Direct-Acting Antivirals as Primary Treatment for Hepatitis C Virus-Associated Indolent Non-Hodgkin Lymphomas: The BArT Study of the Fondazione Italiana Linfomi.

PURPOSE: We prospectively treated patients with hepatitis C virus (HCV)-associated indolent lymphomas with genotype-appropriate direct-acting antivirals (DAAs) with the aim to evaluate virologic and hematologic outcomes. No prospective studies in this setting have been published so far. METHODS: FIL_BArT is a prospective, multicenter, phase II trial that evaluated genotype-appropriate DAAs in untreated HCV-positive patients with indolent lymphomas without criteria for immediate conventional antilymphoma treatment. The primary objective was sustained virologic response, whereas the main secondary objectives were overall response rate of lymphoma and progression-free survival. RESULTS: Forty patients were enrolled, including 27 with marginal zone lymphoma. Median age was 68 years. Extranodal sites were involved in 14 cases (35%). Main genotypes were 1 in 16 patients and 2 in 21 patients. All patients received genotype-guided DAAs: 17 ledipasvir/sofosbuvir, eight sofosbuvir plus ribavirin, and 15 sofosbuvir/velpatasvir. All patients achieved sustained virologic response (100%). DAAs were well tolerated, with only two grade 3-4 adverse events. Overall response rate of lymphoma was 45%, including eight patients (20%) achieving complete response and 10 (25%) partial response, whereas 16 exhibited stable disease and six progressed. With a median follow-up of 37 months, two patients died (3-year overall survival 93%; 95% CI, 74 to 98) and three additional patients progressed, with a 3-year progression-free survival of 76% (95% CI, 57 to 87). CONCLUSION: HCV eradication by DAAs was achieved in 100% of HCV-positive patients with indolent lymphomas not requiring immediate conventional treatment and resulted in non-negligible rate of lymphoma responses. Treatment with DAAs should be considered as the first-line therapy in this setting.

Dose-dense ABVD as first-line therapy in early-stage unfavorable Hodgkin lymphoma: results of a prospective, multicenter double-step phase II study by Fondazione Italiana Linfomi.

We investigated the feasibility and activity of an intensified dose-dense ABVD (dd-ABVD) regimen in patients with early-stage unfavorable Hodgkin lymphoma (HL). This prospective, multicenter, phase II study enrolled 96 patients with newly diagnosed, unfavorable stage I or II classical HL. The patients received four cycles of dd-ABVD followed by radiotherapy. Interim PET (PET-2) was mandatory after two courses. Primary endpoints were the evaluation of dd-ABVD feasibility and activity (incidence of PET-2 negativity). The feasibility endpoint was achieved with 48/52 (92.3%) patients receiving > 85% of the programmed dose. The mean dose intensity in the overall patient population (n = 96) was 93.7%, and the median duration of dd-ABVD was 85 days (range, 14-115) versus an expected duration of 84 days. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%). In total, 90 (93.8%) patients showed complete response at the end of treatment. With a follow-up of 80.9 months (3.3-103.2), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 84 months, PFS and OS rates were 88.4% and 95.7%, respectively. No evidence for a difference in PFS or OS was observed for PET-2-negative and PET-2-positive patients. Infections were documented in 8.3% and febrile neutropenia in 6.2% of cases. Four patients died: one had alveolitis at cycle 3, one death was unrelated to treatment, and two died from a secondary cancer. dd-ABVD is feasible and demonstrates activity in early-stage unfavorable HL. The predictive role of PET-2 positivity in early-stage unfavorable HL remains controversial. The study was registered in the EudraCT (reference number, 2011-003,191-36) and the ClinicalTrials.gov (reference number, NCT02247869) databases.

Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi.

PURPOSE: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050). RESULTS: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases. CONCLUSION: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.

Therapeutic decision based on molecular detection of resistance mechanism in an ALK-rearranged lung cancer patient: a case report.

Background: The use of tyrosine kinase inhibitors (TKIs) of ALK is the therapy of choice for ALK-fusion patients. Unfortunately, all patients under this kind of treatment eventually develop acquired resistance through several well-known mechanisms, such as acquisition of a secondary mutation within the kinase domain, activation of a bypass signaling pathway, or a histological change like small-cell lung cancer transformation. At the time of progression, a tissue re-biopsy may give important molecular and morphological information regarding the mechanisms driving resistance to ALK TKIs. However, this procedure is not always feasible and it may not reflect the tumor heterogeneity, and therefore gives incomplete information. To overcome these drawbacks, the analysis of circulating tumor DNA (ctDNA) isolated from plasma, the so-called liquid biopsy, is emerging as a noninvasive and useful tool for detecting resistance mutations. Secondary resistance mutations are common in second-generation TKIs resistant patients and among these, Gly1202Arg (p.G1202R) emerged as the most frequent mutation. Case presentation: We have treated an ALK-positive lung adenocarcinoma patient with a sequential strategy of ALK TKIs. Patient follow-up was performed combining clinical, radiological, and molecular profiling. ctDNA was isolated from plasma and by means of ultra-deep next generation sequencing; we searched for secondary ALK resistance mutations on exons 21-25. ALK mutation Gly1202Arg (G1202R) was detected. We have documented consistency between plasma levels of G1202R mutation and radiological progression or improvement. Conclusion: Liquid biopsy appears to be a promising tool to anticipate progression and to drive the therapeutic strategy based upon ALK resistance mutations.

Outcomes of ALK positive lung cancer patients treated with crizotinib or second-generation ALK inhibitor: a monoinstitutional experience.

Rearrangement in the anaplastic lymphoma kinase (ALK) gene is one of the oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Several ALK inhibitors (ALKis) have been developed and have demonstrated their efficacy, however the best treatment strategy for ALK positive NSCLC patients has yet to be determined. Our retrospective study has investigated the outcome of 40 ALK-rearranged NSCLC patients treated with two different sequential strategies in our Institute; a "classical group", treated with crizotinib followed by second or third generation ALKis, and the "experimental group", treated upfront with a second generation ALK inhibitor. The primary endpoints investigated were Progression-free survival (PFS) and intracranial activity. The analysis has revealed a significant improvement in PFS (p = 0.050) in the experimental group, furthermore none of these patients developed brain metastasis. There was no statistically significant difference in OS, but all patients in the experimental group were still alive after a median follow up of 15 months. Our retrospective analysis suggests that systemic and intracranial efficacy tends to be better in the experimental group; randomized prospective studies could confirm our observations.

Nonpegylated liposomal doxorubicin combination regimen in patients with diffuse large B-cell lymphoma and cardiac comorbidity. Results of the HEART01 phase II trial conducted by the Fondazione Italiana Linfomi.

The purpose of this phase 2, multicenter study was to determine the activity and safety of nonpegylated liposomal doxorubicin as part of "R-COMP" combination in patients with diffuse large B-cell lymphoma and coexisting cardiac disorders. The study was conducted using a Bayesian continuing assessment method using complete remission rate and rate of cardiac events as study endpoints. Between November 2009 and October 2011, 50 evaluable patients were enrolled (median age, 76 years). Median baseline left ventricular ejection fraction (LVEF) was 60%. Ischemic cardiopathy was the most frequent preexisting cardiac disorder (35%), followed by atrial fibrillation (15%), left ventricular hypertrophy (13%), and baseline LVEF <50% (12%). Based on the intent to treat analysis, overall response rate was 72%, including 28 patients in complete remission (complete remission rate, 56%), and 8 in partial remission (16%). At the end of treatment, grades 3 to 4 cardiac events were observed in 6 patients. No significant modifications from baseline values of LVEF were observed during treatment and follow-up. Nonpegylated liposomal doxorubicin instead of doxorubicin in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is a feasible option for patients with diffuse large B-cell lymphoma presenting with concomitant cardiac disorders.

Modulated chemotherapy according to modified comprehensive geriatric assessment in 100 consecutive elderly patients with diffuse large B-cell lymphoma.

Chemotherapy is associated with toxicity in elderly patients with potentially curable malignancies, posing the dilemma of whether to intensify therapy, thereby improving the cure rate, or de-escalate therapy, thereby reducing toxicity, with consequent risks for under- or overtreatment. Adequate tools to define doses and combinations have not been identified for lymphoma patients. We conducted a prospective trial aimed to evaluate the feasibility and efficacy of chemotherapy modulated according to a modified comprehensive geriatric assessment (CGA) in elderly (aged ≥70 years) patients with diffuse large B-cell lymphoma (DLBCL). In June 2000 to March 2006, 100 patients were stratified using a CGA into three groups (fit, unfit, and frail), and they received a rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone modulated in dose and drugs according to comorbidities and activities of daily living (ADL) and instrumental ADL scores. Treatment was associated with a complete response rate of 81% and mild toxicity: grade 4 neutropenia in 14%, anemia in 1%, and neurological and cardiac toxicity in 2% of patients. At a median follow-up of 64 months, 51 patients were alive, with 5-year disease-free, overall, and cause-specific survival rates of 80%, 60%, and 74%, respectively. Chemoimmunotherapy adjustments based on a CGA are associated with manageable toxicity and excellent outcomes in elderly patients with DLBCL. Wide use of this CGA-driven treatment may result in better cure rates, especially in fit and unfit patients.

Phase 2 study of intrathecal, long-acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus-related non-Hodgkin lymphoma.

BACKGROUND: Patients with aggressive non-Hodgkin lymphoma (NHL) develop central nervous system (CNS) progression or recurrence during the course of their disease. Patients with human immunodeficiency virus (HIV)-NHL often develop CNS progression despite the use of prophylaxis. Liposomal cytarabine (DepoCyte) has shown activity in lymphomatous meningitis, but there are limited data for prophylaxis. METHODS: Between May 2006 and December 2008, a phase 2 study of intrathecal liposomal cytarabine was performed at the dose of 50 mg in 30 patients with HIV-NHL, with the aim of evaluating feasibility and activity for prophylaxis. RESULTS: Liposomal cytarabine was well tolerated, with headache grade I to III being the most frequent side effect in 40% of patients. With a median follow-up of 10.5 months, only 1 (3%) patient developed a combined systemic and meningeal recurrence. The use of liposomal cytarabine allowed significant reduction of the number of lumbar injections in comparison to the standard schedules (around 50%), improving the quality of life of patients and reducing the professional exposure risk. CONCLUSIONS: In this first study on prophylaxis of lymphomatous meningitis in HIV-NHL, liposomal cytarabine seems safe and active; it reduces by approximately 50% the number of lumbar punctures, and exposure risk for health staff as well.

Management of immunocompetent patients with primary central nervous system lymphoma.

Primary central nervous system (CNS) lymphoma (PCNSL) is a non-Hodgkin lymphoma that arises within and is confined to the CNS. Recent data have suggested an increasing incidence in immunocompetent individuals, with a peak of incidence between 60 and 70 years of age. Patients with PCNSL present mostly with symptoms of increased intracranial pressure. The clinical management of these patients remains controversial, and the optimal treatment for patients with PCNSL has not yet been defined. Surgery, even if macroscopically radical, does not improve survival because of the multifocal and infiltrative nature of PCNSL; furthermore, the deep location of most of these tumors makes patients susceptible to serious and irreversible neurologic sequelae. Corticosteroids have a specific role in the treatment of patients with PCNSL, whose disease is sensitive to them as a chemotherapeutic agent. PCNSL is an extremely radiation-sensitive neoplasm; whole-brain radiation therapy plus corticosteroids was the first modality of treatment for patients with this neoplasm until 10 years ago, with a low cure rate and a high local recurrence rate. PCNSL is also a chemosensitive neoplasm; while the optimal choice, sequence, and combination of appropriate agents for efficacious treatment of patients with PCNSL has yet to be determined. An essential component of therapy must include an adequate drug delivery behind a normal blood-brain barrier. Methotrexate is the agent with the most proven activity in PCNSL. Combined-modality therapy has improved survival, but relapse is still common, and late neurologic toxicity is a significant complication, especially in older patients, who represent the majority of immunocompetent patients with PCNSL.

The impact of tobacco smoking and alcohol drinking on survival of patients with non-Hodgkin lymphoma.

Tobacco smoking and alcohol consumption have not been clearly related to the risk of non-Hodgkin lymphoma (NHL), and the impact of these two factors on survival of NHL patients has received little attention. Cases were 268 subjects with incident histologically-confirmed NHL, admitted as inpatients to the Division of Medical Oncology, between 1983 and 2002. These individuals were enrolled as cases in case-control studies conducted at the same institution over the same period. For all patients clinical (histological subtype, major prognostic factors and treatment) and epidemiological data (smoking and drinking habits) were available. Survival analysis was performed using Kaplan-Meier methods. Hazard ratio (HR) was estimated by Cox proportional hazard model. Compared to never smokers, patients who smoked >or=20 cigarettes/day had higher risks of death (HR = 1.70, 95% confidence interval (CI): 1.06-2.73) and lower survivals at 5 years (60 and 46%, respectively). Likewise, patients who drunk >or=4 drinks/day showed 1.69-fold higher probability of death (95% CI: 1.04-2.76) in comparison to drinkers of <2 drinks/day (5-year survival: 47 and 67%, respectively). When combining exposure to alcohol and tobacco, no excess of death emerged in light drinkers (<4 drinks/day), irrespective of their smoking habits, but higher risks of death emerged among heavy drinkers. In the present study, heavy tobacco smoking, and particularly, heavy alcohol drinking were associated with poor survival in NHL patients. Our findings strongly encourage physicians to advice NHL patients to stop smoking and diminish alcohol consumption to obtain improvements in the course of NHL.

Linking inflammation to cell cycle progression.

Risk of gastrointestinal cancers is closely related to increased levels of oxidants in the balance between oxidant and anti-oxidant agents. A possible explanation of this epidemiological observation is the local loss of the epithelial barrier function with a focal inflammatory response. Accordingly, chronic inflammatory diseases represent well-known risk factors for cancer and, on the other hand, it is known that anti-inflammatory agents, demulcents and antioxidants markedly inhibit the development of colon cancer in animal models as well in humans. At molecular level a key role in the process that link inflammation to cellular transformation seems to be played by activation of Cyclooxygenase-2 (COX-2) together with production of Reactive Oxygen Intermediate (ROI). Both these events have been strictly linked with cell proliferation and transformation, although the intracellular pathways involved in these processes are still not completely understood. The uncontrolled proliferation, which is a landmark of cellular transformation, is accompanied by the deregulation of proteins involved in the control of cell cycle checkpoints. Altered expression and function of cyclooxygenase and nitric oxide synthase seem to influence, among others, the expression of proteins involved in the regulation of cell cycle progression. Similarly, anti-inflammatory and antioxidant agents may also act on the expression and function of several cell cycle regulating proteins. Understanding the mechanisms by which chronic inflammation contributes to genetic and epigenetic changes involved in the regulation of critical cell cycle checkpoints may help to develop more and more specific treatment strategies for reducing malignant transformation of these inflammatory diseases.