Luis Fayad is a speaker for and receives research support from Genetech.
Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma
Article first published online: 30 OCT 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 10, pages 2734–2741, 15 November 2008
How to Cite
Wang, M., Fayad, L., Cabanillas, F., Hagemeister, F., McLaughlin, P., Rodriguez, M. A., Kwak, L. W., Zhou, Y., Kantarjian, H. and Romaguera, J. (2008), Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma. Cancer, 113: 2734–2741. doi: 10.1002/cncr.23880
- Issue published online: 3 NOV 2008
- Article first published online: 30 OCT 2008
- Manuscript Accepted: 3 JUN 2008
- Manuscript Revised: 23 MAY 2008
- Manuscript Received: 8 APR 2008
- mantle cell lymphoma;
- survival rates;
- response rates
Relapsed or refractory mantle cell lymphoma has a very poor prognosis. The authors evaluated the response rates and survival times of patients treated with an intense regimen known to be effective against untreated aggressive mantle cell lymphoma: rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab plus methotrexate-cytarabine.
In this prospective, open-label, phase 2 study, patients received this combination for 6 to 8 cycles. Twenty-nine patients were evaluable for response.
The median number of cycles received was 5 (range, 1-7 cycles), and the overall response rate was 93% (45% complete response [CR] or CR unconfirmed [CRu] and 48% partial response [PR]). All 5 patients previously resistant to treatment had a response (1 CR, 4 PR), and both patients whose disease did not change in response to prior therapy had PRs. Toxic events occurring in response to the 104 cycles given included neutropenic fever (11%), grade 3 or 4 neutropenia (74%), and grade 3 or 4 thrombocytopenia (63%). There were no deaths from toxicity. At a median follow-up of 40 months (range, 5-48 months), the median failure-free survival time was 11 months with no plateau in the survival curve.
This combination chemotherapy was effective for refractory/relapsed mantle cell lymphoma. Cancer 2008. © 2008 American Cancer Society.
Mantle cell lymphoma (MCL) currently has the worst prognosis of all malignant lymphomas. Among patients with newly diagnosed MCL who receive standard chemotherapy, complete response (CR) rates range from 21% to 40%, median failure-free survival duration is 10 to 16 months, and median overall survival duration is 3 years1–7
Relapsed or refractory MCL has a poor outcome after autologous stem-cell transplantation.8 The recent use of nonmyeloablative allogeneic stem-cell transplantation has demonstrated promising 2-year continuous progression-free survival,9 suggesting a graft-versus-lymphoma effect. The best outcomes are reserved, however, for patients who achieve a CR after salvage therapy. Thus, the effectiveness of the salvage regimen given before stem-cell transplantation is crucial to the success of these transplants and important to improvement of patient of survival rates.
Intensive therapies that have shown activity in other MCL settings may be applicable to relapsed or refractory disease. In particular, rituximab in combination with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) alternating with rituximab plus methotrexate-cytarabine has resulted in an 87% CR rate among untreated patients with aggressive MCL.10 A logical next step is introduction of this regimen in the management of relapsed or refractory MCL. We report here the results of a phase 2, prospective, clinical trial of this regimen in relapsed or refractory MCL.
MATERIALS AND METHODS
Patients with relapsed or refractory aggressive MCL were recruited and then, if eligible and after signing an informed consent form, were enrolled in this phase 2 prospective clinical trial at the University of Texas M. D. Anderson Cancer Center. The study design was approved by the institutional review board.
Patients eligible for inclusion in the study had MCL with a diffuse or nodular pattern or a blastoid cytologic variant. Patients who had MCL with a pure mantle zone pattern were excluded. Other eligibility criteria included age older than 16 years (no upper limit), good performance status (Zubrod score of 2 or less),11 and adequate organ function, defined as cardiac ejection fraction ≥50%, serum bilirubin level <1.5 mg/dL, and serum creatinine level <2 mg/dL. Moreover, the study required an absolute neutrophil count (ANC) ≥1000/μL and a platelet count ≥100,000/μL, unless a lower value was due to the lymphoma. All patients had to agree to receive transfusions of blood products as needed.
Patients were ineligible if they had central nervous system involvement, were infected with the human immunodeficiency virus, were pregnant, had comorbid physical or mental illness that precluded treatment, or had a second malignancy that caused a predicted chance of 5-year survival <90%.
Pretreatment Clinical Evaluation
Pretreatment evaluation included a physical examination; chest radiography; computed tomography (CT) of the chest, abdomen, and pelvis; bilateral bone marrow biopsy and aspiration; and an optional gallium scan or positron emission tomography (PET). In addition, blood was drawn for serum chemistry analysis, a complete blood count with differential analysis, measurement of serum β2-microglobulin, and flow cytometric analysis of lymphocyte membrane-surface markers.
We reviewed all pathologic materials and performed fine-needle aspiration in recurrent, diseased, lymph nodes to confirm the diagnosis and classification using the World Health Organization system.12 All biopsy specimens from which the original diagnosis was made were reassessed for cyclin D1 expression by sectioning of fixed, paraffin-embedded tissue. Tests for other B-cell and T-cell markers, most commonly CD5 and CD20, were also performed. Bone marrow and peripheral blood specimens were analyzed by flow cytometry. A classic polymerase chain reaction technique was used to detect the presence of t(11;14)(q13;q32), which involves the major translocation cluster for the bcl-1 locus, as previously described.13 In addition, fluorescence in situ hybridization analysis was used to assess specimens for the presence of the 11q13 and 11q14 break points.14 The diagnosis of MCL in each patient in this study was based on the presence of compatible morphologic and immunophenotypic findings along with the expression of cyclin D1 presence of t(11;14)(q13;q32). Endoscopic biopsy specimens from affected sites in the gastrointestinal tract were labeled and assessed separately. For each patient in this study believed to have gastrointestinal tract involvement of MCL, at least 1 (usually 2 and rarely 3) biopsy specimen was assessed immunohistochemically for the presence of CD5, CD20, and cyclin D1 in fixed, paraffin-embedded, tissue sections. For patients without lymph-node biopsy specimens, we made tissue diagnosis by examining gastrointestinal, bone marrow, or peripheral blood specimens.
The treatment scheme was as follows: Cycle 1 (rituximab plus hyper-CVAD) was a 21-day cycle, administered on either an outpatient or inpatient basis, consisting of rituximab at a dose of 375 mg/m2 on Day 1, followed by cyclophosphamide at a dose of 300 mg/m2 per dose given intravenously over 3 hours every 12 hours for 6 doses on Days 2, 3, and 4. Mesna was started 1 hour before the start of cyclophosphamide, at a dose of 600 mg/m2 intravenously and was given over 24 hours daily on Days 2, 3, and 4, with the infusion completed 12 hours after administration of the last dose of cyclophosphamide. Twelve hours after the last dose of cyclophosphamide, doxoribicin at a dose of 16.6 mg/m2 was given by continuous intravenously infusion over 24 hours daily on Days 5, 6, and 7. Vincristine at a dose of 1.4 mg/m2 (maximum absolute dose, 2 mg) was given by intravenously infusion 12 hours after the last dose of cyclophosphamide and was repeated on Day 12 of the cycle. Dexamethasone at a 40-mg absolute dose was given orally or intravenously on Days 2 to 5 and 12 to 15 of the cycle. Patients with evidence of peripheral blood involvement (as determined by flow cytometric analysis at the time of initial presentation) may have had their first dose of rituximab delayed or omitted at the discretion of the clinician when they were believed to be at risk for tumor-lysis syndrome or cytokine-release syndrome. Prophylaxis for each course included granulocyte colony-stimulating factor (G-CSF) at 5 μg/kg subcutaneously, valacyclovir at 500 mg orally, fluconazole at 100 mg orally, and ciprofloxacin at 500 mg orally twice a day, all given daily for 10 days starting 24 to 36 hours after the end of the infusion of doxorubicin.
Cycle 2 (rituximab plus methotrexate-cytarabine) was a 21-day cycle given on an inpatient basis and consisted of rituximab at a dose of 375 mg/m2 on Day 1, followed on Day 2 by methotrexate at a dose of 200 mg/m2 administered intravenously over 2 hours and then methotrexate at a dose of 800 mg/m2 by constant intravenously over 22 hours. Before methotrexate administration began, the patient's urine was alkalinized to a pH of 6.8 or higher and kept at this level until the methotrexate was cleared from the blood. For patients with an initial serum creatinine level >1.5 mg/dL, the dose of methotrexate was decreased by 50%. In patients with evidence of third spacing of fluids, the fluid was tapped completely or, when this was not possible, rituximab plus hyper-CVAD was repeated for the next cycle until the third spacing resolved (this situation was rare). Cytarabine was given at 3000 mg/m2 per dose over 2 hours every 12 hours for 4 doses on Days 3 and 4 of the cycle. The cytarabine dose was automatically reduced to 1000 mg/m2 in patients older than 60 years and in those with a serum creatinine level >1.5 mg/dL. A 1% ophthalmic solution of prednisolone, given at a rate of 2 drops in each eye 4 times daily, was started on Day 3 at the start of cytarabine infusion and was continued for 7 days to prevent chemical conjunctivitis. Folinic acid (citrovorum factor) rescue therapy (50 mg) was given orally 12 hours after the infusion of methotrexate was completed, and then 15 mg orally every 6 hours for 8 doses. Serum methotrexate levels were checked at 24 and 48 hours after the end of the infusion, and the dose of folinic acid was increased to 100 mg intravenously every 3 hours when the serum level was either >1 μM (at 24 hours) or >0.1 μM (at 48 hours). Prophylaxis given with Cycle 2 was otherwise similar to that given with Cycle 1. The use of erythropoietin was permitted throughout therapy.
Evaluation During and After Treatment
The following tests were performed every 2 cycles: CT of the chest, abdomen, and pelvis; gallium scan or PET, and bilateral bone marrow biopsy with unilateral aspiration. To confirm CR, esophagogastroduodenoscopy and colonoscopy were performed, with biopsies performed randomly. Upon completion of therapy, patients underwent the same studies (except for gallium scan or PET and endoscopies) every 3 months during the first year, every 4 months during the second year, every 6 months during the third and fourth years, and yearly thereafter.
Total Number of Chemotherapy Courses
Patients who achieved a CR after the first 2 cycles (1 rituximab plus hyper-CVAD and 1 rituximab plus methotrexate with cytarabine) received 4 more cycles, for a total of 6 cycles. Patients who achieved a partial response (PR) after 2 cycles and a complete remission after 6 cycles received 2 more cycles, for a total of 8 cycles. Patients with evidence of disease after 6 cycles were removed from the study. Patients whose disease was responding could be referred at any time during treatment for consolidation with stem-cell transplantation.
Dose Adjustment due to Toxicity
Grade 3 nonhematologic toxicity required a 1-dose-level decrease of the offending drug.
Grade 4 nonhematologic toxicity was discussed with the principal investigator on a case-by-case basis, with options ranging from dose level reduction to the patient's removal from the study. Grade 3 or 4 hematologic toxicity during the nadir of each cycle did not require dose adjustments. Instead, doses of myelotoxic drugs were adjusted according to the patients' blood counts on Day 21 of the cycle as follows: a platelet count between 75,000/μL and 100,000/μL, or an ANC between 750/μL and 1000/μL warranted a delay in the treatment until the counts recovered to >100,000 platelets/μL and >1000 ANC/μL, without a decrease in the dose; however, when the platelet count was <75,000/μL or the ANC was <750/μL, then therapy was delayed until the platelet count increased to 100,000/μL and the ANC to 1000/μL, and the next similar regimen was administered at a 1-dose-level reduction of the myelotoxic drugs.
Response was assessed according to standard International Workshop Criteria.15 Refractory disease was defined as achievement of less than a partial response or a persistent partial response or progression with additional cycles or appearance of a new lesion during therapy. Treatment failure was defined as recurrence or progression of disease, death due to disease or toxic effects, or death due to treatment-related second malignancies.
Patients who underwent consolidation therapy with stem-cell transplantation were censored for the failure-free survival analysis. The Fisher exact test was used to test for associations between CR and patient characteristics. The Kaplan-Meier product-limit method was used to estimate both failure-free survival and overall survival (OS).16 The log-rank test17 was used to test for differences in failure-free survival and OS between groups of patients aggregated according to several variables, age, presence or absence of bone marrow involvement, presence or absence of any amount of peripheral blood involvement (as judged by morphologic assessment only), blastoid or other cytology, pretreatment serum levels of β2-microglobulin and lactate dehydrogenase (LDH), presence or absence of an enlarged spleen by CT as judged by the radiologist, and International Prognostic Index score for aggressive non-Hodgkin lymphoma.18 A P < .05 was deemed statistically significant. High β2-microglobulin level was defined as a β2-microglobulin level ≥3 mg/L, and high LDH was defined as an LDH level >upper normal range, or 618 U/L. All tests were 2-sided. Patients who underwent stem-cell transplantation were censored at the time of transplant.
Thirty-one patients with relapsed or refractory MCL were enrolled in this prospective trial. Two were lost to follow-up, leaving 29 evaluable for response and toxicity. The patients' median age was 63 years (range, 45-78 years), and the male:female ratio was 5:1.
Tables 1 and 2 show prior therapies and response, respectively. The median number of prior regimens was 1 (range, 1-5 prior regimens). Most patients had received a doxorubicin-containing regimen or a rituximab-containing regimen. First-line therapies were as follows: CHOP (cyclophosphamide, doxoribicin, vincristine, prednisone) with or without rituximab or radiotherapy (17 patients); HyperCVAD or MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) alternating with stem-cell transplantation (1 patient); HyperCVAD/MA with rituximab (2 patients); PROMACE/CYTABOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, folinic acid) followed by stem-cell transplantation (1 patient); fludarabine and cyclophosphamide (1 patient); fludarabine (1 patient); FND (fludarabine, mitoxantrone, dexamethasone) with rituximab (1 patient); CVP (rituximab, cyclophosphamide, vincristine, prednisone) with or without rituximab (3 patients); and rituximab followed by bexxar (1 patient). Overall, including frontline and subsequent therapies, 4 patients had previously received rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine, and 5 patients had a disease relapse after undergoing autologous stem-cell transplantation. Responses to the previous treatment included CR in 10 (35%) patients, PR in 7 (24%) patients, and no response or progression in 12 (41%) patients.
|Therapy||No. of Patients|
|Median prior no. of regimens (range)||1 (1-5)|
|Radiotherapy (excluding TBI)||9|
|Zevalin or Bexxar||2|
|Rituximab plus hyperCVAD alternating with rituximab plus methotrexate-cytarabine||4|
|Autologous stem cell transplantation or TBI||5|
|Less than PR||12 (41)|
Response to Salvage Rituximab Plus Hyper-CVAD Alternating With Rituximab Plus Methotrexate-Cytarabine
Results of this trial are summarized in Table 3. The median number of cycles received was 5 (range, 1-7 cycles), with an overall response rate (ORR) of 93% (45% CR or CR unconfirmed [CRu] and 48% PR). All 5 patients whose disease was resistant to the previous treatment experienced a response (1 CR, 4 PR), and both patients whose disease did not change in response to prior therapy also experienced a response (2 PRs). We evaluated the 14 patients whose current response was classified as PR and found that in 4 of them, this was the best response ever achieved; another 5 patients were referred for stem-cell transplantation while the tumor was still responding. Nine of 29 (31%) of the patients underwent consolidation therapy with nonmyeloablative stem-cell transplantation. Reasons for no transplantation in order of frequency included age (7 patients), no insurance (3 patients), less than a partial response (3 patients), patient refusal (3 patients), and lack of compatible donor (2 patients). One patient had a heart attack and another patient's physician chose not to offer transplantation.
No pretreatment variable (number of prior chemotherapy regimens, response to previous regimens, pretreatment serum levels of β2-microglobulin or LDH, or age) was associated with achievement of a CR. There was no response or duration of response difference by intensity of prior therapy received. Two patients received radioimmunoconjugates as 1 of their prior therapies; 1 patient tolerated well the current regimen, and another patient developed delays in therapy and infections but was able to proceed to stem-cell transplantation.
Toxic effects of the chemotherapy are summarized in Table 4. The principal toxic effects were hematologic. In a total of 104 cycles of chemotherapy given, the rates of grade 4 neutropenia and grade 4 thrombocytopenia were 60% and 54%, respectively. The incidence of neutropenic fever was 11%, and there were no deaths due to toxicity. In 4 cases, toxicity precluded continuation of therapy because of myelosuppression and associated neutropenic infections. These were all patients older than 65 years of age. The number of patients who did not undergo transplantation and who could not finish the 6 cycles of treatment were 4 of 20 (25%).
Failure-Free Survival and Overall Survival
With a median follow-up interval of 40 months (range, 4-58 months), the median failure-free survival (FFS) time was 11 months and the median overall (OS) time was 19 months. Neither the FFS nor the OS curves reached plateau (Fig. 1). No pretreatment variable (number of prior chemotherapy regimens, response to the previous regimen, pretreatment serum levels of β2-microglobulin or LDH, and age) was associated with better FFS.
We previously reported results of a treatment with a novel combination of a monoclonal antibody and intense chemotherapy, in which rituximab plus hyper-CVAD was alternated with rituximab plus methotrexate-cytarabine in newly diagnosed patients with aggressive MCL.10 The rates of overall response and complete response to this regimen, when administered as first-line therapy, were 97% and 87%, respectively, and at 3 years, the median failure-free survival had not been reached. We, therefore, decided to test this regimen in the more challenging setting of relapsed or refractory MCL.
Patients accrued on the current trial showed an excellent overall response rate of 93% and, more importantly, a CR or CRu rate of 45%, thus potentially making more patients eligible for consolidation with stem-cell transplantation than was possible when we used standard therapies.
Our sample of patients is representative of the population of patients with relapsed MCL, in that they previously received doxorubicin-containing chemotherapy, mostly in combination with the monoclonal antibody rituximab. Furthermore, 4 patients had previously received a similar intense regimen, and 5 patients had disease relapse after undergoing autologous stem-cell transplantation. The finding that these patients responded to our regimen supports the efficacy of the combination.
Other salvage therapies have resulted in CR rates of 9% to 80% and PR rates of 21% to 80% (Table 5). (It should be noted that the higher response rates were obtained in studies with only 5 patients.) Combining our intense regimen with other targeted therapies that do not have overlapping toxic effects may further improve outcomes, but this hypothesis remains to be tested. The final treatment recommendation for a patient with a recurrence will depend on his or her potential for consolidation with stem-cell transplantation and his or her performance status.
|Author||Regimen||No. of Patients||% CR||% PR||% ORR|
|Robak32||2-CdA+rituximab or rituximab with cyclophosphamide||9||22||45||67|
No variable predicted CR, possibly because of the regimen's effectiveness. However, our analysis of response was confounded because a portion of the patients with PR underwent stem-cell transplantation while they were still responding to the regimen. Assessment of the relation between pretreatment prognostic variables and failure-free survival was similarly limited.
Hematologic toxicity in the current study was frequent, as is expected for a regimen of such intensity, but only 11% of the cycles were associated with neutropenic fever, and there were no deaths due to toxicity. No patient has developed myelodysplasia or acute leukemia, a complication that has been reported in other trials with a similar regimen.10
The high response rates achieved with rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine in patients with relapsed or refractory MCL lead us to conclude that this regimen is an option for induction therapy before stem-cell transplantation. The data also suggest that this regimen will improve rates of long-term survival in such patients.
We would like to thank Bonnie Baum for typing this article.
- 15Report on an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999; 10: 1244–1253., , , et al.
- 19European phase 2 study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol. 2000; 18: 317–324., , , et al.
- 28The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004; 104: 3064–3071., , , et al.
- 29Fludarabine, mitoxantrone, and rituxan: an effective regimen for the treatment of mantle cell lymphoma [abstract]. Blood. 2002; 100( suppl 1): 361A., , , et al.
- 33R-Dhaox, high dose chemotherapy (HDC) and rituximab maintenance as salvage treatment in relapsed or refractory (R/R) follicular (F) and mantle cell (MC) lymphomas (NHL) [abstract]. J Clin Oncol. 2007: 100( suppl 18): 450S. (Abstract 8036)., , , et al.
- 34Marked activity of bortezomib, rituximab and dexamethasone in relapsed and refractory mantle cell lymphoma [abstract]. Blood. 2006; 108: 779A., , , et al.