scholarly journals Amsacrine, Etoposide and Methylprednisolone As Part of the Therapy Intensification in Children with Acute Lymphoblastic Leukemia: A Retrospective Analysis in the Trial Coall 08-09

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5168-5168 ◽  
Author(s):  
Gabriele Escherich ◽  
Katharina Wos ◽  
Franziska Schramm ◽  
Martin A. Horstmann
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Treatment Intensification ◽  
Childhood All ◽  
Median Treatment ◽  
Treatment Interval ◽  
Late Responder

Abstract Background The combination of amsacrine, etoposide and methylprednisolone (AEP) is regarded as a salvage treatment option in pediatric acute lymphoblastic leukemia (ALL). A recent study already showed a significant response after the treatment with AEP in children with recurrent/refractory ALL without AEP-related mortality, an acceptable morbidity and moderate myelotoxicity. [1] The CoALL study group, that investigates the treatment of childhood ALL, has implemented this block as a part of a therapy intensification in the current CoALL 08-09 protocol, for patients with a high MRD load ( B-Precursor > 10-³ at the end of induction (EOI), T-ALL >10-³ after the first consolidation block) stratified to the High Risk intensified arm or for patients without remission at the EOI defined as late responder. We examined the toxicity profile and the efficacy of this block in patients that have been treated within the current study. Patients and Methods So far 67 of 624 patients enrolled into the CoALL 08-09 trial, received the combination of amsacrine, etoposide and methylprednisolone as they have been treated according to the High Risk intensified arm (36 c-ALL, 8 pre-B-ALL, 3 pro-B-ALL, 8 T-ALL) or as they were specified as late responder (3 c-ALL, 1 pre-B-ALL, 1 pro-B-ALL, 7 T-ALL). The patients were characterized by a median age of 11 years and a median MRD value of 7x10-3 (B-ALL)/ 1x10-2 (T-ALL). All patients had received one cycle amsacrine 100mg/m²/day i.v. for 2 days, etoposide 500mg/m²/day i.v. for 2 days and methylprednisolone 1000mg/m²/day p.i. for 4 days at the end of the consolidation phase. Results Beside a profound myelosuppression 29 of the 67 enrolled patients exhibited toxicities after receiving AEP, mostly reflected by fever in neutropenia. In two cases septicemia was reported as a serious adverse event. Only three fungal infections, two occurrences of mucositis, four cases of a diabetic metabolic state and two cases of cardiac arrhythmia were reported. There was no osteonecrosis and no steroid-related psychosis reported within this patient cohort. No treatment related death occurred. The median treatment interval was 28 days, 8 days longer than the so far reported median treatment interval. A Kaplan-Meier analysis for event free (EFS) and the overall survival (OS), showed a trend in favor of the current cohort compared to patients of the predecessor trial and a comparable MRD load EOI (pOS: 87.7 SE 4.9 vs 76.3 SE 4.4; pEFS:78.8 SE 6.2 vs 61.1 SE 5.1 p= 0.1) . These patients were treated within the High Risk standard arm without the AEP treatment element. Conclusion Treatment intensification with AEP was well tolerated, without an excess of infectious complications in these heavily pretreated patients. AEP treatment intensification shows a trend towards an improved event-free survival. [1] Horstmann, M. A., Hassenflug, W.-A., zur Stadt, U., Escherich, G., Janka, G., & Kabisch, H. (January 2006). Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. Haematologica, S. 1701-3. Disclosures No relevant conflicts of interest to declare.

Effect of Polymorphisms in Folate Related Genes on Side Effects of High Dose MTX Treatment in Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1961-1961
Author(s):  
Wim Tissing ◽  
Lisha Huang ◽  
Robert de Jonge ◽  
Rob Pieters
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
High Risk ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Methionine Synthase ◽  
Hematological Toxicity ◽  
High Dose ◽  
Childhood All ◽  
Methionine Synthase Reductase

Abstract Introduction. High dose (2 – 3 g/m2) methotrexate (MTX, an anti-folate) is used in the treatment of pediatric acute lymphoblastic leukemia (ALL) with side effects in a considerable number of children. We studied the prevalence of MTX related side effects and a possible relation with common polymorphisms in folate metabolism related genes in the treatment of childhood ALL. Methods. In this retrospective study, DNA was isolated from leukemic samples of 81 children with ALL. High risk (HR) ALL patients were treated with 4 courses of 3 g/m2, non-high risk (NHR) patients with 3 times 2g/m2. The following effects were monitored: serum MTX levels, transfusion need, liver toxicity, skin toxicity and hematological toxicity. Common gene mutations in methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), methionine synthase (MS 2756A>G), methionine synthase reductase (MTRR 66A>G), serine hydroxymethyl transferase (SHMT 1420C>T), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), thymidylate synthase (TS 2R3R) and reduced folate carrier (RFC 80G>A) were detected by PCR-RFLP. Results. 57% of the patients had prolonged increased serum levels of MTX in at least 1 course. 59% patients had the MTX courses at the scheduled time, 35% had one course postponed and 6% 2 courses. Mucositis was observed in 22% patients after 1 out of 3 courses, 19% after 2 and 20% after 3 courses. 28% patients had 1 transfusion, 6% had 2 and 1% had 3 transfusions during the MTX courses. Transaminases were elevated 2 times above the normal upper level in 25% of the patients. Skin rash was observed in 32% patients. Using Mann Whitney analysis we found a significant relation between polymorphisms of the MTHFR 1298A>C and for the MTRR 66A>G genes and side effects. The MTHFR 1298A>C polymorphism was related to less transfusions (p<0.05). Recovery of WBC count in HR ALL patients tended to be slower in patients with a MTHFR 1298AA genotype (P=0.053). HR patients with a MTRR 66AG genotype had a slower recovery of platelet count (p=0.004) Conclusion. Common polymorphisms in the MTHFR (677C>T), MS, SHMT, TS, RFC, and MTHFD1 genes are not related to the occurrence of side effects of MTX treatment in childhood ALL. Polymorphisms in the MTHFR (1298A>C) and MTRR (66A>G) gene are related to hematological toxicity.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Outcome of Patients with T-Cell Lymphoblastic Leukemia or Lymphoma: The GRAALL Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2818-2818
Author(s):  
Stéphane Leprètre ◽  
Martine Escoffre-Barbe ◽  
Patrice Chevallier ◽  
Thibaut Leguay ◽  
Laurence Legros ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Cell Phenotype ◽  
High Dose ◽  
Cns Involvement ◽  
Childhood All ◽  
High Risk Disease ◽  
Mediastinal Disease

Abstract In 2003, the GRAALL intergroup initiated two twin protocols for adult patients with acute lymphoblastic leukemia (ALL; ≥ 20% marrow blasts) or lymphoblastic lymphoma (LL; < 20% marrow blasts), namely the GRAALL-2003 and LL-2003 trials. Treatment strategy was inspired by childhood ALL trials, including corticosteroid prephase, 5-drug induction, high dose-intensity consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and 2-year maintenance. An original induction reinforcement with sequential cyclophosphamide (HyperC) was offered to ALL patients with poor early response (cortico- and/or chemo-resistance) and to all LL patients. A total of 108 patients with T-cell phenotype have been treated (76 ALL and 32 LL; median age, 30 years; M/F sex ratio, 86/22; CNS+, 9; median follow-up, 2 years). Baseline characteristics were not different among ALL and LL subgroups, except for marrow blast percentage and mediastinal enlargement (47% vs 78% for ALL vs LL; P=.005), which correlated negatively, as well as for blood counts (WBC, 27 vs 8.7 × 109/L; platelets, 60 vs 328 × 109/L; Hb, 116 vs 134 g/L for ALL vs LL; P<.001). Bulky mediastinal disease was present in 57% LL vs 22% ALL patients (P=.002). Two patients (1 ALL, 1 LL) died early while the 106 remaining (98%) reached CR. With respect to mediastinal involvement, need for a salvage course with idarubicine and high-dose cytarabine to reach CR was more frequent in LL than in ALL patients (10 LL vs 2 ALL, P<.001). Allogeneic stem cell transplantation (SCT) was offered to patients with high-risk disease, defined here as CNS involvement, poor early response, or need for salvage. Among the 55 CR patients with high-risk disease (41 ALL, 14 LL), 26 received allogeneic SCT in first CR (20 ALL, 6 LL). Overall, 23/106 CR patients relapsed (18 ALL, 5 LL) while 8 died in first CR (7 ALL, 1 LL; 4 after SCT). At 2 years, estimated DFS and overall survival were 66% (64% vs 75% for ALL vs LL, P=.59) and 75% (74% vs 78% for ALL vs LL, P=.75), respectively. The only factors which influenced outcome in this risk-adapted strategy were need for salvage (higher relapse incidence) and CNS involvement (shorter survival). As compared to historical experiences, we report here a notable gain in outcome when treating patients with T-cell lymphoblastic disease, including lymphoma, with a pediatric-inspired ALL strategy. The efficacy of this approach leads to comparable outcome for both diseases. The systematic use of HyperC induction in LL patients was well tolerated, but the need for salvage therapy was more frequent in these patients possibly due to difficulty in early mediastinal response evaluation. The presence of CNS disease at diagnosis remains an unfavorable feature. The role of HyperC during induction and the place of allogeneic SCT in first CR deserve further evaluation in this new context.

Prognostic Impact of Different High Risk Features in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2303-2303
Author(s):  
Theis Terwey ◽  
Philipp Hemmati ◽  
Gero Massenkeil ◽  
Bernd Dörken ◽  
Renate Arnold
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Prognostic Impact ◽  
Very High ◽  
First Complete Remission

Abstract Abstract 2303 Poster Board II-280 Introduction: In acute lymphoblastic leukemia (ALL) specific clinical and biological features confer high relapse risk and inferior overall survival (OS) after treatment with conventional chemotherapy alone. The differential prognostic impact of these high risk features after treatment with allogeneic hematopoietic stem cell transplantation (HCT) has not been well studied. Patients and Methods: 79 adult ALL patients in first complete remission (CR) received allogeneic HCT at our center between 1995 and 2008. All patients were high or very high risk according to German Multicenter Study Group for Adult ALL (GMALL) criteria. Median age was 36 years (range: 17-68). Patients received high-dose conditioning consisting of 12 Gy total body irradiation ± etoposide ± cyclophosphamide (n=69, 87%) or reduced intensity conditioning (RIC) consisting of fludarabine/busulfan/ATG (n=10, 13%) and HSCT from related (n=34, 43%) or unrelated (n=45, 57%) donors. Bone marrow (n=17, 22%) or peripheral blood stem cells (n=62, 78%) were given. Graft-versus-host-disease prophylaxis was CSA/MTX for high-dose conditioning or CSA/MMF for RIC. Results: Patients were classified as high risk or very high risk due to Philadelphia chromosome-positive disease (Ph+) (n=30, 38%), leukocytosis>30/nl at diagnosis in B-ALL (n=25, 23%), late response to induction therapy in B-ALL (>week 4) (n=13, 16%), early or mature T-ALL (n=13, 16%), pro-B-ALL/t(4;11) (n=8, 10%), persistence of minimal residual disease (MRD) (>week 16) (n=8, 10%) or complex aberrant karyotype (n=6, 8%). 57 patients (72%) presented with one high risk feature, whereas 20 patients (25%) and 2 patients (3%) presented with two or three features, respectively. Currently, after a median follow-up of 56 months (7-169) 49 patients (62%) remain alive. Projected OS of the whole cohort at 1, 2 and 5 years was 78%, 70% and 55% and leukemia-free survival was 77%, 66% and 55%. Cumulative incidence of non-relapse mortality (NRM) and relapse mortality (RM) at 5 years was 23% and 18%, respectively. In multivariate Cox regression analysis, a non-significant trend for inferior OS was seen for patients with early or mature T-ALL (hazard ratio (HR): 2.03 (95%CI: 0.92-4.52), p=0.082), whereas no differential effect on OS, NRM or RM was seen for any other high risk feature (Table 1). In additional analyses, inferior OS (HR 1.81 (95%CI: 1.02-3.29), p=0.043) and increased RM (HR 2.17 (95%CI 1.16-4.05), p=0.015) was observed for patients with more than one high risk feature. Conclusions: In summary, this single center study on allogeneic HCT in high risk ALL found a negative prognostic trend for early or mature T cell immunophenotype. No differential prognostic impact on OS, NRM and RM was seen for other high risk features as defined by GMALL criteria, however this conclusion is limited by the low patient number in some of the subgroups. Overall survival for the whole cohort was 55% at 5 years, with inferior OS and higher RM being observed in patients with more than one high risk feature. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ANALYSIS OF INDUCTION PHASE GLUCOCORTICOID USE ON ADRENAL SUPPRESSION IN PEDIATRIC PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

2017 ◽  
Vol 52 (1) ◽  
pp. 7
Author(s):  
Octaviana Simbolon ◽  
Yulistiani Yulistiani ◽  
I DG Ugrasena ◽  
Mariyatul Qibtiyah
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
High Risk Group ◽  
Adrenal Suppression ◽  
Induction Phase ◽  
Childhood All ◽  
Cortisol Levels ◽  
Standard Risk

Glucocorticoids play an important role in the treatment of acute lymphoblastic leukemia (ALL). However, supraphysiological doses may cause suppression of the adrenal. Adrenal suppression resulting in reduced cortisol response may cause an inadequate host defence against infections, which remains a cause of morbidity and mortality in children with ALL. The occurrence of adrenal suppression before and after glucocorticoid therapy for childhood ALL is unclear. The aim of this study is to analysis the effect of glucocorticoid on cortisol levels during induction phase chemotherapy in children with acute lymphoblastic leukemia. A cross-sectional, observational prospective study was conducted to determine the effect of glucocorticoid on cortisol levels in children with acute lymphoblastic leukemia. Patients who met inclusion criteria were given dexamethasone or prednisone therapy for 49 days according to the 2013 Indonesian Chemotherapy ALL Protocol. Cortisol levels were measured on days 0, 14, 28, 42 and 56 of induction phase chemotherapy. There were 24 children, among 31 children recruited, who suffered from acute lymphoblastic leukemia. Before treatment, the means of cortisol levels were 228.95 ng/ml in standard risk group (prednisone) and 199.67 ng/ml in high risk group (dexamethasone). In standard risk group, the adrenal suppression occurs at about day 56. There was a significant decrement of cortisol levels in high risk group in days 14, 28, 42 against days 0 of induction phase (p=0.001). Both groups displayed different peak cortisol levels after 6 week of induction phase (p=0.028). Dexamethasone resulted in lower cortisol levels than prednisone during induction phase chemotherapy in children with acute lymphoblastic leukemia.

scholarly journals Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 409-415 ◽  
Author(s):  
SB Murphy ◽  
SC Raimondi ◽  
GK Rivera ◽  
M Crone ◽  
RK Dodge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Term Survival ◽  
Childhood All ◽  
Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

scholarly journals Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1132
Author(s):  
Darlen Cardoso de Carvalho ◽  
Luciana Pereira Colares Leitão ◽  
Fernando Augusto Rodrigues Mello Junior ◽  
Alayde Vieira Wanderley ◽  
Tatiane Piedade de Souza ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Brazilian Amazon ◽  
Childhood All ◽  
Risk Of Death ◽  
Native American Ancestry ◽  
High Contribution ◽  
Tpmt Gene

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient’s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

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