Background. The category of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BL-INT) was introduced into the 2008 WHO classification to define an infrequent subtype of aggressive mature B-cell NHL. It has been suggested that the deregulated expression of MYC and BCL-2 or BCL-6 oncoproteins, along with the genetic complexity of these tumors, contributes to the poor outcome of BL-INT when treated with standard R-CHOP. Aims and Methods. From 1995 we have been treating patients with advanced, aggressive B-NHL using a modified HyperCVAD regimen alternating sequential cyclophosphamide, vincristine and adryamicine plus intrathecal prophylaxis (cycle A) with high-dose methotrex- ate and high-dose cytarabine (cycle B). From 2002 standard-dose Rituximab has been added to each cycle. The diagnostic specimens of all patients treated into this protocol were revised according to the WHO 2008 criteria, and 20 patients were classified as BL-INT. FISH analysis for MYC translocation using a Break Apart probe and additional IHC analyses were performed in more recent cases or when adequate frozen material was available. Results. Median age of 20 BL-INT patients was 40 years (range 19-72), males were 13 (65%). The large majority of patients had high-risk characteristics: Ann Arbor IV stage (n=17, 85%), ECOG Performance Status ≥2 (n=12, 60%), Ki-67 >90% (n=15, 75%), bulky disease (n=13, 65%). A leukemic presentation was present in 7 cases (35%) and 4 patients (20%) had CNS disease. MYC translocation was found in 7/11 cases (63.6%), BCL2 and BCL6 were hyper-expressed in 11/16 (68.7%) and 13/14 (92.8%) cases, respectively. Remarkably, a “mutated” p53+/p21- phenotype was found in 9/9 tested cases. Eighteen patients were evaluable for response to treatment, 4 were treated with chemotherapy alone and 14 received Rituximab plus chemotherapy (median 3 cycles A plus 3 cycles B). Complete remission (CR) was achieved in 17 patients and partial remission in one. Three patients suffered from relapse and another one died of fungal pneumonia while in CR. After a median folllow-up of 69 months the EFS is 72.2%, not different from what seen in BL treated with the same protocol (Todeschini et al, Am J Hematol 2011). Conclusions. Although in a small series, we observed that an intensive, short-term chemotherapy regimen determines a good outcome in BL-INT characterised by a very unfavourable clinical and molecular profile.
Modified HyperCVAD and rituximab for the treatment of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.
BONIFACIO, Massimiliano;Furlani, Lara;ZAMO', Alberto;Corradi, Gabriele;CHILOSI, Marco;TODESCHINI, Giuseppe;AMBROSETTI, Achille
2013-01-01
Abstract
Background. The category of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BL-INT) was introduced into the 2008 WHO classification to define an infrequent subtype of aggressive mature B-cell NHL. It has been suggested that the deregulated expression of MYC and BCL-2 or BCL-6 oncoproteins, along with the genetic complexity of these tumors, contributes to the poor outcome of BL-INT when treated with standard R-CHOP. Aims and Methods. From 1995 we have been treating patients with advanced, aggressive B-NHL using a modified HyperCVAD regimen alternating sequential cyclophosphamide, vincristine and adryamicine plus intrathecal prophylaxis (cycle A) with high-dose methotrex- ate and high-dose cytarabine (cycle B). From 2002 standard-dose Rituximab has been added to each cycle. The diagnostic specimens of all patients treated into this protocol were revised according to the WHO 2008 criteria, and 20 patients were classified as BL-INT. FISH analysis for MYC translocation using a Break Apart probe and additional IHC analyses were performed in more recent cases or when adequate frozen material was available. Results. Median age of 20 BL-INT patients was 40 years (range 19-72), males were 13 (65%). The large majority of patients had high-risk characteristics: Ann Arbor IV stage (n=17, 85%), ECOG Performance Status ≥2 (n=12, 60%), Ki-67 >90% (n=15, 75%), bulky disease (n=13, 65%). A leukemic presentation was present in 7 cases (35%) and 4 patients (20%) had CNS disease. MYC translocation was found in 7/11 cases (63.6%), BCL2 and BCL6 were hyper-expressed in 11/16 (68.7%) and 13/14 (92.8%) cases, respectively. Remarkably, a “mutated” p53+/p21- phenotype was found in 9/9 tested cases. Eighteen patients were evaluable for response to treatment, 4 were treated with chemotherapy alone and 14 received Rituximab plus chemotherapy (median 3 cycles A plus 3 cycles B). Complete remission (CR) was achieved in 17 patients and partial remission in one. Three patients suffered from relapse and another one died of fungal pneumonia while in CR. After a median folllow-up of 69 months the EFS is 72.2%, not different from what seen in BL treated with the same protocol (Todeschini et al, Am J Hematol 2011). Conclusions. Although in a small series, we observed that an intensive, short-term chemotherapy regimen determines a good outcome in BL-INT characterised by a very unfavourable clinical and molecular profile.
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