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Older patients with ALL can tolerate, benefit from intensified chemotherapy
An intensified chemotherapy regimen improved outcomes for older adults with acute lymphoblastic leukemia, according to phase 2 study results.
“Outcomes for patients with ALL aged older than 50 years have traditionally been poor, with a 5-year survival of less than 20%,” Karen K. Ballen, MD, professor of medicine at Harvard Medical School and director of the leukemia program at Massachusetts General Hospital, told HemOnc Today. “Our center has been studying pediatric-inspired treatment regimens in younger patients, and this study in older patients uses a modified regimen from the younger adult experience for older patients.”
Karen K. Ballen
Younger adult patients with ALL have benefitted from the use of pediatric-inspired treatments — which include high doses of asparaginase, corticosteroids, vinca alkaloids and aggressive central nervous system prophylaxis — as opposed to treatment with traditional adult regimens.
Ballen and colleagues enrolled 30 adults (median age, 58 years; range, 51-72; 60% men) with newly diagnosed ALL in a trial investigating a multiagent treatment regimen. All but one patient had B-cell ALL; the remaining patient had T-cell ALL. Forty percent of the cohort (n = 12) had Philadelphia chromosome–positive ALL
Induction therapy consisted of IV vincristine (2 mg on days 1, 8, 15 and 22), prednisone (40 mg/m2 per day; days 1-21 for patients < 60 years; days 1-7 for patients 60 years), doxorubicin (30 mg/m2 per day on days 1 and 2) and pegylated asparaginase (500 units/m2 on day 7).
Patients with Ph+ALL were assigned 400 mg of imatinib (Gleevec, Novartis) beginning on day 14, and did not receive asparaginase.
The first consolidation incorporated clofarabine (Clolar, Genzyme/Sanofi) into the treatment regimen.
Patients in remission after the first consolidation could proceed to allogeneic hematopoietic cell transplantation (HCT). Those who did not received CNS therapy, second consolidation and continuation therapy.
OS at 1 year served as the primary endpoint.
All patients received induction chemotherapy, with 17 patients continuing on to the first consolidation. Seven patients received CNS therapy and four patients received second consolidation therapy. Two patients continued to continuation therapy.
Nineteen patients achieved a complete remission after induction therapy, with an additional patient achieving remission after first consolidation, for an overall response rate of 67%.
Ten patients who achieved complete remission had Ph+ALL.
One patient died of an infection during induction. Five patients became refractory to induction chemotherapy. Four patients chose to discontinue treatment due to adverse events, three of whom died.
Nineteen patients (63%) remained alive at 1 year, which met the study’s predefined primary endpoint. After a median follow-up of 27.4 months, the cohort had a 2-year OS rate of 52% (95% CI, 33-68).
Sixteen patients proceeded to allogeneic HCT, with a median time to transplantation of 3.3 months (95% CI, 2.6-9.7). Undergoing transplantation did not significantly affect 2-year OS (transplantation vs. no transplantation, 65% vs. 53%).
“A surprising but pleasant outcome was that survival was better than historical controls,” Ballen said. “Transplant did not impact survival, although those numbers were very small.”
The 2-year EFS rate was 33% (95% CI, 18-50), and the 2-year DFS rate was 52% (95% CI, 28-72).
Ten patients subsequently relapsed, three of whom had Ph+ALL.
Eight patients experienced grade 3 or grade 4 hyperbilirubinemia, which limited or delayed further therapy. Three patients who developed hyperbilirubinemia prior to first consolidation had a complete reversal of liver toxicity and eventually underwent HCT off protocol. The liver toxicity was thought due to high doses of asparaginase, which were decreased in a protocol amendment.
The researchers acknowledged limitations of their study, including the fact that on-study changes in asparaginase dosing and administration affected their ability to interpret outcomes. Additionally, they noted that the role of clofarabine remained unclear because the majority of patients who received the agent proceeded to HSCT.
“Older patients can tolerate and have good outcomes with this modified chemotherapy regimen,” Ballen said. “We are now studying the ways to improve the complete remission rate by adding oral proteasome inhibitors to the induction and consolidation regimens. The question of transplant in first remission should be studied in a larger cohort.” – by Cameron Kelsall
For more information:
Karen K. Ballen , MD, can be reached at kballen@partners.org.
Disclosure: Genzyme and Sigma Tau funded this study. Ballen reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.