HCL Meeting 2010
weekly doses of rituximab 375 mg/m2. Bone marrow examination was conducted prior to the initiation of therapy, 1 month after cladribine prior to the initiation of rituximab, and after the completion of treatment with rituximab to assess for any evidence of MRD by flow cytometry and consensus primer PCR (Figure 1). We elected to allow the inclusion of patients with the variant form of the disease (HCLv), a group previously reported to be resistant to therapy with the nucleoside analogs [9]. To date, we have treated 43 patients with HCL,
including 31 patients with newly diagnosed disease, five with HCLv, and seven with relapse after one prior therapy (which included cladribine in six patients and chlorambucil in one patient). All 43 patients have achieved CR after the completion of treatment with rituximab. With a median follow-up of 26 months (range, 5–68), the median CR duration has not been reached (range, 3–66 months), and only one patient (with HCLv) has relapsed. This patient was the only one dying from disease-related causes; two others died from unrelated malignancies (meta- static lung cancer and pancreatic cancer). There was no severe, or unexpected, toxicity and
no grade 3 and 4 non-hematological toxicity related to therapy. Fourteen patients had 17 episodes of reversible grade 3 and 4 infections including neu- tropenic fever, cellulitis, and herpes zoster. Other adverse events were grade 1 and 2 and included nausea, rash, fatigue, weight loss, and fever. Although there was a significant decline in the number of CD4 lymphocytes and immunoglobulin G after the treatment in all patients, this was not associated with a significant increase in the incidence of opportunistic infections.
Monitoring minimal residual disease
Using multiparameter flow cytometry, MRD was positive in 89% of evaluable patients in bone marrow specimens obtained approximately 1 month after therapy with cladribine, and became negative in 76% of evaluable patients after the completion of treat- ment with rituximab. MRD by consensus primer PCR was positive in 62% of evaluable patients after treatment with cladribine and became negative in 71% of evaluable patients after rituximab. Specimens for the evaluation of MRD by flow cytometry were
73
available in selected patients during the follow-up period and have remained negative in the majority. In the rare instances of conversion from a negative to a positive, this has not been associated with a morphological relapse.
Discussion
Rituximab is a monoclonal antibody against the pan- B cell antigen (CD20), which is brightly expressed on the surface of hairy cells. Several prior reports have demonstrated the significant but limited activity of rituximab in patients with relapsed and newly diagnosed HCL [10]. The relatively low toxicity of rituximab makes it an ideal agent for the potential eradication ofMRDin the post-response setting, and a number of trials in other low-grade lymphoproli- ferative neoplasms have clearly demonstrated its potential role in extending relapse-free survival [11]. The main concern when combining rituximab with nucleoside analogs has been whether the combination will lead to an increase in the extent of immunosuppression that is already well-character- ized with therapy with cladribine and pentostatin. However, prior experience in chronic lymphocytic leukemia (CLL) and follicular lymphoma has de- monstrated the safety of this approach. In the present trial, we have demonstrated the
Figure 1. Treatment schema. BM, bone marrow; C, cladribine; R, rituximab.
feasibility, safety, and high efficacy of the combination of cladribine followed by rituximab. Of significant interest is the achievement of CR by all patients with HCLv, suggesting a potentially important strategy in this group of patients who are typically resistant to nucleoside analogs. Prior anecdotal reports have previously suggested the efficacy of rituximab in treating this disease [12]. With a median follow-up of 26 months (range, 5–68), no patient withHCLand only one patient with HCLv has relapsed, suggesting the potential durability of these responses. However, in view of the recent reports suggesting the persis- tence of MRD or even morphologically detectable bonemarrow disease in patients alive and well several years after the initiation of therapy, a major socio- economic consideration that needs to be considered is whether all patients with newly diagnosed disease should be treated with the combination. Recent reports have identified patients with HCL with unmutated immunoglobulin heavy chain variable gene (IGHV) and those with VH4-34 IGHV gene rearrangement as being more likely to have a suboptimal response and shorter CR duration after initial therapy with cladribine [13,14]. An alternative strategy would be to target only these and other patients identified as having a high risk for relapse by pretreatment characteristics for the combination chemo-immunotherapy.
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