Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial

Abstract

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.

NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target

“…Thus, the NPM-ALK chimeric protein is typically detected in the nucleus, nucleolus, and cytoplasm, whereas the majority of other ALK partners (TPM3, TPM4, TFG, ATIC, CTLC) are expressed in the cytoplasm whereas a localization in the periphery of the nucleus is noted in the RANBP2-ALK fusion protein, resulting from the association of the fusion protein with wild-type RANBP2 (a nuclear pore protein), and the moesin (MSN)–ALK fusion protein owing to the association of wild-type MSN and other membrane proteins [ 22 , 23 , 24 , 25 ]. Reverse transcriptase-PCR (RT-PCR) best defines the ALK status and detection using RT-PCR of early Minimal Residual Disease (MRD) positivity at diagnosis correlates with a very high relapse risk and lower survival in children with ALK(+) ALCL [ 26 , 27 , 28 , 29 ].…”

Minimal Disease Monitoring in Pediatric Non-Hodgkin’s Lymphoma: Current Clinical Application and Future Challenges

“…Detection of MDD by the qualitative NPM1–ALK -specific reverse transcriptase RT-PCR identifies patients with a significantly higher relapse risk compared to MDD-negative patients in several studies using BFM-type short-pulse chemotherapy [ 44 , 45 , 46 , 48 , 49 ]. The first report of the AIEOP study group detected MDD in BM of 61% of 52 patients at diagnosis.…”

“…These data were further validated in combined analyses establishing MDD in blood or BM as an independent prognostic factor, in addition to the histological subtype and ALK-antibody titers [ 46 , 48 ]. In an analysis of the long-term outcome and risk factors among all patients included in the ALCL99 study, only positive MDD measured by the NPM1-ALK -specific RT-PCR and the small cell/lymphohistiocytic (SH/LH) morphologic subtype were independently associated with the risk of relapse in multivariate analyses [ 49 ].…”

Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

“…In recent years, several biological features emerged as promising prognostic factors for the clinical management of pediatric ALCL, including non-common histology, minimal disseminated and residual disease and anti-ALK antibody titers [ 3 , 4 ]. Despite a continuous improvement in the field of ALCL prognostic stratification, the identification of new, non-invasive disease biomarkers which might further complement those currently in use, while relying on the most relevant disease mechanisms, is still necessary.…”