scholarly journals Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16

2019 ◽  
Vol 37 (35) ◽  
pp. 3377-3391 ◽  
Author(s):  
Sima Jeha ◽  
Deqing Pei ◽  
John Choi ◽  
Cheng Cheng ◽  
John T. Sandlund ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cumulative Risk ◽  
Cranial Irradiation ◽  
Intrathecal Therapy ◽  
Cns Relapse ◽  
Increased Risk ◽  
Total Therapy ◽  
Higher Doses ◽  
Cns Control

PURPOSE Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control. PATIENTS AND METHODS Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m2 versus the conventional 2,500 U/m2. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction. RESULTS The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any—isolated or combined—CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; P = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] v 5.7% [95% CI, 2.8% to 8.6%]; P = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment. CONCLUSION Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.

Triple Intrathecal Therapy Alone With Omission of Cranial Radiation in Children With Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (17) ◽  
pp. 1825-1829 ◽  
Author(s):  
Hsi-Che Liu ◽  
Ting-Chi Yeh ◽  
Jen-Yin Hou ◽  
Kuan-Hao Chen ◽  
Ting-Huan Huang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Cumulative Risk ◽  
Cranial Irradiation ◽  
Intrathecal Therapy ◽  
Newly Diagnosed ◽  
Cns Relapse ◽  
Risk Patients ◽  
A Prospective Study

Purpose To eliminate the toxicities and sequelae of cranial irradiation (CrRT) and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, a prospective study of a modified CNS-directed therapy was conducted in children with acute lymphoblastic leukemia (ALL). Patients and Methods Since June 1999, children with newly diagnosed ALL have been treated with triple intrathecal therapy (TIT) alone without CrRT. The first TIT was delayed until the disappearance of blasts from peripheral blood (PB) for up to 10 days of multidrug induction, and CrRT was omitted in all patients. If PB blasts persisted on treatment day 10 (d10), the TIT was then performed. Results Of a total of 156 patients, 152 were eligible. Seventeen patients did not have PB blasts at diagnosis. Three fourths of the remaining patients achieved complete clearance of PB blasts by d10. Only hyperleukocytosis at diagnosis showed a significantly lower clearance rate. Six standard-risk patients were upgraded to high risk because of detectable PB blasts on d10. TLPs were encountered in four patients (2.6%), but none were contaminated with lymphoblasts. Neither CNS-2 (less than 5 WBCs/μL with blasts in a nontraumatic sample) nor CNS-3 (≥ 5 WBCs/μL with blasts in a nontraumatic sample or the presence of cranial nerve palsy) was present. The 5-year event-free survival and overall survival rates ± SE were 84.2% ± 3.0% and 90.6% ± 2.4%, respectively. No isolated CNS relapse occurred, but two patients experienced combined CNS relapses. The 7-year cumulative risk of any CNS relapse was 1.4% ± 1.0%. Conclusion Delaying first TIT until circulating blasts have cleared may improve CNS control in children with newly diagnosed ALL and preclude the need for CrRT.

Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2690-2696 ◽  
Author(s):  
Ching-Hon Pui ◽  
John T. Sandlund ◽  
Deqing Pei ◽  
Dario Campana ◽  
Gaston K. Rivera ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cumulative Dose ◽  
Lower Risk ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Intrathecal Chemotherapy ◽  
Remission Induction ◽  
Cns Relapse ◽  
Risk Patients ◽  
Total Therapy

Abstract St Jude Total Therapy Study XIIIB for childhood acute lymphoblastic leukemia (ALL) incorporated more stringent risk classification, early intensification of intrathecal chemotherapy, reinduction treatment, and the addition of dexamethasone to postremission therapy to increase the proportion of event-free survivors without jeopardizing their quality of life. Cranial irradiation was reserved for the 12% of patients who had T-cell ALL and a presenting leukocyte count of 100 × 109/L or more, or CNS-3 (5 or more leukocytes/μL with identifiable blast cells in an atraumatic sample or the presence of cranial nerve palsy) status. Among the 247 consecutive patients enrolled in the study, 117 were classified as having lower-risk leukemia and received mainly antimetabolite-based continuation therapy; the 130 cases with higher-risk leukemia received more intensive continuation chemotherapy with multiple drug pairs administered in weekly rotation. The 5-year event-free survival estimate was 80.8% ± 2.6% (SE); the 8-year rate was 78.6% ± 5.8%. The 5-year cumulative risk of an isolated central nervous system (CNS) relapse was 1.7% ± 0.8%, and that of isolated plus combined CNS relapse was 3.0% ± 1.1%. The 5-year cumulative risks of etoposide-related myeloid malignancies were 1.8% ± 1.3% in the lower-risk patients who received a cumulative dose of 1.2 g/m2 and 5.0% ± 2.0% in the higher-risk patients who received a cumulative dose of up to 14.4 g/m2 (P = .18). Independent adverse prognostic features included the presence of MLL-AF4 or BCR-ABL fusion gene and minimal residual leukemia of 0.01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether. (Blood. 2004;104:2690-2696)

Prognostic Factors for CNS Control in Children with Acute Lymphoblastic Leukemia Treated Without Cranial Irradiation

Blood ◽  
2021 ◽  
Author(s):  
Jingyan Tang ◽  
Jie Yu ◽  
Jiaoyang Cai ◽  
li zhang ◽  
Shaoyan Hu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cerebrospinal Fluid ◽  
Prognostic Factors ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Intrathecal Therapy ◽  
Dexamethasone Treatment ◽  
Intravenous Anesthesia ◽  
Cns Relapse ◽  
Cns Control

To identify the prognostic factors that are useful to improve CNS control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on China Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% CI, 78.9%-81.7%), and overall survival 91.1% (95% CI, 90.1%-92.1%). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5%-2.3%), and any CNS relapse 2.7% (95% CI, 2.2%-3.2%). The isolated CNS relapse rate was significantly lower in patients with B-ALL than in those with T-ALL (1.6%; 95% CI,1.2%-2.0% vs 4.6%; 95% CI 2.9%-6.3%; P <0.001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1%-3.0%; P=0.03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0%-7.3%; P <0.001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5%-12.2%; P=0.007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04%-0.7%; P=0.02) and flow cytometry examination of diagnostic cerebrospinal fluid (HR, 0.2; 95% CI, 0.06%-0.6%; P=0.006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic cerebrospinal fluid may improve CNS control in childhood ALL.

Impact of Traumatic Lumbar Puncture on CNS Relapse in Children with Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 879-879
Author(s):  
Charline Normand ◽  
Estelle Thébaud-Léculée ◽  
Francoise Mazingue ◽  
Anne Lambilliotte ◽  
Pascale Lepelley ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lumbar Puncture ◽  
Relapse Rate ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Cns Relapse ◽  
Diagnostic Lumbar Puncture

Abstract Rationnal: In children with de novo acute lymphoblastic leukemia (ALL) event-free survival (EFS) and overall survival (OS) could be decreased when the diagnostic lumbar puncture is traumatic, as showed by two previous studies. The cerebrospinal fluid (CSF) should be contaminated with circulating leukemic blasts. Purpose: The aim of this study is to further investigate the influence of traumatic diagnostic lumbar puncture (LP) on CNS relapse rate as first endpoint and then on OS in a single center (Lille Academic Hospital, France) from 1989 to 2004. Patients and Methods: A total of 352 patients were restrospectively evaluated. These patients were treated according to the EORTC pediatric cooperative protocols 58 881 and 58 951. In these protocols, the neuroprophylaxy consisted in high-dose methotrexate (5g/m2/course x 4 to 11 courses according to the risk-group therapy) and intrathecal therapy (methotrexate +/− aracytine and corticosteroids), without any cranial irradiation. Traumatic lumbar puncture was defined as the presence of 10 erythrocytes/mm3 or more in cerebro-spinal fluid. Results: The median follow-up was 5.9 years (0.05–14). The CNS relapse rate is increased in patients with traumatic diagnostic LP (p=0.023), and their OS is also significantly decreased (p=0.04). However, a “true” CNS involvement (i.e. CNS 3) at diagnostis is a risk factor for further CNS relapse, and in this study, the number of CNS3 child was more important in the traumatic LP group. In order to avoid this major biased error, the analysis was repeated with CNS1 and CNS2 child (n=339)only and without CNS3 patients. In this subgroup, when the diagnostic LP is traumatic, the CNS relapse rate and the OS are not statistically different than in non traumatic LP group (p=0.06 and p=0.087, respectively). However, there is a trend for worse results. Conclusion: This study does not confirm the pejorative character of the traumatic diagnostic LP. Further investigations in larger study should be conducted to achieve more definitive conclusion. Moreover, an adequate biologic criteria is necessary to discriminate CSF contaminated with circulating leukemic blasts and real CNS primitive involvement to improve prognostic analysis and to adjust the treatment.

scholarly journals Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (9) ◽  
pp. 949-959 ◽  
Author(s):  
Deepa Bhojwani ◽  
Noah D. Sabin ◽  
Deqing Pei ◽  
Jun J. Yang ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Asymptomatic Patients ◽  
A Genome ◽  
Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study

2000 ◽  
Vol 18 (6) ◽  
pp. 1285-1294 ◽  
Author(s):  
Donald H. Mahoney ◽  
Jonathan J. Shuster ◽  
Ruprecht Nitschke ◽  
Stephen Lauer ◽  
C. Philip Steuber ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lower Risk ◽  
Lymphoblastic Leukemia ◽  
Effective Therapy ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Continuation Therapy ◽  
Increased Risk ◽  
Significant Difference ◽  
Prevention Of Relapse

PURPOSE: To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m2 plus IV MP 1,000 mg/m2 (regimen A) or IV MTX 1,000 mg/m2 alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS: Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P = .5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION: Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

Risk of adverse events in children completing treatment for acute lymphoblastic leukemia: St. Jude Total Therapy studies VIII, IX, and X.

1991 ◽  
Vol 9 (8) ◽  
pp. 1341-1347 ◽  
Author(s):  
C H Pui ◽  
R K Dodge ◽  
A T Look ◽  
S L George ◽  
G K Rivera ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Rank Test ◽  
Late Failure ◽  
Increased Risk ◽  
Viii And Ix ◽  
Total Therapy ◽  
Therapy Studies ◽  
The Impact

We studied the frequency, causes, and predictors of adverse events in 624 patients who had completed treatment for acute lymphoblastic leukemia (ALL) in three consecutive total therapy studies (VII, IX, and X, 1972 to 1983). Event-free survival in study X was significantly better overall than that in studies VIII and IX (P less than .0001 by the log-rank test). In study X, 75% of the patients were electively taken off therapy, compared with 54% in studies VIII and IX. However, the risks of having an adverse event during the first 5 years after completion of therapy were remarkably similar: 22% (95% confidence interval, 17% to 29%) in study X versus 24% (20% to 29%) in studies VIII and IX. Bone marrow, testicular, and CNS relapses accounted for the majority of failures in both groups (85% in study X and 92% in studies VIII and IX). Late adverse events consisted largely of hematologic relapses and the development of solid tumors. Black race (P = .001) and leukemia without an anterior mediastinal mass (P = .05) were associated with an increased risk of failure after completion of treatment in the two earlier clinical trials, whereas a lower leukemic cell DNA content (DNA index less than 1.16) was the only predictor of late treatment failure in the more recent trial (P = .019). None of the other presenting features that were examined (eg, age, leukocyte count, and sex) had value as predictors of late failure. Thus, improved treatment altered the impact of specific prognostic factors and the distribution of sites of relapse, but it did not significantly affect the risk of delayed failure.

Treatment of CNS relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study.

1993 ◽  
Vol 11 (2) ◽  
pp. 271-278 ◽  
Author(s):  
N J Winick ◽  
S D Smith ◽  
J Shuster ◽  
S Lauer ◽  
M D Wharam ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Intrathecal Therapy ◽  
Oncology Group ◽  
Treatment Comparison ◽  
Cns Relapse ◽  
Cranial Radiation ◽  
Pediatric Oncology Group

PURPOSE To assess the efficacy and toxicity of chemotherapy and cranial radiation for the treatment of children with acute lymphoblastic leukemia (ALL) following first isolated CNS relapse. PATIENTS AND METHODS One hundred twenty children were treated on Pediatric Oncology Group (POG) protocol 8304. All children had received prophylactic CNS therapy during their initial treatment. The treatment protocol included a four-drug reinduction and six weekly doses of triple intrathecal therapy (TIT). Cranial radiation, 24 Gy, was followed by monthly TIT. Systemic consolidation and maintenance therapy included 6-week cycles of mercaptopurine/methotrexate (6MP/MTX) and vincristine/cyclophosphamide (VCR/CTX), with randomization to intervening pulses of prednisone/doxorubicin (PDN/DOX) or teniposide (VM26)/cytarabine (Ara-C) for a total of 88 weeks. RESULTS All 120 patients achieved a second complete remission. There have been 61 protocol failures. Thirty-five patients had a bone marrow relapse, four with simultaneous CNS involvement and one with concurrent testicular leukemia. Thirteen patients had a second isolated CNS relapse, 10 a testicular relapse, and two relapsed in other sites. One patient died in remission. Overall event-free survival (EFS) at 4 years was 46% +/- 7%. The toxicity associated with this protocol was minimal except for leukoencephalopathy, which occurred in 20 (17%) patients. The treatment comparison between VM26/Ara-C or PDN/DOX pulses showed a trend toward superior EFS (P = .12) in favor of VM-26/Ara-C. CONCLUSION To date, this represents the largest series of patients with ALL treated uniformly for an isolated CNS relapse. Since marrow relapse remains the primary site of failure, future protocols must intensify systemic therapy.

Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 142-146 ◽  
Author(s):  
Ching-Hon Pui
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Central Nervous System Disease ◽  
Cranial Irradiation ◽  
Childhood All ◽  
Excellent Outcome ◽  
Cns Relapse

Abstract Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients—those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.

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