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.

Pediatric ALL-like Therapy in Adults with T-Cell Lymphoblastic Lymphoma: Results of the Graall-Lysa LL03 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 371-371
Author(s):  
Stephane Lepretre ◽  
Aurore Touzart ◽  
Thomas Vermeulin ◽  
Jean-Michel Picquenot ◽  
Aline Tanguy-Schmidt ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Prognostic Value ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Lymphoblastic Lymphoma ◽  
Adult Patients ◽  
High Dose ◽  
Genetic Profile ◽  
Cns Involvement

Abstract Background: It has been suggested that using an acute lymphoblastic leukemia (ALL) rather than non-Hodgkin lymphoma protocol to treat patients with lymphoblastic lymphoma (LL) might be associated with better results (Hoelzer, Best Pract Res Clin Haematol 2002). To address this issue, the GRAALL and LYSA groups have conducted the Phase 2 LL03 trial in adult patients with LL, using the GRAALL-2003 protocol, which yielded good results in adult patients with ALL (Huguet, JCO 2009). Patients and Methods: Between 2004 and 2012, 155 patients aged 18-59 years were enrolled, including 131 evaluable patients with T-cell LL (T-LL). The pediatric-inspired ALL treatment included a corticosteroid prephase, a 5-drug induction with sequential cyclophosphamide, high dose consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and a 2-year maintenance. Response, including complete remission (CR) and unconfirmed CR (CRu), were assessed using Cheson criteria (Cheson, JCO 1999). Allogeneic stem cell transplantation (SCT) was offered to CR/CRu patients with high-risk disease (defined as need for a second-induction salvage course and/or CNS disease) and a donor. Results: Of 131 T-LL patients (median age, 33 years; M/F ratio 4.0; mediastinal enlargement, 95%; CNS involvement, 5%), 119 patients (91%) reached CR/CRu (30 patients needing a salvage course) and 34 relapsed. Response evaluation was based on CT scan, as PET scan was performed in only 73/131 and 20/30 patients after first induction and salvage, respectively. At 5 years, estimated DFS, EFS and overall survival were 71%, 61% and 66%, respectively. The lymphoma IPI-score had no prognostic value, but increased serum LDH level (observed in 71% of the patients) was associated with a significant decrease in EFS (HR = 2.8 [1.3 – 6.1]) and OS (HR = 3.5 [1.4 – 9.1]) in multivariable analysis. Of note, need for a salvage course was not associated with shorter DFS in CR/CRu patients. In a subset of 49 patients studied for oncogenetic markers, the 4-gene risk classifier (based on NOTCH1, FBXW7, N/K-RAS and PTEN status) we have recently reported to be a powerful predictor in T-ALL patients (Trinquand, JCO 2013) also demonstrated strong prognostic value in T-LL. Among these patients, 29 (60%) had a high-risk genetic profile (defined as no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN deletion). At 3 years, the high-risk genetic profile was predictive of shorter EFS (HR = 14.3 [1.9 – 107.8]), DFS (HR = 9.5 [1.2 – 74.3]) and OS (HR = 11.5 [1.5 – 87.5]) in univariable analysis, as well as in multivariable analysis after adjustment on age, ECOG-PS and LDH level (HR = 20.5 [2.6 – 164.1], 12.6 [1.5 – 104.8] and 17.0 [2.1 – 136.8], respectively. A total of 30 CR/CRu patients were eligible for allogeneic SCT (25 for late CR/CRu, 4 for CNS involvement, and 1 for both criteria) and 17 of them were actually transplanted in first CR/CRu. When analysed as a time-dependent event, allogeneic SCT was not associated with prolonged DFS in these high-risk patients. Finally, Grade III/IV adverse events were those commonly observed with the GRAALL regimen. Overall, 46 patients died during the study (37 after relapse or progression; 5 during induction; 3 from allograft toxicity and 1 after a highway accident). Conclusion: As compared to historical studies, we report here a relatively good outcome in T-LL patients treated with a pediatric-inspired ALL strategy. Very interestingly, the NOTCH1/FBXW7/RAS/PTEN T-ALL risk classification was also a strong prognostic factor in these T-LL patients. Allogeneic SCT did not appear to significantly influence the outcome of selected T-LL patients. Disclosures No relevant conflicts of interest to declare.

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.

The Outcome of Children with T-Cell Acute Lymphoblastic Leukemia: A Single Institution Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4526-4526
Author(s):  
Ali Al-Ahmari ◽  
Asim F. Belgaumi ◽  
Abdelmuniem Al-Dalee ◽  
Mohammed Al-Mahr ◽  
Abdulrahman Al-Musa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mediastinal Mass ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Current Treatment ◽  
High Dose ◽  
Childhood All ◽  
Number Of Patients ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Background: T-cell acute lymphoblastic leukemia (T-ALL) constitutes 10% to 15 % of childhood ALL cases in the Western literature. However, higher proportions, up to 40%, have been reported in certain developing countries. While the outcome of childhood T-ALL has improved dramatically over the last decades, by using intensive multi-agent chemotherapeutic regimens, about 30% to 40% of these patients still experience relapses. Patients and methods: Medical records of the 411 pediatric patients (0–13 years old) diagnosed with ALL and treated at our institution between January 1999 and December 2004 were retrospectively reviewed. Result: Fifty-three (12.9%) of the patients had T-ALL. 52 of these were treated according to a multi-drug chemotherapy protocol, based on a modification of the St. Jude Total XIII-B protocol, including high-dose methotrexate (HD-MTX), at 2gm/m2, and non-cross-resistant drug pair administered weekly during the continuation phase. The remaining one patient received a standard ALL therapy with a single delayed intensification and anti-metabolite based maintenance therapy. Early response to induction chemotherapy was assessed using a bone marrow (BM) evaluation at Day-14 of induction. The mean age was 7.1 years and 36 patients (68%) were males. Twenty (39%), out of 51 patients with available results, had CNS involvement. Of these eight (15.5%) were categorized as CNS-3, while 12 (23.5%) were CNS-2. 50% of the patients presented with mediastinal mass. Nine (18%) of the patients with available initial WBC (n=49) had hyperleukocytosis with a WBC &gt;100 × 109/L. 8 out of the 51 patients with a Day-14 evaluation had &gt;5% blasts in the BM. All patients subsequently achieved remission at the end of induction. The 5-year event-free survival (EFS) and overall survival (OS) rates were 63.9% and 76.4%, respectively. 13 (24.5%) patients relapsed at a median time of one year. Six relapses occurred in the BM, 5 isolated-CNS relapses, one CNS+BM and one in the skin+BM. Only 2 of these relapsed patients are long-term survivors. The disease-related and treatment toxicity-related deaths occurred in 11(20.7%) and 2(3.7%) patients, respectively. The initial WBC count, mediastinal mass, CNS status or the Day-14 BM results were not found to impact negatively on the outcome, by multivariate analysis. Conclusion: Our current treatment strategy has resulted in potential cure for about two-thirds of the patients with childhood T-ALL. However, a significant number of patients do fail treatment and novel strategies need to be devised for them. Unfortunately, as specific clinical features that could determine outcome have not as yet been identified, risk stratification, similar to that utilized for precursor-B cell ALL, is not feasible. Further study into risk determining variables at the molecular level, such as activating NOTCH1 mutations, may be promising in predicting outcome and determining treatment intensity in children with T-ALL.

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

Abstract 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.

Outcome of Children with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Standard Risk (SR) Features: Results of CCG-1952, CCG-1991 and POG 9404.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 680-680 ◽  
Author(s):  
Yousif Matloub ◽  
B.L. Asselin ◽  
Linda C. Stork ◽  
Meenakshi Devidas ◽  
Harland Sather ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trials ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Intensified Chemotherapy ◽  
Standard Risk

Abstract Children with T-ALL have generally had a poorer prognosis than patients with precursor-B ALL. Patients with T-ALL are more likely than those with B-precursor ALL to be > 9 years and present with WBC > 50,000/ul, bulky lymphadenopathy and mediastinal mass. Since 1996, the former CCG has stratified protocol eligibility for patients with ALL based on NCI defined Standard Risk (SR = age between 1-9.99 years; WBC < 50,000/ul) or High Risk (HR) groups, regardless of immunophenotype. In contrast, the former POG has treated all T-cell patients on protocols separate from those for precursor-B ALL. This report compares the outcomes among children with T-cell ALL treated on recently completed or ongoing CCG and POG phase III trials for ALL. CCG-1952 enrolled 2176 eligible children with SR ALL between 1996 and 2000; 106 (5%) had T-cell immunophenotype. Treatment was a standard BFM regimen with prednisone and 2 phases of delayed intensification (DI) with a 2x2 randomization of IT methotrexate (MTX) v ITT and MP v TG. From June 2000 to March 2004, CCG-1991 has enrolled 1794 SR ALL patients: 80 (4%) had T-ALL. Treatment included a similar BFM backbone with substitution of dexamethasone and a 2x2 randomization between escalating IV v oral MTX and 1 v 2 DIs. POG-9404 (opened 1996; closed 2001) was developed exclusively for T-cell disease and enrolled 363 patients with T-ALL; 84 (23%) fit the NCI SR group criteria. On the latter protocol, patients received treatment similar to that developed by the Dana-Farber Leukemia Consortium for high risk B-precursor ALL, with randomization to ± 4 cycles of high dose MTX (5 Gm/m2) and leucovorin. All patients on 9404 received 1800 cGy prophylactic cranial radiation while CCG patients did not. Outcome for T-ALL on CCG-1952 is substantially worse than for B-precursor ALL, with 5 year event-free survival (EFS) of 73% compared to 82% (p = 0.007). Interim analysis of CCG-1991 also shows a significantly worse outcome for T-ALL compared to B-precursor ALL: 3y estimated EFS 78% v 90%, p = 0.0002. In contrast, estimated 5y EFS for patients with SR T-ALL on POG-9404 is 88% (90% on the superior high dose MTX regimen). Comparison of the SR v HR T-ALL patients treated on POG 9404 shows a significant advantage for the SR group (5y EFS of 90% v 75%, p < 0.004). This is in contrast to comparison of T-ALL patients on CCG-1952 (SR) v the concurrent CCG-1961 HR study where T-ALL patients have similar outcome (5y EFS 73% v 72%, p = 0.77). These data suggest that patients with T-ALL and SR features have better EFS when treated with more intensified chemotherapy regimens. Because early EFS for T-cell patients treated on CCG-1991 is worse than on POG 9404, the former study was closed to further accrual of patients with T-ALL. The COG ALL Committee is developing a study for exclusive enrollment of patients with T-ALL using intensive therapy based on the current COG HR ALL regimen, regardless of SR or HR features.

Difference in Outcome of Adolescents with Acute Lymphoblastic Leukemia (ALL) Enrolled in Pediatric (AIEOP) and Adult (GIMEMA) Protocols.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1954-1954 ◽  
Author(s):  
Anna Maria Testi ◽  
Maria Grazia Valsecchi ◽  
Valentino Conter ◽  
Marco Vignetti ◽  
Francesca Paoloni ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Treatment Modalities ◽  
High Dose ◽  
Cranial Radiotherapy ◽  
Childhood All ◽  
High Risk Patients ◽  
Drug Induction ◽  
Risk Patients

Abstract Progress in the treatment of acute lymphoblastic leukaemia (ALL) has led to better survival rates; however, children have had a greater benefit from improved treatment modalities than adolescent who show an overall lower event-free survival (EFS) compared to younger patients. Some differences in the clinical and biologic characteristics of adolescents compared to childhood ALL may partly account for the different outcome, but adolescents treated on pediatric ALL trials seem to have a significantly better EFS than those treated on adult trials. We retrospectively compared the results obtained in a series of 245 patients ranging in age from 14 to 18 years diagnosed and enrolled in specific Italian children and adult ALL trials, between 4/1996 and 10/2003. One hundred and fifty patients, from 30 pediatric centers, underwent the childhood AIEOP ALL 95 and 2000 protocols; the other 95, from 28 adult centers, were enrolled in the GIMEMA ALL 0496 and 2000 protocols. The AIEOP 95 and 2000 trials are BFM-like protocols with a 7 drug induction followed by risk-modulated post-remission therapy that includes high-dose MTX and reinduction for low and intermediate groups, and intensive blocks (high-dose MTX and cytarabine) for high-risk patients. Standard maintenance therapy is administered up to a total of 2 years. Cranial radiotherapy is limited to high-risk patients. Stem cell transplantation is planned for very high-risk patients. The GIMEMA regimens are instead based on an induction with high-dose anthracyclines (cumulative dose 550 mg/m2), high-dose cytarabine as consolidation and do not include high-dose MTX and the reinduction phase. Standard maintenance with vincristine + daunorubicin/cyclophosphamide pulses is given for 2 years. Cranial radiotherapy is administered to all patients. The main patients characteristics at diagnosis, in the two groups under examination, were comparable except for age: median age was 15 and 16 years, respectively in the AIEOP and GIMEMA trials.Poor risk cytogenetic translocations and T-immunophenotype were equally dinstributed. Adolescents in the AIEOP protocols had a higher CR rate (94% vs 89%) and a lower relapse rate (17% vs 45%) compared to the adolescents enrolled in the GIMEMA trials. The 2-year overall survival rate was 80% in the AIEOP protocols and 71% in the GIMEMA trials. Detailed results according to the different clinical and biologic features of the adolescents analyzed will be presented. The results of our comparative study indicate that adolescents enrolled in pediatric trials have a more favourable clinical outcome.

Long Term Survival Using Intensive Multiagent Chemotherapy for Relapses of Pediatric Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1953-1953 ◽  
Author(s):  
Susan R. Rheingold ◽  
Nancy J. Bunin ◽  
Richard Aplenc ◽  
Ann M. Leahey ◽  
Beverly J. Lange
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Term Survival ◽  
Childhood All ◽  
Long Term Survival ◽  
Chemotherapy Protocol ◽  
Multiagent Chemotherapy ◽  
Standard Risk

Abstract Relapses of childhood ALL that occur on therapy are associated with a dismal survival. To improve the prognosis for these patients, we developed an intensive multiagent chemotherapy protocol consisting of an induction with idarubicin, vincristine (VCR), dexamethasone (DEX), and peg-asparaginase (PEG). Consolidation included high-dose cytarabine (ARA-C), etoposide (VP-16), and PEG followed by VCR and methotrexate (MTX). After an interim maintenance (IM), induction and consolidation were repeated followed by maintenance therapy lasting two years. Maintenance and IM consisted of alternating two week cycles of VP-16, ARA-C, and PEG, with MTX ,VCR, DEX, and PEG. Between 1992 and 2002, 53 pts (32M, 21F) received treatment according to this protocol, 21 of whom were treated as part of the original study (Leahey AM et al., Med Ped Onco34(5):313–8, 2000). Median time to relapse was 37 months from diagnosis (range 12–86 mos). Twenty-one pts were on therapy at relapse and 25 pts were <36 months from diagnosis. Relapses included isolated bone marrow (BM) (32 pts), BM and central nervous system (CNS) (9 pts), BM and testicular (3 pts), and extramedullary (EM) (9 pts). By present day criteria 26 pts were standard risk (SR), 23 were high risk (HR), and 4 were infants. Two patients died in induction, and 2 never achieved a second remission. All others achieved remission by the end of induction (92%). Five-year event-free survival (EFS) and overall survival (OS) are both 56% +/−7% (CI 41%–68%), at a mean of 47 months from relapse (range 0–141 mos). Patients with a first complete remission (CR1) duration <36 months have an EFS of 40% +/−10% (CI 21%–58%); >36 months CR1 is associated with an EFS of 70% +/−9% (CI 50%–84%). Of the events in all pts who initiated therapy,13 were from refractory/recurrent ALL (25%), and 10 pts died of toxicity (19%). Four pts died from chemotherapy induced toxicity (8%), and 6 died from transplant (BMT) related toxicities (11%). Fourteen pts in second remission proceeded to BMT at a mean of 5 months from relapse (range 4.5–8 mos), and 7 of these pts remain in CR2. Of the 39 pts who continued on chemotherapy, 6 pts (35%) with CR1<36 months remain in CR2 and 16 patients (57%) with CR1>36 months remain in CR2 or 3. The 19 pts who were treated on modern standard risk (SR) protocols (CCG-1881 to present) were more salvagable than their 20 high risk (HR) counterparts (CCG-1882 to present). Five year EFS for SR and HR pts is 67% +/−8% (CI 48%–80%) and 38% +/−12% (CI 16%–59%) respectively. Intensive rotating therapy with reinduction and reconsolidation improves EFS. Children with early EM relapses of ALL, CR1 > 36 months, and SR patients all have very good long term survival. Novel therapies need to be integrated into intensive relapse protocols for children with early BM relapse and children treated upfront on HR protocols. Figure Figure Figure Figure

Post Induction Minimal Residual Disease Levels Identifies a Group of High Risk Relapsed Childhood Acute Lymphoblastic Leukemia (rALL) with a Favorable Outcome Independent of Induction Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1294-1294
Author(s):  
Catriona Anne Parker ◽  
Marie Reeves ◽  
Sharon Love ◽  
Jeremy Hancock ◽  
Peter M Hoogerbrugge ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Favorable Outcome ◽  
Childhood All ◽  
Post Induction

Abstract BACKGROUND: The determinants of outcome in children with rALL are the duration of first remission (CR1), site of relapse and immunophenotype. High risk (HR) relapses are defined as those occurring with a CR1 of <18 months; B-cell precursor (BCP) with bone marrow (BM) relapse within 6 months of stopping therapy and T-cell BM or combined relapses at any time. All other relapses are defined as standard risk (SR). In the UKALLR3 clinical trial for rALL, HR patients had a lower CR2 rate, higher post induction MRD and inferior survival when compared to SR patients treated in identical fashion. We investigated the effect of further intensifying induction therapy with clofarabine in HR patients. METHODS: Clofarabine was added to the UKALLR3 consolidation block of cyclophosphamide, etoposide (CCE) and used as induction therapy, with dexamethasone and PEG-Asparaginase for HR patients. The previous induction block with mitoxantrone (M) was given as consolidation and all patients were eligible for stem cell transplantation (SCT) with any donor after a third intensification block. The outcomes assessed were improvements in CR2, MRD and progression-free survival (PFS) when compared to historical controls of patients receiving idarubicin (I) or M induction in UKALLR3. A Fleming-style design, based on observed response and toxicity, was incorporated to allow an increase in the dose of cyclophosphamide from 300 mg/m2 to 440 mg/m2. RESULTS: 61, 39 at lower and 22 at the higher dose of cyclophosphamide, CCE patients were compared to 30 I and 69 M patients with HR rALL. Patients in the CCE group had a lower median age at presentation, but other prognostic variables were comparable. CR2 rates of 73%, 83%, 71% and low MRD (≤10-4) was seen in 32%, 0%, 25% of CCE, I and M groups. The higher cyclophosphamide dose was associated with improved CR rates, lower MRD but also increased toxicity levels in CCE compared to M group patients. The proportions of patients reaching transplantation were 43%, 60% and 55% of CCE, I and M patients respectively. 73/82 eligible patients received a SCT, 48 (66%) with matched and 25 (34%) with mismatched donors. The 2-year PFS with CCE, M and I regimens were 17% (11,23), 27% (19,34) and 30% (25,36) respectively (p=0.08). Outcomes of matched sibling, matched unrelated and mismatched SCT were comparable (p=0.9). Seventeen patients with a post induction MRD<10-4, had a 2-year PFS of 63% (50,75), compared to 21% (15,27) for 53 patients with MRD≥10-4 and 21% (17, 25) for the 90 patients with unknown MRD (p=0.005). All 4 patients with MRD≥10-3 prior to SCT and 8/9 not transplanted suffered a second relapse. Overall outcomes of BCP (2-year PFS 21% (15,28)) and T-cell ALL (2-year PFS 26% (16,35)) were comparable (p=0.9). PFS in BCP-ALL was 31% (24,38) and 13% (6,20) (p=0.1) for those receiving M and CCE respectively. CONCLUSIONS: We define two groups of HR rALL patients based on MRD levels attained post induction, independent of the induction regimen. Approximately a quarter of HR patients continue to have chemosensitive disease as evidenced by rapid MRD clearance (<10-4 at week 5). This group includes high-risk cytogenetics and T-cell rALL with MRD as the single discriminatory factor for outcome. These patients have a favorable outcome after SCT with any donor. In the other group (MRD≥10-4) over half of HR patients do not reach SCT primarily due to refractory disease (27%) or disease recurrence (14%). One third of patients relapse post SCT. For this group novel agents and newer treatment strategies are urgently required. Disclosures Off Label Use: Clofarabine 1st relapse childhood ALL.

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.

Treatment of High Risk T-Cell Acute Lymphoblastic Leukemia (T-ALL): Comparison of Recent Experience of the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 681-681 ◽  
Author(s):  
Nita L. Seibel ◽  
Barbara L. Asselin ◽  
James B. Nachman ◽  
Peter Steinherz ◽  
Bruce Camitta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
High Dose ◽  
Recent Experience ◽  
Cancer Group ◽  
Cns Relapse ◽  
Prolonged Duration

Abstract Recent CCG and POG treatment stategies for patients with T-ALL are significantly different. POG treats T-ALL patients on a separate protocol from that used for B precursor ALL (B-ALL) while CCG treats T-ALL patients on the same protocols utilized for B-ALL patients with protocol assignment determined by the NCI risk classification. We recently reviewed the outcome of patients with T-ALL and high-risk features (age ≥ 10 years and/or initial WBC > 50,000/ul) treated on either the CCG-1961 or POG-9404 clinical trials. POG utilized an intensive anthracycline based multidrug regimen based on the DFCI treatment program and randomized patients at registration to receive or not receive additional high dose methotrexate(HDMTX) with leucovorin rescue. All patients received cranial irradiation (CRT). CCG therapy for high risk T-ALL was based on CCG modified BFM(S-BFM) and Augmented BFM(A-BFM). Patients with <25% blasts on day 7 bone marrow(RER) who achieved remission were randomized in a 2X2 design to standard or augmented intensity and standard duration(1 interim maintenance(IM) and 1 delayed intensification(DI) phase or prolonged duration (2 IM and DI phases). Only RER patients with CNS-3 status received CRT. Patients with a slow response(SER) to induction therapy received A-BFM therapy +/− idarubicin/cyclophosphamide courses during DI phases. All SER patients received CRT. In the POG trial, HDMTX produced a significant improvement in event free survival (EFS). In the CCG trial, for RER patients, augmented intensity regimens produced a better EFS than standard intensity regimens. There was no difference in outcome for patients receiving standard or prolonged duration therapy. Thus we compared the high dose MTX arm from POG 9404 to a composite EFS result for CCG l961 based on induction failure/toxic death rate, augmented intensity therapy(1 or 2 DI phases) for RER patients and A-BFM therapy for SER patients. POG 9404, (opened 6/1996; closed 9/2001) and enrolled 363 T-ALL patients, with 77% having high risk features of which 155 were randomized to HDMTX arms. 5 yr EFS for patients on these arms was 75% and overall survival (S) of 84%. CCG 1961(opened 11/1996;closed 5/2002) entered 2077 patients of which 410 had T-cell disease with 263 RERs. The projected composite 5 year EFS and S estimated for high risk T-ALL patients treated on CCG l961 was 76.9% and 82.5% respectively. Isolated CNS relapse accounted for approximately 2/3 of the relapses in RER patients patients.CNS 3 patients treated on 9404 demonstrated 75% 5 yr EFS as compared to 82% for patients on 1961. Outcome for higher risk T-ALL patients treated by POG and CCG were quite similar. However, the BFM based strategy utilizes significantly less anthracycline and appears to produce a lower rate of bone marrow relapse. We postulate that incorporating low dose cranial RT(1200 cGy) will significantly reduce the incidence of CNS relapse and improve the overall EFS rate. Therefore, COG will utilize an augmented intensity BFM backbone for the first T-ALL protocol.

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