Ask the Hematologist January-February 2006

What are the best options for the treatment of a patient with relapsed mantle cell lymphoma?

A 63-year-old male had been otherwise healthy until he noticed some left cervical lymphoadenopathy. After no improvement on antibiotics, the patient was referred for an excisional lymph node biopsy, which revealed a monotonous population of small lymphoid cells. The immunophenotype revealed the cells to be positive for CD20, CD5, bcl-2, and Cyclin D1, and negative for CD3, CD23, with a MIB-1 index of about 60 percent, consistent with mantle cell lymphoma (MCL). CT scans revealed diffuse adenopathy above and below the diaphragm, with some sites of retroperitoneal disease measuring up to 5 cm in greatest transverse diameter. A bone marrow biopsy revealed involvement by MCL, and an upper endoscopy and colonoscopy with random biopsies were both negative. He was treated with six cycles of conventionally-dosed and scheduled R-CHOP-based chemotherapy, achieving a PR by CT after four cycles, with mild persistent PET avid disease. He was referred for an ICE-based peripheral blood stem cell transplant, achieving a PET negative CR at the end of his ICE-based treatment. Unfortunately, approximately 27 months post transplant, he developed recurrent hilar adenopathy incidentally noted on a re-staging CT scan in the chest. A CT-guided biopsy of one lymph node revealed relapse of his MCL.

Typically, one should start by asking three fundamental questions: (1) Is the patient a candidate for allogeneic stem cell transplant? (2) Is the patient a candidate for a clinical trial? (3) Is the patient a candidate for additional systemic chemotherapy?

Allogeneic hematopoietic cell transplantation for MCL is rapidly emerging as a very promising treatment for patients with relapsed MCL. Recently, Maris et al. published their results on 33 patients (16 receiving HLA-matched related and 17 receiving matched unrelated transplants) receiving a nonmyeloablative conditioning regimen with fludarabine and 2 Gy total body irradiation. Of the 33 patients, 31 had stable engraftment, while two experienced non-fatal graft rejections. The incidence of acute grades II, III, and IV graft-versus-host disease (GVHD) was 27 percent, 17 percent, and 13 percent, respectively, while 64 percent of patients experienced chronic GVHD. At two years, the relapse and non-relapse mortalities were 9 percent and 24 percent, respectively. The overall response rate in the 20 patients who had measurable disease at the time of HCT was 85 percent, with a 75 percent complete remission rate. Perhaps even more promising is the Kaplan-Meier probabilities of overall and disease-free survival at two years, which were 65 percent and 60 percent, respectively. Clearly, MCL is emerging as one sub-type of lymphoma where a significant graft-versus-lymphoma effect exists, though future trials will need to focus on how best to reduce the acute and chronic GVHD. Alemtuzumab, a CD52 targeted monoclonal antibody, may offer a unique opportunity to reduce the incidence of GVHD, though several studies have shown that it may also compromise the graft-versus-lymphoma effects as well. Future studies will obviously focus on how best to reduce transplant-related morbidity and mortality without adversely affecting efficacy.

Once a patient with MCL has relapsed, enrollment on a clinical trial becomes our highest priority. We typically use Phase I and II clinical trials as a bridge to other treatment programs, which oftentimes can give us an opportunity to employ novel non-cross resistant agents to control disease, while HLA-typing and the appropriate consultations can occur for consideration of possible allogeneic stem cell transplantation. Fortunately, there are a number of exciting and promising new drugs being developed, many of which appear to have activity in the treatment of mantle cell lymphoma. One such agent, bortezomib, a unique first in its class of drugs capable of inhibiting the proteasome, appears to have promising activity across several clinical trials in MCL, with overall response rates of approximately 40 percent. Bortezomib has recently received a compendium listing for the treatment of MCL. Other promising new agents include the mTOR inhibitor temsirolimus (CCI-779). Witzig and colleagues recently presented data demonstrating that temsirolimus had an overall response rate of 38 percent with a median time to progression in responders of 6.9 months. A host of other promising agents are also being studied in MCL, including agents that target bcl-2-like oblimersen, novel alkylating agents like bendamustine, the IMIDs-like thalidomide and its derivatives, and radioimmunotherapies like Zevalin and Bexxar. Because there is such an urgent need to identify promising new drugs for MCL, we believe every effort possible should be made to integrate a clinical trial in the management of this disease as early as possible.

Unfortunately, after a patient relapses with MCL, there is little to no consensus regarding the next best line of treatment. Historically, because these diseases have been managed like other small lymphocytic lymphomas, purine analogs have been integrated into the second and third line management of patients with MCL. Single agent fludarabine is typically not a very active drug in MCL with an overall response rate of approximately 30 percent, with no complete remissions, and typically short durations of remission. Regimens that combine fludarabine with other drugs active in MCL appear slightly more promising, however. Forstpointner et al. recently published on the use of a fludarabine, cyclophosphamide, mitoxantrone, and rituximab (R-FCM)-based treatment program in the treatment of relapsed MCL. These authors demonstrated rituximab markedly improved both the overall response rate (58 vs. 79 percent), the CR rate (13 percent vs. 33 percent), and the overall survival in patients with MCL. Other treatment programs that may have reasonable palliative benefit include ICE; infusional chemotherapy programs like EPOCH or HyperCVAD (which may have excessive toxicity in this setting); 2-chlorodeoxyadenosine; oral chemotherapy-based approaches with agents like etoposide, cyclophosphamide, procarbazine, and prednisone (oral CEPP); or even single agent cyclophosphamide +/- rituximab. Unfortunately, single agent rituximab in these patients tends to be associated with very poor response rates, with short durations of remission.

The patient's overall status tends to govern the selection of the least toxic regimen. This patient was enrolled in an NCI-sponsored Phase II study of bortezomib for patients with indolent and MCL. He achieved a partial remission that lasted over 19 months. He was re-treated with a second course of therapy, to which he attained a second PR which lasted approximately another seven to eight months. Interestingly, he developed a vasculitic rash, which, based on a review of collected cases, seems to portend a response to treatment. Most recently, he has relapsed after being maintained on bortezomib for nearly two years, and has been successfully induced into a complete remission with cyclophosphamide (1000 mg/m² ) and rituximab administered on an every-other-week basis with Neulasta. The development of new agents, integrated into the use of active conventional programs for the treatment of MCL, can afford treating physicians unique opportunities to control this disease, and, hopefully, build time from their last conventional therapy. These strategies can give patients meaningful quality of life and hope, while giving us an opportunity to learn more about how to treat this challenging disease.