Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol

Abstract

Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P ‫؍‬ .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [ IntroductionAcute lymphoblastic leukemia (ALL) in infants (up to 1 year of age) is known to be biologically different from ALL in older children diagnosed with ALL. ALL in infants is more often associated with a higher tumor load at diagnosis, 1,2 a rearrangement in the mixed lineage leukemia (MLL) gene, and very immature B-cell phenotype (pro-B ALL) without CD10 expression. 1-3 Infant ALL cells are more resistant to several standard chemotherapeutic agents, 3,4 and the disease is also characterized by a poorer prognosis compared with older children. [5][6][7][8][9][10][11][12][13][14] Congenital ALL is diagnosed at birth or within the first month of life and is very rare. Although it is assumed to be inevitably fatal and the toxicity of the chemotherapeutic agents in these very young infants is unclear, to the best of our knowledge, no series have been published on congenital ALL except for case reports. Bresters et al 15 reviewed 24 patients with congenital ALL diagnosed over 25 years who were described in case reports: all patients died.We recently reported the results of a large international collaborative trial, Interfant-99, in infants younger than 1 year with ALL. 14 Here, we detail the outcome and characteristics of 30 patients with congenital ALL who received uniform therapy with curative intent. Methods PatientsThe Interfant-99 trial design, the inclusion criteria, and recruitment methods have been published earlier. 14 Individual study groups obtained ethics approval from all participating institutions, and patient informed consent was obtained in accordance with the Declaration of Helsinki. Of the 518 infants diagnosed with ALL, which account for approximately 3% of the ALL population, 35 patients were younger than 1 month, confirming the rarity of congenital ALL (ϳ 2 children per every 1000 with ALL). The present study reports on 30 cases that were treated with Interfant-99 (Figure 1). ProceduresEnrolled patients were stratified into standard-risk and high-risk groups on the basis of their response to 1 week of daily systemic prednisone (at a dose of 60 mg/m 2 ) and 1 intrathecal dose of methotrexate. Patients were classified as standard risk if their peripheral bloo...

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

“…2,7 There was no difference in median age at diagnosis between primary RAS mutationnegative MLL-rearranged infant ALL patients (3.8 months; range 0.0-11.5 months) and the RAS-mutated group (5.3 months; range 0.8-11.8 months) (P=0.89). Likewise, RAS mutations did not seem to affect disease latency when we analyzed t(4;11)-positive infant ALL patients alone.…”

“…3,5 Moreover, in MLL-rearranged infant ALL, short disease latency is strongly associated with a poor clinical outcome. 2,7 Collectively, these inconsistencies form the basis of the question whether MLL fusion proteins (like MLL-AF4) alone are sufficient to induce ALL, or whether these chimeric proteins require co-operative genetic lesions. Bursen et al recently found that not MLL-AF4 but its reciprocal fusion protein AF4-MLL (independent of the presence of MLL-AF4) was capable of inducing pro-B ALL in mice, suggesting that in t(4;11)-positive ALL both fusions may function as co-operative oncoproteins.…”

Congenital Acute Lymphoblastic Leukemia: A Rare Presentation in a One Month Old Boy

“…My index case expired on the second day of chemotherapy possibly because of leukostasis, coagulopathy or DIC. Two year event free survival and survival of CALL patients treated on the Interfant-99 protocol was 20% [41] but in comparison the outcome of our index case is very much poor because of limited number of case and the baby expired on the day second of chemotherapy.…”

Congenital Acute Leukemia: A Rare Hematological Malignancy

“…Combination chemotherapy can achieve remission induction rates in congenital AML similar to those in older infants and children. In congenital ALL, induction failure rates are not significantly different from older infants [3,4]. Herein we report two cases of congenital acute leukemia who presented to our tertiary care hospital.…”