Response-based therapy intensification improves prognosis in leukemia subgroup

Early response–based risk stratification and therapy intensification improved the prognosis for adults with early thymic precursor acute lymphoblastic leukemia, according to a study published in Journal of Clinical Oncology.

Early thymic precursor (ETP)-ALL — originally identified in pediatric cases and associated with a poor prognosis — is an immunophenotypical subgroup of T-cell ALLs, or malignant monoclonal proliferations of cells that exhibit developmental arrest at varying stages of differentiation and partially mirror normal T-lymphoid ontogeny.

“Recent survival data suggest that pediatric cases have a neutral prognosis in the context of minimal residual disease response–directed protocols, suggesting that the negative impact of early therapeutic resistance can be abrogated by timely treatment intensification,” Jonathan Bond, MD, PhD, post-doctoral clinical researcher at Hôpital Necker-Enfants Malades in Paris, and colleagues wrote. “Similar data in adults are lacking, and although ETP-ALL has been reported to have a poor outcome when treated using traditional regimens, prognostic analyses are both scarce and conflicting.”

Whether early intensification with chemotherapy or allogeneic stem cell transplantation might impact outcomes was unknown.

Researchers conducted comprehensive clinicobiologic, genetic and prognostic analyses of 213 adults with T-cell ALL from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)–2003 and –2005 studies. This group included 47 patients with ETP-ALL.

In the studies, adults received the pediatric treatment strategy of therapy intensification with allogeneic stem cell transplantation after early treatment resistance.

Analyses based on the gene-expression signature defined in children showed that the ETP and non-ETP groups formed distinct transcriptional clusters, and that adult and pediatric ETP-ALL have a similar genotype of immunophenotypically defined adult T-cell ALL.

In the targeted next-generation sequencing of available leukemic DNA from 172 patients, researchers found mutations in 89.2% of patients with ETP–ALL compared with only 63.7% of the non-ETP group (P = .03).

Compared with the non-ETP group, those with ETP-ALL had higher rates of mutations in factors involved in cytokine receptor and RAS signaling (62.2% vs. 37.8%; P = .008), hematopoietic development (29.7% vs. 11.9%; P = .008), chemical modification of histones (48.6% vs. 29.6%; P = .03) and mutation in PRC2 genes, (32.4% vs. 7.4%; P < .001).

However, mutations in DNA methylation factor genes also appeared common in adults (32.4%) — including DNMT3A, IDH1, IDH2, TET2, TET3 and WT1 — but were not detected at all in two large-scale studies of pediatric patients.

A greater proportion of patients with ETP–ALL experienced corticosteroid resistance (63.8% vs. 36.8%; P = .001) and early bone marrow chemotherapy resistance (87% vs. 33.7%; P < .001) than non-ETP patients.

However, both groups demonstrated similar 5-year OS (59.6% vs. 66.5%) and 5-year EFS (51.1% vs. 58.1%).

Allogeneic stem cell transplantation correlated with a trend toward better OS in those with ETP–ALL (HR = 0.36; P = .07), but not in the non-ETP group. Multivariable analysis demonstrated a significant interaction between ETP status and allogeneic stem cell transplantation (P = .034).

“Taken together, these results suggest that the implementation of allogeneic stem cell transplantation in first complete response confers a survival benefit that abrogates the negative effects of intrinsic therapeutic resistance in ETP–ALL,” the researchers wrote.

The researchers noted they were unable to test whether allogeneic stem cell transplantation benefitted patients with ETP achieving molecular remission; however, they hope to address this in the future.

“Additional studies should also determine whether outcomes may be further improved by treatments targeting pathways that are preferentially mutated in ETP–ALL (eg, JAK-STAT inhibition) or by the addition of nelarabine (Arranon, Novartis), which is being evaluated in our current study GRAALL-2014/T.” – by Kristie L. Kahl

Disclosure: Bond reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.