Marginal Zone non-Hodgkin Lymphoma Research Articles

PULMONARY MALT LYMPHOMA PRESENTING WITH EXTENSIVE CYSTIC LUNG DISEASE

TYPE: Case Report TOPIC: Signs and Symptoms of Chest Diseases INTRODUCTION: MALT (mucosa-associated lymphoid tissue) lymphoma is type of marginal zone non-Hodgkin lymphoma of B-cell origin that can rarely involve the lungs. We hereby present a case of pulmonary MALT lymphoma in a patient with Sjögren’s syndrome that presented with extensive cystic lung changes that was initially confused with lymphangioleiomyomatosis (LAM). CASE PRESENTATION: A 44-year-old former smoker female presented with worsening dyspnea on exertion and dry eyes and mouth. Chest CT had previously demonstrated numerous thin-walled cysts that had been present for several years. Due to worsening dyspnea and pulmonary cystic disease (image 1), she underwent a non-diagnostic VATS lung biopsy 3 years prior to consultation due to concern for LAM. Past medical history was notable for rheumatoid arthritis treated with adalimumab and leflunomide. Laboratory evaluation showed markedly elevated SSA and SSB antibody titers, which along with keratoconjuctivitis sicca and xerostomia was consistent with the diagnosis of Sjögren’s syndrome. The VATS lung biopsy was re-reviewed and showed atypical lymphoplasmacytic infiltrates with kappa light chain deposition, consistent with MALT lymphoma. Esophagogastroduodenoscopy and bone marrow biopsy were negative and staging PET-CT scan revealed no evidence of extrathoracic lymphoma. She was treated with weekly rituximab for 4 doses. DISCUSSION: Pulmonary MALT lymphoma is a rare disorder associated with autoimmune disorders, such as Sjögren’s syndrome. Extensive bilateral cysts are rare. Prognosis is typically good, although progression into high-grade B-cell lymphoma may occur. Treatment depends on symptoms and extent of disease. CONCLUSIONS: Pulmonary MALT lymphoma should be on the differential in patients presenting with bilateral extensive cystic disease. Image1: DISCLOSURE: Nothing to declare. KEYWORD: MALT Lymphoma

Anti-Spike (S) Antibody Production Post Covid-19 Vaccination after B Cell Depleting Therapy (BCDT) for Non-Hodgkin Lymphoma (NHL)

Introduction:Patients with NHL have a longer duration of illness and higher mortality rate after infection with Covid-19 1-3. Vaccination is strongly recommended to mitigate these problems in the general population, however, patients with cancer were not eligible to enter the pivotal vaccine trials. Furthermore, patients with NHL as well as other hematologic malignancies are frequently treated with B cell depleting therapies (BCDT) such as Rituximab and other anti-CD20 antibodies which in theory affect antibody production after vaccination. There are no data in the literature regarding patients with NHL and scarce data on other tumors concerning the antibody response against the S protein of Sars-Cov-2. To investigate the production of antibodies against the spike protein following vaccination against Sars-Cov-2, we studied 180 patients with cancer. We also aimed to determine if factors such as timing of BCDT in relation to number of days elapsed between such treatment and vaccination, as well as other features such as peripheral blood absolute B cell count correlate with antibody production.Materials and Methods:Anti-spike protein antibody production was evaluated in 104 patients with NHL and 76 with other malignancies. Eligible participants were aged 21 years or older. Study inclusion criteria included diagnosis of lymphoma or other hematological malignancy as well as solid tumors.The Dimension Exel 200 method for qualitative detection of total antibodies was used to determine antibody production. The antibody test was performed > 14 days after the second Moderna or Pfizer vaccine dose or after the Johnson & Johnson single dose.We prospectively evaluated antibody production following administration of BCDT as well as cytotoxic chemotherapy in 104 patients with NHL, 27 hematologic malignancies and in 49 solid tumors. In addition, we explored the timing of such treatments in relation to the vaccination date as well as the type of vaccine administered.Results:Median age was 61 and 59% were females. Of 180 entered, 104 had NHL. Of these, 95 (91.3%) were treated with BCDT, including rituximab (89), obinutuzumab (5) or anti-CD19 CAR-T cell therapy (1). BCDT was usually given together with induction chemotherapy and followed by maintenance. Histologic types of NHL treated with these therapies were: aggressive NHLs (N=35), follicular low grade (N=33), marginal zone NHL (14) and others (N=13). There were 49 patients with solid tumors. We also included 10 patients with other hematologic tumors who received BCDT and were analyzed together with the 95 NHLs to determine if this treatment interfered with anti-spike antibody production.Conclusions:These results imply a deleterious effect of BCDT on the humoral immune response to the SARS-Cov-2 vaccine. The correlation between the administration of BCDT and poor production of anti-spike antibodies is very robust, particularly in those cases who were vaccinated 9 months or less after BCDT. However, administration of cytotoxic chemotherapy without BCDT was not associated with reduced production of antibodies. In fact, almost all patients (94%) who received cytotoxic chemotherapy without BCDT, produced antibodies against spike protein (table 2). However, when chemotherapy was combined with BCDT there was a significant reduction of antibody production. These results strongly suggest that the major problem with poor antibody production following vaccination against Sars-Cov-2 relates to the use of BCDT and not so much to cytotoxic chemotherapy. The same findings apply to the 104 cases of NHL where half of patients treated with BCDT did not produce antibodies while 88% who did not receive BCDT produced antibodies (table 2). Almost all patients with solid tumors in our study (95.9%) were able to produce antibodies, irrespective of whether they received chemotherapy or not.These data raise the question whether vaccinated patients treated with BCDT who failed to make antibodies against the spike protein, could also benefit from a third dose. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcome of Patients with Marginal Zone Non-Hodgkin Lymphoma (MZL) Treated with Yttrium-90 Ibritumomab Tiuxetan: The Mayo Clinic Experience

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (>5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

Sofosbuvir-based therapy in patients with chronic hepatitis C virus infection and malignancies: A prospective study of 143 patients.

e18152 Background: Data on the management of chronic hepatitis C virus (HCV) infection in cancer patients (pts) are sparse with many of them excluded from cancer clinical trials (CCT). We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in such pts. Methods: Consecutiveptstreated with SOFBT at MD Anderson (1/2014-2/2017) were included in a prospective observational study. Efficacy (sustained virological response 12 weeks [SVR12] after SOFBT) was assessed based on intention to treat (ITT) analysis. A posthoc per-protocol analysis (PPA) was performed on pts with 12 weeks of follow-up post SOFBT. Adverse events (AEs) and drug-drug interactions (DDIs) were evaluated. Results: Of the 143 pts studied, the majority were men (102; 89%), white (89; 62%) and had genotype 1 (103; 72%). The most common cancers were non-Hodgkin lymphoma (NHL), hepatocellular carcinoma (HCC) (24; 17%, each) and breast cancer (11; 8%). Of the 31 infected pts excluded from CCTs, 27 (87%) were granted access after SVR. The overall SVR12 were 90% ITT (129/143) and 91% PPA (118/130). SVR12 ITT were 80% (8/10) for SOF+peg-interferon+ ribavirin, 86% (24/28) for SOF+ ribavirin, 95% (20/21) for SOF+simeprevir, 90% (64/71) for SOF/ledipasvir, 100% (8/8) for SOF+daclatasvir and 100% (5/5) for SOF/velpatasvir. The most common AEs were grade 1 (50; 35%), predominantly anemia (22%). DDIs or grade 4 AEs did not occur. Two pts died during the study period, both from reasons unrelated to SOFBT. In 3 pts with HCV-associated NHL, SOFBT was used alone without chemotherapy. Two of them had splenic marginal zone NHL and achieved complete remission (CR); the remaining pt had follicular lymphoma with stable cancer (SC) after SOFBT. No cases of de novo HCC occurred within 6 months of SOFBT. In the same period, 10% (4/40) of pts with SC had progression (acute leukemia, breast cancer, HCC and NHL in 1 each) and 5% (4/75) of pts with CR developed relapse (acute leukemia in 3, NHL in 1). More pts who failed SOFBT had cirrhosis (77% vs 27%, P = .001) and poorer adherence (≥ 2 missed appointments) (43% vs 4%, P = .001) than those with SVR. Conclusions: SOFBT is effective and safe in cancer pts; it improves access to CCT and may induce CR in selected NHL pts.

P1.03-047 Community-Based Low-Dose Computed Tomography (LDCT) Lung Cancer Screening in the US Histoplasmosis Belt: One Year Followup

LDCT lung cancer screening has been incorporated into most major American medical societies' screening guidelines. However, its performance in a non-tertiary care community setting with a high prevalence of fungal infections has not been sufficiently studied. Beginning in April 2013, high-risk adults ages 55-80 with at least a 30 pack-year smoking history, including former smokers who had quit within the previous 15 years, were prospectively evaluated with an LDCT scan performed at our community hospital (UnityPoint Health Medical Center in Quad Cities, Illinois). Standard National Lung Screening Trial exclusion criteria were followed with minor modifications. All participants’ scans were evaluated using Lung-RADS version 1.0 assessment categories. An oncology nurse navigator contacted and monitored all participants. CTs were interpreted by a local radiology group, with two radiologists spearheading the program and ensuring consistent interpretations. As of June 2016, we present data on 466 evaluable participants (compared to 176 from one year ago), 234 of whom were men (50%). The median age of the studied population remains 64 years (range 55-80). Screening adherence has dropped from 97% to 91%, with 40 participants lost to followup. 27 participants have completed all required phases of the screening. 192 participants (41%) had positive baseline screening tests. 26 of those participants (6% of the total population) required further evaluation with PET scans. 15 of these PET scans were followed by invasive procedures, including lung biopsy. 13 biopsy-proven malignancies (3%) were detected as a direct result of the screening. 12 malignancies were NSCLCs, of which 9 were early-stage (stages I-II). The thirteenth malignancy, a stage I Marginal Zone Non-Hodgkin Lymphoma of the lung, was confirmed by a lung wedge biopsy. Of the other two participants requiring invasive diagnostic procedure, one had a biopsy “negative for malignancy” and the other was diagnosed with histoplasmosis. No biopsy-related complications occurred. Twelve of thirteen participants with biopsy-proven malignancies are still alive and doing well. One participant died secondary to an advanced NSCLC detected by the screening program. This report represents an update on, to our knowledge, the first community hospital-based study evaluating the results of LDCT lung cancer screening in an area of the United States endemic for both histoplasmosis and blastomycosis. Only one case of histoplasmosis has been confirmed by invasive diagnostic procedure. A significant number of early stage lung cancers were detected without excessive testing or complications.

P147 Unexpected things flow crossmatch can reveal

Aim Flow cytometric crossmatch (FCXM) has become the preferred method of crossmatching due to its superior sensitivity and specificity over the traditional complement-dependent cytotoxicity-assays. Here we report a case of undiagnosed lymphoma identified during a routine living kidney donor FCXM. Methods FCXM was performed on a BD FACSCanto II flow cytometer using pronase-treated donor peripheral blood mononuclear cells (PBMC). Staining included CD45 for leukocytes, CD3 for T-cells, CD19 for B-cells, and goat anti-human IgG for the detection of surface-bound donor-specific antibody. G46-2.6 and Tu39 were included to measure the expression level of HLA class I and II antigens on donor cells. Immunophenotyping was performed by a reference lab. Results A 65-year-old Caucasian female with unremarkable medical history was evaluated for living kidney donation to an unrelated recipient candidate. In the initial allo crossmatch, while the gated donor lymphocyte population displayed a typical FSC/SSC architecture, normal staining profile with all the cell surface markers and normal HLA expression level, the cell type composition appeared grossly altered. Specifically, the T-cell to B-cell ratio was reversed at 1 to 4.4 (typically observed between 4 to 1 and 9 to 1, based on a retrospective analysis of 44 living donor crossmatches). The allo crossmatch was repeated using freshly collected donor blood and the findings were identical. Morphological examination of donor PBMC with Wright’s stain revealed many disrupted mononuclear cells, and immunophenotyping showed the PBMC consisted of primarily abnormal B cells stained dimly for CD19 and CD20 and negative for CD3, CD5, CD10, CD11c, CD23, and CD38, with the light chain displaying a lambda restriction with a complete absence of kappa chain (normal lambda-to-kappa ratio = 1:2). Taken together, the immunophenotypic profile suggested a diagnosis of B-cell marginal zone non-Hodgkin lymphoma or lymphoplasmacytic lymphoma, with lambda light-chain restriction. The donor was subsequently deferred and referred for follow up. Conclusion This case report illustrates the possibility of identifying undiagnosed hematological malignancies using the conventional histocompatibility crossmatch setup even with limited lymphocyte markers.

Remission Induction in a Phase I/II Study of an Anti-CD20-Interleukin-2 Immunocytokine DI-Leu16-IL2 in Patients with Relapsed B-Cell Lymphoma

DI-Leu16-IL2 immunocytokine is a recombinant fusion protein composed of interleukin 2 (IL2) and a CD20 targeting monoclonal antibody. Pre-clinical studies have shown it maintains the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system and induction of an anti-cancer vaccine effect. In a SCID mouse model,DI-Leu16-IL2 is more effective than the individual components (IL-2 and CD20) given either alone or in combination (Gillies SD; 2005). DI-Leu16-IL2 administered intravenously to 8 relapsed/refractory Non-Hodgkin's Lymphoma (NHL) patients at a maximum dose of dose of 0.5 mg/m2 resulted in 1 complete, 1 possible partial response and 4 patients with stable disease (Nakamura R; 2013).In this multicenter open label, dose escalation trial the safety, efficacy and tolerability of subcutaneously (SC) administered DI-Leu16-IL2 was evaluated as well as the maximum tolerated dose (MTD) and optimal biological dose in patients with relapsed or refractory B cell CD20 positive lymphoma (NCT01874288). DI-Leu16-IL2 was administered on three consecutive days every 21 days up to 6 cycles. Peripheral B cell depletion was achieved with low-dose rituximab (50mg/m2) on day 1 if needed to keep rituximab levels >10µg/mL. The starting dose was 0.5 mg/m2 and followed a modified accelerated titration until dose limited toxicity (DLT) occurred. To be evaluable for response patients had to receive at least 2 cycles of DI-Leu16-IL2 and were then evaluated by PET/CT imaging.To date, 13 patients in 3 cohorts have been enrolled. The median age is 63 years (range, 48-83 years). Ten patients had diffuse large B cell lymphoma, 2 follicular and 1 marginal zone NHL. All were previously treated with rituximab-containing chemotherapy - median of 3 (range 1-6) prior regimens, including radiation therapy (n=5) and autologous transplantation (n=3). All patients had relapsed or refractory disease with biopsy-confirmed tumor cells expressing CD20.DI-Leu16-IL2 dose levels were 0.5 mg/m2 (n=3), 1 mg/m2 (n=3), 2 mg/m2 (n=7). DI-Leu16-IL2 was detectable in the serum at the lowest dose level. Median number of cycles were 4 (range 1-11). No DLTs have been observed. The most common drug-related adverse events (AEs) were grade 1-2 transient skin reactions with erythema, painless induration of injection site, pruritus, edema and mild constitutional symptoms (grade 1-2 chills, low-grade fever, fatigue, low appetite) suggesting an immune stimulatory response. Lymphocyte margination occurred with nadir of 0.3x103 /mL for median 2.7 days (range 1-5). Two grade 3 non-DLT toxicities (diarrhea and QTc prolongation with pre-existing RBBB) resulted in DI-Leu16-IL2 dose reduction. Transiently prolonged QTc (grade 1-2) occurred in 3 additional patients. Routine laboratory monitoring revealed grade 1-2 transient eosinophilia, anemia and thrombocytopenia in most subjects, grade 1-2 neutropenia (n=3) without neutropenic fever, grade 1 elevation of alkaline phosphatase or bilirubin. All AEs resolved completely within one week.Twelve patients are evaluable for response. After 2 cycles, tumor regression or stabilization was noted in 10 of 12 patients with mean tumor reduction of 30% (range 0%-80%). Six had sustained disease control after 4 cycles. One patient with small tumor bulk marginal zone lymphoma achieved a complete response by PET criteria, 3 patients had a partial response (55%, 55% and 80% tumor size reduction) and continue on therapy. Stable disease (SD) response was observed in all dose cohorts; best responses occurred at the highest dose level (2mg/m2) administered thus far. Three patients have had SD for up to 1 year.In conclusion, we have observed promising clinical efficacy of the novel immunocytokine DI-Leu16-IL2 in relapsed/refractory B cell NHL. SC administration has permitted higher doses than could be achieved with IV treatment and the MTD has yet to be reached. DI-Leu16-IL2 is biologically active in doses up to 2mg/m2. Repetitive SC dosing elicits clinical immune activation associated with clinical activity. Further dose escalation of DI-Leu16-IL2 is in progress.Prior DI-Leu16-IL2 therapy After 2 cycles at dose 2mg/m2 [Display omitted] DisclosuresBachanova:Seattle Genetics Inc.: Consultancy, Research Funding.

Efficacy and Tolerability Of Frontline Oral Fludarabine and Cyclophosphamide Combination Therapy For Elderly Patients With Chronic B-Cell Lymphocytic Leukaemia and Low Grade Non Hodgkin Lymphoma

BackgroundTreatment of elderly patients needs to be considered in view of patients' physical condition and social environment in addition to diagnosis, staging and risk factors.Fludarabine was the first purine analogue with an oral formulation available for clinical use. The oral formulation offers equivalent efficacy and improved tolerability profile compared to the intravenous (IV) formulation. IV fludarabine requires several administrations that may expose patients to the risk of clinical side effects and potential logistic problems. AimsTo assess whether frontline oral fludarabine and cyclophosphamide (FC) combination therapy for elderly or clinical unfit patients with B-cell chronic lymphocytic leukemia (B-CLL) and low grade non Hodgkin lymphoma (NHL), is well tolerated, effective and cost-saving. MethodsBetween April 2005 and March 2013, 10 elderly untreated patients (mean age 75, range 68-86) with B-CLL requiring treatment, according to ESMO guidelines, and 21 stage ≥3 indolent NHL (mean age 73, range 47 -89) received therapy with low dose oral fludarabine (25mg/mq/die) and cyclophosphamide (150mg/mq/die) from day 1 to 3. Study design consisted of 6 cycles repeated at 4 weeks intervals in the outpatient clinic. Patients received antibiotic prophylaxis with trimethoprim/sulphamethoxazole (160/800 mg once a day, 3 times a week) and allopurinole (300 mg once a day from days 0 to 4). Four follicular NHL, 6 small lymphocytic NHL, 7 marginal zone NHL, 2 indolent mantle cell NHL and 2 lymphoplasmacytic NHL were treated. Performance status was WHO £ 2 in all patients. Comorbidities, which included diabetes, hypertension and chronic heart disease, were present in 12 patients (grade ≤ 2). The median number of cycles was 4 (range 2-6). No patients reduced either the dose or the number of cycles because of hematologic and extra-hematologic toxicities. Specifically, only 2 patients experienced grade III neutropenia, treated with G-CSF. ResultsDefinition of response was reported according to the updated IWCLL-NCI 2008 international general practice criteria, valuated after 3 and 6 cycles. Twenty seven of 31 patients (87%) obtained a clinical response (14 CR and 13 PR). Only 1 responding patient (90 years old) died after 24 months from therapy because of aplastic anemia. In particular, the response rate was 4/4 for follicular NHL (1RP, 3RC), 5/6 for small lymphocytic NHL (2 RC, 3 RP), 7/7 for marginal zone NHL (3 RC, 4RP),1/2 for lymphoplasmacytic and 2/2 mantle cell NHL (PR), 8/10 for B-CLL (3 RC, 5 RP).We consider as Event Free Survival (EFS) time to progression, adverse event with a grade >3 (CTCAE) during treatment, relapse or death. Overall survival (OS) was defined as the time from the start of treatment to death or last follow-up. Survival distributions were calculated using the method of Kaplan and Meier. With a median follow-up of 67 months (range 16-187), we observed a median EFS about 38 months and median OS has not been reached.We used Genzyme-sponsored Excel program to compare direct hospital cost of oral to IV FC (both 3 days regimen). IV treatment required 18 day service admissions with a total cost of € 7.527 while the oral therapy required 6 ambulatory visits with total cost of € 1.642 (costs including: pharmacy, nurses and physicians costs). In this analysis we did not consider social and psychological cost such as transportation, care giver loss of working hours, trauma of repeated venipunctures. ConclusionsThese results suggest that oral FC could be effective and well tolerated for elderly patients unfit for more aggressive treatments. The efficacy of our therapeutic regimen is comparable to intravenous FC (20 mg/m2 and 600 mg/m2) regimen used by Flinn et al. (Blood 2000) with an ORR about 90 %. Hovewer, in that study 17/60 patients experienced a grade 3 or 4 neutropenia with 1 death due to sepsis. In conclusion, most of our patients did not experience severe toxic side effects or required hospitalizations, enjoing a good quality of life. Disclosures:No relevant conflicts of interest to declare.

Low-Dose Radiotherapy in Patients with Non Hodgkin Lymphoma

AbstractAbstract 4875 Background:Some studies have showed high activity for low-dose radiotherapy (LDRT) in low-grade Non-Hodgkin Lymphoma (NHL). However, this therapeutic approach is often forgotten and other approaches are used - chemotherapy and/or conventional radiotherapy - associated with greater toxicity. The efficacy of total body LDRT (1.5–2 Gy, fractions 0.1–0.25 Gy in 2 – 5 times a week) in disseminated disease is associated with 10 year progression free survival (PFS) of 15 – 25%, with response rates of 70 – 90% (Gérard et al., IJ Radiation Oncology 2010; 78), despite hematologic toxicity and leukemogenic effects. Although its mechanism of action is unknown, its effectiveness has been confirmed (Jones et al., Cancer 1973; 32) suggesting that low dose radiation induces localized lymphocytes apoptosis that can trigger local and systemic benefits. More recently, LDRT was used in palliative treatment for patients with localized disease (4Gy into two fractions, for 3 days) with a low toxicity, and with an objective response (partial or complete) in 24/37 patients, 89% (G Ganem et al., Hematol Oncol1997; 42). Objectives:To assess the response to treatment with LDRT. Explore the predictive factors of response. Determine the progression-free survival (PFS) after LDRT. We will present PFS after LDRT and compare PFS in second line treatment: LDRT vs convencional chemotherapy. Methods:Retrospective study of 44 patients with new or recurrent NHL, treated with LDRT (4Gy in 2 fractions) in 1stor more lines, in a cancer care centre between 2004 and 2011.All transformed lymphomas were excluded (4 patients), as well all diagnosis that weren't centrally reviewed. Patients with complete resolution of the disease according to clinical and/or image studies were considered to have achieved complete response (CR). Results:We identified 40 patients undergoing LDRT, with a median follow-up of 69,5 months after LDRT ([28–87]). 52,5% (n = 21) were male, median age at the time of LDRT was 69 years ([31–85]). 75% of patients (n = 30) had follicular NHL, 12,5% (n = 5) Mantle cell NHL, 10% (n = 4) Marginal Zone NHL and 2,5% (n = 1) lymphoplasmacytic lymphoma.The median numbers of lines of chemotherapy completed before LDRT were 2 lines ([0–5]). There wasn’t any impact on PFS on using Rituximab containing regimens after LDRT (p> 0,05). The overall response rate to LDRT was 92,5% (n = 37): 42,5% (n = 17) achieved complete response (CR), 50% (n = 20) partial response (PR) and 7,5% (n = 3) had disease progression. There weren’t any treatment related toxicities, nor was histological transformation recorded after treatment with LDRT. The logistic regression analysis showed that irradiated areas with dimension <40mm are an independent predictive factor of response (p <0,031, 95% CI [1,268-133,285]). We find a median PFS of 4 months ([0–72]) for patients that went on LDRT, and 50% of these patients relapsed after a median 5 months ([0–35]). 56,5% (n = 13) showed relapse at the same location of the irradiated area. Patients who have completed one chemotherapy scheme after relapsing following LDRT, showed a rate of 6 months-PFS of 50% such as the patients that have done a second LDRT treatment.Concerning follicular NHL patients who relapsed after 1st line conventional chemotherapy, 43,8% (n = 7) were treated with LDRT and 56,2% (n = 9) were treated with conventional 2nd line chemotherapy. Comparing these two groups of patients, there weren’t any difference for PFS for both groups (mean 9,5 vs 9 months p> 0,05, for LDRT vs 2ndline chemotherapy), for equal overall survival. Conclusion:LDRT is an effective treatment for patients with relapsed or recurrent advanced stage NHL. We can obtain high response rates with negligible toxicity. In the treatment of first relapse, PFS is similar when using LDRT or 2nd line chemotherapy. Considering that Rituximab promotes a synergistic effect with LDRT-induced apoptosis and decrease the cell turnover (Skvortsova I et al., J Radiat Res (Tokyo) 2006), comparative studies with conventional chemotherapy regimens should be promoted. Treatment with conventional radiotherapy should be used in patients with relapsed low-stage and localized disease, having curative intention or locally controlling involved areas. Disclosures:No relevant conflicts of interest to declare.

A Phase I Study of PRO131921, a Novel Anti-CD20 Monoclonal Antibody in Patients with Relapsed/Refractory CD20+ Indolent NHL: Correlation Between Clinical Responses and AUC Pharmacokinetics.

Abstract 3742Poster Board III-678PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody engineered to have significantly increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab as shown in in vitro models. In preclinical in vivo lymphoma models, PRO131921 has superior anti-tumor efficacy compared to rituximab. In this Phase I study, PRO131921 was administered as a single agent to patients (pts) with CD20+, relapsed or refractory indolent non-Hodgkin's lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The aim of the study was to determine the safety and tolerability of PRO131921, the maximum tolerated dose (MTD), its pharmacokinetics (PK), and to establish a Phase II dose. Pts were treated with PRO131921 by intravenous infusion (premedication with acetaminophen and anti-histamine) weekly for 4 weeks on days 1, 8, 15 and 22. The dose of the first infusion was approximately 50% that of subsequent infusions. The dose was escalated based on safety in a 3+3 design. PK samples were obtained pre- and post-infusion on days 1, 8, 15, and 22, and once each on days 2, 23, 29, 50, and 78 (and at later time points for up to a year).Twenty-four pts were treated with PRO131921 at doses from 25 mg/m2 to 800 mg/m2. Median age was 58 yrs (38-78). Histologies were follicular NHL (n=20), small lymphocytic lymphoma (n=3) or marginal zone NHL (n=1). Pts had received a median of 2 (range 1-6) prior regimens. PRO131921 was generally well-tolerated and no MTD was reached in the study. The most common adverse events were Grade 1 or 2 (CTCAE V3.0) chills, flushing, itching, fatigue, fever, nausea, dizziness, diarrhea, and hypotension, most of which were part of infusion-related reactions limited in general to the first infusion. These responded well to slowing or interruption of the infusion, and symptomatic treatment (including steroids). Grade 3 AEs (related and unrelated to study drug) included 3 episodes each of transient neutropenia and hypoxia, and single episodes of throat tightness, bronchospasm, syncope, fatigue, periarthritis, pneumonia, and deep venous thrombosis. There was 1 unrelated Grade 4 pulmonary embolism. Two pts did not receive all 4 doses of therapy due to DLTs. One dose limiting toxicity (DLT) was observed in the 200/400 mg/m2 dose cohort due to a significant infusion reaction, and a second was observed at the 300/800 mg/m2 dose cohort due to Grade 3 joint pain and fatigue after 2 infusions. Detailed PK studies of PRO131921 in all patients were broadly similar to rituximab with a dose-dependent increase in exposure, but with significant inter- and intra-patient variability. Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and both tumor shrinkage (p=0.049) and clinical response (p=0.034), consistent with the hypothesis that rapid drug clearance (e.g. by tumor in excess of drug) may result in decreased clinical efficacy. Best investigator-assessed responses to treatment in the 22 evaluable pts by day 78 or later were 6 PR, 13 SD, and 3 PD; 5/10 pts in the two highest dose cohorts responded.In conclusion, PRO131921 has shown clinical activity in rituximab-relapsed and refractory indolent NHL pts. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy. Disclosures:Friedberg:Genentech, Inc.: Honoraria, Research Funding. Vose:Genentech, Inc.: Consultancy, Research Funding. Kahl:Genentech, Inc.: Consultancy, Research Funding. Brunvand:Genentech, Inc.: Speakers Bureau. Goy:Genentech/Biogen IDEC: Consultancy, Speakers Bureau. Kasamon:Genentech/Biogen IDEC: Research Funding. Burington:Genentech, Inc.: Employment. Li:Genentech, Inc.: Employment. Ho:Genentech, Inc.: Employment. Cheson:Genentech, Inc.: Consultancy, Speakers Bureau.

Phase I Trial of Combination Therapy with 90Y Ibritumomab Tiuxetan (Zevalin) and Gemicitabine in Patients with Non-Hodgkin's Lymphoma.

Y90-ibritumomab tiuxetan radioimmunotherapy, or Zevalin (Y90-RIT), is an effective therapy against CD20+ lymphoma. While it is approved for use in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), it is not curative and ways to enhance its efficacy would be useful. Gemcitabine (G) is a potent radiation sensitizer that also is active against NHL. Its radiation sensitizing ability and activity against NHL provide the rationale for our ongoing phase I trial to assess the safety of concomitant administration of Y90-RIT and gemcitabine in patients with NHL. Nine patients in three cohorts have been treated with 250 mg/m2 of gemcitabine IV on days 1 and 8 of the Y90-RIT treatment program of rituximab + In 111-ibritumomab on day 1 and rituximab + Y90 ibritumomab on day 8, with Y90 at 0.2, 0.3 or 0.4 mCi/kg respectively. Subsequent cohorts only accrued after all patients in the prior cohort had resolution of hematologic toxicities to grade 0–2 or after 60 days from the date of the last treated patient in the previous cohort. One patient has been treated with 300mg/m2 of G and 0.4 mCi/kg of Y90-RIT. No DLTs have been observed so far. The dose of G is continuing to be escalated according to a Bayesian based system. Response evaluation is by standard criteria. Eligibility criteria include: any histology of recurrent B cell NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Ten patients have been treated thus far, five with follicular (FL), four with diffuse large B cell (DLBCL) and one with marginal zone NHL. Median age is 70 (range 55–82). The median number of prior treatments is 2 (range 1–6). Patients 1–3 received Y90 at 0.2 mCi/kg, patients 4–6 at 0.3 mCi/kg and patients 7–9 received standard 0.4 mCi/kg of Y90, all with 250 mg/m2 of gemcitabine on days 1 and 8. Patient number 10 has received full dose of Y90 and G at 300 mg/m2. Grade 3 or 4 toxicities have consisted only of: one grade 3 neutropenia, three grade 3 leukopenia and six grade 3 and three grade 4 lymphopenia. One grade 3 infection occurred, unrelated to the protocol or the study drugs. Grade 3 or 4 non-hematologic toxicities have included one case each of increased bilirubin, increased GGT and increased calcium. In follow up, responses have included: 2 stable disease (one patient each with FL and marginal zone NHL, mean duration of response: 7.2 months), 2 CRu and one CR all in patients with FL (mean duration of response: 17.5 months), one PR and 4 progression of disease (DLBCL). One patient with CRu, and one with SD have ongoing responses. Three additional patients have met the protocol defined criteria for progression but have not had a need for initiation of any other treatments. One patient was diagnosed with a new lung cancer after achieving a PR.Conclusion: Our findings demonstrate that Y90-RIT (Zevalin) at the standard dose of 0.4 mCi/kg can be safely combined with gemcitabine at 250 and 300 mg/m2 days 1 and 8 in the treatment of patients with NHL. Accrual to cohorts with 0.4 mCi/kg of Y90-RIT and escalating doses of gemcitabine is continuing.

Incidence, clinical characteristics and survival of malignant lymphomas: a population‐based study from a cancer registry in northern Italy

We conducted a population-based study of peripheral lymphomas (PL) that had been diagnosed between 1997 and 2003 in the province of Modena, Italy, with the aim of providing updated incidence, clinical and survival data for these cancers. We evaluated the incidence patterns and time trends of 1582 cases of PL that had been reclassified according to the WHO classification of hematological malignancies. Data regarding clinical characteristics, treatment and outcome were also collected for each case. The World Age-Standardized Rate (ASR) was calculated as 13.4, 2.2 and 3.4 per 100,000 people for B-cell non-Hodgkin's lymphoma (NHL), T-cell NHL and Hodgkin's Lymphoma (HL), respectively, with an increase of 1.62% per year during the study period. The lymphoma subtype showing the highest incidence was found to be diffuse large B-cell lymphoma (DLBCL) with an ASR of 4.8. Compared with reports from other western countries, our series is characterized by a higher incidence of HL and indolent B-NHL in general, and of CLL/SLL (ASR = 3.3) and marginal zone NHL (ASR = 1.5), in particular, and also by a lower incidence of FL (ASR = 2). After a median follow-up of 54 months, the 5-year relative survival for the whole series was found to be 70% with a statistically significant improvement for cases diagnosed during 2002-2003 (from 66 to 74%; p = 0.03). Survival improvement within the study period was also evident for patients with DLBCL, HL and T-NHL. Our study provides a comprehensive description of both the epidemiological and clinical features of PL cases in Modena and our data also reflect the major advances in the curability of some histological subtypes of this disease. The usefulness of a population-based approach to better characterizing different lymphoma subtypes is also demonstrated.

Lymphoma Cell Detection and Follow-Up in the Rituximab Era: Concordance between Flow Cytometry, Qualitative/Quantitative PCR and FISH in the Marrow and Blood from 647 Patients.

The anti-CD20 monoclonal antibody Rituximab is now widely used in B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) patients. Its administration is associated with a profound reduction of the number of normal and malignant CD20+ B cells, so that the procedures used so far for NHL and CLL diagnosis, detection of minimal residual disease (MRD) and follow-up (F-UP) should be revised. We have retrospectively evaluated our consecutive 4-year record of 647 NHL and CLL patients. Our aims were: 1) to compare sensitivity and concordance between 4-colour flow cytometry, qualitative and quantitative PCR and FISH. 2) to compare concordance between bone marrow (BM) and peripheral blood (PB). Sensitivity of the procedures (evaluated by serial dilution of NHL cell lines in healthy donors' BM and PB) were found to be 10−5, 10−6, 10−4/5 and 10−3 for 4-colour flow cytometry, qualitative PCR, quantitative PCR and FISH, respectively. A total of 955 paired BM and PB samples were investigated. Most frequent diagnoses were follicular NHL (29%), diffuse large B-cell NHL (22%), marginal zone NHL (11%), CLL (10%), and mantle cell NHL (8%). In 236/955 cases (25%), 4-color flow cytometry identified a monoclonal or a phenotypically aberrant cell population. Concordance between BM and PB was 87% (p<0.001). Most frequent diagnosis of discordant cases was lymphoplasmocytoid-Waldenstrom NHL (36% of discordant cases). Qualitative and quantitative PCR were used to investigate clonality (Fr2A/VLJH and Fr2A/VLJH genes) and the presence of translocations involving BCL-1 or BCL-2 genes (in mantle cell or follicular NHL, respectively). A total of 91/333 samples (27%) were positive. Concordance between BM and PB was 91% (p<0.001). Discordance was found in 11% of mantle cells NHL and 8% of follicular NHL cases. When 118 patients were evaluated 3-month after Rituximab (alone or in combination with chemotherapy), qualitative PCR still detected malignant cells in 95% of previously PCR-positive patients, flow cytometry in 72% of previously cytometry-positive patients. On the other hand, at 7 month after Rituximab, in these patients malignant cells were found by qualitative PCR in 14/72 (19%) cases, by flow-cytometry in 22/118 (19%) cases. These procedures identified disease persistence or recurrence significantly earlier than quantitative PCR (evaluated in 98 cases, p<0.01) and FISH (evaluated in 11 cases, p<0.001). We conclude that 1) BM and PB examination by means of 4-color flow cytometry and qualitative PCR offer nearly-overlapping results. In Rituximab-treated patients, differences seen at 3-month F-UP, probably due to the higher sensitivity of qualitative PCR, are no more observed at 7-month F-UP. 2) Four-color flow cytometry and qualitative PCR have higher sensitivity and detect MRD and relapses significantly earlier than quantitative PCR and FISH. 3) With the exception of lymphoplasmocytoid-Waldenstrom NHL, PB examination may be considered a sensitive and specific alternative to BM examination in NHL and CLL patients, including those treated with Rituximab.

Hepatitis C virus infection and non-Hodgkin lymphoma: results of the NCI-SEER multi-center case-control study.

Several studies have noted elevated hepatitis C virus (HCV) prevalence among patients with non-Hodgkin lymphoma (NHL), suggesting that HCV infection increases NHL risk through chronic immune stimulation. Population-based data from the U.S. are lacking. In a population-based case-control study of NHL in the United States, we identified HCV infection using an enzyme immunoassay, confirmed by recombinant immunoblot assay or HCV RNA detection. The association between HCV and NHL was assessed using logistic regression, adjusting for demographic factors, illicit drug use or medical history. Thirty-two of 813 (3.9%) NHL cases and 14 of 684 (2.1%) controls were HCV-infected [odds ratio (OR) 1.96, 95%CI 1.07-4.03]. For separate NHL subtypes, numbers were limited. Nonetheless, positive associations were noted for follicular (OR 2.46, 95%CI 1.01-5.81), marginal zone (3.99, 0-13.6) and mucosa-associated lymphoid tissue (2.04, 0-7.20) NHLs. For all NHLs combined, the HCV-NHL association changed little after adjustment for sex, age, race and study center (OR 1.89, 95%CI 1.00-4.00). HCV was common in controls who had injected drugs (40%) or used other illicit drugs (6.5%), but adjustment for drug use did not affect the HCV-NHL association (OR 1.87, 95%CI 0.95-4.10). Transfusion history was unrelated to HCV status, and adjustment for this exposure did not attenuate the HCV-NHL association (OR 2.15, 95%CI 1.12-4.76). Excluding 4 subjects with a history of hemodialysis or 3 subjects with organ transplants also did not affect the results. Our study demonstrates an association between HCV infection and NHL in the United States. HCV infection may be a cause of NHL.

Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren's syndrome-associated B-cell aggressive non-Hodgkin's lymphomas.

To determine the safety and therapeutic response of a regimen consisting of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) plus rituximab in patients with Sjögren's syndrome (SS) and aggressive non-Hodgkin's lymphoma (NHL). Four SS patients with aggressive marginal zone NHL were enrolled in this trial. All patients were classified according to the newly proposed revised European-American classification of lymphoid neoplasms. Three out of four patients also had mixed cryoglobulinaemia (MC) of type II. They were treated every 3 weeks for eight cycles of CHOP. Patients also received rituximab, at a dose of 375 mg per square metre, on day 1 of each of the eight cycles of CHOP. Four weeks after completion of the eighth course of CHOP plus rituximab and every 6 months thereafter, patients were re-evaluated for response. Complete remission of lymphoma was achieved in all four patients. The lymphoma patients remained in remission for a period of 23, 15, 12 and 10 months respectively, while certain signs and symptoms of MC type II (purpura, peripheral neuropathy and arthralgias) significantly improved with treatment. In addition, the titres of circulating cryoglobulins and RF decreased, while C4 levels returned to normal. CHOP plus rituximab was well tolerated and proved effective in SS patients with aggressive NHL. Our observations may warrant a larger controlled trial to assess the effectiveness of this regimen in such patients.

Autologous Bone Marrow Transplantation for Marginal Zone Non-Hodgkin's Lymphoma

The marginal zone non-Hodgkin's lymphomas are a recently defined group of related low-grade B cell malignancies whose natural history is heterogeneous. The optimal therapy is often unclear, particularly for the subset of patients with disseminated disease that behaves aggressively. We have retrospectively analyzed the outcomes of 11 patients with chemosensitive but disseminated marginal zone lymphomas who underwent uniform conditioning with cyclophosphamide and total body irradiation followed by bone marrow transplantation (BMT) with anti-B cell monoclonal antibody-purged autologous bone marrow between January 1994 and September 1999. All patients had stage IV disease and received multiple chemotherapy regimens prior to autologous BMT. Only 36% were in complete remission at the time of bone marrow harvest, and 36% had overt bone marrow infiltration at that time. Two treatment-related deaths occurred between 100 days and 6 months. Three patients relapsed and died of disease. One patient developed and died of myelodysplasia. Five patients remain in continuous complete remission at a median follow-up of 52 months (45%). The median progression-free survival for these patients was 56 months, with median overall survival 58 months. The only significant predictor of disease-free and overall survival was age at the time of transplant; no patient under 45 at the time of transplant has relapsed or died of any cause (P = 0.003). Outcomes of autologous BMT in patients with disseminated marginal zone NHL are similar to those in follicular NHL, and suggest that certain patients may experience prolonged disease-free survival.

Frequent nuclear localization of ICAD and cytoplasmic co-expression of caspase-8 and caspase-3 in human lymphomas.

Lymphoma cells often display in vitro resistance to FAS-induced apoptosis, in which caspases act as crucial cell death effectors. Following FAS stimulation, caspase-8 activates caspase-3, which in turn activates the caspase-activated DNAse (CAD) by proteolysis of its inhibitor (ICAD). To investigate the mechanism of FAS resistance, the expression of caspase-8 was analysed by immunohistochemistry, together with that of the substrates caspase-3 and ICAD, in 52 representative samples from non Hodgkin's lymphoma (NHL), 12 from Hodgkin's disease (HD), and eight benign lymphoid tissues. In benign tissues, caspase-8 was co-expressed with caspase-3 in the cytoplasm in germinal centre (GC) cells and was co-expressed with ICAD in the nuclei of the mantle and marginal zone cells. ICAD expression was weak or absent in GC cells. Cytoplasmic staining for both caspase-8 and caspase-3 was present in 11/12 cases of diffuse large cell B-NHL. Caspase-8 positivity was nuclear and cytoplasmic in 9/9 follicular NHLs, in 5/5 mantle cell NHLs and in 6/6 marginal zone NHLs. Five out of six peripheral T-cell NHLs expressed cytoplasmic caspase-8. Ten out of the 12 HD cases lacked significant cytoplasmic staining for caspase-3 and caspase-8 in the majority of Reed-Sternberg cells. All lymphoma cases exhibited predominant nuclear ICAD positivity. Subcellular fractionation analysis of three lymphoma samples and normal mantle zone cells confirmed that ICAD and caspase-8 were at least partly localized in the nucleus. These results show that the profile of caspase-8 expression is correlated with histological lymphoma subtypes; that caspase-8 is co-expressed with caspase-3 in GC cells and their neoplastic counterparts; that ICAD has an immunohistochemical nuclear localization in vivo; and that caspase-8 and ICAD can be co-expressed in the nuclei of mantle zone and marginal zone cells; their unexpected nuclear localization allows a reappraisal of the biochemical cascade of caspase activation.

CD10 positive thyroid marginal zone non-Hodgkin lymphoma.

A 72 year old woman presented with swelling of the right lobe of her thyroid gland. Fine needle aspiration and flow cytometry showed a clonal population of B cells expressing...