5-year-EFS 53.5% (SE 3.1), 5-year-survival 66.6% (SE 2.9)], 19 died in CR1, 6 presented with a second malignancy, and 113 (35%) relapsed at a median of 15 months after diagnosis, mostly in the bone marrow (81%: 66% isolated, 15% combined) or in an extramedullary site (19%, 15% in the central nervous system) at a median time of 9 ms after diagnosis. The 3-year-survival after relapse was only 26.0% (SE 5.1) for the 113 patients overall, 38.7% (SE 7.8) for the 55 who underwent transplantation in CR2 and 16.2% (SE 5.3) for the 58 who were not transplanted in CR2. Interestingly the 3-year-survival after relapse by VHR criteria was only 7.1% (SE 9.3) in the IF, 28.6% (SE 7.1) in the VHR-MRD and 33.1% (SE 6.7) in the PPR+ subgroups. In conclusion very few VHR-ALL children could be rescued after relapse, particularly among those carrying most unfavourable criteria at the onset (IF and VHR MRD), confirming that transplantation should be performed in CR1. Transplantation in CR2 was feasible in only half of the patients and presumably their outcome was influenced by MRD response after relapse; this aspect is under investigation. New strategies are needed for this dismal subset of patients.

Sign in / Sign up

Export Citation Format

Share Document