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Keywords:

  • mantle cell lymphoma;
  • R-cyclophosphamide;
  • oncovin;
  • adriamycin;
  • prednisolone;
  • high-dose Ara-C;
  • carmustine;
  • etoposide;
  • Ara-C;
  • melphalan

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Mantle cell lymphoma (MCL) has a dismal outcome when treated with conventional chemotherapy. This single arm phase 2 study evaluated intensive consolidation treatment of patients with newly diagnosed MCL up to the age of 65 years, responsive to R-CHOP (rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone). Endpoints for evaluation were toxicity, failure-free survival (FFS) and overall survival (OS). Eighty-seven patients were treated with three cycles of R–CHOP. Sixty-six patients responded to R-CHOP with at least a partial response, 62 continued protocol treatment with high-dose cytarabine (Ara-C; 2000 mg/m2, bid. over 4 d) and 61 patients received rituximab and stem cell harvest, followed by BEAM (carmustine, etoposide, Ara-C, melphalan) and autologous stem cell rescue. Non-haematological toxicity, grades III and IV, was seen in 8% of the patients after R-CHOP, in 22% after high-dose Ara-C and in 55% after BEAM. The overall response rate was 70% (complete response rate 64%, partial response rate 6%), FFS and OS at 4 years were 36 ± 7% and 66 ± 6%, respectively. The FFS and OS at 4 years from the evaluation after BEAM in the 61 R-CHOP responsive patients was 46 ± 9% and 79 ± 7%, respectively. In conclusion, high-dose Ara-C and BEAM with stem cell rescue in newly diagnosed MCL patients responsive to R-CHOP is a manageable treatment with respect to toxicity. This regimen leads to long-term, but probably not durable, remissions.

Mantle cell lymphoma (MCL) is defined in the World Health Organization (WHO) classification of malignant diseases as a separate entity within the group of B cell lymphomas, based on its distinct morphology, immunophenotype and the association with the cytogenetic translocation t(11;14) (Jaffe et al, 2001).

MCL has a dismal outcome when treated with doxorubicin containing regimens e.g. CHOP (cyclophosphamide, oncovin, adriamycin, prednisolone) (Teodorovic et al, 1995; Velders et al, 1996; Vandenberghe et al, 1997; Hiddemann et al, 1998). The overall response rate (ORR) is about 70% and the complete response (CR) rate 10%. The median overall survival (OS) with this regimen is 3–4 years.

Several additions to the CHOP regimen have improved the prognosis. The anti-CD20 antibody rituximab, given as a single drug, showed an ORR of about 30% (27–38%) in treated and previously untreated patients (Foran et al, 2000; Ghielmini et al, 2005). Combination of this antibody with CHOP (R-CHOP) resulted in about 95% ORR and 40% CR, a longer remission duration, but not in a survival advantage (Howard et al, 2002; Lenz et al, 2005). Cytarabine (Ara-C) as a single drug has never been tested in MCL, but survival was largely influenced by regimens containing high doses of this drug. With hyperCVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone), containing high-dose Ara-C (Khouri et al, 1998), and R-hyperCVAD (Romaguera et al, 2005) more than 80% of patients reached CR and the 3-year OS was about 80%. Toxicity, however, was high. High-dose Ara-C, given in a DHAP (high dose Ara-C, cisplatin, dexamethasone) regimen has been tested by Lefrère et al (2002, 2004) with good results.

Autologous peripheral blood stem cell transplantation (auto-PSCT) as a consolidation therapy in first line treatment after CHOP induction was compared in a randomized fashion with interferon-alpha maintenance treatment (Dreyling et al, 2005) and demonstrated an advantage in the auto-PSCT arm with respect to progression-free survival (PFS) rate at three years (54% vs. 25%) for patients who reached partial response (PR) or CR after induction therapy. The 2-years survival probability was 86% for the transplantation arm and 82% for the control arm. Also in comparison with matched historical controls treated with conventional therapy alone, high-dose consolidation treatment with stem cell rescue is superior (Gianni et al, 2003; Mangel et al, 2004).

This report presents the results of a single arm, multicentre, phase 2 study, conducted by the Dutch Haematology-Oncology Cooperative Group (HOVON), in which rituximab, high-dose Ara-C and consolidation with high-dose chemotherapy followed by autologous stem cell rescue were combined in a primary treatment for patients with advanced MCL responsive to R-CHOP.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients

This phase 2 study (HOVON 45) was conducted from March 2002 until November 2005. Patients with newly diagnosed MCL, Ann Arbor stage II–IV, aged 18–65 years, WHO performance scale better than grade 3 and with normal liver and kidney function and no secondary malignancy, were eligible. One patient of 66 years was included in the study, because of a good performance status, according to the judgment of the local physician. The diagnosis was made based on the WHO criteria (Jaffe et al, 2001) and reviewed by one of the authors. The patients were treated in 14 Dutch hematology centres, which are listed in the Acknowledgements. This study was approved by the ethics committee of the Erasmus MC Rotterdam and by the local ethics committees. The study was conducted in accordance with the modified Helsinki Declaration. All patients gave their written consent, after having been informed about the purpose and investigational nature of the study.

Treatment and response evaluation

Eligible patients were treated with three courses of R-CHOP (rituximab 375 mg/m2, day 1, cyclophosphamide 750 mg/m2, day 1; oncovin 1·4 mg/m2, day 1; adriamycin 50 mg/m2, day 1; and prednisolone 100 mg, day 1–5), once every 3 weeks. Patients in PR or CR continued protocol treatment with one course of high-dose Ara-C (2000 mg/m2 twice a day, day 1–4). Rituximab was given on day 11 and stem cell mobilization was enhanced with granulocyte colony-stimulating factor (G-CSF). Autologous stem cell re-infusion was performed after BEAM (carmustine 300 mg/m2, day −7, etoposide 2 × 100 mg/m2, day −6 until day −3, Ara-C 2 × 100 mg/m2 day −6 until day −3, melphalan 140 mg/m2, day −2). After this treatment, local radiotherapy (40 Gy) was allowed on residual masses. Response according to the International Working Group criteria (Cheson et al, 2007) was evaluated after three courses of R-CHOP, after high-dose Ara-C and 6 weeks after the end of treatment and included physical examination and computed tomography (CT) scan of the neck, thorax and abdomen and bone marrow histology and immunophenotyping, if positive at diagnosis. Response duration was measured every 3 months by history, physical examination and peripheral blood examination. Imaging was performed on clinical indication. Toxicity was graded according to the Common Toxicity Criteria Grading System of the National Cancer Institute (NCI-CTC), version 2.0 (http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf).

Prognostic factors

The prognostic factors studied included age, gender, WHO performance status, Ann Arbor stage, presence of B symptoms, serum lactate dehydrogenase level, International Prognostic Index (IPI) and the MCL International Prognostic Index (MIPI) (Hoster et al, 2008). Immunohistochemical assessment of the cell cycle marker Ki67 (MIB-1, DAKO, Glostrup, Denmark) (Ek et al, 2004; Determann et al, 2008) and of the over-expression of the oncogene TP53 (Do-7, DAKO, Glostrup, Denmark) (Kienle et al, 2007) was performed according to standard methods in 42 patients for whom adequate biopsy material was available for tissue microarray studies.

Study end points and statistical methods

The primary end point for this study was response (CR or PR). Secondary end points were failure-free survival (FFS), PFS, OS and the incidence of adverse events. Patients were considered as failure for PFS at progression, relapse or death, whichever came first, while patients were failure for FFS at no response [stable disease (SD) or progressive disease (PD)] after three cycles of R-CHOP, or at progression or relapse after response or at death, whichever came first. All survival times are measured from the date of registration, unless otherwise indicated.

Survival probabilities were calculated by the method of Kaplan and Meier. Cox regression analysis and the associated likelihood ratio test was used to test for differences in survival between subgroups and to test for trends with continuous or ordinal variables. P-values <0·05 were considered significant.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patient characteristics

In this study 88 patients were enrolled, of whom one was not eligible because of previous treatment with radiotherapy. The characteristics of the 87 evaluable patients are listed in the first two columns of Table I. The median age of the 87 evaluable patients was 55 years (range 32–66 years). Seventy patients were male and 17 female. Most patients had stage IV disease, due to bone marrow involvement. The prognostic index was performed according both to the IPI score (The International Non Hodgkin’s Lymphoma Prognostic Factor Project 1993) and the MIPI score (Hoster et al, 2008).

Table I.   Patients characteristics and overall survival at 4 years.
 Patients, n (%)4-year OSP-value*
  1. M, male; F, female; LDH, lactodehydrogenase; IPI, international prognostic index; MIPI, mantle cell international prognostic index.

  2. *Test for trend.

 8766 ± 6 
WHO performance
 051 (58)79 ± 7<0·001
 1 and 233 (38)48 ± 12
Ann Arbor stage
 II and III2 (2)40 ± 300·69
 IV82 (98)68 ± 6
B symptoms
 No46 (53)78 ± 70·03
 Yes40 (47)51 ± 11
LDH
 ≤1×53 (61)69 ± 90·17
 1–2×28 (32)63 ± 10
 >2×6 (7)50 ± 20
IPI
 Low4 (5)38 ± 290·69
 Low/interm39 (45)72 ± 11
 High/interm33 (38)67 ± 9
 High11 (12)47 ± 21
MIPI
 Low risk45 (51)64 ± 100·21
 Interm risk25 (29)83 ± 8
 High risk17 (20)49 ± 13

Response evaluation

A cumulative contribution of the consecutive treatments to response is given in Table II.

Table II.   Cumulative contribution of the consecutive treatments to response.
TreatmentnCR (%)PR (%)
  1. n, number of patients; CR, complete remission; PR, partial remission; R-CHOP, rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone; BEAM, carmustine, etoposide, cytarbine (Ara-C), melphalan; PSCT, peripheral blood stem cell transplantation.

  2. Percentages are given of the patients included in the study.

R-CHOP (3×)8713 (15)53 (61)
high-dose Ara-C (1×)6225 (29)37 (43)
BEAM + PSCT6152 (60)9 (7)
Radiotherapy456 (64)5 (6)

Response to R-CHOP.  According to the protocol, 13 of the 87 evaluable patients did not receive rituximab at the first course of CHOP, because the circulating lymphoma cell count was >10 × 109/l. At the second and third cycle R was withdrawn for this reason in four and two patients, respectively. Three patients went off protocol after two courses because of PD (n = 2) and intercurrent death (n = 1). After three courses 18 (21%) patients went off study, because they showed less than PR: SD was seen in 16 patients and PD in two patients. The ORR after three cycles of R-CHOP was 76%: 13 patients (15%) reached CR, 53 patients (61%) reached PR on R-CHOP. Of the 21 patients who went off protocol because of SD or PD, 20 received additional treatment off protocol, of whom four patients were treated with high dose therapy and an autograft. Of these patients, five reached CR, six reached PR. Eight of the 11 responding off treatment patients were still alive at the time of writing, while all nine patients without a response had died.

Four patients in PR went off protocol after cycle III. Two refused further protocol treatment and received additional chemotherapy off protocol. One patients’ condition was poor and he died early in PR. One patient went off study due to a protocol violation. This patient received an allogeneic transplant and has been disease free for 3+ years.

Response after high-dose Ara-C.  Sixty-two patients continued the protocol with the intensification treatment consisting of one course of high-dose Ara-C. For 12 of the 49 patients who were in PR before intensification the response improved to CR. One patient who reached CR on Ara-C went off protocol and received additional R-CHOP cycles instead of BEAM.

Response after completion of the protocol treatment.  Stem cells were mobilized after the high-dose Ara-C course in 61 patients. All harvesting procedures were successful. The mean number of CD34-positive cells was 4·1 × 106/kg (range 3·3–17·4). A monoclonal B cell population was detected by immunophenotyping in four of 47 harvests tested, the remaining 14 patients were not tested. All 61 patients received their stem cells after BEAM. Nine of the 37 patients with PR before BEAM remained in PR after this consolidation. Four patients in PR after BEAM and stem cell rescue received additional local radiotherapy. All were in CR after radiotherapy. Thus, after completion of protocol treatment 56 (64%) patients had reached CR and five (6%) patients PR.

Toxicity

Toxicity of the treatment was mainly hematological, as was expected. Non-hematological toxicity CTC grade III–IV was seen during R-CHOP treatment in 8%, after high-dose Ara-C in 22% (gastro-intestinal 6%, neurological 5%) and after BEAM consolidation in 55% of the patients, mainly gastro-intestinal. Infections CTC grade III–IV occurred in 8% of the patients during R-CHOP, mainly sinusitis and pneumonitis, in 32% after high-dose Ara-C, mainly related to the gastro-intestinal tract or fever of unknown origin, and in 66% after BEAM, mainly of pulmonary or gastro-intestinal origin.

Response duration and survival

The median follow-up was 41·7 months (range 29–68 months). Sixty-one patients were alive, 26 died. The cause of death was progressive disease in 20 patients. One patient died after two cycles of R-CHOP, possibly due to cardiac problems. One patient died in PR shortly after 3 × R-CHOP, the cause was not documented. One patient died after 11 months in CR due to severe heart failure possibly related to chemotherapy (3 × R-CHOP followed by 5 × CHOP off protocol). One patient, who had received the complete protocol treatment, died after 4 years in CR with cause of death unknown. One patient died after PD due to liver cirrhosis and ascites and another patient died after PD due to sepsis and multi-organ failure. The 4-year-PFS was 44 ± 7%, the 4-year-FFS was 36 ± 7% and the 4-year-OS was 66 ± 6% (Fig 1).

image

Figure 1.  Overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS) (intent-to-treat).

Download figure to PowerPoint

To investigate if R-CHOP sensitivity is a prognostic factor, we calculated FFS and OS from evaluation after BEAM. The 4-year-FFS and OS of the 61 R-CHOP responsive patients from the evaluation after BEAM was 46 ± 9% and 79 ± 7%, respectively. For the 13 patients in CR and the 48 patients in PR after three courses of R-CHOP the FFS was 51 ± 23% and 44 ± 10%, respectively (P = 0·200). The 4-year-OS in these patients was 100% and 73 ± 9%, respectively (P = 0·110).

Prognostic factors for OS

The characteristics of the patients (Table I), were analysed for prognostic value. Only WHO performance status and B symptoms were shown to be prognostic.

Lymph nodes from 42 patients were scored for MIB-1 in three classes, 0–10% positive, 11–50% positive and >50% positive. In patients with >50% positivity (n = 11) 4-year-OS was 36 ± 18%, compared to 71 ± 13% for 23 patients with 11–50% and 75 ± 15% for the eight patients with ≤10% positive cells (P = 0·13).

Immunohistochemical overexpression for TP53 was scored in three classes: 0–10% (n = 4), 10–80% (n = 34) and >80% positive cells (n = 4). No trend with 4-year-OS was apparent (P = 0·17). There were four patients whose graft was known to be contaminated with monoclonal B cells. These four patients have relapsed within 11–56 months.

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

MCL is characterized by a rapidly progressive course and a dismal outcome when treated with conventional chemotherapy. Although there may be some controversy (Martin et al, 2008), most recent studies showed that the outcome has been improved by a more acute lymphoblastic leukemia approach, such as hyperCVAD (Khouri et al, 1998) and the addition of rituximab (Howard et al, 2002; Lenz et al, 2005; Romaguera et al, 2005). High-dose treatment with stem cell rescue improved remission duration in comparison with historical controls treated with conventional therapy (Gianni et al, 2003; Mangel et al, 2004) and in a randomized trial compared with interferon alpha maintenance treatment (Dreyling et al, 2005).

In this study, CHOP was combined in a standard dose with an intensification course consisting of high-dose Ara-C, followed by BEAM with stem cell rescue. Rituximab was used throughout the treatment to enhance efficacy of the chemotherapy and to purge the stem cell graft in vivo. It is difficult to estimate the contribution of each of these components to response or survival. After three courses of conventional R-CHOP we found an OR of 75% (CR 15%, PR 61%). These response rates are in line with those studies that used R-CHOP-like therapies only and reported an OR rate of about 70%, but a higher percentage of CR, probably due to the higher number of courses (Howard et al, 2002; Lenz et al, 2005). Our results are also comparable with those of the Nordic MCL-1 trial (Andersen et al, 2003). They used three courses of maxi-CHOP and reported an OR of 76% (CR 27%, PR 49%), the higher CR rate being probably due to the higher doses in maxi-CHOP. One may argue that only three R-CHOP courses may jeopardize the results as compared with the Nordic MCL-2 study (Geisler et al, 2008), but our study differs in dose and schedule, not in number.

In this study, R-CHOP was used to select responsive patients for high-dose treatment. Responsive patients did better, although it has to be taken into account that a substantial number of non-responders on R-CHOP, who went off study, still proceeded to other therapies, including those with high-dose rescue treatment. From our data it is not clear if patients who reached CR after R-CHOP did have longer PFS and OS than those who had PR, because the numbers are too small. In another study (Lefrere et al, 2002, 2004), in which high-dose Ara-C was given in a DHAP regimen to patients who reached no CR after four cycles of CHOP, followed by high-dose therapy and autologous stem cell rescue, the event-free survival (EFS) rate at 5 years was 38%, the OS rate 74%. The Nordic MCL-2 protocol consisted of three cycles of R-maxi-CHOP, alternated with three cycles of high-dose Ara-C plus rituximab. Responders received BEAM/BEAC (carmustine, etoposide, Ara-C, cyclophosphamide) and stem cell rescue. Six-year FFS and OS was 66% and 70%, respectively (Geisler et al, 2008). It is likely that these superior results may be attributed more to the higher number of courses with Ara-C, than to the higher doses in the maxi-CHOP, compared to our study. Three CHOP courses, mobilization with Dexa-BEAM or DHAP and cyclophosphamide with total body irradiation as conditioning to which two doses of rituximab were added, resulted in an EFS of 83% and an OS of 87% at 4 years (Dreger et al, 2007). A small study (Evens et al, 2008) that treated patients with four to six cycles with CHOP-like therapy alternating with combination chemotherapy including high-dose Ara-C and methotrexate followed by autologous stem cell infusion after busulphan plus cyclophosphamide conditioning described a 5-year EFS of 54% with OS of 75%. This study found a median remission duration of 67 months.

Studies without CHOP that combine high-dose Ara-C plus high-dose treatment with stem cell rescue show similar results with respect to survival parameters. Hyper-CVAD + R and high-dose busulphan and melphalan as conditioning for autologous stem cell transplantation resulted in both an EFS and OS at 36 months of 92% in 12 patients (Ritchie et al, 2007). Gianni et al (2003) rescued their patients after high-dose sequential chemotherapy with three autologous stem cell re-infusions. The OS and EFS at 54 months was 89% and 79%, respectively.

These studies show that high-dose Ara-C is an essential component in the treatment of newly diagnosed younger MCL patients. More courses of high-dose Ara-C seem to result in more durable remissions and longer survival, as shown in the hyper-CVAD and DHAP studies. High-dose treatment with stem cell rescue may contribute to the duration of remission after high-dose Ara-C. None of the studies, except the Nordic MCL-2 study, has shown a plateau in the survival curves, so far.

In MCL many prognostic factors are proposed but most are controversial. In this study only WHO performance status and the presence of B symptoms were indicative for OS. Both the IPI and MIPI (Hoster et al, 2008) score were not prognostic in our patient cohort. MIPI may not have been discriminative due to the presence of only younger patients and the high-dose treatment given in this study. Age as a single factor was not a predictor for outcome in our group (data not shown). MIB-1 may be a good candidate, but did not reach statistical significance, most probably due to the small numbers.

In conclusion, the addition of rituximab, high-dose Ara-C and high-dose treatment with stem cell rescue to CHOP in first line treatment of younger patients with MCL is associated with a tolerable toxicity, a high response rate, prolonged remission duration and survival. With this multi-agent high-dose regimen, however, relapse seems to be postponed, not prevented. For this reason, CHOP sensitivity and other prognostic factors are of limited value in selecting patients for high-dose treatment. Maintenance therapy, molecular or immunological monitoring of the remission status with therapeutic interventions at early signs of minimal disease progression and the incorporation of new, less toxic, agents, like bortezomib, temserolimus or lenalidomide are future directions to enhance prognosis in MCL.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The following hospitals (physicians) participated in the HOVON 45 MCL trial:

Amersfoort: Meander Medical Centre (S. Wittebol); Amsterdam: Amsterdam Medical Hospital (M.H.J. van Oers); Amsterdam: VU Medical Centre (J. Zijlstra); Enschede: Medical Spectrum Twente (R. Schaafsma); Groningen: University Medical Centre Groningen (J.C. Kluin-Nelemans); The Hague: Leyenburg Hospital (P.W. Wijermans); Leiden: Leiden University Medical Centre (R.Willemze); Nieuwegein: St Anthonius Hospital (D.H. Biesma); Nijmegen: University Medical Centre (M. McKenzie); Rotterdam: Erasmus Medical Centre location Daniel den Hoed (M.B. van ‘t Veer); Rotterdam: Erasmus Medical Centre, location Centre (P. Sonneveld); Utrecht: University Medical Centre (L.F. Verdonck); Utrecht: Diakonessen Hospital (R. van de Griend); Zwolle: Isala Clinics (M. van Marwijk Kooy).

This study was supported by grant number: CKTO 2000-04 from The Dutch Cancer Foundation KWF, Amsterdam, The Netherlands.

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  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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