Examining The Range of Therapy for Elderly Patients with Hematological Malignancy

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: The management of acute myelogenous leukemia in elderly patients has been challenging and there has developed a pervasive pessimism about the role of chemotherapy in management. Two recent reports may counter this with demonstration of a benefit for induction chemotherapy and, in selected cases, both efficacy and safety of stem cell transplantation using nonmyeloablative conditioning.

Sources: Baz R, et al. Cancer. 2007;110:1752-1759; Falda M, et al, for the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Am J Hematology. 2007; 82:863-866.

Malignant disease occurring in older people is not, in general, more resistant to treatment but the presence of comorbidities and functional impairments may preclude the application of effective treatment.1 A notable exception to this is acute myelogenous leukemia, the successful treatment of which is markedly reduced in the elderly, even when standard chemotherapy is administered.2 This may be because the disease is quite different in older patients with more frequent antecedent myelodysplasia and acquired genetic mutations rendering cells resistant to treatment.3 In a wide range of clinical protocols employing chemotherapy combinations of varying intensity a common thread has been a low response rate and high treatment related mortality.4,5 In fact, some have questioned the value of chemotherapy in this setting compared with supportive care alone.6 In one study conducted nearly two decades ago newly diagnosed patients over the age of 65 were treated with daunorubicin, vincristine and cytarabine or supportive care alone and the modest benefit for treated patients in terms of overall survival (10 weeks) was almost entirely spent in the hospital.7 In a separate trial, Tilly and colleagues compared less intense chemotherapy (low-dose cytarabine) vs standard induction chemotherapy (daunorubicin and cytarabine) only to find no statistically significant survival difference between the 2 groups (median survival 8.8 months in the nonintensive chemotherapy group vs 12.8 months in the induction chemotherapy group). As with the prior study, those receiving the more intensive therapy had more time in the hospital and also required more transfusions and sustained greater treatment-related mortality.8

Although there has not been a significant change in standard chemotherapy approaches to AML over the past two decades, there have been significant advances in supportive care. Furthermore, with the rapidly aging population the issue of optimal approach to aggressive hematological malignancy has resurfaced as a critical domain for clinical research. Accordingly, two recent publications are of interest.

Baz and colleagues from the Cleveland Clinic performed a retrospective review of AML patients 60 years and older evaluated and/or treated at their Center. Forty-four patients who, for one reason or another, did not receive induction chemotherapy were matched as best possible (by propensity analysis) to 138 patients who received an anthracycline-based regimen. The unadjusted median survival of patients who did not receive induction chemotherapy was 53 days, compared with 197 days (P < 0.001) for those who did. Upon adjusting for age, gender, race, leukocyte count at presentation, cytogenetic changes, history of prior hematological disorder, and comorbidities, not receiving induction chemotherapy was still associated with worse survival (hazard ratio [HR] of 1.88; 95% confidence interval [CI] 1.15-3.05, P = 0.01). The authors conclude that for older adults with AML, treatment with induction chemotherapy is associated with improved outcomes.

The second report was that of an Italian multicenter group (Gruppo Italiano Trapianto Midollo Osseo, GITMO) who treated a total of 32 patients over the age of 60 years (median age 62 years, range 60-70) with hematological malignancy with nonmyeloablative allogeneic stem cell transplantation. The great majority of these patients had either AML or myelodysplastic syndrome. Treatment consisted of fludarabine (30mg/m2 x 3-5 days) and 200 cCy total body irradiation (TBI) followed by hematopoietic stem cell transplantation (HSCT) from a matched-sibling donor. Neutrophil recovery occurred in all patients at a median time of 16 days (range 9-34 days) and by day 30, 10 patients had > 95% donor chimerism and 19 patients had mixed chimerism. Transplant-related mortality at 100 days and at 1 year was 6% and 10% respectively. The probabilities of 2-year overall survival (OS) and progression-free survival (PFS) for patients with early disease were 77% and 64% respectively. However, for those who were transplanted with advanced stage disease, none were alive at 2 years.

Commentary

The data from these two articles are far from conclusive with regard to management of elderly patients with AML or other advanced hematological malignancy. Nonetheless, they support an evolving intensified effort to define optimal management for those patients in this age group. Notable in this regard is that those patients who received treatment (median age 68 years in the Cleveland Clinic study and 62 years in the Italian study) might not reflect the typical leukemic patient in the community, who is likely to be older and have more comorbidities than those included herein.

Yet, it appears that older patients (Cleveland Clinic study) benefit from induction therapy and that selected patients in the 60-70 year age group without a large tumor burden from nonmyeloablative HSCT (GITMO). These findings would have been unlikely two decades ago and probably speak to the advances in supportive care, including better antibiotics, the use of growth factors, attention to nutrition and, for the case of HSCT lower dose preparative regimens and better prevention and treatment of graft vs host disease.

The bottom line is that we still have a lot to learn about the management of leukemia in the elderly. Nonetheless, these reports are encouraging, and provide rationale for continued investigation to define optimal treatment strategies. Furthermore, we now have ammunition (albeit limited) to combat the pervasive therapeutic nihilism that had settled in on the basis of those investigations of two decades ago.

References

1. Balducci L, Ershler WB. Nat Rev Cancer. 2005;5(8):655-662.

2. Kantarjian H, et al. Cancer. 2006;106(5):1090-1098.

3. Lancet JE, et al. Hematol Oncol Clin North Am. 2000;14(1):251-267.

4. Stone RM, et al. Cancer and Leukemia Group B. N Engl J Med. 1995;332(25):1671-1677.

5. Stone RM, et al. Blood. 2001;98(3):548-553.

6. Sekeres MA, et al. Leukemia. 2004;18(4):809-816.

7. Lowenberg B, et al. J Clin Oncol. 1989;7(9):1268-1274.

8. Tilly H, et al. J Clin Oncol. 1990;8(2):272-279.