Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty

Mariani, Stefania; Basciani, Sabrina; Fabbri, Andrea; Agati, Luciano; Ulisse, Salvatore; Lubrano, Carla; Spera, Giovanni; Gnessi, Lucio

doi:10.1016/j.fertnstert.2010.08.060

Cited by 38 publications

(18 citation statements)

References 19 publications

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“…Endocrine functions are indeed affected by imatinib as some patients develop gynecomastia associated with low levels of testosterone, likely caused by decreased Leydig cell function (40). Imatinib given during puberty has more severe effects as this is the time the adult stem spermatogonia and Leydig cells are being formed; indeed gynecomastia, low sperm count, and increased inhibin B/FSH ratio, also indicative of spermatogenic failure, have been observed during imatinib treatment during puberty (41, 42). Other tyrosine kinase inhibitors, dasatinib and suntinib, have also been reported to induce gynecomastia.…”

Section: Biological Targeted Therapiesmentioning

confidence: 99%

Effects of chemotherapy and radiotherapy on spermatogenesis in humans

Meistrich

2013

Fertility and Sterility

317

221

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Treatment of cancer with chemo- or radiotherapy causes reduction of sperm counts often to azoospermic levels which may persist for several years or be permanent. The time course of declines in sperm count can be predicted by the sensitivity of germ cells, with differentiating spermatogonia being most sensitive, and the known kinetics of recovery. Recovery from oligoor azoospermia is more variable and depends on whether there is killing of stem cells and alteration of the somatic environment that normally supports differentiation of stem cells. Of the cytotoxic therapeutic agents, radiation and most alkylating drugs are the most potent at producing long-term azoospermia. Most of the newer biological targeted therapies, except those used to target radioisotopes or toxins to cells, seem to have only modest effects, mostly on the endocrine aspects of the male reproductive system, however their effects when used in combination with cytotoxic agents have not been well studied.

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Section: Biological Targeted Therapiesmentioning

confidence: 99%

Effects of chemotherapy and radiotherapy on spermatogenesis in humans

Meistrich

2013

Fertility and Sterility

317

221

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“…Although the treatment with imatinib is well tolerated by the majority of children, there are adverse side effects associated with the drug (Millot et al, 2011;Steegmann et al, 2016;Suttorp et al, 2018). Besides the cardiac side effects observed in adult patients (Kerkela et al, 2006;Ribeiro et al, 2008), long-term side effects of imatinib treatment specifically described in children and young adolescents comprise longitudinal growth suppression and possible impaired fertility (Christopoulos et al, 2008;Mariani et al, 2011;Zamah et al, 2011;Millot et al, 2014a). Also, lifelong treatment with an expensive TKI, such as imatinib, one of the most successful cancer targeted therapies, poses a financial burden on health care systems (Experts in Chronic Myeloid Leukemia 2013).…”

Section: Discussionmentioning

confidence: 99%

Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study

et al. 2019

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Summary This international study aimed to assess the effect of imatinib discontinuation in paediatric patients with chronic myeloid leukaemia (CML) after deep molecular remission (DMR) had been achieved and maintained for at least 2 years. The primary endpoint of this analysis was the molecular relapse‐free survival, estimated by the non‐parametric Kaplan‐Meier method. Major endpoint was the estimated rate of patients without molecular relapse at 6 months. Fourteen patients were enrolled; 4 patients maintained DMR with a follow‐up of 24 (two patients), 34 and 66 months, respectively, whereas 10 patients relapsed. All molecular relapses occurred within 6 months (median 3 months, range 1–6) after imatinib discontinuation. The overall probability of maintaining DMR at 6 months was 28·6%. No parameters associated with molecular relapse could be identified. Keeping in mind the rarity of paediatric CML, which contributed to the small size of the cohort, our findings illustrate that imatinib cessation after sustained DMR is successful in only limited numbers of patients, whereas much higher rates are reported in adult patients. Further research is needed to extend the cohort of paediatric CML patients who might achieve treatment‐free remission with an ideal prerequisite of predicting the occurrence of molecular relapse l after imatinib cessation.

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“…Experiments in neonatal rats reveal permanent deleterious effects on the maturation of testes after short-term exposure to imatinib, although fertility was preserved, leading to speculation that pre-pubertal exposure to TKIs may have more adverse effects on fertility than later exposure (34). Interestingly, the two case reports of oligospermia after imatinib exposure are from patients started on therapy during childhood (35, 36) and azoospermia was observed in a post-pubertal patient treated only with dasatinib for Ph + leukemia (Personal Communication, Dr. C. M. Zwann). While there are reports of successful pregnancy in men and women treated with imatinib, its use is not recommended during pregnancy due to potential teratogenicity, and the extent and reversibility of impaired fertility due to tyrosine kinase inhibition in children with cancer remain to be defined.…”

Section: Adverse Effects Of Targeted Agents In Childrenmentioning

confidence: 99%

Targeting developmental pathways in children with cancer: what price success?

Gore

DeGregori

Porter

2013

The Lancet Oncology

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Much of current cancer research is aimed at exploiting cancers’ molecular addictions with targeted therapeutics, with notable successes documented in clinical trials. By their nature, these agents have different side effect profiles than conventional chemotherapeutics. While very few targeted agents have attained regulatory approval for use in children, pediatric oncologists are gaining experience with these drugs, which may have unique effects, both short- and long-term, on the developing child, unrecognized in adults. This Review summarizes the rationale for targeted therapy, challenges in pediatric drug development, unique side effect profiles of targeted agents, limited data from children treated with targeted agents, as well as implications of the current knowledge and gaps thereof. The demonstrated and potential impacts of targeted therapies on normal tissue development and function are discussed. We conclude that future clinical trial design should include carefully considered assessment of developmental effects of targeted therapy, as well as informed supportive care recommendations.

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Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty

Cited by 38 publications

References 19 publications

Effects of chemotherapy and radiotherapy on spermatogenesis in humans

Effects of chemotherapy and radiotherapy on spermatogenesis in humans

Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study

Targeting developmental pathways in children with cancer: what price success?

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