Rituximab Therapy for Patients With Newly Diagnosed, Asymptomatic Advanced-Stage Follicular Grade I Non-Hodgkin's Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group T. E. Witzig, A. M. Vukov, T. M. Habermann, S. Geyer, W. R. Friedenberg, W. L. White, M. Salim, P. J. Flynn, T. R. Fitch, R. F. Morton Hematology, Mayo Clinic, Rochester, Minnesota; OHACI, Peoria, Illinois; Medical Oncology/Hematology, Guthrie Clinic, Milan, Pennsylvania; Medical Oncology, Allan Blair Cancer Center, Regina, Saskatchewan, Canada; Oncologic Consultants, PA, Minneapolis, Minnesota; Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona; Medical Oncology and Medical Association, Iowa Oncology Research Association CCOP, Des Moines, Iowa Patients with newly diagnosed advanced-stage follicular grade I non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy without compromising survival. Rituximab (Rituxan) immunotherapy offers a new nonchemotherapy approach to this group of patients. Our goal was to assess the rate of complete remission (CR) and partial remission (PR) to rituximab and to determine the time to progression (TTP) and time to subsequent chemotherapy (TTSC). Eligible patients had biopsy-proven follicular grade I NHL, measurable disease, stage III or IV, no prior therapy, CD20+, and performance status (PS) 0-2. Patients received rituximab 375 mg/m2 IV weekly * 4 doses. No maintenance therapy was provided. Patients were followed with physical exam, laboratory tests, and CT scans every 3 months for the first year and every 6 months thereafter. A total of 37 patients were accrued to this study between July 1999 and May 2001. Forty-three percent of patients were male; 89% were PS 0 and 11% were PS 1. The median age was 59 years (range: 29 to 83 years). All patients were white except for 1 patient, who was Asian. Sixteen percent of patients had elevated lactate dehydrogenase levels pretreatment. Thirty-eight percent of patients had a low International Prognostic Index (IPI), 46% low intermediate IPI, and 16% high intermediate IPI. No patients had B symptoms. All patients completed treatment as per protocol. The overall response rate (ORR) was 61%, with 25% CR. To date, 20 patients remain in unmaintained remission, 2 died without disease progression, 3 died of disease progression, and 12 have progressed and are still alive. The median TTP was 1.67 years (range: 0.014 to 3+ years); and the TTSC was 1.75 years (range: 0.014 to 3+ years). In general, rituximab was well tolerated in this patient population. Severe (grade 3+) toxicity was seen in 4 patients (11%), where 2 patients (5%) had severe hematologic toxicity and 3 patients (8%) had severe nonhematologic toxicity. These severe toxicities included rash (2), neutropenia (1), leukopenia (1), infection without neutropenia (1), and urticaria (1). CONCLUSION: Rituximab can be safely administered to patients with previously untreated advancedstage follicular grade I NHL with minimal toxicity. This therapy produces an ORR of 61% and prolonged remissions have been documented. Rituximab offers an acceptable alternative to observation in this patient population. Abstract #604
Prolonged Treatment With Rituximab Significantly Improves Event-Free Survival and Duration of Response in Patients With Follicular Lymphoma: A Randomized SAKK Trial M. Ghielmini, S.-F. H. Schmitz, S. Cogliatti, G. Pichert, M. Fey, D. Betticher, G. Martinelli, F. Peccatori, U. Hess, R. Stahel, E. Zucca, R. Stupp, T. Kovacsovics, C. Helg, A. Lohri, M. Bargetzi, D. Vorobiof, T. Cerny Lymphoma Working Group, Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland Clinical and pharmacokinetic data suggest that the effect of rituximab (Rituxan) could be improved by prolonged exposure to the drug. To verify this hypothesis we performed a randomized trial of rituximab given at the standard schedule vs a prolonged rituximab treatment with additional maintenance cycles. A total of 202 patients with newly diagnosed or resistant/relapsed follicular lymphoma (FL) were enrolled. After a standard induction treatment with rituximab (375 mg/m2 weekly * 4), patients responding or with stable disease at week 12 were randomized to either observation or maintenance therapy with an additional rituximab administration (375 mg/m2) every 8 weeks (at months 3, 5, 7, and 9). In 185 evaluable patients, response to induction therapy was 46% (59/128) in pretreated patients and 67% (38/57) in chemotherapy-naive cases (P < .01). Adverse predictors of response were bulky disease (P = .002) and male gender (P = .04). The characteristics of the 151 patients randomized to observation vs maintenance therapy were as follows: median age, 57; performance status 0/1, 97%; stage III/IV, 85%; bone marrow involvement, 52%; elevated lactate dehydrogenase, 30%; previous radiotherapy, 18%; previous chemotherapy, 66% (mean 2.3 regimens); all characteristics were equally balanced between both arms. At a median follow-up of 35 months, the median event-free survival from the initiation of induction treatment was 12 months for the observation arm vs 23 months for the maintenance arm (P = .02), with a hazard ratio of 0.57, the difference being more pronounced in the subgroup of chemotherapy-naive patients (19 vs 36 months, P = .009). Among patients responding at week 12, 56% were still in remission at 12 months in the observation arm vs 80% in the maintenance arm (P = .01). The median response duration was 17 vs 36 months (P = .0009), with a hazard ratio of 0.45. After induction treatment, 34 patients further improved the quality of response, and complete remission rate increased from 10% at randomization to 16% at month 7, 23% at month 12, and 29% (44/151) at further follow-up (no difference between the two arms). The number of circulating B lymphocytes tended to return to pretreatment levels after 1 year of observation, while they remained low in patients receiving prolonged treatment (65% vs 33% of baseline level, P = .04). However, in both arms the IgG, IgA, and IgM plasma levels remained stable and the incidence of infections and other side effects was low. CONCLUSION: The study shows that in patients with FL, stable or responding after standard rituximab treatment, the administration of an additional four single doses of rituximab at 2-month intervals reduces the risk of progression or relapse by 43% among all randomized patients and by 55% among responders, as well as significantly improves the chance of remaining in remission at 1 year, without inducing additional toxicity. This effect is obtained mainly by the capacity of maintenance treatment to prevent relapse in responding patients. The antitumor effect of rituximab continues long after the end of its administration. Abstract #1390
Rituximab Re-Treatment in B-Cell Lymphoma Patients: Efficacy and Toxicity in 59 Patients Treated in One Center B. Coiffier, F. Bouaffia, C. Thieblemont, O. Hequet, P. Arnaud, C. Dumontet, D. Espinouse, G. Salles Department of Hematology, CH Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France During the past 4 years, 483 patients with B-cell lymphoma were treated in our department with rituximab (Rituxan) alone (166 patients), in combination with chemotherapy (302 patients), or as maintenance therapy (15 patients) in different studies or as registered treatment. Out of these 483 patients, 429 (89%) responded to treatment (complete response [CR] + partial response [PR]): 132/166 (80%) to rituximab alone and 282/302 (93%) to a combination with chemotherapy. Out of these 429 patients, 117 (27%) had presented a disease progression at time of analysis (median follow-up of around 18 months), 54/132 (41%) after rituximab alone, and 59/282 (21%) after rituximab in combination with chemotherapy. Out of these 117 patients, 59 (50%) received a second treatment with rituximab alone or in combination with chemotherapy. Rituximab was administered alone at the dose of 375 mg/m2/wk for 4 weeks or in combination with chemotherapy the same day at 375 mg/m2 for all chemotherapy cycles. These 59 patients were analyzed for the response to the second rituximab treatment. For the first treatment, rituximab was given alone in 30 patients and associated with chemotherapy in 29 patients and for the second treatment, in 32 and 27 patients, respectively. All but 4 patients responded to this second treatment (CR 42%, PR 51%). The median time to progression and time to next treatment were 12 and 13 months after the first rituximab treatment and 20 and 21 months after the second rituximab treatment, respectively. Eight patients had a shorter time to progression after the second rituximab cycle and in 4 patients it was identical. Progression and time to progression after the second treatment were not associated with the number of treatments before rituximab, the association or not with chemotherapy for the first or second rituximab cycle, the response to the first or second rituximab treatment, or the status at time of second rituximab treatment (progressive disease or partial response to previous cycle). Of the 20 patients who progressed after the second rituximab treatment, 12 received a third rituximab cycle-6 alone and 6 with chemotherapy; all 12 responded to the treatment and only 3 had progressed at time of analysis with a median time to progression of 13 months. No special adverse events were observed with the different cycles of rituximab but 3 patients had herpes zoster infection during or just after the second cycle.
CONCLUSION: In conclusion, re-treatment with
rituximab alone or in combination with chemotherapy
was associated with very good response rates and
a longer progression-free survival after the second
rituximab treatment than after the first one. Rituximab,
alone or in combination with chemotherapy, is
recommended for re-treatment of patients who progressed
after a first rituximab treatment.
Abstract #3073Rituximab Plus Chlorambucil(Drug information on chlorambucil) in Low- Grade Non Hodgkin's Lymphomas: Clinical Results of a Phase II Study G. Martinelli, D. Laszlo, P. Mancuso, P. Santoro, G. Pruneri, A. Vanazzi, E. Zucca Hematoncology Division, European Institute of Oncology, Milan, Italy; Medical Oncology Department, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland The monoclonal anti- CD20 antibody rituximab (Rituxan) has a well-established efficacy in the treatment of low-grade non- Hodgkin's lymphomas (NHLs), principally the follicular subtype (60%). More recently, the combination of chemotherapy plus rituximab has been demonstrated in a randomized study of aggressive NHL patients to produce better clinical results than chemotherapy alone. Chlorambucil (Leukeran) is considered the drug of choice for the treatment of low-grade NHL, mainly for follicular: chlorambucil alone induces a response rate of 70% with 30% to 40% of complete remission. No data are available about the combination of chlorambucil plus rituximab. The aim of this study is to define the feasibility, toxicity, and efficacy of rituximab plus chlorambucil in low-grade NHL. Twenty-nine NHL patients (20 follicular, 6 marginal zone, 3 chronic lymphocytic leukemia), median age 40 years, were enrolled in the study between November 2001 and April 2002. Fourteen patients had received previous therapy. The treatment plan consisted of chlorambucil at 6 mg/m2 daily administered for 6 consecutive weeks combined with the standard 4-weekly rituximab at 375 mg/m2 administration schedule. Patients responding to this induction phase received further therapy with chlorambucil (2 weeks every month for four additional cycles) in combination with four monthly administrations of rituximab. All patients were monitored weekly with white blood cell counts during induction phase and then once monthly. Peripheral blood immunophenotype evaluation was performed at baseline, after the induction phase, and then at the end of the treatment. Clinical evaluation was performed after the induction phase, then at the end of the entire therapy program. All patients are evaluable for toxicity and response. The most important hematologic toxicity observed was National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 neutropenia, experienced by 13% of patients. Only one patient developed severe anemia and thrombocytopenia. All hematologic toxicity recorded was observed among pretreated patients. Twelve patients developed an absolute lymphopenia (NCI grade 3), and significant CD4+ reduction; however, no patients had an imbalance in CD4+/CD8+ ratio and no severe infections were recorded. Among 27 patients evaluable for response, 24 (89%) achieved an objective response with approximately 53% complete remissions. CONCLUSION: The combination of rituximab plus chlorambucil is well tolerated and active. Clinical results achieved seem to confirm the possible synergistic or additive effect of the combination, also in low-grade NHL patients. A randomized trial is now ongoing to further evaluate this promising combination. Abstract #2246
Phase II Study With Fludarabine and Cyclophosphamide(Drug information on cyclophosphamide) Plus Rituximab in Relapsed Follicular Lymphoma Patients S. Sacchi, A. Tucci, F. Merli, L. Orsucci, G. Cervetti, U. Occhini, M. Liberati, G. Tarantini, V. Callea, M. Brugiatelli, V. M. Lauta, L. Baldini, S. Luminari, M. Federico Dipartimento di Oncologia ed Ematologia, Università di Modena e Reggio Emilia, Modena, Italy; Servizio di Ematologia, Spedali Civili, Brescia, Italy; Servizio di Ematologia, Az. Osp. Santa Maria Nuova, Reggio Emilia, Italy; Divisione di Ematologia, Az. Osp. Santo Giovanni Battista, Torino, Italy; Divisione di Ematologia, Az. Osp. Pisana Ospedale Santa Chiara, Pisa, Italy; Servizio di Ematologia, Az. Osp. Arezzo, Arezzo, Italy; Istituto di Scienze Oncologiche, Policlinico Monteluce, Perugia, Italy; Divisione di Ematologia, Osp. Civ. Santa Nicola Pellegrino, Trani, Italy; Divisione di Ematologia, P. Osp. Riuniti "Bianchi, Melacrino, Morelli," Reggio Calabria, Italy; Divisione di Ematologia, Az. Osp. "Papardo," Messina, Italy; Sezione di Medicina Interna ed Oncologia Clinica, Az. Osp. Policlinico, Bari, Italy; Divisione di Ematologia, Ospedale Maggiore, IRCCS, Milano, Italy Both cyclophosphamide (Cytoxan, Neosar) and fludarabine (Fludara) have individual antilymphoma activity, and the combination of rituximab (Rituxan) plus fludarabine has been shown to have synergistic activity against resistant lymphoma cell lines in vitro. In March 2000, we started a phase II multicenter clinical trial to test the safety and efficacy of the fludarabine/ cyclophosphamide plus rituximab combination in patients with relapsed follicular lymphoma. We have recently completed the enrollment of 48 patients in the trial. Patients received four doses of rituximab (375 mg/ m2/d) in combination with 4 cycles of fludarabine (30 mg/m2/d for 3 days) and cyclophosphamide (300 mg/m2/d for 3 days) every 21 days. Patient characteristics: 45% males, 55% females; median age: 62 years (range: 44-71); stage IV, 47% patients; systemic symptoms, 8.5% of patients; elevated lactate hydrogenase, 15% of patients. Rearrangement of the bcl-2 gene was evaluated with polymerase chain reaction in 38 patients (79%) on bone marrow or peripheral blood mononucleated cells; 22 patients showed bcl-2 rearrangement (58%). Median number of previous chemotherapy regimens was 1.7 (range: 1-4); median duration of last remission before registration into the trial was 12 months (range: 1-68 months). Thirty-nine patients were available for evaluation at the time of current analysis. One patient did not complete therapy due to severe cytopenia. The response rate in the intent-to-treat analysis was 97%, with 74% complete responses and 23% partial responses. Out of 18 patients with molecular monitoring of disease before and after chemotherapy, 15 patients (83%) obtained molecular remission in the bone marrow. After a median follow-up of 12 months (range: 1- 25 months), median duration of remission was 13 months; 20% of patients were only recently registered into the trial and had a short follow-up (less than 4 months). Overall, 8 patients relapsed (21%). One patient died due to severe neutropenia that occurred during chemoterapy; two patients died due to lymphoma progression. Complete responses are ongoing in 28 patients. As far as toxicity is concerned, World Health Organization (WHO) grade III/IV leukopenia was observed in 10 patients, with 4 patients presenting a WHO grade IV granulocytopenia. WHO grade IV infections were observed in only one patient, who had a pulmonary infection after the third cycle. Nonhema- tologic toxicity was minimal. During follow-up, one patient had a renal cell tumor and one patient had myelodysplasia, 3 and 6 months after the end of treatment, respectively. CONCLUSION: The combination of fludarabine/ cyclophosphamide plus rituximab is associated with acceptable toxicity and an excellent response rate in this group of heavily pretreated patients with relapsed follicular lymphoma. Further follow-up is required to evaluate response duration and survival in the whole group of patients. Abstract #1401
Combined Fludarabine, Mitoxantrone(Drug information on mitoxantrone), and Rituximab Achieves a High Response as Initial Treatment for Advanced Low-Grade Non-Hodgkin's Lymphoma S. A. Gregory, P. Venugopal, S. Adler, S. Enschede, F. Yunus, T. M. O'Brien, K. F. O'Donnell, E. L. Robin Section of Hematology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois; Boston Baskin Cancer Group, Memphis, Tennessee; The Community Hospital of Munster, Munster, Indiana This phase II study was undertaken to evaluate the safety and efficacy of fludarabine (Fludara) plus mitoxantrone (Novantrone) followed by consolidation with the anti-CD20 monoclonal antibody rituximab in treating low-grade non- Hodgkin's lymphoma. This regimen uses the synergistic effect of fludarabine and mitoxantrone observed in vitro, and combines it with a third agent with a complementary mode of action and proven activity in low-grade lymphoma. For eligibility, patients must have previously untreated CD20-positive low-grade non-Hodgkin's lymphoma, with a Karnofsky performance status of 70. Treatment consists of 4 to 6 cycles of chemotherapy, which includes fludarabine at 25 mg/m2 on days 1-3 plus mitoxantrone at 12 mg/m2 on day 1 of each 28- day cycle. If patient attains a complete remission (CR) after 4 cycles of chemotherapy, rituximab is administered at 375 mg/m2 weekly for 4 weeks, 4-6 weeks after the last dose of chemotherapy. If CR is not attained after 4 cycles, the patient receives 2 more cycles of chemotherapy and then proceeds to rituximab therapy after a 4-6 week delay. The total number of patients registered is 41; 33/41(80%) were stage IV, 3 (8%) stage III, and 5 (12%) stage II. The histologic classification of the 41 patients is as follows: 11(27%) small lymphocytic lymphoma, 18 (44%) follicular small cleaved, 6 (15%) follicular mixed, 2 (5%) mantle cell lymphoma, 3 (7%) maltoma, and 1 (2%) marginal zone. Ten patients were inevaluable for the following reasons: 1 has not completed therapy, 2 ineligible, 3 patient removal, 1 autoimmune hemolytic anemia, 1 death not related to treatment, and 2 patients were removed due to prolonged cytopenia. Of 31 patients evaluated for response, 30 responded. The overall response rate is 97%(n = 30) (CR 45%, n = 14, and PR 52%, n = 16); 50% (n = 7) of patients in CR have remained in remission longer than 24 months (24+, 24+, 30+, 24+, 34+, 24+, 24+ months). 31% (n = 5) of patients in PR have remained in remission for longer than 12 months (12+, 15+, 15+, 18+, 28+ months). 30% (n = 9) of patients have progressed after achieving a remission (3+, 3+, 5+, 7+, 7+, 11+, 13+, 13+, and 25+ months). Serious adverse events included grade 3 and 4 neutropenia (n = 64 episodes in 163 cycles of chemotherapy), neutropenic fever (n = 7), shortness of breath (n = 2), one epsiode of retinal detachment, and one episode of thrombus formation. Three patients had 25% dose adjustments for prolonged neutropenia. Two patients were discontinued due to neutropenia. Grade 1/2 neutropenias, anemias, and thrombocytopenias usually resolved during or before rituximab infusion. Documented infections were rare with one episode of pneumonia. Antimicrobial anaphylaxis was not used. CONCLUSION: A regimen of fludarabine plus mitoxantrone followed by rituximab is highly effective and well tolerated when used as primary therapy in advanced-stage low-grade non-Hodgkin's lymphoma. Moderate to severe neutropenia occurred during therapy, but documented infection occurred in only one patient and neutropenic fevers in seven patients. This treatment results in a high rate of overall response and durable remissions.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
