R‐CHOP followed by consolidative autologous stem cell transplant and low dose rituxan maintenance therapy for advanced mantle cell lymphoma

Abstract

We have read with great interest the report by Evens et al (2008) on the result of a phase II study of intensive chemotherapy followed by consolidative autologous stem cell transplant (SCT) for newly diagnosed mantle cell lymphoma (MCL) patients. In this study, an intensive induction chemotherapeutic regimen consisted of alternating cycles of cyclophosphamide, teniposide, doxorubicin and prednisone with vincristine, high dose methotrexate and cytarabine was used. Thirteen patients ≤65 years then proceeded to consolidative high dose busulfan/cyclophosphamide followed by autologous SCT. With this approach, the 5-year event-free survival (EFS) and overall survival (OS) was 54% and 75%, respectively. These results are encouraging, especially taking into account the long follow-up of the study. Further analysis of the whole group of 25 patients treated with this induction regimen showed that the one single factor predicting for improved survival was consolidative autologous SCT. High dose chemotherapy followed by autologous SCT has been investigated previously, but the results have been conflicting (Andersen et al, 1997;Khouri et al, 2003; Dreger et al, 2000). Furthermore, except for the report by Evens et al (2008), the median follow-up of these patients have generally been short. The conflicting results are probably related to the use of different chemotherapeutic agents as conditioning regimens for the transplant and also to different post-transplant therapy. We have chosen to induce newly diagnosed advanced stage MCL with R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab), followed by a consolidative autologous SCT after single agent high dose melphalan. This regimen has not been previously tested in MCL. Furthermore, we reasoned that, as most patients relapse within the first two years after transplant, maintenance rituximab therapy might also be useful during the first two years after autologous SCT. Because the tumor load following autologous SCT is low, the patients may only need intermittent low dose rituximab over a 2 year-period. Following consent, eight consecutive patients with newly diagnosed advanced Stage III or IV MCL were treated. The clinical characteristics of these patients are shown in Table I. There were five males and three females, with a median age of 61 years (range 47–72 years). One patient had Stage III and the other seven had Stage IV disease. All eight patients received remission + 2 cycles of R-CHOP as induction chemotherapy. Autologous stem cells were harvested upon recovery from the last cycle of R-CHOP and autologous SCT carried out within 6 weeks from the last cycle of R-CHOP. High dose intravenous melphalan (200 mg/m2) was administered, followed 24 h later by the infusion of a minimum of 2 × 106/kg of CD34+ autologous stem cells. Rituximab maintenance therapy was initiated at a dose of 375 mg/m2, given as a single infusion once every three months starting Day +100. This approach was well tolerated. Despite the higher median age of the patients, treatment-related mortality was 0%. Complete remission (CR), documented clinically and by a positron emission tomography scan, was achieved in all eight patients before autologous SCT. Median time to engraftment following autologous SCT was 13 d (range 9–30 d). Not surprisingly, due to the older age of the group, two patients died from non-lymphoma causes, without evidence of lymphoma. One patient died due to metastatic breast cancer at 34 months and another one to myocardial infarction at 40 months. Lymphoma relapse occurred in only one patient, 28 months from diagnosis and during the rituximab maintenance period. This patient is still alive and is being re-induced with velcade/dexamethasone. As of February 2008, with a median follow-up of 54 months (range 28–76 months), the EFS and OS for the group was 57% and 67%, respectively (Fig 1). Adverse effects were as expected from the high dose melphalan, except that delayed immunoglobulin reconstitution, as reported previously (Lim et al, 2005), was observed in all eight patients. The delayed immunoglobulin reconstitution persisted beyond the rituximab maintenance period (Lim et al, 2008). Four of these hypogammaglobulinemic patients had recurrent infections (three with recurrent respiratory tract infection and one with a chronic diarrhoea that was Vancomycin sensitive) and three required monthly intravenous immunoglobulin replacement. Kaplan–Meier estimate of event-free survival (EFS) and overall survival (OS) of patients. The results presented here are, therefore, extremely encouraging for a group of patients who normally have a very poor clinical outcome, and support the notion, as suggested by Evens et al (2008), of an early consolidative autologous SCT for these patients. This approach is well tolerated and could be applied to even older patients.