Summary Adjuvant chemotherapy with fluorouracil (FU) and levamisole or FU/leucovorin (LV) has been established as effective adjuvant treatment for patients with stage IlIl colon cancer. Among several other promising treatment strategies in resected colon cancer, intraperitoneal anti-cancer drug administration with its appealing rationale of counteracting microscopic residual disease on peritoneal surfaces and occult metachronous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation. To determine whether a combination of this locoregional therapeutic concept with systemic intravenous administration of FU/LV would yield better results than conventional adjuvant chemoimmunotherapy with FU/levamisole, the present randomized study was initiated. A total of 241 patients with resected stage IlIl or high-risk stage II (T4NOMO) colon cancer were randomly assigned to 'standard therapy' with FU and levamisole, given for a duration of 6 months, or to an investigational arm, consisting of LV 200 mg m-2 plus FU 350 mg m-2, both administered intravenously (days 1-4) and intraperitoneally (days 1 and 3) every 4 weeks for a total of six courses. In patients with stage 11 disease, no significant difference was noted between the two arms after a median follow-up time of 4 years (range 2.5-6 years). Among 196 eligible patients with stage IlIl disease, however, a comparative analysis of the two treatment groups suggested both an improvement in disease-free survival (P= 0.0014) and a survival advantage (P= 0.0005), with an estimated 43% reduction in mortality rate (95% confidence interval 26-70%) in favour of the investigational arm. In agreement with its theoretical rationale, combined intrapertoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or other organ site involvement (9 vs 25 patients in the FU/levamisole arm; P= 0.005). Treatment-associated side-effects were infrequent and generally mild in both arms, although a lower rate of severe (WHO grade 3) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy (3% vs 12%; P = 0.01). The results of this trial suggest that combined intraperitoneal plus systemic intravenous chemotherapy with FU/LV is a promising adjuvant treatment strategy in patients with surgically resected stage IlIl colon carcinoma.

Richter Syndrome, an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia (CLL), has a generally poor prognosis and anthracycline-based chemoimmunotherapy regimens designed to treat de novo diffuse large B-cell lymphoma achieve modest clinical benefit. R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) has demonstrated greater activity against aggressive B-cell histologies but has not been studied in Richter Syndrome. We conducted a retrospective cohort study of 46 Richter Syndrome patients treated with first-line R-EPOCH at our institution between 1 January 2006 and 31 May 2014. The median progression-free survival (PFS) was 3·5 months [95% confidence interval (CI): 2·0-7·6] and median overall survival (OS) was 5·9 months (95% CI: 3·2-10·3). Toxicity was high and 30% of patients died without progression or response. Patients with a complex CLL karyotype had significantly shorter PFS and OS (P = 0·005 and P = 0·002, respectively). Multivariable analysis identified complex CLL karyotype as the most significant predictor of decreased survival [Hazard ratio (HR) 2·72, 95% CI: 1·14-6·52, P = 0·025], adjusting for number of prior CLL treatments (P = 0·036). Richter Syndrome patients with complex CLL karyotype experience poor survival with R-EPOCH treatment and novel approaches are needed for these patients. In contrast, survival of patients without a complex CLL karyotype was similar to patients with de novo diffuse large B-cell lymphoma.

The appropriate dose of antithymocyte globulin (ATG) been utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) is yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG – 39 patients) and 6 mg/kg (r-ATG- 97 patients). The cumulative incidences of acute graft-versus-host-disease (aGVHD) grade II–IV at 180 days were 46% and 41% and aGVHD grade III–IV were 11% and 18% in r-ATG and R-ATG, respectively (P>0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (P>0.3). There was no significant difference in non-relapse mortality (p=0.22), cumulative incidence of relapse (p=0.53), progression-free survival (p=0.69) or overall survival (p=0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD as 7.5 mg/kg ATG. Given the increasing number of RIC HSCT performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.

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Background: Richter's transformation (RT), the occurrence of an aggressive lymphoma in patients with prior chronic lymphocytic leukemia (CLL), occurs in up to 10% of CLL patients. Anthracycline-based chemoimmunotherapy remains standard, but outcomes are poor (median survival approximately 12 months). R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) has demonstrated superior efficacy to R-CHOP in HIV-associated diffuse large B-cell lymphoma, Burkitt's lymphoma, and primary mediastinal B-cell lymphoma. We conducted a single-institution retrospective cohort study to characterize efficacy and toxicity of R-EPOCH as first-line treatment for RT. Methods: The study included patients treated with R-EPOCH as first-line therapy for histologically confirmed RT at the Ohio State University between January 1st 2006 and May 31st 2014. Characteristics of the CLL and RT, ECOG performance status, and laboratory assessment of bone marrow and organ function were abstracted from medical records. Toxicity of R-EPOCH was assessed by reviewing the frequency of adverse events (AE). R-EPOCH treatment outcomes were assessed as documented by the treating physician and not secondarily verified. Progression free survival (PFS) and overall survival (OS) durations were calculated from date of Richter's biopsy until date of event (PFS: relapse/death; OS: death), censoring patients without event at last follow-up. PFS and OS estimates were obtained using the Kaplan-Meier method. Univariable proportional hazards models were used to model PFS and OS as a function of each clinical variable. Results: The study included 46 patients. Median age at RT diagnosis was 67 (range 38-83). Median number of months from CLL to RT diagnosis was 53 (range 0.4-198). A median of 3 (range 0-13) prior CLL treatments had been given with 10 (22%) patients receiving ibrutinib as the most recent. The majority of patients where CLL risk was evaluable demonstrated poor-risk disease: 24/43 (56%) complex karyotype, 20/41 (49%) del(17)(p13.1), 27/32 (84%) unmutated IGHV. The majority of evaluable patients had an ECOG performance status of 0 or 1 (18/28, 64%). Table 1 shows RT characteristics for these patients. Treatment with R-EPOCH was started a median of 5 days after RT diagnosis (range 0-110). The majority of patients did not complete 6 cycles: 16 (35%) completed 1 cycle, 10 (22%) 2 cycles, 5 (11%) 3 cycles, 4 (9%) 4 cycles, 2 (4%) 5 cycles, and 9 (19%) 6 cycles. Of 131 cycles given, 114 (87%) were fully evaluable for AE with results in table 2. Outcome of R-EPOCH treatment was known for 44 patients: 9 (20%) achieved complete response, 8 (18%) clinical response documented by the treating physician, 14 (32%) progressive disease, and 13 (30%) died without (known) lymphoma progression. With a median follow up of 39 (range 13-54) months, 9 (20%) patients were alive without lymphoma progression. All patients with lymphoma progression died. Median PFS was 3.5 months (95% CI: 2.0-7.6) and median OS was 5.9 months (95% CI: 3.2-10.3) (Figure 1). In univariable analysis, risk of death was higher for patients with complex CLL karyotype (HR 4.38, p=0.0002), del(17)(p13.1) (HR 3.04, p=0.003), higher number of CLL treatments (HR 1.16, p=0.004), higher bilirubin (HR 1.68, p=0.04), and higher serum creatinine (HR 1.65, p=0.05). Conclusions: Patients with RT treated with first-line R-EPOCH had poor PFS (median 3.5 months) and OS (median 5.9 months) with only 20% of patients alive at last follow up. Characteristics of underlying CLL influenced outcomes of R-EPOCH with worse PFS and OS in deletion 17p and complex karyotype patients. Better therapies for RT are urgently needed, especially in patients with poor risk CLL. Table 1. Characteristics of Aggressive Lymphoma n=46 Histology, no. (%)- Large Cell- Early large-cell/Prolymphocytic- Plasmablastic (EBV+)- High-grade B-cell 42 (91) 2 (4) 1 (2) 1 (2) Extranodal Disease- Yes- No 20 (43) 26 (57) Bulky Disease, no. (%)- Yes ≥5, <10 cm- Yes ≥10 cm- No- Unknown 16 (42) 8 (21) 14 (37) 8 Table 2. Adverse Events by Cycle Cycle 1 (n=40) Cycle 2 (n=29) Cycle 3 (n=15) Cycle 4 (n=12) Cycle 5 (n=11) Cycle 6 (n=7) Any AE* Infection Neutropenic Fever Hospitalization ICU Stay 29 (72%) 14 14 14 4 17 (59%) 7 4 7 0 7 (47%) 1 0 1 0 4 (33%) 1 0 1 0 2 (18%) 1 1 1 0 1 (14%) 0 0 1 0 *Hospitalization, infection, neutropenic fever, non-neutropenic fever, ICU stay, transfusion, mucositis, fatigue requiring treatment delay, and ileus. Disclosures Stephens: Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Byrd:Acerta Pharma BV: Research Funding. Maddocks:Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding. Jones:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.