Estrella Carrillo

Clinical Prognostic Factors for Survival and Risk of Progression to Acute Myeloid Leukemia in Patients With Myelodysplastic Syndromes With 10% Marrow Blasts and Non-Unfavorable Cytogenetic Categories

UNLABELLED Prognosis of myelodysplastic syndromes (MDS) is an area of ongoing interest. Identification of patients with poor outcome in the categories of lower risk disease is critical. In this study, we classify a cohort of 332 lower risk MDS into 3 groups with differences in survival and risk for leukemic progression that could drive treatment approaches to improve prognosis in a fraction of these patients. BACKGROUND Prognosis of MDS and particularly in patients categorized as lower risk (< 10% blasts or low and intermediate-1 International Prognostic Scoring System [IPSS]) is very heterogeneous and includes patients with very different outcomes with current scoring systems. Recently, a new cytogenetic classification has been proposed for the revised IPSS in predicting the outcome for MDS. PATIENTS AND METHODS To evaluate the prognostic significance of multiple variables for survival and risk of progression to acute myeloid leukemia, we analyzed baseline characteristics of 332 lower risk MDS patients within the lower risk cytogenetic categories by IPSS and the recent proposal for the new cytogenetic classification. RESULTS In multivariate analysis, severity of cytopenias, age > 60 years, bone marrow blasts (5%-9%) and transfusion dependency significantly influenced outcome. The combination of these variables allowed development of a model which categorizes patients in 3 different groups with median survival of 95, 44, and 13 months for groups 1, 2, and 3, respectively (P < .001). In addition, this score also stratified patients for their risk for leukemic progression, estimated at 2 years in 3.1%, 7.6%, and 21.3% for each group (P = .024). CONCLUSION Although karyotype remains the main prognostic factor in MDS, the current study identifies clinical parameters predicting outcome among patients with the better cytogenetic profile. Degree of cytopenias, blasts 5%-9% and transfusion dependence might identify a subset of patients within the nonadverse karyotype, in which early or more aggressive approaches could possibly be required to improve survival or prevent disease progression.

The presence of genomic imbalances is associated with poor outcome in patients with burkitt lymphoma treated with dose-intensive chemotherapy including rituximab

The introduction of Rituximab has improved the outcome and survival rates of Burkitt lymphoma (BL). However, early relapse and refractoriness are current limitations of BL treatment and new biological factors affecting the outcome of these patients have not been explored. This study aimed to identify the presence of genomic changes that could predict the response to new therapies in BL. Forty adolescent and adult BL patients treated with the Dose‐Intensive Chemotherapy Including Rituximab (Burkimab) protocol (Spanish Programme for the Study and Treatment of Haematological Malignancies; PETHEMA) were analysed using array‐based comparative genomic hybridization (CGH). In addition, the presence of TP53, TCF3 (E2A), ID3 and GNA13 mutations was assessed by next‐generation sequencing (NGS). Ninety‐seven per cent of the patients harboured genomic imbalances. Losses on 11q, 13q, 15q or 17p were associated with a poor response to Burkimab therapy (P = 0·038), shorter progression‐free survival (PFS; P = 0·007) and overall survival (OS; P = 0·009). The integrative analysis of array‐CGH and NGS showed that 26·3% (5/19) and 36·8% (7/19) of patients carried alterations in the TP53 and TCF3 genes, respectively. TP53 alterations were associated with shorter PFS (P = 0·011) while TCF3 alterations were associated with shorter OS (P = 0·032). Genetic studies could be used for risk stratification of BL patients treated with the Burkimab protocol.

To freeze or not to freeze peripheral blood stem cells prior to allogeneic transplantation from matched related donors.

The standard practice in allogeneic stem cell transplant (alloSCT) is to infuse peripheral blood stem cells (PBSC) the same day or the day after collection once the patient has received conditioning regimen. To obtain and freeze PBSC prior to SCT would be desirable to get a better logistic and to confirm the quality of the product. Unfortunately, studies comparing both approaches are lacking.

Intermediate doses of cytarabine plus granulocyte–colony‐stimulating factor as an effective and safe regimen for hematopoietic stem cell collection in lymphoma patients with prior mobilization failure

High‐dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available.

Improvement Over the Years of Long-Term Survival in High-Risk Lymphoma Patients Treated with Hematopoietic Stem Cell Transplantation as Consolidation or Salvage Therapy

The role of hemopoietic stem cell transplantation (HSCT) is not well established in certain types of lymphoma, such as those with a high relapse risk or relapsing after initial therapy. New chemotherapeutic schemes and immunotherapy have improved survival of these patients. Nevertheless, there is not enough evidence regarding whether transplantation is the best therapeutic approach. Moreover, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 177 consecutive patients diagnosed with a high risk of relapse or with relapsed lymphoma who underwent HSCT after induction with standard chemotherapy in a tertiary academic center from 1989 to 2013. The median age was 40 years. Diagnoses were Hodgkin disease (n = 56), diffuse large B-cell lymphoma (n = 44), follicular lymphoma (n = 29), mantle cell lymphoma (n = 15), T-cell lymphoma (n = 18), and others (n = 15). Patients received either an autologous graft (n = 154) in first complete remission (1CR; n = 59) or more advanced stages (AS; n = 95), or an allogeneic graft (n = 23) in 1CR (n = 4) or AS (n = 19). In the autologous group, overall survival (OS) at 5 years was 57% and 75% in the periods 1989-2001 and 2002-2013, respectively (P = .05). Patients receiving an allogeneic graft presented an OS of 25% and 43% in the 2 periods. With a mean follow-up of 5 years (95% confidence interval 3.5-6.6), for patients receiving a transplant in 1CR, OS at 5 years was 80%, and for those receiving a transplant in AS it was 59% (P = .003). Nonrelapse mortality (NRM) at 5 years was 3.1% in the autologous group and 27.9% in the allogeneic group (P < .001). The main cause of NRM was infection (44%) in the whole cohort. All this leads to the conclusion that transplantation, as a therapeutic strategy, has shown a high long-term OS in this subgroup of patients with such a poor prognosis. OS improved over the years and reaching 1CR was a good prognostic feature. Infections were the main cause of NRM.

MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo-HSCT response and prognostic factor of MLL 3′ region mRNA expression

MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected genes expression, in this work, we have studied a cohort of 20 MLL‐rearranged acute myeloid leukemia (AML).

KIT D816V− chronic myelomonocytic leukemia progressing to KIT D816V+ associated to mast cell leukemia responding to allogeneic hematopoietic cell transplantation

Dear Editor, A 63-year-old male was diagnosed with a chronic myelomonocytic leukemia (CMML) type 1, with normal karyotype and an IgG-kappa monoclonal gammopathy of undetermined significance (MGUS). Blood cell counts showed the following: hemoglobin, 86 g/L; leucocytes, 8.2 × 10/L (neutrophils, 3.7 × 10/L; monocytes 1.4 × 10/L); and platelets, 199 × 10/L. A splenomegaly of 14 cm by ultrasound was observed. Qualitative and quantitative assessment of KIT D816V by realtime polymerase chain reaction (RT-PCR) was negative. Nextgeneration sequencing (NGS) by using PGM sequencer (Ion TorrentTM) was performed including 19 candidate genes (The Ion AmpliSeqTM AML Cancer Research Panel): CEPBA, DNMT3A, GATA2, TET2, TP53, ASXL1, BRAF, CBL, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, PTPN11, RUNX1,WT1. No additional mutations were identified. After 8 months, the patient’s condition rapidly deteriorated. An abdominal ultrasound demonstrated splenomegaly 30 cm. Laboratory test showed the following: hemoglobin, 78 g/L; leukocytes, 12.3 × 10/L (neutrophils, 9.5 × 10/L; monocytes, 1.4 × 10/L); platelets, 34 × 10/L; serum IgGmonoclonal protein, 1.3 g/dl; serum tryptase, 84 mcg/L (N, 1–15 mcg/ L). Progression of CMML was suspected. The bone marrow (BM) aspirate was normocellular. Additionally, the presence of 25% of atypical mast cells was noted, with scattered clusters on the edges of the films (Fig. 1a). These cells showed a wide morphological variability, sometimes spindle-shaped and occasionally with a pseudopodium formation (Fig. 1b). Nuclei were oval-shaped, lobed, or multinucleated (Fig. 1c). Cells contained azurophilic granules ranging from agranular to hypergranular and vacuoles were occasionally observed (Fig. 1c). Isolated images of hemophagocytosis by mast cells were seen (Fig. 1d). Five percent of leukemic cells showed morphological differences, similar to atypical basophils with hypogranularity. Cytochemical studies showed periodic acid–Schiff positivity and intense metachromasia on toluidine blue staining (Fig. 1e). No evidence of CMML progression was noted. Flow cytometry identified a high forward scatter and intermediate side scatter population CD117/CD203c/ CD123/HLA-DR/CD38/CD25/CD2. In addition, 2.5% pathological plasma cells were observed. Cytogenetic testing revealed a normal karyotype. The presence of KIT D816V mutation was demonstrated in selected cell populations separated by FACSAria: mast cells, CD34+ cells, monocytes, granulocytes, and lymphocytes. BCR/ABL was negative by interphase fluorescence in situ hybridization. KIT D816V mutation was again confirmed in both, mast cells and granulocytes by NGS, without other additional mutations. Aleukemic variant of mast cell leukemia (MCL) with associated CMML and MGUS was diagnosed. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-017-3187-3) contains supplementary material, which is available to authorized users.