To the editor:

Gupta et al1  concluded that young adult patients with acute lymphoblastic leukemia (ALL) aged 15 to 35 years should be treated in first remission with allogeneic transplant. They based their judgment on a meta-analysis of 13 studies, each of which had a control regimen used historically for adult patients, such as hyper-fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone, as the comparator. Although they did state that “… several groups have reported good outcomes of standard risk adult ALL patients treated with pediatric-inspired chemotherapy protocols,” we submit that this acknowledgment should be the crux of a different conclusion rather than a passing comment.

Table 1 lists outcomes from multiple adult and pediatric studies in North America and Europe that treated adolescent and young adult ALL patients. When comparing survival of patients treated using a regimen from an adult-based consortium with either a pediatric consortium or an adult consortium utilizing a pediatric-inspired regimen, the results achieved were not only substantially improved, but better than those achieved with blood and bone marrow transplant.2-10  Comparisons of similar aged patients treated using pediatric vs adult protocols are shown for the first 5 countries listed in Table 1. In France, 15- to 20-year-old patients treated using the pediatric FRALLE-93 protocol had complete remission induction of 94% and a 5-year event-free survival (EFS) of 67% compared with 83% and 41%, respectively (P = .04 and <.0001), using the adult LALA-94 protocol. In the United States, 16- to 20-year-old patients had a superior 7-year EFS of 63% on Children’s Cancer Group (CCG) trials compared with 34% on Cancer and Leukemia Group B trials (P < .05). In subsequent trials, CCG investigators reported a 5-year EFS of 71.5% for patients aged 16 to 21 years. In the United Kingdom, 15- to 17-year olds had a 5-year EFS of 65% on the pediatric ALL87 trial but only 49% using the adult UKALLXII/E2993 regimen (P = .01). In The Netherlands, 15- to 18-year olds had a 5-year overall survival of 79% and 38% using pediatric and adult study group treatment regimens, respectively. Analogous differences between pediatric and adult treatment regimens in adolescent and young adult ALL patients have been reported from Sweden, Mexico, and a third group in France (references available upon request).

Table 1

Outcomes for adolescent and young adult patients treated with pediatric-based vs adult-based treatment protocols

CountryClinical trials, pediatric/adultAge range, ySurvival: E or DOverall survival
Pediatric regimenAdult regimenPediatric regimen/Adult regimen
United States2  CCG*/CALGB 16-21 E: 63% at 7 y E: 34% at 7 y 67%/46% at 7 y 
United States3 * CCG100 series 16-21 E: 72% at 5 y 
France4  FRALLE93*/LALA94 15-20 D: 68% at 6 y D: 32% at 4 y 78% at 6 y/45% at 4 y 
France5  GRAALL 2003 15-60 E: 55% at 4 y 58% at 4 y/ 
Great Britain6  ALL97*/UKALLXII 15-17 E: 65% E: 49% at 5 y 71% at 5 y/56% at 5 y 
United Kingdom7  MRC UKALLX, Xa/ 15-20 D: 35% at 5 y 60% at 5 y/ 
The Netherlands8  DCOG*/HOVON 15-18 E: 69% at 5 y E: 34% at 5 y 79% at 5 y/38% at 5 y 
Spain9  /ALL96 14-18   /71% at 2 y 
Italy10 * AIEOP ALL95, 2000/ 14-18   80% at 2 y/ 
CountryClinical trials, pediatric/adultAge range, ySurvival: E or DOverall survival
Pediatric regimenAdult regimenPediatric regimen/Adult regimen
United States2  CCG*/CALGB 16-21 E: 63% at 7 y E: 34% at 7 y 67%/46% at 7 y 
United States3 * CCG100 series 16-21 E: 72% at 5 y 
France4  FRALLE93*/LALA94 15-20 D: 68% at 6 y D: 32% at 4 y 78% at 6 y/45% at 4 y 
France5  GRAALL 2003 15-60 E: 55% at 4 y 58% at 4 y/ 
Great Britain6  ALL97*/UKALLXII 15-17 E: 65% E: 49% at 5 y 71% at 5 y/56% at 5 y 
United Kingdom7  MRC UKALLX, Xa/ 15-20 D: 35% at 5 y 60% at 5 y/ 
The Netherlands8  DCOG*/HOVON 15-18 E: 69% at 5 y E: 34% at 5 y 79% at 5 y/38% at 5 y 
Spain9  /ALL96 14-18   /71% at 2 y 
Italy10 * AIEOP ALL95, 2000/ 14-18   80% at 2 y/ 

D, disease-free survival; E, event-free survival.

*

Pediatric oncology organization.

Adult oncology organization.

In addition, when adult study groups have used pediatric-inspired therapy, improvements in outcome have been noted. In Spain, 14- to 18-year olds treated using a pediatric-inspired protocol by the adult consortium had a 2-year overall survival of 71%. In addition, a comparison of patients treated by the pediatric and adult study groups in Finland revealed a 5-year EFS of 67% and 60%, respectively, a difference that was not statistically significant.11  Of note, the Finnish Leukemia Group utilizes therapy that is similar to the pediatric Nordic (NOPHO) study group in Finland, illustrating the benefit of evolving toward pediatric-inspired therapy.

By limiting their control studies to those that used chemotherapy regimens derived from prior adult studies, Gupta and colleagues may be correct in concluding that blood and bone marrow transplant is superior to chemotherapy alone. However, at least for adults up to the age of 40 or 50 years, the appropriate comparator has become the pediatric-inspired regimen. Therefore, we stress that the more appropriate conclusion to be drawn is the importance of using more effective, conventional, pediatric-inspired ALL treatment regimens in the adolescent and young adult population, rather than the clearly suboptimal regimens historically used for adults. Barring other specific risk factors portending a poor prognosis, when pediatric-based therapy is used for this population, the case for using blood and bone marrow transplant in first remission is far less compelling.

Contribution: M.S.I., D.R.F., and A.B. contributed equally to the writing of this manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Michael S. Isakoff, Center for Cancer and Blood Disorders, Connecticut Children’s Medical Center, 282 Washington St, Hartford, CT 06106; e-mail:[email protected].

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