Outcomes for Adult Lymphoblastic Leukemia (ALL) Are Mainly Influenced by Age and Status of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) After Therapy with the Modified Hyper-CVAD (with or without Rituximab) Regimen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1524-1524
Author(s):  
Deborah A. Thomas ◽  
Hagop M Kantarjian ◽  
Jeffrey L. Jorgensen ◽  
Stefan Faderl ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Adolescent And Young Adult ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cns Disease ◽  
Cd20 Expression ◽  
Consolidation Phase

Abstract Abstract 1524 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for pts aged 60 years or older. Rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) was administered for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009]. Early anthracycline intensification with liposomal daunorubicin and cytarabine was incorporated from 1999–2000 then omitted from the regimen [Thomas D, Cancer 116: 4580, 2010]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). Maintenance therapy was extended from 24 to 30 months inclusive of early and late intensifications (hyper-CVAD followed by weekly MTX and L-asparaginase mos 6 & 7 then mos 18 & 19) to reduce incidence of late relapses. Results in the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab were encouraging; 3-yr rates of CR duration (CRD) and survival (OS) were 60% and 50% overall, respectively. In younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (70% v 38%; P <.001% and 75% v 47%, P =.003) [Thomas D, JCO 28: 3830, 2010]. Historical experience in the adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (now treated with pediatric augmented BFM regimen) showed that the addition of rituximab improved the 3-yr CRD rates from 26% to 65% (P =.001) and 3-yr OS rates from 47% to 75% (P =.05) compared with standard hyper-CVAD. There were no significant differences in outcome for the AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). In contrast to the Burkitt leukemia experience, elderly pts with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab did not benefit (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR. For the modified hyper-CVAD regimen (no anthracycline intensification), the rate of MRD negativity by 4- or 6-color MFC (sensitivity 0.01%, assay now 8-color MFC) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% v 21%, P =.01) and lower 3-yr CR duration rates (45% v 78%, P =.01). CD20 positive pts treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% v 58%, P =.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% v 82%, P =.002), but survival rates were not statistically different (27% v 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR did not influence 3-yr CR duration rate (58% v 63%). Additional doses of rituximab have been added to the consolidation cycles (Day 1 of cycles 5 – 8) and during the maintenance phase. Upfront dose reductions have been implemented for the induction-consolidation phase according to age and performance status in order to reduce deaths in CR. MTX-cytarabine cycles now include vincristine. All pts receive 8 IT treatments in the absence of CNS disease. Younger pts age 40 – 50 yrs receive pegylated asparginase (2000 Units/m2 with capping) during the induction-consolidation phase and early/late intensifications (augmented hyper-CVAD). Elderly pts or younger pts with B-lymphoblastic leukemia with contraindications to asparaginase are now treated with the hyper-CVAD and ofatumumab regimen regardless of CD20 expression. The cumulative experience of the serial modifications to the hyper-CVAD regimen stratified by age/MRD status and the preliminary experience with the frontline version of the augmented hyper-CVAD regimen will be presented. Disclosures: Off Label Use: Rituximab in Lymphoblastic Leukemia.

Chemoimmunotherapy with a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome for Patients with De Novo Philadelphia Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 836-836
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cd20 Expression

Abstract Abstract 836 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004, Thomas, Blood 104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999. Induction chemotherapy was given in a protective environment owing to higher mortality in patients (pts) aged 60 years or older (17% vs 3%). Course 2 of liposomal daunorubicin and cytarabine was incorporated owing to reports suggesting benefit of early anthracycline intensification. Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of methotrexate-cytarabine) was given if CD20 expression was 20% or greater due to its association with disease recurrence [Thomas, Blood 113:6330, 2009]. The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) pts with ALL (n=204) or LL (n=27) were treated on the two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with modified hyper-CVAD with anthracycline intensification (9 induction-consolidation courses). Course 2 was then eliminated from the regimen (8 courses), with an additional 162 pts treated to date (pts age 30 years or less are now treated with augmented BFM). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the evaluable group (n=225) was 93%; 7 pts achieved PR (LL with residual disease), five failed to respond, and 4 died during the induction phase. Three-yr CRD and OS rates were 70% and 62%, respectively after a median follow-up of 50 months (range, 2–106+). In the younger CD20 positive precursor B-cell ALL subset (n=99), rituximab improved outcome compared to historical experience with hyper-CVAD alone (n=127), with 3-yr CRD rates (75% vs 45%, p<.001) and OS rates (65% vs 38%, p<.001) approaching those of their CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 28% vs 34%, p NS). Anthracycline intensification did not improve outcome. The addition of rituximab to the hyper-CVAD regimen appears to benefit the younger pts (age less than 60 yrs) with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens for ALL should be investigated systematically. Disclosures: No relevant conflicts of interest to declare.

Outcome of 136 Children with Advanced Lymphoblastic Lymphoma Receiving an BFM-Type Therapy with Intensified Maintenance: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3049-3049
Author(s):  
Shosuke Sunami ◽  
Masahiro Sekimizu ◽  
Tetsuya Takimoto ◽  
Tetsuya Mori ◽  
Tetsuo Mitsui ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Lymphoblastic Lymphoma ◽  
High Dose ◽  
Induction Phase ◽  
Pediatric Leukemia ◽  
Cns Disease ◽  
Stage 4 ◽  
Mediastinal Disease ◽  
Significant Difference

Abstract BACKGROUND: Lymphoblastic lymphoma (LBL) accounts for 30% of childhood non Hodgkin’s lymphoma in Japan. From European and North American groups, favorable results have been reported, using treatment strategies for acute lymphoblastic leukemia, over 80% of event free survival rate even in advanced LBL. However there were few data on Japanese or Asian patients with LBL. Here we report final outcome of first nation-wide prospective study over one hundred cases with advanced childhood LBL from Japan. PATIENTS & METHOD: Patients with stage 3 or 4 LBL received for 9 weeks induction phase, which consisted of 7 drugs and triple IT , followed by three courses of high dose MTX(5g/m2). After high dose MTX, re-induction, early maintenance, and late maintenance phase were administered. With an attempt to intensify maintenance therapy,early maintenance was consisted by two cycles of four courses of six drugs(MTX, PSL,VCR, L-ASP, 6MP, THP#) and late maintenance was five cycles of five drugs(MTX, PSL,VCR, 6MP,AraC). We omitted local radiotherapy including prophylactic cranial radiotherapy except patient with initial central nervous system (CNS) disease. The total duration of the treatment was 24 month‚“. RESULTS: From November 2004 to October 2010, 154 children with newly diagnosed advanced stage LBL were entered in this study. A total of 136 cases were eligible. Ages ranged from four month to 15 years, with a median of 9.07 years. Of the 136 patients, 36 were girls and 100 were boys. The distribution of clinical stage 3 and stage 4 was 82 and 54 patients respectively. 94 patients had primary mediastinal disease. 41 patients had BM disease, 31 patients had CNS disease and 8 patients had BM and CNS disease. 104 patients (76.5%) had precursor T LBL (T-LBL), 31 patients (22.8%) had precursor B LBL (B-LBL), onepatient (0.7%) had bi phenotype LBL. The follow-up time ranged from 2.8 to 94 months, with a median 58 months. For the 136 patients analyzed in this study, 5-year OS was 82.9% and 5-year EFS was 77.9%. There was no significant difference in outcome by gender (5-year EFS, male 78.2% vs. female 73.0%), or by immunophenotype (5-year EFS, B-LBL 80.7% vs. T-LBL 76.9%). Of note, the 5-year EFS for stage 3 T-LBL patients were worse than that of stage 4 T-LBL patients (70.6% vs. 88.9%, P=0.031). There were also significant difference in 5-year EFS for T-LBL patients who achieved CR and CRu at end of induction, 86.9%, and 69.7% (P=0.034), respectively.Most events were observed as mediastinum enlargement before initiation of intensified maintenance therapy. CONCLUSIONS: Our firstnationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve survival outcome. Our result also emphasize the significant difference between T-LBL stage 3 and stage 4 and might suggest the difference in ethnicity for the composition of biological subgroup in T-LBL. THP: Pirarubicin Disclosures No relevant conflicts of interest to declare.

Significance of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) In Adults with De Novo Acute Lymphoblastic Leukemia (ALL) After Therapy with the Modified Hyper-CVAD Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2145-2145
Author(s):  
Deborah A. Thomas ◽  
Susan O'Brien ◽  
Jeffrey Jorgensen ◽  
Sa A. Wang ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Increased Risk ◽  
Cd20 Expression

Abstract Abstract 2145 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted with early and late intensifications. The regimen was modified in 1999 in order to improve on the results. Induction chemotherapy was administered in a laminar air flow room for pts aged 60 years or older owing to high induction mortality rate (17%). Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of MTX-cytarabine for 8 total doses) was given if CD20 expression was > 20% owing to association with increased propensity for relapse [Thomas D, Blood 113:6330, 2009]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). The maintenance phase was extended from 24 to 30 mos with modifications of the early and late intensifications (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19) in order to reduce incidence of late relapses. Newly diagnosed or primary refractory (1 course only) pts with Philadelphia chromosome negative B-lymphoblastic leukemia (n=126) were treated with this modified hyper-CVAD regimen without anthracycline intensification (pts age 30 years or less have been allocated to treatment with the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen since 2006). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the group was 93%; the rate of MRD negativity by 4- or 6-color MFC (sensitivity of 0.01%) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% versus 21%, p=.01) and lower 3-yr CR duration rates (45% versus 78%, p=.01). The CD20 positive pts (n=57) who were treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% versus 58%, p=.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% versus 82%, p=.002), but survival rates were not statistically different (27% versus 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR was not associated a with lower 3-yr CR duration rate (58% versus 63%). Dectectable MRD by MFC at the time of CR, despite subsequent eradication with consolidation chemotherapy in the majority of patients, predicts for increased risk of disease recurrence. Strategies to improve the MRD negativity rate at the time of CR (e.g., addition of monoclonal antibodies directed at other lymphoblast antigens such as CD22 for the CD20 negative subset and use of the newer anti-CD20 monoclonal antibodies for the CD20 positive subset) may further improve outcome after frontline therapy with the modified hyper-CVAD regimens. Disclosures: Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Off Label Use: Imatinib for de novo Philadelphia positive ALL. Dasatinib for de novo Philadelphia positive ALL. Rituximab for CD20 positive ALL and Burkitt leukemia/lymphoma. Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.

Outcome of Pediatric-Type Therapy for Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA): A Study by the Japan Adult Leukemia Study Group (JALSG ALL202-U study)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1464-1464 ◽  
Author(s):  
Toru Sakura ◽  
Fumihiko Hayakawa ◽  
Toshiaki Yujiri ◽  
Yasutaka Aoyama ◽  
Eisei Kondo ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Therapy ◽  
Childhood Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Intrathecal Chemotherapy ◽  
High Dose ◽  
Consolidation Phase ◽  
Grade 3

Abstract Abstract 1464 Background: Retrospective studies have shown that AYA with ALL treated with pediatric protocols have better outcomes than similarly aged patients with adult protocols, but prospective studies comparing AYA with pediatric schedules are scarce. So, we conducted a phase II multicenter study (JALSG ALL202-U) in collaboration with the Japan Association of Childhood Leukemia Study (JACLS) to determine the efficacy and safety of pediatric type therapy (JACLS ALL-02-HR). Methods: From June 2002 to September 2009, patients (age range 16–24 years) with previously untreated ALL (excluding Philadelphia-positive ALL and mature B-cell ALL) were consecutively registered in this study. For patients with t (4; 11), allogeneic stem cell transplantation (HSCT) was recommended during their first complete remission (CR), if donors were available; whereas for patients without t (4; 11), there were no criteria for choosing HSCT. This protocol consisted of induction therapy (pre-phase with oral corticosteroids and 5-drug induction), consolidation phase including 1) consolidation therapy, 2) sanctuary therapy with two cycles of high dose MTX, 3) reinduction therapy, 4) reconsolidation therapy and 2-year maintenance therapy. Intrathecal chemotherapy was administered during each cycle. In comparison with the former JALSG ALL-97 adult protocol, the pediatric-type therapy showed an increase in cumulative dose of CPM (1.5-fold), VCR (1.2-fold), L-asp (18-fold) and MTX (3.7-fold), respectively. As for the intrathecal chemotherapy, the duration was longer (ALL97; 4 to 21 week, ALL202; 1 to 94 week) and the frequency was increased from 8 to 15 times. Results: There were 138 eligible patients: median age was 19 years old and 56% were male. Of the eligible patients, 134 patients (97.1%) achieved CR. The estimated the 4-year OS rate was 74% and 4-year DFS rate was 71%, respectively. Compared with previous JALSG ALL-97 study, CR rate (97.1% ALL202, 84% ALL97; p=0.01), 4-year DFS rate (fig 1, 71% ALL202, 46% ALL97; p=0.0001) and 4-year OS rate (fig 2, 74% ALL202, 46% ALL97; p=0.0002) were significantly higher in this study. During induction therapy, major grade III-IV adverse events (AEs) were FN, DIC, pancreatitis and AST/ALT. The frequency of FN was higher with ALL202-U protocol (43%) than with ALL-97 protocol (12%). During consolidation phase and maintenance therapy, the most common toxicity was FN. The treatment duration during induction therapy and consolidation phase was longer than planned. In comparison with the outcome of JACLS ALL-02-HR protocol, grade 3 to 4 AEs were similar. Conclusion: This pediatric-type therapy was very efficient, yielding a 97.1% CR rate, 71% 4-year DFS and 74% 4-year OS in AYA patients. The protocol was tolerable, but FN and treatment prolongation were observed. Grade 3 to 4 AEs were similar to pediatric group. The data reported here were collected at the time of interim analysis. The latest data including AEs are currently being reviewed and will be disclosed at the presentation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Children with Standard Risk Acute Lymphoblastic Leukemia in Induction And Consolidation Phase

2018 ◽  
Vol 54 (1) ◽  
pp. 59
Author(s):  
Adinugraha Amarullah ◽  
Didik Hasmono ◽  
IGD Ugrasena ◽  
Yulistiani Yulistiani
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cortisol Level ◽  
Lymphoblastic Leukemia ◽  
Adrenal Suppression ◽  
High Dose ◽  
Induction Phase ◽  
Prednisone Therapy ◽  
Consolidation Phase ◽  
Standard Risk ◽  
Dose Prednisone

Prednisone has an important role in the therapy of patient with standard risk ALL. Patients with standard risk ALL receiving high dose prednisone as therapy and supraphysiology dose of prednisone are expected to cause suppression in HPA-axis (Hypothalamic Pituitary Adrenal axis). This suppression could reduce immune system in children with ALL and increase infection risk because reduction of cortisol level. In Indonesia, we did not find study about the incident of adrenal suppression after high dose prednisone therapy, especially in induction to consolidation phase ALL patient. The aim of this study was to analyze adrenal suppression after high dose prednisone therapy on children with standard risk acute lymphoblastic leukemia in induction and consolidation phase. This study has received a certificate of Ethical Clearance No. 588/Panke.KKE/X/2016, a longitudinal observational, prospective, non-randomized trial involving children with ALL who received prednisone for 49 days during the induction phase. We collected and compared laboratory result of cortisol level in children with ALL and received prednisone therapy during induction to consolidation phase. Sample was taken at week 0,4,5,6,7,8,10,12 in the course of ALL chemotheraphy Indonesian protocol year 2013. Serum was examined using methods CLIA ADVIA Centaur® XP. Between June 2016 – January 2017, 13 patients (8 males, 5 females) were included in this study. Decrease of cortisol level after prednisone therapy occured in week-10 as much as 53% compared with week-0  (p=0.027). Cortisol level increased 64% of week-12 compared with week-10 (p=0.003). In conclusion, high dose prednisone is not significant to causing adrenal suppression in induction phase of ALL patients, and the reducing cortisol level is reversible.

Unexpectedly severe toxicity from intensive early treatment of childhood lymphoblastic leukemia.

1985 ◽  
Vol 3 (2) ◽  
pp. 201-206 ◽  
Author(s):  
G K Rivera ◽  
W E Evans ◽  
D K Kalwinsky ◽  
J Mirro ◽  
J Ochs ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Disease Free Survival ◽  
Gastrointestinal Toxicity ◽  
High Dose ◽  
Induction Phase ◽  
Severe Toxicity ◽  
Free Survival ◽  
Consolidation Phase ◽  
Life Threatening

In early 1984, we treated 13 consecutive patients with acute lymphoblastic leukemia (ALL) using an induction regimen of rapidly rotated combinations of prednisone, vincristine, asparaginase, teniposide (VM-26), cytosine arabinoside, and high-dose methotrexate (MTX) followed by leucovorin rescue. The intent of this clinical trial, designated Total Therapy Study XI, is to test the hypothesis that greater initial leukemia cell kill will decrease opportunities for the development of drug-resistant mutants, with resultant improvement in the length of disease-free survival. Five patients experienced life-threatening gastrointestinal toxicity within three weeks of the start of treatment. One died. Three other patients had severe abdominal pain, abdominal distention, diarrhea, and weight loss, but not gastrointestinal bleeding. In the remaining five patients, toxicity was rapidly reversible, and each child was able to complete the planned course of chemotherapy. The study was then amended to switch high-dose MTX from the induction phase to the consolidation phase, allowing at least one week for mucosal recovery. Among the next 28 patients who were treated, none showed evidence of severe gastrointestinal toxicity. Patients now receive high-dose MTX alone as consolidation therapy and are tolerating it adequately. Drug timing should be examined critically when intensified multiple-agent regimens are being devised for initial treatment of ALL.

Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.

1998 ◽  
Vol 16 (4) ◽  
pp. 1505-1511 ◽  
Author(s):  
R Surtees ◽  
J Clelland ◽  
I Hann
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Reference Population ◽  
Intrathecal Methotrexate ◽  
High Dose ◽  
Induction Phase ◽  
Cranial Radiotherapy ◽  
End Of Treatment ◽  
Carbon Transfer ◽  
Consolidation Phase

PURPOSE To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population. RESULTS There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups. CONCLUSION Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.

Outcome after Frontline Therapy with the Modified Hyper-CVAD Regimen with or without Rituximab for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1931-1931 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
The Elderly ◽  
High Dose ◽  
Induction Phase ◽  
Intensive Chemotherapy ◽  
Cd20 Expression ◽  
Laminar Air Flow

Abstract The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO18:547, 2000; Kantarjian, Cancer101:2788, 2004, Thomas, Blood104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate and cytarabine every 21 days for 8 courses, followed by maintenance with POMP (6-mercaptopurine, methotrexate, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999 to address the following: higher induction mortality in patients (pts) aged 60 years or older (17% vs 3%); possible benefit of early anthracycline intensification; worse survival with CD20 expression [Thomas D, Blood, e-pub]; and late relapses after completion of POMP therapy. Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age ≥60 yrs Dose-intensive anthracycline No C2 lipo DNR & ara-C Rituximab No For CD20 ≥20% Intrathecal CNS prophylaxis 4, 8 (16 BL) 6, 8 (16 BL) POMP maintenance 24 mos 30 months Intensifications Months 7, 11 Months 6, 7 & 18, 19 Newly diagnosed or primary refractory (1 course only) pts with ALL (n=184) or LL (n=27) were treated on two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with the modified regimen as detailed above (9 courses of intensive chemotherapy). Course 2 was then eliminated from the regimen (8 courses of intensive chemotherapy), with an additional 145 pts treated to date. Median age was 40 yrs (range 15–83). CD20 expression was noted in 40%. Overall CR rate of the group (n=211) was 90%; 4 pts achieved PR, five failed to respond, and 3 died during the induction phase. After a median follow-up of 42 months (range, 2–80), outcome appeared favorable for the younger group (30 yrs or less) with 3-year remission duration (CRD) and survival (OS) rates of 70% and 80%. In the CD20 positive precursor B-cell ALL subset (n=88), rituximab improved outcome compared to historical experience, with 3-yr CRD rates (68% vs 28%, p&lt;.001) and OS rates (65% vs 35%, p=.01) approaching those of the CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 48% vs 35%, p NS). Anthracycline intensification appeared to worsen outcome. Rituximab appears to benefit the younger pts with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens should be investigated systematically.

scholarly journals Effect of glucocorticoid therapy on adrenal function in children with acute lymphoblastic leukemia

2014 ◽  
Vol 54 (1) ◽  
pp. 15
Author(s):  
Gita Widyapuri ◽  
Djajadiman Gatot ◽  
Aman Bakti Pulungan ◽  
Badriul Hegar
Keyword(s):  
Hpa Axis ◽  
Standard Dose ◽  
Lymphoblastic Leukemia ◽  
Adrenal Function ◽  
High Dose ◽  
Induction Phase ◽  
Acth Test ◽  
Before And After ◽  
Response To Stress ◽  
Cortisol Levels

BackgroundGlucocorticoids play an important role in thetreatment ofacute lymphoblastic leukemia (ALL), but can causeside effects such as suppression of the hypothalamic-pituitaryadrenal (HPA) axis. Suppression of the HPA axis causes adrenal insufficiency, disturbs the cortisol response to stress, and may be a cause of morbidity and mortality in children with ALL.ObjectiveTo evaluate adrenal function in children with ALL afterinduction chemotherapy with high dose glucocorticoids.MethodsThe adrenal function of 20 children with ALL wasevaluated using a standard dose (250 μ g) adrenocorticotropinhormone (ACTH) test performed before and after a 6 week oftreatment with glucocorticoids induction phase chemotherapy,which was followed by a week period tapering off. Adrenalinsuffien cy was defined as blood cortisol level of < 18 μg/dLResultsAdrenal insufficiency was found in 14/20 subjects afterthe induction phase followed by a week period of tapering off.Median cortisol levels pre- and post-stimulation before inductionphase were 14.72 (range 2.0 1- 46. 1) μg/dL and 29.29 (range 21.65 - 55 .15) μg/dL, respectively. Median cortisol levels pre- and poststimulation after induction phase were 5.87 (range 0.2 - 20.53)μg/dL and 10.49 (range 0.33 - 28.69) μg/dL, respectively. Clinicalsigns and symptoms did not differ between those with and withoutadrenal insufficiency.ConclusionOf 20 children with ALL, 14 develop adrenalinsufficiency after a 6-week induction therapy with glucocorticoidsand followed by a week period of tapering off. No specific clinicalsigns and symptoms are identified to be related to the adrenalinsufficiency.

High-Dose Methotrexate and Early Intensification of Therapy Do Not Improve 3 Year EFS in Children and Adolescents with Disseminated Lymphoblastic Lymphoma. Results of the Randomized Arms of COG A5971

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3610-3610 ◽  
Author(s):  
Minnie Abromowitch ◽  
Amanda Termuhlen ◽  
Myron Chang ◽  
Sherrie L. Perkins ◽  
Thomas Gross ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Bone Marrow Involvement ◽  
Disease Free Survival ◽  
Lymphoblastic Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Disease ◽  
Dose Methotrexate ◽  
Significant Difference

Abstract The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival. From June 2000 to October 2005, 257 patients with Murphy’s Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification. The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here). Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms. These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.

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