Pubertal development and fertility in survivors of childhood acute myeloid leukemia treated with chemotherapy only: A NOPHO-AML study

Molgaard-Hansen, Lene; Skou, Anne-Sofie; Juul, Anders; Glosli, Heidi; Jahnukainen, Kirsi; Jarfelt, Marianne; Jónmundsson, Guđmundur; Malmros, Johan; Nysom, Karsten; Hasle, Henrik

doi:10.1002/pbc.24715

Cited by 27 publications

(17 citation statements)

References 31 publications

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“…However those with certain cytogenetic abnormalities or relapsed/refractory disease continue to have a poor prognosis. Additionally, intensive cytotoxic regimens often lead to life-long toxicities (1–4) and are contraindicated in elderly patients due to significant mortality (5, 6). Thus, new approaches are needed.…”

Section: Introductionmentioning

confidence: 99%

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

DeRyckere

Lee-Sherick

Huey

et al. 2017

Clinical Cancer Research

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Purpose MERTK tyrosine kinase is ectopically expressed in 30–50% of acute lymphoblastic leukemias (ALL) and over 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia. Experimental Design Pre-clinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were utilized to evaluate anti-leukemic effect of UNC2025. Results UNC2025 potently inhibited pro-survival signaling, induced apoptosis and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. Additionally, UNC2025 increased sensitivity to methotrexate in vivo, suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction. Conclusions The broad spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, support continued development of MERTK inhibitors for treatment of leukemia.

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Section: Introductionmentioning

confidence: 99%

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

DeRyckere

Lee-Sherick

Huey

et al. 2017

Clinical Cancer Research

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“…However, the four studies give a similar impression of significantly more endocrine late‐effects in HSCT survivors, whereas the risk of cardiac failure seems comparable with and without HSCT. Puberty and fertility problems seem less frequent after chemotherapy only (Molgaard‐Hansen et al , ).…”

Section: Late Adverse Effects Of Hsct In Childrenmentioning

confidence: 99%

A critical review of which children with acute myeloid leukaemia need stem cell procedures

Hasle

2014

Br J Haematol

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SummaryThe last decades have seen parallel improvements in chemotherapy-based and haematopoietic stem cell transplantation (HSCT) regimens for acute myeloid leukaemia (AML) in children. There has been no consensus on indication for HSCT. Reserving HSCT for high-risk and relapsed patients spare many patients from the long-term toxicity of this treatment. The results of matched unrelated donor HSCT equal family donor transplantation and the presence of a matched sibling should no longer be a transplant indication. Minimal residual disease measured by flow cytometry may identify poor responders benefitting from HSCT in first complete remission (CR1) and those with a favourable response to induction therapy who do not need HSCT even with adverse cytogenetic aberrations. FLT3-internal tandem duplication without NPM1 mutation has a very high relapse rate despite favourable response and HSCT is indicated in CR1 in these cases. Finding the optimal indications for HSCT is a delicate balance between risk of relapse and late effects.

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“…The high-intensity chemotherapy needed to induce remission in AML is often prohibitive in elderly patients due to excessive mortality [3, 4], and is known to cause concerning long-term toxic side effects, including growth abnormalities, cardiac dysfunction, neurocognitive deficits, and gonadal failure in pediatric patients [5–7]. Novel therapies that effectively achieve cancer cell killing with minimal toxicity to normal cells are urgently needed to improve both patient outcomes and long-term quality of life.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia

et al. 2015

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Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony formation. In summary, UNC1666 is a novel potent small molecule tyrosine kinase inhibitor that decreases oncogenic signaling and myeloblast survival, thereby validating dual Mer/Flt3 inhibition as an attractive treatment strategy for AML.

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Pubertal development and fertility in survivors of childhood acute myeloid leukemia treated with chemotherapy only: A NOPHO-AML study

Abstract: Most AML survivors treated with chemotherapy had normal pubertal development and fertility, however, AMH levels were decreased in 13% of postpubertal females. Longer follow-up is necessary to evaluate possible risk of premature ovarian failure.

Cited by 27 publications

References 31 publications

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

A critical review of which children with acute myeloid leukaemia need stem cell procedures

Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia

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