Outcome of Infants Less Than One Year of Age with Acute Lymphoblastic Leukemia Treated with the Interfant-99 Protocol.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 145-145 ◽  
Author(s):  
Rob Pieters ◽  
M. Schrappe ◽  
P. de Lorenzo ◽  
I. Hann ◽  
A. Vora ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Prognostic Value ◽  
Cox Model ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Study Groups ◽  
High Dose ◽  
Improve Outcome ◽  
Poor Outcome

Abstract Introduction Acute lymphoblastic leukemia (ALL) in infants under 1 year of age is rare and has a poor outcome compared to ALL in older children. It is characterized by a high expression of MLL gene rearrangements, high tumor load and myeloid features. In 1999, a large collaborative international study, Interfant-99, was initiated with the aims to determine: (1) the outcome of a new treatment protocol including ALL and AML elements; (2) in a randomised way the value of a late intensification course with high dose araC and methotrexate; (3) which clinical and biological factors have independent prognostic value within infant ALL. Event-free survival (EFS) and overall survival (OS) were primary endpoints and analysed on an intention to treat basis. Results 17 study groups representing >20 countries enrolled 482 patients leading to by far the largest trial ever reported in infant ALL. 79% of cases had an MLL rearrangement. Of these, 53% was t(4;11), 20% t(11;19), 11% t(9;11) and 16% had other MLL partner fusion genes. Death in induction rate was 3.8% and 2.3% did not achieve CR at the end of induction, so CR rate was 94%. Death rate in CCR was 5.2%. Relapses occurred in 36% of cases and were mainly isolated bone marrow relapse. Median time from 1st CR to relapse was 8 months. The overall 4-year EFS is 47% and OS is 55%. This is at least comparable to the best historical controls and better than most of those of the participating study groups. Especially outcome of high-risk patients, defined by poor response to one week prednisone, had improved. The late intensification course with HD-araC and HD-MTX did not improve outcome. Cox model showed that MLL rearrangement and age <6 months were strong independent prognostic factors for poor outcome. WBC > 300x10e9/L and poor prednisone response were also of independent prognostic value. The outcome was not depending on the type of MLL rearrangement. Conclusions Results of this first international treatment protocol for infant ALL are very satisfactory. Early bone marrow relapse remains the major cause of treatment failure indicating that early treatment intensification is necessary. The large international collaboration has enabled the start of studies to improve outcome for infant ALL. The new Interfant-06 study will stratify the patients based upon MLL status, age and WBC and will study the value of the use of two early "AML" courses in a randomised way.

Genomic Characterization Of Histiocytic Lesions Following Pediatric T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4940-4940
Author(s):  
Richard McMasters ◽  
Brian K. Turpin ◽  
Michael J. Absalon ◽  
Christine L. Phillips ◽  
Karen Burns ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Previous History ◽  
Genomic Analysis ◽  
High Dose ◽  
Pet Ct ◽  
History Of ◽  
Genomic Characterization ◽  
Notch1 Mutations

Abstract Introduction The development of histiocytic lesions after acute lymphoblastic leukemia (ALL) is rare, occurring in 6 of 971 patients enrolled on BFM treatment regimens for T-ALL (Trebo 2005).  Few cases of histiocytosis arising after a history of T-ALL have been characterized at the molecular level for genomic alterations. One case of fatal Langerhans cell histiocytosis (LCH) following treatment of T-ALL revealed activating mutations in NOTCH1; in contrast, no NOTCH1 mutations were identified in 24 other cases of LCH or Rosai-Dorfman disease without a previous history of T-ALL (Rodig 2008). In patients without prior leukemia, BRAF V600 mutations have been identified in a significant proportion of patients with LCH or Erdheim-Chester Disease but not in other histiocytoses (Haroche 2012). Methodology and Principal Findings Next generation focused exomic sequencing of 236 genes and 47 Introns was conducted on samples of histiocytic lesions from two patients with a previous history of T-ALL. Case 1 A 2 year-old male presented with marked adenopathy, mediastinal mass and white blood cell count 67,000 cells/uL with 30% blasts. The blasts expressed CD45, CD2, CD3 (surface/cyto), CD5, CD7, CD38, CD45 (bright), TCR gamma-delta, but were negative for CD4, CD8, and TdT.  Karyotype was 46,XY,t(8;14)(q24;q11.2),der(12)t(12;20)(q11;q13.3),der(20)t(12;20)(q21;q13.3) with rearrangement of MYC (8q24) confirmed by FISH. He was treated for T-ALL per Children’s Oncology Group (COG) protocol AALL0434 and had 5% residual bone marrow blasts at day 29 of induction. MRD-negative remission was ultimately achieved with high-dose cytarabine and methotrexate followed by consolidation with nelarabine.  He underwent matched unrelated cord blood transplant following conditioning with cyclophosphamide and total body irradiation with cranial boost, and engrafted at day +14. Surveillance bone marrow at day +110 revealed systemic juvenile xanthogranuloma (JXG) without T-ALL. PET/CT revealed FDG-uptake in the diffusely enlarged spleen and throughout the skeleton. Due to progressive cytopenias, therapy was initiated with vinblastine and prednisone as per LCHIII. However, refractory cytopenias exacerbated by splenic sequestration developed following induction, and he was then treated with thalidomide and splenectomy. The spleen weighed 404 grams (expected 40 grams) and was diffusely infiltrated with JXG. The cytopenias dramatically improved and he continued thalidomide for 2 months until PET scan demonstrated progression. Genomic analysis of the JXG lesion revealed NRAS G13D mutation, and FISH demonstrated MYC rearrangement identical to the initial T-ALL sample. Case 2 A 12-year-old male presented with WBC 142,700 cells/uL and CNS leukemia. Flow cytometry showed T-ALL with CD2, surface CD3, CD4, CD5, CD7, CD8, CD24 (subset), CD71, HLA-DR (subset) and TdT (partial). There was a clonal TCR gamma gene rearrangement and a biallelic CDKN2A (p16) deletion by FISH. He was enrolled on COG AALL0434 and had a rapid response with remission in both CNS and marrow at induction day 29.  Following completion of high-dose methotrexate interim maintenance he developed hepatosplenomegaly, pancytopenia and elevated serum bilirubin, ferritin, and triglycerides.  Bone marrow aspirate showed rare hemophagocytosis but no evidence of T-ALL.  He was treated with dexamethasone and etoposide with no response. Follow-up bone marrow revealed brisk hemophagocytosis and a diffuse histiocytic neoplasm. Karyotype was 48,XY,+7,+11[2] /49,idem,+18[3] /46,XY[14]. PET/CT showed hepatosplenomegaly with FDG uptake in anterior mediastinum, hepatic nodules, spleen, and bone marrow. He was treated with Campath and then with intensive chemotherapy with fludarabine, cytarabine, and liposomal daunorubicin with no response and ultimately succumbed to disease. Genomic analysis of the clonal histiocytic infiltrate revealed KRAS G12C, BRAF G469V, NOTCH1 Q2440, and CCND2 G268R mutations, and FISH positive for biallelic CDKN2A (p16) deletion similar to original T-ALL. Conclusions Our extensive genomic characterization suggests a unique molecular pathogenesis for histiocytic disorders arising after T-cell ALL and identified RAS signaling pathway and NOTCH1 mutations. Furthermore, these findings strongly indicate a potential derivation or trans differentiation from the malignant leukemic stem cell clone. Disclosures: No relevant conflicts of interest to declare.

Concordance and Prognostic Significance of Minimal Residual Disease Detection in Peripheral Blood and Bone Marrow Samples of Infants with MLL-rearranged Acute Lymphoblastic Leukemia Treated By MLL-Baby Protocol

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2404-2404
Author(s):  
Grigory Tsaur ◽  
Alexander Popov ◽  
Tatyana Riger ◽  
Alexander Solodovnikov ◽  
Tatyana Nasedkina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Prognostic Value ◽  
Residual Disease ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Remission Induction ◽  
Gene Transcripts ◽  
Minimal Residual

Abstract Background. Minimal residual disease (MRD) is powerful tool for prediction of treatment outcome in leukemia patients of various age groups, including infants with acute lymphoblastic leukemia (ALL). In the vast majority of cases only bone marrow (BM) samples are used for MRD detection. Objective. To estimate prognostic significance of MRD in peripheral blood (PB) and BM by qualitative detection of different MLL fusion gene transcripts in infant ALL enrolled into MLL-Baby protocol. Methods. Fifty three infants (20 boys and 33 girls) with median age of 5.3 months (range 0.03-11.80) and defined MLL rearrangements were included in the current study. Among them there were 25 patients (47.2%) carrying MLL-AFF1 fusion gene transcripts, 10 (18.9%) MLL-MLLT3-positive cases, 9 (17.0%) MLL-MLLT1-positive cases, 5 (9.4%) MLL-MLLT10-positive cases and 4 (7.5%) MLL-EPS15-positive ones. MRD evaluation was performed by detection of MLL fusion gene transcripts in BM and PB samples using real-time PCR and nested RT-PCR with sensitivity non-less than 1E-04. MRD-negativity was defined as absence of fusion gene transcripts in both assays. Median of follow-up period in the observed group was 5.2 years. Time points (TP) for MRD assessment were as follows: day 15 of remission induction (TP1), at the end of remission induction (TP2), after each course of ATRA administration (TP3-TP7). Informed consent was obtained in all cases. Results. We estimated 142 paired BM/PB samples. 77 samples were double positive, 43 were double negative Thus concordance between MRD results in BM and PB samples achieved 84.5%. Concordance varied between different TPs of MLL-Baby protocol from 79.0% to 100%. The highest concordance rate was at TP4 and TP7 (92.3% and 100%, respectively). Interestingly, all discrepant results (22 samples 15.5%) were BM-positive/PB-negative. Median level of ABL gene, used for normalization, was similar in BM and PB samples (4.85E+04 vs 4.95E+04, respectively, p=0.760). Evaluation of prognostic significance of MRD in BM in TP1-TP7 revealed that TP4 was the earliest TP when discriminative data between MRD-positive and MRD-negative patients were obtained. MRD-positivity at TP4 in BM led to unfavorable outcome. Event-free survival was significantly lower in MRD-positive group (n=22) in comparison to MRD-negative one (n=31) (0.06±0.06 vs 0.70±0.09 p=0.0001), while cumulative incidence of relapse in MRD-positive patients was remarkably higher (0.92±0.01 vs 0.29±0.08, p<0.0001). MRD-positivity at this TP in BM was the only significant factor in the diagnostic model where initial risk factors (age at diagnosis, initial WBC count, immunophenotype, CNS disease, presence of MLL-AF4) were combined to response criteria (number of blast cells at day 8 of dexamethasone prophase and MRD in BM at TP4) (Table). The only TP when MRD data obtained from PB samples had prognostic value was TP6. In this TP cumulative incidence of relapse in MRD-positive patients was significantly higher in comparison to MRD-negative ones (0.88±0.11 vs 0.25±0.13, respectively, p=0.003). However these data did not bring any extra advantages as compared to TP4 in BM. Conclusions. Despite high qualitative concordance rate between MRD detection in BM and PB samples we could not show prognostic value of MRD monitoring in PB by fusion gene transcripts. Univariate and multivariate analysis revealed that MRD-positivity at TP4 in BM was the only significant and independent prognostic factor of unfavorable outcome in the observed group of patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute and long-term neurological complications in children with acute lymphoblastic leukemia

1970 ◽  
Vol 34 (3) ◽  
pp. 90-93 ◽  
Author(s):  
A.T.M. Atikur Rahman ◽  
M.A. Mannan ◽  
Samia Sadeque
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Neurological Complications ◽  
Intrathecal Chemotherapy ◽  
High Dose ◽  
Remission Period ◽  
Dose Methotrexate ◽  
Complications Rate

The pattern of acute and long-term neurological complications in 133 children with acute lymphoblastic leukemia (ALL) treated with two treatment protocol was reviewed. Twenty patients developed neurological complications. Nine out of 20 patients received MRC UK ALL X and the remaining 11 received MRC UK ALL XI protocol. There was no difference of neurological complications between MRC UKALL X and UK ALL XI protocol groups. The numbers of patients who developed neurological complications during induction of remission period were 11 of 133 patients (8.2%). 122 patients were observed during the maintenance period of treatment (from 6 months to 36 months). Six out of 122 patients developed neurological complications during this period. 88 patients were followed for a period of up to 6 months after the cessation of chemotherapy, i.e., in the late period. Neurological complications were found in 3 during this period. Neurological complications rate was 4 times higher in the relapsed group than in the no relapsed group (p < 0.05). Systemic chemotherapy (including vincristine, high-dose methotrexate) and intrathecal chemotherapy seem to be the most common predisposing factors.Keywords: Acute lymphoblastic leukemia; children; neurological complicationOnline: 29-1-2009DOI: 10.3329/bmrcb.v34i3.1858Bangladesh Med Res Counc Bull 2008; 34: 90-93

scholarly journals Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

Blood ◽  
2011 ◽  
Vol 118 (19) ◽  
pp. 5099-5107 ◽  
Author(s):  
Raouf Ben Abdelali ◽  
Vahid Asnafi ◽  
Thibaut Leguay ◽  
Nicolas Boissel ◽  
Agnès Buzyn ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Prognostic Value ◽  
Recent Progress ◽  
Prognostic Markers ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Good Prognosis ◽  
Mutation Status ◽  
Mutational Status ◽  
Adult Acute Lymphoblastic Leukemia

Abstract Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.

Acute Lymphoblastic Leukemia Treated With Modified Hyper C-VAD Protocol In Iran

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5014-5014
Author(s):  
Hassan Jalaeikho ◽  
Ahmad Ahmadzadeh deylami ◽  
Manoutchehr Keyhani
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Marrow Transplant ◽  
Intrathecal Methotrexate ◽  
Included Patient ◽  
Induction Regimen ◽  
Enzyme Elevation

Abstract Background Relapse and mortality remains high in Acute Lymphoblastic Leukemia (ALL) with reported 5-year survival less than 39%. Bone marrow transplant (BMT) has been offered to some patients; however, 70% of patients do not have a donor-matched sibling and transplant beds are limited in Iran. We treated a cohort of 251 patients by inducing a remission and then treating with Hyper-CVAD rather than treating with Hyper-CVAD at induction and examined survival compared to reports in the literature. Methods We conducted a retrospective review of survival of 251 treated with a modified protocol of Hyper-CVAD between 2005 and 2012. The treatment protocol used 4-week induction regimen with Vincristine, Daunorubicin, and Dexamethasone. BCR-ABL positive patients also received daily Imatinib. Intrathecal methotrexate and cytarabine were given to patients with brain involvement. Remission was evaluated by a bone marrow biopsy and aspiration. If patient had T-Cell ALL then we add cyclophosphamide to the induction regimen. Hyper-CVAD treatment was initiated two weeks after last dose of Vincristine. Any patient with brain or bone involvement received radiotherapy post induction. BMT was offered to all BCR-ABL positive patients or those who had a suitable donor. All patients in complete remission received monthly vincristine prednisone for 5 days ,6- mercaptopurine every night and methotrexate every week up to 30 months .Patient with persistent liver enzyme elevation received cyclophosphamide instead of methotrexate. Result The mean age was 26 (range 14 to 70). The cohort included patient with T ALL (11%), Burkitt’s type ALL (15%), Pre-B ALL (67%), Pro-B ALL (4%) and BCR-ABL (3%). Sixteen patients died during the first month. Mortality increased to 45 patients at the end of six months. Relapse was the main cause of death. BMT was conducted after complete second remission and suitable patient with BCR-ABL positive patients on 13 occasions but none survived. At 5 years of follow up 129 patients were alive (50.1% survival). Conclusion Our patients experienced an improved survival compared to reports in the literature and many did not have complication of radiotherapy. A modified Hyper-CVAD protocol should be the subject of further investigation for the treatment of ALL. Disclosures: No relevant conflicts of interest to declare.

Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 43-47 ◽  
Author(s):  
John T. Sandlund ◽  
Patricia L. Harrison ◽  
Gaston Rivera ◽  
Frederick G. Behm ◽  
David Head ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Treatment Protocol ◽  
Cell Lineage ◽  
Remission Induction ◽  
Prognostic Impact ◽  
Dna Index ◽  
Risk Patients

Abstract We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (± 1 day) and 218 on days 22 to 25 (± 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (≥ 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% ± 6%) or on days 22 to 25 (4% ± 3%) as compared to those without lymphoblasts on these dates (78% ± 2% and 76% ± 2%, respectively, P &lt; .001 for both comparisons). A worse prognosis was observed even for patients with a low percentage of lymphoblasts (ie, 1%-4%) at either day 15 (5-year EFS = 56% ± 8%) or days 22 to 25 (5-year EFS = 0%) compared to those without morphologically identifiable persistent lymphoblasts at these times (P &lt; .001 for both comparisons). The prognostic impact of persistent lymphoblasts on both dates remained significant after adjusting for other known risk factors, including treatment protocol, age, white blood cell count, DNA index, cell lineage, and central nervous system status, and National Cancer Institute/Rome criteria simultaneously. Hence, persistence of lymphoblasts (even 1%-4%) on day 15 of remission induction was associated with a poor prognosis and on days 22 to 25 signified a particularly dismal outcome; these very high-risk patients require novel or more intensive therapy to improve outcome.

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