Abstract
Introduction
Diffuse large B–cell lymphoma (DLBCL) is the most common subtype of non–Hodgkin‘s lymphoma in adults. Rituximab and Anthracycline–based chemotherapy are the standard treatment, ...complete remission (CR) is achived in approximately 67% of patients. About one third of patients have refractory disease or relapse after standard therapy, mostly within 5 years of achieving CR.
Clinical Case
A 62–year–old patient, current smoker, without previous cardiovascular diseases presented to our ER for dyspnea and asthenia. Medical history showed GBC–DLBCL at third stage that achieved CR with R–CHOP therapy and intrathecal prophylaxis. The ECG documented sinus tachycardia with normal ventricular repolarization. Arterial blood gas analysis showed a condition of respiratory distress (pO2 71 mmHg, pCO2 27 mmHg). For suspicion of pulmonary embolism, chest CT with contrast was done showing a bulky mass extending from the right atrium to the right ventricle, also involving the pericardial sac (image 1). Transthoracic echocardiography showed a bulky mass (area 31 cm2) occupying almost the entire right atrium (5.9 x 4.4 cm) and extended, through the tricuspid valve, into the right ventricle, displacing the interventricular septum (image 2). Endomyocardial biopsy confirmed the diagnosis of GBC–DLBCL cardiac recurrence. Assumed the good systolic function of the left ventricle and the age of the patient, chemotherapy debulking was performed with Gemcitabine, followed by R–CHOP and MTX. One month after therapy post–treatment Total Body CT shows a good response with no evidence on echocardiogram of pathological tissue in the right ventricle (image 3).
Conclusions
Cardiac DLBCL is a rare tumor with few cases reported in the literature. There is currently no standard therapy, particularly for those who are unsuitable for high–dose chemotherapy a/o autologous stem cell transplantation. The multidisciplinary cardiological and hematological approach has proved to be fundamental these patient‘s therapeutic management.
Anti-tumour activity of triazene compounds of clinical interest i.e. dacarbazine and temozolomide (TMZ) relies mainly on the generation of methyl adducts to purine bases of DNA. Two DNA repair enzyme ...systems, i.e. the O
6-guanine-alkyl-transferase (MGMT) and mismatch repair (MMR), play a predominant role in conditioning the cytotoxic effects of triazenes. In particular, high levels of MGMT associated with target cells are responsible of resistance to triazenes. On the contrary, the presence of MMR is required for the cytotoxic effects of these compounds. Previous studies performed by our group and a more recent clinical investigation reported by Karen Seiter, pointed out that triazene compounds could play an important role in the treatment of refractory acute leukaemia. Leukaemia blasts, especially of lymphoblastic leukaemia, show frequently high levels of MGMT activity. Therefore, it reasonable to hypothesize that combined treatment of leukaemia patients with triazene compounds along with MGMT inhibitors could lead to a better control of the disease. PaTrin-2 (O
6-(4-bromothenyl)guanine, PAT) is a potent and scarcely toxic MGMT inhibitor recently introduced in clinical trials. This drug is used in combination with triazene compounds in order to augment their anti-tumour efficacy against neoplastic cells endowed with high MGMT activity. The present report describes, for the first time, pre-clinical in vitro studies on the cytotoxic activity of combined treatment with PAT
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TMZ against long-term cultured leukaemia cells and primary leukaemia blasts obtained from patients with acute lymphoblastic leukaemia or acute myeloblastic leukaemia. The results point out that, both in long-term cultured leukaemia cell lines and in primary blast samples, PAT could improve dramatically the sensitivity of malignant cells to the cytotoxic effects of TMZ. This sensitizing effect is detectable when leukaemia cells show resistance mechanisms based on a MGMT-proficient phenotype. On the contrary, when resistance to TMZ is dependent on MMR deficiency, no influence of PAT can be detected in various experimental conditions. In conclusion, these results appear to provide disease-oriented rational basis to design novel clinical protocols for the treatment of acute leukaemia with combined administration of PAT and triazene compounds.
To improve long-term survival by reducing toxicity in intermediate stage Hodgkin's disease patients, we compared the effects of involved field (IF) versus extended field (EF) irradiation administered ...after four cycles of ABVD regimen.
Two hundred and ten Hodgkin's disease patients, at clinical stage II with risk factors and III without risk factors, were enrolled in the randomized study HD94. After four courses of ABVD regimen, patients who achieved complete remission (CR) or partial remission (PR) were randomly assigned to the IF or EF arm. The Kaplan-Meier method was adopted to estimate overall survival (OS) and relapse-free survival (RFS).
After a median follow-up of 78 months (range 13-111 months), OS was 98% and 96%, respectively, in the EF and IF arms; RFS was 94% and 91%, respectively, in the EF and IF arms.
We confirm the efficacy of four cycles of ABVD regimen, with suitable dose intensity, and radiotherapy as consolidation therapy, in intermediate stage Hodgkin's disease patients (CR = 99.5% and OS = 95%). We also found that involved field radiotherapy results were as effective as extended field, without acute toxicity.
Venetoclax (ABT-199) is a small-molecule selective oral inhibitor of the antiapoptotic protein Bcl-2 that promotes programmed cell death of chronic lymphocytic leukemia (CLL) cells regulating the ...release of proapoptotic factors, such as Smac/Diablo, apoptosis-inducing factor (AIF) and cytochrome c. In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to venetoclax for patients diagnosed with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. This review will focus on the mechanism of action, preclinical studies and clinical development of venetoclax both as a monotherapy and in combination with other drugs for CLL in the current milieu of therapy dominated by novel tyrosine kinase inhibitors such as ibrutinib and idelalisib.
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