Low-grade non-Hodgkin's Lymphoma Patients Research Articles

Antibody Response to SARS-CoV-2 Vaccination in Patients With Lymphoproliferative Disorders and Plasma Cell Dyscrasias: Anti-Lymphoma Therapy as a Predictive Biomarker of Response to Vaccination.

We retrospectively analyzed SARS-CoV-2 vaccination antibody responses in a cohort of 273 patients with lymphoproliferative disorders or plasma cell dyscrasias who were seen at a single tertiary cancer center. Semi-quantitative anti-spike protein serologic testing was performed with enzyme immunoassay method. We found that the antibody response rate to SARS-CoV-2 vaccination was 74.7% in our patient cohort with no difference based on gender, age or race. The highest response rate was found in patients with Multiple Myeloma (MM) (95.5%). The response rates found in Diffuse Large B-Cell Lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL), and Low-Grade Non-Hodgkin Lymphoma (LG-NHL) were 73.2%, 61.5% and 53% respectively. We also evaluated the effects of receiving active chemo-immunotherapy on SARS-CoV-2 vaccination antibody response. We found that the patients on treatment had lower response than the patients off treatment (62.1% versus 84.4% p<0.001). Thirty-four of 58 LG-NHL patients were receiving anti-lymphoma treatment with a lower SARS-CoV-2 vaccination response as compared to the patients who were not on treatment (29.4% v 87.5% p<0.001). We observed a similar pattern in CLL patients receiving treatment (48.1 v 76.0 p:0.049). We found that only disease type and treatment status (on-treatment vs. off- treatment), but not gender, age or race were significant predictors of non-response in the multivariable logistic regression model. The interaction between disease type and treatment status was not statistically significant by multivariate analysis. In conclusion, receiving anti-cancer treatment was found to play a significant role in decreasing the response to COVID-19 vaccination.

PB2078: A RETROSPECTIVE ANALYSIS OF THE EFFICACY OF LOW-DOSE METRONOMIC CYCLOPHOSPHAMIDE FOR TREATMENT IN PATIENTS WITH LOW GRADE NON-HODGKIN LYMPHOMA

Background: Low-dose metronomic cyclophosphamide chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. Aims: We evaluated the efficacy and safety of low-dose metronomic cyclophosphamide in patients with low grade non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data. Methods: The patients received oral cyclophosphamide (50 mg per day) and/or oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted. Results: Of the 36 patients, 17 (47.2%) were male, median age was 66.4 years (range, 37-91 years), and subtypes of NHL were mucosa associated lymphoid tissue lymphoma (55.6%), small lymphocytic lymphoma (13.9%), follicular lymphoma (11.1%), mantle cell lymphoma (8.3%), nodal marginal zone lymphoma (4.5%), splenic marginal zone lymphoma (2.8%), and lymphoplasmacytic lymphoma (2.8%). The stage I, II, III, IV were 38.9%, 13.9%, 11.1%, 36.1%, respectively and 55.6% of patients received this regimen as the first-line treatment, mainly due to frailty, refusal to standard chemotherapy. The overall best response rate (ORR) was 73.5% (12 complete responses, CRs and 13 partial responses, PRs), with 29.1 months of the median duration of response and the disease control rate was 88.2%. The median treatment duration was 8.8 months (range, 0.1-38.4 months); the median progression-free survival (PFS) was 43.5 months, and the median overall survival (OS) was not yet reached. Especially, the ORR in patients who were treated with metronomic cyclophosphamide as the first line treatment and as more than the second line treatment were 78.9% (10 CRs, 5 PRs) and 66.6% (2 CRs, 9 PRs), respectively. The median PFS were not reached in the first line cyclophosphamide treatment group and 26.5 months (range, 5.7-47.2 months) in the other group (p=0.110), and similarly, the median OS were not reached and 64.4 months (0-135.7 months) (p=0.058), respectively. The regimen was generally well tolerated, with small numbers of grade 3-4 toxicities; neutropenia (2%), anemia (3%), thrombocytopenia (3%), fatigue (4%), and anorexia (1%). Summary/Conclusion: We concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients.

A Retrospective Analysis of the Efficacy of Low-Dose Metronomic Cyclophosphamide for Treatment in Patients with Low Grade Non-Hodgkin Lymphoma

BackgroundLow-dose metronomic cyclophosphamide chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. We evaluated the efficacy and safety of low-dose metronomic cyclophosphamide in patients with low grade non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data.MethodThe patients received oral cyclophosphamide (50 mg per day) and/or oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted.ResultsOf the 36 patients, 17 (47.2%) were male, median age was 66.4 years (range, 37-91 years), and subtypes of NHL were mucosa associated lymphoid tissue lymphoma (55.6%), small lymphocytic lymphoma (13.9%), follicular lymphoma (11.1%), mantle cell lymphoma (8.3%), nodal marginal zone lymphoma (4.5%), splenic marginal zone lymphoma (2.8%), and lymphoplasmacytic lymphoma (2.8%). The stage I, II, III, IV were 38.9%, 13.9%, 11.1%, 36.1%, respectively and 55.6% of patients received this regimen as the first-line treatment, mainly due to frailty, refusal to standard chemotherapy.The overall best response rate (ORR) was 73.5% (12 complete responses, CRs and 13 partial responses, PRs), with 29.1 months of the median duration of response and the disease control rate was 88.2%. The median treatment duration was 8.8 months (range, 0.1-38.4 months); the median progression-free survival (PFS) was 43.5 months, and the median overall survival (OS) was not yet reached. Especially, the ORR in patients who were treated with metronomic cyclophosphamide as the first line treatment and as more than the second line treatment were 78.9% (10 CRs, 5 PRs) and 66.6% (2 CRs, 9 PRs), respectively. The median PFS were not reached in the first line cyclophosphamide treatment group and 26.5 months (range, 5.7-47.2 months) in the other group (p=0.110), and similarly, the median OS were not reached and 64.4 months (0-135.7 months) (p=0.058), respectively.The regimen was generally well tolerated, with small numbers of grade 3-4 toxicities; neutropenia (2%), anemia (3%), thrombocytopenia (3%), fatigue (4%), and anorexia (1%).ConclusionWe concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients. DisclosuresNo relevant conflicts of interest to declare.

PD-1 Blockade with Pembrolizumab in Relapsed Low Grade Non-Hodgkin Lymphoma

Background: The natural history of low grade non-Hodgkin lymphoma (NHL) typically includes multiple relapses and short responses to therapy after each relapse. The development of novel therapies for NHL patients with multiple relapses is therefore clinically needed. In previous studies, we demonstrated the presence of PD-1 positive exhausted T cells in the nodal tissue of low grade NHL patients. We therefore hypothesized that blocking PD-1 will activate tumor infiltrating T cells to induce effector cell-mediated cytotoxicity. To test this hypothesis, we performed a phase 2 trial (MC1485) to test the efficacy of the PD-1 blocking antibody pembrolizumab in relapsed/refractory low grade NHL.Methods: Relapsed/refractory low grade NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL) who had ECOG performance 0-2 and normal organ function were included in arm B of the MC1485 trial. Patients with prior allogeneic stem cell transplant were excluded. Pembrolizumab 200 mg was administered intravenously every 3 weeks until progression, excessive toxicity, or completion of 2 years of therapy. The primary end point of this study was overall response rate. Tumor T cell infiltration and expression of PD-1 and PD-L1 were assessed with standard immunohistochemical (IHC) staining.Results: 23 patients including 18 FL, 2 MZL and 3 LPL were enrolled and the median age was 67 years (47-82). The median number of prior therapies was 4 (1-20). 17 out of 23 (74%) patients had received more than 2 prior therapies. 100% of patients had received an anti-CD20 antibody and 22/23 (96%) had received chemoimmunotherapy. 6 (26%) had a prior autologous stem cell transplant. 10 (43%) had received prior novel agents including lenalidomide or idelalisib or other experimental therapies. The median number of pembrolizumab doses received was 4 (range, 1 to 16), administered over a median treatment duration of 13.9 weeks (range, 2.6 to 50.8). Drug-related adverse events (AE) occurred in 17 patients (74%) with the common ones being thrombocytopenia in 6 (26%), neutropenia in 5 (22%), anemia in 5 (22%), nausea in 5 (22%), diarrhea in 4 (17%), lymphocyte decrease in 4 (17%), nausea, vomiting and cough each in 3 (13%), and dyspnea in 2 (8%) patients. Drug-related grade 3 or above AE occurred in 9 (39%) patients with most common ones being thrombocytopenia (3, 13%), anemia (3, 13%), neutropenia (2, 8%) and dyspnea (2, 8%). One possibly related death occurred in a patient who had baseline obstructive sleep apnea and developed respiratory failure after two doses of therapy without clear cause. He eventually refused to receive further supportive care. Based on the investigator assessment, 2 FL patients had partial responses (PR, 9%). One LPL patient had minor response using LPL/Waldenstrom macroglobulinemia response criteria (MR, 4%). 11 patients (48%) had stable disease (SD). These two responders had durations of response of 5.5 and 4.9 months respectively (Figure). One MZL patient had ~40% tumor reduction with ongoing therapy. 7 patients (30%) had progressive disease. With a median follow-up being 6.5 months (1.6-24.7), the median progression free survival is 3.4 months (95% CI: 2.1-5.7). The median overall survival has not been reached.Conclusion: Pembrolizumab had an acceptable safety profile in low grade NHL patients. In selected NHL patients, pembrolizumab has activity as single-agent therapy. Biomarker evaluation is needed to select patients who can benefit from this therapy. Further combination therapy will be required to improve efficacy. [Display omitted] DisclosuresDing:Merck: Research Funding. Witzig:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Kura: Research Funding; Novartis: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Abbvie: Consultancy; celgene: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Genetech: Consultancy, Research Funding; pharmacyclics: Consultancy; Nanostring: Research Funding. Reeder:Millennium: Research Funding; Celgene: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Kapoor:Takeda, Celgene and Amgen: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Merck: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding.

Prognostic Factors in Patients with Low-Grade Nonhodgkin Lymphoma.

Low-grade Nonhodgkin lymphoma (LG-NHL) is characterized by indolent clinical course, which consist of marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, waldenstrom macroglobulinemia (WM) as the most common subtypes. Factors affecting prognosis and treatment need in these patients have long been the subject of research. A retrospective study was conducted with patients diagnosed with LG-NHL in Hematology Departments of two centres between 2010 and 2018. At the time of diagnosis, demographic and disease characteristics, hematological and biochemical parameters were examined. Using these data, treatment requirements, response and survival rates were calculated. The effect of parameters on survival and need to treatment were analyzed. 93 LG-NHL patients were included in this study. 40 (43%) of these patients were MZL, 28 (30.1%) were FL and 25 (26.8%) were others. In comparison of patients required treatment with patients without treatment, there was significant difference among the number of comorbidity, platelet count, neutrophil count, disease subgroups and ferritin levels. Logistic regression analysis revealed that disease subgroup (other than MZL and FL) and ferritin levels were independent risk factors for need to treatment. Only ferritin level was found to be associated with overall survival. The current study demonstrated an association between serum ferritin levels and prognosis in patients with LG-NHL. Given that it is easily available and low-cost, the initial ferritin level can be used as a prognostic marker for patients with indolent lymphoma.

Hepatitis B Virus Associated B-Cell Non-Hodgkin Lymphoma in Non-Endemic Areas

IntroductionHepatitis B virus (HBV) is a hepatotropic virus accounting for chronic hepatitis and cirrhosis. HBV is also known as oncogenic, leading to increased risks of not only hepatocellular carcinoma but also other cancers including B-cell non-Hodgkin lymphoma (NHL) (Odd-ratio: 1.9-2.0). According to the World Health Organization, 257 million people in the world have an active HBV infection, areas of high prevalence being in Africa, Western Pacific, and Southeast Asia. While some studies were performed in endemic area, little is known concerning the characteristics of HBV-related NHL in Occident. Moreover, although the need for antivirals to prevent HBV reactivation is well known in patients with HBV receiving chemo or immunotherapy, their impact on their prognosis is unknown. Our aim is to describe the characteristics and outcomes of patients with NHL and active HBV in non-endemic areas.MethodsThirty-nine consecutive patients diagnosed with active HBV infection and B-cell NHL between 2002 and 2017 were enrolled retrospectively in France and Italy. Active HBV infection was defined by positive antigen HbS (AgHbs) and/or positive HBV-DNA in serum. HCV or HIV positive patients were excluded. Their characteristics and outcomes were analyzed and, for Diffuse Large B-cell Lymphoma (DLBCL), compared with those of HBV-negative patients enrolled in R-CHOP arms of LYSA trials.ResultsMost patients were men (29/39), and median age at NHL diagnosis was 59 years ranging from 29 to 88 years. Twenty-two patients (57%) were born in Europe, 13 in Africa (33%), 4 in Asia (10%). Thirty-three patients had positive AgHbs and 28, positive viral load. The histological subtype distribution was: 23 (59%) DLBCL; 13 low-grade NHL (LG-NHL) including 4 follicular lymphoma (FL), 3 spleen marginal zone lymphoma (SMZL), 3 mucosa associated lymphoid tissue lymphoma and 3 not otherwise specified LG-NHL; 2 mantle cell and one Burkitt lymphoma. Of note, none of the primary DLBCL had a low-grade component but 2 FL and one LG-NHL transformed to DLBCL during follow-up. Five patients had a monoclonal immunoglobulin component. Overall, 26 patients (67%) had an extra-nodal involvement (bone marrow (10), liver (8), digestive (6), and bone (5)).All but one DLBCL patients were treated with R-CHOP/R-CHOP-like regimen leading to complete remission in 19 out of 22 (84%). Treatment of LG-NHL patients was diverse: Rituximab monotherapy, immuno-chemotherapy (R-CHOP, R-Chlorambucil, R-Bendamustine), corticosteroids alone or with radiotherapy, Helicobacter pylori treatment or wait and watch. After front-line therapy, 20 DLBCL patients (87%) and 9 LG-NHL (69%) patients achieved complete remission (CR). Thirty-six patients received antiviral treatment following NHL diagnosis while 3 did not (one DLBCL, 2 LG-NHL). Seven patients (18%) died during follow-up: 4 due to progression of lymphoma (3 DLBCL and one LG-NHL), 2 to hepatocellular carcinoma, one to infection. Median overall survival was 81 months without difference between DLBCL and LG-NHL patients. Lastly, the comparison of the outcomes of the 23 DLBCL patients with those of HBV-negative patients did not show significant difference.ConclusionsTo our knowledge, this is the first study exploring HBV-related NHL in non-endemic areas. Interestingly, more than 40% of patients were born in high-endemic areas. The strong predominance of DLBCL (59%) is concordant with studies performed in high-incidence areas. Strikingly, it contrasts with the peculiar distribution of HCV-related NHL supporting that some different pathophysiological mechanisms contribute to NHL in HBV. However, as in HCV-related NHL, frequent hepatic or digestive involvement raises the hypothesis of home privileged lymphomagenesis favored by viral induced inflammation or by infection of B-cells. No difference was detected when comparing HBV DLBCL outcomes with non HBV patients. Remarkably, all patients, except one, received antiviral therapy combined with chemotherapy. In endemic areas, while some studies reported that patients with HBV NHL had a poorer prognostic, others suggested that antivirals could overcome this pejorative impact.This study, performed in Western Europe, area of low HBV prevalence, underlines the predominance of DLBCL among patients with active HBV infection and the similar outcomes of DLBCL patients to non-HBV patients when treated with a combination of R-CHOP and antivirals. DisclosuresNo relevant conflicts of interest to declare.

Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Low Grade Non Hodgkin's Lymphoma: Preliminary Results at Hospital De CliÃŒnicas De Porto Alegre (HCPA), Porto Alegre, RS, Brazil.

AbstractAbstract 4557 INTRODUCTION:Advanced low grade non-Hodgkin Lymphomas have many and varied treatment options. For patients with relapsed or refractory disease, outcome following only chemotherapy protocols remains poor. The standard Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) might be an alternative for relapsed low grade non-Hodgkin lymphomas, but its high Transplant Related Mortality (TRM), varying from 24% to 54%, accounts for a lower overall survival in this group. Reduced Intensity Conditioning (RIC) HSCT has been shown to be a good alternative to myeloablative regimens, with lower TRM, Graft versus Lymphoma Effect, and appears to be associated with improved outcome, presenting a 3 years disease free survival and overall survival from 32% to 66% and from 32% to 73%, respectively, depending on factors such as disease stage before transplantation. PATIENTS, METHODS AND RESULTS:Sixteen heavily pretreated patients with low grade non-Hodgkin Lymphoma (NHL) were submitted to RIC HSCT with matched related donors at the Bone Marrow Transplantation Unit at HCPA between the period of September 2002 to October 2009. The mean age was 43 years and were 7 patients male and 9 female. Fifty percent (8) of the patients had refractory disease pre-HSCT, 43.8% (7) were at third complete remission (CR) and 6.2% (1) at second CR. Median of CD34/kg infused was 10.7 × 106 and the median of days for engraftment was 14.53. Conditioning regimens were Fludarabine + Cyclophosphamide in 3 patients, Fludarabine + Melphalan in 7, Fludarabine + Cyclophosphamide + Rituximab in 2, Fludarabine + Cyclophosphamide + Melphalan in 1, Cyclophosphamide + Total Body Irradiation (TBI) in 1 and Fludarabine + Cyclophosphamide + TBI in 2. Acute Graft versus Host Disease (aGVHD) occurred in 50%, with 37.5% of those were steroids resistant; and 62.5% of the patients evolved to chronic GVHD, with 80% of them classified as extensive. Chimerism from 9 patients was analyzed, and 89% of them were complete. Mean overall survival was 2.95 years; 62.5% of patients were alive within 1 year and 40% within 3 years. TRM was 6.66%. Eight patients died, five of them were transplanted with refractory disease. Only 2 patients died of relapse, 5 of infections and 1 of aGVHD. CONCLUSION:Low grade NHL patients treated at HCPA with RIC HSCT had an overall survival and TRM comparable to the observed at other centers, appearing as a good alternative for this heavily treated group of patients with less toxicity than myeloablative regimens. Disclosures:No relevant conflicts of interest to declare.

Immune reconstitution after autologous hematopoietic transplantation with Lin −, CD34 +, Thy-1 lo selected or intact stem cell products

In sequential studies, we compared immune reconstitution following high-dose chemotherapy (HDT) and stem cell transplantation (SCT) using intact mobilized peripheral blood stem cell (PSC) in intermediate grade non-Hodgkin's lymphoma (NHL) patients and CD34 +, lineage-negative (Lin −), Thy-1 lo (CD34 +Lin −Thy-1 lo) stem cells in low-grade NHL patients. Cytokine expression and cellular phenotype and function were used as the basis of comparison. Despite differences in cellular composition of the stem cell grafts, immune reconstitution in both groups was similar. Significantly higher levels of type 1- and 2-associated cytokine messenger ribonucleic acid (mRNA) were observed both prior to and following transplant in the peripheral blood (PB) of both cohorts as compared to normal individuals. Similar levels of interleukin (IL)-4, IL-10, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) messenger ribonucleic acid (mRNA) were seen in PB mononuclear cells following transplant with either product. In contrast, patients receiving isolated CD34 +Lin −Thy-1 lo cells expressed significantly higher IL-2 levels at all times examined post-transplant. Despite the high levels of cytokine gene expression and rapid restoration to pretransplant levels of CD3 cell number by day 30, T cell function and CD4:CD8 and CD4 +CD45RA:CD4 +CD45RO + ratios were significantly depressed in both cohorts compared to normal donors, and significantly lower in patients transplanted with CD34 +Lin −Thy-1 lo compared to patients receiving an intact PSC product. These data suggest that the peripheral tolerance in patients receiving HDT and an autologous SCT occurs independent of graft composition, although immune function and CD4 recovery are better facilitated by transplantation of an intact product.

Clinical outcome of low‐grade NHL patients with bone marrow involvement

Bone marrow (BM) involvement in low-grade non-Hodgkin's lymphoma (NHL) has a clear impact on patients' survival. The standard practice is morphological examination of BM biopsy at diagnosis. The clinical significance of flow cytometry (FC) analysis of BM aspirates is largely unknown. The medical charts of 70 low-grade NHL patients, who underwent BM biopsy and FC analysis between 1994 and 2004, were reviewed. Forty-three patients (61.4%) were BM+ by morphology, while in those without morphological involvement by lymphoma FC was positive in 9 (BM-FC+, 12.9%) and negative in 18 (BM-FC-, 25.7%). The median treatment-free period was shorter in the BM+ and BM-FC+ groups compared with the BM-FC- group (1 and 4 months vs. 31 months, respectively) (log-rank test, P = 0.0195). The median survival time was not reached for the BM-FC- patients, whereas for BM+ and BM-FC+ patients it was 129 and 89 months, respectively, with no significant difference between them [the difference between the BM-FC- and the two other groups was statistically significant (log-rank test, P = 0.029)]. The outcome of low grade NHL in patients who had BM involvement by FC alone or by morphology was similar. If confirmed, these findings suggest a modification in the workup and management of localized low grade NHL.

Investigation of FcγR Polymorphisms and Response to IL-2 (Proleukin®) and Rituximab Treatment in Rituximab-Resistant NHL Patients: Importance of the F/F Polymorphism at Position 158 of the Fcγ.

Background: Antibody-dependent cellular cytotoxicty (ADCC) is an important mechanism of rituximab activity. Genetic polymorphisms in FcγRIIIa have been reported to influence response to rituximab in follicular non-Hodgkin's lymphoma (NHL) patients, and the F/F polymorphism at position 158 has been associated with decreased response (Cartron, et al. Blood 2004). IL-2 induces expansion and activation of FcR bearing cells, enhancing ADCC (Gluck, et al. Clin Cancer Res 2004).Methods: The combination therapy of IL-2 and rituximab (IL-2+R) was evaluated in low grade NHL patients who were rituximab-resistant by standard criteria. Rituximab was administered weeks (wks) 1–4 at 375 mg/m2 IV; IL-2 was administered SC 3 times/wk at 14 MIU wks 2–5 and at 10 MIU wks 6–9.Results: 57 patients (pts) were enrolled. Twenty-nine pts are evaluable with at least week 8 response data, all of whom have been genotyped. Best response to date: 4 responders (1 CR, 3 PR), 22 patients with stable disease (SD), and 3 pts have progressed (PD) on therapy. Follow-up is on-going. FcγRIIIa polymorphism analysis at position 158 from 36 pts typed to date shows a frequency of 53% F/F, 36% V/F, and 11% V/V as compared to 35%F/F, 45%V/F and 20% V/V in previously untreated pts (Cartron et al, 2004). To date, the data has shown a higher response rate for the F/F pts (4/17; 24%) than the overall population (4/29; 14%). Best response to date for 17 F/F pts: 4 responders and 13 SD; for the 9 V/F pts: 0 responders, 7 SD, and 2 PD; for the 3 V/V pts: 0 responders, 2 SD, and 1PD. In addition, 9 pts had responses lasting = 4 months with 6/9 being F/F and 3/9 being V/F. Patients will be followed periodically up to 2 years or until disease progression. The regimen was well tolerated and the majority of adverse events (AEs) were CTC grade 0, 1, or 2 (flu like symptoms, injection site reactions and rash). No grade 3 or 4 AEs occurred in 10% or more of pts.Conclusions: These data support an association of the genetic polymorphism of FcγRIIIa 158F/F with prior failure to respond to rituximab. Immunotherapy with IL-2+R may achieve a critical threshold to drive ADCC more effectively in patients carrying the low affinity F/F IgG FcR polymorphism, restoring their response to monoclonal antibody therapy. All pts with this F/F polymorphism either responded to therapy or achieved SD as their best response to date. This outpatient regimen was generally well tolerated. The role of the FcγRIIIa F/F polymorphism is currently being evaluated in a prospective randomized trial comparing rituximab to rituximab + IL-2 in patients with follicular lymphoma.

CHOP Plus Rituximab (CHOP-R) in Waldenström's Macroglobulinemia (WM).

Recently, a consensus panel of experts recommended alkylator therapy, nucleoside analogues and rituximab as appropriate first line therapies for WM (Semin Oncol 2003; 30:121). It was also recommended that candidates for future autologous transplantation should have limited alkylator or nucleoside analogue exposure due to potential stem cell harm. CHOP-R (cyclophosphamide, adriamycin, vincristine, prednisone, rituximab) is a highly active, stem cell sparing regimen that has been extensively evaluated in other low-grade Non-Hodgkin's lymphoma patients. No published experience in WM exists. As such, we analyzed the outcome of 13 patients with WM who received CHOP-R at our Institution. Patients had a median age of 54 (range 44–72) yrs, and a median of 1 (range 0–5) prior therapies. 8 of 13 (62%) patients had relapsed (n=2) or were refractory (n=6) to fludarabine. Five patients had received rituximab previously. Patients received a median of 6 cycles (range 2–6) of standard dose CHOP, and 6 infusions (range 2–6) of Rituximab (375 mg/m2). Three patients received additional rituximab (4 weekly infusions every 6 months) as maintenance therapy. Median IgM for all patients declined from 4,975 (range 1,960–12,400) to 1,575 (range 62–8,230) mg/dL (p=7 x 10−5); median S.V. 2.8 (range 1.5–12) declined to 1.6 (range 1.3–4.8) CP (p=0.04). Importantly, the median hematocrit rose from 30.7 (range 21.9–35.6) to 39 (range 24.3–43.2) p=0.005. Clinical responses were as follows: 3 CR/CRu; 7 PR; 2 MR. One patient is in stable disease after 3 cycles of CHOP-R. With a median follow-up of 8 (range 3–28) months, no patient has progressed. Therapy was well tolerated for most patients. Two patients had febrile neutropenia with documented bacteremia and recovered without any complication. Circulating effector cell levels pre- and post-CHOP-R were also evaluated in 6 patients since rituximab activity is mediated in part by ADCC activity. No significant change in CD3+, CD4+, CD8+, and CD16+/CD56+ effector cell levels occurred following CHOP-R as assessed by multicolor flow cytometry.

Radioimmunotherapy for NHL: Experience of 90Y-Ibritumomab Tiuxetan in Clinical Practice

Radioimmunotherapy (RIT) is a novel treatment modality that combines the benefits of radiotherapy and immunotherapy, enabling multiple sites of disseminated disease to be treated simultaneously and effectively, while minimizing toxicity to normal tissues. 90Y-ibritumomab tiuxetan consists of the anti-CD20 monoclonal antibody (MAb) ibritumomab covalently linked to tiuxetan for chelation of 90Y for therapy. Early work established that a dose of 14.8 MBq/kg (0.4 mCi/kg) is safe and effective in patients with < 25% bone marrow involvement and adequate marrow reserves, as is a dose of 11.1 MBq/kg (0.3 mCi/kg) in patients with mild thrombocytopenia (platelet counts 100 × 109 – 150 × 109/l). To date, 5 clinical trials using 90Y-ibritumomab tiuxetan have been reported, one of which assessed the efficacy in rituximab-refractory patients with follicular non-Hodgkin's lymphoma (NHL) histology. Within the 54 follicular lymphoma patients, an overall response (OR) rate of 74% and a complete response (CR) rate of 15% were achieved, despite patients having received a median of 4 prior therapies and 73% having tumors ⩾ 5 cm in diameter. In addition, a major phase III randomized trial directly compared 90Y-ibritumomab tiuxetan with the unlabeled anti-CD20 MAb rituximab. Results from the randomized trial demonstrated that OR and CR rates were significantly higher with 90Y-ibritumomab tiuxetan, compared with rituximab (OR rate 80% vs. 56%, P = 0.002; CR rate 30% vs. 16%, P = 0.004). Time to progression (TTP) was 11.2 vs. 10.1 months (P = 0.173). Treatment was generally well tolerated; the primary toxicity associated with 90Y-ibritumomab tiuxetan therapy is reversible myelosuppression, which correlates with the degree of bone marrow involvement at baseline. In an integrated analysis of safety data from 5 90Y-ibritumomab tiuxetan studies, only 7% of patients were hospitalized due to infection during the treatment period. In addition, 90Y-ibritumomab tiuxetan therapy was not shown to increase the risk of developing secondary malignancies (myelodysplastic syndrome/acute myeloid leukemia), or preclude subsequent therapy upon relapse. Current investigations are focussing on the potential role of 90Y-ibritumomab tiuxetan earlier in the treatment algorithm, including as single-agent therapy for relapsed diffuse large B-cell lymphoma patients not eligible for transplantation, and consolidation treatment for low-grade NHL patients after first-line, alkylating agent-based therapy.

Long-Standing Resolution of Anemia in Symptomatic Low-Grade Non-Hodgkin's Lymphoma Patients Treated with Recombinant Human Erythropoietin as Sole Therapy

Anemia is a predominant clinical problem in the management of patients with non-Hodgkin's lymphoma and often an indication to initiate chemotherapy. However, many elderly patients, especially those with concomitant disorders, do not tolerate such therapy very well. This report describes three patients with low-grade non-Hodgkin's lymphoma who were treated solely with recombinant human erythropoietin (rhEPO) for lymphoma-associated anemia. The rhEPO was given at an initial dose of 150 U/kg three times weekly, with dose reduction when a response had been achieved. All three patients normalized their hemoglobin level and severe anemia-related symptoms disappeared. Responses are ongoing in two patients after 10 and 12 mo of therapy, respectively. The third patient maintained a response to rhEPO for over 5 yr, without any need for further therapeutic interventions, before dying of an unrelated event. This treatment strategy seems worthy of further investigation in selected lymphoma patients where anemia is the major complication of the disease.

Subcutaneous administration of interleukin-2 triggers Fcgamma receptor I expression on human peripheral blood neutrophils in solid and hematologic malignancies.

Freshly isolated human polymorphonuclear cells (PMNCs) constitutively express Fcgamma receptor (Fc-gammaR) II and FcgammaRIII on the cell surface but not FcgammaRI. Cytokines such as interferon-gamma (IFNgamma), granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF trigger FcgammaRI expression on (PMNCs). Because PMNCs express interleukin (IL)-2 receptor, we investigated whether IL-2 can induce FcgammaRI expression on PMNCs isolated from IL-2-treated metastatic renal cell carcinoma (MRCC) and low-grade non-Hodgkin lymphoma (LGNHL) patients. Pretherapy flow cytometry analysis of Fcgamma receptors on PMNCs did not show FcgammaRI expression. Interestingly, 3 days after therapy, PMNCs displayed a detectable amount of FcgammaRI on the cell surface. Kinetic studies on the in vivo effects of IL-2 on MRCC patients showed that FcgammaRI was transiently expressed, starting within 3-6 days of therapy, remaining expressed for 10-15 days, and rapidly declining, whereas such expression remained stable for months in LGNHL patients. In contrast, Fc-gammaRII was not affected. In addition, FcgammaRI+ PMNCs coated in vitro with a bispecific antibody Fab anti-FcgammaRI x anti-HER-2/neu formed intercellular conjugates with a human HER-2/neu-transfected 3T3 cell line (HER-2/neu-3T3). Interleukin-2 treatment increased the number of FcgammaRIII low eosinophils, leading to a change in FcgammaRIII distribution among granulocyte cell subsets. In vitro IL-2 treatment of purified PMNCs failed to generate Fc-gammaRI expression, suggesting that IL-2 indirectly causes FcgammaRI expression. During the IL-2 administration, we did not observe significant changes in IFNgamma serum level. In conclusion, our observation may be used to potentiate the antitumor effects of IL-2 in novel immunotherapy regimens, perhaps by redirecting FcgammaRI+ PMNCs against cancer cells by heteroconjugate antibodies and monitoring the biologic activity of subcutaneous IL-2 in cancer patients.

Salvage Chemotherapy Using a Combination of Fludarabine and Cyclophosphamide for Refractory or Relapsing Indolent and Aggressive Non-Hodgkin's Lymphomas

The prognosis of patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) after primary therapy is poor and multi-drug salvage treatments are associated with less than 60% response rates, usually of short duration. Here we report the results of a phase II study using a fludarabine-cyclophosphamide (FAMP-Cy) combination as a salvage failure regimen in refractory and relapsing low-grade (6) and intermediate-grade (9) NHL patients. Fifteen patients, who had received up to 4 regimens prior to therapy with FAMP-Cy were treated with fludarabine (25 mg/ml2) and cyclophosphamide (300 mg/m2) for 3 consecutive days followed by G-CSF (5 μg/kg). The overall response was 74%, 4 achieving complete responses (CR) and 7 partial responses (PR). All patients with low-grade NHL responded (4 CR, 2 PR); 5 patients with intermediate-grade NHL achieved PR lasting for a median of 5 months. The main toxicity encountered was moderate myelosuppression. Three patients had febrile neutropenia, one had drug-induced fever and a single patient developed severe neurotoxicity. Opportunistic infections due to lymphopenia were not seen.The combination of fludarabine and cyclophosphamide used as a salvage regimen showed an impressive response in a small group of heavily pretreated low-grade NHL patients who had previously received a large number of prior regimens. FAMP-Cy had limited effect in a similar group of intermediate-grade NHL patients. Results with this “failure” regimen are encouraging, however further studies are needed in order to confirm these observations in a larger series of patients.

Activity of 2-chlorodeoxyadenosine (cladribine) in 2-hour intravenous infusion in 94 previously treated patients with low grade non-hodgkin's lymphoma

The purpose of our study was to determine the efficacy of 2-chlorodeoxyadenosine (2-CdA) administered in 2-hour intravenous infusions in previously treated patients with low grade non-Hodgkin's lymphoma (LGNHL). We treated 94 LGNHL patients with 2-CdA at a dosage of 0.12 mg/kg/24h in 2-hour intravenous infusion for 5 consecutive days. The treatment consisted of from 1 to 7 courses (median 3), repeated usually at monthly intervals. All patients were refractory to or relapsed after standard chemotherapy. Of these 94 patients 78 (83%) had clinical stage IV of the disease. Complete response (CR) was obtained in 12 (12.8%) and partial response (PR) in 36 (38.3%) giving an overall response rate of 51.1%. In 12 (12.8%) grade 4 thrombocytopenia with haemorrhagic diathesis was noted, grade 4 neutropenia was observed in 12 (12.8%) and infections complicated the course of treatment in 38 (40.4%) patients. 2-CdA treatment was the cause of death of 3 patients. The results of our study show that 2-CdA given in 2-hour infusions is an effective agent in advanced, heavily pretreated patients with LGNHL.

Clinical implications of serum levels of soluble CD23 and tumor necrosis factor alpha in low-grade non-Hodgkin's lymphoma.

In the last few years the research for new biological features in low-grade non-Hodgkin's lymphoma has provided important results. Several biological parameters are under evaluation and, in particular, cytokines and soluble receptors levels are showing their importance as prognostic parameters. In the present study, serum levels of tumor necrosis factor alpha (TNF-alpha) and soluble CD23 (sCD23) were measured at the time of diagnosis and after induction polychemotherapy in 40 patients with newly diagnosed low-grade non-Hodgkin's lymphoma (LG-NHL). The treatments were CIOP (cyclophosphamide, idarubicin, vincristine, prednisone) regimen for 28 patients and FMP (fludarabine, mitoxantrone, prednisone) scheme for 12 patients. Pretreatment levels of TNF-alpha were highly elevated in patiets with LG-NHL compared with healthy controls (p = 0.005) and were significantly correlated with the Ann Arbor stage (p = 0.001). sCD23 was detected in 35 patients at diagnosis and were markedly increased in LG-NHL patients when compared to healthy controls (p = 0.005); patients with advanced stage presented higher values than those with early stage disease (p = 0.002). All the complete responders (20/40, 50%) showed a decrease of TNF-alpha and sCD23 levels. By contrast, the combination of high levels of TNF-alpha and sCD23 correspond to a group of non-responders. Our results suggest that TNF-alpha and sCD23 are specific prognostic parameters for LG-NHL, and that they could be used as tumor markers within a potential biological prognostic index.

Feasibility of Total Body Irradiation in Chronic Lymphocytic Leukemia and Low-Grade Non-Hodgkin's Lymphomas

Combined total body irradiation (TBI) and Prednimustine were prospectively evaluated in 30 patients affected either with chronic lymphocytic leukemia (CLL) or with low-grade non-Hodgkin's lymphoma (NHL) eleven patients were previously treated. Between January 1984 and May 1987, 20 evaluable patients with CLL, median age 66 years (range 43-82), classified according to Rai (4 in stage I, 10 in stage II, 4 in stage III, 2 in stage IV) and 10 evaluable patients with NHL low-grade malignancy according to the Working Formulation, Stages III and IV, median age 54 years (range 32-71) were treated using a 6 MeV Linear Accelerator, applying two opposite alternating fields including total body, with a fraction of 15 cGy, 2 fractions weekly (3-day interval) for a total dose of 150 cGy given over 5 weeks. Prednimustine (100 mg/m2, orally, for 5 consecutive days, every 3-4 weeks, for 6-9 courses) was administered 2 months after TBI treatment, as consolidation therapy. By May 1989, a total of 85% hematological responses (defined as normalization of the differential white cell count, of the total blood cell count and of bone marrow infiltration) were obtained after combined treatment in CLL patients; moreover 3 CR (according to the WHO criteria), 75% with splenomegaly reduction and 40% with lymphadenopathy reduction were seen. Ninety percent objective responses (5 CR and 4 PR) were observed in the NHL patients, with 50% having splenomegaly reduction and 67% lymphadenopathy reduction. The median response time in the two groups was, respectively, 14 and 23 months. The overall toxicity (WHO grades 1,2,3,4) after combined treatment was 65% and 70% in the two patient groups. WHO grade III toxicity, completely reversible, was verified in only 16.6% of the cases; all cases, except one, were previously treated. Additionally, 1 toxic death (grade IV thrombocytopenia and leukopenia) was observed in a heavily pretreated patient affected with CLL after TBI alone. Prednimustine regimen was generally well tolerated. The high response rate and acceptable toxicity, confirms the feasibility and the usefulness of TBI in the context of a combined treatment for CLL and low-grade NHL patients. However in order to further reduce the severe toxic side effects, observed in one patient, white blood cells and platelet count should be plotted and monitored carefully, particularly in pretreated patients.