Clonal Myeloproliferative Disorders in Patients with Down Syndrome-Treatment and Outcome Results from an Institution in Argentina.

Children with Down syndrome (DS) are at an increased risk of developing clonal myeloproliferative disorders. The balance between treatment intensity and treatment-related toxicity has not yet been defined. We analyzed this population to identify risk factors and optimal treatment. This single-center retrospective study included 78 DS patients <16 years-old with Transient Abnormal Myelopoiesis (TAM, n = 25), Acute Myeloblastic Leukemia (DS-AML, n = 41) of which 35 had classical Myeloid Leukemia associated with DS (ML-DS) with megakaryoblastic immunophenotype (AMKL) and 6 sporadic DS-AML (non-AMKL). Patients with DS-AML were treated according to four BFM-based protocols. Classical ML-DS vs. non-DS-AMKL were compared and the outcome of ML-DS was analyzed according to treatment intensity. Only four patients with TAM required cytoreduction with a 5-year Event-Free Survival probability (EFSp) of 74.4 (±9.1)%. DS-AML treatment-related deaths were due to infections, with a 5-year EFSp of 60.6 (±8.2)%. Megakaryoblastic immunophenotype was the strongest good-prognostic factor in univariate and multivariate analysis (p = 0.000). When compared ML-DS with non-DS-AMKL, a better outcome was associated with a lower relapse rate (p = 0.0002). Analysis of administered treatment was done on 32/33 ML-DS patients who achieved CR according to receiving or not high-dose ARA-C block (HDARA-C), and no difference in 5-year EFSp was observed (p = 0.172). TAM rarely required treatment and when severe manifestations occurred, early intervention was effective. DS-AML good outcome was associated with AMKL with a low relapse-rate. Even if treatment-related mortality is still high, our data do not support the omission of HDARA-C in ML-DS since we observed a trend to detect a higher relapse rate in the arm without HDARA-C.

No benefit of Interfant protocols compared to BFM-based protocols for infants with acute lymphoblastic leukemia. Results from an institution in Argentina.

BACKGROUND: Infant acute lymphoblastic leukemia (ALL) is an infrequent disease characterized by clinical and biological features related to poor prognosis. Adapted therapies were designed without a clear consensus regarding the best treatment options. We aimed to compare the outcome between infant ALL cases receiving Interfant versus BFM-based protocols. PROCEDURE: This is a retrospective observational study. From April 1990 to June 2018, infant ALL cases were enrolled in one of the five consecutive treatment protocols. Clinical, demographic, and biological features and outcome were evaluated. A comparative analysis was performed between Interfant protocols and BFM-based protocols. RESULTS: During the studied period, 1913 ALL patients were admitted and 116 (6%) were infants. Treatment administered was: ALL-BFM'90 (n = 16), 1-ALL96-BFM/HPG (n = 7), Interfant-99 (n = 39), Interfant-06 (n = 35), and ALLIC-BFM'2009 (n = 19). The 5-year event-free survival probability (EFSp) was 31.9(standard error [SE] 4.6)% for the entire population, with a significant difference among risk groups according to Interfant-06 criteria (P = .0029). KMT2A-rearrangement status was the strongest prognostic factor (P = .048), independently of the protocol strategy. The median time for relapse was 24.1 months for patients with minimal residual disease (MRD)-negative versus 11.5 months for those with MRD-positive (P = .0386). EFSp and cumulative relapse risk probability (CRRp) were similar. Interfant protocols showed comparable induction (8.1% vs 7.1%, P = .852) and complete remission mortality (21.6% vs 28.6%, P = .438), failing to reduce the relapse rate (48.5% vs 30.7%, P = .149). CONCLUSIONS: Interfant protocols and BFM-based protocols presented comparable results. The risk group stratification proposed by Interfant-06 was validated by our results, and MRD seems useful to identify patients with an increased risk of early relapse.

Leucemia linfoblástica aguda en niños con síndrome de Down: análisis comparativo con pacientes sin síndrome de Down / Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome

Introducción: Los niños con síndrome de Down (SD) tienen mayor frecuencia de leucemia linfoblástica aguda (LLA) y menor supervivencia que pacientes sin síndrome de Down (NSD). Analizamos las características clínicas, demográficas-biológicas y respuestas al tratamiento en SD-LLA versus NSD-LLA. Pacientes y métodos: Pacientes (0-19 años) con LLA desde enero de 1990 a noviembre de 2016. Se compararon características demográficas biológicas y respuestas al tratamiento con chi cuadrado y Wilcoxon rank sum. La supervivencia global y el intervalo libre de eventos (ILE) se analizaron con Kaplan-Meier y el test log-rank. Resultados: Se incluyeron 1795 pacientes, 54 con SD. Los SD-LLA presentaron edad mayor (p= 0,0189). T odos inmuno fenotipo precursor-B, con menor incidencia de anomalías recurrentes (p < 0,0001). Demostraron mejor tasa de respuesta a prednisona (p= 0,09) y mayor mortalidad en inducción y remisión completa (p < 0,0001). Todas las muertes de los SD-LLA fueron relacionadas con el tratamiento. La sobrevida libre de eventos en niños SD-LLA vs.NSD-LLA fue 47 (± 8)% vs. 73 (± 1)% (p= 0,006) y el ILE de los SD-LLA vs. NSD-LLA fue 54 (± 9)% vs. 75 (± 1)% (p= 0,0297). La tasa de recaídas fue similar en ambos grupos (p= 0,6894). El ILE de los SD-LLA fue menor en el grupo de 6-9 años: 39 (± 19)% (p= 0,7885). Conclusiones: Los niños de 6-9 años con SD-LLA años presentó menor sobrevida. Aunque estos niños presentaron una mejor respuesta temprana, la sobrevida libre de eventos e ILE fueron menores debido a la mortalidad relacionada con el tratamiento.

Introduction. Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS-ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the χ² and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. Results. 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (± 8%) versus 73% (± 1%) (p= 0.006) and the EFI was 54% (± 9%) versus 75% (± 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6-9 years: 39% (± 19%) (p= 0.7885). Conclusions. A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality.

Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome. / Leucemia linfoblástica aguda en niños con síndrome de Down: análisis comparativo con pacientes sin síndrome de Down.

INTRODUCTION: Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS-ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the χ² and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. RESULTS: 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (± 8%) versus 73% (± 1%) (p= 0.006) and the EFI was 54% (± 9%) versus 75% (± 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6-9 years: 39% (± 19%) (p= 0.7885). CONCLUSIONS: A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality.

Introducción: Los niños con síndrome de Down (SD) tienen mayor frecuencia de leucemia linfoblástica aguda (LLA) y menor supervivencia que pacientes sin síndrome de Down (NSD). Analizamos las características clínicas, demográficas-biológicas y respuestas al tratamiento en SD-LLA versus NSD-LLA. Pacientes y métodos: Pacientes (0-19 años) con LLA desde enero de 1990 a noviembre de 2016. Se compararon características demográficas biológicas y respuestas al tratamiento con chi cuadrado y Wilcoxon rank sum. La supervivencia global y el intervalo libre de eventos (ILE) se analizaron con Kaplan-Meier y el test log-rank. Resultados: Se incluyeron 1795 pacientes, 54 con SD. Los SD-LLA presentaron edad mayor (p= 0,0189). Todos inmuno fenotipo precursor-B, con menor incidencia de anomalías recurrentes (p < 0,0001). Demostraron mejor tasa de respuesta a prednisona (p= 0,09) y mayor mortalidad en inducción y remisión completa (p < 0,0001). Todas las muertes de los SD-LLA fueron relacionadas con el tratamiento. La sobrevida libre de eventos en niños SD-LLA vs.NSD-LLA fue 47 (± 8)% vs. 73 (± 1)% (p= 0,006) y el ILE de los SD-LLA vs. NSD-LLA fue 54 (± 9)% vs. 75 (± 1)% (p= 0,0297). La tasa de recaídas fue similar en ambos grupos (p= 0,6894). El ILE de los SD-LLA fue menor en el grupo de 6-9 años: 39 (± 19)% (p= 0,7885). Conclusiones: Los niños de 6-9 años con SD-LLA años presentó menor sobrevida. Aunque estos niños presentaron una mejor respuesta temprana, la sobrevida libre de eventos e ILE fueron menores debido a la mortalidad relacionada con el tratamiento.

Second Neoplasms in Children Following a Treatment for Acute Leukemia and/or Lymphoma: 29 Years of Experience in a Single Institution in Argentina.

INTRODUCTION: Childhood acute leukemias (AL) and lymphomas achieve good survival rates. However, second neoplasms (SN) are a devastating event. METHODS: From August 1987 to December 2016, 34 of 3321 (1%) patients with diagnosis of AL or lymphoma developed SN. SN were AL (n=16), CNS tumors (n=5), endocrinal tumors (n=3), lymphomas (n=2), schwannoma (n=2) assorted sarcomas (n=4), retinal melanoma (n=1), and Vanek tumor (n=1). Median latency was 51 (range, 10 to 110) months for hematological malignancies and 119 (range, 25 to 236) months for solid tumors (P=0.001). RESULTS: A total of 33 patients with SN were treated taking into account cumulative doses of anthracyclines and radiotherapy. Twenty-three (67.6%) patients achieved complete remission (CR), 5 died early during therapy and 5 were refractory or partial responders. Six patients presented relapses of the SN and 1 died in CR. Seventeen patients remain alive in CR, with a median follow-up of 110 (range, 4 to 276) months. CONCLUSIONS: (1) The latency period was significantly longer for patients developing solid tumors than for those developing AL. (2) AL was the most frequent SN. (3) Our results strongly encourage giving standard therapy to SN, considering cumulative doses of previous treatment, since similar probabilities of surviving as "de novo" counterparts can be achieved.

Experience with four consecutive BFM-based protocols for treatment of childhood with non-promyelocytic acute myeloblastic leukemia in Argentina.

Childhood acute myeloid leukemia (AML) achieves event-free-survival (EFS) rates of ∼50%. Double induction phase has been introduced for improving these results. Four consecutive protocols for AML treatment were evaluated to assess the impact of the addition of a second induction course in our setting. From January 1990 to January 2014, 307 evaluable AML patients were accrued. They were classified into low-risk (LR) and high-risk (HR) according to cytogenetic/molecular findings and response on day 15. The first two studies administered one induction cycle while the latter two protocols administered double induction. Relapse was the most frequent event and early-deaths were reduced by 50% in the last protocol. Statistically significant differences were observed when comparing EFS in LR and HR groups. Patients from both risk-groups who received double induction achieved significantly better outcome. EFS improved in protocols with double induction and early-deaths rate was decreased. Cytogenetic/molecular features and early-response were confirmed as prognostic factors.

Prognostic impact of t(1;19)/ TCF3-PBX1 in childhood acute lymphoblastic leukemia in the context of Berlin-Frankfurt-Münster-based protocols.

Historically, t(1;19)(q23;p13.3) has been related to pre-B acute lymphoblastic leukemia (ALL) and associated with a poor prognosis. Current treatments have overcome this dismal outcome, but advantages in survival for the unbalanced group have been reported. We compared the outcome of balanced and unbalanced der(19)t(1;19) cases and also patients with t(1;19)/TCF3-PBX1 versus patients without this translocation, to assess its prognostic value. From January 1990 to December 2010, t(1;19)(q23;p13)/TCF3-PBX1 was detected in 48 cases. Patients were treated with Berlin-Frankfurt-Münster (BFM)-based protocols and classified into balanced (n = 17) and unbalanced (n = 23) groups. The probability of event-free survival (pEFS) (standard error) of patients with t(1;19)/TCF3-PBX1 was 85% (6%), for the unbalanced group 78% (10%), and 88% (8%) for the balanced. The pEFS of patients with t(1;19)/TCF3-PBX1 was significantly superior to that of patients without t(1;19)/TCF3-PBX1 (p-value <0.0001). Patients with t(1;19)/TCF3-PBX1 presented a good outcome with no differences between balanced and unbalanced subgroups. Thus, risk-adjustment therapy would not be necessary for cases with t(1;19)/TCF3-PBX1.

No advantage of a rotational continuation phase in acute lymphoblastic leukemia in childhood treated with a BFM back-bone therapy.

BACKGROUND: Our aim was to compare two different schedules of maintenance in pediatric acute lymphoblastic leukemia (ALL) treated with a BFM-based therapy, in a randomized study: an Arm with 6-MP + MTX (with or without vincristine and dexamethasone pulses) versus a more intensive continuation phase. PROCEDURE: From January 1996 to November 2002, 429 eligible children with ALL were enrolled in a protocol with BFM-based back-bone, followed by a randomized continuation phase in standard (SRG) and intermediate (IRG) risk groups. Patients were randomized between Arms A and B for SRG and B or C for IRG. Arms A and C consisted of 6-MP and MTX and in Arm C, six pulses of VCR and dexamethasone were added. Arm B combined four pairs of drugs rotated weekly. All risk-groups received maintenance until completing 2 years of therapy from diagnosis. RESULTS: With a median follow-up of 138 (range: 96-178) months, the overall pEFS (SE) was 72 (6)% for all patients and the different risk groups showed: SRG: 85 (3)%, IRG: 71 (1)%, and HRG: 42 (7)% (P-value ≤ 0.0001). The pDFS (SE) according to the assigned arm of maintenance was, for Arm A: 89 (3)% and for Arm B: 85 (4)% in SRG, and, for Arm B: 77 (4)% and for Arm C: 75 (4)% in IRG, at 10 years follow-up. There were no statistically significant differences in outcome between arms of maintenance for both risk groups. CONCLUSIONS: In protocols with initial BFM-based strategy, a more intensive continuation phase did not benefit any risk group of patients.

Complex chromosome 8;21 translocation with associated hyperdiploidy in acute myeloid leukemia (FAB-M2).

We present a case of acute myeloblastic leukemia (AML-M2) with a complex t(8;21) translocation and additional acquired chromosomes yielding a hyperdiploid karyotype. AML1/ETO transcript was observed by reverse transcription-polymerase chain reaction. Fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), and comparative genomic hybridization (CGH) were performed to further identify the chromosomes observed by G banding. The patient was treated according to our current protocol for AML. He remains in complete remission +11 months from diagnosis. Further follow-up of this patient and the analysis of a larger number of children are needed to define whether the gains of the specific extra chromosomes modify the good prognosis that t(8;21) confers to this subgroup of AML.

Acute leukemia of dendritic cell lineage in childhood: incidence, biological characteristics and outcome.

CD4+ CD56+ malignancies have only recently been related to dendritic cell (DC) lineage. The few cases described, mostly adults and elderly, typically present with cutaneous lesions, followed by disseminated tumor localizations within a few months, with a generally very aggressive course and fatal outcome, despite the different therapeutic approaches employing chemotherapy and/or radiotherapy. Considering that leukemias in childhood and in adults are different diseases, we describe three pediatric cases to help compare the biological characteristics, immunophenotype, clinical features, treatment response and incidence of this disease in both age groups. From a total 1363 new patients with acute leukemia (AL), we report three cases with blasts of French - American - British L2 morphology, an absence of the most specific markers for myeloid, T or B lineage and lacking CD34, which led us to evaluate the blasts with an extensive panel of antibodies, including those related to the other putative pathways of lymphoid differentation: natural killer and DC. The cells expressed CD4, CD56, HLA-DR, BDCA-2 and BDCA-4. None of our cases presented with skin involvement. All three children showed good response to acute lymphoblastic leukemia (ALL) protocols, achieving complete remission even when one of the patients relapsed and received an allogeneic transplant. These findings, in spite of the small number of patients, suggest that the clinical course in children might be less aggressive, and that regular ALL protocols would be effective. We emphasize the importance of including antibodies for DC lineage in cases of CD34(-) unclassifiable AL to further characterize these rare cases (0.22%), considering that the tumor cell affiliation to DC lineage relies exclusively on immunophenotypic criteria.

Caracterización molecular en leucemia linfoblástica aguda pediátrica en una institución hospitalaria / Pediatric lymphoblastic leukemia molecular charactherization in a single institution

Si bien los rearreglos moleculares y alteraciones citogen éticas se encuentran entre los factores pronósticos demayor relevancia en leucemia linfoblástica aguda (LLA) pediátrica, en Argentina el acceso a estas eterminaciones se encuentra limitado en el ámbito hospitalario. Las alteraciones gen éticas más frecuentes en esta patología son TEL-AML1, E2A-PBX1, BCR-ABL y MLL-AF4. La detección de estos rearreglos por RT-PCR ofrece gran sensibilidad, siendo especialmente importante en translocaciones crípticas (como TEL-AML1), sólo detectables por técnicas moleculares (PCR ó FISH). Entre Diciembre-O2 y Septiembre-O5 ingresaron en el Hospital de Pediatría Garrahan 151 niños (M:84/F:67) con diagnóstico de LLA. De ellos, 136 fueron mayores y 15 menores de un año de edad. La búsqueda por RT-PCR de los 4 rearreglos mencionados se realizó en 129/151 pacientes (85,4 porciento). El ARN de células mononucleares de la muestra diagnóstica fue retrotranscripto utilizando hexámeros al azar, y se realizaron las PCR correspondientes a cada rearreglo utilizando los primers y las condiciones descriptos en el protocolo BIOMED-1. Los resultados fueron los siguientes: TEL-AML1: 15(11,6 porciento); E2A-PBX1: 5(3,9 porciento); MLL-AF4: 11(8,5 porciento); BCR-ABL: 2(1,6 porciento); negativo para los 4 rearreglos: 92(71,3porciento); positivo para otros rearreglos: 4(3,1porciento). El estudio molecular confirmó la caracterización citogenética convencional (CC) en 11 casos y la amplió en otros 22: 15 TEL-AML1, 1 E2A-PBX1, 5 MLL-AF4 y 1 BCR-ABL. Sólo una t(1;19) observada por CC no demostró el rearreglo E2A-PBX1 característico. En conclusión, el diagnóstico molecular de LLA aumenta la detección de anomalías contribuyendo a una mejor caracterización de las leucemias. Su incorporación y estandarización en el ámbito público son fundamentales para optimizar la estratificación de los pacientes de acuerdo al grupo de riesgo con la consiguiente adecuación del tratamiento.

Caracterización molecular en leucemia linfoblástica aguda pediátrica en una institución hospitalaria / Pediatric lymphoblastic leukemia molecular charactherization in a single institution

Si bien los rearreglos moleculares y alteraciones citogen éticas se encuentran entre los factores pronósticos demayor relevancia en leucemia linfoblástica aguda (LLA) pediátrica, en Argentina el acceso a estas eterminaciones se encuentra limitado en el ámbito hospitalario. Las alteraciones gen éticas más frecuentes en esta patología son TEL-AML1, E2A-PBX1, BCR-ABL y MLL-AF4. La detección de estos rearreglos por RT-PCR ofrece gran sensibilidad, siendo especialmente importante en translocaciones crípticas (como TEL-AML1), sólo detectables por técnicas moleculares (PCR ó FISH). Entre Diciembre-O2 y Septiembre-O5 ingresaron en el Hospital de Pediatría Garrahan 151 niños (M:84/F:67) con diagnóstico de LLA. De ellos, 136 fueron mayores y 15 menores de un año de edad. La búsqueda por RT-PCR de los 4 rearreglos mencionados se realizó en 129/151 pacientes (85,4 porciento). El ARN de células mononucleares de la muestra diagnóstica fue retrotranscripto utilizando hexámeros al azar, y se realizaron las PCR correspondientes a cada rearreglo utilizando los primers y las condiciones descriptos en el protocolo BIOMED-1. Los resultados fueron los siguientes: TEL-AML1: 15(11,6 porciento); E2A-PBX1: 5(3,9 porciento); MLL-AF4: 11(8,5 porciento); BCR-ABL: 2(1,6 porciento); negativo para los 4 rearreglos: 92(71,3porciento); positivo para otros rearreglos: 4(3,1porciento). El estudio molecular confirmó la caracterización citogenética convencional (CC) en 11 casos y la amplió en otros 22: 15 TEL-AML1, 1 E2A-PBX1, 5 MLL-AF4 y 1 BCR-ABL. Sólo una t(1;19) observada por CC no demostró el rearreglo E2A-PBX1 característico. En conclusión, el diagnóstico molecular de LLA aumenta la detección de anomalías contribuyendo a una mejor caracterización de las leucemias. Su incorporación y estandarización en el ámbito público son fundamentales para optimizar la estratificación de los pacientes de acuerdo al grupo de riesgo con la consiguiente adecuación del tratamiento.(AU)