Successful Pregnancy After Planned Pregnancy‐Oriented TKI Interruption and Embryo Transfer Following Ponatinib Re‐Consolidation in Chronic‐Phase Chronic Myeloid Leukemia

ABSTRACT

Introduction

Pregnancy after unsuccessful treatment‐free remission (TFR) in chronic‐phase chronic myeloid leukemia (CP‐CML) remains challenging.

Case Presentation

A woman lost major molecular response (MMR) after stopping a BCR::ABL1 tyrosine kinase inhibitor (TKI). Ponatinib re‐consolidation enabled a second TKI‐free interval, with MMR maintained but deep molecular response unstable. With diminished ovarian reserve, embryos were cryopreserved using assisted reproductive technology (ART), separating fertility preservation from pregnancy timing. Further ponatinib re‐consolidation restored MR4.5; ponatinib was stopped before embryo transfer, resulting in pregnancy and live birth without TKI exposure.

Conclusion

Sequential ponatinib re‐consolidation and ART may enable planned TKI interruption for pregnancy.

Trial Registration

The authors have confirmed clinical trial registration is not needed for this submission.

1.

The introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) has enabled patients with chronic‐phase chronic myeloid leukemia (CP‐CML) to achieve a life expectancy approaching that of the general population [1]. Accordingly, treatment goals in CP‐CML now extend beyond disease control to encompass quality of life and major life events, including pregnancy. As selected patients with a sustained deep molecular response (DMR) can discontinue TKI therapy without molecular relapse [2, 3], treatment‐free remission (TFR) is now recognized as an important therapeutic goal that may facilitate such life events in patients with CP‐CML.

Although the median age at CP‐CML diagnosis is approximately 55 years, the disease also affects women of childbearing age [4]. TKI exposure, particularly during early pregnancy, is associated with fetal abnormalities and spontaneous abortion; therefore, TKI therapy should generally be avoided during pregnancy [5, 6]. Planned pregnancy during TFR is thus considered the preferred strategy for women with CP‐CML who wish to conceive [3, 7]. Successful pregnancies following planned TKI discontinuation have been reported [8]; however, evidence regarding pregnancy after an unsuccessful initial discontinuation attempt remains limited.

Here, we report a young woman with CP‐CML who lost major molecular response (MMR) after her first TKI discontinuation attempt but subsequently achieved pregnancy and live birth through strategic integration of assisted reproductive technology (ART), embryo cryopreservation, ponatinib re‐consolidation, and planned pregnancy‐oriented TKI interruption.

An 18‐year‐old woman was referred to our department 12 years previously because of marked leukocytosis. Peripheral blood examination showed a white blood cell count of 66.3 × 10⁹/L with basophilia and circulating immature granulocytes, mild anemia with a hemoglobin level of 10.3 g/dL, and thrombocytosis with a platelet count of 996 × 10⁹/L. Blasts were not increased. Bone marrow examination demonstrated hypercellular marrow with 1.0% blasts, and the Philadelphia chromosome was identified. She was therefore diagnosed with CP‐CML. The EUTOS long‐term survival score was low, and no high‐risk additional chromosomal abnormalities were detected.

The patient was enrolled in the Japan Adult Leukemia Study Group (JALSG) CML212 study [9] and randomized to the nilotinib arm. Nilotinib 300 mg twice daily was initiated, resulting in an excellent response, with sustained molecular response (MR) 4.5 from April, X−8 onward. Because she desired future pregnancy, a first TKI discontinuation was attempted in April, X−4, at 26 years of age, after 4 years of sustained MR4.5 on nilotinib. However, MMR was lost 4 months later. Nilotinib 300 mg twice daily was restarted in August, X−4, and MR4.5 was regained.

A second discontinuation attempt was subsequently planned, and she was enrolled in the JALSG CML RE‐STOP219 study [10]. Ponatinib 15 mg once daily was initiated in May, X−3, and discontinued after MR4.5 had been maintained for 1 year. During this second TKI‐free interval, BCR::ABL1 IS values were initially 0.0001% in May and July, X−2, and subsequently fluctuated around the MR4 threshold, ranging from 0.0036% to 0.0206% through June, X−1, without loss of MMR.

During the same interval, the patient sought fertility preservation and was referred to an ART clinic. Her anti‐Müllerian hormone level was decreased, suggesting diminished ovarian reserve, and embryos were cryopreserved. Although MMR was maintained, the MR remained unstable. An additional course of ponatinib was therefore planned to deepen the MR before pregnancy.

The patient withdrew consent from the JALSG CML RE‐STOP219 study at 28 years of age in December, X−2. Ponatinib 15 mg once daily was restarted in June, X−1. After 8 months of ponatinib re‐consolidation, MR4.5 was regained. Ponatinib was then discontinued, and embryo transfer was performed 1 month later in March, X, at 30 years of age, resulting in pregnancy. TKI therapy was withheld throughout pregnancy, and she delivered a healthy infant vaginally in November, X. MMR was maintained throughout pregnancy, although BCR::ABL1 IS levels increased after embryo transfer.

The clinical course, including TKI treatment, discontinuation attempts, ART procedures, pregnancy, delivery, and MRs, is summarized in Figure 1.

FIGURE 1.

Clinical course of TKI discontinuation, assisted reproductive technology, and planned pregnancy in a patient with chronic myeloid leukemia. The patient received frontline nilotinib and maintained MR4.5 for 4 years before the first treatment‐free remission (TFR) attempt. Following loss of major molecular response (MMR), nilotinib was restarted and MR4.5 was regained. A second discontinuation was attempted after ponatinib re‐consolidation. During this interval, MMR was maintained despite fluctuations around the MR4 threshold, and embryos were cryopreserved. Ponatinib was subsequently resumed, MR4.5 was regained, and treatment was interrupted close to frozen embryo transfer. Pregnancy and live birth were achieved without TKI exposure during gestation. BID, twice daily; IS, International Scale; MMR, major molecular response; MR, molecular response; QD, once daily; TFR, treatment‐free remission.

The most notable feature of this case is the strategic integration of ART with CP‐CML treatment after an unsuccessful initial TFR attempt. This approach allowed fertility preservation and disease control to be coordinated without requiring durable TFR before pregnancy. Pregnancy during established TFR is generally preferred because it avoids fetal TKI exposure. However, sustained DMR or durable TFR is not an absolute prerequisite for pregnancy. Planned TKI interruption for conception may also be considered in selected patients, with close molecular monitoring and individualized management [3, 7]. A nationwide Japanese survey by Kondo et al. [8] demonstrated favorable pregnancy outcomes in the TKI era, with TFR more frequently maintained among patients fulfilling the ELN 2020 discontinuation criteria. Pregnancy planning should therefore be individualized according to MR, relapse kinetics, fertility considerations, and available treatment options during pregnancy.

A conventional TFR attempt is generally considered only for patients fulfilling established criteria, including prolonged TKI exposure and sustained DMR [3]. Nevertheless, only approximately 40%–50% achieve durable TFR, and most molecular relapses occur within 6 months of discontinuation [3]. Clinical trials evaluating a second discontinuation after an unsuccessful initial TFR attempt have reported lower success rates than first discontinuation attempts [11, 12, 13]. In these studies, TKI retreatment for approximately 24–65 months was generally required before re‐discontinuation, whereas the median time to molecular relapse remained relatively short at approximately 3–8 months. Thus, repeated attempts may substantially prolong the time to pregnancy. Because both natural fertility and ART outcomes decline with age, waiting for ideal long‐term TFR may compromise future opportunities for pregnancy.

The JALSG CML RE‐STOP219 study [10] was a multicenter Phase II study evaluating a second TKI discontinuation strategy after an unsuccessful initial TFR attempt. Approximately 85% of enrolled patients had received second‐generation TKIs as first‐line therapy. Patients who regained MR4.5 after TKI re‐initiation were switched to ponatinib 15 mg once daily, which was discontinued after MR4.5 had been maintained for 12 months. The 12‐month TFR rate was 36.6%. Although not designed to address pregnancy management, the study demonstrated that DMR and a new TKI‐free interval could be re‐established after an unsuccessful initial TFR attempt, with potential implications for pregnancy planning.

In the present case, the original goal was durable long‐term TFR. During the second TKI‐free interval, however, stable DMR was not maintained, although MMR was preserved. Continued treatment‐free observation with close monitoring remained a reasonable option. The decision to restart ponatinib after embryo cryopreservation was therefore an individualized pre‐conception strategy intended to deepen the MR before pregnancy, rather than a required intervention for loss of MMR. The clinically relevant objective was to secure a well‐controlled TKI‐free interval sufficient for pregnancy, rather than to pursue durable lifelong TFR.

If molecular relapse occurs during pregnancy, interferon can be administered throughout gestation. After placentation, imatinib or nilotinib may also be cautiously considered from approximately 16 weeks because of their relatively limited placental transfer [3, 7]. Nevertheless, completing pregnancy and delivery without additional therapy, as in this case, may reduce the patient's psychological burden.

The clinical value of ART in this setting extends beyond facilitating conception. Achieving TFR can take several years, and unsuccessful discontinuation attempts may further delay pregnancy. Embryo cryopreservation can separate the time‐sensitive process of fertility preservation from the later decision of when to attempt pregnancy. This allows fertility preservation to be completed without waiting for the optimal timing of pregnancy, while TKI therapy can subsequently be resumed or continued to optimize molecular disease control. Treatment can then be continued until shortly before embryo transfer, shortening the pre‐conception TKI‐free interval and concentrating the treatment‐free period around pregnancy. This strategy may be particularly useful when durable TFR is uncertain or fertility is time‐sensitive.

This approach was especially relevant in the present patient because her anti‐Müllerian hormone level was decreased. Her embryos were preserved during the second TKI‐free interval, allowing ponatinib to be resumed and MR4.5 to be regained before planned embryo transfer. Previous case series have included women with CP‐CML who underwent medically assisted reproduction, supporting the role of reproductive medicine in individualized pregnancy planning [14]. Takayama et al. [15] also reported a woman with CP‐CML who underwent embryo cryopreservation during a TKI‐free interval, resumed TKI treatment, and subsequently achieved pregnancy and live birth following frozen embryo transfer after another TKI discontinuation. A distinctive feature of the present case was the deepening of the MR within a relatively short period of ponatinib retreatment before TKI interruption and embryo transfer.

Future strategies may also incorporate newer agents capable of inducing DMR, such as asciminib. However, evidence supporting pregnancy‐oriented TKI interruption after re‐consolidation remains limited. Further clinical experience is needed to determine how best to coordinate MR, TKI retreatment, fertility preservation, and embryo transfer.

In conclusion, this case illustrates how ART can be strategically integrated with CP‐CML treatment when durable TFR is uncertain. Embryo cryopreservation allowed fertility preservation to be completed independently of pregnancy timing, followed by individualized ponatinib re‐consolidation and TKI discontinuation shortly before embryo transfer. This approach minimized the pre‐conception treatment‐free interval and enabled pregnancy and live birth without TKI exposure during gestation. The case supports a pregnancy‐oriented strategy in which CP‐CML treatment and embryo transfer are coordinated through close collaboration between hematology and reproductive medicine.

Author Contributions

F.T. and T.O. drafted the manuscript. All authors critically revised the manuscript and approved the final version.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report.

Conflicts of Interest

Takaaki Ono received honoraria from Novartis, Otsuka Pharmaceutical, and Pfizer. The other authors declare no conflicts of interest.

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.