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

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Recruiting

CT.gov ID

NCT01752062

Collaborator

(none)

148

Enrollment

Locations

115

Anticipated Duration (Months)

2.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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	Intervention/Treatment	Phase
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

Study Type:

Observational

Anticipated 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

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Outcome Measures

Primary Outcome Measures

Number of normal birth, elective termination and spontaneous abortion [At 3 years from study entry]
Pregnancy outcome: it will be calculated in terms of normal birth, elective termination, spontaneous abortion
Number of patients with major molecular remission loss [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.
Number of patients with disease progression [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.
Number of patients with CCgR loss [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

Number of male and female patients conceiving during treatment [At 3 years from study entry]
Proportion of male and female patients conceiving during the treatment with TKI
Number of spontaneous abortion [At 3 years from study entry]
Proportion of spontaneous abortion
Number of of foetal abnormalities [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.
Number of patients surviving [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.
Number of patients alive with no disease progression [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.
Number of patients with molecular response. [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.
Number of patients with major molecular remission [At 3 years from study entry]
Evaluation of Major Molecular Remission (MMR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Unità Operativa di Oncologia - Presidio Ospedaliero N. Giannetasio - Azienda ASL 3 Rossano (CS)	Rossano	Cosenza	Italy
2	Azienda Ospedaliera - Nuovo Ospedale "Torrette"	Ancona		Italy
3	S.G. Moscati Hospital	Avellino		Italy
4	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari		Italy
5	Divisione di Ematologia - Ospedali Riuniti Bergamo	Bergamo		Italy
6	Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi	Bologna		Italy
7	Spedali Civili - Azienda Ospedaliera - U.O. Ematologia	Brescia		Italy
8	Divisione di Ematologia Ospedale A. Perrino	Brindisi		Italy
9	ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO	Cagliari		Italy
10	Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi	Catania		Italy
11	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania		Italy
12	Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna	Ferrara		Italy
13	Policlinico di Careggi, Università Degli Studi Firenze	Firenze		Italy
14	Clinica Ematologica - DiMI - Università degli Studi di Genova	Genova		Italy
15	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina		Italy
16	Ospedale Niguarda "Ca Granda"	Milano		Italy
17	UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico	Milano		Italy
18	N. Osp. divisione di Ematologia "S.Gerardo dei Tintori"	Monza		Italy
19	Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" Napoli	Napoli		Italy
20	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli		Italy
21	Ospedale San Gennaro - ASL Napoli 1	Napoli		Italy
22	S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro	Novara		Italy
23	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Prof. Giuseppe Saglio	Orbassano		Italy
24	Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"	Palermo		Italy
25	Ospedale La Maddalena - Palermo	Palermo		Italy
26	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo		Italy
27	Div. di Ematologia IRCCS Policlinico S. Matteo	Pavia		Italy	27100
28	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro		Italy
29	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara		Italy
30	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza		Italy
31	Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia	Pisa		Italy
32	Ematologia - Ospedale San Carlo	Potenza		Italy
33	Ospedale S. M. delle Croci	Ravenna		Italy	I-48100
34	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria		Italy
35	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia		Italy
36	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma		Italy
37	Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo	Roma		Italy
38	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
39	U.O.C. Ematologia - Ospedale S.Eugenio	Roma		Italy
40	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma		Italy
41	UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"	Roma		Italy
42	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo		Italy
43	Ematologia - Dipartimento di Medicina Clinica e Sperimentale	Sassari		Italy
44	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena		Italy
45	U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati	Taranto		Italy
46	Azienda ospedaliera S. Maria di Terni	Terni		Italy
47	SCDO Ematologia 2 AOU S. Giovanni Battista	Torino		Italy
48	Sezione di Ematologia - Med.II Div. Presidio Ospedaliero S. Chiara di Trento	Trento		Italy
49	Azienda U.L.S.S.9 - U.O. di Ematologia	Treviso		Italy
50	Policlinico Universitario - Clinica Ematologia	Udine		Italy	33100
51	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona		Italy
52	ULSS N.6 Osp. S. Bortolo	Vicenza		Italy