Key Points In children with newly diagnosed ITP, IVIg treatment at diagnosis does not result in a lower rate of chronic ITP. Upfront treatment with IVIg led to faster recovery and less severe bleeding events.
BackgroundMethotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously.MethodsWe have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis were also broadly characterized with respect to MTX resistance. This included measurement of concentrations of MTX polyglutamates in leukemic cells, mRNA expression of enzymes involved in MTX metabolism (FPGS, FPGH, RFC, DHFR, and TS), MTX sensitivity as determined by the TS inhibition assay, and FPGS activity.ResultsHerein we demonstrate that higher accumulation of long-chain polyglutamates of MTX is strongly associated with better overall (10-year OS: 90.6 vs 64.1 %, P = 0.008) and event-free survival (10-year EFS: 81.2 vs 57.6 %, P = 0.029) of ALL patients. In addition, we assessed both the association of several MTX resistance-related parameters determined in vitro with treatment outcome as well as clinical characteristics of pediatric ALL patients treated with MTX-containing combination chemotherapy. High MTX sensitivity was associated with DNA hyperdiploid ALL (P < 0.001), which was linked with increased MTX accumulation (P = 0.03) and elevated reduced folate carrier (RFC) expression (P = 0.049) in this subset of ALL patients. TEL-AML1 fusion was associated with increased MTX resistance (P = 0.023). Moreover, a low accumulation of MTX polyglutamates was observed in MLL-rearranged and TEL-AML1 rearranged ALL (P < 0.05).ConclusionsThese findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0158-9) contains supplementary material, which is available to authorized users.
Background and objectives: Management in children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or treatment with corticosteroids or intravenous immunoglobulin (IVIg). Observational studies suggest a lower risk of chronic ITP in children treated with IVIg. Based on these findings, we designed the multicenter randomized 'Treatment with or without IVIg for Kids with ITP' (TIKI) trial (NTR study ID TC1563) . Primary endpoint was the development of chronic ITP. Secondary objectives were evaluating recovery and response rates as well as identifying predictors of response and recovery. Patients and methods: Children aged 3 months-16 years with newly diagnosed ITP, platelet counts ≤20 x 109/L and mild to moderate bleeding were included in 48 hospitals. Within 72 hours after diagnosis patients were randomized to receive either a single infusion of 0.8 g/kg IVIg or careful observation and treatment only in case of severe bleeding. Clinical data were collected and laboratory studies were performed at diagnosis, after one week, one month, three, six and twelve months. Results: Between May 2009 and May 2015, 200 patients were enrolled, 109 males and 91 females. After randomization, 100 received IVIg and 100 received careful observation. No statistically significant differences regarding baseline characteristics were found between the IVIg and observation group. No statistically significant differences were seen regarding development of chronic ITP (currently defined as a platelet count <100 x 109/L at 12 months) between both groups: 10.2% in the IVIg group en 10.4% in the observation group. The rate of chronic ITP was equal in different age groups: <1 year, 1-10 years, > 10 years. Complete recovery, defined as a platelet count ≥ 100 x 109/L, was significantly more often observed in the IVIg group than in the observation group at 1 week, 1 month and 3 months after diagnosis. Complete response to IVIg at 1 week was seen in 68.7%. No clinical or laboratory predictors of complete response to IVIg were found. Predictors for complete recovery at 12 months were younger age (p=0.03), shorter duration of symptoms prior to diagnosis (p<0.001), mucosal bleeding at diagnosis (p=0.038), higher leukocyte count at diagnosis (p=0.044) and a higher lymphocyte count at diagnosis (p=0.018). In patients randomized to the IVIg group, absence of complete response to IVIg at one week was associated with development of chronic ITP: 20.7% chronic ITP in patients without complete response versus 5.9% in complete responders (p=0.028). Eight patients in the observation group needed rescue treatment (IVIg, methylprednisolone) because of grade 4-5 bleeding, versus one patient in the IVIg group. Seven out of 9 bleeding events occurred within the first month after diagnosis. All 9 patients recovered completely and fast from their bleeding events. Conclusion: In this phase 3 multicenter randomized controlled trial evaluating the efficacy of IVIg treatment versus careful observation in children aged 3 months -16 years with newly diagnosed ITP, the primary end point - the rate of chronic ITP- did not differ significantly between both groups. However, in the IVIg group recovery rates were higher during the first three months after diagnosis and bleeding events occurred less frequently than in the observation group. These results suggest that treatment with IVIg solely to prevent a chronic course of the disease is not justified, but that treatment with IVIg might be beneficial in order to provide adequate hemostasis in selected patient groups. Disclosures Porcelijn: Sanquin: Employment.
Methotrexate (MTX) is an essential component of contemporary ALL treatment regimens. This antifolate eradicates leukemic cells by disrupting de novo biosynthesis of nucleotides, leading to inhibition of DNA replication and consequent cell death. Over the past decades, MTX-containing chemotherapy has proven to be crucial in achieving curation in ALL. However, drug resistance continues to be a major obstacle to curative ALL treatment. A number of alterations in MTX metabolism, resulting in impaired accumulation of this antifolate in cancer cells, have been identified as determinants of MTX resistance. However, it remains unclear which of these molecular mechanisms have clinical relevance. Therefore, the current study aimed at determining the relation between MTX resistance and long-term clinical outcome of ALL. Towards this end, we collected the available clinical data of 235 childhood ALL patients, including clinical data with a follow-up time of 10 years. For these patients, samples obtained at the time of diagnosis were also characterized with respect to MTX resistance. This included determination of MTX polyglutamate levels in leukemic cells, mRNA expression of enzymes involved in (anti)folate metabolism and transport (i.e. FPGS, FPGH, DHFR, TS and RFC); MTX sensitivity was determined by the thymidylate synthase inhibition assay (TSIA) and in vitro FPGS activity assay was performed. High levels of long-chain MTX polyglutamates was strongly associated with favorable long-term event-free survival (EFS, p = 0.029) and overall survival (OS, p = 0.008) of ALL patients (10-year EFS 81% and OS 91%, compared to EFS 58% and OS 64% in patients with low levels of this active metabolite). Similar relations were observed for the total accumulation of MTX polyglutamates and FPGS activity, which were associated with overall survival (p = 0.018 and p = 0.039, respectively). In the multivariate Cox regression model, including clinical variables, the level of long chain MTX polyglutamates showed a trend towards an association with event-free survival (p = 0.073) but not with overall survival (p = 0.465). In addition, we assessed the association between MTX resistance-related variables and the treatment outcome in patients with different cytogenetic alterations. High MTX sensitivity was associated with hyperdiploid ALL (P<0.001), which was also associated with increased MTX accumulation (p = 0.03) and elevated RFC expression (p = 0.049). Moreover, cells characterized by TEL-AML1 fusion displayed elevated MTX resistance (p = 0.023) compared to samples devoid of this aberration, while MLL-rearrangements were associated with low accumulation of cellular MTX polyglutamates (p = 0.012). These findings emphasize the central role which MTX lays in ALL treatment thereby highlighting the necessity for further exploration of the molecular mechanisms underlying MTX resistance in ALL patients. Financial support by Kika (Children cancer-free) Citation Format: Anna Wojtuszkiewicz, Godefridus J. Peters, Nicole L. van Woerden, Boas Dubbelman, Gabrielle Escherich, Kjeld Schmiegelow, Edwin Sonneveld, Rob Pieters, Peter M. van de Ven, Gerrit Jansen, Yehuda G. Assaraf, Gertjan J L Kaspers, Jacqueline Cloos. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1624. doi:10.1158/1538-7445.AM2015-1624
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