Introduction. Approximately 3-5% of pediatric ALL patients present with the Philadelphia chromoso... more Introduction. Approximately 3-5% of pediatric ALL patients present with the Philadelphia chromosome (Ph+). In the past, Ph+ ALL was associated with a poor prognosis, with long-term event-free-survival (EFS) rates of approximately 30% and most patients allocated to hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1). The COG AALL0031 study showed that continuous high imatinib exposure improved outcome with no increase in toxicity and that HSCT offered no advantage over intensive chemotherapy plus imatinib (Schultz et al, JCO2009). Contemporarily, the EsPhALL 2004-2009 intergroup study of post-induction treatment of Ph+ ALL randomly tested the discontinuous use of imatinib added to BFM ALL high risk chemotherapy after the Induction phase in patients with early response, showing an approximate 10% advantage in long-term DFS. All non-responding patients received imatinib and overall 80% received HSCT in CR1 (Biondi et al, Lancet Oncology 2012). Based on both studies, in 2010 the EsPhALL trial was amended into a single arm study to give all patients, on top of the BFM ALL high risk chemotherapy, imatinib 300/mg/m2/day continuously since day 15 of Induction and to gradually decrease the use of HSCT. We present here the results of this EsPhALL 2010-2014 study. Methods. Ph+ ALL patients aged 1-17 years were enrolled by 10 national study groups (AIEOP, BFM-G/CH, COALL, FRALLE-EORTC, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG), mainly in Europe. MRD was assessed by PCR using IG/TR targets or BCR/ABL1 in hierarchical order, according to Euro-MRD rules. Eligibility to HSCT depended on early response and, after 2012, on MRD at end of Protocol IB (≥ 5 x 10-4) and at the end of consolidation block 3 (any positivity in patients with MRD< 5 x 10-4 at end of IB). Imatinib was recommended throughout the first year after transplant. Patients who continued on chemotherapy received treatment until 24 months after diagnosis. Results. Overall 158 patients were registered from January 2010 to December 2014; 3 were not eligible, leaving 155 evaluable patients. Sixty-two patients (40%) were ≥ 10 years, 73 (47%) had ≥50,000 WBC count at diagnosis, 103 (84%) had p190. 102 (66%) patients achieved both early good response and CR1 at end of IA and were classified as good risk, while the remaining 53 (34%) were at poor risk. CR1 was achieved by 151 patients (97%) at the end of Induction and by the remaining 4 at the end of IB. Overall, 59 patients (38%) underwent HSCT in CR1. Nineteen patients discontinued treatment, 17 during chemotherapy, 15 due to serious adverse events (SAE, of which 9 related to imatinib - mainly infections) and the remaining 2 to MRD increase (1) and to transfer to adult unit (1). Among patients who underwent HSCT in CR1, 2 discontinued imatinib after HSCT, due to MRD increase (1) and gastrointestinal toxicity related to imatinib (1). Overall, 185 SAE were observed in 86 (55%) patients. The most frequent SAE was infection which occurred in 50 (32%) patients. Other toxicities included osteonecrosis (7 patients, 5%) and gastrointestinal disorders (9 patients, 6%). On the complete cohort of 155 patients, with a median follow-up of 57 months (range 1-86), the 5-year EFS and survival were 57.0 (SE 4.1) and 71.8 (SE 3.8), respectively. The 5-year cumulative incidence of relapse was 26.9 (SE 3.7). Overall, 65 events occurred, 46 in 96 patients who received chemotherapy only (32 relapses and 14 deaths in CCR) and 19 in 59 HSCT in CR1 (8 relapses and 11 deaths in CCR). Overall, relapses occurred in the BM (22), BM+CNS (11), BM+eye (1) and CNS (6). All deaths in CCR, except for 1 in chemotherapy and 3 after HSCT, were due to infection. Half of the deaths in CCR (12/25) occurred in 2 unexpected clusters, in HSCT performed in 2010-2011 and in chemotherapy-only patients ≥ 10 years. Further investigations did not reveal any common pattern within the clusters. Conclusions: Addition of imatinib given continuously since day 15 of induction markedly increased CR rate to 97% from 50% of the EsPhALL 2004-2009 study. Moreover, in EsPhALL 2010-2014 only 38% of patients underwent HSCT in CR1 (decreasing from 56% in 2010 to 28% in 2014), compared with 81% in the previous study. In spite of this marked decrease in HSCT, the outcome was similar in the 2 studies: 5-year EFS and survival were 57.0% and 71.8% versus 60.3% and 71.6%, respectively in EsPhALL 2010-2014 versus EsPhALL 2004-2009. Disclosures Cazzaniga: Fondazione Tettamanti onlus: Employment; Italian Association for Cancer Research: Research Funding. Saha: Shire: Research Funding. Schrappe: Medac: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding.
... El primer intento sistemático de clasificación morfológica-clínica-biológica es la propuesta ... more ... El primer intento sistemático de clasificación morfológica-clínica-biológica es la propuesta por el grupo Franco-Americano-Bri-tánico (FAB) en 1982 y que se resume en la tabla 1 7 . A pesar de ser la más ampliamente aceptada, en pediatría es solo parcialmente aplicable ...
ABSTRACT Se presenta el caso clínico de una paciente de 12 años con el diagnóstico de enfermedad ... more ABSTRACT Se presenta el caso clínico de una paciente de 12 años con el diagnóstico de enfermedad de Kikuchi-Fujimoto que evolucionó con fiebre dos meses previos acompañado de adenopatías cervicales bilaterales, baja de peso de 5 kilos y compromiso del estado general. Sin respuesta a tratamiento antibiótico, se descartaron causas habituales de fiebre. La biopsia ganglionar mostró necrosis difusa, abundantes inmunoblastos, histiocitos, restos celulares necróticos y ausencia de neutrófilos. Evolucionó en forma favorable con caída de la fiebre a los 3 meses desde el inicio del cuadro y regresión de las adenopatías. Se destaca la importancia del diagnóstico diferencial de adenopatías cervicales persistentes acompañado de síndrome febril prolongado. (Palabras clave: Enfermedad de Kikuchi-Fujimoto). Rev. Chil. Pediatr. 73 (5); 483-488, 2002.
The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concen... more The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.
Abstract 873 Background. Philadelphia chromosome positive (Ph+) ALL accounts for 3–5% of pediatri... more Abstract 873 Background. Philadelphia chromosome positive (Ph+) ALL accounts for 3–5% of pediatric ALL. An international survey on 640 children diagnosed between 1995 and 2005 and treated with chemotherapy and stem cell transplantation (SCT) without the use of tyrosin kinase inhibitors (TKI) recently reported an overall 7-year event free survival (EFS) and overall survival (OS) of 31.2% and 44.2%, respectively. In those years, only limited experience was accumulated on the use of Imatinib (IM) for children with Ph+ leukemia. The EsPhALL study was designed as an intergroup, open-label, randomized Phase II/III study, within the I-BFM-SG network, to assess the safety and efficacy of IM in association with chemotherapy. Ten national study groups participated in the study: AIEOP, BFM-G/CH, COALL, FRALLE, NOPHO, MRC, DCOG, CPH, PINDA and HONG KONG. Methods. Patients 1 to 18 years of age diagnosed with Ph+ ALL were eligible to the study. After the induction phase according to national treatment protocol, patients were classified as Good Risk (GR) or Poor Risk (PR) according to their response to treatment. GR patients were those who achieved both the early response (i.e. blast cell count <1000/ml in peripheral blood after 7 days of prednisone and a single dose of intrathecal methotrexate or M1/M2 bone marrow at day 15 or M1 at day 21) and the complete remission after the frontline Induction course (1st complete remission, CR1). They were randomized to receive IM in combination with chemotherapy (GR-IM) or chemotherapy alone (GR-noIM). PR patients (those who did not achieved early response or CR1 or both) received IM in combination with chemotherapy. Due to the availability of external evidence, the randomization in GR was stopped in 2009 and an amended trial started, with all patients receiving IM continuously. The chemotherapy regimen was modeled upon a BFM high risk backbone and IM was delivered at the dose of 300 mg/m2/day. SCT in CR1 was recommended for all PR patients (any donor) and for GR patients if a genotype-matched donor (9/10 or 10/10 alleles) was available. The primary analysis for the randomized question (ITT) was on disease-free survival (DFS) in GR and EFS in PR patients, not censoring for SCT in CR1, with comparison based on the log-rank test. Results. Between 01-Jan-2004 and 31-Dec-2009, 178 patients (age 1.5–17.9 years) were enrolled and stratified as GR (108; 61%) or PR (70; 39%). Ninety GR patients were randomized (18 excluded for parental refusal or clinical decision); of these, 77% underwent SCT in CR1. Out of 35 PR patients who were resistant to Induction, 80% achieved CR1 after consolidation (Phase IB). 84% of PR patients received SCT in CR1. Relapse was the first event in 23 (33%), 12 (27%) and 10 (22%) of PR, GR-noIM and GR-IM patients, respectively. The most common site was the bone marrow (74%, 92% and 60% in PR, GR-noIM and GR-IM patients, respectively). Deaths in CR1 were 8, 4 and 2 in PR, GR-noIM and GR-IM patients respectively, none being related to IM. The 4-year DFS was 73% (95% CI: 56% – 84%) in the GR-IM arm and 62% (95% CI: 45% – 75%) in the GR-noIM arm (p=0.24), with a 4-year OS of 85% (95% CI: 70% – 93%) and 73% (95% CI: 54% – 85%), respectively (p= 0.37). A secondary ‘as treated' analysis was performed accounting for 13 patients who switched from GR-noIM to GR-IM, with 4-year DFS of 56% (95% CI: 36% – 72%) and 75% (95% CI: 61% – 85%), respectively (p=0.06). The EFS in PR patients was 54% (95% CI: 40% – 65%) at 2-years and remained constant through 3 and 4 years, with a 4-year OS of 64% (95% CI: 50% – 74%).The most frequently reported adverse events (AEs) across the treatment arms were decreased leukocytes, platelets and granulocyte counts, decreased hemoglobin, and infections. There was no significant difference in the overall frequency of AEs across all 3 patients' groups. Severe adverse events rate was 28% in GR-IM group, 32% in GR-noIM and 34% in PR group. Conclusions. Results suggest that the addition of IM to intensive BFM-type chemotherapy regimens was associated with an approximate 10% advantage in long-term DFS in GR patients which, however, the study was not powered to detect. The PR group treated with IM had improved EFS and OS as compared to historical controls. IM was generally well tolerated on top of intensive chemotherapy with a reassuring safety profile. Disclosures: Biondi: BMS, Novartis, Micromed: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Resumo: Entre julio de 1993 y abril de 1996 ingresaron a la Unidad de Oncología del Hospital Robe... more Resumo: Entre julio de 1993 y abril de 1996 ingresaron a la Unidad de Oncología del Hospital Roberto del Río 113 pacientes con neutropenia febril, que en conjunto sumaron 179 episodios. Al ingreso se efectuaron cultivos, Rx de tórax y se inició tratamiento ...
Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imati... more Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imatinib after induction in Ph ALL patients receiving BFM therapy and HSCT. Other contemporary studies showed an advantage from continuous protracted exposure to imatinib challenging the indications to transplant. Methods. Patients aged 1-17 years were enrolled in EsPhALL2010 trial and received imatinib 300/mg/m2 continuously from day 15 of induction, during chemotherapy. MRD was measured by IG/TR. Eligibility to HSCT depended on early morphological response and MRD. Imatinib was recommended throughout the first year after transplant. Findings. 155 evaluable patients were registered between 2010-2014. 151 (97%) achieved CR1 after induction and 4 after consolidation phase IB. 59 patients (38%) underwent HSCT in CR1. The 5-year EFS and OS were 57·0 (SE 4·1) and 71.8 (SE 3·8), respectively. The 5-year cumulative incidence of relapse was 26·9% (SE 3·7, 8 relapses in 59 transplanted patients and 32 relapses in 96 patients who received chemotherapy). In patients MRD negative at end of IB, there were no relapses in those transplanted (N=17) and 9 relapses in those (N=30) treated with chemotherapy. In patients with positive MRD at end of IB, 5 relapses each occurred in 15 transplanted and 12 not transplanted patients. WBC count at diagnosis ≥100x109/L was associated with a poor prognosis (HR 3·47, 95% CI 1·74-6·89, p=0·0004). Interpretation. Imatinib given since day 15 of induction markedly improved CR rates to 97% from 78% in EsPhALL2004. Though HSCT rates were significantly lower (38% versus 81%), outcomes were similar in the two studies: 5-year EFS and survival were 57·0% and 71·8% versus 60·3% and 71·6%, respectively. WBC ≥100x109/L was the most relevant independent prognostic factor. Funding. Projet Hospitalier de Recherche Clinique-Cancer and Novartis (France); Bloodwise and CRUK (UK). Wellcome-DBT Margdarshi fellowship (VS). MH CZ- DRO, 00064203 (Czech Republic). AIRC 5‰, Ref. 21147 (AB). AIRC2013, ID 14634 (MGV). Conflict of interest statements. No conflicts of interest have been declared by the authors. Ethics approval statement: EsPhALL2010 is a prospective, single arm trial derived from an amendment of the EsPhALL2004 protocol (EudraCT No. 2004-001647-30) which was approved by the ethics committee of each participating institution in ten national study groups (AIEOP, BFM-G/CH, COALL, French ALL-group, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG).
Purpose Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A gene rearrangements a... more Purpose Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A gene rearrangements and a poor outcome. Therefore, infants are treated with specific protocols. In older children, minimal residual disease (MRD) is used for risk group stratification. In infant ALL, data on MRD are scarce. We evaluated the prognostic value of MRD in a large series of infants with KMT2A rearranged ALL, treated within Interfant-06 in order to establish how to use MRD in these patients. This protocol included a randomization between lymphoid-style consolidation (protocol IB) versus a myeloid-style consolidation (ADE/MAE). Patients and methods MRD was measured in 249 infants with KMT2A-rearranged ALL by DNA-based PCR of rearranged KMT2A, immunoglobulin and/or T-cell receptor genes, at end of induction (EOI) (n=210), end of consolidation (EOC) (n=173) and after MARMA (n=164). MRD results were classified as negative, intermediate (<5x10-4), and high (≥5x10-4). Results In samples with both data on KMT2A MRD PCR and IG/TR MRD targets available (n=223), results were concordant in 94% (n=210/223) of samples. EOI MRD levels predicted outcome with 6-year disease free survival (DFS [SE]) of 60.2% (7.9), 45.0% (5.6), 33.8 % (5.3), for infants with negative, intermediate and high EOI MRD levels, respectively (p=0.0039). Strikingly, when analyzing MRD results according to consolidation treatment given, MRD levels at EOI predicted treatment outcome for patients treated with lymphoid-style consolidation, but not for patients treated with myeloid style consolidation. In patients treated with lymphoid-style consolidation 6-year DFS (SE) was 78.2% (9.8), 47.2% (7.1), 23.2% (7.1) for negative, intermediate and high MRD levels, (figure 1a) respectively (p<0.0001), whilst in myeloid-style treated patients the corresponding figures were 45.0% (10.7), 41.3% (9.4) and 45.9% (8.2) (figure 1b) This implies that patients with low EOI MRD benefit from protocol IB lymphoid consolidation (DFS 78.2% versus 45.0%, figure 1c), while patients with high MRD benefit from ADE/MAE myeloid consolidation (DFS 45.9% versus 23.2%, figure 1d)). In line with these findings, co-expression of myeloid markers was found in a higher percentage of patients with high EOI MRD (81%) versus those with low EOI MRD (50%) (p=0.0186). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2 %(5.8), 40.1% (6.2), 11.9% (8.7) for infants with negative, intermediate and high EOC MRD levels respectively (p<0.0001). Patients that had positive EOI MRD and became negative at EOC also had a good outcome (6-DFS (SE) 65.7% (7.8)) Conclusion Induction therapy selects infant ALL patients for the type of subsequent therapy; infants with high EOI MRD benefit from AML-like consolidation, whereas patients with low MRD benefit from ALL-like consolidation. This hypothesis is further supported by the more pronounced expression of myeloid markers in patients with high EOI MRD levels. Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol. Brethon: Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Introduction. Approximately 3-5% of pediatric ALL patients present with the Philadelphia chromoso... more Introduction. Approximately 3-5% of pediatric ALL patients present with the Philadelphia chromosome (Ph+). In the past, Ph+ ALL was associated with a poor prognosis, with long-term event-free-survival (EFS) rates of approximately 30% and most patients allocated to hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1). The COG AALL0031 study showed that continuous high imatinib exposure improved outcome with no increase in toxicity and that HSCT offered no advantage over intensive chemotherapy plus imatinib (Schultz et al, JCO2009). Contemporarily, the EsPhALL 2004-2009 intergroup study of post-induction treatment of Ph+ ALL randomly tested the discontinuous use of imatinib added to BFM ALL high risk chemotherapy after the Induction phase in patients with early response, showing an approximate 10% advantage in long-term DFS. All non-responding patients received imatinib and overall 80% received HSCT in CR1 (Biondi et al, Lancet Oncology 2012). Based on both studies, in 2010 the EsPhALL trial was amended into a single arm study to give all patients, on top of the BFM ALL high risk chemotherapy, imatinib 300/mg/m2/day continuously since day 15 of Induction and to gradually decrease the use of HSCT. We present here the results of this EsPhALL 2010-2014 study. Methods. Ph+ ALL patients aged 1-17 years were enrolled by 10 national study groups (AIEOP, BFM-G/CH, COALL, FRALLE-EORTC, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG), mainly in Europe. MRD was assessed by PCR using IG/TR targets or BCR/ABL1 in hierarchical order, according to Euro-MRD rules. Eligibility to HSCT depended on early response and, after 2012, on MRD at end of Protocol IB (≥ 5 x 10-4) and at the end of consolidation block 3 (any positivity in patients with MRD&lt; 5 x 10-4 at end of IB). Imatinib was recommended throughout the first year after transplant. Patients who continued on chemotherapy received treatment until 24 months after diagnosis. Results. Overall 158 patients were registered from January 2010 to December 2014; 3 were not eligible, leaving 155 evaluable patients. Sixty-two patients (40%) were ≥ 10 years, 73 (47%) had ≥50,000 WBC count at diagnosis, 103 (84%) had p190. 102 (66%) patients achieved both early good response and CR1 at end of IA and were classified as good risk, while the remaining 53 (34%) were at poor risk. CR1 was achieved by 151 patients (97%) at the end of Induction and by the remaining 4 at the end of IB. Overall, 59 patients (38%) underwent HSCT in CR1. Nineteen patients discontinued treatment, 17 during chemotherapy, 15 due to serious adverse events (SAE, of which 9 related to imatinib - mainly infections) and the remaining 2 to MRD increase (1) and to transfer to adult unit (1). Among patients who underwent HSCT in CR1, 2 discontinued imatinib after HSCT, due to MRD increase (1) and gastrointestinal toxicity related to imatinib (1). Overall, 185 SAE were observed in 86 (55%) patients. The most frequent SAE was infection which occurred in 50 (32%) patients. Other toxicities included osteonecrosis (7 patients, 5%) and gastrointestinal disorders (9 patients, 6%). On the complete cohort of 155 patients, with a median follow-up of 57 months (range 1-86), the 5-year EFS and survival were 57.0 (SE 4.1) and 71.8 (SE 3.8), respectively. The 5-year cumulative incidence of relapse was 26.9 (SE 3.7). Overall, 65 events occurred, 46 in 96 patients who received chemotherapy only (32 relapses and 14 deaths in CCR) and 19 in 59 HSCT in CR1 (8 relapses and 11 deaths in CCR). Overall, relapses occurred in the BM (22), BM+CNS (11), BM+eye (1) and CNS (6). All deaths in CCR, except for 1 in chemotherapy and 3 after HSCT, were due to infection. Half of the deaths in CCR (12/25) occurred in 2 unexpected clusters, in HSCT performed in 2010-2011 and in chemotherapy-only patients ≥ 10 years. Further investigations did not reveal any common pattern within the clusters. Conclusions: Addition of imatinib given continuously since day 15 of induction markedly increased CR rate to 97% from 50% of the EsPhALL 2004-2009 study. Moreover, in EsPhALL 2010-2014 only 38% of patients underwent HSCT in CR1 (decreasing from 56% in 2010 to 28% in 2014), compared with 81% in the previous study. In spite of this marked decrease in HSCT, the outcome was similar in the 2 studies: 5-year EFS and survival were 57.0% and 71.8% versus 60.3% and 71.6%, respectively in EsPhALL 2010-2014 versus EsPhALL 2004-2009. Disclosures Cazzaniga: Fondazione Tettamanti onlus: Employment; Italian Association for Cancer Research: Research Funding. Saha: Shire: Research Funding. Schrappe: Medac: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding.
... El primer intento sistemático de clasificación morfológica-clínica-biológica es la propuesta ... more ... El primer intento sistemático de clasificación morfológica-clínica-biológica es la propuesta por el grupo Franco-Americano-Bri-tánico (FAB) en 1982 y que se resume en la tabla 1 7 . A pesar de ser la más ampliamente aceptada, en pediatría es solo parcialmente aplicable ...
ABSTRACT Se presenta el caso clínico de una paciente de 12 años con el diagnóstico de enfermedad ... more ABSTRACT Se presenta el caso clínico de una paciente de 12 años con el diagnóstico de enfermedad de Kikuchi-Fujimoto que evolucionó con fiebre dos meses previos acompañado de adenopatías cervicales bilaterales, baja de peso de 5 kilos y compromiso del estado general. Sin respuesta a tratamiento antibiótico, se descartaron causas habituales de fiebre. La biopsia ganglionar mostró necrosis difusa, abundantes inmunoblastos, histiocitos, restos celulares necróticos y ausencia de neutrófilos. Evolucionó en forma favorable con caída de la fiebre a los 3 meses desde el inicio del cuadro y regresión de las adenopatías. Se destaca la importancia del diagnóstico diferencial de adenopatías cervicales persistentes acompañado de síndrome febril prolongado. (Palabras clave: Enfermedad de Kikuchi-Fujimoto). Rev. Chil. Pediatr. 73 (5); 483-488, 2002.
The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concen... more The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.
Abstract 873 Background. Philadelphia chromosome positive (Ph+) ALL accounts for 3–5% of pediatri... more Abstract 873 Background. Philadelphia chromosome positive (Ph+) ALL accounts for 3–5% of pediatric ALL. An international survey on 640 children diagnosed between 1995 and 2005 and treated with chemotherapy and stem cell transplantation (SCT) without the use of tyrosin kinase inhibitors (TKI) recently reported an overall 7-year event free survival (EFS) and overall survival (OS) of 31.2% and 44.2%, respectively. In those years, only limited experience was accumulated on the use of Imatinib (IM) for children with Ph+ leukemia. The EsPhALL study was designed as an intergroup, open-label, randomized Phase II/III study, within the I-BFM-SG network, to assess the safety and efficacy of IM in association with chemotherapy. Ten national study groups participated in the study: AIEOP, BFM-G/CH, COALL, FRALLE, NOPHO, MRC, DCOG, CPH, PINDA and HONG KONG. Methods. Patients 1 to 18 years of age diagnosed with Ph+ ALL were eligible to the study. After the induction phase according to national treatment protocol, patients were classified as Good Risk (GR) or Poor Risk (PR) according to their response to treatment. GR patients were those who achieved both the early response (i.e. blast cell count &lt;1000/ml in peripheral blood after 7 days of prednisone and a single dose of intrathecal methotrexate or M1/M2 bone marrow at day 15 or M1 at day 21) and the complete remission after the frontline Induction course (1st complete remission, CR1). They were randomized to receive IM in combination with chemotherapy (GR-IM) or chemotherapy alone (GR-noIM). PR patients (those who did not achieved early response or CR1 or both) received IM in combination with chemotherapy. Due to the availability of external evidence, the randomization in GR was stopped in 2009 and an amended trial started, with all patients receiving IM continuously. The chemotherapy regimen was modeled upon a BFM high risk backbone and IM was delivered at the dose of 300 mg/m2/day. SCT in CR1 was recommended for all PR patients (any donor) and for GR patients if a genotype-matched donor (9/10 or 10/10 alleles) was available. The primary analysis for the randomized question (ITT) was on disease-free survival (DFS) in GR and EFS in PR patients, not censoring for SCT in CR1, with comparison based on the log-rank test. Results. Between 01-Jan-2004 and 31-Dec-2009, 178 patients (age 1.5–17.9 years) were enrolled and stratified as GR (108; 61%) or PR (70; 39%). Ninety GR patients were randomized (18 excluded for parental refusal or clinical decision); of these, 77% underwent SCT in CR1. Out of 35 PR patients who were resistant to Induction, 80% achieved CR1 after consolidation (Phase IB). 84% of PR patients received SCT in CR1. Relapse was the first event in 23 (33%), 12 (27%) and 10 (22%) of PR, GR-noIM and GR-IM patients, respectively. The most common site was the bone marrow (74%, 92% and 60% in PR, GR-noIM and GR-IM patients, respectively). Deaths in CR1 were 8, 4 and 2 in PR, GR-noIM and GR-IM patients respectively, none being related to IM. The 4-year DFS was 73% (95% CI: 56% – 84%) in the GR-IM arm and 62% (95% CI: 45% – 75%) in the GR-noIM arm (p=0.24), with a 4-year OS of 85% (95% CI: 70% – 93%) and 73% (95% CI: 54% – 85%), respectively (p= 0.37). A secondary ‘as treated' analysis was performed accounting for 13 patients who switched from GR-noIM to GR-IM, with 4-year DFS of 56% (95% CI: 36% – 72%) and 75% (95% CI: 61% – 85%), respectively (p=0.06). The EFS in PR patients was 54% (95% CI: 40% – 65%) at 2-years and remained constant through 3 and 4 years, with a 4-year OS of 64% (95% CI: 50% – 74%).The most frequently reported adverse events (AEs) across the treatment arms were decreased leukocytes, platelets and granulocyte counts, decreased hemoglobin, and infections. There was no significant difference in the overall frequency of AEs across all 3 patients' groups. Severe adverse events rate was 28% in GR-IM group, 32% in GR-noIM and 34% in PR group. Conclusions. Results suggest that the addition of IM to intensive BFM-type chemotherapy regimens was associated with an approximate 10% advantage in long-term DFS in GR patients which, however, the study was not powered to detect. The PR group treated with IM had improved EFS and OS as compared to historical controls. IM was generally well tolerated on top of intensive chemotherapy with a reassuring safety profile. Disclosures: Biondi: BMS, Novartis, Micromed: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Resumo: Entre julio de 1993 y abril de 1996 ingresaron a la Unidad de Oncología del Hospital Robe... more Resumo: Entre julio de 1993 y abril de 1996 ingresaron a la Unidad de Oncología del Hospital Roberto del Río 113 pacientes con neutropenia febril, que en conjunto sumaron 179 episodios. Al ingreso se efectuaron cultivos, Rx de tórax y se inició tratamiento ...
Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imati... more Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imatinib after induction in Ph ALL patients receiving BFM therapy and HSCT. Other contemporary studies showed an advantage from continuous protracted exposure to imatinib challenging the indications to transplant. Methods. Patients aged 1-17 years were enrolled in EsPhALL2010 trial and received imatinib 300/mg/m2 continuously from day 15 of induction, during chemotherapy. MRD was measured by IG/TR. Eligibility to HSCT depended on early morphological response and MRD. Imatinib was recommended throughout the first year after transplant. Findings. 155 evaluable patients were registered between 2010-2014. 151 (97%) achieved CR1 after induction and 4 after consolidation phase IB. 59 patients (38%) underwent HSCT in CR1. The 5-year EFS and OS were 57·0 (SE 4·1) and 71.8 (SE 3·8), respectively. The 5-year cumulative incidence of relapse was 26·9% (SE 3·7, 8 relapses in 59 transplanted patients and 32 relapses in 96 patients who received chemotherapy). In patients MRD negative at end of IB, there were no relapses in those transplanted (N=17) and 9 relapses in those (N=30) treated with chemotherapy. In patients with positive MRD at end of IB, 5 relapses each occurred in 15 transplanted and 12 not transplanted patients. WBC count at diagnosis ≥100x109/L was associated with a poor prognosis (HR 3·47, 95% CI 1·74-6·89, p=0·0004). Interpretation. Imatinib given since day 15 of induction markedly improved CR rates to 97% from 78% in EsPhALL2004. Though HSCT rates were significantly lower (38% versus 81%), outcomes were similar in the two studies: 5-year EFS and survival were 57·0% and 71·8% versus 60·3% and 71·6%, respectively. WBC ≥100x109/L was the most relevant independent prognostic factor. Funding. Projet Hospitalier de Recherche Clinique-Cancer and Novartis (France); Bloodwise and CRUK (UK). Wellcome-DBT Margdarshi fellowship (VS). MH CZ- DRO, 00064203 (Czech Republic). AIRC 5‰, Ref. 21147 (AB). AIRC2013, ID 14634 (MGV). Conflict of interest statements. No conflicts of interest have been declared by the authors. Ethics approval statement: EsPhALL2010 is a prospective, single arm trial derived from an amendment of the EsPhALL2004 protocol (EudraCT No. 2004-001647-30) which was approved by the ethics committee of each participating institution in ten national study groups (AIEOP, BFM-G/CH, COALL, French ALL-group, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG).
Purpose Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A gene rearrangements a... more Purpose Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A gene rearrangements and a poor outcome. Therefore, infants are treated with specific protocols. In older children, minimal residual disease (MRD) is used for risk group stratification. In infant ALL, data on MRD are scarce. We evaluated the prognostic value of MRD in a large series of infants with KMT2A rearranged ALL, treated within Interfant-06 in order to establish how to use MRD in these patients. This protocol included a randomization between lymphoid-style consolidation (protocol IB) versus a myeloid-style consolidation (ADE/MAE). Patients and methods MRD was measured in 249 infants with KMT2A-rearranged ALL by DNA-based PCR of rearranged KMT2A, immunoglobulin and/or T-cell receptor genes, at end of induction (EOI) (n=210), end of consolidation (EOC) (n=173) and after MARMA (n=164). MRD results were classified as negative, intermediate (<5x10-4), and high (≥5x10-4). Results In samples with both data on KMT2A MRD PCR and IG/TR MRD targets available (n=223), results were concordant in 94% (n=210/223) of samples. EOI MRD levels predicted outcome with 6-year disease free survival (DFS [SE]) of 60.2% (7.9), 45.0% (5.6), 33.8 % (5.3), for infants with negative, intermediate and high EOI MRD levels, respectively (p=0.0039). Strikingly, when analyzing MRD results according to consolidation treatment given, MRD levels at EOI predicted treatment outcome for patients treated with lymphoid-style consolidation, but not for patients treated with myeloid style consolidation. In patients treated with lymphoid-style consolidation 6-year DFS (SE) was 78.2% (9.8), 47.2% (7.1), 23.2% (7.1) for negative, intermediate and high MRD levels, (figure 1a) respectively (p<0.0001), whilst in myeloid-style treated patients the corresponding figures were 45.0% (10.7), 41.3% (9.4) and 45.9% (8.2) (figure 1b) This implies that patients with low EOI MRD benefit from protocol IB lymphoid consolidation (DFS 78.2% versus 45.0%, figure 1c), while patients with high MRD benefit from ADE/MAE myeloid consolidation (DFS 45.9% versus 23.2%, figure 1d)). In line with these findings, co-expression of myeloid markers was found in a higher percentage of patients with high EOI MRD (81%) versus those with low EOI MRD (50%) (p=0.0186). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2 %(5.8), 40.1% (6.2), 11.9% (8.7) for infants with negative, intermediate and high EOC MRD levels respectively (p<0.0001). Patients that had positive EOI MRD and became negative at EOC also had a good outcome (6-DFS (SE) 65.7% (7.8)) Conclusion Induction therapy selects infant ALL patients for the type of subsequent therapy; infants with high EOI MRD benefit from AML-like consolidation, whereas patients with low MRD benefit from ALL-like consolidation. This hypothesis is further supported by the more pronounced expression of myeloid markers in patients with high EOI MRD levels. Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol. Brethon: Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Uploads