Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts

Respuesta al tratamiento y pronóstico del linfoma de Hodgkin clásico en estadio avanzado y del linfoma/leucemia de Burkitt asociados a la infección por el virus de la inmunodeficiencia humana

El linfoma de Hodgkin (LH) y el linfoma-leucemia de Burkitt (LB) asociados a la infección por el virus de la inmunodeficiencia humana (VIH) se presentan en pacientes con un estado inmunológico menos deteriorado que el presente en otros tipos de linfoma. Los pacientes con infección por el VIH y linfoma han sido tratados tradicionalmente con pautas de quimioterapia (QT) no intensiva, principalmente debido a su estado inmunológico deteriorado, al riesgo de infecciones oportunistas (IO) y muertes durante el tratamiento, lo cual les ha conllevado un peor pronóstico. En la era del TARGA ha mejorado la supervivencia de los linfomas asociados a la infección por el VIH debido a la mejoría del estado inmunológico de los enfermos y del tratamiento de soporte. Ello ha animado a tratar a estos enfermos con las mismas pautas de QT empleadas en los pacientes no inmunodeprimidos. Con ellas y siempre que exista respuesta al TARGA y se administre el tratamiento de soporte adecuado cabe pensar que, en el LH y LB asociados a la infección por el VIH los mismos tratamientos administrados a pacientes no inmunodeprimidos sean aplicables y eficaces y que se puedan aplicar los mismos índices pronósticos empleados en pacientes no inmunodeprimidos y/o se puedan identificar factores pronósticos específicos. Aunque se considera que el esquema ABVD es la pauta de QT estándar en el tratamiento del LH, se dispone de poca información sobre los resultados de este enfoque terapéutico en los pacientes infectados por el VIH. El índice de Hasenclever (IPS) ha demostrado su utilidad para predecir el pronóstico en pacientes con LH en estadios avanzados y no asociados a inmunodepresión pero existen pocos estudios que analicen la utilidad de este índice en los pacientes con infección por el VIH. En el ámbito del LB, son muy escasos los estudios que comparen los esquemas no intensivos tipo CHOP con esquemas de tratamiento específico. Por otro lado, estudios preliminares con rituximab asociado a QT tipo CHOP o específica intensiva para el LB sugerían que este enfoque terapéutico era aplicable y eficaz en enfermos con LB asociado a la infección por el VIH. La presente tesis doctoral incluye estudios centrados en los resultados del tratamiento y pronóstico del LH clásico en estadio avanzado y LB asociados a la infección por el VIH. El primer estudio analizó retrospectivamente los resultados del tratamiento con ABVD y TARGA y la aplicabilidad del IPS en 62 pacientes con LH clásico en estadio avanzado e infección por el VIH. El tratamiento con ABVD y TARGA fue factible y eficaz y la respuesta inmunológica al TARGA se asoció a una mejor supervivencia global (SG) y supervivencia libre de enfermedad (SLE). Se observó una tendencia a una SG más prolongada en los pacientes con un IPS más bajo cuando se consideró el punto de corte de 3. En al ámbito del LB asociado a la infección por el VIH se realizó por un lado, un análisis retrospectivo que comparaba una serie de 31 pacientes tratados con CHOP, con o sin rituximab, con una serie de 44 pacientes tratados con dos protocolos consecutivos de QT específica e intensiva (PETHEMA-LAL3/97 y PETHEMALAL3/ LB-04). El tratamiento con QT específica intensiva fue factible, con una tasa de remisión más alta que la obtenida con los esquemas tipo CHOP y se observó una SG más prolongada en los pacientes que recibieron QT específica e intensiva. Por otro lado, un análisis conjunto de dos cohortes de pacientes tratados con el mismo protocolo en España (39 pacientes, protocolo BURKIMAB) y Alemania (42 pacientes, protocolo B-ALL/NHL2002) demostró que la inmunoquimioterapia específica intensiva adaptada a la edad fue factible, con una alta tasa de RC y baja tasa de recidivas. Sin embargo, la toxicidad fue relevante, en especial debida a infecciones y mucositis. Los factores pronósticos identificados con influencia negativa en la muerte en inducción, SG y SLE fueron el índice de ECOG>2, la cifra de linfocitos CD4 <200/μL y la afección de médula ósea, respectivamente. En definitiva, los resultados de los estudios de la presente Tesis Doctoral confirman la aplicabilidad y eficacia de los tratamientos convencionales para el LH y el LB en pacientes con infección por el VIH. Los factores pronósticos identificados en pacientes con inmunidad preservada son asimismo aplicables a los enfermos VIH-positivos.Human immunodeficiency virus (HIV) associated Hodgkin’s lymphoma (HL) and Burkitt’s lymphoma/leukemia (BL) arise in patients with less impaired immune function than in other types of lymphomas. These patients have been traditionally treated with non-intensive chemotherapy (QT) schedules, mainly due to their impaired immune function, the risk of opportunistic infections (OI) and early deaths under treatment, thereby explaining their poor outcome. In the highly active antiretroviral therapy (HAART) era, improvements have been observed in survival of patients with HIV infection and lymphomas, due to an improvement of their immunological status and a best supportive therapy. Thus, in recent years some groups treat these patients with the same QT schedules than those used in non-immunosuppressed patients. These treatments have proven to be effective and have allowed identifying the same prognostic factors as observed in non-immunosuppressed patients. Although ABVD is the standard QT schedule in HL treatment, there is scarce information about the results of this therapeutic approach in HIV infected patients. The Hasenclever score (IPS) is useful to predict prognosis in non-immunosuppressed patients with HL in advanced stages but the utility of this score in HIV infected patients is unclear. In BL there are scarce studies comparing non-intensive schedules like CHOP with specific treatments. On the other hand, preliminary results with rituximab together with CHOP-like or intensive and specific QT for BL suggested that this therapeutic approach is feasible and effective in patients with HIVassociated BL. This thesis includes studies on treatment and prognosis in HIV-associated advanced stage classical stage HL and BL. The first study analyzed retrospectively the results of treatment with ABVD together with HAART and the applicability of the IPS in 62 patients with HIV-related classical HL in advanced stage. This study showed that ABVD treatment together with HAART was feasible and effective and that the immunological response to HAART was associated with a better overall survival (OS) and disease-free survival (DFS). There was also a trend for a better OS in patients with IPS when the cut-off of score 3 was considered. Regarding to HIV-related BL two studies were conducted. The first study was a retrospective analysis comparing a series of 31 patients treated with CHOP schedule, with or without rituximab, with a series of 44 patients treated with two consecutive protocols of specific and intensive QT (PETHEMA-LAL3/97 y PETHEMA-LAL3/LB-04). Specific and intensive QT was feasible, with a remission rate higher and a better OS than that observed with CHOP schedule. The second study was an analysis of two cohorts of patients treated with the same protocol in Spain (39 patients, BURKIMAB trial) and Germany (42 patients, B-ALL/NHL2002 trial) and proved that age-adapted specific and intensive immunochemotherapy was feasible, with a high remission rate and low rate of relapse. Nevertheless, toxicity was relevant, especially infections and mucositis. The prognostic factors with a negative influence in induction death, OS and DFS were, ECOG score >2, CD4 lymphocyte counts <200/μL and bone marrow involvement, respectively. In conclusion, the results of the studies of the this thesis confirm the applicability and efficacy of conventional treatments for HL and BL in patients with HIV infection. Prognostic factors identified in patients with preserved immunity are also applicable in patients HIVpositive

Hidden myelodysplastic syndrome (MDS): A prospective study to confirm or exclude MDS in patients with anemia of uncertain etiology

[Introduction]: Diagnosis of myelodysplastic syndromes (MDSs) when anemia is the only abnormality can be complicated. The aim of our study was to investigate the primary causes of anemia and/or macrocytosis of uncertain etiology. [Methods]: We conducted a multicenter, prospective study over 4 months in three hematology laboratories. In step 1, we used an automated informatics system to screen 137 453 hemograms for cases of anemia and/or macrocytosis (n = 2702). In step 2, we excluded all patients whose anemia appeared to be due to a known cause. This left 290 patients had anemia of uncertain etiology. In step 3, we conducted further investigations, including a peripheral blood smear, and analysis of iron, vitamin B12, folate, and thyroid hormone levels. [Results]: A differential diagnosis was obtained in 139 patients (48%). The primary causes of anemia were iron deficiency (n = 59) and megaloblastic anemia (n = 39). In total, 25 hematologic disorders were diagnosed, including 14 patients with MDS (56%). The median age of MDS patients was 80 years, 12 had anemia as an isolated cytopenia, and most (n = 10) had lower‐risk disease (IPSS‐R ≤ 3.5). SF3B1 mutations were most frequent (n = 6) and correlated with the presence of ring sideroblasts (100%) and associated with better prognosis (P = 0.001). [Conclusions]: Our prospective, four‐step approach is an efficient and logical strategy to facilitate the diagnosis of MDS on the basis of unexplained anemia and/or macrocytosis, and may allow the early diagnosis of the most serious causes of anemia. Molecular analysis of genes related to MDS could be a promising diagnostic and prognostic approach.This work was also partially financed by the Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII) (PI 17/01741 from MDC and PI 17/01966 from JMB)