Has bone marrow suppression or anemia been described as a side effect of goserelin?

Fråga: Has bone marrow suppression or anemia been described as a side effect of goserelin?

A man have been receiving goserelin (Zoladex) therapy for 5 years due to prostate cancer.

Sammanfattning: The hematologic event that could be found in the literature and connected to goserelin is a decline in haemoglobin level and it was reported after combination therapy with flutamide. Similar cases of decline in haemoglobin level have been reported for other androgen deprivation therapies, both monotherapy and combined GnRH agonists and/or testosterone antagonists. With regards to the enrolment of testosterone in erythrocytosis, a possible effect of goserelin on haemoglobin level cannot be excluded, although the time relationship between drug exposition and event is not convincing in this case. Other causes of this clinical picture should first be excluded.

Svar: Goserelin is a synthetic gonadotropin releasing hormone (GnRH) agonists. It is used for the suppression of gonadal sex hormone production in the treatment of malignant neoplasms of the prostate, in breast cancer and in the management of endometriosis (1). Repeated administration inhibits secretion of luteinizing hormone, causing a decrease in serum testosterone in men and serum estradiol in women.

In the summary of products characteristics, hematologic events were seen post marketing, and therefore with unestimated frequency (1). There were no reports on hematologic side effects in association to goserelin in the Swedish adverse drug reactions registry BiSi except one case of thrombocytopenic purpura/hemolytic-uremic syndrome (2). The WHO adverse drug reactions register has in total 4800 reports concerning goserelin. These reports contain 38 ADR´s with anaemia, 5 aplastic anaemia and 6 bone marrow failure (3). Note that not all reports in the WHO database have been assessed for association.

The only hematologic event connected to goserelin therapy that could be identified in the literature was a decline in hemoglobin levels. A mean haemoglobin decline of 2.8 g/dL at 4 months was observed in 81% (106/131) patients with locally advanced prostate cancer after a combined therapy of goserelin and another androgen deprivation; flutamide. The decrease in hemoglobin levels paralleled the decrease in testosterone levels. No evidence of blood loss or hemolysis was found. Return to hemoglobin baseline levels has not been observed yet for most patients at 1 year of follow-up (4).

The decline in haemoglobin levels has however been reported for other GnRH agonists. For the leuprolide, a mean decline of 1.66 g/dL was observed in 11 patients three to nine months after initiation of the therapy (5). A combined therapy GnRH agonists of buserelin; with testosterone antagonists nilutamide resulted in a decline of mean haemoglobin level by 0.83 g/dL in 72 patients at 24 months after the therapy (5). Furthermore, similar events have been reported to other androgen deprivation and testosterone antagonists such as finasteride and flutamide (6,7). Overall, the decline in haemoglobin levels generally occurs within 2 to 6 months of therapy initiation, and often into the normocytic-anaemic range (5). In patients who developed symptoms of anemia, erythropoietin treatment resulted in symptom improvement.

The stimulatory effects of testosterone on erythropoiesis; haem synthesis and erythroid colony-forming cells within the bone marrow have long been recognized. With a decline in androgen levels produced by GnRH-agonists and/or testosterone antagonists, bone marrow stem cells are no longer exposed to this stimulus, and thus a decline in the number of new erythrocytes and a decline in the measured haemoglobin value results (5).

For other hematological events with other GnRH-agonists, we found a case report of leukopenia induced by leuprolide (8). Otherwise documentation is sparse. SPC Zoladex (goserelin). AstraZeneca AB. (citerad 2017-11-16) BiSi (åtkomst 2017-11-16) Vigibase (åtkomst 2017-11-16) Choo R, Chander S, Danjoux C, Morton G, Pearce A, Deboer G, et al. How are hemoglobin levels affected by androgen deprivation in non-metastatic prostate cancer patients? The Canadian journal of urology. 2005;12(1):2547-2552. (endast abstract) Curtis KK, Adam TJ, Chen SC, Pruthi RK, Gornet MK. Anaemia following initiation of androgen deprivation therapy for metastatic prostate cancer: a retrospective chart review. The aging male : the official journal of the International Society for the Study of the Aging Male. 2008;11(4):157-161. Ornstein DK, Beiser JA, Andriole GL. Anaemia in men receiving combined finasteride and flutamide therapy for advanced prostate cancer. BJU international. 1999;83(1):43-46. Qian LX, Hua LX, Wu HF, Sui YG, Cheng SG, Zhang W, et al. Anemia in patients on combined androgen block therapy for prostate cancer. Asian journal of andrology. 2004;6(4):383-384. Grau E, Torrecilla T, Real E, Sempere J. Leukopenia induced by leuprolide acetate depot. Ann Pharmacother. 1994;28(2):283-284. (endast abstract)