A case of a patient with chronic myeloid leukemia resistant to tyrosine‐kinase inhibitors is reported.
Abstract
The development of tyrosine‐kinase inhibitors (TKIs) has improved survival of patients with chronic myeloid leukemia (CML). Some patients may become resistant to TKIs and require hematopoietic stem cell transplant (HSCT) that is highly gonadotoxic. Fertility preservation with ovarian stimulation might be indicated but is challenging if patients need to remain on TKIs until HSCT because TKIs may compromise follicular development and response to ovarian stimulation. We report the case of a patient with CML resistant to TKI and planned for an HSCT, in which treatment by TKI was replaced by interferon‐α before and during ovarian stimulation for fertility preservation. Successful ovarian stimulation was performed, allowing cryopreservation of nine zygotes. Hematopoietic stem cell transplantation was performed, and at present, 3 years later, the patient presents a sustained major molecular response.
Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome (Ph), which induces the expression of an active tyrosine kinase by the oncogene BCR‐ABL1, resulting in abnormal cell proliferation and ultimately in the development of CML [1], [2]. Tyrosine kinase inhibitors (TKIs) target abnormally expressed tyrosine kinases—in the case of CML, the BCR‐ABL1 fusion protein—and have improved survival rates of patients with CML [3]. Some patients will become resistant to TKIs and require hematopoietic stem cell transplantation (HSCT), known to be highly gonadotoxic. Fertility preservation options such as ovarian stimulation need to be discussed with these patients. There is a single case report of a patient with CML on imatinib requiring HSCT who had an abnormal ovarian response during ovarian stimulation for fertility preservation (low estradiol level compared with the number of follicles, lower than expected number of oocytes retrieved). Two months after the cessation of imitinib, a second cycle of ovarian stimulation was performed, and the ovarian response was normal, with the expected number of oocytes retrieved. This case suggested that TKIs might have a potential deleterious effect on follicular development during ovarian stimulation [4]. There is currently no guidance for the management of TKIs during ovarian stimulation.
In February 2005, a 26‐year‐old woman was diagnosed with CML and treatment with imatinib 400 mg daily was commenced, with a complete hematologic response. In May 2011, the bone marrow aspirate showed a partial cytogenetic response. The presence of neutropenia and a diagnosis of bronchitis necessitated a dose reduction of imatinib to 300 mg daily. In March 2012, imatinib was withdrawn for secondary resistance and the patient was treated with a second‐generation TKI: dasatinib 100 mg daily. In the presence of severe neutropenia, the dose was reduced to 70 mg daily. In March 2013, dasatinib was replaced by another second‐generation TKI, nilotinib at a dose of 300 mg/b.i.d., for partial cytogenic response. Six months later, the bone marrow aspirate revealed monosomy 7 on Ph‐negative cells that indicates a progression to accelerated‐phase CML. Consequently, HSCT was planned.
Prior to conditioning chemotherapy (busulfan, cyclophosphamide, and antilymphocyte serum), the patient and her husband were referred to our reproductive medicine unit to discuss fertility preservation options such as ovarian tissue cryopreservation, ovarian stimulation, and cryopreservation of oocytes/embryos and gonadotropin‐releasing hormone (GnRH) agonist administration during HSCT. The patient's ovarian reserve was assessed by ultrasound and hormonal profile, with an antral follicular count of 9, anti‐müllerian hormone (AMH) level of 8.7 pmol/L, and an follicle‐stimulating hormone (FSH) level of 7.2 UI/L indicating a potentially good response to ovarian stimulation. The couple opted for ovarian stimulation and cryopreservation of zygotes (until September 2017, Swiss law only allowed cryopreservation of zygotes and not embryos) because the procedure is not considered experimental in the context of fertility preservation. The patient received GnRH agonist during HSCT for ovarian protection, although this practice is still considered experimental. The patient did not want to undergo a laparoscopy for ovarian tissue cryopreservation as the procedure is still considered experimental. After publication of a report report describing a case of severely compromised ovarian response to ovarian stimulation while on imatinib [4], and considering the risk of disease progression without treatment, nilotinib was replaced by the interferon‐α 2a (INF‐α) [5]. Nineteen days after stopping nilotinib and while on INF‐α, ovarian stimulation was started using an antagonist protocol synchronized with an oral contraceptive containing 0.03 mg of ethinylestradiol and 0.15 mg of levonogestrel (Elyfem 30; Berlis, Zurich, Switzerland). The stimulation involved 2,475 IU of urinary gonadotropin (Merional HG; IBSA Institut Biochimique, Massagno, Switzerland) at a daily dose of 225 IU for 11 days and pituitary suppression with a daily injection of the GnRH antagonist ganirelix 0.25 mg (Orgalutran; MSD Merck Sharp & Dohme, Kenilworth, NJ) starting from the 5th day of stimulation. Serum estradiol peaked at 9.32 nmol/L the day of recombinant human chorionic gonadotropin (r‐hCG) administration (Ovitrelle; Merck, Kenilworth, NJ), with 11 follicles measuring ≥13 mm, for an average of 0.84 nmol/L per mature follicle. Thirty‐six hours after hCG trigger, 12 oocytes were retrieved and were mature (metaphase II (MII)). Intracytoplasmic sperm injection was performed, and nine zygotes could be cryopreserved. During INF‐α administration, the patient had classic flu‐like symptoms but no serious side effects. The INF‐α was stopped a week prior to starting the conditioning regimen.
The evaluation of the disease in the bone marrow prior to transplantation showed a BCR‐ABL/ABL ratio of 44% on International Scale (IS). Allogenic hematopoietic stem cell transplantation from peripheral blood was performed with myeloablative conditioning containing busulfan and cyclophosphamide on February 27, 2014, from an human leukocyte antigen (HLA)‐matched 12/12 unrelated donor. Graft‐versus‐host prophylaxis was performed with administration of cyclosporine, a short course of methotrexate, antithymocyte globulin (ATG Fesenius; Fresenius Medical Care, Oberdorf, Switzerland), and partial in vitro T‐cell depletion with alemtuzumab [6]. Three years after the transplantation, the medical check‐up showed a complete hematologic response with major molecular response with a BCR‐ABL/ABL of 0.071% IS.
To our knowledge, this is the first case report of a patient with CML resistant to TKIs in whom successful ovarian stimulation for fertility preservation was performed after switching from TKIs to INF‐α before HSCT. Ovarian stimulation was started 19 days after interrupting nilotinib with an appropriate ovarian response (number of follicles, estradiol levels, and number of oocytes retrieved) in relation to the tests of ovarian reserve without significant side effect of INF‐α treatment.
There are numerous reports of women conceiving while on TKIs, suggesting that gonadal function is not completely suppressed [7]. Off‐target effect on ovarian function can theoretically occur as tyrosine kinases are found in the ovaries and are key elements of follicular development [8], [9]. A recent study on mice has explored over the course of 5 weeks the effect of sunitinib administration on ovulation and ovarian reserve [10]. Compared with control, mice treated with sunitinib showed a significant decrease in the number of corpora lutea and AMH level, with no difference in primordial and growing follicles. After stopping administration of sunitinib, both groups could obtain litters. These results suggest a transient inhibitory effect on follicular activation during treatment without long‐term effect on ovarian reserve. During the same study, mice were also stimulated with mare's serum gonadotropin, with a significant decrease in the number of oocytes ovulated in sunitinib‐treated mice. These results are in line with the case report of a CML patient treated with imatinib who had an abnormal ovarian response to ovarian stimulation [4].
Female patients with CML on TKI treatment requiring HSCT may require ovarian stimulation for fertility preservation. Because TKI administration might have a potential negative impact on follicular development during ovarian stimulation, a switch to INF‐α could represent an option to avoid a potential abnormal ovarian response in patients not eligible to treatment cessation because of the risk of disease progression. This case highlights that research is warranted to determine the exact effect of TKIs on ovarian physiology.
Acknowledgments
We acknowledge the Réseau Romand de Cancer et Fertilité (RRCF) for allowing multidisciplinary management of patients requiring fertility preservation. Informed consent was obtained from the patient included in this report. No funding was obtained for this report.
Footnotes
For Further Reading: Zeev Blumenfeld, Hilli Zur, Eldad J. Dann. Gonadotropin‐Releasing Hormone Agonist Cotreatment During Chemotherapy May Increase Pregnancy Rate in Survivors. The Oncologist 2015;20:1283–1289
Implications for Practice: The use of gonadotropin‐releasing hormone analogs (GnRHa) for fertility preservation is not unequivocally accepted and is even controversial. This study compared 286 patients who received GnRHa with chemotherapy with 188 patients who were treated with chemotherapy alone. Ovarian function could be determined in 217 patients. The odds ratio for preserving cyclic ovarian function was 6.87 for the patients who received GnRHa. Furthermore, the total and spontaneous pregnancy rate was significantly higher for those who received the agonist (p = .006). Adding GnRHa to chemotherapy significantly increased the odds ratio for spontaneous conception, in addition to preserving regular ovarian function. It is suggested that GnRHa cotreatment should be administered to young women in conjunction with gonadotoxic chemotherapy.
Editor's Note: See the related commentary, “Fertility Preservation in Leukemia,” by Zeev Blumenfeld, on page 645 of this issue.
Disclosures
Nicolas Vulliemoz: IBSA Institut Biochimique SA, Ferring Pharmaceuticals (Other [travel expenses]); Yves Chalandon: Novartis, Bristol‐Myers Squibb, Pfizer, Incyte (H, SAB). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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