Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
