Continuous Pattern Of Relapse Research Articles

The hyper-CVAD–rituximab chemotherapy programme followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma

The hyper-CVAD + rituximab (R) programme consists of fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + R alternating with high-dose methotrexate + cytarabine (HD MTX/ARA-C) + R. This regimen, when used as initial therapy for patients under 65 years of age with previously untreated mantle cell lymphoma (MCL), results in remission rates of > 85% with a median event-free survival (EFS) of > 50 months, but with a pattern of continuous relapse out to 60 months. We performed a study of hyper-CVAD + R, followed by consolidative peripheral blood progenitor cells autograft [autologous stem cell transplant (AuSCT)] with high-dose busulfan and melphalan (Bu/Mel) conditioning, in patients with responsive disease. Thirteen patients with a median age of 54 (range = 33-61) were treated. Complete remission (CR) was achieved in 12 patients (92%) after hyper-CVAD + R and 12 completed AuSCT after Bu/Mel conditioning. One patient died during the autograft and another declined AuSCT after achieving a CR with hyper-CVAD + R. With a median follow-up from diagnosis of 36 months (range = 16-53 months), the observed 36 months overall survival and EFS are both 92% for the whole cohort. These data confirm the excellent CR rates achieved by the use of hyper-CVAD + R in patients with MCL and suggest that consolidation with Bu/Mel and AuSCT may improve durable disease control when compared to published outcomes of hyper-CVAD + R alone.

Prospective Management of Primary Testicular Lymphoma (PTL) with Doxorubicin-Based Chemotherapy, Prophylactic Intrathecal (IT) Methotrexate and Radiotherapy (RT), but without Rituximab: Results from IELSG.

Introduction: PTL is a rare extranodal lymphoma characterized by a continuous pattern of systemic relapses in spite of doxorubicin-based therapy. There are also frequent relapses in the contralateral testis and the central nervous system (CNS). Therefore we decided to determine whether prophylaxis of the CNS and the contralateral testis would modify the pattern of relapse of PTL.Patients and methods: From 1993 to February 2002 in IELSG member institutions patients with PTL (presenting with testicular enlargement) were managed with doxorubicin-based therapy according to institutional policy, with the addition of four doses of IT methotrexate (15 mg) during the first 6 weeks. At the end of chemotherapy scrotal RT (30 Gy) was given to all patients and 30–36 Gy nodal RT to those with stage II disease. Rituximab was not used in this cohort because it was not yet generally available for patients with diffuse large B-cell lymphoma.Results: There were twenty seven patients; two refused chemotherapy and/or RT/IT therapy and one RT, leaving 24 eligible for analysis. Median age was 60 years (range 31–80). Ann Arbor stage was I in 17, II in four, and four in three patients. B-symptoms were present in one patient. The right testis was involved in 13 and the left in 11 patients. Serum LDH was elevated in four of 21 with available values. No patient had CNS involvement at diagnosis. Pathology was diffuse large B-cell lymphoma in all patients. Treatment was CHOP in 21, alternating triple therapy in two, and hyper-CVAD in one patient. Three patients died during therapy: one from neutropenic sepsis and two from toxicity of systemic methotrexate. The remaining 21 patients achieved a complete remission. With a median follow-up of 57 months (range 8–123) for survivors, seven patients have relapsed, three in the CNS. There were no testicular relapses. Eight patients have died: three from toxicity during induction, three from relapsed lymphoma, one from gastric carcinoma and one from sudden death, both in complete remission. At 5 years the projected progression-free survival was 78%, and survival 66%, but both without an apparent plateau. Freedom from progression in the CNS was 84%, with a plateau.Conclusions: Patients with PTL treated prospectively with doxorubicin-based therapy before the availability of rituximab exhibit the continuous pattern of relapse previously reported. Scrotal RT seems eliminate testicular relapses, and prophylactic IT methotrexate seems to reduce, but not eliminated CNS relapses. These need to be confirmed by longer follow-up. The ongoing IELSG-10 should determine whether the addition of rituximab alters the continuous pattern of systemic relapses. Future studies should determine the molecular basis of the continuous relapses and minimize both systemic and CNS relapses.

Phase II study of rituximab + CHOP followed by 90Y-ibritumomab tiuxetan in patients with previously untreated mantle cell lymphoma: An Eastern Cooperative Oncology Group Study (E1499)

7503 Background: Because mantle cell lymphoma (MCL) has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr were eligible if they had measurable/evaluable disease, adequate organ function (WBC >2,500/μl; platelets >100,000/μl unless marrow-positive) and gave informed consent. At 4–8 weeks after 4 cycles of R-CHOP, stable and responding pt meeting standard marrow and hematologic criteria received 0.4 mCi/kg 90Y-ibritumomab tiuxetan. Objectives were to evaluate response and toxicity after R-CHOP and 90Y-RIT with a primary endpoint of time to treatment failure (TTF). Results: 56 of 57 accrued patients are eligible pending central pathology review. Characteristics included 73% male, median age 60 (33–83) yrs, 91% stage III/IV, 64% >1 extranodal site, 75% marrow-positive. IPI was 0–2 in 50%, 3–5 in 43% and unknown in 7%. After 90Y-RIT 53% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 19/20 pt. 50 pt are evaluable for response after R-CHOP and 44 pt after 90Y-RIT. Best response after R-CHOP (n = 50) was: CR/CRu 14% (n = 7), PR 58% (n = 29), SD 26% (n = 13), PD 2% (n = 1). After 90Y-RIT, responses improved in 15 of 37 pt with <CR/CRu: PR to CR/CRu (n = 12) and SD to CR (n = 1) or PR (n = 2) for a final response rate of 84% and CR rate of 45%. Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. Further follow-up is needed to determine TTF. [Table: see text]

A Phase II Trial of FM (Oral Fludarabine and Mitoxantrone) Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) for Previously Untreated Follicular Lymphoma (FL) Patients.

Follicular lymphoma (FL) has been considered as low-grade malignant B-cell lymphoma usually characterized by an indolent course with a continuous pattern of relapse and a median survival of 10 years. The therapeutic approach to FL is particularly controversial. One of the effective strategies is the combination of fludarabine-containing regimens (particularly, Fludarabine and Mitoxantrone) with anti-CD20 monoclonal antibody. Single-agent radioimmunotherapy activity, in particular Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin), has been demonstrated in heavily pretreated FL patients. The results of these studies support a further evaluation of 90Y Ibritumomab Tiuxetan in combination with chemotherapy earlier in the time course of FL. Recently, some phase II trials showed that the sequential combination of conventional chemotherapy (CHOP) and 90Y Ibritumomab Tiuxetan has useful activity in the treatment of FL patients, with no unexpected toxicities observed. We conducted a prospective, single-arm, open-label, non-randomized, multicenter, phase II to evaluate the efficacy and safety of 90Y Ibritumomab Tiuxetan of a novel new approach combining induction chemotherapy with oral Fludarabine and Mitoxantrone (FM) followed by consolidation with 90Y Ibritumomab Tiuxetan for patients with previously untreated elderly FL. Patient eligibility was represented by: patients age 18 years or older with biopsy-proven, untreated, bidimensionally measurable stage II, stage III, or stage IV FL expressing the CD20 antigen; performance status of 0 to 2, a pretreatment granulocyte cell count of 1500/μL or greater, and a platelet count of 100.000/μL or greater. All patients were notified of the investigational nature of this study and signed a written informed consent approved in accordance with institutional guidelines, including the Declaration of Helsinki. The study was approved by the institutional review board. Patients were treated with standard FM chemotherapy (in this case, Fludarabine was administered orally at the dose 40 mg/m2/day for 3 consecutive days) every 21 days for 6 cycles. Patients were restaged 4 to 8 weeks after completion of the sixth cycle of FM chemotherapy. Patients achieving at least a partial response after 6 cycles of FM chemotherapy were eligible for consolidation with 90Y Ibritumomab Tiuxetan provided the granulocyte count was greater than 1500/μL, the platelet count exceeded 100.000/μL, and the bone marrow examination at the completion of CHOP chemotherapy demonstrated no more than 25% involvement with lymphoma. All patients were to receive a single dose of 90Y Ibritumomab Tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). A total of 60 patients have to be enrolled and preliminary results of this trial will be presented.

Follicular lymphoma: Have we made any progress?

Follicular lymphomas are characterized by relatively long median survivals and a continuous pattern of relapse. The heterogeneity in these diseases is increasingly appreciated, leading to concerted efforts to define prognostic factors and risk-adapted strategies. The status of multiple options for treatment including interferon, fludarabine, dose intensification with autologous transplantation, therapy targeting the CD20 antigen and novel approaches is reviewed. The long natural history of follicular lymphoma requires mature data for accurate analysis. However, the achievement of molecular remission as a surrogate endpoint is under active investigation. This is an exciting era for the clinical investigation of follicular lymphoma given the large number of candidate therapies and their potential combinations and permutations. Although the goal of primary treatment remains durable remission and cure, the sequential application of effective, non-cross-resistant treatments may also result in a prolongation of median survival time. It is essential that physicians treating patients with follicular lymphoma demonstrate restraint in the application of new treatments and cooperate in the study of new therapies in carefully designed phase II and phase III trials.