Should young adults with ALL be treated as children?

In this issue of Blood, Stock et al report the results of a large multicenter phase 2 study that evaluated the use of a pediatric chemotherapy regimen to treat older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).¹ 

This Cancer and Leukemia Group B (CALGB) 10403 (Alliance) trial enrolled 295 evaluable patients age 16 to 39 years with Philadelphia chromosome–negative (Ph^–) ALL. The CALGB 10403 trial used the same chemotherapy regimen as that used in one of the arms for children with high-risk ALL in the randomized Children’s Oncology Group (COG) AALL0232 protocol.²  More precisely, the treatment used in this AYA trial was the same as the prednisone-Capizzi methotrexate treatment used for rapid early responders in the original COG protocol. Interestingly, because pediatric indications for allogeneic stem cell transplantation (SCT) in first complete remission (CR1) were retained, only 20 of the 263 patients who achieved a CR received allogeneic SCT in CR1. Consequently, the very good 59% (95% confidence interval [CI], 54%-65%) event-free survival and 73% (95% CI, 68%-78%) overall survival estimates at 3 years essentially reflect the effects of chemotherapy.

At the end of the twentieth century, it was generally accepted that the outcomes of adult ALL would remain markedly and indefinitely worse than those of childhood ALL. This was thought to be mostly a result of the lower incidence of good-risk ALL subsets and the higher incidence of high-risk ALL subsets in adults compared with children, a fact that has been documented more often in B-lineage cases.³  Between 2003 and 2008, 6 retrospective analyses from 6 different countries reported much better outcomes when using pediatric vs adult regimens in narrow age ranges of patients (ranging from 14 to 20 years old). It became evident that differences in biology might not explain everything and that differences in therapy might matter.⁴ 

Cooperative groups for adult patients with ALL then decided either to adapt pediatric regimen protocols by introducing their key components (as was done in the so-called pediatric-inspired protocols from the German Multicenter Study Group for Adult ALL, Italian Northern Italy Leukemia Group, French-Belgium-Swiss Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), and Spanish Programa Español de Tratamientos en Hematología groups) or to simply use an unmodified pediatric regimen (as in UKALL-2003,⁵  Nordic Group ALL2008,⁶  or CALGB 10403). The main differences between these 2 strategies were the upper age limit for eligibility, which was lower in trials using unmodified pediatric regimens (age 24-45 years) than in pediatric-inspired trials (age 55-65 years) and the rate of receipt of allogeneic SCT in CR1, which was usually higher in pediatric-inspired trials.

To date, the lack of randomized trials and the variability in all these regimens make it very difficult to determine which of these 2 strategies should be recommended. Likewise, we do not know what the upper age limit should be for AYAs treated with an unmodified pediatric protocol rather than a modern pediatric-inspired protocol. There are variations in treatment intensity in both adult and pediatric chemotherapy regimens. The word “pediatric” does not always mean chemotherapy of greater intensity. In this respect, one questions whether some patients treated in the CALGB 10403 study would have benefited from a more intensive regimen. The COG AALL0232 protocol included more intensive treatment arms for slow early responders. In the CALGB 10403 study, the therapy designed for rapid early responders was used in all patients, probably for safety concerns. Early minimal residual disease levels were not prospectively used for treatment intensification or allogeneic SCT indication in CR1, as is currently done in most European ALL protocols.

There is also uncertainty regarding the upper age limit for adults for using intensive pediatric or pediatric-inspired chemotherapy regimens that maintain treatment intensity with acceptable toxicity. This issue was retrospectively addressed in the GRAALL-2005 trial, in which the upper age limit was determined to be 54 years.⁷  Again, several factors may have had an impact on this age determination, including chemotherapy intensity, the rate of allogeneic SCT, the number of participating centers, and the learning curve for centers learning to administer complex multidrug and multiphase protocols.

In summary, the article by Stock et al confirms the value of intensifying chemotherapy in AYAs with Ph^– ALL. Stock et al note that the first-line introduction of antibody-based therapy in B-cell precursor ALL patients, kinase inhibitors in Ph-like ALL patients, and nelarabine in T-cell ALL patients provides exciting new opportunities for improving the outcome of adult ALL. Paradoxically, this might lead to a selective reduction of intensity as new combinations of chemotherapy and new agents are studied, as was the case with Ph⁺ ALL when tyrosine kinase inhibitors were introduced.⁸