scholarly journals Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children’s Oncology Group Study AALL1131

2020 ◽  
Vol 38 (23) ◽  
pp. 2628-2638
Author(s):  
Wanda L. Salzer ◽  
Michael J. Burke ◽  
Meenakshi Devidas ◽  
Yunfeng Dai ◽  
Kristina K. Hardy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Intrathecal Methotrexate ◽  
Oncology Group ◽  
Free Survival ◽  
Oncology Group Study ◽  
Cns Prophylaxis ◽  
Disease Free

PURPOSE The high-risk stratum of Children’s Oncology Group Study AALL1131 was designed to test the hypothesis that postinduction CNS prophylaxis with intrathecal triple therapy (ITT) including methotrexate, hydrocortisone, and cytarabine would improve the postinduction 5-year disease-free survival (DFS) compared with intrathecal methotrexate (IT MTX), when given on a modified augmented Berlin-Frankfurt-Münster backbone. PATIENTS AND METHODS Children with newly diagnosed National Cancer Institute (NCI) high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) or NCI standard-risk B-ALL with defined minimal residual disease thresholds during induction were randomly assigned to receive postinduction IT MTX or ITT. Patients with CNS3-status disease were not eligible. Postinduction IT therapy was given for a total of 21 to 26 doses. Neurocognitive assessments were performed during therapy and during 1 year off therapy. RESULTS Random assignment was closed to accrual in March 2018 after a futility boundary had been crossed, concluding that ITT could not be shown to be superior to IT MTX. The 5-year postinduction DFS and overall survival rates (± SE) of children randomly assigned to IT MTX versus ITT were 93.2% ± 2.1% v 90.6% ± 2.3% ( P = .85), and 96.3% ± 1.5% v 96.7% ± 1.4% ( P = .77), respectively. There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse rates, or in toxicities observed for patients receiving IT MTX compared with ITT. There were no significant differences in neurocognitive outcomes for patients receiving IT MTX compared with ITT. CONCLUSION Postinduction CNS prophylaxis with ITT did not improve 5-year DFS for children with HR B-ALL. The standard of care for CNS prophylaxis for children with B-ALL and no overt CNS involvement remains IT MTX.

scholarly journals Triple Intrathecal Therapy (Methotrexate/Hydrocortisone/Cytarabine) Does Not Improve Disease-Free Survival Versus Intrathecal Methotrexate Alone in Children with High Risk B-Lymphoblastic Leukemia: Results of Children's Oncology Group Study AALL1131

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 35-35 ◽  
Author(s):  
Wanda L. Salzer ◽  
Michael J. Burke ◽  
Meenakshi Devidas ◽  
Lia Gore ◽  
Joanne M. Hilden ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Clinical Signs ◽  
Disease Free Survival ◽  
Intrathecal Methotrexate ◽  
Intrathecal Therapy ◽  
Free Survival ◽  
Prognostic Features ◽  
Post Induction ◽  
Disease Free

Abstract Background: With current multi-agent chemotherapy, 88-90% of children diagnosed with High Risk B-Acute Lymphoblastic Leukemia (HR B-ALL) will be cured. However, for those patients who relapse, ~ 1/3 will have central nervous system (CNS) involvement. Thus, adequate CNS disease control for children with HR B-ALL remains a challenge. AALL1131 was designed to determine if the administration of post-Induction age-adjusted triple intrathecal therapy (ITT) with methotrexate, hydrocortisone, and cytarabine, on a modified augmented Berlin-Frankfurt-Münster (MBFM) backbone, would improve 5-year disease free survival (DFS) of children with HR B-ALL compared to age-adjusted intrathecal methotrexate (IT MTX) alone. Methods: Patients with HR B-ALL included: National Cancer Institute (NCI) HR patients <13 years of age at diagnosis without adverse prognostic features [CNS leukemia at diagnosis (≥ 5 white blood cells in the cerebral spinal fluid with blasts on cytospin and/or clinical signs of CNS leukemia), iAMP21, KMT2A (MLL) rearrangement, or hypodiploidy (<44 chromosomes and/or DNA index <0.81)] who had bone marrow minimal residual disease (BM MRD) <0.01% on Induction day 29; and NCI standard risk (SR) patients lacking favorable cytogenetics (ETV6-RUNX1 fusion or trisomy of chromosomes 4 and 10) who had peripheral blood MRD ≥1% on day 8 and BM MRD <0.01% on Induction day 29, and NCI SR B-ALL patients with favorable cytogenetics who had BM MRD ≥0.01% on Induction day 29. Newly diagnosed children with HR B-ALL were randomized post-Induction in a 1:1 fashion to receive ITT versus IT MTX. A total of 21-26 doses of post-Induction intrathecal therapy was administered during Consolidation (n=4), Interim Maintenance (n=2), Delayed Intensification (n=3), and Maintenance (n=12 for girls, n=16 for boys). Results: The post-Induction HR B-ALL randomization was closed to accrual on March 19, 2018 following planned interim monitoring that revealed a futility boundary was crossed, concluding the inability to show the superiority of ITT compared to IT MTX. Five-year DFS rates for IT MTX versus ITT were 93±3.8% and 90±4.3%, p value=0.86. The corresponding estimated hazard ratio (HR) of IT MTX vs ITT is 1.285; 95% CI of (0.822, 2.01). There were no differences in toxicities observed in patients receiving ITT compared to IT MTX. As such, the study was amended to prescribe IT MTX to all patients. Conclusion: The administration of post-induction age adjusted ITT did not improve 5-year DFS of children with HR B-ALL without CNS leukemia. IT MTX remains the standard of care for CNS prophylaxis. Disclosures Burke: Shire: Speakers Bureau; JAZZ: Speakers Bureau; AMGEN: Speakers Bureau.

scholarly journals Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 1923-1927 ◽  
Author(s):  
NJ Chao ◽  
SJ Forman ◽  
GM Schmidt ◽  
DS Snyder ◽  
MD Amylon ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free

Abstract Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.

scholarly journals Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 1923-1927
Author(s):  
NJ Chao ◽  
SJ Forman ◽  
GM Schmidt ◽  
DS Snyder ◽  
MD Amylon ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free

Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Groupe d'Etude de la Greffe de Moelle Osseuse.

1989 ◽  
Vol 7 (6) ◽  
pp. 747-753 ◽  
Author(s):  
P Bordigoni ◽  
J P Vernant ◽  
G Souillet ◽  
E Gluckman ◽  
D Marininchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free

Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse (one of 28 long-term survivors) precluded the determination of the prognostic significance of the different poor-outcome features. Moreover, two infants treated with busulfan, CPM, and cytarabine (Ara-C) relapsed promptly in the marrow. In summary, as a means of providing long-term disease-free survival and possible cure, BMT should be considered for children with ALL presenting poor-prognostic features, particularly certain chromosomal translocations [t(4;11), t(9;22)], very high WBC counts, notably if associated with a non-T immunophenotype, and, perhaps, a poor response to initial therapy with corticosteroids (CS), or infants less than 6 months of age.

Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

1987 ◽  
Vol 5 (10) ◽  
pp. 1646-1654 ◽  
Author(s):  
J A Ortega ◽  
M E Nesbit ◽  
H N Sather ◽  
L L Robison ◽  
G J D'Angio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Current Status ◽  
Intrathecal Methotrexate ◽  
Childhood All ◽  
Cns Disease ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Significant Difference

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

scholarly journals Therapy of 4s Chimeric Antigen Receptor T Cells Achieves Long-Term Disease-Free Survival with No Severe CRS or Cres in Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2696-2696 ◽  
Author(s):  
Sanfang Tu ◽  
Rui Huang ◽  
Lan Deng ◽  
Xuan Zhou ◽  
Yanjie He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymphoblastic Leukemia ◽  
Objective Response ◽  
Disease Free Survival ◽  
Tumor Burden ◽  
Fourth Generation ◽  
Free Survival ◽  
Car T ◽  
Disease Free

Abstract Background: CD19 targeting chimeric antigen receptor T cells(CART19) therapy have shown great therapeutic potential in relapsed and refractory B cell acute lymphoblastic leukemia (ALL), but associated with risk of life-threatening adverse effects as severe cytokine release syndrome (sCRS) and CAR-T-cell-related encephalopathy syndrome (CRES).It's been reported that high leukemia burden before CART therapy, and high does infused CART cells are associated with severity of CRS and CRES. To decrease the risk of severe adverse effect, we applied integrated therapeutic strategy of using fourth generation CART cells , reducing leukemia blasts burden in bone marrow, and decreasing the dose of infused CART cells (www.clinicaltrials.gov; #NCT03407859 and #NCT03125577 ). Methods: Between May 23, 2016 and July 2, 2018,the trial enrolled 20 patients (pts) who were exhausted with all available treatment options, life expectancy >2 months,CD19-positive and diagnosis of B lineage ALL.T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentivector CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). In vitro amplication of CART was not performed. In pts with bone marrow blasts exceeding 50.0%, VDCP or similar chemotherapy was given to reduce the tumor burden, and then received FC conditioning regimen (FLU 30mg/m2, d1-3; CTX 300mg/m2, d1-3), while FC regimen was directly carried out in pts with bone marrow blasts less than 50.0%.In this trial, Pts received single CD19-targeted CARTs or multi-CARTs targeting CD19 and an additional antigen of CD22 or CD123.The level of CAR-T cells and cytokines in peripheral blood, as well as tumor burden was measured after infusion. Results: 20 pts were enrolled and infused with CAR-T cells. The median age is 37.5 (16-67) years old. Of these pts, 5 had prior HSCT and 14 had adverse genetic abnormalities, including 4 pts (20%) who were Philadelphia chromosome-positive(Ph+). All pts were previously treated with 2-22 courses of cytotoxic chemotherapy regimens. The overall objective response rate was 85%(17/20), and the complete response(CR) rate was 80%(16/20). The complete remission rate of 12 pts receiving single CD19-targeted CART therapy was 83 %(10/12), while 33%(4/12) of them had disease relapse at 6 months after infusion. Of the 7 people who received multi-CARTs infusion, 71%(5/7) achieved complete remission, with relapse rate of 29%(2/7) at 6 months after infusion. 3 pts who relapsed post transplantation received combination therapy of anti-CD19 CART and anti-CD123 CART, and all achieved minimal residual disease-negative CR within 1 month after CART infusion, 2 of whom maintained disease-free survival for 7 months and 11 months to date, respectively. Among the 7 people who underwent HSCT after achieving CR, 6 of them maintained disease-free survival for 3 months to 9 months. At a median follow-up of 115.5 days (ranging from14 to 384), the median overall survival was 269 days and the median event-free survival was 232 days. During treatment and follow-up, the most common adverse events were grade 1-2 cytokine release syndrome (CRS), with an incidence of 55%.No grade 3 or higher CRS was observed.12 pts were infused with a dose equal to or exceeding 5*10^5/kg, 10 of whom had CRS response. While only 2 of the 8 pts who received the infusion dose of less than 5*10^5/kg had CRS reaction and both of them were grade 1 CRS, suggesting low CAR-T cell doses decrease the risk of CRS (P=0.009). Interestingly, the objective response rate did not differ significantly between the low dose and high dose group. Conclusions: Based on fourth generation CART system, a therapeutic strategy of low tumor burden and low CART infusion dose shows a safer profiling while remaining potent efficacy against leukemia. Disclosures No relevant conflicts of interest to declare.

General Outcome of Four Years Experience in the Treatment of Acute Lymphoblastic Leukemia in the National Hospital Edgardo Rebagliati Martins. Lima- Peru.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4105-4105
Author(s):  
Mariela Moreno ◽  
Sergio Murillo ◽  
Jackeline Rodriguez ◽  
Juan Ramon JN Navarro ◽  
Lourdes Aranda ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
National Hospital ◽  
Free Survival ◽  
Disease Free ◽  
Very High

Abstract Abstract 4105 Considering our Pediatric Hematology Unit (PHU), as a social security national reference Unit, one third of the hospitalized children population have acute leukemia in the Pediatrics Department of the National Hospital Hospital Edgardo Rebagliatti Martins- ESSALUD, Lima - Perú. PURPOSE: To analyze survival outcome and behavioral of the disease in children with acute lymphoblastic leukemia (ALL) in a Social Security Hospital of a Developing country. PATIENTS AND METHODS: We analyze 100 pediatrics patients (less than 14 years old) diagnosed with acute lymphoblastic leukemia (ALL) since 2005 to 2008. Disease-free survival (DFS) was computed according to the Kaplan-Meier method and long rank test, using the SPSS 15.0. RESULTS: A total of 100 children were evaluated. The major incidence according to age was in the group of children between 1 and 9 years old (76%); there were no difference between gender: 51% females and 49% males. The B type was the most common diagnosed leukemia: The B CALLA positive (CD10, CD19, HLA, DR) was the most frequent inmunophenotype, present in 87 children (87%). T-cell ALL was seen in 7%, bi-phenotype and Pro B in 3%. According to our risk stratification protocol, 34 patients were in the very high risk group (VHR), 47 patients in the high risk (HR) group and 19 patients in the intermediate-low risk (ILR) group. About Kariotype evaluation, the most common presentations were normal and hyperdiploid kariotype (67%). We achieved Complete Remission in 95% of our patients post 4 weeks Induction therapy (“A” Induction period). The Total 4th year disease free survival was 48.9% (36.3% VHR, 50.4% HR and 75.9% ILR); of these 61.8 ± 6.2% had DFS after 2 years of therapy and 55.9±6.9 % after 3 years. The Disease Free Survival was significantly increased on those with the following risk factors at diagnosis: white blood cell count &lt; 100 000/mm3 (P= 0.002), normal or hyperdiploid kariotype (P&lt;0.0001). However age, gender and type of ALL in our small group do not have statistical significance. The groups of patients not responding to prednisone have identical DFS than the Responding patients, but the no responding patients received treatment as an immediately superior group (High or Very High Risk). All the patients that have more than 1% of Minimal Residual Disease after a 4 week Induction therapy and achieved a Complete Remission with other chemotherapy treatment, had a poor DFS of less than 10 months (P = 0.015). CONCLUSION: The Total DFS was 48.9%. WBC count below 100,000 mm3; normal and hyperdiploid kariotypes, correlate with best DFS. The MDR &gt;1%, was correlated with poor DFS (less than 10 months). The no responding prednisone group must receive a more intensive chemotherapy (the treatment of the immediately superior risk group). The poor DFS at 4 years explain the reason of our therapeutic decision to perform a sibling stem cell Transplant, in those pediatric patients with HR or VHR Acute Lymphoblastic Leukemia (BMT with a 12 year disease free survival of 59.8%). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 381-388 ◽  
Author(s):  
R Dinsmore ◽  
D Kirkpatrick ◽  
N Flomenberg ◽  
S Gulati ◽  
N Kapoor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free ◽  
Relapse Group

Fifty-two patients with acute lymphoblastic leukemia (ALL) underwent allogeneic bone marrow transplantation following cytoreduction with total body irradiation and cyclophosphamide. Twenty-two patients were in second remission, 15 in a later remission, and 15 were in relapse at the time of the transplant. At a median follow-up of 24 mo, 14 of those in second remission survive in continuous remission compared to 5 in later remission and 4 in the relapse group. Statistical analysis showed an improved disease-free survival for the second remission group (p = 0.09). Patients transplanted in later remission or relapse had a similar survival. The improved survival in second remission resulted from a decreased relapse rate posttransplant, as the early mortality from nonleukemic causes was similar among the groups (p = 0.01). In the second remission patients, no characteristics of the initial leukemia were identified that significantly affected outcome. In the combined later remission and relapse group, poor prognosis posttransplant was associated with initial WBC greater than 20K, age at diagnosis older than 10, or initial remission duration less than or equal to 1 yr. These results suggest that extended disease-free survival may be achieved by second remission transplantation and that improved therapy is necessary for later remission or relapse transplants due to the high rate of posttransplant relapse.

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