Anti-Idiotype Antibodies Can Induce Long-Term Complete Remissions in Non-Hodgkin’s Lymphoma Without Eradicating the Malignant Clone

The immunoglobulin on the surface of B-cell lymphomas can be a tumor-specific target for monoclonal antibody therapy. Between 1981 and 1993, 45 individuals with low grade B-cell lymphoma were treated with 52 courses of custom-made anti-idiotype antibodies. The antibodies were used either alone or in combination with -interferon, chlorambucil, or interleukin-2 (IL-2). The majority of these patients responded to treatment, with a 66% overall and 18% complete response rate. Six patients (13%) experienced prolonged complete remissions, five of which are ongoing from 4 to 10 years after therapy and are the subject of this report. We asked whether residual lymphoma could be found in these patients with prolonged remissions. We performed enzyme-linked immunosorbent assay (ELISA) assays for idiotype protein or anti-idiotype antibodies in serum. Blood and bone marrow samples were examined by flow cytometry for idiotype positive cells, and by polymerase chain reaction (PCR) for clonal gene rearrangements of immunoglobulin CDR3 sequences or t(14;18) translocations. Using these sensitive and specific tests it was possible to detect very low levels of residual lymphoma in five of these patients who had been in clinical remission for 3 to 8 years before this evaluation. These five have continued without recurrence for up to 3 years since. Thus, we have found a pattern of residual inactive disease in patients treated with anti-idiotype antibodies. The biology of follicular lymphoma evidently includes the potential for tumor dormancy after therapies with varied mechanisms of action, resulting in clinical inactivity for many years. Thus, long-term control of the disease is possible at a clinical level despite persistence of the malignant clone. © 1998 by The American Society of Hematology.

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Anti-Idiotype Antibodies Can Induce Long-Term Complete Remissions in Non-Hodgkin’s Lymphoma Without Eradicating the Malignant Clone

Blood ◽

10.1182/blood.v92.4.1184 ◽

1998 ◽

Vol 92 (4) ◽

pp. 1184-1190 ◽

Cited By ~ 128

Author(s):

Thomas A. Davis ◽

David G. Maloney ◽

Debra K. Czerwinski ◽

Tina-Marie Liles ◽

Ronald Levy

Keyword(s):

B Cell ◽

Interleukin 2 ◽

B Cell Lymphoma ◽

Complete Response ◽

Inactive Disease ◽

Enzyme Linked Immunosorbent Assay ◽

Low Grade ◽

Custom Made ◽

Residual Lymphoma

Abstract The immunoglobulin on the surface of B-cell lymphomas can be a tumor-specific target for monoclonal antibody therapy. Between 1981 and 1993, 45 individuals with low grade B-cell lymphoma were treated with 52 courses of custom-made anti-idiotype antibodies. The antibodies were used either alone or in combination with -interferon, chlorambucil, or interleukin-2 (IL-2). The majority of these patients responded to treatment, with a 66% overall and 18% complete response rate. Six patients (13%) experienced prolonged complete remissions, five of which are ongoing from 4 to 10 years after therapy and are the subject of this report. We asked whether residual lymphoma could be found in these patients with prolonged remissions. We performed enzyme-linked immunosorbent assay (ELISA) assays for idiotype protein or anti-idiotype antibodies in serum. Blood and bone marrow samples were examined by flow cytometry for idiotype positive cells, and by polymerase chain reaction (PCR) for clonal gene rearrangements of immunoglobulin CDR3 sequences or t(14;18) translocations. Using these sensitive and specific tests it was possible to detect very low levels of residual lymphoma in five of these patients who had been in clinical remission for 3 to 8 years before this evaluation. These five have continued without recurrence for up to 3 years since. Thus, we have found a pattern of residual inactive disease in patients treated with anti-idiotype antibodies. The biology of follicular lymphoma evidently includes the potential for tumor dormancy after therapies with varied mechanisms of action, resulting in clinical inactivity for many years. Thus, long-term control of the disease is possible at a clinical level despite persistence of the malignant clone. © 1998 by The American Society of Hematology.

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The Long Term Clinical Outcome of B Cell Lymphoma Patients Treated with Anti-Idiotype Monoclonal Antibody Correlated with the Isotype of the Therapeutic Antibody.

Blood ◽

10.1182/blood.v108.11.692.692 ◽

2006 ◽

Vol 108 (11) ◽

pp. 692-692

Author(s):

Wen-Kai Weng ◽

Debbie Czerwinski ◽

Ronald Levy

Keyword(s):

Monoclonal Antibody ◽

Clinical Outcome ◽

B Cell ◽

Response Rate ◽

Cell Lymphoma ◽

Interleukin 2 ◽

B Cell Lymphoma ◽

Killer Cells ◽

Custom Made

Abstract The unique sequences of immunoglobulin (idiotype, Id) on the surface of B cell lymphoma can be a tumor-specific target for monoclonal antibody (Ab) therapy. Between 1981 and 1993, 54 patients with B cell lymphoma (51 follicular lymphoma, 3 diffuse large B cell lymphoma) were treated with a total of 57 courses of custom made rodent derived anti-Id Abs. The antibodies were given either alone (N=20) or in combination with chlorambucil (N=14), α-interferon (N=10) or interleukin-2 (N=13). While single custom-made monoclonal anti-Id Ab was given in most of the courses, 13 courses used a combination of multiple clones of monoclonal anti-Id Abs. The overall response rate (CR + PR) was 49% with some patients experiencing extremely prolonged remission (greater than 20 years). The mechanism of the anti-tumor effect of these anti-Id Abs is unclear. We previously noted a correlation of outcome with anti-Id Ab-mediated signal transduction in the malignant B cells (Blood 83:899). However, a monoclonal anti-Id Ab of mouse γ2a showed a significantly better anti-tumor effect than its γ1 variant against a murine B cell lymphoma, suggesting the importance of effector mediated mechanisms (JI 136:1123). We and others have recently identified the importance of the interaction between constant region (Fc) of the therapeutic antibody and the FcγR on effector killer cells in the anti-tumor effect of rituximab, implicating the process of antibody-dependent cellular cytotoxicity (ADCC). Since mouse Abs of different isotypes have different affinity for the human FcγR, their ability to mediate ADCC may differ, leading to different clinical efficacy. Mouse Abs of γ2a or γ2b bind to human FcγRIIIa much better than mouse Abs of γ1 and therefore would be expected to be more efficacious. In this report, we analyzed whether the clinical outcome of the patients treated with anti-Id Abs related to the isotype of the therapeutic murine antibody. Mouse γ1 alone were given in 39 courses, and combination of mouse γ2a or γ2b together with γ1 were given in 13 courses. Patients who received only mouse γ1 had a similar initial response rate to that of patients who received at least one mouse γ2a or γ2b (46% vs 62%, p=0.523). However, more patients who received mouse γ2a or γ2b stayed in remission at 6 months and 12 months after initial therapy. The response rate for patients with mouse γ1 alone and patients receiving mouse γ2a or γ2b were 18% and 54% for the two groups, respectively, at 6 months (p=0.027), and 11% and 50%, respectively, at 12 months (p=0.010). In addition, median time to progression was 2.47 years for treatments with mouse γ1 only vs 12.17 years for treatments with mouse γ2a or γ2b Abs using the Kaplan-Meier estimation (p=0.008 by log-rank statistic). In a multivariate analysis, mouse γ2a/γ2b antibody emerged as the only independent positive predictor for longer PFS (relative benefit 2.44, 95% confidence interval 1.12–5.33, p=0.025), whereas age, FcγRIIIa V/V, FcγRIIa H/H genotype, addition of chlorambucil, interferon, or interleukin-2 had no impact. Our results support the hypothesis that custom-made monoclonal anti-Id Abs mediate at least part of their anti-tumor effect via ADCC and that the isotype of these Abs influences their interaction with FcγR-bearing effector killer cells such as NK cells. ADCC can result in tumor killing and control only as long as the antibody persists. Extremely long term remission, such as those observed here must have additional explanation.

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Tandem HD-chemotherapy and myeloablative radioimmunotherapy with 131I-anti-CD20 rituximab in relapsed and refractory B-cell lymphoma: Results of a phase II study of the German RAIT Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13007 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13007-13007 ◽

Cited By ~ 1

Author(s):

K. Hohloch ◽

G. Wulf ◽

W. Jung ◽

E. Stitz ◽

J. Meller ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Phase Ii Study ◽

B Cell Lymphoma ◽

Response Rates ◽

Low Grade ◽

Severe Toxicity ◽

B Cell Lymphomas ◽

Anti Cd20

13007 Background: Radioimmunotherapy has been shown to be effective in CD20 + B-cell lymphomas. Both non-myeloablative as well as myeloablative regimens have been employed for low grade and high grade lymphomas with impressive response rates and remission durations. Recently, the Press group and our group published data on myeloablative 131-I-anti-CD20 RAIT with high response rates and favourable long term survival especially in follicular lymphomas and transformed FL. Therefore, a phase II study is currently being done within the German Radioimmunotherapy Group, interim analysis data are presented. Methods: Patients were to receive R-Dexa-BEAM, followed by BEAM and HD-RAIT 2–6 months after BEAM. 131-I-Rituximab was administered with a maximum kidney and lung dose of 25 Gy. Sample size was calculated to be 16 to evaluate toxicity and feasibility of the tandem approach as primary endpoint. Results: 16 pts with relapsed (14) or primary refractory (2) B-cell lymphomas (FLI,II: 4pts; DLBCL: 4pts (all early relapses); transformed FL: 6 pts; MCL:1 pt, marginal zone lymphoma: 1 pt) were treated with 1 (15 pts) or 2 cycles (1 pt) of R-Dexa-BEAM. 13/16 pts achieving PR (5) or CRu (8) were treated with BEAM, 2 pts with PD and 1 with subdural hematoma were drop outs. After BEAM, 9/13 pts were in CR, 3/13 PR, 1/13 PD. Of 12 responding pts, 6 received HD-RAIT (1 pancytopenia, 1 hepatic, 2 pulmonary toxicity, 3 too early). After HD RAIT, 5/6 pts were in CR, 1 in PR. 4/6 pts (3 CR, 1 PR) are alive for 22–31 months, 2 pts died in CR, 1 of interstitial lung disease 2 months after HD-RAIT, 1 pt of pneumonia 8 months after HD-RAIT. Conclusions: Myeloablative RAIT is a feasible and effective treatment modality for relapsed poor prognosis CD20+ B-NHL not having severe toxicity due to the salvage regimen and HD-chemotherapy. HD RAIT offers the potential for long term relapse free survival. Final analysis of toxicity and outcome of this phase II study will be presented at the meeting. No significant financial relationships to disclose.

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Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Induces Long-Term Responses in Patients with Relapsed or Refractory Follicular Lymphoma (FL).

Blood ◽

10.1182/blood.v104.11.2629.2629 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2629-2629

Author(s):

Russell J. Schilder ◽

Thomas E. Witzig ◽

Ian Flinn ◽

Leo I. Gordon ◽

Christos Emmanouilides ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Complete Response ◽

Low Grade ◽

Ibritumomab Tiuxetan ◽

Bulky Disease ◽

Prior Therapy ◽

Yttrium 90

Abstract Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin’s lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized. Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients. Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates. Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.

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Tositumomab and I 131 Tositumomab Achieves Complete Remissions Lasting > 10 Years In Patients with Chemotherapy-Refractory Low-Grade and Transformed B-Cell Lymphomas

Blood ◽

10.1182/blood.v116.21.3960.3960 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3960-3960

Author(s):

Mark S. Kaminski ◽

Andrew D. Zelenetz ◽

Oliver W. Press ◽

Mansoor N. Saleh ◽

John P. Leonard ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Response Duration ◽

Complete Response ◽

Median Number ◽

Low Grade ◽

Duration Of Response ◽

Long Term Follow Up

Abstract Abstract 3960 Introduction: The efficacy and safety of tositumomab and iodine I 131 tositumomab (TST/I-131-TST), the Bexxar® Therapeutic Regimen, were evaluated in 60 patients (pts) with chemotherapy-refractory low-grade (LG) or transformed B-cell non-Hodgkin's lymphoma (B-NHL) who had received at least 2 chemotherapy regimens and had either not responded to (72%) or had progressed within 6 months of their last regimen (28%) (J Clin Onc 2001; 19:3918 and Blood 2004; Abstract 2631). The primary efficacy endpoint was comparison of the number of pts who had a longer duration of response to TST/I-131-TST with the number of pts with a longer duration of response to their last qualifying chemotherapy (LQC). Thirty-nine (65%) pts, including 20% who attained a complete response (CR), responded to TST/I-131-TST, compared to 17 (28%) pts, including 3% CR, after their LQC (p<0.001). Seventy-four percent of pts had a longer response duration after TST/I-131TST compared to the LQC. Four pts developed myelodysplasia (MDS), and 5 pts developed human anti-mouse antibodies (HAMA). We report final results of long term follow-up of these 60 pts. Patients and Methods: Pts were enrolled from 22 November 1996 to 06 March 1998. Pts alive at the last report date (1 March 2004) were followed for long-term safety and survival, and pts in remission at the last report date were followed for continued response. Results: Sixty pts received the dosimetric dose, and 58 of 60 pts received both the dosimetric and therapeutic doses of TST/I-131-TST. The median number of prior chemotherapies was 4 (range, 2–13). Fifty-nine of 60 (98%) pts had stage III/IV disease, 56% had bone marrow (BM) involvement, and 88% had ≥ two IPI risk factors at study entry. Thirty-six pts had LG B-NHL, 23 pts had a history of transformed B-NHL, and 1 pt had mantle cell NHL (MCL). Forty-eight (80%) pts have died, of whom 77% died due to lymphoma progression. Twelve pts were alive, and 6 pts were in CR at last follow-up. One pt withdrew consent for further follow-up but was in CR at 5.0 years, and the other 5 pts (4 LG, 1 transformed B-NHL) were in CR of ≥ 10 years' duration. The pts who continued in CR had received a median of 3 different prior chemotherapy regimens (range, 2–5), and no pts had received prior rituximab. For all 12 pts who attained CR, the median duration of response was 9.9 years (range, 0.7–11.7 years). Long-term toxicity included 7 pts who developed hypothyroidism. Secondary cancers included 1 lung adenocarincoma, 1 colon cancer, and 7 skin cancers which were reported previously. In addition, 1 developed a myeloproliferative disorder (MPD). No cases of MDS beyond the 4 previously reported were observed. Conclusion: A single course of TST/I-131-TST achieved durable remissions in chemotherapy-refractory LG and transformed B-NHL pts, with 5 of the 12 pts who achieved CR still in remission ≥ 10 years later. No additional cases of MDS were observed, but 1 pt developed a MPD since the last report. Thus, the final results of this study demonstrate that TST/I-131-TST is able to attain long-lasting durable CRs, with an acceptable toxicity profile, in a subset of pts with chemotherapy-refractory LG and transformed B-NHL. Disclosures: Kaminski: GlaxoSmithKline: Patents & Royalties, Research Funding. Zelenetz:GlaxoSmithKline: Research Funding. Press:GlaxoSmithKline: Research Funding; Spectrum Pharmaceuticals: Honoraria; Roche/Genentech: Honoraria. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Leonard:GlaxoSmithKline: Consultancy. Lister:GlaxoSmithKline: Chairman of Safety Monitoring Board for GSK. Horner:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Vleisides:GlaxoSmithKline: Employment. Knox:GlaxoSmithKline: Research Funding. Wahl:GlaxoSmithKline: Consultancy, Patents & Royalties; Nihon Medi Physics: Consultancy; Spectrum Pharmaceuticals: Consultancy; Naviscan PET systems: Consultancy; Threshold Pharmaceuticals: Equity Ownership. Vose:GlaxoSmithKline: Research Funding.

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Ocular adnexal lymphoma in Denmark: a nationwide study of 387 cases from 1980 to 2017

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-315637 ◽

2020 ◽

pp. bjophthalmol-2019-315637

Author(s):

Frederik Holm ◽

Lauge Hjorth Mikkelsen ◽

Peter Kamper ◽

Peter Kristian Rasmussen ◽

Thomas Stauffer Larsen ◽

...

Keyword(s):

B Cell ◽

Survival Data ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Low Grade ◽

High Grade ◽

Term Survival ◽

Ocular Adnexal Lymphoma ◽

Long Term Study

BackgroundNationwide studies of ocular adnexal lymphoma (OAL) are very rare in the literature, and knowledge on incidence, subtype distribution and long-term survival data is limited. This is the largest national study of OAL to date. This study sought to find information on incidence, changes in incidence, clinical findings, distribution of subtypes, survival and prognostic factors.MethodsPatients diagnosed with OAL from January 1, 1980 to December 31, 2017 were identified in Danish registers, and clinical as well as survival data were collected. The data were analysed with Kaplan-Meier plots and log-rank test.Results387 patients were included in the study. The major lymphoma subtypes were extranodal marginal-zone B cell lymphoma (EMZL) (55%), diffuse large B cell lymphoma (DLBCL) (13%), mantle cell lymphoma (MCL) (11%) and follicular lymphoma (FL) (10%). OAL is a disease of the elderly (median age 69 years). The incidence of lymphoma of the ocular adnexal region has increased significantly throughout the time period of the study (Pearson correlation coefficient, r=0.65; P<0.001). In the period 1980–1984, the incidence was 0.086 per 100 000, which increased to 0.307 per 100 000 in the period 2013–2017. Low-grade, low-stage primary lymphomas were treated with radiotherapy, whereas patients with high-stage, high-grade and/or relapsed disease were treated with chemotherapy. Low-grade subtypes EMZL (89%) and FL (56%) had better 10-year disease-specific survival than the high-grade lymphomas DLBCL (38%) and MCL (31%)(p<0.001).ConclusionOAL is increasing in incidence in the Danish population for unknown reasons. However, the prognosis for most OAL is favourable, as highlighted in this national long-term study.

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