María Elena Cabrera

Chlamydophila Psittaci Eradication With Doxycycline As First-Line Targeted Therapy for Ocular Adnexae Lymphoma: Final Results of an International Phase II Trial

PURPOSE The pathogenic association between Chlamydophila psittaci (Cp) and ocular adnexal marginal zone lymphoma (OAMZL) and the efficacy of doxycycline monotherapy have been investigated in retrospective series with variations in stage, management, and follow-up duration. To our knowledge, this is the first international phase II trial aimed at clarifying Cp prevalence and activity of first-line doxycycline in a homogeneous series of consecutive patients with newly diagnosed stage I OAMZL. PATIENTS AND METHODS Forty-seven patients were registered. Tumor tissue, conjunctival swabs, and peripheral blood from 44 patients were assessed for seven Chlamydiaceae infections by three polymerase chain reaction protocols. Thirty-four patients with measurable or parametrable disease were treated with doxycycline and assessed for chlamydial eradication and lymphoma response (primary end point). RESULTS Cp DNA was detected in biopsies of 39 patients (89%); no other Chlamydiaceae were detected. Twenty-nine patients had Cp DNA in baseline swabs and/or blood samples and were evaluable for chlamydial eradication, which was achieved in 14 patients (48%). Lymphoma regression was complete in six patients and partial in 16 (overall response rate, 65%; 95% CI, 49% to 81%); 11 had stable disease, and one had progressive disease. At a median follow-up of 37 months (range, 15 to 62 months), 20 patients remained relapse free (5-year progression-free survival [PFS] ± standard deviation, 55% ± 9%). Cp eradication was associated with improved response rate (86% v 47%; P = .02) and 5-year PFS (68% v 47%; P = .11). CONCLUSION Upfront doxycycline is a rational and active treatment for patients with stage I Cp-positive OAMZL. Lymphoma regression is consequent to Cp eradication, which can easily be monitored on conjunctival and blood samples. Prospective trials aimed at identifying more effective administration schedules for doxycycline are warranted.

Improved outcome for acute lymphoblastic leukemia in children of a developing country: Results of the Chilean National Trial PINDA 87

BACKGROUND The National Chilean Pediatric Oncology Group, PINDA, reports the first prospective, nonrandomized trial for acute lymphoblastic leukemia (ALL), using a modified version of the Berlin-Frankfurt-Munster protocol (ALL BFM 86). The aim of this study was to classify immunophenotypes, to decrease cranial irradiation, and to assess whether this protocol would improve the survival rate. PROCEDURE From June, 1987, to June, 1992, 444 unselected children were diagnosed with ALL. Of them, 425 were evaluable. Therapy was stratified by risk. Standard-risk (SR) and high-risk (HR) patients received protocols I, M, II, and maintenance therapy. Very-high-risk (VHR) patients received protocol E instead of protocol M. All patients received a prephase treatment consisting of prednisone and intrathecal methotrexate (MTX). HR and VHR patients received cranial irradiation (12-18 Gy). The following changes were made to the ALL BFM 86 protocol: in protocol M, MTX 1 g/m2 instead of 5 g/m2; in protocol E, citarabine 1 g/m2 instead of 2 g/m2; mithoxantrone and ifosfamide were substituted by teniposide and cyclophosphamide. RESULTS Immunophenotypes: pro-B-ALL, 14%; common ALL, 67.4%; pre-B-ALL, 4.3%; T-ALL, 10%; undifferentiated leukemia (AUL), 4.3%. The overall 5-year event-free survival (EFS) rate was 60% +/- 2% (SE). The 5-year EFS rate for each risk group was: SR 75%, HR 62%, VHR 28%, with a median follow-up of 6.5 years (range 4.5-9.5 years). The cumulative incidence of central nervous system (CNS) relapse was 5.4%. CONCLUSIONS We have been able successfully to perform a nationwide study. Our strategy to adapt the BFM protocol to our population of patients trial was effective in improving the EFS. The immunophenotype distribution is similar to that in other reported series.

Discordant clinical presentation and outcome in infant twins sharing a common clonal leukaemia.

We report the different presentation features and clinical outcome between two identical infant twins with acute lymphoblastic leukaemia with a shared clonal disease and MLL gene rearrangement. One twin relapsed and died, but the other is in complete remission >4 years after diagnosis. These data, and similar observations on other twin infants with leukaemia, suggest that despite a common clonal in utero, post‐natally these leukaemias can evolve independently, at different rates, in the twinned individuals, and that the usually fatal leukaemia associated with t(4;11) MLL gene rearrangement can be effectively treated when the leukaemic burden is small.

T-Cell Lymphomas in South America and Europe

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.

Role of radiotherapy in patients with early-stage diffuse large B-cell lymphoma of Waldeyer's ring in remission after anthracycline-containing chemotherapy.

Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyers ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.

Non-Hodgkin lymphoma in Chile: a review of 207 consecutive adult cases by a panel of five expert hematopathologists.

Abstract The distribution of subtypes of non-Hodgkin lymphoma (NHL) in Latin America is not well known. This Chilean study included 207 consecutive cases of NHL diagnosed at five cancer centers in the capital, Santiago, and one center in Viña del Mar. All cases were reviewed and classified independently by five expert hematopathologists according to the 2001 World Health Organization classification of NHL. A consensus diagnosis of NHL was reached in 195 of the 207 cases (94%). B-cell lymphomas constituted 88% of NHL, and diffuse large B-cell lymphoma (DLBCL, 38.5%) and follicular lymphoma (25.1%) were the most common subtypes. There was a high frequency of marginal zone B-cell lymphoma (10.3%), as well as of extranodal natural killer (NK)/T-cell lymphoma, nasal type (2.6%) and adult T-cell leukemia/lymphoma (0.5%). Extranodal presentation was seen in 74 of the 195 cases (38%) and the most common extranodal presentation was in the stomach (37.6%). The most common gastric lymphoma was DLBCL (54.5%) followed by mucosa-associated lymphoid tissue (MALT) lymphoma (41%). Overall, the frequency of NHL subtypes in Chile is between that reported in Western and Eastern countries, which is probably a reflection of the admixture of ethnicities as well as the environment and socioeconomic status of its population.

TRANSCRIPTOS DE FUSIÓN DEL GEN BCR/ABL EN PACIENTES CON LEUCEMIA MIELOIDE CRÓNICA

La anormalidad citogenetica mas comun en la leucemia mieloide cronica (LMC) es el cromosoma Philadelphia, producida por la t(9;22), cuya expresion molecular es el gen de fusion BCR-ABL, que codifica proteinas con actividad tirosinquinasa. Segun el punto de ruptura de los genes BCR o ABL se produce una proteina de fusion de 210-kD(p210) o 190-kD(p190). La presencia de este gen de fusion en pacientes con LMC tiene implicancia diagnostica. Con el proposito de detectar transcriptos de fusion del gen BCR/ABL en pacientes con leucemia mieloide cronica, procedentes de la IX Region de Chile, se estudiaron 14 muestras de sangre de 11 pacientes con LMC. A 2 de ellos, se les realizo seguimiento durante su tratamiento con Gleevec. Se aplico la tecnica de reaccion en cadena de la polimerasa con transcriptasa reversa (RT-PCR), usando una PCR en nido. Para la deteccion de los transcriptos de fusion p210 y p190 del gen BCR/ABL, se utilizaron 4 pares de iniciadores. En 9/14 muestras se detecto el transcripto de fusion p210 y en 5/14 los transcriptos de fusion p210 y p190. En los 2 pacientes en seguimiento, hubo desaparicion del transcripto p190, permaneciendo el transcripto p210. Estos resultados reafirman la importancia de detectar transcriptos de fusion BCR/ABL para el diagnostico y seguimiento durante el tratamiento de la LMC

International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

Pitfalls and major issues in the histologic diagnosis of peripheral T-cell lymphomas: Results of the central review of 573 cases from the T-Cell Project, an international, cooperative study

Peripheral T‐cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post‐thymic lymphoid cells at different stages of differentiation with different morphological patterns, phenotypes and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub‐classified using World Health Organization (WHO) 2008 criteria. In 2006 the International T‐Cell Lymphoma Project launched the T‐Cell Project, building on the retrospective study previously carried on by the network, with the aim to prospectively collect accurate data to improve knowledge on this group of lymphomas. Based on previously published reports from International Study Groups it emerged that rendering a correct classification of PTCLs is quite difficult because the relatively low prevalence of these diseases results in a lack of confidence by most pathologists. This is the reason why the T‐Cell Project requested the availability of diagnostic material from the initial biopsy of each patient registered in the study in order to have the initial diagnosis centrally reviewed by expert hematopathologists. In the present report the results of the review process performed on 573 cases are presented. Overall, an incorrect diagnosis was centrally recorded in 13.1% cases, including 8.5% cases centrally reclassified with a subtype eligible for the project and 4.6% cases misclassified and found to be disorders other than T‐cell lymphomas; 2.1% cases were centrally classified as T‐Cell disorders not included in the study population. Thus, the T‐Cell Project confirmed the difficulties in providing an accurate classification when a diagnosis of PTCLs is suspected, singled out the major pitfalls that can bias a correct histologic categorization and confirmed that a centralized expert review with the application of adequate diagnostic algorithms is mandatory when dealing with these tumours. Copyright

Linfoma relacionado a infección por virus de la inmunodeficiencia humana en un hospital público de Santiago, Chile

Background: Cancer is the third cause of death in patients infected with human immunodeficiency virus (HIV) and lymphoma is the most common type. Aim: To describe the clinical characteristics, histology, risk factors and prognosis of these patients, in a Chilean public hospital in Chile. Material and Methods: Records of 55 patients (45 males) aged between 23 and 67years with lymphoma and HIV positive serology, diagnosed between 1992-2008, were reviewed. Results: Six patients (11%) had Hodgkin lymphoma (HL) and the rest, non-Hodgkin lymphoma (NHL). B-cell phenotype constituted 83.7% of NHL cases. The most common subtypes of all the lymphoma were diffuse large B cell lymphoma in 24 cases (43.6%), Burkitt lym-phoma in 12 cases (21.8%), andplasmablastic lymphoma in 5 cases (9.1%). Thirty five patients (64%) underwent curative intended chemotherapy (CT) concomitantly with highly active antiretroviral therapy (HAART). Three year survival of the whole cohort was 27%. By multivariate analysis, the most important prognostic factors for long term survival, were complete responses to CT, (p < 0.01) and a low international prognostic index (IPI) score for NHL, (p = 0.01). HAART, histologic subtype and CD4 lymphocyte count at diagnosis, did not influence survival. Conclusions: The most important prognostic factors for HIV patients with lymphoma, were achieving CR with CT and low IPI score. Prognosis remains poor, even with HAART therapy.BACKGROUND Cancer is the third cause of death in patients infected with human immunodeficiency virus (HIV) and lymphoma is the most common type. AIM To describe the clinical characteristics, histology, risk factors and prognosis of these patients, in a Chilean public hospital in Chile. MATERIAL AND METHODS Records of 55 patients (45 males) aged between 23 and 67 years with lymphoma and HIV positive serology, diagnosed between 1992-2008, were reviewed. RESULTS Six patients (11%) had Hodgkin lymphoma (HL) and the rest, non-Hodgkin lymphoma (NHL). B-cell phenotype constituted 83.7% of NHL cases. The most common subtypes of all the lymphoma were diffuse large B cell lymphoma in 24 cases (43.6%), Burkitt lymphoma in 12 cases (21.8%), and plasmablastic lymphoma in 5 cases (9.1%). Thirty five patients (64%) underwent curative intended chemotherapy (CT) concomitantly with highly active antiretroviral therapy (HAART). Three year survival of the whole cohort was 27%. By multivariate analysis, the most important prognostic factors for long term survival, were complete responses to CT, (p < 0.01) and a low international prognostic index (IPI) score for NHL, (p = 0.01). HAART, histologic subtype and CD4 lymphocyte count at diagnosis, did not influence survival. CONCLUSIONS The most important prognostic factors for HIV patients with lymphoma, were achieving CR with CT and low IPI score. Prognosis remains poor, even with HAART therapy.