First-line treatment with rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group

Abstract

The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with ⁹⁰Y-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of ⁹⁰Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60–93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4–59.6), 52% (95% confidence interval 32.4–71.6) and 81% (95% confidence interval 67.28–94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48–78.52) and 87% (95% confidence interval 70–100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3–4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with ⁹⁰Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. Trial registration: clinical.gov identifier: NCT004400-37

Introduction

The treatment of mantle cell lymphoma (MCL) is a clinical challenge. The overall survival of patients has improved over recent years, but the median survival still remains poor, being around 5 years in the majority of patients.1 With the standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen, complete remission rates are lower than 50% and the median failure-free survival is short, ranging from 16 months to 2 years.2,3

The outcome has improved most for young, fit patients with the use of intensive first-line strategies, particularly those containing high-dose Ara-C (HDAC) followed or not by autologous stem cell transplantation (ASCT).4–7 With intensive treatment, complete remission rates rise to 80–100% and median failure-free survivals of up to 5 years have been reported.5–10 In spite of this improvement, the updated long-term results obtained with these approaches have shown a continuous pattern of relapse.11,12 After relapse, the outcome becomes dismal for most patients, who frequently require sequential treatments until death.

Maintenance and consolidation strategies in MCL are a matter of active study in order to achieve longer lasting responses. In fact, the European Mantle Cell Lymphoma Network recently demonstrated a significant improvement in progression-free survival and overall survival when maintenance rituximab therapy is used after R-CHOP although no benefit could be documented for patients treated with rituximab-fludarabine-cyclophosphamide.13

Radioimmunotherapy with an anti-CD20 antibody conjugated to a β-emitting radioisotope is a treatment with demonstrated efficacy in follicular lymphoma.14–17 Efficacy data for radioimmunotherapy in MCL are more limited although it has efficacy as monotherapy in relapsed or refractory disease.18 In fact, its efficacy appears to be heterogeneous since good results were reported when it was used as consolidation after standard therapy19,20 whereas the Nordic Group found no benefit from introducing radioimmunotherapy into the conditioning regimen in their MCL3 trial compared to their previous MCL2 trial.21 To our knowledge, only one other preliminary communication on radioimmunotherapy as consolidation after intensive treatment has been reported so far.22

Here we report the results of a prospective, multicenter, pilot phase 2 study, conducted by the Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea (GELTA-MO) in patients with untreated MCL, who received induction therapy with rituximab (R)-hyperCVAD/R-methotrexate-AraC (R-MA) followed by consolidation with Y-ibritumomab tiuxetan.

Methods

The study was performed in 12 Spanish institutions. It was approved by local and central committees and registered at the Clinical Trials Gov web-site (NCT00505232). More detailed information is provided in the Online Supplementary Material.

Patients and assessments

Patients between 18 and 70 years old and diagnosed with MCL23 were eligible. Cyclin D1 or t(11;14) )(q13;q32) translocation positivity was required for the diagnosis. Inclusion and exclusion criteria, pre-treatment evaluations and work-up studies are described in detail in the Online Supplementary Material.

Complete disease evaluation was carried out before treatment, after the 4 cycle and at the end of the induction treatment. After consolidation, disease was evaluated every 4 months until the 2 year and every 6 months thereafter.

Treatment

Patients received R-hyperCVAD therapy alternating with R-MA every 21 days.5 Dose adjustments were considered for patients older than 60 years, those with creatinine values >1.5 mg/dL or after development of febrile neutropenia, hematologic toxicity (platelet count <100×10/L or granulocyte count <1×10/L on day 21 of each cycle) or non-hematologic grade 3 toxicity at any moment. Treatment was discontinued if patients did not reach hematologic recovery 5 weeks after chemotherapy, had less than a partial response after four cycles or developed grade 4 non-hematologic toxicity. The number of induction cycles was fixed at six.

Support therapy with pegylated-filgastrim and Pneumocystis jirovecci prophylaxis were required by protocol. Peripheral blood stem cell collection as back-up was mandatory in the first six patients and recommended for the remaining patients.

Consolidation with Y-ibritumomab tiuxetan was scheduled 12 weeks after the 6 cycle. The drug was kindly provided by Bayer-Schering and administered following the manufacturer’s written instructions. Although a dose escalation to 0.4 mCi/kg was allowed for, the dose for Y-ibritumomab tiuxetan was fixed at 0.3 mCi/kg.

Study endpoints and definition of study variables

The main objective was to evaluate the feasibility, safety and efficacy of the whole treatment. Clinical efficacy was evaluated in terms of response and survival. The toxicities were evaluated according to the National Cancer Institute’s Common Toxicity Criteria (CTCAE v3.0).

Response criteria were assessed according to The International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphoma.24 Patients without response assessment were considered non-responders.

Failure-free survival was defined as the time from the date of study entry until date of recurrence, progression, death from any cause or any toxic event that prohibited treatment. Responding patients who did not complete the whole treatment were censored at the moment this deviation occurred. Progression-free survival was defined as the time from inclusion into the trial until progression, recurrence or death as a result of lymphoma. Overall survival was defined as the interval between the date of study entry until death from any cause.

Variables were calculated in the intent-to-treat population, defined as patients who had received at least one cycle of treatment. For the analysis of survival and serious adverse events, all patients were followed until the closure of the study regardless of treatment discontinuation.

Statistical analysis

The statistical methods are described in the Online Supplementary Material.25,26

Results

Patients’ characteristics

Between February 2006 and July 2008, 38 patients with untreated MCL from 12 institutions were registered for this study. Eight patients were not enrolled in the study because of: positive serology for hepatitis B virus (2 patients), central nervous system involvement (1 patient), old age (1 patient), localized disease (1 patient), patient’s refusal (1 patient), protocol deviation (1 patient) and urgency for treatment (1 patient). Therefore, 30 patients were evaluable for results.

The patients’ characteristics are described in Table 1. The median age of the group was 59 years (range, 41–70 years). Blastic MCL variant was diagnosed in 21% of the cases. Most patients had advanced disease (97%), with documented bone marrow involvement (93%) and 40% were in the intermediate/high risk group of the Mantle International Prognostic Index (MIPI) classifications.27 The results of cytogenetic studies on bone marrow/peripheral blood samples to detect t(11;14)(q13;q32) and other cytogenetic abnormalities (del 13q14, +12, del 17p, del 11q22.3) are also shown in Table 1.

Treatment outcome

Twenty-eight (93.3%) out of the 30 patients were evaluable for response after the 4 cycle and 24 (80%) after the 6. After the 4 cycle, 19 patients achieved complete remission or unconfirmed complete remission (68%, 95% CI: 67%–69%) and nine had partial responses (32%, 95% CI: 31%–33%). Response at the 4 cycle could not be assessed in two patients because of grade 4 infection in one and an unexpected suicide in another patient without a previously known psychiatric disorder. Four additional patients discontinued treatment between the 4 and 6 cycles due to grade 4 and grade 5 bacterial infections (1 patient each), pulmonary aspergillosis (1 patient) and grade 4 neurological toxicity (1 patient).

At the end of induction treatment 23 patients (77%; 95% CI: 60%–93%) achieved complete remission/unconfirmed complete remission and one patient had progressive disease (3%).

The dose of Y-ibritumomab tiuxetan was maintained at 0.3 mCi/kg. Five out of the first six patients treated had lower peripheral blood counts than those required for full dose at 12 weeks after completion of induction therapy.

Eighteen patients (60%), all in complete remission/unconfirmed complete remission, received consolidation treatment. Treatment failed in six patients, because of grade 4 infection (1 patient), patient’s decision (1 patient), delayed recovery of peripheral blood counts (2 patients), protocol deviation (1 patient) and progressive disease (1 patient). The study throughput is shown in Figure 1.

Table 1.Characteristics of the patients and cytogenetic findings at diagnosis

Table 2.Hematologic toxicity during the induction treatment.

Failure-free survival, progression-free survival and overall survival

The median follow-up for survivors was 3.9 years (range, 0.45 – 5.4 years). Two- and 4-year failure-free survival rates were 57% (95% CI: 37.4%–76.6%) and 40% (95% CI: 20.4%–59.6%) respectively. The progression-free survival rates at 2 and at 4 years were 72% (95% CI: 54.36% – 89.64%) and 52% (95% CI: 32.4% – 71.6%), respectively. The median progression-free survival was 4.9 years (range, 2.7 to 7.1 years). The overall survival rates at 2 and 4 years were 89% (95% CI: 79.2% – 98.8%) and 81% (95% CI: 67.28 %– 94.72%) (Figures 2A–2C).

In the group of 18 patients who received the whole treatment, failure-free survival rates at 2 and at 4 years were 78% (95% CI: 58.4% – 97.6%) and 55% (95% CI: 31.48 – 78.52), respectively. Overall survival rates at 2 and at 4 years were 93.8% (95% CI: 82% – 100%) and 87% (95% CI: 70% – 100%), respectively.

High-dose cytarabine (HDAC) has proven to have an outstanding effect on outcome; we, therefore, studied the survival variables according to a cut-off age of 60 years, when significant Ara-C dose adjustments are made. The 4-year failure-free survival rate for older patients was 30% (95% CI: 4.5% – 55.5%) versus 50% (95% CI: 22.5% –77.4%) for the younger ones (P=0.57). The 4-year overall survival rate was not affected by age. In fact, the overall survival rate of older patients was 92% (95% CI: 78% – 100%) versus 73% (95% CI: 51.4% – 94.5%) for those younger than 60 years. Other characteristics were similarly distributed between the groups.

Figure 1.Treatment flow chart. CR/CRu: complete response/unconfirmed complete response; PR: partial response; PD: progressive disease; RIT: radioimmunotherapy.

The failure-free survival of patients in low or intermediate-high MIPI risk groups was significantly different (P=0.003). The median failure-free survival for low risk patients was 4.8 years (95% CI: 2.7–6.9) versus 1.4 years (95% CI: 0.15–3.2) for the intermediate-high risk group. Overall survival was also significantly different (P= 0.003), being 93% (95% CI: 81.24% – 100%) for the low-risk group versus 31% (95% CI: 0% – 76%) for the intermediate-high risk group (Figures 3A, 3B). No other patients’ characteristics had an impact on survival.

Figure 2.(A) Failure-free survival, (B) progression-free survival and (C) overall survival of the 30 patients by intent-to-treat analysis.

Six (20%) out of 30 patients died during the study. Causes of death were unexpected suicide (1 patient), infection (1 patient due to septic shock), relapsed disease (1 patient) and secondary malignancies in three patients (myelodysplastic syndrome, bladder carcinoma and rectal carcinoma). Two of these patients died without evidence of lymphoma.

Toxicity

Six out of 30 patients (20%) did not complete their intended number of cycles during induction treatment because of toxicity (5 patients) and suicide (1 patient).

Figure 3.(A) Failure-free survival and (B) overall survival by MIPI: low risk versus intermediate-high risks.

One hundred and seventy cycles were administered during this phase. Adverse and serious adverse events are reported in Tables 2 and 3. The principal toxicity was hematologic, which was significantly greater during R–MA cycles; indeed, more than 90% of the cycles were associated with grade 3–4 neutropenia and thrombocytopenia, and 50% with grade 3–4 anemia (P<0.0001). Neutropenic fever and infection accounted for 56 out of 69 serious adverse events (81%) reported during this phase and were again significantly higher in R-MA cycles (49% versus 18%; P< 0.05). There was one toxic death due to septic shock during this period.

Hematologic toxicity was the main adverse event during consolidation. Grade 3–4 neutropenia was seen in 72% of the patients and lasted a median of 5 weeks (range, 2–24 weeks). Grade 3–4 thrombocytopenia was observed in 83% of the patients with a median duration of 12.5 weeks (range, 4–56 weeks). No patient received the back-up peripheral blood stem cells collected.

Secondary malignancies (7 events) and infection with normal neutrophils (5 events) accounted for the total of 16 serious adverse events communicated after consolidation treatment. Six of these neoplasms were reported after the first-line treatment and one occurred after the patient’s subsequent exposure to other treatments for relapsed disease. A detailed description of these malignancies is given in Table 4. The crude incidences of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) and solid tumors were 10% each. The 2 and 4-year cumulative incidences were 4% and 17%, respectively. Cytogenetic analysis in two cases with MDS revealed complex karyotypes, with abnormalities of chromosomes 5 and 7. For solid tumors, the 2-year cumulative incidence was 13%. No further solid tumor was diagnosed later on, with a median follow up for the survivors of 3.9 years.

Table 3.Non-hematologic toxicity during the induction treatment.

Table 4.Description of the second malignancies diagnosed during the study.

Discussion

The use of intensive treatment approaches in young, fit patients with MCL has significantly improved their outcome. The best strategy remains uncertain so far, although the more extended practice includes performance of ASCT as consolidation of first response. Our trial considered the up-front intensive regimen hyperCVAD alternating with methotrexate-AraC, both in association with rituximab, developed by the MD Anderson Cancer Center (MDACC), given the reported good response rates and their prolonged duration. Of note, updated MDACC results showed a progression-free survival of 43% and an overall survival of 56%, quite similar to those reported by the Nordic Group using consolidation with ASCT, with progression-free and overall survival rates of 43% and 58%, respectively.

In this study, treatment with R-hyperCVAD alternating with R-MA (3 cycles of each) followed by consolidation with Y-ibritumomab-tiuxetan produced poorer results than expected. Toxicity was unacceptably high and the complete remission rate, median failure-free survival and progression-free survival were 77%, 2.6 years and 4.9 years, respectively, without a plateau.

In our hands, the feasibility of R-hyperCVAD alternating with R-MA was less than previously reported.5,7 At the MDACC, 70% of the patients received eight cycles. In a multicenter setting, the Gruppo Italiano Studio Linfomi administered six cycles to 75% of their patients without mandatory growth factor support. In our study, safety withdrawal events accounted for 83% of the discontinuations throughout the induction phase. Hematologic toxicity was high, particularly in the R-MA cycles, during which grade 3–4 neutropenia and thrombocytopenia were practically universal. Accordingly, febrile neutropenia and infections were observed in 17% and 32% respectively, which are significantly higher rates than those for the toxic events detected in the R-hyperCVAD cycles (7% and 11%, respectively). The toxicity detected in the R-MA cycles was higher than previously reported for the same schedule of treatment5,7 and significantly higher than that reported for other intensive strategies.6,28 Probably, the concomitant administration of methothrexate with HDAC in the R-MA cycles increases hematologic toxicity and impairs renal clearance. In spite of the hematologic toxicity, the mortality rate due to infection was 3.3%, which is similar or even inferior to that reported previously for this treatment.

HDAC seems crucial for improving remission rates and failure-free survival in MCL, as was recently reported by the Mantle Cell Lymphoma Network. In their trial,28 the introduction of HDAC within the R-CHOP treatment significantly improved patients’ outcome compared with that of patients treated only with R-CHOP and followed by consolidation with ASCT. With this information, it would be desirable to clarify the best dose and schedule of this agent. In this study, the total dose of HDAC planned to be administered was 36 g/m, similar to that used by the Nordic Group in the MCL2 trial6 and higher than the doses of 14 g/m to 16 g/m used in other treatment regimens4,8,28 for which compliance rates of up to 89% were reported with a similar median failure-free survival of around 4.5 years.

Even using intensive approaches to treat MCL, a continuous pattern of relapse has been documented.11,12 Currently, consolidation and/or maintenance approaches are a matter of active clinical research in order to improve the duration of the response achieved. In this study, consolidation with a single dose of Y-ibritumomab tiuxetan was planned and administered to 60% of the patients. This finding is concordant with the results recently communicated by Beaven et al., who used consolidation with I-tositumomab after an intensive induction regimen22 in patients with MCL and diffuse large B-cell lymphoma, and significantly lower than that described when radioimmunotherapy was administered after a non-intensive regimen such as R-CHOP.19 To our knowledge, there are no other published reports on radioimmunotherapy used as consolidation after first-line treatment in patients with MCL.

In this pilot study, consolidation with radioimmunotherapy after intensive treatment did not increase the complete remission rate, failure-free survival or progression-free survival when compared with those in other studies. The 4-year failure-free survival of 55% in our study, which is inferior to that observed by other authors,4,5,7,8 might have been a consequence of the lesser feasibility of the treatment and the higher related mortality. The high incidence of secondary malignancies observed in patients who received consolidation with radioimmunotherapy is a major concern: in our series three patients (10%) developed MDS/AML and three (10%) developed solid tumors at a median time of 1.22 years (range, 0.4–3.12 years) after radioimmunotherapy.

With regards to the solid tumors, the observed crude and cumulative incidences were 10% and 12.7%, respectively. An unusually increased incidence of second malignancies was suggested for 156 patients with MCL treated with R-hyperCVAD/R-MA, 37% of whom were also transplanted and 32% treated with total body irradiation.29 With a median follow up of 2 years, the crude incidence of invasive neoplasms was 4.5% soon after the treatment. However, this observation was not confirmed by the same authors in more recent reports, neither has it been mentioned by others using the same induction treatment.5,7 Geisler et al. report a crude incidence of 3% with a median follow up of more than 6 years although they did not consider the malignancies to be treatment-related. With I-tositumomab, Bennet et al. reported a crude incidence of less than 5% of solid tumors in MCL patients with relapsed and refractory disease previously treated with a median of three chemotherapy lines.

More information about the risk of MDS/AML is available. The incidence in our study was higher than that found by other authors using intensive approaches with or without ASCT but without radioimmunotherapy, ranging from 0% to 5%. Romaguera et al. reported a crude incidence of 4% with a median follow-up of 3.3 years,5 data that remained practically unchanged (5%) in the updated results, with a follow-up of 8 years.11 The Nordic Group reported an incidence of 0.6% in the updated results of the MCL2 trial, with a median follow up of 6.5 years.6 Interestingly, the same group in their MCL3 trial, which added Y-ibritumomab tiuxetan to the BEAM (BCNU, etoposide, Ara-C, melphalan) conditioning regimen, did not report an increased incidence of MDS/AML with a median of follow-up of 3.2 years.21 Other authors, using intensive regimens and including ASCT as consolidation, did not mention any secondary malignancies in patients followed for a similar period of time.4,8

The reported crude incidence of MDS/AML in patients treated with radioimmunotherapy after R-CHOP or fludarabine-mitoxantrone-rituximab in first-line treatment for MCL and follicular lymphoma was 0%–0.5%.19,30,31 More accurate data on this complication come from compassionate-use studies in patients exposed to a median of two to three lines of treatment.32,33 The 2- and 5-year cumulative incidences ranged from 1.7% to 6.3%, respectively. Our figures were 4% and 15%, higher than those reported by Guidetti et al. in previously treated patients who were autografted after conditioning with myeloablative doses of radioimmunotherapy.34

The cytogenetic findings in the cases of MDS diagnosed were those commonly associated with prior exposure to cytotoxic drugs and radiation therapy. Complex karyotypes involving chromosomes 5 and 7 are genetic events associated with these therapies.35–37 None of the patients with MDS/AML had additional genetic abnormalities besides the Bcl-1 translocation, such as p53, ATM or 13q deletions, detected in 23% of our patients at diagnosis.

To our knowledge, an unacceptable increase in the incidence of either secondary MDS/AML or solid tumors has not been described despite the widespread use of hyperCVAD/MA, which requires the use of stem cell factors in order to decrease toxicity and maintain an adequate dose intensity. The toxicity found in our study could be due to the high cumulative dose of cyclophosphamide followed by systemic radiation, as is radioimmunotherapy, which may entail a second oncogenic event on previously sensitized cells.

In summary, R-hyperCVAD/R-MA followed by consolidation with Y-ibritumomab tiuxetan is effective although less feasible than expected. The substantial toxicity observed advises against the use of this strategy. The number of new drugs available for MCL is increasing and it is, therefore, crucial to focus on minimizing adverse events.

Acknowledgments

The authors would like to thank Dr Victor Abraira for his statistical advice.

Footnotes

• We dedicate this paper to the memory of our dear colleague Javier Pérez-Calvo who passed away last year.
• The online version of this article has a Supplementary Appendix.
• Authorship and DisclosuresInformation on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.

• Received March 22, 2013.
• Accepted May 30, 2013.