Outcome and toxicities associated to chemotherapy in children with acute lymphoblastic leukemia and Gilbert syndrome. Usefulness of UGT1A1 mutational screening.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood. Although intensive chemotherapy has improved survival in those patients, important side effects, including hyperbilirubinemia, are frequent. Gilbert syndrome (GS) is a frequent condition that causes a reduction in glucuronidation and intermittent hyperbilirubinemia episodes. This could provoke a greater exposure to some cytotoxic agents used in ALL, increasing the risk of toxicity. On the other hand, unexplained hyperbilirubinemia could lead to unnecessary modifications or even treatment withdrawals, which could increase the risk of relapse, but data regarding this in ALL pediatric population are scarce. METHODS: Retrospective study to analyze toxicity, outcome and treatment modifications related to GS in children diagnosed with ALL. RESULTS: A total of 23 of 159 patients were diagnosed with GS. They had statistically higher hyperbilirubinemias during all treatment phases (P < 0.0001) and a slower methotrexate clearance when it was administered during a 24-hr infusion at high doses (patients with GS: 74 hr ± 19 vs. patients without GS: 64 hr ± 8; P < .002). However, no relevant toxicity or delays in treatment were found in them. Finally, changes in treatment due to hyperbilirubinemia were only done in 5 patients with GS. CONCLUSIONS: Differences in outcome were not found in patients with GS. Universal screening for GS appears to be not necessary in pediatric patients with ALL. However, when hyperbilirubinemia is observed, it must be rule out in order to avoid unnecessary changes in treatment.

The transcriptional repressor HDAC7 promotes apoptosis and c-Myc downregulation in particular types of leukemia and lymphoma.

The generation of B cells is a complex process requiring several cellular transitions, including cell commitment and differentiation. Proper transcriptional control to establish the genetic programs characteristic of each cellular stage is essential for the correct development of B lymphocytes. Deregulation of these particular transcriptional programs may result in a block in B-cell maturation, contributing to the development of hematological malignancies such as leukemia and lymphoma. However, very little is currently known about the role of transcriptional repressors in normal and aberrant B lymphopoiesis. Here we report that histone deacetylase 7 (HDAC7) is underexpressed in pro-B acute lymphoblastic leukemia (pro-B-ALL) and Burkitt lymphoma. Ectopic expression of HDAC7 induces apoptosis, leads to the downregulation of c-Myc and inhibits the oncogenic potential of cells in vivo, in a xenograft model. Most significantly, we have observed low levels of HDAC7 expression in B-ALL patient samples, which is correlated with the increased levels of c-Myc. From a mechanistic angle, we show that ectopically expressed HDAC7 localizes to the nucleus and interacts with the transcription factor myocyte enhancer factor C (MEF2C) and the corepressors HDAC3 and SMRT. Accordingly, both the HDAC7-MEF2C interaction domain as well as its catalytic domain are involved in the reduced cell viability induced by HDAC7. We conclude that HDAC7 has a potent anti-oncogenic effect on specific B-cell malignancies, indicating that its deregulation may contribute to the pathogenesis of the disease.

Multiplex real-time PCR for prompt diagnosis of an outbreak of human parainfluenza 3 virus in children with acute leukemia.

INTRODUCTION: Human parainfluenza virus type 3 (HPIV-3) causes significant morbimortality in immunocompromised patients. Outbreaks of severe pneumonitis have been previously described in this setting. MATERIALS AND METHODS: Retrospective observational study in children diagnosed with acute leukemia and a documented HPIV-3 infection in the context of a nosocomial outbreak occurred in a single center. RESULT: During summer 2012, an HPIV-3 infection was detected in six hospitalized children with acute leukemia. All the patients had respiratory symptoms and one of them suffered from parotitis. CONCLUSION: Early diagnoses using multiplex real-time polymerase chain reaction (PCR) let us control this outbreak. A phylogenetic analysis confirmed person-to-person transmission of a single HPIV-3 variant.

Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene.

Acute myeloid leukemia (AML) with t(8;16)(p11;p13) (t(8;16) AML) has unique clinico-biological characteristics, but its microRNA pattern is unknown. We analyzed 670 microRNAs in seven patients with t(8;16) AML and 113 with other AML subtypes. Hierarchical cluster analysis showed that all t(8;16) AML patients grouped in an independent cluster. Supervised analysis revealed a distinctive signature of 94-microRNAs, most of which were downregulated, including miR-21 and cluster miR-17-92. The mRNA expression analysis of two known transcription factors of these microRNAs (STAT3 and c-Myc, respectively) showed significant downregulation of STAT3 (P=0.04). A bioinformatic analysis showed that 29 of the downregulated microRNAs might be regulated by methylation; we treated a t(8;16) AML sample with 5-aza-2'-deoxycytidine (5-AZA-dC) and trichostatin A and found that 27 microRNAs were re-expressed after treatment. However, there was no difference in methylation status between t(8;16) and other AML subtypes, either overall or in the microRNA promoter. Cross-correlation of mRNA and microRNA expression identified RET as a potential target of several microRNAs. A Renilla-luciferase assay and flow cytometry after transfection with pre-microRNAs confirmed that RET is regulated by miR-218, miR-128, miR-27b, miR-15a and miR-195. In conclusion, t(8;16) AML harbors a specific microRNA signature that is partially epigenetically regulated and targets RET proto-oncogene.

Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma.

AIM: To analyze toxicity, response and outcome of a phase II trial with intensive chemotherapy plus autologous stem-cell transplantation (ASCT) for young patients with peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Forty-one patients [30 males and 11 females, median age 47 years] consecutively diagnosed with PTCL received three courses of high-dose cyclophosphamide 2000 mg/m(2)/day, adriamycin 90 mg/m(2)/day, vincristine and prednisone alternating with three courses of etoposide, cisplatin, cytarabine and prednisone. Responders were submitted to ASCT. RESULTS: Sixty-eight percent of patients received the planned treatment. After chemotherapy, 20 patients reached complete response (CR), 4 partial response and 17 failed. ASCT was carried out in 17 of 24 candidates due to lack of mobilization (three cases), toxicity (two), early relapse and patient decision (one each). CR rate after treatment was 51%. With a median follow-up of 3.2 years, 5 of 21 CR patients relapsed and 2 died in CR due to secondary neoplasms. Four-year progression-free survival was 30%. Twenty-two patients have died, with a 4-year overall survival of 39%. International Prognostic Index was the main variable predicting survival. No differences were seen among the 24 candidates according to whether or not they underwent ASCT. CONCLUSION: This intensive regimen resulted in moderate CR rate, with manageable toxicity in PTCL. The contribution of ASCT in preventing relapse is debatable. Novel strategies to increase CR warrant investigation.

Predictive value of Follicular Lymphoma International Prognostic Index (FLIPI) in patients with follicular lymphoma at first progression.

BACKGROUND: Different prognostic scores have been proposed to predict the outcome of follicular lymphoma (FL) patients at diagnosis. A new prognostic index specifically addressing FL patients, the Follicular Lymphoma International Prognostic Index (FLIPI), has recently been developed, which might also be useful in patients with progression. PATIENTS AND METHODS: One hundred and three patients (55 male, 48 female; median age 59 years) with FL in first relapse/progression after an initial response to therapy (50 complete responders/ 53 partial responders) were included in the study. RESULTS: Five-year survival from progression (SFP) was 55% (95% confidence interval 44%-66%). The distribution according to the FLIPI at relapse was 39% good prognosis, 24% intermediate prognosis and 37% poor prognosis. Five-year SFP for these groups were 85%, 79% and 28%, respectively (P < 0.0001). Other variables at relapse with prognostic significance for SFP were age, presence of B symptoms, performance status, bulky disease, number of involved nodal sites, lactate dehydrogenase level, hemoglobin level, histological transformation, the Italian Lymphoma Intergroup prognostic index for FL and the International Prognostic Index for aggressive lymphomas. In the multivariate analysis bulky disease (P=0.01), presence of B symptoms (P=0.03) and FLIPI at relapse (P=0.0003) were the most important variables for predicting SFP. CONCLUSIONS: In patients with FL at first relapse/progression, the FLIPI, along with the presence of bulky disease and B symptoms, are features that predict SFP and thus could be useful to select candidates for experimental treatments.

Survival after progression in patients with follicular lymphoma: analysis of prognostic factors.

BACKGROUND: The purpose of this study was to identify prognostic parameters for patients with follicular lymphoma (FL) in first progression/relapse. These would be useful for selection of high-risk patients for inclusion in trials aimed at determining the effect of new treatment approaches in such patients. PATIENTS AND METHODS: Ninety patients (48 male, 42 female, median age 56 years) diagnosed with FL, in a single institution during a 20 year period and relapsing/progressing after an initial response to therapy, were recruited. The main end-point of the study was survival from progression (SFP). Univariate and multivariate analyses were performed, including among the predictive variables the response duration (RD) after the initial treatment and the main features of the patients at the first progression or relapse. RESULTS: Five-year SFP was 47% (95% confidence interval 35% to 58%). Patients with RD following initial therapy >2 years had a longer SFP (5-year SFP 63 versus 33%, P = 0.012). Other variables with prognostic interest for SFP were stage at diagnosis and the following variables at relapse: age, bulky disease, performance status, serum lactate dehydrogenase level, serum beta2-microglobulin level, bone marrow involvement, stage and International Prognostic Index rating. In the multivariate analysis, poor performance status at progression and a RD <2 years were the most important unfavorable variables to predict SFP. CONCLUSION: In patients with FL, RD along with performance status at progression are features that predict SFP. These variables could thus be useful to select candidates for experimental treatments.

Blastic natural killer cell leukemia/lymphoma presenting as overt leukemia.

Blastic natural killer (NK)-cell leukemia/lymphoma is a neoplasm of NK origin with aggressive behavior. The disease affects mainly elderly people and often presents with skin lesions and overt leukemia. Blastic morphology, an NK-cell immunophenotype, and lack of association with Epstein-Barr virus are the clues for the diagnosis. We report herein, the case of a patient with a blastic NK-cell leukemia/lymphoma with overt leukemia at diagnosis, who achieved a complete response after CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy. However, the patient relapsed a few months later and died due to disease progression. Cases of blastic NK-cell leukemia/ lymphoma previously reported are briefly reviewed.

Hybrid chemotherapy consisting of cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (C-MOPP/ABV) as first-line treatment for patients with advanced Hodgkin disease.

BACKGROUND: Combination chemotherapy, including hybrid regimens, is the standard treatment for patients with advanced Hodgkin disease (HD). Although a prolonged complete response (CR) is achieved in up to 70-80% of patients, long term complications, such as secondary leukemia, are of concern. Cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (C-MOPP/ABV) is a hybrid chemotherapy in which cyclophosphamide is substituted for mechlorethamine, an agent that has been implicated as the cause of secondary malignancies. METHODS: Seventy-three patients (37 males and 36 females; median age, 35 years) diagnosed with Stage III or IV HD or Stage II with bulky disease, B-symptoms, elevated erythrocyte sedimentation rate, or hilar adenopathy were treated with 8 courses of C-MOPP/ABV at a single institution during a 6-year period. Radiotherapy (RT) was administered when bulky disease or residual masses were present. Endpoints of the study were response to therapy, failure free survival (FFS), overall survival (OS), and toxicity. RESULTS: Sixty-five patients (90%) received the 8 planned courses, with 49 of them (70%) receiving the full prescribed doses. After chemotherapy, 57 patients (78%) reached CR. Seven additional patients who achieved partial response (PR) reached CR after complementary radiotherapy, with an overall CR rate of 88%. The median follow-up was 31 months. Twelve patients relapsed; the 4-year FFS was 66% (95% CI, 54-78%). Two patients died during treatment because of sepsis and four due to disease progression. The 4-year OS was 92% (95% CI, 86-98%). Age > 60 years and bone marrow involvement were related to severe infectious complications. No late toxicity was reported. CONCLUSIONS: C-MOPP/ABV induces CR with acceptable toxicity in a high proportion of advanced HD patients.

[Philadelphia chromosome-positive chronic myeloid leukemia in the elderly: presenting features, natural history and survival]. / Leucemia mieloide crónica cromosoma Filadelfia positivo en sujetos de edad avanzada: características iniciales, historia natural y supervivencia.

BACKGROUND: Among patients with chronic myeloid leukaemia (CML) old people represent a minority whose disease characteristics are not well known. The aim of the study was to analyze the presenting features, the evolutive course, and the survival of older persons with Ph-positive CML. PATIENTS AND METHODS: Forty-four individuals > 65 years diagnosed with Ph-positive CML in a single centre were compared with 292 younger patients. RESULTS: Comparison of the presenting features of chronic phase Ph-positive CML patients yielded the following significant differences: predominance of female sex (15 males/29 females versus 155/137; p = 0.02), higher proportion of patients with anaemic syndrome (12% versus 2%; p = 0.001), lower frequency of splenomegaly (41% versus 68%; p = 0.001), and higher serum levels of uric acid (p = 0.0006) in the older group. Although the latter patients survived significantly less (median survival 36.6 months, 95% CI: 27-46.2, versus 57.6 months, 95%: 51.2-64.1; p = 0.004), 9 of the 33 deaths registered in this group (27%) occurred in the chronic phase of CML, versus 15 (9%) of the 166 deaths in the younger group (p = 0.003). When chronic phase deaths were excluded and leukaemia-related deaths only considered (i.e., those occurring in the BC or the accelerated phase of CML), old patients still had a shorter survival but the difference was no longer significant. CONCLUSIONS: Ph-positive CML features are essentially the same in older and young individuals, since most of the differences observed are attributable rather to the patients' advanced age than to the leukaemia itself.

[Non-gastric mucosa-associated lymphoid tissue (MALT) lymphomas: analysis of 14 patients]. / Linfomas del tejido linfoide asociado a mucosas (MALT) de localización extragástrica: análisis de 14 casos.

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphomas are a well defined group of B-cell non-Hodgkin's lymphomas, that arise in a wide variety of extranodal sites, most frequently in the stomach and related to Helicobacter pylori infection. The aim of the present study was to analyze the presenting features, natural history and outcome in 14 patients with non-gastric MALT lymphoma. PATIENTS AND METHODS: The main clinical data, treatment and outcome were recorded for the 14 patients with non-gastric MALT lymphoma diagnosed at a single institution in a 12 year period. The median age was 68 years and 13 patients were females. Diagnosis was made according to the REAL classification criteria. RESULTS: The initial location was thyroid (3 patients), parotid (three), submaxilar gland (three), skin (two), Waldeyer's ring (one), breast (one), lung (one), small bowel (one), liver (one) and ovary (one). At diagnosis 3 patients had > or = 2 extranodal involved sites. Autoimmune disorders were present in 5 patients: Hashimoto's thyroiditis (three), Sjögren's syndrome (one) and both (one). Two patients had a poor performance status (ECOG > 1) and B-symptoms. Five patients (36%) were in stage IV, two of them because of bone marrow infiltration. All patients had a normal serum LDH level, and 5 had high beta 2-microglobulin level. The treatment consisted in surgical resection (2 patients), surgery and radiotherapy (one), surgery and chemotherapy (two), chemotherapy and radiotherapy (two) and chemotherapy alone (7 patients, three of them with doxorubicin-containing regimens). Twelve patients were evaluable for response. Complete response, partial response and failure rates were 75, 17 and 8%, respectively. Two of the 11 responders progressed, one of them with advanced stage disease. The actuarial 4-year disease-free survival was 77% (CI 95%: 47-100%). After a median follow-up of 3.4 years, 100% of the patients were alive. CONCLUSION: Non-gastric MALT lymphomas may be associated with autoimmune disorders, may present as disseminated disease and have a very good outcome.

Acute lymphoid leukemia following polycythemia vera.

The tendency to evolve into acute leukemia is a well-known characteristic of polycythemia vera (PV), which is shared with the remaining chronic myeloproliferative disorders and increases after the administration of cytotoxic agents. Acute transformation is usually of myeloid phenotype, whereas acute lymphoid leukemia (ALL) following PV is seldom observed. A 63-year-old woman is described who developed ALL at 6 years from the initial diagnosis of PV, for which she had received radioactive phosphorus and hydroxyurea. The ALL was of B-cell type, corresponding to the L-3 subtype of the FAB classification. Despite the administration of combination chemotherapy the patient died shortly after the diagnosis of acute leukemia. The present case adds to seven previously described patients with the above association, all of whom had received cytotoxic therapy for PV. Median interval from PV to ALL diagnosis was 10 years, and there was a predominance of the B-cell phenotype. The prognosis was poor since all but one of the patients had a short survival after ALL diagnosis. The possible etiological and pathogenetic link between PV and the subsequent ALL is discussed.