Treatment of ALL in the Elderly
ABSTRACT & COMMENTARY
By William B. Ershler, MD
Synopsis: Experience treating acute lymphoblastic leukemia in the elderly using pediatric full-dose regimens has met with high rates of toxicity and induction-related mortality. Recognizing this, Martell and colleagues at the Princess Margaret Hospital in Toronto modified the standard pediatric-based protocol to reduce anticipated toxicity. Analysis of 51 patients treated on the modified regimen was associated with an excellent complete remission rate (75%) and overall survival at 5 years. Yet, induction-related mortality remained high at 20%. Thus, the modified protocol represents a step forward but further adjustments will be required to optimize treatment outcomes.
Source: Martell MP, et al. Treatment of elderly patients with acute lymphoblastic leukemia using a pediatric based protocol. Br J Haematol 2013;163:458-464.
Much has been written about the treatment of acute myelogenous leukemia in the elderly but considerably less about acute lymphoblastic leukemia (ALL). Yet, approximately 30% of all ALL occurs in adults over the age of 60 years,1 and the treatment successes documented for younger patients has not resulted in enhanced survival for this subset.2-4 It has been speculated that a higher frequency of comorbidities and impaired functional status often limit dose, appropriate scheduling, or even utilization at all of effective chemotherapy. Furthermore, established ALL adverse prognostic factors have been demonstrably worse in elderly patients.3,4
Improved outcomes in younger adult ALL patients have been largely attributed to the widespread adoption of pediatric-based protocols, including intensification of certain drugs such as corticosteroids, vinca alkaloids, and asparaginase, and adhering strictly to the treatment schedule. The applicability of such intense protocols has been questioned for older patients in light of anticipated toxicity. For example, Brandwein and colleagues reporting the 11-year experience in treating ALL in those ≥ 60 years at the Princess Margaret Hospital found a 56% complete remission (CR) rate with 27% induction-related mortality rate in those receiving multiagent chemotherapy.5 Further, the median overall survival was 9 months, while the median progression-free survival (PFS) for those achieving CR was 10 months. These authors concluded that aggressive induction regimens designed for younger patients proved very toxic in the elderly and suggested the investigation of less aggressive regimens in older patients.
In the current report, this group at the Princess Margaret Hospital now retrospectively report their experience with a modified-for-age protocol for older patients. Over a 7-year period, all newly diagnosed ALL patients aged 60-79 years received induction chemotherapy with a dose- and drug-adjusted pediatric-based regimen (n = 51, median age 65 years). As with the standard pediatric protocol (DFCI 91-01), the treatment regimen consisted of induction, central nervous system prophylaxis, seven cycles of intensification, and 24 cycles of maintenance. However, the standard protocol was modified by substituting pulse dexamethasone for daily prednisone, reducing methotrexate dose from 4 g/m2 to 40 mg/m2, reducing asparaginase dose from 25,000 IU/m2 to 12,000 IU/m2, and removing one vincristine dose. BCR-ABL positive patients were given imatinib 400 mg daily for 16 days instead of asparaginase. In the CNS prophylaxis phase, cranial radiation was removed. In the intensification phase, seven cycles were given instead of 10, the cumulative dexamethasone dose was reduced by approximately 75%, and the cumulative asparaginase dose reduced by 66%, compared to the full regimen. In the maintenance phase, parenteral methotrexate was switched to oral, and the dexamethasone dose was reduced from 6 mg/m2 to 6 mg. For patients who developed progressive grade ≥ 2 neuropathy, intravenous vinblastine 10 mg was substituted for vincristine. For patients with low left ventricular ejection fraction, amsacrine 75 mg/m2 was substituted for doxorubicin.
The complete response rate was 75%, with an induction mortality of 20%; 6% of patients had resistant disease. Thirty-seven percent of patients who achieved a complete remission relapsed. The estimated 5-year overall survival was 40% for BCR-ABL negative and 47% for BCR-ABL positive patients; the 5-year disease-free survival was 57% and 39%, respectively (P = NS). The post-induction phase was generally well tolerated, with 81% able to complete the intensification phase and proceed to maintenance.
This report on the treatment of older adults with ALL is of great interest and represents a step forward in achieving optimal management for this subset of patients. The prior application of the more aggressive DFCI or comparable regimens resulted in unacceptable induction-related mortality rates and relatively low survival numbers as detailed in their prior report.5 The modified protocol, using basically the same metrics, proved significantly better, including a CR rate of 75% and an estimated disease-free survival at 5 years of 40% and 47% for BCR-ABL negative and positive patients, respectively. Yet, induction mortality remained quite high (20%), indicating a continued need for exploration of treatment regimens, particularly during the early phase.
The patients included in the current report had been referred to the Princess Margaret Hospital for treatment and the authors mention that only two otherwise eligible patients were excluded because of comorbidities. There is concern that the study population may not reflect typical elderly ALL patients, many of whom are not referred to academic centers but are treated in the community. Thus, the current report may help guide ALL treatment for otherwise well elderly, but there remains much to be learned on optimal management for those more frail. This will become increasingly relevant as older patients tend to be managed in the community rather than referred to academic centers, and the numbers of such patients are expanding dramatically. n
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- Sancho JM, et al. Eur J Haematol 2007;78:102-110.
- Sive JI, et al. Br J Haematol 2012;157:463-471.
- Brandwein JM, et al. Leuk Res 2005;29:1381-1386.