Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial.

We report the 12-year follow-up of the prospective randomized EBMT LYM1 trial to determine whether the benefit of brief duration rituximab maintenance (RM) on progression-free survival (PFS) in patients with relapsed follicular lymphoma (FL) receiving an autologous stem cell transplant (ASCT) is sustained. One hundred and thirty-eight patients received RM with or without purging. The median follow-up after random assignment is 12 years (range 10-13) for the whole series. The 10-year PFS after ASCT is 47% (95% CI 40-54) with only 4 patients relapsing after 7.5 years. RM continues to significantly improve 10-year PFS after ASCT in comparison with NM [P = 0.002; HR 0.548 (95% CI 0.38-0.80)]. Ten-year non-relapse mortality (NRM) was not significantly different between treatment groups (7% overall). 10-year overall survival (OS) after ASCT was 75% (69-81) for the whole series, with no significant differences according to treatment sub-groups. 10-year OS for patients who progressed within 24 months (POD24T) was 60%, in comparison with 85% for patients without progression. Thus the benefit of rituximab maintenance after ASCT on relapse prevention is sustained at 12 years, suggesting that RM adds to ASCT-mediated disease eradication and may enhance the curative potential of ASCT.

Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia.

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

Salivary gland lymphoproliferative disorders: a Canadian tertiary center experience.

Salivary gland lymphoproliferative disorders (SGLD) are very rare tumors and clinicopathological data is sparse. In a Canadian series of 30 cases, extracted from the surgical pathology files of The Ottawa Hospital between 1990 and 2010, a clinical, histopathological, and immunophenotypic analysis was conducted. Tumors were staged using the Ann Arbor staging and classified using the World Health Organization 2008 classification. There were 15 salivary gland (SG) primary lymphomas with localized disease, predominantly mucosa associated lymphoid tissue type marginal zone lymphoma (MALT-L), but with a significant incidence of low grade follicular lymphoma (FL) and diffuse large B cell phenotype as well. There were 7 systemic SG lymphomas and 5 patients were diagnosed with lymphoproliferative disorders originating from intra-parotid lymph nodes. Finally, the remaining 3 cases represented reactive sialadenitis. A literature review was conducted and our primary lymphoma group was compared to those from other countries. SGLDs are predominantly B cell lymphomas that develop in older adults. Primary tumors, which have MALT-L and low grade FL characteristics, have a favorable survival, however MALT-L have a high rate of relapse. A minority of SG lesions are excised secondary to lymphomas that definitely arose from intra-parotid lymph nodes.

Monoclonal B cells detected in autologous PBSC grafts from patients with classical Hodgkin lymphoma: impact on relapse and survival following transplantation.

Autologous peripheral blood stem cell transplantation (PBSCT) for Hodgkin lymphoma (HL) is curative for many patients with relapsed or refractory disease. Relapsing disease, however, remains a major problem. Neoplastic transformation of B-lymphocytes probably underlies the development of classical HL. Whether clonal B cells are critical for disease evolution and response to therapy in HL remains uncertain. We investigated the impact of clonal B cells detected in peripheral blood stem cell (PBSC) collections on the outcome of patients with HL undergoing transplant. Qualitative semi-nested PCR was carried out on genomic DNA from mononuclear cells from PBSCs to determine the presence of clonal immunoglobulin heavy chain (IgH) complementary-determining region 3 (CDR3) gene rearrangements. Clinical factors were assessed for their association with relapse, overall survival (OS) and progression-free survival (PFS). Among 39 patients undergoing PBSCT, 12 grafts (31%) were PCR positive for clonal IgH rearrangements. OS was better in the PCR-negative group (logrank test, P=0.041). The OS at 5 years was 81% in PCR-negative versus 39% in PCR-positive patients; hazard ratio was 3.23 (95% confidence interval: 0.98-10.63). There was a trend towards better PFS (logrank test, P=0.12), estimated as 71% at 5 years in PCR-negative versus 41% in PCR-positive patients. Clonal B-lymphocytes in PBSC collections of patients with HL identify patients at risk of poor outcome. Larger series are needed to confirm our observations. Insight regarding the role of monoclonal B cells may lead to improved therapies.

Performing allogeneic and autologous hematopoietic SCT in the outpatient setting: effects on infectious complications and early transplant outcomes.

This retrospective single-center study compared the incidence, spectrum and effect of infections in 1045 consecutive allogeneic (allo) and autologous (auto) hematopoietic SCT (HSCT) performed between 1995 and 2006 in the inpatient (IP) or outpatient (OP) setting. We analyzed 374 allo-HSCT (196 IP and 178 OP) and 671 auto-HSCT (163 IP and 508 OP). The incidence of infection was lower both in auto-OP (25% OP vs 33% IP, P=0.042) and allo-OP cohorts (42.7% OP vs 55.6% IP, P=0.012). The mean number of infections per transplant was lower in both auto-OP (0.39 OP vs 0.57 IP, P=0.05) and in allo-OP cohorts (0.78 OP vs 1.09 IP, P=0.018). The 100-day non-relapse mortality (NRM) for OP auto-HSCT was 4.72% and for IP 3.95% (P=0.68). The 100-day NRM for OP allo-HSCT was lower at 14.1% than it was for IP at 22.6% (P=0.041). Time to onset of first infection and spectrum of infections was similar in all groups. We conclude that performing allo- and auto-HSCT in the OP setting results in short-term outcomes, including infections complications that are comparable to the standard IP setting.

Contaminating tumour cells in autologous PBSC grafts do not influence survival or relapse following transplant for multiple myeloma or B-cell non-Hodgkin's lymphoma.

Relapsed disease remains a major obstacle following autologous haematopoietic SCT (HSCT) for non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Studies regarding the importance of detectable tumour cells in PBSC collections have been inconclusive. Patients undergoing autologous HSCT for NHL and MM between 2001 and 2006 were enrolled (n=158). PBSC grafts were assessed for clonal IgH CDR3 gene rearrangements using qualitative semi-nested PCR. In comparison to patients with PCR-positive PBSC grafts, patients negative for detectable disease had no improvement in overall survival (OS) or PFS for MM (P=0.91 and 0.91) or NHL (P=0.82 and 0.85). Further, no significant difference in OS was observed between patients with PCR-positive compared with PCR-negative PBSC grafts with aggressive NHL histology (P=0.74) or indolent disease (P=0.29). Patients with contaminating tumour cells in autologous PBSCs do not have worsened OS or PFS in MM or NHL. Tumour cells detected by sensitive molecular methods in PBSC collections may be distinct from cells contaminating marrow and appear to have limited utility in identifying patients with MM and B-cell NHL who would benefit from purging strategies.

Outpatient total body irradiation as a component of a comprehensive outpatient transplant program.

Outpatient total body irradiation (TBI) as part of a comprehensive outpatient transplant program was delivered to 142 of 167 (85%) consecutive patients receiving TBI-based conditioning therapy. Outpatients received either a single fraction of 500 cGy (110 patients) or 1200 cGy in six fractions over 3 days (32 patients). Patients were assessed daily and were administered oral ondansetron and dexamethasone for prophylaxis of nausea and vomiting as well as i.v. hydration. Accommodation during outpatient TBI-based conditioning was either the patient's home if within 30 min of the hospital, a hotel on the hospital grounds or on a closed hospital ward. None of the 142 patients required admission to the inpatient program during their TBI. There was no difference in 100-day mortality between those receiving TBI as an outpatient (9%) vs as an inpatient (16%). Of four deaths occurring within the first 14 days post transplant, none could be attributed to receiving TBI as an outpatient. Two hundred and six inpatient days were saved through the delivery of outpatient TBI. A comprehensive outpatient program, appropriate patient selection, daily hydration, the use of prophylactic 5HT3 antagonist anti-emetic therapy all contribute to the safe delivery of outpatient TBI.

Use of PEG-rHuMGDF in platelet engraftment after autologous stem cell transplantation.

This paper summarizes a pilot, sequential dose-escalation study of PEG-rHuMGDF in patients with advanced malignancies who had delayed platelet recovery after autologous stem cell transplantation (ASCT). Patients were randomized to receive either placebo (n = 11) or PEG-rHuMGDF at 5 (n = 9), 10 (n = 6), or 25 (n = 7) microg/kg/day by subcutaneous injection for 14 days and were monitored for 5 weeks. Across all treatment groups, eight patients had platelet recovery to > or = 20 x 10(9)/l by day 21. The proportion of patients achieving platelet recovery, the median number of days and units of platelet transfusions were similar for the placebo and the PEG-rHuMGDF groups. PEG-rHuMGDF was well tolerated at all dosages. The incidence rates of adverse events in all groups were similar. No deaths on study, no drug-related serious adverse events, and no development of neutralizing antibodies to MGDF occurred.

Autologous blood and marrow transplantation in patients 60 years and older.

Although many hematologic malignancies are more common in older patients, autologous blood and marrow transplantation (ABMT) has traditionally been restricted to patients younger than 60 years because of concerns that older patients would be either unable to provide a graft or unable to tolerate the therapy. From June 1995 to May 1998, 30 patients > or = 60 years underwent ABMT at our institution for low-grade lymphoma (4 patients), relapsed intermediate-grade lymphoma (17 patients), or multiple myeloma (9 patients). The median patient age was 62.5 years (range 60-73). Pretransplantation conditioning regimens were CBV (cyclophosphamide, BCNU [carmustine], etoposide) or BEAM (carmustine, etoposide, cytarabine, melphalan) for intermediate-grade lymphoma patients and melphalan 140 mg/m2 + etoposide 60 mg/kg + total body irradiation 500 cGy for the others. The rescue product was bone marrow (BM; 4 patients), peripheral blood stem cells (PBSC; 23 patients), or BM+PBSC (3 patients). The median number of CD34+ cells/kg infused was 3.60 x 10(6) (range 0.53-31.0), by the International Society for Hematotherapy and Graft Engineering method. The treatment-related mortality at day 100 and at 6 months was 10% and 16.7%, respectively. The median days to neutrophil > 0.5 x 10(9)/L was 11 (range 9-25) and platelets > 20 x 10(9)/L was 16 (range 6-70). Three patients died of infection (days 26, 27, and 38), and 1 died of an intracranial hemorrhage related to persistent thrombocytopenia (day 130). Bearman regimen-related toxicity was moderate, with most toxicities < or = grade 2. Seven patients developed significant gut toxicity: 4 patients with Clostridium difficile colitis and 3 patients with neutropenic enterocolitis. Depressive symptoms and signs were noted in 4 patients. Three male patients developed decreased gonadal function after transplantation. These transplantations accounted for 997 patient days, of which 266 days (27%) were in the outpatient BMT program--a smaller percentage than in patients < 60 years (56%, P = .002). Twenty patients are alive 153 to > or = 1224 days after transplantation. ABMT in patients > or = 60 years of age is feasible. Further studies addressing supportive care particular to older patients and comparisons of ABMT with traditional approaches to multiple myeloma and relapsed non-Hodgkin's lymphoma in older patients are needed. Further work to identify elderly patients most likely to benefit from this approach is also required.

Fluorescence in situ hybridization analysis of complex translocations in two newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia patients.

Two different complex translocations from newly diagnosed cases of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) were characterized by G-banding and fluorescence in situ hybridization (FISH) analysis. In one case, a unique balanced t(9;22;9;11) (q34;q11;p22;q23) was identified by G-banding, and confirmed by FISH using MBCR/ABL and painting probes. In the second case, an apparently balanced t(19;22) was identified by G-banding analysis. FISH using MBCR/ABL probe detected the fusion gene on the derivative chromosome 22, indicating the involvement of chromosome 9. Further FISH analysis with selected painting probes showed that the t(19;22) was a result of a complex translocation involving chromosomes 9, 19, 21, and 22.

A randomized trial of granulocyte colony-stimulating factor (Neupogen) starting day 1 vs day 7 post-autologous stem cell transplantation.

The purpose of the study was to evaluate the effect of delayed granulocyte colony-stimulating factor (G-CSF) use on hematopoietic recovery post-autologous peripheral blood progenitor cell (PBPC) transplantation. Patients were randomized to begin G-CSF on day +1 or day +7 post transplantation. Thirty-seven patients with lymphoma or myeloma undergoing high-dose therapy and autologous PBPC rescue were randomized to daily subcutaneous G-CSF beginning on day +1 or day +7 post-transplant. Patients < or =70 kg received 300 microg/day and >70 kg 480 microg/day. All patients were reinfused with PBPCs with a CD34+ cell count >2.0 x 10(6)/kg. Baseline characteristics of age, sex and CD34+ cell count were similar between the two arms, the median CD34+ cell count being 5.87 x 10(6)/kg in the day +1 group and 7.70 x 10(6)/kg in the day +7 group (P=0.7). The median time to reach a neutrophil count of >0.5 x 10(9)/l was 9 days in the day +1 arm and 10 days in the day +7 arm, a difference which was not statistically significant (P=0.68). Similarly, there was no difference in median days to platelet recovery >20000 x 10(9)/l, which was 10 days in the day +1 arm and 11 days in the day +7 arm (P=0.83). There was also no significant difference in the median duration of febrile neutropenia (4 vs 6 days; P=0.7), intravenous antibiotic use (7 vs 8 days; P=0.54) or median number of red blood cell transfusions (4 vs 7 units; P=0.82) between the two arms. Median length of hospital stay was 11 days post-PBPC reinfusion in both groups. The median number of G-CSF injections used was 8 in the day +1 group and 3 in the day +7 group (P < 0.0001). There is no significant difference in time to neutrophil or platelet recovery when G-CSF is initiated on day +7 compared to day +1 post-autologous PBPC transplantation. There is also no difference in number of febrile neutropenic or antibiotic days, number of red blood cell transfusions or length of hospital stay. The number of doses of G-CSF used per transplant is significantly reduced with delayed initiation, resulting in a significant reduction in drug costs. For patients with an adequately mobilized PBPC graft, the initiation of G-CSF can be delayed until day +7 post-PBPC reinfusion.

Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.

BACKGROUND: Monoclonal antibodies are being utilized for treatment of patients with low-grade non-Hodgkin's lymphoma as well as other cancers. Results from phase I and II clinical studies has shown that the chimeric monoclonal antibody Rituximab has minimal toxicity and significant therapeutic activity in low grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: We have recently reported on a multicentre pivotal phase III clinical trial involving 166 patients with recurrent low-grade lymphoma who were treated with four infusions of Rituximab. Eighty patients (48%) achieved objective responses including 10 patients (6%) with complete responses. Overall, 126 patients (76%) had a > or = 20% reduction in overall tumor size. The median response duration and time to progression are 11.6 and 13.2 months, respectively. The infusional and long term toxicities were limited. RESULTS: In this report we describe the pharmacokinetic data obtained on these patients. Measurable concentrations of Rituximab were detected in all patients after the first infusion and increased throughout the treatment course. The half-life of the monoclonal antibody increased from 76.3 hours after the first infusion to 205.8 hours after the fourth infusion and was concomitant with a four-fold decrease in the antibody clearance. At three months and six months post-treatment, the median Rituximab serum levels were 20.3 micrograms/ml (range 0.0 to 96.8 micrograms/ml in 104 patients) and 1.3 micrograms/ml (range 0.0-28.7 micrograms/ml in 13 patients), respectively. A statistically significant correlation was found between the median antibody concentration and response for multiple time points during the treatment and followup. The mean serum antibody concentration was also inversely correlated with measurements of tumor bulk and with the number of circulating B cells at baseline. CONCLUSIONS: We conclude that Rituximab is therapeutically effective against B-cell lymphoma. Pharmacokinetic data suggests that certain subsets of patients may possibly benefit from increased dosing and studies to address this are currently underway.

Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Cost analysis of the introduction of PBPC for autologous transplantation: effect of switching from bone marrow (BM) to peripheral blood progenitor cells (PBPC).

Increasingly, PBPC instead of BM are used for autologous transplantation. Limited data exist on the economic effects of this change. Using a resource-based utilization model we prospectively determined the costs of 48 autologous transplants (eight BM, 17 BM + PBPC, 23 PBPC), isolating the post-reinfusion period (day 0 to discharge) to better determine the effect of the rescue product. Length of stay post-reinfusion was significantly shorter in patients receiving PBPC (median 13 days) or BM + PBPC (median 14 days) vs BM alone (median 20 days) (P < 0.01). Accordingly, transplant admission costs were less in the PBPC groups (PBPC $22089, BM + PBPC $23179) vs the BM alone group ($32289) (P < 0.05). Rescue product acquisition costs were higher for PBPC (range $3439-$5157) vs BM ($2766) but these costs were offset by the more rapid recovery of patients receiving PBPC. Overall transplant costs depend on the conditioning regimen with a 10-fold cost variation among regimens. Modeled costs for autologus transplantation using various approaches to rescue product acquisition are given. The introduction of PBPC for autologus transplantation has resulted in cost savings at our institution. Although the acquisition costs of PBPC rescue product are greater than for BM, this incremental expense is more than offset by a less expensive post-reinfusion period.