Clinical trial NCT01752062: Observational Study of Conception/Pregnancy in Adult Patients With CML Treated With Tyrosine Kinase Inhibitors
Official title: Observational Study of Conception/Pregnancy in Adult Patients With Chronic Myeloid Leukemia (CML) Treated With Tyrosine Kinase Inhibitors
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Chronic Myeloid Leukemia
Pregnancy
Keywords: Chronic Myeloid Leukemia
CML
Pregnancy
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2012-12-18
Enrollment: 148
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility 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

Primary outcomes:
measure: Number of normal birth, elective termination and spontaneous abortion
timeFrame: At 3 years from study entry
measure: Number of patients with major molecular remission loss
timeFrame: At 3 years from study entry
measure: Number of patients with disease progression
timeFrame: At 3 years from study entry.
measure: Number of patients with CCgR loss
timeFrame: At 3 years from study entry
Secondary outcomes:
measure: Number of male and female patients conceiving during treatment
timeFrame: At 3 years from study entry
measure: Number of spontaneous abortion
timeFrame: At 3 years from study entry
measure: Number of of foetal abnormalities
timeFrame: At 3 years from study entry
measure: Number of patients surviving
timeFrame: At 3 years from study entry
measure: Number of patients alive with no disease progression
timeFrame: At 3 years from study entry
measure: Number of patients with molecular response.
timeFrame: At 3 years from study entry
measure: Number of patients with major molecular remission
timeFrame: At 3 years from study entry
Other outcomes:
Locations:
city: Rossano
country: Italy
facility: Unità Operativa di Oncologia - Presidio Ospedaliero N. Giannetasio - Azienda ASL 3 Rossano (CS)
state: Cosenza
city: Ancona
country: Italy
facility: Azienda Ospedaliera - Nuovo Ospedale "Torrette"
city: Avellino
country: Italy
facility: S.G. Moscati Hospital
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bergamo
country: Italy
facility: Divisione di Ematologia - Ospedali Riuniti Bergamo
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Brescia
country: Italy
facility: Spedali Civili - Azienda Ospedaliera - U.O. Ematologia
city: Brindisi
country: Italy
facility: Divisione di Ematologia Ospedale A. Perrino
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
city: Catania
country: Italy
facility: Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Ferrara
country: Italy
facility: Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
city: Firenze
country: Italy
facility: Policlinico di Careggi, Università Degli Studi Firenze
city: Genova
country: Italy
facility: Clinica Ematologica - DiMI - Università degli Studi di Genova
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
city: Milano
country: Italy
facility: Ospedale Niguarda "Ca Granda"
city: Milano
country: Italy
facility: UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
city: Monza
country: Italy
facility: N. Osp. divisione di Ematologia "S.Gerardo dei Tintori"
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" Napoli
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Napoli
country: Italy
facility: Ospedale San Gennaro - ASL Napoli 1
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Prof. Giuseppe Saglio
city: Palermo
country: Italy
facility: Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
city: Palermo
country: Italy
facility: Ospedale La Maddalena - Palermo
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Pavia
country: Italy
facility: Div. di Ematologia IRCCS Policlinico S. Matteo
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
city: Pisa
country: Italy
facility: Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Ospedale S. M. delle Croci
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Roma
country: Italy
facility: Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo
city: Roma
country: Italy
facility: S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena- I.F.O. Istituto Nazionale Tumori Regina Elena Roma
city: Roma
country: Italy
facility: U.O.C. Ematologia - Ospedale S.Eugenio
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Roma
country: Italy
facility: UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Ematologia - Dipartimento di Medicina Clinica e Sperimentale
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Taranto
country: Italy
facility: U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati
city: Terni
country: Italy
facility: Azienda ospedaliera S. Maria di Terni
city: Torino
country: Italy
facility: SCDO Ematologia 2 AOU S. Giovanni Battista
city: Trento
country: Italy
facility: Sezione di Ematologia - Med.II Div. Presidio Ospedaliero S. Chiara di Trento
city: Treviso
country: Italy
facility: Azienda U.L.S.S.9 - U.O. di Ematologia
city: Udine
country: Italy
facility: Policlinico Universitario - Clinica Ematologia
city: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
city: Vicenza
country: Italy
facility: ULSS N.6 Osp. S. Bortolo
Study officials:
affiliation: Hematology, S. Eugenio Hospital, Rome
name: Elisabetta Abruzzese
role: PRINCIPAL_INVESTIGATOR
References: