Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK–positive anaplastic large-cell lymphoma

Abstract

Key Points• Early MRD positivity in NPM-ALK-positive ALCL correlates with a very high relapse risk and inferior survival.Detection of minimal disseminated disease (MDD) at diagnosis correlates with relapse risk in children with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL). We investigated whether minimal residual disease (MRD) positivity by qualitative reverse-transcriptase polymerase chain reaction (RT-PCR) for Nucleophosmin (NPM)-ALK during treatment identifies patients at the highest relapse risk. Blood and/or bone marrow of 180 patients with NPM-ALK-positive ALCL treated with Berlin-Frankfurt-Münster-type protocols were screened for NPM-ALK transcripts at diagnosis; 103 were found to be MDD-positive. MRD before the second therapy course could be evaluated in 52 MDD-positive patients. MRD positivity correlated with uncommon histology. The cumulative incidence of relapses (CIR) of 26 MDD-positive/MRD-positive patients (81% 6 8%) was significantly higher than the CIR of 26 MDD-positive/MRDnegative (31% 6 9%) and 77 MDD-negative patients (15% 6 5%) (P < .001). Five-year survival of MDD-negative and MDD-positive/ MRD-negative patients was 91% 6 3% and 92% 6 5%, respectively, compared with 65% 6 9% of MDD-positive/MRD-positive patients (P < .001). Early evaluation of MRD in NPM-ALK-positive ALCL identifies patients with a very high relapse risk and inferior survival. (Blood. 2014;123(3):334-337) IntroductionThe relapse rate of children with anaplastic large-cell lymphoma (ALCL) reaches 25% to 35% with current chemotherapy.1-4 More than 95% of childhood ALCL expresses anaplastic lymphoma kinase (ALK) fusion proteins, 90% of which carry the translocation t(2;5)(p23;q35), resulting in the specific fusion gene NPM-ALK. 5,6NPM-ALK-expressing cells can be detected in bone marrow (BM) or peripheral blood (PB) by RT-PCR in 50% to 60% of patients with NPM-ALK-positive ALCL as a sign of minimal disseminated disease (MDD). 7,8 MDD turned out to be a significant prognostic factor 7-9 in addition to the histologic subtype and clinical risk factors. 10,11 In vivo response to chemotherapy measured by minimal residual disease (MRD) has been established as the strongest prognostic factor for children with acute lymphoblastic leukemia. [12][13][14] In Burkitt leukemia, early detection of MRD could identify patients at the highest risk of relapse as well. 15 We therefore investigated whether detection of MRD by qualitative RT-PCR for NPM-ALK in MDD-positive patients in BM or PB early during treatment allows for identification of patients at the highest risk of relapse in ALCL. Patients and methods EligibilityALCL patients treated according to the protocols Non-Hodgkin Lymphoma-Berlin-Frankfurt-Münster 95, Linfomi Non-Hodgkin 97, or ALCL 99 (Italian and German patients) between August 1998 and December 2008 were potentially eligible. Three patients with completely resected stage I disease were excluded because they received no prephase and only 3 courses of chemotherapy. Eligibility was confirme...

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

“…The progression-free survival rates were 28% and 68% in these 2 groups, respectively [36]. Furthermore, patients with MDD at diagnosis and minimal residual disease after their first course of CHOP-based chemotherapy showed an 81% cumulative incidence of relapse and only had a 65% 5-year overall survival rate [37]. These findings stress the urgent need to develop more specific and effective approaches to treat NPM-ALK + ALCL.…”

Hematopoietic stem cell transplantation in relapsed ALK+ anaplastic large cell lymphoma in children and adolescents: a study on behalf of the SFCE and SFGM-TC

“…They might lead to the identification of patients at high risk of failure with conventional approaches. 37,38 Altogether, despite its obvious limitations due to the small number of patients and the heterogeneity of the indications, this report shows that allo-SCT is an efficient treatment for the management of pediatric patients with high-risk relapsed or refractory ALK+ ALCL. Defining the role of this procedure in the treatment of relapsed ALCL will require a better knowledge of prognostic factors after relapse and an evaluation of the long-term outcome of patients treated with vinblastine and targeted therapy, such as brentuximab vedotin and ALK inhibitors.…”

NHL in adolescents and young adults: A unique population

“…57,58 Given the worse outcome of ALK-ALCL, more intensive chemotherapy including consolidative therapy with stem cell transplant at first remission are being evaluated in adults, but none has proven its efficacy yet. 59 Several factors have been shown to be associated with a higher risk of treatment failure in children and adolescents, such as the presence of a small cell or histiocytic component, 55 the positivity of PCR for NPM-ALK fusion transcript in bone marrow or blood at diagnosis (minimal disseminated disease) 60 and after the first chemotherapy cycle (minimal residual disease), 61 or a low antibody against ALK at diagnosis. 53 The prognostic impact of most of these factors has not been evaluated in adults, whereas in adult studies, the main factors shown to be associated with a poor prognosis are the ALK status, age >40 years, bone marrow involvement, and high international prognostic index.…”