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.

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.

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)

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.

Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3381-3384 ◽  
Author(s):  
Amar Gajjar ◽  
Patricia L. Harrison ◽  
John T. Sandlund ◽  
Gaston K. Rivera ◽  
Raul C. Ribeiro ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
Lumbar Puncture ◽  
Lymphoblastic Leukemia ◽  
Prognostic Indicator ◽  
Intrathecal Chemotherapy ◽  
Intrathecal Therapy ◽  
Newly Diagnosed ◽  
Diagnostic Lumbar Puncture ◽  
Blast Cells

Abstract The effect of traumatic lumbar puncture at the time of initial diagnostic workup on treatment outcome in children with newly diagnosed acute lymphoblastic leukemia (ALL) was investigated. The findings of the first 2 lumbar punctures performed on 546 patients with newly diagnosed ALL treated on 2 consecutive front-line studies (1984-1991) at St Jude Children's Research Hospital were retrospectively reviewed. Lumbar punctures were performed at the time of diagnosis and again for the instillation of first intrathecal chemotherapy. The event-free survival (EFS) experience for patients with 1 cerebrospinal fluid (CSF) sample contaminated with blast cells was worse than that for patients with no contaminated CSF samples (P = .026); that of patients with 2 consecutive contaminated CSF samples was particularly poor (5-year EFS = 46 ± 9%). In a Cox multiple regression analysis, the strongest prognostic indicator was 2 consecutive contaminated CSF samples, with a hazard ratio of 2.39 (95% confidence interval, 1.36-4.20). These data indicate that contamination of CSF with circulating leukemic blast cells during diagnostic lumbar puncture can adversely affect the treatment outcome of children with ALL and is an indication to intensify intrathecal therapy.

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.

scholarly journals BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991–1996)

Leukemia ◽  
2002 ◽  
Vol 16 (6) ◽  
pp. 1099-1111 ◽  
Author(s):  
WA Kamps ◽  
JPM Bökkerink ◽  
FGAJ Hakvoort-Cammel ◽  
AJP Veerman ◽  
RS Weening ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Risk Patients ◽  
Standard Risk

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.

Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica.

1995 ◽  
Vol 13 (10) ◽  
pp. 2497-2502 ◽  
Author(s):  
V Conter ◽  
M Aricò ◽  
M G Valsecchi ◽  
C Rizzari ◽  
A M Testi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Intrathecal Chemotherapy ◽  
Intrathecal Methotrexate ◽  
Intermediate Risk ◽  
Intensive Chemotherapy ◽  
Free Survival ◽  
Cns Disease ◽  
Cns Relapse

PURPOSE To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy. PATIENTS Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients. RESULTS Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group. CONCLUSION Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.

Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study.

1993 ◽  
Vol 11 (5) ◽  
pp. 839-849 ◽  
Author(s):  
J Pullen ◽  
J Boyett ◽  
J Shuster ◽  
W Crist ◽  
V Land ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Chemotherapy ◽  
Oncology Group ◽  
Poor Risk ◽  
Cns Relapse ◽  
Risk Patients ◽  
Pediatric Oncology Group ◽  
Good Risk

PURPOSE The Pediatric Oncology Group (POG) acute leukemia in childhood (ALinC) 13 study tested two treatment regimens that used different CNS chemoprophylaxis for children older than 12 months with non-T, non-B acute lymphoblastic leukemia (ALL) and with no demonstrable CNS disease at diagnosis. PATIENTS AND METHODS With the first regimen, standard (S), six injections of triple intrathecal chemotherapy (TIC), consisting of methotrexate (MTX), hydrocortisone (HC), and cytarabine (ara-C), were administered during intensification treatment and at every-8-week intervals throughout the maintenance phase for 17 additional doses. The second regimen, standard and MTX pulses (SAM), also specified six TICs during intensification, but substituted every-8-week pulses of intermediate-dose parenteral methotrexate (IDM; 1 g/m2) for the 17 maintenance TIC injections, with a low-dose intrathecal (IT) MTX boost administered with the first four maintenance IDM pulses. Otherwise, systemic therapy on regimen SAM was identical to regimen S. There were 1,152 patients randomized to the S and SAM regimens after stratification by risk group (age/leukocyte count) and immunophenotype. RESULTS The 5-year probabilities (+/- SE) of an isolated CNS relapse were regimen S: good risk (n = 381), 2.8% +/- 1.3%; poor risk (n = 196), 7.7% +/- 3.2%; good + poor risk (n = 577), 4.7% +/- 1.5%; regimen SAM: good risk (n = 388), 9.6% +/- 2.2%; poor risk (n = 187), 12.7% +/- 4.2%; good + poor risk (n = 575), 10.9% +/- 2.2%. In poor-risk patients, approximately one third of the isolated CNS relapses occurred before preventive CNS therapy was begun at week 9. Hence, regimen S has provided better CNS preventive therapy for both good- and poor-risk patients (P < .001 overall). The difference is statistically significant for good-risk patients (P < .001), but not for poor-risk patients (P = .20). Neither treatment has shown a significant advantage in terms of general outcome. CONCLUSION TIC injections extended throughout the intensification and maintenance periods are superior to IDM pulses for prevention of CNS leukemia. Our results with TIC seem comparable with those achieved with other contemporary methods of CNS preventative therapy. Thus, extended TIC affords a reasonable alternative to CNS irradiation plus upfront IT MTX for patients with B-progenitor ALL.

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