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Observational Study of Conception/Pregnancy in Adult Patients With CML Treated With Tyrosine Kinase Inhibitors (CML1012)

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ClinicalTrials.gov Identifier: NCT01752062
Recruitment Status : Recruiting
First Posted : December 18, 2012
Last Update Posted : January 5, 2022
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

Study Description
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Brief Summary:
The objective of this study is to acquire more information about what we are doing during pregnancy in CML patients, in order to possibly establish in the future a consensus on the management of patients receiving TKIs who wants to father a child or become/are pregnant.

Condition or disease
Chronic Myeloid Leukemia Pregnancy

Detailed Description:
The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continued debate. The introduction of the TKIs in clinical practice has dramatically changed the prognosis of CML. Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life. Thus, the need to address issues related to fertility and pregnancy have arisen. Physicians are frequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. The management of fertility begins at diagnosis. This means that immediate and future treatments should be considered at the very beginning. Therefore, the maintenance of fertility should be taken into account since diagnosis. Imatinib is not genotoxic but might lead to a decrease in sperm counts. Nevertheless, Imatinib is teratogenic in rats when given during organogenesis at doses higher than 100 mg/kg, approximately equivalent to 800 mg/day in men. Until now, approximately 60 pregnancies were reported in partners of men on Imatinib. No suggestions of any problems in conception, pregnancy, delivery or any increase in congenital abnormalities were reported. Regarding women, 204 patients were exposed to Imatinib, and 180 were reported in literature (76, 77). Of 180 women exposed to imatinib during pregnancy, outcome data are available for 125 (69%). Of those with known outcomes, 50% delivered normal infants and 28% underwent elective terminations, 3 following the identification of abnormalities. There were a total of 12 infants in whom abnormalities were identified, 3 of which had strikingly similar complex malformations that are clearly a cause for concern. It appears that although most pregnancies exposed to imatinib are likely to have a successful outcome, there remains a risk that exposure may result in serious fetal malformations. Although numbers are small there has been a disturbing cluster of rare congenital malformations such that imatinib cannot be safely recommended, particularly during the period of organogenesis. Last but not least, it has recently been reported a poor outcome after reintroduction of Imatinib in patients who interrupt therapy for pregnancy without having achieved an optimal response (78), introducing another variable in the management of women pregnant while receiving Imatinib. Only few data are available about the use of second generation TKIs, Nilotinib and Dasatinib, during pregnancy. Dasatinib is not mutagenic in rats (in vitro and in vivo tests), but is clastogenic in CHO cells. It does not seem to have such effect on fertility of male and female rats. However, it gives skeletal alterations in rats and rabbits and has embryolethality in rats if administered during pregnancies. Eleven pregnancies were reported while in dasatinib: 5 patients delivered normal infants, while 3 elective termination and 2 spontaneous abortion were reported. On the other hand, 9 male patient conceived during dasatinib: 8 normal infants were delivered, and 1 case was ongoing at the time of the report. Nilotinib is not mutagenic in rats. It does not have any effect on fertility in male and female rats. When administered during pregnancy, there is no evidence of teratogenicity but it is embryo and foetotoxic in the rat and in the rabbit. Only sporadic cases of patients who had been pregnant/had conceived during Nilotinib have been reported, and no speculation should be made from these data. In summary, there are virtually no data regarding II generation TKIs, that must be discontinued by women wishing to become pregnant. Several questions still remains unanswered regarding the management of patients receiving TKIs who want to conceive, or who have been exposed to TKI during pregnancy/conception.
Study Design
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Study Type : Observational
Estimated Enrollment : 148 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Observational Study of Conception/Pregnancy in Adult Patients With Chronic Myeloid Leukemia (CML) Treated With Tyrosine Kinase Inhibitors
Actual Study Start Date : May 2, 2013
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

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Groups and Cohorts
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Outcome Measures
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Primary Outcome Measures :
  1. Number of normal birth, elective termination and spontaneous abortion [ Time Frame: At 3 years from study entry ]
    Pregnancy outcome: it will be calculated in terms of normal birth, elective termination, spontaneous abortion

  2. Number of patients with major molecular remission loss [ Time Frame: At 3 years from study entry ]
    Cumulative Incidence of MMR loss: it will be calculated from the date of achievement of MMR using the cumulative incidence method, where death will be considered as competing risk. Patients still alive, in first MMR, will be censored at the moment of last follow-up.

  3. Number of patients with disease progression [ Time Frame: At 3 years from study entry. ]
    Cumulative Incidence of Disease Progression: it will be calculated from the date of diagnosis using the cumulative incidence method, where death without signs of disease progression will be considered as competing risk. Patients still alive, without a date of progression, will be censored at the moment of last follow-up.

  4. Number of patients with CCgR loss [ Time Frame: At 3 years from study entry ]
    Cumulative Incidence of CCgRloss: it will be calculated from the date of achievement of CCgR using the cumulative incidence method, where death in CCgR will be considered as competing risk. Patients still alive, in first CCgR, will be censored at the moment of last follow-up.


Secondary Outcome Measures :
  1. Number of male and female patients conceiving during treatment [ Time Frame: At 3 years from study entry ]
    Proportion of male and female patients conceiving during the treatment with TKI

  2. Number of spontaneous abortion [ Time Frame: At 3 years from study entry ]
    Proportion of spontaneous abortion

  3. Number of of foetal abnormalities [ Time Frame: At 3 years from study entry ]
    Proportion of foetal abnormalities: it will be calculated with respect to the study population and with respect to normal population.

  4. Number of patients surviving [ Time Frame: At 3 years from study entry ]
    Overall Survival (OS): it will be calculated from the date of CML diagnosis until date of death (whatever the cause). Patients still alive will be censored at the moment of last follow-up.

  5. Number of patients alive with no disease progression [ Time Frame: At 3 years from study entry ]
    Progression Free Survival (PFS): it will be calculated from the date of CML diagnosis until the date of first progression to A-B phase or until death (whatever the cause), whichever occurs first. Patients still alive, without a date of progression, will be censored at the moment of last follow-up.

  6. Number of patients with molecular response. [ Time Frame: At 3 years from study entry ]
    Duration of CCgR/ Molecular response (MR): it will be calculated from the date of achievement of CCgR, MR until first date of CCgR loss or until death (whatever the cause), whichever occurs first. Patients still alive, in first CCgR/MR, will be censored at the moment of last follow-up.

  7. Number of patients with major molecular remission [ Time Frame: At 3 years from study entry ]
    Evaluation of Major Molecular Remission (MMR)


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Adult (>18 years old) patients with a diagnosis of chronic myeloid leukemia (CML) who had been pregnant / had conceived while diagnosed with CML and treated with TKIs.
Criteria

Inclusion Criteria:

  • Age > 18 years;
  • Ph+/BCR-ABL+ CML in any phase of disease;
  • Conception/pregnancy while diagnosed with CML
  • Treatment with TKIs (before or after pregnancy);
  • Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

  • Patient < 18 years
  • Patients that suffer from any condition or illness that could prevent the patient to participate
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01752062


Contacts
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Contact: Paola Fazi, Dr. p.fazi@gimema.it
Contact: Enrico Crea e.crea@gimema.it

Locations
Show Show 52 study locations
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
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Principal Investigator: Elisabetta Abruzzese Hematology, S. Eugenio Hospital, Rome
More Information
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Additional Information:

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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT01752062    
Other Study ID Numbers: CML1012
First Posted: December 18, 2012    Key Record Dates
Last Update Posted: January 5, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Chronic Myeloid Leukemia
CML
Pregnancy
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
 Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases