Dose-escalated CHOP and tailored intensification with IFE according to early response and followed by BEAM/autologous stem-cell transplantation in poor-risk aggressive B-cell lymphoma: a prospective study from the GEL-TAMO Study Group.

OBJECTIVES: The role of high-dose therapy and autologous stem-cell transplantation (HDT/ASCT) in the up-front treatment of poor-risk aggressive lymphoma is still unknown. We conducted a prospective multi-centre trial with dose-escalated CHOP (MegaCHOP) and tailored intensification prior to HDT/ASCT according to early response assessed by CT and gallium scan (Ga67S). PATIENTS AND METHODS: Eighty-six patients with newly diagnosed and Ga-67 avid aggressive B-cell lymphoma received MegaCHOP for three courses and were evaluated for response by CT and Ga67S. Patients with CT response and negative Ga67S received another MegaCHOP cycle followed by BEAM and ASCT. Those patients with positive Ga67S or without CT response received salvage treatment with two courses of ifosfamide and etoposide (IFE) followed, whenever response had been achieved, by BEAM and ASCT. RESULTS: Response rate before HDT/ASCT was 85% and, with 34 months of median follow-up, progression-free survival (PFS), overall survival (OS) and treatment-related mortality were 56%, 64% and 7%, respectively. For transplanted patients (81% of the whole series), PFS and OS were 67% and 74%, respectively. No different outcomes were observed between patients achieving an early negative Ga67S response treated with MegaCHOP and BEAM/ASCT and patients with mid-treatment positive Ga67S who received IFE prior BEAM/ASCT. CONCLUSIONS: This response-adapted strategy including early treatment modifications prior HDT/ASCT have yielded encouraging PFS and OS in patients with poor-risk B aggressive non-Hodgkin's lymphoma.

Mixedema grave como causa de transformación gelatinosa de la médula ósea reversible tras tratamiento tiroideo sustitutivo / Gelatinous transformation of bone marrow caused by severe myxedema reversing after thyroid hormone replacement therapy

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Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination.

B cell neoplasms present heterogeneous patterns of lymphoid organ involvement, which may be a result of the differential expression of chemokine receptors. We found that chemokine receptor (CCR)7, CXC chemokine receptor (CXCR)4, or CXCR5, the main chemokine receptors that mediate B cell entry into secondary lymphoid tissues and their homing to T cell and B cell zones therein, were highly expressed in B malignancies with widespread involvement of lymph nodes. Conversely, those pathologies with little or no nodular dissemination showed no expression to very low levels of CCR7 and CXCR5 and low to moderate levels of CXCR4. These findings provide evidence for the role of CCR7, CXCR4, and CXCR5 in determining the pattern of lymphoid organ involvement of B tumors. Functional studies were performed on B malignancies expressing different levels of CCR7, CXCR5, and CXCR4. Multiple myeloma (MM) cells did not express CCR7 nor CXCR5 and did not migrate in response to their ligands; a moderate expression of CXCR4 on MM cells was accompanied by a migratory response to its ligand, CXCL12. By contrast, cells from B cell chronic lymphocytic leukemia (B-CLL) expressed the highest levels of these chemokine receptors and efficiently migrated in response to all ligands of CCR7, CXCR4, and CXCR5. In addition, the migration index of B-CLL cells in response to both of the CCR7 ligands correlated with the presence of clinical lymphadenopathy, thus indicating that the high expression of functional chemokine receptors justifies the widespread character of B-CLL, representing a clinical target for the control of tumor cell dissemination.

The prevalence of hepatitis C virus infection in patients with non-Hodgkin's lymphoma.

AIM: Lymphomagenesis is a multifactorial process in which genetic, environmental and infectious factors can be involved. The aim of the present study was to assess the prevalence of hepatitis C virus (HCV) infection among patients with non-Hodgkin's lymphoma (NHL), and to compare it with that of a control group of voluntary blood donors. METHODS: All consecutive patients with a histological diagnosis of NHL from January 1996 to December 2001 were included in this prospective study. As control group for HCV infection, voluntary blood donors recruited over the same time period from the same geographical area were considered. The presence of anti-HCV antibodies was investigated by ELISA-II and RIBA-II, and viraemia (HCV RNA) was tested by using a polymerase chain reaction (PCR). HCV genotyping was also performed. RESULTS: Ninety-nine patients (mean age 48 years) with NHL were diagnosed during the study period. Histological classification of NHL was high-intermediate grade (63 patients), and low grade (36 patients). Immunophenotype distribution was type B (86 patients) and type T (13 patients). Seven of the 99 NHL patients (7%) were infected with HCV (both using serology and PCR), five of them with immunophenotype B and two with immunophenotype T. The prevalence of HCV infection according to NHL phenotype was 5.8% in B-cell NHL and 15.4% in T-cell NHL. The HCV genotype was 1b in six cases, and 3a in one. In voluntary blood donors (mean age 45 years), HCV infection was detected in 517/55 587 (0.93%). Therefore, HCV infection was more frequent in NHL patients than in controls (odds ratio = 8.1; 95% CI = 3.7-17.6). The odds ratio for the association of HCV and B-cell NHL was 6.2 (95% CI = 2.5-15.3), and for T-cell NHL 16.4 (95% CI = 3.7-72.8). CONCLUSION: The prevalence of HCV infection in patients with NHL (both B- and T-type) is higher than that observed in controls, suggesting a role of HCV in lymphoma aetiopathogenesis.

Chronic myeloid leukemia patients resistant to or intolerant of interferon alpha and subsequently treated with imatinib show reduced immunoglobulin levels and hypogammaglobulinemia.

BACKGROUND AND OBJECTIVES: Imatinib mesylate inhibits ABL tyrosine kinase. This protein serves a complex role in cell cycling and is important in lymphopoiesis. We describe the immunologic findings in patients with chronic myeloid leukemia resistant to or intolerant of interferon (IFN) a who were treated with imatinib. This aspect could be of interest since patients with these characteristics may be exposed to this treatment for long periods. DESIGN AND METHODS: Immunologic and hematologic evaluation (including immunoglobulin levels and parameters of autoimmunity), immunophenotyping analysis of peripheral blood and bone marrow, and cytogenetic bone marrow analysis were performed at sequential time points of the treatment (0, 3, 6, and 9 and 12 months). The relationships among immunologic variables, and between the immunologic findings and response, were investigated. RESULTS: Hypogammaglobulinemia IgG, IgA and IgM developed in 28%, 14% and 22% of the patients, respectively. Lymphocyte counts decreased significantly along the treatment. No correlation was found between Ig levels and lymphocyte counts or CD4, CD8 or CD19 subpopulations in peripheral blood, nor between Ig levels and bone marrow B-lineage precursors. No autoimmune phenomena were detected. Hypogammaglobulinemia had no clinical repercussions in patients who developed it. The percentage reductions of IgG, IgA and IgM levels were higher in patients with major genetic response to imatinib. INTERPRETATION AND CONCLUSIONS: Hypogammaglobulinemia can develop in as many as 20-25% of patients with chronic myeloid leukemia previously exposed to IFN a and who are then treated with imatinib. The reduction of Ig is greater in patients with a better cytogenetic response, perhaps reflecting that the efficacy of imatinib in blocking BCR-ABL kinase activity runs in parallel with ABL inhibition, leading to a dysregulation of B-lymphocyte function. Close immunologic evaluation is recommended in these patients.

High molecular response rate and clinical correlation in patients with follicular lymphoma treated with cyclophosphamide-vincristine-prednisone plus interferon alpha 2b.

PURPOSE: The role of molecular monitoring of minimal residual disease (MRD) in low-grade non-Hodgkin's lymphoma is controversial. We have performed a prospective study of the molecular behavior of 35 patients with follicular non-Hodgkin's lymphoma who received cyclophosphamide-vincristine-prednisone chemotherapy in conjunction with IFN-alpha 2b. EXPERIMENTAL DESIGN: Bcl-2 and clonal immunoglobulin heavy chain (IgH) gene rearrangements were assayed at diagnosis by PCR in lymph node and bone marrow (BM) and sequentially after treatment. RESULTS: Molecular markers were detected in BM of 29 (83%) patients at diagnosis: Bcl-2 rearrangement in 20 patients (90% major breakpoint and 10% minor cluster) and clonal IgH rearrangement in 9 of 15 patients negative for Bcl-2. Molecular and clinical response was noted in 25 (86%) patients after induction treatment. Progression-free survival at 5 years was 78.1 +/- 8%. A correlation between clinical and molecular response was found in 24 patients with molecular markers in BM at diagnosis and >2 years of follow-up: 94% of patients with undetectable MRD showed continuous clinical remission, whereas 50% of patients who reverted back to positive molecular markers relapsed (P < 0.05). CONCLUSIONS: The rate of molecular response is high in patients treated with cyclophosphamide-vincristine-prednisone and IFN and MRD sequential analysis is useful for disease surveillance.

Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older.

BACKGROUND AND OBJECTIVES: The population of elderly patients with hematologic malignancies is increasing and so will the activity of stem cell transplantation (SCT) in this population. The aim of this study was to analyze the toxicity and survival of allogeneic SCT in patients 50 years and older (elderly group), and compare the results with a standard adult population (young group). DESIGN AND METHODS: Thirty-two elderly patients (median age 52.5, range 50-59 years) and 97 young patients (median 32, range 20-40) received a myeloablative, allogeneic SCT from HLA-identical siblings at a single institution, and formed the basis of this retrospective study. The majority of transplants in both groups were performed with non-T-cell-depleted bone marrow, conditioned with busulfan + cyclophosphamide and received cyclosporine + methotrexate as graft-versus-host disease (GVHD) prophylaxis. The percentage of high-risk patients was nearly double in the elderly group (41% vs. 23%, p = 0.06). RESULTS: We observed a low incidence of toxicities in the elderly group, including veno-occlusive disease, acute and chronic GVHD, transplant-related mortality, time to engraftment, and relapse incidence, without significant differences compared within the young group. The 3-year survival rates were not statistically different between the elderly and young groups: 51% vs. 55% for all patients; 87% vs. 69% in chronic myeloid leukemia; 79% vs. 62% in standard risk patients and 13% vs. 31% in high risk ones. In multivariate analyses no significant difference in overall survival was found between age groups. INTERPRETATION AND CONCLUSIONS: According to our experience, age alone (between 50-59), should not be considered a contraindication to a conventional HLA identical sibling transplant.

CA-125 como marcador tumoral en una paciente con linfoma no hodgkiniano / Ca-125 as a tumor marker in a patient with non Hodgkin's lymphoma

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Deletion of sequences flanking the t(9;22) breakpoint: a secondary genetic event associated with loss of cytogenetic response to interferon in a Philadelphia-positive chronic myeloid leukaemia patient.

We present a Ph-positive chronic myeloid leukaemia patient who lost a complete cytogenetic response (CCR) of 23 months duration at the time of detection of a deletion, not previously observed, of chromosomes 9 and 22 sequences flanking the translocation breakpoint on the derivate 9 chromosome. To our knowledge, this is the first case in which a deletion at the t(9;22) breakpoint has arisen as a secondary genetic alteration produced after formation of the t(9;22) translocation. It remains to be determined whether this genetic abnormality has the same prognostic importance as when observed at diagnosis.

Different patterns of relapse after autologous peripheral blood stem cell transplantation in multiple myeloma: clinical results of 280 cases from the Spanish Registry.

BACKGROUND AND OBJECTIVES: Autologous peripheral blood stem cell (PBSC) transplantation is widely used to treat patients with multiple myeloma (MM). However, only a small fraction of patients remain free of disease in the long-term and most patients will finally relapse. The clinical presentation of relapse after transplantation is very heterogeneous and few reports have analyzed this situation. We report the clinical patterns of relapses after autologous transplantation of 280 patients with MM included in a Spanish Multicenter Registry. DESIGN AND METHODS: The medical records of 560 patients with MM transplanted in different centers in Spain, included in the Spanish Registry of Transplant in Multiple Myeloma, were reviewed. At diagnosis, 48 (8%) had stage I disease, 143 (25%) stage II and 369 (65%) stage III. The median time from diagnosis to transplantation was 13 months (4-143). The median age was 53 years (23-70). Of the 502 patients assessable for response to intensification therapy after transplantation, 241 (48%) achieved a complete response and 220 (43%) a partial response. The clinical characteristics of 280 patients (52%) who had relapsed after transplantation were retrospectively assessed during long-term post-transplantation follow-up. RESULTS: At a median follow-up of 23 months, 280(52%) patients had relapsed or progressed after transplantation. The median overall survival was 52 months (SE 8), (CI 95% 37-68) and median estimated progression-free survival was 33 months (SE 2.2, CI 95% 27-38). The median period for relapse was 30 months (2-84) with an actuarial risk of progression or relapse at 60 months after transplantation of 78%. The clinical patterns of relapse were very heterogeneous: 40 cases (14%) presented extramedullary manifestations with multiple plasmacytomas as the main symptoms of relapse, with a minimum or null monoclonal component (MC). In 51 cases (18%) only an insidious increase of MC protein in serum or urine was detected without other clinical manifestations. In 6 cases (2%) the relapse had criteria of plasmacytic leukemia. The remaining patients presented progressive increase of MC associated with plasmacytic bone marrow infiltration and different clinical myeloma symptoms, mainly new osteolytic lesions. The therapeutic approach was also very heterogeneous, with a global antitumoral response of 30%. Median overall survival after relapse was 14 months (SE 1.4) (CI 95% 11-17). INTERPRETATION AND CONCLUSIONS: The patterns of relapse of MM after high-dose therapy are very heterogeneous. The different clinical expressions of relapse may be due to clonal selection after high-dose therapy and could indicate the persistence of a resistant clone. Some patients relapse with extraosseous plasmacytomas without systemic disease. These findings suggest the need for an individualized approach during clinical follow-up after transplantation. Regarding treatment response, patients with myeloma who relapse after high-dose chemotherapy have been classically considered to have few therapeutic options. However, we observed that after different lines of treatment, at least one-third of patients responded, with a median overall survival, after relapse of 14 months. New drugs, such as thalidomide, have been recently proved to be effective in MM patients and could increase the response rate and survival of these patients.

Estudio comparativo de Piperacilina/tazobactam frente a Imipenem/cilastatina en la neutropenia febril (1994-1996) / Initial empiric therapy of febrile neutropenia with antibiotic monotherapy. Piperacillin/tazobactam versus imipenem/cilastatin (1994-1996)

FUNDAMENTO: La monoterapia antibiótica de amplio espectro es una práctica aceptada hoy día para el tratamiento empírico inicial de la neutropenia febril. Existe una amplia experiencia con el uso de imipenem (IMI).La piperacilina-tazobactam (PIP-TAZ) es un agente de desarrollo más reciente, que ofrece un espectro similar, y sobre el que existe menos experiencia como agente único, no asociado a un aminoglucósido. PACIENTES Y MÉTODO: Se aplicó una estrategia secuencial de adición antibiótica si a las 72 h persistía la fiebre o se aislaban microorganismos, y cobertura antifúngica si a los 5-7 días persistía fiebre no documentada. RESULTADOS: Se evaluaron 137 pacientes obteniendo un porcentaje de éxito a las 72 h con PIP-TAZ similar al de IMI (32,2 y 35,2 por ciento, respectivamente). El tiempo de defervescencia con PIP-TAZ fue menor que con IMI (3,6 y 4,2 días, respectivamente), y mayor la erradicación bacteriana (el 69,2 y el 50 por ciento; p = NS). La respuesta clínica final en ambos grupos fue del 91 por ciento. El 18,2 por ciento de los episodios fueron bacteriológicamente documentados. El microorganismo más frecuente fue Staphylococcus coagulasa negativo (48,8 por ciento). Sólo hubo un caso de shock séptico con IMI, y la mortalidad global del grupo fue del 8,7 por ciento. Destaca la significativa mayor frecuencia de vómitos con IMI que con PIP-TAZ (el 39,9 frente al 5,6 por ciento; p < 0,0001). CONCLUSIONES: La eficacia de PIP-TAZ fue equivalente a la de IMI, por lo que constituye una buena opción como monoterapia empírica inicial de los episodios de neutropenia febril (AU)

Piodermia gangrenosa asociada a leucemia linfocítica crónica / Pyoderma gangrenosum associated with chronic lymphocytic leukemia

La piodermia gangrenosa es un proceso ulcerativo asociado frecuentemente a enfermedades linfoproliferativas. La asociación a leucemia linfocítica crónica es un hecho excepcional. Describimos el caso de un varón de 72 años que presentó úlceras cutáneas en piernas de 4 meses de evolución y que posteriormente fue diagnosticado de leucemia linfocítica crónica. El paciente presentó curación total de las lesiones cutáneas tras tratamiento con ciclosporina (AU)

Trasplante de células progenitoras hematopoyéticas como tratamiento de rescate en pacientes con linfomas no hodgkinianos agresivos / Hematopoietic stem cell transplantation as salvage treatment in patients with aggresive non-Hodgkin's lymphoma

Fundamento: La realización precoz del trasplante de células progenitoras hematopoyéticas (TPH) en pacientes con linfomas no hodgkinianos (LNH) agresivos es una indicación controvertida. Métodos: Análisis retrospectivo de 86 pacientes con LNH agresivos tratados con quimioterapia MACOP/VACOP-B. El TPH se utilizó como tratamiento de rescate en pacientes con edad inferior o igual a 65 años con progresión o recaída quimiosensible. Se determinaron las supervivencias libre de progresión (SLP) y global (SG) con el método de Kaplan-Meier. Se compararon los porcentajes de respuesta y las funciones de supervivencia entre los grupos del Índice Pronóstico Internacional (IPI) mediante las pruebas *2 y log-rank, respectivamente Resultados: La mediana de edad de los pacientes fue de 48 años. El 22 por ciento tenían LNH-T y el 57 por ciento tenían IPI de intermedio-alto y alto riesgo. Hubo 6 muertes por toxicidad (7 por ciento), y 42 (48,8 por ciento) pacientes fracasaron al tratamiento de primera línea. De ellos, 31 fueron candidatos a TPH por edad inferior o igual a 65 años, aunque finalmente se trasplantaron 21 (incluyendo 13 de mayor riesgo). Se observó una asociación estadísticamente significativa entre la SLP y el IPI: 61,9 por ciento para los grupos bajo y bajo-intermedio (menor riesgo) frente al 28,2 por ciento para los de mayor riesgo (p = 0,0007). Con una mediana de seguimiento de 4,8 años, la SG fue del 80,5 por ciento para los grupos de menor riesgo frente al 52,6 por ciento (p = 0,01) para los de mayor riesgo, y del 83,7 por ciento frente al 62,0 por ciento (p = 0,02) para los mismos grupos en pacientes con edad inferior o igual a 65 años. La mediana de seguimiento posfracaso del tratamiento quimioterápico fue de 42,7 meses. Conclusiones: En este análisis retrospectivo la SG de los pacientes con LNH agresivos utilizando el TPH como tratamiento de rescate es similar a la comunicada utilizando el TPH más precozmente. (AU)