Search

Introduction: Febrile neutropenia (FN) is a serious potential adverse event of myelosuppressive chemotherapy. Dose-adjusted EPOCH-R (DA-EPOCH-R: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, with doses adjusted to induce neutropenia of < 0.5 x 10 9/L) is a chemoimmunotherapy regimen used for aggressive lymphomas including diffuse large B-cell lymphoma, double/triple hit, Burkitt, primary mediastinal, and HIV-associated large cell lymphoma. It is associated with high rates of FN (13-25% of cycles) despite use of prophylactic Septra and granulocyte colony stimulating factor (G-CSF). Fluoroquinolone antibiotics have been used in various hematological malignancies to reduce infection rates while on chemotherapy, but this strategy has never been reported with DA-EPOCH-R. This study was conducted to assess the impact of adding routine Levofloxacin prophylaxis on FN and infection rates in patients receiving DA-EPOCH-R. Methods: This is a combined cohort study comparing the patients who received DA-EPOCH-R for newly diagnosed aggressive lymphoma at the London Regional Cancer Program in London, Ontario, Canada before and after the initiation of routine Levofloxacin prophylaxis in July 2020. The prospective cohort received Levofloxacin 500 mg x 7 days with each cycle starting on cycle day 8 in addition to standard supportive care with Septra and G-CSF. The primary objective was the rate of febrile neutropenia. Secondary objectives included days hospitalized, deaths related to infections, and adverse events secondary to Levofloxacin. Results: Thirty patients who received DA-EPOCH-R in the 5 years preceding the initiation of routine prophylactic Levofloxacin were included in the retrospective cohort. Median age was 58 (range 18-79), 66% were male, and 90% had stage III/IV disease. Total number of cycles of DA-EPOCH-R received was 110, with a median of 4 cycles per patient (range: 1-6). FN developed in 14 patients (46%), and complicated a total of 20 cycles (18%) of DA-EPOCH-R. There were 19 hospital admissions due to FN, with a median duration of hospitalization of 12 days (range 3-120). Two patients died, both due to infection. Thirteen patients have been treated so far in the prospective cohort, 12 of whom received levofloxacin prophylaxis. Median age was 59 (range 23-69), 66% were male, and 76% had stage III/IV disease. Total number of cycles of DA-EPOCH-R received was 60, with a median of 5 cycles per patient (range: 1-6 ). Only 1 patient (8%) developed FN, which complicated a total of 3 cycles (5%) of chemotherapy. All 3 episodes of FN resulted in hospitalization for a median duration of 30 days (range 20-49). There have been no deaths due to infection in this cohort thus far. No concerning adverse effects from Levofloxacin have been observed. Conclusions: Although enrollment in the prospective cohort is ongoing, preliminary data are highly encouraging, with significantly lower rates of FN and death due to infection observed since the introduction of routine Levofloxacin prophylaxis. The addition of Levofloxacin to standard prophylaxis with Septra and G-CSF seems to be an effective way to mitigate the risks to patients on DA-EPOCH-R for aggressive lymphomas, and this strategy is worthy of further study. Disclosures Lam: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.

BACKGROUND Between March 2012 and March 2013, a miscommunication in labelling between the drug compounder supplier and cancer centre pharmacies resulted in accidental overdilution of cyclophosphamide and gemcitabine used by several cancer centres in Canada. At our centre, 177 hematology patients were affected, among whom the largest subset of patients was those with diffuse large B-cell lymphoma. In this study, we evaluated the effect of such underdosing on disease response. METHODS We conducted a retrospective cohort study involving all patients with diffuse large B-cell lymphoma who received at least 1 chemotherapy cycle containing diluted cyclophosphamide at our centre and compared them with a historical group of patients matched by stage and age. The primary outcome was event-free survival (a composite of disease progression or death). Secondary outcomes included complete remission and overall response rate. Groups were compared using unpaired Student t, χ2 or Fisher exact tests, as appropriate. Survival analysis was done using the Kaplan-Meier method. RESULTS Event-free survival was no different between groups (log-rank p = 0.99). At a median follow-up of 548 days, progression or death occurred in 21 of 77 patients in the case group (27.3%) and in 24 of 74 patients in the control group (32.4%) (p = 0.5). At the end of treatment, complete remission was achieved in 41 patients in the case group (53.2%) and 43 patients in the control group (57.3%) (p = 0.6), whereas overall response rate was 71.4% in the case group and 66.7% in the control group (p = 0.5). INTERPRETATION Compared with a historical control group, we found no differences in event-free survival or response rates among patients with diffuse large B-cell lymphoma who received 1 or more doses of accidentally diluted cyclophosphamide-containing chemotherapy.

Background: Recurrent/refractory (r/r) DLBCL presents a major treatment challenge, especially in the setting of patients who are ineligible for, or relapsing after, potentially curative treatments such as autologous stem cell transplant (ASCT) and chimeric antigen receptor T cell (CAR-T) therapy. Efficacious treatment options that are well-tolerated and easily accessible in this population represent a critical unmet medical need. DPX-Survivac is a targeted T cell activation therapy against cancers expressing survivin. Survivin plays an essential role in cancer biology and represents a target of choice to disrupt tumour progression. DPX-Survivac's mechanism of action relies on its ability to generate robust and durable survivin-specific T cells that migrate to, infiltrate and kill tumour cells. DPX-Survivac is administered with intermittent, low dose cyclophosphamide (CPA) used as an immunomodulator. In nonclinical studies, treatment with DPX-Survivac increases PD-L1 and PD-1 expression providing the rationale for combination with pembrolizumab. Methods: "SPiReL" is a Phase 2 non-randomized, open label, efficacy and safety study. Subjects with r/r DLBCL with confirmed survivin expression are eligible for participation. Subjects must also be ineligible for potentially curative therapy. The treatment and testing regimen is shown in the figre below. The primary objective of SPiReL is to document a minimum Objective Response Rate (ORR) of 24% (in 6/25 subjects) using the modified Cheson criteria (2007). Secondary objectives include safety, duration of response and time to next treatment. Exploratory endpoints include T cell response, tumour immune cell infiltration, and biomarker analysis. Results: At data cut-off, 22 subjects have been enrolled in the study. The median age is 75.5 years (50-82). Thirteen of 22 subjects (59.1%) are GCB sub-type, 8 subjects (36.4%) are non-GCB and 1 subject (4.5%) has primary cutaneous DLBCL, leg type. The median number of prior therapies is 2 (1-7), with 4 subjects having previously undergone ASCT and 5 subjects with transformed disease. Of the 22 enrolled subjects, 8 are not evaluable per protocol for clinical efficacy due to early disease progression. Four subjects are active on treatment, 3 of which have not yet reached the first time point for assessment. Clinical outcome was analyzed for the Full Analysis Set (FAS) (n=19) and in the Per Protocol (PP) analysis (n=11). Of 11 subjects in the PP, 7 subjects (63.6%) have achieved an objective response, meeting the study's primary endpoint; 3 subjects (27.3%) with a CR and 4 subjects (36.4%) with a PR. Three subjects (27.3%) achieved SD and thus clinical benefit was demonstrated in 10/11 (90.9%) of evaluable subjects. Two subjects (18.2%) have completed the 1 year treatment period, 8 subjects (72.7%) discontinued treatment due to disease progression, and 1 subject (9.2%) discontinued treatment due to an unrelated Adverse Event (AE). Including the entire FAS, the objective response rate was 7/19 (36.8%). This treatment combination is well-tolerated, only 11% of Treatment Related AEs (TRAEs) were assessed as Grade 3 or higher. The majority of the Grade 1 and 2 TRAEs were Injection Site Reactions (ISRs) related to DPX-Survivac. Ten serious AEs were reported, of which 3 were considered related to study treatment. No subjects have discontinued study treatment due to a TRAE. Analyses of peripheral blood T cell responses to survivin by ELISpot assay shows that 7/7 subjects who achieved an objective response have survivin-specific T cell response. One subject with PD also showed a survivin-specific T cell response, supporting the mechanism of action and the role of DPX-Survivac in anti-tumor activity. Summary: DPX-Survivac and low dose CPA in combination with pembrolizumab, demonstrates promising clinical activity in recurrent/refractory DLBCL with 10/11 (90.9%) of evaluable subjects deriving clinical benefit with minimal toxicity. The primary endpoint of this study has been reached with 7/11 (63.6%) of evaluable subjects achieving an objective response warranting further exploration of DPX-Survivac in this population. Enrollment is continuing to further define the patient population most likely to benefit from this well-tolerated therapy. Figure 1 Disclosures Bence-Bruckler: Merck: Membership on an entity's Board of Directors or advisory committees. Forward:Seattle Genetics: Research Funding; IMV: Research Funding; Merck: Research Funding; Astellas: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; IMV: Membership on an entity's Board of Directors or advisory committees; Calgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Stewart:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria. Bramhecha:IMV Inc.: Current Employment. Conlon:IMV Inc.: Current Employment. OffLabel Disclosure: Keytruda (pembrolizumab). Indicated for use in melanoma, nonÃÆ'Ã'¢Ã¢ââ'¬Å¡Ã¢â€šâ'¬ÃƒÂ¢Ã¢â€šâ'¬Ã…“small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma (MCC), and renal cell carcinoma (RCC).

Introduction: Historically, CNS lymphomas have been associated with a very poor prognosis High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) with promising results in small recent small prospective phase 1/2 results and retrospective series. We hypothesized that the use of R-BuMelTt (rituximab, busulfan, melphalan, thiotepa) conditioning regimen with ASCT regimen will be effective for both patients with PCNSL and SCNSL as used in previously reported promising data by Oh et al 2016 for patients with SCNSL with higher remission and survival rates. Patients and Methods: A retrospective analysis was performed of 6 consecutive patients who had undergone R-BuMelTt conditioning regimen with ASCT for 3 patients with PCNSL and 3 patients with SCNSL from December 2017 to March 2020. The median age of this patient population was 62 years at the time of ASCT. The induction chemotherapy regimen used for patients with SCNSL was R-CHOMP except one patient who received DHAP, and for patients with PCNSL MATRix regimen was used. The median duration of chemotherapy cycles was 4, and all of them had achieved remission prior to transplant based on PET/CT scan/MRI scan. All patients were planned to undergo ASCT using the Conditioning Regimen of Rituximab 375 mg/m2 on Day-7, Thiotepa 250 mg/m2 on Day-6,-5, Busulfan 3.2 mg/kg on Day-4,-3,-2 and Melphalan 100 mg/m2 on Day-1. Supportive cares measures were given at treating physician's discretion. Results: Patients received a median cell dose of 4.4x106 CD34+cells/kg (range: 2.5-5.7), had neutrophil engraftment at 11.5 days (range:9-13), platelet recovery was achieved on days 11,15 and 16 for three patients but was delayed at 27, 46, 89 days for 3 patients. Infectious complications were common with documented bacteremia in in 3 out of 6 patients, 2 patients with c. difficile infection and with significant platelet support due to thrombocytopenia. At a median follow up of 24.5 months (range: 6-30 months), 5 out of 6 patients had complete metabolic response on radiological imaging with PET/CT in conjunction with MRI head. One of the patients with SCNSL died after transplant due to CNS relapse 223 days post ASCT giving an overall survival of 66.6%. Amongst the 2 patients with SCNSL that survived there was no relapse after 30 month follow-up. None of the patients with PCNSL died or relapsed during or after transplant therefore having a 100% overall survival. Although this is a small retrospective study, our results are comparable to current literature. Toxicities included nausea/vomiting, diarrhea, mucositis with 5/6 patients requiring TPN. Also busulfan PK levels were not done. Conclusions: R-BuMelTt regimen can be used successfully as conditioning regimen for ASCT for patients with PCNSL and SCNSL, however with increased hematological toxicity, most notably delayed platelet engraftment. The rate of progression free and overall survival is promising with short median follow up of 24 months. Disclosures Lam: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau.

Patients with mantle cell lymphoma (MCL) have a particularly poor prognosis when treated with standard chemotherapy, with a median overall survival of only 3 years. These patients have therefore been considered for first-line treatment with more aggressive or experimental strategies, such as high-dose therapy (HDT) with autologous stem cell transplantation (ASCT). While high rates of clinical remission have been achieved with HDT/ASCT, this procedure alone is not believed to be curative and different treatment strategies are being developed to improve outcomes in this group of patients. Single-agent rituximab is active in both newly diagnosed and relapsed MCL and therefore the addition of rituximab to chemotherapy regimens and/or HDT/ASCT may enhance their efficacy. Outside the transplantation setting, rituximab plus chemotherapy has been shown to be highly active in MCL, and preliminary data from randomized trials suggest that the combination may yield superior results compared with chemotherapy alone. The addition of rituximab to transplantation protocols appears to be a very promising strategy for patients with MCL, given as an in vivo purge before HDT/ASCT and/or as posttransplant maintenance therapy. Two phase II clinical trials with rituximab given as an in vivo purge during stem cell mobilization and as posttransplant immunotherapy in patients with previously untreated MCL have generated very promising data. Rituximab is an important addition to cytotoxic therapy and with HDT/ASCT represents a highly active therapy that may be superior to conventional treatment or HDT/ASCT alone in MCL. Randomized prospective studies and longer follow-up are needed to determine whether these regimens can achieve longer survival or possibly cure in this disease.

Desmopressin (DDAVP) is commonly used in the treatment of patients with type 1 von Willebrand disease (VWD) and mild hemophilia A. A patient's responsiveness to DDAVP based on a 0.3 μg/kg dose determines future therapeutic efficacy of the drug. The aim of the study was to determine whether a capped dose of 15 μg subcutaneous DDAVP is able to achieve the same level of DDAVP responsiveness as previously reported. This is a retrospective chart review of patients from 1995 to 2013 in adults and children with type 1 VWD and hemophilia A weighing more than 50 kg. Levels of factor VIII, ristocetin cofactor, and von Willebrand factor antigen were measured before and after 1 h of administration of 15 μg of DDAVP. In patients with type 1 VWD, the complete response rate was 82.5% with a partial response rate of 12.5% and 5% nonresponders. In patients with mild hemophilia A, the complete response rate was 53.8% with a partial response rate of 38.5% and 7.7% nonresponders. These results using a capped 15-μg dose of DDAVP are similar to previously published reports using the 0.3-μg/kg dose.

Radioimmunotherapy offers a unique treatment modality for indolent non-Hodgkin lymphoma (iNHL). We report 5-year outcomes and quality of life (QoL) in tositumomab and iodine(131)-tositumomab (TST/I(131)-TST) treated patients with iNHL previously treated with rituximab. Ninety-three patients with ≥ 2 lines of therapy, responding to last treatment, were enrolled at 12 Canadian centers. Median age, disease duration and number of prior therapies (#PTx) were 59 years, 4.9 years and 5, respectively. Outcomes were response rate (43.0%), median progression-free survival (mPFS) (12.0 months), 5-year PFS (27%) and median overall survival (OS) (59.8 months). In responders, median response duration and mPFS were not reached. Improvements in QoL were seen by week 7. In univariate and multivariate analyses, hemoglobin, disease bulk and body surface area (BSA) predicted OS, whereas lactate dehydrogenase (LDH), bulk, BSA and #PTx predicted PFS. Most common adverse events (AEs) were fatigue and nausea. Two cases of myelodysplastic syndrome (MDS) were reported. TST/I(131)-TST was associated with durable responses, and prolonged OS and PFS in heavily pretreated iNHL.

Background: There is no current standard of care therapy for the management of patients with aggressive lymphomas in the relapsed or refractory (R/R) setting who are not candidates for intensive salvage chemotherapy and/or autologous stem cell transplant (ASCT). The combination of lomustine (CCNU), etoposide and prednisone (CEP) is an oral chemotherapeutic regimen that is modified from CCEP used in Hodgkin Lymphoma (CCNU, chlorambucil, etoposide and prednisone). CEP consists of alternating A & B cycles as follows (Figure 1): 'A' cycles contain lomustine 80 mg/m2 on day 1 as well as etoposide 100 mg/m2 and prednisone 100 mg on days 1-7. 'B' cycles contain only the etoposide and prednisone. Cycles are given every 21 days apart. To date there has been no published data on CEP's efficacy and tolerability in aggressive R/R lymphoma. In this study, we describe our institutional experience with CEP at the London Regional Cancer Program (LRCP) in London, Ontario for patients with R/R aggressive lymphomas unable to tolerate intensive chemotherapy. Methods: We conducted a retrospective review of patients who received CEP at LRCP between January 2014 and May 2018 for R/R aggressive lymphomas. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse effects related to CEP. Kaplan-Meier survival curves modeled PFS and OS. We also performed univariate and multivariate analyses to assess whether pre-specified variables (age, IPI score at diagnosis, LDH at time of treatment, and the number of prior lines of therapy) were independently associated with response to CEP (using linear regression) or progression-free survival (using the Cox proportional hazards model). IPI score (0-2 vs. 3-5) and the number of prior lines (1-2 vs. ≥ 3) were analyzed as binary variables due to the overall sample size. Results: 46 patients received CEP at LRCP during the study period. Diffuse large B-cell lymphoma was the most common diagnosis (70%) with Hodgkin lymphoma (6.5%) and peripheral T-cell lymphoma (6.5%) being the next most common. The median age of patients starting CEP was 76, with the median number of prior therapies being 2 (range 1-6). The primary outcome was ORR, which was 41% in our population, with a median time to response of 23 days. The median PFS was 2 months while the median OS was 4 months (Figure 2). The 2-year PFS and OS were both 8.7%. The median CEP treatment period was 1.5 full cycles while the longest CEP treatment period was 21 consecutive cycles. Univariate analysis revealed that lower IPI score (p=0.037) was significantly associated with ORR, while lower LDH (p=0.029) was significantly associated with PFS. Multivariate analyses revealed no factors associated with ORR, while lower LDH (p=0.017) and lower IPI (p=0.037) were associated with PFS. Toxicities were manageable with 48% with cytopenias of any grade and the most common grade 3-4 toxicity was febrile neutropenia in 13%. Conclusions: CEP is a safe, and convenient, all-oral palliative regimen for R/R aggressive lymphoma who are not eligible for intensive salvage chemotherapy or ASCT. The median OS in our population is comparable to pooled clinical trial and academic center data from non-transplant eligible patients with R/R DLBCL (Crump et al, Blood, 2017). Some patients even in spite of low performance statuses were able to tolerate many cycles of CEP with a long period of disease control, suggesting it is a reasonable treatment option for frail patients to balance disease control with an acceptable side-effect profile. Disclosures Lam: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Other: Education Grant; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Phua:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

This phase 1 study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of obinutuzumab (GA101), a glycoengineered type II anti-CD20 monoclonal antibody administered as induction followed by 2 years of maintenance. Cohorts of 3 to 6 patients received obinutuzumab (200-2000 mg) intravenously weekly for 4 weeks. Patients with a complete or partial response (or stable disease and clinical benefit) continued to receive obinutuzumab every 3 months, for a maximum of 8 doses. Twenty-two patients with relapsed CD20-positive non-Hodgkin lymphoma or chronic lymphocytic leukemia with an indication for treatment and no therapy of higher priority were enrolled. Patients received a median of 4 prior regimens; 86% had received at least 1 rituximab-containing regimen. No dose-limiting or unexpected AEs were observed. Infusion-related reactions were most common (all grades, 73%; grade 3/4, 18%), followed by infection (32%), pyrexia (23%), neutropenia (23%), headache (18%), and nausea (18%). At end of induction, 5 (23%) patients achieved partial responses and 12 (54%) had stable disease. Eight patients received maintenance; best overall response was 32% (6 partial responses/1 complete response). Obinutuzumab induction and maintenance therapy was well tolerated with promising efficacy in this heterogeneous, highly pretreated population and warrants further investigation. This study was registered at www.clinicaltrials.gov (identifier NCT00576758).

It is estimated that 4-10% of patients with chronic lymphocytic leukemia (CLL) will develop autoimmune hemolytic anemia (AIHA) over the course of their disease. Ibrutinib has proven to be effective in treatment of relapsed, refractory, 17p deleted, and treatment naïve CLL. The effect of ibrutinib on AIHA in the context of CLL has not been established since patients with active hemolysis were excluded from major trials. In this abstract, we present a case series of patients that were actively hemolyzing at the start of ibrutinib therapy and in which their AIHA achieved prolonged response. Patient characteristics and laboratory data are shown in Table. Five patients (3 women, 2 men), median age 61 years (range 57 to 78), with CLL and active, uncontrolled AIHA at the time of ibrutinib initiation were identified. Uncontrolled AIHA was defined as anemia with evidence of hemolysis (at least two of the following: increased reticulocyte count, elevated lactate dehydrogenase, elevated indirect bilirubin, and reduced haptoglobin and a positive direct antiglobulin test (DAT)). Patients had a median hemoglobin of 70 g/L (range 69-96) prior to start of ibrutinib and 3 of them required transfusion support for symptomatic anemia. All patients were receiving prednisone for management of AIHA at the time of ibrutinib initiation and had been on it for a median of 10 days (range 9 - 25) without AIHA resolution. 1 patient received intravenous immunoglobulin concurrently. All patients had received at least one line of therapy for CLL in the past and 3 had experienced previous AIHA responsive to steroids. AIHA in 2 patients was related to previous fludarabine exposure but had responded to a prednisone tapering schedule and were off steroids by the time of the new AIHA flare. Median hemoglobin of 130 g/L (range 113-149) was reached at time of AIHA response. All 5 patients tolerated 420mg oral daily of ibrutinib therapy and AIHA was controlled in a median of 6.5 weeks (range 6-10). Discontinuation of steroids was achieved in all patients at a median of 10 weeks (range 6-17) without evidence of further hemolysis. All patients except one are receiving ongoing follow up and have been followed up for a median of 130 weeks (range 15-150) since ibrutinib start. Patients have not shown evidence of AIHA relapse and continue off AIHA treatment (prednisone). One patient required discontinuation of ibrutinib 6 months after starting due to neutropenia but there was no evidence of AIHA relapse in follow up. The patient has passed away from unrelated GI bleed 2 years after the initial AIHA event. This is the largest case series to our knowledge on the safe start of ibrutinib in CLL complicated by active AIHA. Hemolysis in all patients responded to a short prednisone taper with ibrutinib concurrently and obtained a sustained response at follow up without any flare ups or further AIHA treatment use. These cases suggest that it is safe to start ibrutinib during uncontrolled, active hemolysis in contrast to 2 previous case reports that suggested causal relationship between ibrutinib and onset of severe CLL-associated AIHA (Rider et al, 2015; Hodskins et al, 2014). As previously reported, AIHA occurrence or relapse once ibrutinib has been started is rare (Rogers et al, 2016). Disclosures No relevant conflicts of interest to declare.

Mediastinal radiation can accelerate atherosclerosis in Hodgkin lymphoma survivors (HLS), and early detection is optimal. Peripheral arterial tonometry (PAT), a non-invasive measure of endothelial function, is a surrogate marker of sub-clinical atherosclerosis. The objective of our study was to evaluate endothelial function in HLS and controls using PAT and to determine the influence of mediastinal radiation.Cross-sectional evaluation was performed on 26 HLS aged 12-30 years who were a minimum of 2 years from therapy, and their healthy age and gender matched controls. Evaluation included assessment for cardiovascular risk factors and completion of the Habitual Activity Estimation Score (HAES) questionnaire to assess activity level. Endothelial Function was measured using PAT hyperemia ratios (PAT-HR).HLS and controls were similar for baseline variables (mean age 23.3 +/- 5 yrs vs. 23.4 +/- 4.8 yrs, p = 0.92). HLS were on average 6.7 +/- 4.6 yrs post treatment. No differences in endothelial function or cardiovascular risk factors were observed between HLS and controls. However, impaired endothelial function, as evidenced by lower PAT-HR (1.67 +/- 0.39 vs. 2.03 +/- 0.37, p0.01) was seen in HLS (n = 13) who received mediastinal radiation (mean radiation dose 2,600 +/- 840 cGy) compared to controls.Impaired endothelial function was preferentially observed in HLS who received mediastinal radiation, while no difference was observed between the HLS and control groups overall. This finding, assessed using a non invasive test of endothelial function, confirms that mediastinal radiation is an additional cardiovascular risk factor in this young cohort of patients. Further studies of endothelial function in this patient population are warranted.

Background Little is known about the pharmacokinetics of rituximab in an autologous stem cell transplant (ASCT) setting. Patients and methods We evaluated serum rituximab levels in 26 patients with follicular or mantle cell lymphoma treated with a combination of ASCT and immunotherapy. Patients received nine infusions of rituximab (375 mg/m2): one dose as an ‘in vivo purge’ prior to stem cell collection, and two 4-week cycles at 8 and 24 weeks following ASCT. Pre- and post-infusion serum rituximab levels were measured during the purging dose, with doses 1 and 4 of both sets of maintenance rituximab cycles, and 12 weeks and 24 weeks following treatment. Results Rituximab levels were detectable after the first infusion, and peaked at a mean concentration of 463.8 µg/ml after the final dose. Levels remained detectable 24 weeks after completion of treatment. There was a trend toward higher rituximab levels in patients with follicular lymphoma. Serum concentrations achieved during the maintenance cycles were similar to levels observed in patients with measurable lymphoma treated during ‘the pivotal trial’. No correlation was observed between serum rituximab levels achieved in the minimal disease state and the risk of later clinical relapse, nor with the ability to achieve a molecular remission following ASCT. Conclusions The finding that patients treated in minimal disease states and at the time of active disease both achieve similar final serum rituximab concentrations after four infusions suggests that the pharmacokinetics are complex, and may not necessarily correlate with disease burden. The precise factors influencing rituximab clearance in patients with lymphoma are unresolved, and this remains an area of active research.

Patients with relapsed or refractory lymphoma often require treatment with aggressive chemotherapy. At McGill University, a combination of high dose VP-16 and cyclophosphamide (VP-CY) is commonly used as a salvage regimen. In recent years, cytogenetic abnormalities of the long arm of chromosome 11 at band 23 (11q23) have been linked to the use of VP-16, and may be associated with secondary myelodysplastic syndrome or acute leukemia. Therapy related 11q23 anomalies have not been widely studied in lymphoma patients. We have identified and reviewed the course of 107 patients who have been treated with VP-CY. Thirty-five patients remain alive and 21 consented to participate in our study. Patient bone marrows were studied morphologically, cytogenetically and molecularly, to identify any new changes that may have developed over the course of their treatment, with a special emphasis on the search for 11q23 rearrangements. Mean time between VP-CY treatment and marrow evaluation was 3.6 years. Of the 21 patients, 5 had Hodgkin's disease (HD) and 16 had non Hodgkin's lymphoma (NHL). They received a total of 30 cycles of VP-CY. Response rate was 100%, with 16 complete and 5 partial responses. Eighteen patients later underwent autologous stem cell transplantation. At the time of study, 19 of the patients were disease free and 2 were in relapse. On morphological analysis, 12 marrows appeared normal and 6 showed mild dyserythropoiesis. Standard cytogenetics was done to examine for any new chromosomal translocations or deletions. All cytogenetic studies yielded normal results. Molecular analysis by Southern blot was done on 15 patients in a search for 11q23 rearrangements, including the partial tandem duplication of ALL-1. All molecular studies were normal. We conclude that the use of VP-CY, given in our treatment schedule, does not appear to be associated with an increased risk of developing 11q23 rearrangements.

The long median survival time of patients with follicular non-Hodgkin's lymphoma (NHL), means that the efficacy of new treatments are difficult to assess in the short term. Bcl-2 is an inhibitor of apoptosis and overexpression of the bcl-2 gene in the blood or bone marrow is a feature in up to 85% of patients with follicular NHL. Levels of bcl-2+ cells in the peripheral blood or bone marrow therefore are a useful measure of disease status in such patients and can be detected by polymerase chain reaction (PCR). Complete bcl-2 clearance from the bone marrow (molecular remission) following autologous stem cell transplant (ASCT) for follicular NHL is considered to be an important prognostic factor for disease-free survival. Tumour cell contamination of the stem cell grafts used in ASCT is commonly associated with relapse. This can be addressed by purging the stem cell harvest prior to transplantation. Various methods of in vitro purging after stem cell collection have been shown to reduce the level of contamination but yield is invariably reduced and grafts remain bcl-2 positive. However, in vivo purging with rituximab during the process of collection has been used to obtain bcl-2-negative stem cell harvests without compromising the yield. Rituximab is a monoclonal antibody licensed for treatment of relapsed and refractory low-grade or follicular NHL. Rituximab targets the CD20 antigen, which is found on cells of the B cell lineage. When used for in vivo purging it depletes the peripheral blood of CD20-positive cells and prevents contamination by lymphoma cells. Molecular remission, as measured by bone-marrow bcl-2 clearance, has been achieved in 7/7 patients with follicular NHL at 1 year after treatment with ASCT using rituximab as an ‘in vivopurse’, followed by rituximab maintenance. Early clinical outcomes are also encouraging. Bone Marrow Transplantation (2002) 29, Suppl. 1, S14–S17. doi:10.1038/sj.bmt.1703297

Although patients with Hodgkin lymphoma treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy frequently develop neutropenia, febrile neutropenia is uncommon. Three retrospective trials reported that ABVD could be safely administered without dose delays or granulocyte-colony stimulating factor (G-CSF) support. We retrospectively reviewed the charts of 89 patients treated with ABVD and found that the incidence of febrile neutropenia was 0.5% (five of 927 treatments). This prompted a change to our institutional policy so that patients receiving ABVD no longer receive routine G-CSF for uncomplicated neutropenia. We then prospectively assessed the safety of this policy change. Thirty-three patients received a total of 327 ABVD treatments, 185 (57%) of which were administered with a neutrophil count

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL). However, combined therapy is associated with increased neurotoxicity. In an effort to limit this toxicity, we treated a series of non-immunocompromised patients with HDMVP, a HD-MTX based regimen, with deferral of WBRT until progression. Twenty-three patients were treated with the HDMVP regimen consisting of MTX, vincristine, and procarbazine. The mean age at diagnosis was 60.9 years (range 45-79 years). The overall response rate was 65% (14 complete responses and one partial response). For patients achieving an initial response with HDMVP the median response duration was 40.4 months (95% confidence interval [CI] 19.5-61.3). The median progression-free survival was 4.6 months (95% CI 0.0-20.4) and median overall survival was 41.4 months (95% CI 0.0-95.5). Fourteen patients received WBRT for relapsed or progressive disease. The conclusion of this trial is that HDVMP results in good initial response rates but only moderate disease control. Ultimately the majority of the patients in this series required WBRT for salvage treatment, potentially enabling a delay in treatment-associated neurotoxicity.

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61-95%) and 59% (95% CI 38-80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P

Background: An error at the drug compounder source resulted in accidental over-dilution of the chemotherapy drugs cyclophosphamide and gemcitabine utilized by several cancer centers in Ontario and New Brunswick in Canada between March 2012 and March 2013. The exact degree of unintentional dose reduction for each patient is unknown, but the estimate is between 3-20% given the type of dilution error. One thousand two-hundred and two cancer patients were affected overall, including 177 hematology patients at London Regional Cancer Center (LRCP). We evaluated the effect of cyclophosphamide under-dosing on patients with diffuse large B cell lymphoma (DLBCL) treated with chemotherapy containing cyclophosphamide (mostly R-CHOP), the largest subset of patients affected. Methods: We conducted a retrospective cohort study of all DLBCL patients at LRCP who received at least one cycle of chemotherapy containing diluted cyclophosphamide between March 2012 and March 2013. The affected cohort was compared to a historical group of DLBCL patients matched by stage (early versus advanced) and age (±5 years) who were treated prior to the dilution error from January 2008 to December 2010. The main study outcome was event-free survival defined as a composite of disease progression or death. Groups were compared using unpaired Student’s t-test, Chi-squared or Fisher’s exact tests, as appropriate. Survival analysis was done using the Kaplan-Meier method. Results: Seventy-seven patients received diluted cyclophosphamide and were matched to 74 historical controls. There were no differences in the baseline characteristics between groups ( Table 1 ). Complete remission was achieved in 41 (53.2%) cases and 43 (58.1%) controls (p= 0.55). Overall response rate was 71.2% in cases and 67.6% in controls. At a median follow up of 490 days, progression or death occurred in 21 (27.3%) cases and 24 (32%) controls (P= 0.49). Survival analysis of the main outcomes showed no difference between the two study groups (log rank 0.999). Conclusion: There is no difference in the rate of response or in event-free survival among DLBCL patients receiving one or more doses of accidentally diluted cyclophosphamide, compared to a matched historical control group. This suggests that a minor dose reduction in 1 drug in multi-agent chemotherapy may be inconsequential in terms of disease response and risk of relapse. | Variable | Cases N=77 | Control N= 74 | P value | | ----------------------------------------------- | -------------------------- | -------------------------- | ------- | | Male [N (%)] | 39 (52) | 36 (48) | 0.87 | | Age (Mean) Interquartile range | 77 (SD ± 16) 55-79 | 66 (SD±14) 56 - 77 | 0.665 | | Age > 60 [N (%)] | 29 (37.7) | 24 (32.4) | 0.5 | | LDH [Mean (SD)] | 408 (375) | 394 (50) | 0.819 | | WBC [Mean (SD)] | 8.2 (4) | 7.5 (3) | 0.193 | | Hemoglobin[Mean (SD)] | 117 (22) | 120 (21) | 0.348 | | Platelets [Mean (SD)] | 259 (175) | 253 (128) | 0.82 | | Extra-nodal > 1 [N (%)] | 18 (23.4) | 18 (24.3) | 0.89 | | Stage III/IV [N (%)] | 53 (68.9) | 51 (68.8) | 0.99 | | B-symptoms [N (%)] | 44 (57.1) | 43 (49.4) | 0.83 | | ECOG ≥ 2 [N (%)] | 33 (42.9) | 36 (49.3) | 0.4 | | High LDH [N (%)] | 52 (67.5) | 43 (58.1) | 0.23 | | High risk (R-IPI of score ≥3) [N (%)] | 27 (35.1) | 28 (37.8) | 0.5 | | Prescribed (intentional) dose reduction [N (%)] | 23 (30) | 25 (34.7) | 0.52 | | Radiation therapy [N (%)] | 33 (42.9) | 34 (46.6) | 0.53 | | Febrile neutropenia [N (%)] | 21 (27.3) | 15 (20.3) | 0.31 | | GCSF use [N (%)] | 48 (62.3) | 38 (53.5) | 0.28 | Table 1 Baseline Characteristics ![Figure 1][1] Figure 1 Disclosures No relevant conflicts of interest to declare. [1]: pending:yes

Abstract 4987 Introduction: Central nervous system (CNS) involvement by non-Hodgkin lymphoma (NHL) is a rare but serious complication with a high mortality rate and few effective therapeutic options. Rituximab is an anti-CD20 monoclonal antibody that is administered systemically in combination with chemotherapy, but can also be given intrathecally. When administered intrathecally (IT), rituximab achieves more predictable and higher cerebrospinal fluid (CSF) concentrations compared to its intravenous administration, however the efficacy and safety of IT rituximab are unknown (Rubenstein et al., J Clin Oncol 2007). We recently treated a 52 year old woman for a CNS relapse of diffuse large B-cell lymphoma (DLBCL) using a combination of IT rituximab, cytarabine, methotrexate and hydrocortisone, as well as craniospinal radiation. After initial improvement, she developed subacute combined degeneration (SCD) of the spinal cord. This prompted the present systematic review of the literature in order to explore the efficacy and safety of administering rituximab directly into the CSF for the treatment of CNS involvement by NHL. Methods: We identified all relevant citations in MEDLINE/EMBASE/CINAHL/BIOSIS Previews from their date of inception to June 20th, 2011. Prospective studies, case reports and case series reporting on intrathecal or intraventricular (via ommaya-reservoir) use of rituximab in relapsed primary (PCNSL) or secondary CNS-lymphoma were included. All articles citing the included articles, as well as the reference lists of included articles were reviewed to ensure capture of all relevant studies. In some cases, authors were contacted to gather additional information. Two authors independently evaluated study eligibility. Disagreements were resolved by consensus and agreement was assessed using the kappa statistic. All non-human studies were excluded. Due to the nature of the studies, a meta-analysis was not performed. Results: The search strategy identified 148 potential reports published between 2002–2011 of which 22 were included (3 prospective trials, 2 phase-I trials, 2 case-series and 15 case reports). The kappa value for inter-author agreement was 0.881. A total of 74 patients, aged 4–84 years old (Mean age 48), with PCNSL (28%) or secondary CNS-Lymphoma (ALL 14%, DLBCL 8%, Burkitt's 4%, Mantle Cell Lymphoma 5%, Post-transplant lymphoproliferative disorder 4%, Unknown histology 37%), received 1 to 22 doses of 10–50mg of intrathecal (43%) or intraventricular (IVT) rituximab, either alone or in combination with other therapies. At a mean follow-up of 43 weeks (Range 2–178), 34% of patients were in complete remission and 28% showed a partial response. Patients having both leptomeningeal and parenchymal involvement of CNS lymphoma were the most likely to have progression of disease with IT/IVT rituximab (44%), as compared to those with isolated disease in the leptomeninges (29%) or parenchyma (33%). Fifty percent of patients with isolated disease in the leptomeningeal compartment showed complete remission with IVT/IT rituximab therapy. Fatigue, nausea/vomiting and paresthesias were the most commonly reported side effects. In one series, seven patients developed arachnoiditis. There was a single case of Hepatitis B virus reactivation in a patient with parenchymal PCNSL. In addition, our patient developed symptoms and findings consistent with SCD and in whom a relation between SCD and rituximab could not be ruled out. Conclusion: In case series and reports, IT rituximab appears to be a safe and modestly effective therapy when used in conjunction with other salvage therapies for the management of refractory CNS-lymphoma. The overall proportion of complications appears to be reasonably low. To our knowledge, our patient is the first case of SCD reported in a patient who received IT rituximab. Further studies with a particular emphasis on safety are needed before widespread use can be recommended. Disclosures: Off Label Use: Systematic literature review on the use of intrathecal rituximab for CNS lymphoma (off-label use). Lazo-Langner:Leo Pharma: Honoraria; Pfizer Inc.: Honoraria.

Abstract 3112 Objective: To compare the utility of high sensitivity (5-colour) flow cytometry (FCM) vs. conventional cytology (CC) for detecting cerebrospinal fluid (CSF) involvement in patients with hematological lymphoid malignancies. Methods: The results of diagnostic evaluations on all CSF samples analyzed for involvement by neoplastic lymphoid cells between January 2005 and February 2010 were reviewed retrospectively. Cases were identified by reviewing logs of all FCM procedures performed during that time period. FCM was performed on the CSF using a 5-antibody panel (“high sensitivity”). Result: 108 patients (62M/46F) diagnosed with non-Hodgkin lymphoma or acute lymphoblastic leukemia underwent a total of 609 lumbar punctures (LP). The 359 samples that were sent for both CC and FCM form the basis of this analysis. The majority of the LP's (312/359, 87%) were negative for malignant cells by both FCM and CC (FCM-/CC-). 47 samples showed infiltration by tumor cells; of these, 25 (7%) were FCM+/CC+, and 22 (6%) were FCM+/CC-. No cases (0%) were FCM-/CC+. Using FCM as the gold standard, CC had a specificity of 100%, but a sensitivity of only 53%. Conclusion: High-sensitivity FCM has superior sensitivity to CC for diagnosing leptomeningeal involvement by lymphoid malignancies. CC failed to identify any additional cases that were not seen on FCM. This raises the question of whether performing CC on CSF samples to search for neoplastic lymphoid cells is of any additional diagnostic value. Disclosures: No relevant conflicts of interest to declare.

2502 Poster Board II-479 Background: Patients with Hodgkin Lymphoma (HL) being treated with ABVD chemotherapy frequently develop neutropenia, though the complication of febrile neutropenia is relatively uncommon. In most cancer centres, including our own until recently, the presence of neutropenia on the planned day of chemotherapy administration (absolute neutrophil count (ANC)

Abstract 934 Background: GA101 (RO5072759) is the first humanized glycoengineered type II anti-CD20 monoclonal antibody to enter clinical trials. Preclinical studies have shown superior efficacy compared to rituximab and an initial phase I trial with 3-weekly dosing (Salles, ASH 2008) has demonstrated promising activity. The current phase I study has investigated the pharmacokinetics, safety and tolerability of escalating doses of GA101 administered on a weekly x 4 schedule followed by maintenance therapy. Methods: Patients with relapsed/refractory CD20+ malignant disease for whom no therapy of higher priority was available were treated with GA101 monotherapy administered as a flat dose on days 1, 8,15 and 22 (with first infusion administered at 50% of cohort dose). Cohort doses were escalated based on safety in a 3+3 design. Tumor response was assessed at 3 months. Patients achieving a CR or PR were eligible to receive 3-monthly maintenance GA101 × 2 years. Select patients with stable disease (SD) and major clinical benefit were also permitted to receive maintenance therapy. Results: Since January 2008, 22 patients at 5 Canadian sites have been treated with GA101 at doses ranging from 100 mg to 2000 mg. Safety data is available on all patients, 20 of whom are evaluable for response following induction. The median age was 59 yrs (47-77). Histologies included follicular lymphoma (10), CLL (5), DLBCL (3), SLL (2), MCL (1) and MZL with high-grade transformation (1). Patients were highly pretreated, receiving a median of 4 (1-7) prior therapies: 19/22 (86%) had been treated with rituximab at least once, median was twice (1-4). 11/22 patients (50%) were refractory to rituximab. GA101 was well tolerated with no dose limiting toxicities observed across the escalating dose cohorts. The most common adverse events were grade 1/2 infusion-related reactions (IRRs), characterized by fever, chills, hypo/hypertension, nausea and vomiting. IRRs were mainly associated with the first infusion (16 events), with decreased frequency in subsequent infusions (only 8 events for all subsequent infusions). There were 4 grade 3 IRRs (one associated with tumour lysis syndrome) and one grade 4 IRR (with hypoxia) on day 1, the grade 4 event leading to the only permanent discontinuation from the protocol. During the induction period, a total of 6 minor infections and one episode of febrile neutropenia were reported in 4 patients. Five cases of grade 3/4 neutropenia (1 febrile) were reported in 4 patients and 1 case of grade 3 thrombocytopenia. To date, 8 serious adverse events have been reported in 7 patients (two of which were IRRs). Two patients have died, one with DLBCL who completed induction but progressed and died prior to efficacy assessment and one with follicular lymphoma who progressed and died on day 133. Measurement of plasma cytokines during and immediately after the first infusion showed an increase in IL6 and IL8 with a smaller increase in IL10 and TNF , a pattern of change that is broadly similar to other anti-CD20 antibodies. Minimal change in complement fractions was observed, which is in keeping with the known pre-clinical profile of GA101. GA101 pharmacokinetics in this study was characterized by two clearance components, one linear and one saturable, consistent with target-mediated disposition. Peak serum concentration levels were achieved by the third dose with significant inter-patient variability in peak levels noted. The overall response rate was 25% (5 pts, all PRs) with 13 patients having SD and 2 progressing. Of those patients with SD, 6/13 had objective evidence of tumour shrinkage, with one consolidating to a PR with maintenance treatment. Clinical benefit was seen across all dosing cohorts, including rituximab-refractory patients. The overall (best) response rate in patients with lymphoma was 38% (6 PRs). In all, 8 patients have continued on to maintenance treatment following induction, 3 of whom have subsequently progressed (2 aggressive lymphoma, 1 CLL). 5 patients remain on maintenance therapy; 4 in remission with durations ranging from 73 to 258 days and one patient with SD. Conclusion: GA101 is a novel type II anti-CD20 monoclonal antibody that appears to have a safety profile similar to rituximab with promising efficacy in a clinically heterogeneous, heavily pretreated, end-stage patient population. Following review of pharmacokinetic and efficacy data, a dose of 1000 mg has been selected for ongoing phase II trials. Disclosures: Sehn: Roche, Inc: Consultancy, Honoraria, Research Funding. Stewart:Roche, Inc: Honoraria, Research Funding. Pisa:F Hoffman La Roche: Employment. Kothari:Roche Products Limited : Employment. Crump:Roche, Inc: Honoraria.

Background: Central nervous system (CNS) involvement by non-Hodgkin’s lymphoma (NHL) portends a very poor prognosis. There is no consensus in the literature on the “high- risk” features that predict for leptomeningeal disease, and no standardized clinical guidelines exist regarding CNS surveillance, prophylaxis or treatment for patients at increased risk. 2–4 colour flow cytometry (FCM) has been reported to be more sensitive than standard cytology in detecting occult leptomeningeal disease (Blood 2005,105:496). The current study evaluates the utility of a high-sensitivity (5-colour) flow cytometry technique for detecting occult lymphoma cells in the cerebrospinal fluid (CSF) of high-risk patients with NHL. Method: Patients with a new diagnosis of histologically aggressive B or T cell NHL were included in this study if they displayed one or more “high-risk” features for CNS involvement. Patients suspected of CNS relapse of NHL were also eligible for participation. Patients underwent routine staging investigations, with the addition of a diagnostic lumbar puncture (LP) during initial assessment. CSF was tested by standard cytology, cell count and biochemistry, and an additional 5 ml was obtained for analysis by high-sensitivity FCM on a Beckman Coulter FC500. The antibody panel (5 antibodies per tube) was customized according to the phenotype of the lymphoma. The key markers for B cell lymphoma were CD19/kappa/lambda with CD5 or CD10. CD45 was used to identify all white blood cells in the sample. Results: Seventeen patients (8M/9F) with a median age of 59 (range 36–85) have been tested. Patients displayed anywhere from 2–6 “high-risk” features for CNS involvement. These included: HIV positivity (2), primary mediastinal B-cell lymphoma (4), bone marrow (5), multifocal bone (2), paraspinal (1), nasopharyngeal (2) or orbital (1) involvement, elevated serum LDH (12), multiple extranodal sites of disease (5), poor performance status (2), high IPI (3), B-symptoms (9), stage IV disease (11), and otherwise unexplained neurological symptoms (3). 14 patients underwent CSF analysis at time of initial diagnosis, one of whom had cranial nerve palsies secondary to a nasopharyngeal mass extending to the skull base. The other 3 were tested at relapse, transformation, and suspected CNS relapse ultimately diagnosed as a stroke. Despite the presence of these features, CSF analysis was negative for lymphoma cells by both cytology and FCM in all but one of the patients tested. However this patient had very high numbers of circulating lymphoma cells in the peripheral blood (PB), and the positive result was felt to be due to PB contamination of the CSF during a “bloody tap.” One patient with vague neurological symptoms had a negative LP at diagnosis, and later developed frank CNS involvement by lymphoma, but was too unwell to undergo a repeat LP. Conclusions: Given the limited number of patients enrolled thus far and the low prevalence of patients with NHL and CNS involvement (2/17), it is difficult to fully assess the utility of high-sensitivity FCM in the diagnosis of occult leptomeningeal disease. It is of interest that CSF analysis was negative even in the patient with cranial nerve palsies and in the patient who later developed multiple CNS lesions secondary to lymphoma, suggesting that this technique may have limited sensitivity in diagnosing leptomeningeal disease. The systematic screening of high-risk patients cannot yet be recommended as standard clinical practice.

Background: Central venous catheters (e.g., PICC lines and Hickman-type catheters) in patients with cancer are associated with development of DVT in 1–3%. Patient management varies from immediate removal of the line, with or without anticoagulation, to the extreme of thrombolytic therapy. This multicenter cohort clinical trial was designed to assess the safety and effectiveness of a management strategy for central venous catheter-related UEDVT in cancer patients consisting of dalteparin and warfarin as a means of salvaging the line without the need for line removal. Methods: Patients greater than 18 years-of-age with an active malignancy and who had symptomatic, acute, objectively documented UEDVT were eligible. Patients were excluded if the catheter was a dialysis catheter, they had active bleeding or a high risk for major bleeding, platelet count 177μmol/l, if they were currently on therapeutic doses of warfarin, inability to infuse through the catheter after a trial of intraluminal thrombolytic therapy (2mg TPA), had AML or ALL or bone marrow/stem cell transplant planned in the next 3 months or if they did not provided written informed consent. Four centers in Canada participated. Patients were treated with dalteparin 200 IU/kg per day for 5–7 days and simultaneously initiated on warfarin with a target INR of 2.0–3.0. Patients were followed for 3 months for recurrent venous thromboembolism, major hemorrhage and survival of the central venous catheter. Results: There were 74 patients (48 males) enrolled from November 2002 to December 2005. The average age was 58 years. Seventy-one UEDVTs were diagnosed by ultrasound and three by CT. There were 57 PICC lines, 14 portacaths and 3 Hickman catheters. Sixty-four patients (86%) completed three-month follow-up. Of the 10 who did not, 7 died (6 due to cancer and 1 due to a major bleed) and 3 others were no longer evaluable (2 patients were treated with LMWH only and another patient had the line removed against protocol). There were no episodes of recurrent venous thromboembolism and 3 (4%) major bleeds. For the endpoint of line survival, 42 (57%) of the lines were in situ and still functional at three months. No lines were removed due to infusion failure or recurrence/extension of DVT. In the 32 patients who had line removal before the study three-month endpoint, 21 were due to the end of therapeutic need, 2 were due to infection and 9 for other reasons such as falling out, skin irritation, patient request, etc. Hence, 63 (85%) patients were able to maintain the central line until it was no longer needed, or for at least three months. For the 11 others, none were removed due to venous thrombosis or line failure. Conclusion: Treatment of UEDVTs secondary to central catheters in cancer patients with standard dalteparin/warfarin can allow the central line to remain in situ with little risk of line failure or recurrence/extension of the DVT.

Background: We previously reported that 20 patients with newly diagnosed, stage III/IV mantle cell lymphoma (MCL) treated prospectively with an in vivo rituximab purge, autologous stem-cell transplantation (ASCT) and rituximab maintenance experienced superior progression free survival (PFS) compared to 40 matched, historical controls treated with conventional chemotherapy. We now report extended follow-up from this trial. Methods: Eligible patients were treated with 4–6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by high dose therapy (cyclophosphamide, carmustine and etoposide) and ASCT. Rituximab (375 mg/m2) was given once 5 days prior to stem cell collection (as an in vivo purge), and as two, 4-week maintenance courses 8 and 24 weeks after ASCT. Historical control patients matched for age, stage and gender were randomly selected from a lymphoma database maintained by the British Columbia Cancer Agency. Two control-patients were selected for every trial patient. All control patients were treated with either an anthracycline based-regimen, or a regimen containing fludarabine and cyclophosphamide. Results: Median follow-up is 5.3 years for the experimental cohort and 10.1 years for the control cohort. In the ASCT cohort, 8 patients have relapsed and 4 patients have died, 2 of progressive disease, 1 of a presumed cardiac event 7 months post-ASCT, and one of hepatitis B reactivation 11 months post-ASCT. Five-year OS and 5-year PFS were superior in MCL patients treated with ASCT+ rituximab compared to matched, historical MCL patients treated with conventional chemotherapy (5y OS 80% vs. 38%, P=0.0017; 5y PFS 72% vs. 19%, P=0.0001). One patient developed myelodysplastic syndrome 5.5 years after ASCT, and one patient was diagnosed with breast cancer 4.8 years after ASCT. Conclusions: With more than 5 years of follow-up MCL patients treated with ASCT plus rituximab continue to experience significantly improved OS and PFS compared to matched, historical controls. Overall Survival Overall Survival

Background: Cancer patients may experience significant delays along the clinical pathway from the onset of symptoms to initiation of treatment. Few studies have examined the nature or the extent of these delays in patients with non-Hodgkin’s lymphoma (NHL). Method: London Regional Cancer Program (LRCP) is a tertiary care centre with a referral base of 1.5 million people in Southwestern Ontario. In this study, the charts of all patients with newly diagnosed NHL that were seen at the LRCP between Jan 1 – Dec 31, 2004 were reviewed retrospectively in order to measure and document the amount of time spent at each stage of the cancer pathway. Key time intervals from symptom onset to initiation of treatment were recorded. Associations between the waiting times and clinical/sociodemographic factors were also explored. Results: The charts of 116 patients were reviewed. The median overall waiting time from symptom onset to the initiation of treatment was 137 days. Median waiting time for each interval in the pathway were as follows: from symptom onset to first visit with primary care physician: 17 days; from first visit with physician to surgical consultation: 28 days; from surgical consult to the definitive biopsy: 13 days; from definitive biopsy to pathological diagnosis: 10 days; from pathological diagnosis to hematology referral: −5 days; from hematology referral to hematology consultation: 8 days; from hematology consult to completion of staging: 8 days; and from final staging to initiation of treatment: 5 days. The time from symptom onset to treatment initiation varied somewhat by clinical factors such as gender, age, and presence of B-symptoms. Patients with B-symptoms experienced shorter delays (119 d) than patients without B-symptoms (154 d). Male patients had shorter pathway times (113 d) compared to female patients (138 d). Patients at the extremes of age (age 20–29 & age >80) tended to have shorter delays than patients between the ages of 30–79 (ages 20–29: 60d, age >80: 85d, ages 30–79:137 d). Whether patients were referred from London vs. from another municipality did not appear to influence delays (137 d). Conclusions: NHL patients are experiencing significant delays in the assessment and treatment of their cancer. Most prior studies have focused primarily on delays from the point of referral to a cancer specialist to initiation of treatment. The results from our study suggest that a significant proportion of the patient’s clinical path is being spent at the prediagnosis phase (from the time of first physician visit until pathological diagnosis, 57 days) as opposed to from the time of diagnosis until the initiation of treatment (18 days). Efforts to reduce delays at both the pre- and post-diagnosis phases of the patient path may reduce patient anxiety with subsequent improvements in quality of life. The clinical impact of these delays on patient outcome is uncertain and requires further study.

Background: DDAVP (desmopressin) is commonly used for the prophylaxis and treatment of bleeding in patients with mild forms of von Willebrand disease (VWD) and Hemophilia A (HemA). The standard dose is 0.3 ug/kg IV, to a maximum of 20 ug. In 1995, our Bleeding Disorders Program began to use a maximum dose of 15 ug both for DDAVP challenges and for therapeutic purposes. This dosing change was triggered by the new availability of 15 ug (1 ml) vials of DDAVP. We also switched to subcutaneous administration rather than intravenous, given the smaller volume (1 ml), and the body of evidence supporting this route of administration (De Sio et al, Thrombosis and Hemostasis1985; 54:387–9). With this strategy, patients weighing Method: In order to evaluate this new dosing regimen, a retrospective review was performed of 62 patients with VWD (n=36) or mild hemophilia (n=26) weighing ≥ 50kg who underwent DDAVP challenges using a 15 ug s/c dose of DDAVP. Data was also collected on the 9 patients (5 VWD, 4 HemA) tested prior to 1995 who received 20 ug IV of DDAVP. Results: Levels of von Willebrand factor antigen (vWFag), ristocetin cofactor activity (RCof) and factor VIII (FVIII) were measured immediately prior to and 1 hour after administration of DDAVP. In the VWD patients (14M, 22F), median baseline levels of vWFag, RCof and FVIII were 31, 27 and 45 U/ml respectively, and rose to a median of 93, 90 and 177 U/ml following a 15 ug dose of DDAVP. This resulted in a median increase of 64 for vWFag (range 0–180), 55 for RCof (24–191) and 121 for FVIII (21–237). Results were comparable in the 5 pts who received 20 ug doses of DDAVP, achieving median increases of 77 (range 17–125), 53 (40–91) and 98 (79–184) respectively. In the HemA patients (19M, 7F), median baseline level of FVIII was 23 U/ml, and rose to a median of 57 U/ml following 15 ug DDAVP. Median increase in FVIII levels was 33 U/ml (range 2–108). These results compare favorably to the 4 patients who received 20 ug DDAVP and achieved a median FVIII increase of 19 U/ml (range 9–60). Chart review identified 26 patients (14 VWD, 12 HemA) who successfully received 15 ug doses of DDAVP in 44 clinical settings, either for the treatment of an acute bleeding episode or as prophylaxis prior to a planned surgical or dental procedure. Conclusions: DDAVP given subcutaneously to a maximum dose of 15 ug appears to be a safe and effective alternative to 20 ug IV for pts > 50 kg with VWD or mild hemophilia A.

High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is associated with prolonged remissions in relapsed follicular lymphoma (FL). Molecular remission in the graft and post ASCT predicts durable remissions and is a desirable endpoint. Rituximab (R) as an in vivo purge prior to HDT/ASCT and as consolidation after ASCT may help achieve this. To study this question, patients with relapsed FL were enrolled in a prospective, non-comparative phase II study between January 1998 and April 2000. Methods: 23 consecutive patients age Results: Median cohort age at assessment was 50 yrs (32–57). Median number of prior regimens was 3 (1–7) and total treatment cycles was 9 (3–28). Median response duration to the preceding regimen was 10 months (1–86). Transplants were a median 2.4 years after diagnosis. At median follow-up of 4.5 yrs (1.3–6.3), there have been 10 relapses at a median of 2.8 yrs. 3 patients have died, 2 with relapse and one of presumptive sudden cardiac death. Significant toxicities were seen: 11 episodes of pneumonia (1 fungal), 4 episodes of herpes zoster (1 grade 3), 4 early episodes of grade 3/4 interstitial pneumonitis, and 1 episode each of grade 4 TTP and grade 3 optic neuritis. One patient developed AML at 4.7 years post-ASCT. Immune recovery has been delayed; at 600 days post ASCT, 16/18 (89%) of evaluable patients had not recovered IgG levels to normal. At baseline, 12/23 patients had detectable markers by PCR analysis (sensitivity 0.01%) for t(14;18) or patient-specific VDJ rearrangements in marrow or blood. Of these, all achieved at least a brief molecular remission in blood and marrow, 11/12 doing so pre-R consolidation. 5/12 patients have since relapsed at a median 3 yrs (2–4.5) post ASCT. Molecular relapse preceded clinical in 3/5 cases. 6/12 have had prolonged (median 4.8 yrs, range 3–5) molecular and clinical remissions. Median event-free survival for all patients is 63 months, with median overall survival not reached. Conclusions: HDT/ASCT with R for in vivo purging and post-ASCT consolidation for relapsed FL is feasible and associated with prolonged clinical and molecular remission. Delay in recovery of humoral immunity may play a role in the high incidence of infectious complications. A single infusion of Rituximab for in-vivo purging did not eradicate PCR detectable disease in the graft, although sustained molecular remissions of at least 24 months were achieved in 75% of evaluable patients post transplant, possibly due to post ASCT Rituximab consolidation. Whether this translates into survival benefit will require longer follow-up and further comparative studies.

Background: Patients with relapsed or refractory aggressive B-cell lymphoma have a poor prognosis. If sensitive to salvage chemotherapy, high dose therapy followed by autologous stem cell transplant (ASCT) can result in long-term survival for some. Unfortunately, 50% of patients are insensitive to standard salvage regimens and thus are ineligible for ASCT. Hypothesis: Combining Rituximab with ESHAP may improve chemosensitivity and ASCT eligibility, of patients with CD20+, relapsed or refractory aggressive lymphoma, or CD20+ transformed indolent lymphoma. Objectives: The primary outcome was response rate (CR + CRu + PR) to R-ESHAP. Secondary outcomes were toxicity, ability to undergo ASCT, presence of minimal resdidual disease in the stem cell harvest, and progression free and overall survival. Methods: Eligible patients were 16–65 years old, had ECOG performance status 0–2, and had pathologically confirmed CD20+, relapsed/refractory aggressive lymphoma or transformed indolent lymphoma. Patients with refractory disease had a PR with initial anthracycline-based therapy. ESHAP (etoposide 40mg/m2 day 1–4, solumderol 500mg day 1–5, cytosine arabinoside 2g/m2 day 5, cisplatin 25mg/m2 day 1–4) was given every 28 days with GCSF support until < 15% bone marrow involvement was achieved (2–4 cycles). Eight infusions of Rituximab (375mg/m2) were administered weekly concurrent with the first 2 cycles of ESHAP. GCSF mobilized stems cells were collected on day 10 or 11 when < 15% bone marrow involvement was achieved (mainly in cycles 1 or 2). Results: Preliminary results of 14 of 44 planned patients are presented. Median age was 54 years (range 42–64). All pts had CD20+ aggressive lymphoma, 6 had relapsed aggressive lymphoma, 2 had refractory aggressive lymphoma (with PR after initial therapy) and 6 had transformed indolent lymphoma. Twelve of 14 patients were stage III/IV. The response rate to R-ESHAP was 93% (2 CR, 2 CRu, 9 PR, 1 PD). Thirteen of 14 patients proceeded to ASCT. Data on minimal residual disease in the stem cell harvest is pending. Grade 3–4 thrombocytopenia, neutropenia and anemia occurred with 53%, 31%, and 20% of R-ESHAP cycles respectively. Two of 14 patients had febrile neutropenia, one with bacteremia. Two patients had non-neutropenic bacteremia (1 with septic shock). There were no toxic deaths. Median follow-up post-ASCT is 5 months (range 1–18). Two patients progressed 4 and 5 months post-ASCT respectively. There were 3 deaths, 2 lymphoma related and 1 due to accelerated Parkinson’s Disease. Median PFS has not yet been reached. Conclusions: This trial is still accruing patients. However, preliminary results are promising. R-ESHAP appears to be well tolerated with a high response rate. This regimen may enable more patients with relapsed/refractory aggressive lymphoma or transformed indolent lymphoma to proceed to ASCT.