Eugenia Piliotis

Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature.

Central nervous system (CNS) prophylaxis for diffuse large B‐cell lymphoma (DLBCL) is controversial with even less evidence in the era of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R‐CHOP at a tertiary care centre over a 7‐year period. CNS prophylaxis was recommended for ‘higher risk’ patients and consisted of intrathecal methotrexate and/or high‐dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow‐up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R‐CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.

Chemoimmunotherapy resistant follicular lymphoma: predictors of resistance, association with transformation and prognosis

Abstract Follicular lymphoma (FL) is characterized by an initial response to treatment with inevitable relapse. We evaluated chemoimmunotherapy resistance (CIR resistance) including transformation. We identified patients who received rituximab combination therapy for symptomatic FL. CIR resistance was defined as disease progression during rituximab-based chemoimmunotherapy, rituximab maintenance or within 6 months of treatment completion. Our primary outcome was time to early progression (CIR resistance). Between July 2006 and April 2010, 132 patients met the inclusion criteria and 22 (16.7%) demonstrated CIR resistance with a median follow-up of 33 months. High-risk Follicular Lymphoma International Prognostic Index (FLIPI) score was predictive of CIR resistance (hazard ratio [HR] 2.43; 95% confidence interval [CI], 1.4–4.1; p = 0.001). Overall, eight patients (36.3%) transformed (biopsy-proven), with no transformation in the chemoimmunotherapy responder group. Median overall survival in the CIR resistant group was 47 months. Patients with CIR resistance had high rates of histologic transformation and shorter survival with poor response to next therapy.

A phase I study of romidepsin, gemcitabine, dexamethasone and cisplatin combination therapy in the treatment of peripheral T-cell and diffuse large B-cell lymphoma; the Canadian cancer trials group LY.15 study†

Abstract We investigated GDP (gemcitabine, 1000 mg/m2 IV d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 IV d1) combined with romidepsin on days 1 and 8 every 21 days to a maximum of six cycles in a standard 3 + 3, phase I dose escalation trial for patients with relapsed/refractory peripheral T-cell (PTCL) or diffuse large B-cell (DLBCL) lymphoma (NCT01846390). After treating four patients, gemcitabine and romidepsin were given on days 1 and 15 every 28 days. On the 21-day schedule at 6 mg/m2 romidepsin, there were three dose-limiting toxicities (DLTs) among four patients. On the 28-day schedule, there were no DLTs at the 6, 8, or 10 mg/m2 dose. At 12 mg/m2, there were four observed grade 3 DLTs among six evaluable patients. Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 if given on a day 1, 15 every 28 days schedule.

Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90Y ibritumomab tiuxetan in a phase II study

Five‐year overall survival for high‐risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high‐risk follicular lymphoma. Front‐line treatment with chemo‐immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio‐ immunotherapy with 90‐Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5‐year overall survival for intermediate and high‐risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio‐immunotherapy. Three months post radio‐immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo‐immunotherapy and converted to complete response after radio‐immunotherapy. The 5‐year progression‐free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow‐up of 48 months (range 3‐84 months). Post radio‐immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%‐36% and 10%‐24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B‐cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

PROLONGED MOLECULAR AND CLINICAL REMISSIONS IN FOLLICULAR LYMPHOMA PATIENTS TREATED WITH HDT/ASCT AND COMBINATION IMMUNOTHERAPY WITH RITUXIMAB AND INTERFERON α

underwent 1 line of therapy prior to R‐DHAP/Ox, 11 (22.9%) underwent 2 lines of therapy, and 3 (6.3%) had 3 or more lines before R‐DHAP/Ox. The median TTNT from first‐line was 14.3 months (range 10.6‐19.4). With a median follow‐up of 66 months, the 5‐year OS was 73.1% (95% CI, 61‐85%). Among the 34 patients that underwent ASCT, the 5‐year OS was 84% (95% CI, 72‐98%). Time to next treatment (TTNT) after DHAP/Ox was 30.9 months (95% CI, 18‐47%). Stem cell collection failure was reported in 6 cases (12.5%). Four cases (8.3%) of transformation to DLBCL and 3 (6.2%) secondary malignancies (2 myeloid disorders, 1 bladder carcinoma) were reported. Conclusions: In this population of high‐risk, early relapsing FL, R‐ DHAP/Ox +/− ASCT was found to be active, with aTTNT significantly longer than that experienced following first‐line therapy. This population had very similar FLIPI risk scores compared to the LymphoCare study population but appears to have experienced better survival outcomes. Late events continue to occur, and cure appears unlikely. Prospective studies of R‐DHAP/Ox +/− ASCT are warranted in this high‐risk FL population.