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

Pregnancy Clinical Trial

— CML1012  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01752062
• Other study ID #: CML1012
• Status: Recruiting
• Start date: May 2, 2013
• Est. completion date: December 2022

Study information

• Verified date: January 2022
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: Paola Fazi, Dr.
• Email: p.fazi[@]gimema.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 148
• Est. completion date: December 2022
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Pregnancy

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera - Nuovo Ospedale "Torrette"	Ancona
Italy	S.G. Moscati Hospital	Avellino
Italy	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari
Italy	Divisione di Ematologia - Ospedali Riuniti Bergamo	Bergamo
Italy	Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi	Bologna
Italy	Spedali Civili - Azienda Ospedaliera - U.O. Ematologia	Brescia
Italy	Divisione di Ematologia Ospedale A. Perrino	Brindisi
Italy	ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO	Cagliari
Italy	Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi	Catania
Italy	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania
Italy	Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna	Ferrara
Italy	Policlinico di Careggi, Università Degli Studi Firenze	Firenze
Italy	Clinica Ematologica - DiMI - Università degli Studi di Genova	Genova
Italy	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina
Italy	Ospedale Niguarda "Ca Granda"	Milano
Italy	UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico	Milano
Italy	N. Osp. divisione di Ematologia "S.Gerardo dei Tintori"	Monza
Italy	Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" Napoli	Napoli
Italy	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli
Italy	Ospedale San Gennaro - ASL Napoli 1	Napoli
Italy	S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro	Novara
Italy	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Prof. Giuseppe Saglio	Orbassano
Italy	Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"	Palermo
Italy	Ospedale La Maddalena - Palermo	Palermo
Italy	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo
Italy	Div. di Ematologia IRCCS Policlinico S. Matteo	Pavia
Italy	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro
Italy	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza
Italy	Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia	Pisa
Italy	Ematologia - Ospedale San Carlo	Potenza
Italy	Ospedale S. M. delle Croci	Ravenna
Italy	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria
Italy	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma
Italy	Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo	Roma
Italy	S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena- I.F.O. Istituto Nazionale Tumori Regina Elena Roma	Roma
Italy	U.O.C. Ematologia - Ospedale S.Eugenio	Roma
Italy	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma
Italy	UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"	Roma
Italy	Unità Operativa di Oncologia - Presidio Ospedaliero N. Giannetasio - Azienda ASL 3 Rossano (CS)	Rossano	Cosenza
Italy	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	Ematologia - Dipartimento di Medicina Clinica e Sperimentale	Sassari
Italy	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena
Italy	U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati	Taranto
Italy	Azienda ospedaliera S. Maria di Terni	Terni
Italy	SCDO Ematologia 2 AOU S. Giovanni Battista	Torino
Italy	Sezione di Ematologia - Med.II Div. Presidio Ospedaliero S. Chiara di Trento	Trento
Italy	Azienda U.L.S.S.9 - U.O. di Ematologia	Treviso
Italy	Policlinico Universitario - Clinica Ematologia	Udine
Italy	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona
Italy	ULSS N.6 Osp. S. Bortolo	Vicenza

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of normal birth, elective termination and spontaneous abortion	Pregnancy outcome: it will be calculated in terms of normal birth, elective termination, spontaneous abortion	At 3 years from study entry
Primary	Number of patients with major molecular remission loss	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.	At 3 years from study entry
Primary	Number of patients with disease progression	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.	At 3 years from study entry.
Primary	Number of patients with CCgR loss	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.	At 3 years from study entry
Secondary	Number of male and female patients conceiving during treatment	Proportion of male and female patients conceiving during the treatment with TKI	At 3 years from study entry
Secondary	Number of spontaneous abortion	Proportion of spontaneous abortion	At 3 years from study entry
Secondary	Number of of foetal abnormalities	Proportion of foetal abnormalities: it will be calculated with respect to the study population and with respect to normal population.	At 3 years from study entry
Secondary	Number of patients surviving	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.	At 3 years from study entry
Secondary	Number of patients alive with no disease progression	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.	At 3 years from study entry
Secondary	Number of patients with molecular response.	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.	At 3 years from study entry
Secondary	Number of patients with major molecular remission	Evaluation of Major Molecular Remission (MMR)	At 3 years from study entry

External Links

•   GIMEMA Foundation