Recently an increasing number of therapies across a wide range of haematological cancers have been investigated in the elderly population. These have included rituximab in patients with chronic lymphocytic leukaemia (CLL) and diffuse large B-Cell lymphoma (DLBCL), dasatinib and imatinib in chronic myeloid leukaemia (CML), dasatinib in de novo Philadelphia positive acute lymphocytic leukaemia (Ph+ ALL) and lenolidamide in multiple myeloma (MM). The results of these trials were presented at ASH 2010.
Two of the largest trials ever conducted in patients with CLL have shown that the addition of rituximab to fludarabine plus cyclophosphamide (R-FC) significantly improves outcome. However, myelotoxicity and immunosuppression limit the use of this regimen in patients with impaired performance status and pre-existing co-morbidities, predominantly in the elderly. Chlorambucil (CLB) remains a first-line treatment option for such patients.
The use of CLB in combination with rituximab is an attractive therapeutic option in view of the potentially increased activity compared to CLB alone and the likely good tolerability. The interim results from a study designed to assess the rituximab-CLB combination in elderly patients with CLL were presented at ASH 2010.1 The data was based on the first 54 evaluable patients from 19 Italian centres, over half of whom were over the age of 70 years. The overall response (OR) was over 80%. Of the serious adverse events, only one was considered related to the treatment, and the most common toxicities were neutropenia and thrombocytopenia. No grade III-IV infections occurred. It was concluded that rituximab-CLB was active and well tolerated in elderly patients with previously untreated CLL.
A reduced dosage chemotherapy regimen associated with rituximab has also been investigated in elderly patients with DLBCL, where half of all cases occur in patients over 65 years but where few data are available for patients over 80 years.2 As these older patients seem to respond as equally well as younger patients when treatment is tolerated, the Groupe d'Etude Des Lymphomes De l'Adulte (GELA) decided to initiate a prospective, multicenter, phase II study in 2005 to evaluate treatment of this patient population. The study found that, in patients with a good performance status, immunochemotherapy with rituximab-mini-CHOP appeared to be safe and effective. The results indicated that a substantial proportion of very old patients could be cured. It was concluded that this regimen should be considered as a platform for the introduction of new drugs in the first line treatment of this patient population.
Although a phase III dose optimisation study has shown that dasatinib at 100 mg once daily improves its safety profile while maintaining efficacy versus the previously recommended dose of 70 mg twice-daily in patients with CML-CP, few data exist on the efficacy and safety of dasatinib in elderly patients. A study that investigated the impact of dose reduction on dasatinib efficacy in patients over the age of 60 years was presented at ASH 2010.3 The results showed that dasatinib, given at a lower dose than currently recommended, was still effective in elderly CML patients. However, it was recognised that closer molecular monitoring would be needed in this population.
Dasatinib has also been investigated in elderly patients with de novo Ph+ ALL. Based on the rapid and clinically meaningful activity observed when dasatinib was used as a single agent, a consensus was reached by the EWALL (European Working Group for Adult ALL) to conduct an international study evaluating the combination of dasatinib and low-intensity chemotherapy in patients with Ph+ ALL aged 55 years or more.4 The study results, which were presented at ASH 2010, showed that dasatinib combined with low-intensity chemotherapy was highly effective in these patients, with a 90% complete response (CR) and a 22.1 months relapse-free survival (RFS). Cytogenetics at diagnosis was found to be a strong predictive factor for RFS; most relapses were associated with the T315I mutation, which could be monitored serially so as to predict for haematological relapse and potentially offer an opportunity to adapt therapy before relapse.
A phase II explorative study in more than 78 elderly (≥ 65 years) patients with Ph + CML investigated the ability of 1 year of intermittent Imatinib (IM) treatment (InterIM) to maintain a complete cytogenetic response (CCgR) achieved after at least 2 years standard IM therapy (any dose between 300 and 800 mg/day).5 It was found that InterIM was sufficient to maintain the CCgR at 12 months in 84% of patient who had previously achieved a response with standard IM therapy and who had a 99% major molecular response at baseline. This regimen has the potential to offer older patients significant benefits in terms of dose reduction and cost of therapy.
The combination of melphalan-prednisone-lenalidomide (MPR) has shown promising results in elderly newly diagnosed myeloma patients. In the transplant setting, low-dose chemotherapy (induction) precedes high-dose chemotherapy (autologous transplantation consolidation). This approach reduces tumour mass, with few side effects, before achieving the maximum cytoreduction with autologous transplantation. The same approach has been designed for elderly patients. Accordingly induction with lenalidomide plus corticosteroids precedes consolidation with MPR. A two-stage phase II clinical trial evaluating the safety and efficacy of lenalidomide-prednisone (RP) as induction, followed by MPR as consolidation and lenalidomide as maintenance in elderly myeloma patients has demonstrated a manageable safety profile and reduced the risk of anaemia, thrombocytopenia and non-haematological toxicity.6
There is extensive evidence from numerous studies in the transplant setting that achievement of CR or at least very good partial response (VGPR) in myeloma patient is significantly associated with prolonged PFS and OS. In elderly myeloma patients CR was a rare event until new drugs were added to standard melphalan-prednisone (MP). Now CR represents an achievable goal, even outside the transplant setting. In a recent retrospective analysis of 1175 patients, CR predicted a significantly prolonged OS versus VGPR (p<0.001).7 Also, patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006). This analysis has highlighted the importance of CR outside of the transplant setting, regardless of age, International Staging System and treatment administered, and lends support to the use of new drugs in older patients so as to achieve and maintain maximal response to therapy.
1. R Foa, S Ciolli, F Di Raimondo et al A Phase II Study of Chlorambucil Plus Rituximab Followed by Maintenance Versus Observation In Elderly Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results of the First Interim Analysis Abstract 2462 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
2. F Peyrade, F Jardin, C Gisselbrecht et al Rituximab and Reduced Dose CHOP (R-mini-CHOP) for Patients Over 80 Years with Diffuse Large B-Cell Lymphoma (DLBCL) – Groupe d'Etude Des Lymphomes De l'Adulte (GELA) Study LNH03-7B Abstract 853 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
3. R Porrini, E Montefusco, R Latagliata et al Low-Dose Dasatinib as Front-Line Therapy for Elderly (> 60 Years) Patients with CML Abstract 2293 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
4. P Rousselot, JM Cayuela, S Hayette et al Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment In Elderly Patients with De Novo Philadelphia Positive ALL (EWALL-PH-01): Kinetic of Response, Resistance and Prognostic Significance Abstract 172 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
5. D Russo, G Martinelli, M Malagola et al One Year of Intermittent Imatinib (IM) Treatment (InterIM) Maintains the Complete Cytogenetic Response (CCgR) Previously Achieved with Standard IM Therapy In Elderly (≥ 65 years) Ph+ CML Patients – EudraCT Number 2007-005102-42, ClinicalTrials.Gov NCT 00858806 Abstract 3412 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
6. A Palumbo, P Falco, G Benevolo et al A Multicenter, Open Label Study of Oral Lenalidomide and Prednisone (RP) Followed by Oral Lenalidomide Melphalan and Prednisone (MPR) and Oral Lenalidomide Maintenance In Newly Diagnosed Elderly Multiple Myeloma Patients Abstract 1940 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
7. AF Gay, A Larocca, PW Wijermans et al Achievement of Complete Response Is a Strong Prognostic Factor In Elderly Newly Diagnosed Myeloma: Retrospective Analysis of 1175 Patients Abstract 1949 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.