PH negative acute lymphoblastic leukemia in adolescents and young adults treated according a MRD adapted BFM ALL IC 2009 protocol: Argentine real-world data on 171 patients.

Intensified pediatric chemotherapy regimens to treat adolescents and young adults (AYA) patients with Philadelphia negative acute lymphoblastic leukemia (ALL) have been associated with better outcomes. The local BFM 2009-based scheme complements the risk stratification assessing the measurable residual disease (MRD) along the induction phase with increasing levels of sensitivity. The present retrospective multicenter analysis included 171 AYA (15-40 years) patients treated accordingly between 2013 and 2019. Ninety-one percent obtained morphological complete remission, 67% a negative (<0.1%) MRD at day 33 (TP1), and 78% a negative (<0.01%) MRD at day 78 (TP2). The overall survival (OS) and the event-free survival (EFS) at 2 years were 62%±4.1 and 55%±4.1, respectively. The OS and EFS were significant better for prednisone responders, who achieved <10% BM blast at day 15, a negative MRD at TP1 or at TP2, and for low-risk patients. Age ≤30 years and WBC <30×109/L, particularly among B-phenotype, were also associated with longer OS. In the multivariable analyses, TP1 MRD positive (OS HR 2.8, 95% CI 1.4-5.7, p=0.004; EFS HR 3.0, 95% CI 1.6-5.7, p=0.001) and at TP2 (OS HR 2.6, 95% CI 1.3-5.3, p=0.012; EFS HR 2.6, 95% CI 1.3-5.1, p=0.006) were independently associated with earlier events. Age >30 years was also associated with a shorter survival (HR 3.1, 95% CI 1.3-7.5, p=0.014). Therefore, those 68 patients ≤30 years with TP1/TP2 negative MRD depicted a longer OS (2 years 85%±4.8). Based on our real-world data, the pediatric-based scheme is feasible in Argentina associated with better outcomes for younger AYA patients who achieved negative MRD at day 33 and 78.

Clinical Outcomes of Patients With B-Cell Non-Hodgkin Lymphoma in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSE: Real-world evidence on non-Hodgkin lymphoma (NHL) management in Latin America is currently lacking. The objective of this study was to describe treatment characteristics and outcomes of NHL in Latin America. METHODS: A total of 2,967 patients with NHL with aggressive and indolent subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), and mucosa-associated lymphoid tissue (MALT) lymphoma, with incident or prevalent diagnosis between 2006 and 2015, were retrospectively identified using clinical charts registered in the Hemato-Oncology Latin America Observational Registry. Associations between treatment regimen and age at diagnosis with clinical outcomes within each subtype were estimated using Cox proportional hazard regression. RESULTS: Most patients with NHL received 1L chemoimmunotherapy, most commonly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with/without rituximab. Five-year survival rates were higher for MALT lymphoma (90.8%) and FL (87.6%) versus DLBCL (69.0%) and MCL (57.1%), with variations between countries. The median overall survival from first relapse for patients with DLBCL was 6.6 years, with lower risk of death for those diagnosed at age < 65 years (hazard ratio = 0.732; P = .0161). Patients achieved a longer median progression-free survival with 1L rituximab-CHOP (R-CHOP) versus CHOP or rituximab, cyclophosphamide, vincristine, and prednisone (RCVP) (7.7 v 3.0 or 1.8 years, respectively). Use of regimens other than R-CHOP was associated with a higher risk of death/progression for patients with DLBCL (rituximab, ifosfamide, carboplatin, and etoposide/ifosfamide, carboplatin, and etoposide) and FL (CHOP). There was no relationship between treatment prescribed and age at diagnosis with outcomes from first/second relapse in DLBCL and FL. CONCLUSION: Differences in treatment outcomes between NHL subtypes were observed, reflecting variations in NHL management and barriers to treatment access in Latin America. These data provide necessary evidence to understand NHL management in this region and highlight the need to improve treatment outcomes for these patients.

PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review.

It has been suggested that 1-2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

Novel EZH2 mutation in a patient with secondary B-cell acute lymphocytic leukemia after deletion 5q myelodysplastic syndrome treated with lenalidomide: A case report.

RATIONALE: The gene deletion (5)(q22q35) is reported in 10-20% of myelodysplastic syndrome (MDS) cases and is associated with response to lenalidomide and favorable prognosis. The authors report here a clinical case of MDS transformation to B-cell acute lymphocytic leukemia (B-ALL) with an associated accrual of an additional mutation following treatment with lenalidomide. PATIENT CONCERNS: A 69-year-old man presented with progressive anemia, normal white blood cell count, and thrombocytopenia consistent with MDS. He was administered lenalidomide for 27 months, then developed acute B-cell lymphocytic leukemia and acquired a previously unreported mutation in the gene enhancer of zeste homolog 2 (EZH2). DIAGNOSES: After 27 months of therapy with lenalidomide, a surveillance bone marrow aspiration (BMA) revealed 90% cellularity with persistent multilineage dysplasia and a population of blasts comprising 54% of all bone marrow elements by morphology, consistent with B-ALL, even though the patient was asymptomatic. Conventional karyotype showed no signs of del(5)(q22q35) MDS, however bone marrow next-generation sequencing (NGS) demonstrated the accrual of a nonsense mutation (c.211del pL71*) in exon 3 of EZH2. A confirmatory BMA yielded 70% blasts and clinical features indicative of B-ALL. INTERVENTIONS: Mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m × 4 doses) was administered for 21 days. OUTCOMES: A follow-up BMA was performed 2 months after mini-hyper-CVD therapy, showing dysplastic features with 25% ring sideroblasts, but no evidence of B-ALL. The patient is currently receiving monthly-low dose decitabine, ofatumumab, and dexamethasone, and is transfusion independent and asymptomatic after 7 cycles. LESSONS: The present study shows an extremely rare progression of del(5)(q22q35) MDS to B-ALL with accompanying NGS data and a newly described acquisition of an EZH2 frameshift mutation. This case highlights the importance of NGS as a diagnostic and surveillance tool for MDS.

[Chronic myelogenous leukemia: monitoring and predictors of a favorable response to treatment with imatinib]. / Leucemia mieloide crónica. Monitoreo y factores predictivos de una respuesta favorable en el tratamiento con imatinib.

The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.

Leucemia mieloide crónica: Monitoreo y factores predictivos de una respuesta favorable en el tratamiento con imatinib / Chronic myelogenous leukemia: monitoring and predictors of a favorable response to treatment with imatinib

La supervivencia a cinco años de los pacientes con leucemia mieloide crónica en fase crónica tratados con inhibidores de tirosina quinasa es superior al 90%. Existen escasos datos a nivel local. Esta información puede ser de interés, ya que el imatinib genérico se encuentra disponible en la región. El objetivo del presente estudio es proporcionar información del monitoreo y los resultados a largo plazo del tratamiento con imatinib fuera de un ensayo clínico controlado, así como analizar el valor predictivo de respuestas tempranas para el logro de respuesta molecular 4.0 y la detección de variables que puedan condicionar falla al tratamiento. Se incluyeron 106 pacientes tratados con imatinib 400 mg diarios como inhibidor de primera línea durante una mediana de 8.9 años IQR (5.8-11.7) entre junio del 2000 y diciembre del 2015. La supervivencia global fue de 93%. En la última evaluación, 74% de los pacientes continuaba recibiendo el imatinib inicial. La obtención de respuesta en los objetivos temporales específicos (6, 12 meses) se asoció con mayor supervivencia libre de falla: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 y mayor adquisición de respuesta molecular 4.0: OR 5.6 (IC 95% 1.6-19.0) p = 0.003; OR 5.3 (IC 95% 1.4-21.0) p = 0.006. Luego del prolongado seguimiento, el imatinib proporcionó altas tasas de respuesta y supervivencia. Se confirmó el valor pronóstico de la respuesta en momentos temporales específicos. Este estudio refuerza la importancia del monitoreo estandarizado en los puntos temporales conocidos, que debe continuar siendo un objetivo en Argentina.

The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.

Long-term follow-up of essential thrombocythemia patients treated with anagrelide: subgroup analysis according to JAK2/CALR/MPL mutational status.

BACKGROUND: Anagrelide represents a treatment option for essential thrombocythemia, although its place in therapy remains controversial. AIM: To assess the impact of mutational status in response rates and development of adverse events during long-term use of anagrelide. METHODS: We retrospectively evaluated 67 patients with essential thrombocythemia treated with anagrelide during 68 (4-176) months. RESULTS: Mutational frequencies were 46.3%, 28.3%, and 1.5% for JAK2V617F, CALR and MPL mutations. Anagrelide yielded a high rate of hematologic responses, which were complete in 49.25% and partial in 46.25%, without differences among molecular subsets. The rate of thrombosis during treatment was one per 100 patient-years, without excess bleeding. Anemia was the major adverse event, 30.3% at 5-yr follow-up, being more frequent in CALR(+) (P < 0.05). Myelofibrotic transformation developed in 14.9% (12.9%, 21%, and 12.5% in JAK2V617F(+), CALR(+), and triple-negative patients, respectively, P = NS) and those treated >60 months were at higher risk, OR (95% CI) 9.32 (1.1-78.5), P < 0.01, indicating the need for bone marrow monitoring during prolonged treatment. CONCLUSION: Although CALR(+) patients were at higher risk of developing anemia, anagrelide proved effective among all molecular subsets, indicating that mutational status does not seem to represent a major determinant of choice of cytoreductive treatment among essential thrombocythemia therapies.