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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pregnancy; Chronic Myeloid Leukemia

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 Type: Observational
• Enrollment (Anticipated): 148

Contacts and Locations

• Study Contact: Name: Paola Fazi, Dr.; Email: p.fazi@gimema.it
• Study Contact Backup: Name: Enrico Crea; Email: e.crea@gimema.it

Study Locations

• Italy
  • Ancona, Italy
    • Recruiting
    • Azienda Ospedaliera - Nuovo Ospedale "Torrette"
    • Contact: Anna Rita Scortechini, Dr.
    • Principal Investigator: Anna Rita Scortechini, Dr.
    • Sub-Investigator: Serena Rupoli, Dr.
  • Avellino, Italy
    • Not yet recruiting
    • S.G. Moscati Hospital
    • Contact: Fausto Palmieri, Dr.
    • Principal Investigator: Fausto Palmieri, Dr.
    • Sub-Investigator: Antonio Volpe, Dr.
  • Bari, Italy
    • Recruiting
    • UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
    • Contact: Giorgina Specchia
    • Principal Investigator: Giorgina Specchia
  • Bergamo, Italy
    • Recruiting
    • Divisione di Ematologia - Ospedali Riuniti Bergamo
    • Contact: Alessandro Rambaldi, Dr.
    • Principal Investigator: Alessandro Rambaldi, Dr.
    • Sub-Investigator: Tamara Intermesoli, Dr.
  • Bologna, Italy
    • Recruiting
    • Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
    • Contact: Fausto Castagnetti, Dr.
    • Principal Investigator: Fausto Castagnetti, Dr.
    • Sub-Investigator: Gianantonio Rosti, Dr.
  • Brescia, Italy
    • Recruiting
    • Spedali Civili - Azienda Ospedaliera - U.O. Ematologia
    • Contact: Mariadele Capucci, Dr.
    • Principal Investigator: Mariadele Capucci, Dr.
    • Sub-Investigator: Lara Cavalli, Dr.
  • Brindisi, Italy
    • Recruiting
    • Divisione di Ematologia Ospedale A. Perrino
    • Contact: Angela Melpignano, Dr.
    • Sub-Investigator: Mariella Girasoli, Dr.
    • Principal Investigator: Angela Melpignano, Dr.
  • Cagliari, Italy
    • Recruiting
    • ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
    • Contact: Emilio Usala, Dr.
    • Principal Investigator: Emilio Usala, Dr.
    • Sub-Investigator: Maria Pina Simula, Dr.
  • Catania, Italy
    • Recruiting
    • Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi
    • Sub-Investigator: Stefania Impera, Dr.
    • Contact: Ugo Consoli, Dr.
    • Principal Investigator: Ugo Consoli, Dr.
  • Catania, Italy
    • Recruiting
    • Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
    • Contact: Fabio Stagno, Dr.
    • Principal Investigator: Fabio Stagno, Dr.
    • Sub-Investigator: Alessandra Cupri, Dr.
  • Ferrara, Italy
    • Not yet recruiting
    • Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna
    • Contact: Antonio Cuneo, Dr.
    • Principal Investigator: Antonio Cuneo, Dr.
    • Sub-Investigator: Francesco Cavazzini, Dr.
  • Firenze, Italy
    • Recruiting
    • Policlinico di Careggi, Università Degli Studi Firenze
    • Contact: Alberto Bosi, Dr.
    • Principal Investigator: Alberto Bosi, Dr.
    • Sub-Investigator: Anotonella Gozzini, Dr.
  • Genova, Italy
    • Recruiting
    • Clinica Ematologica - DiMI - Università degli Studi di Genova
    • Contact: Ivana Pierri, Dr.
    • Principal Investigator: Ivana Pierri, Dr.
    • Sub-Investigator: Micaela Bergamaschi, Dr.
  • Messina, Italy
    • Recruiting
    • Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
    • Contact: Caterina Musolino, Dr.
    • Principal Investigator: Caterina Musolino, Dr.
    • Sub-Investigator: Sabina Russo, Dr.
  • Milano, Italy
    • Recruiting
    • Ospedale Niguarda "Ca Granda"
    • Contact: Ester Pungolino, Dr.
    • Principal Investigator: Ester Pungolino, Dr.
    • Sub-Investigator: Anna Frustaci, Dr.
  • Milano, Italy
    • Recruiting
    • UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
    • Contact: Alessandra Iurlo, Dr.
    • Principal Investigator: Alessandra Iurlo, Dr.
  • Monza, Italy
    • Recruiting
    • N. Osp. divisione di Ematologia "S.Gerardo dei Tintori"
    • Contact: Carlo Gambacorti Passerini, Dr.
    • Principal Investigator: Carlo Gambacorti Passerini, Dr.
    • Sub-Investigator: Rocco Piazza, Dr.
  • Napoli, Italy
    • Recruiting
    • Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
    • Contact: Fabrizio Pane, Dr.
    • Principal Investigator: Fabrizio Pane, Dr.
    • Sub-Investigator: Luigia Luciano, Dr.
  • Napoli, Italy
    • Recruiting
    • Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" Napoli
    • Contact: Felicetto Ferrara, Dr.
    • Principal Investigator: Felicetto Ferrara, Dr.
    • Sub-Investigator: Mario Annunziata, Dr.
  • Napoli, Italy
    • Recruiting
    • Ospedale San Gennaro - ASL Napoli 1
    • Contact: Lucia Mastrullo, Dr.
    • Principal Investigator: Lucia Mastrullo, Dr.
    • Sub-Investigator: Maria Rosaria Esposito, Dr.
  • Novara, Italy
    • Recruiting
    • S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
    • Contact: Gianluca Gaidano, Dr.
    • Principal Investigator: Gianluca Gaidano, Dr.
    • Sub-Investigator: Monia Lunghi, Dr.
  • Orbassano, Italy
    • Recruiting
    • Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2 Prof. Giuseppe Saglio
    • Contact: Giovanna Rege, Dr.
    • Principal Investigator: Giovanna Rege, Dr.
    • Sub-Investigator: Carmen Fava, Dr.
  • Palermo, Italy
    • Recruiting
    • Ospedali Riuniti "Villa Sofia-Cervello"
    • Contact: Diamante Turri, Dr.
    • Principal Investigator: Diamante Turri, Dr.
  • Palermo, Italy
    • Recruiting
    • Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
    • Contact: Clementina Caracciolo, Dr.
    • Principal Investigator: Clementina Caracciolo, Dr.
    • Sub-Investigator: Ilenia Barbello, Dr.
  • Palermo, Italy
    • Not yet recruiting
    • Ospedale La Maddalena - Palermo
    • Contact: Maurizio Musso, Dr.
    • Principal Investigator: Maurizio Musso, Dr.
    • Sub-Investigator: Ferdinando Porretto, Dr.
  • Pavia, Italy, 27100
    • Recruiting
    • Div. di Ematologia IRCCS Policlinico S. Matteo
    • Contact: Ester Orlandi, Dr.
    • Principal Investigator: Ester Orlandi, Dr.
    • Sub-Investigator: Chiara Elena, Dr.
  • Pesaro, Italy
    • Not yet recruiting
    • Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
    • Contact: Giuseppe Visani
    • Principal Investigator: Giuseppe Visani, Dr.
    • Sub-Investigator: Alessandro Isidori, Dr.
  • Pescara, Italy
    • Recruiting
    • U.O. Ematologia Clinica - Azienda USL di Pescara
    • Contact: Roberto Di Lorenzo, Dr.
    • Principal Investigator: Roberto Di Lorenzo, Dr.
    • Sub-Investigator: Giuseppina Ricciuti, Dr.
  • Piacenza, Italy
    • Recruiting
    • Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
    • Contact: Elena Trabacchi, Dr.
    • Principal Investigator: Elena TRABACCHI, Dr.
    • Sub-Investigator: Daniele Vallisa, Dr.
  • Pisa, Italy
    • Recruiting
    • Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
    • Contact: Sara Galimberti, Dr.
    • Principal Investigator: Sara Galimberti, Dr.
  • Potenza, Italy
    • Recruiting
    • Ematologia - Ospedale San Carlo
    • Contact: Michele Pizzuti, Pr.
    • Principal Investigator: Michele Pizzuti, Pr.
  • Ravenna, Italy, I-48100
    • Recruiting
    • Ospedale S. M. delle Croci
    • Contact: Marzia Salvucci, Dr.
    • Principal Investigator: Marzia Salvucci, Dr.
  • Reggio Calabria, Italy
    • Recruiting
    • Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
    • Contact: Francesco Nobile, Dr.
    • Principal Investigator: Francesco Nobile, Dr.
    • Sub-Investigator: Bruno Martino, Dr.
  • Reggio Emilia, Italy
    • Recruiting
    • Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
    • Contact: Paolo Avanzini, Dr.
    • Principal Investigator: Paolo Avanzini, Dr.
    • Sub-Investigator: Isabella Capodanno, Dr.
  • Roma, Italy
    • Recruiting
    • Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
    • Contact: Enrico Montefusco, Dr.
    • Principal Investigator: Enrico Montefusco, Dr.
    • Sub-Investigator: Raffaele Porrini, Dr.
  • Roma, Italy
    • Recruiting
    • Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
    • Principal Investigator: Simona Sica, Dr.
    • Sub-Investigator: Federica Sorà, Dr.
  • Roma, Italy
    • Recruiting
    • Padiglione Cesalpino - I piano - Divisione di Ematologia - Ospedale S. Camillo
    • Contact: Leonardo Pacilli, Dr.
    • Principal Investigator: Leonardo Pacilli, Dr.
  • Roma, Italy
    • Recruiting
    • S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena- I.F.O. Istituto Nazionale Tumori Regina Elena Roma
    • Contact: Atelda Dr. Romano
    • Principal Investigator: Atelda Romano, Dr.
    • Sub-Investigator: Mariella D'Andrea, Dr.
  • Roma, Italy
    • Recruiting
    • U.O.C. Ematologia - Ospedale S.Eugenio
    • Contact: Elisabetta Abruzzese, Dr.
    • Principal Investigator: Elisabetta Abruzzese, Dr.
  • Roma, Italy
    • Recruiting
    • UOC Pronto Soccorso e Accettazione Ematologica - Dipartimento Biotecnologie Cellulari ed Ematologia - Università degli Studi di Roma "Sapienza"
    • Contact: Giuliana Alimena, Dr.
    • Principal Investigator: Giuliana Alimena, Dr.
    • Sub-Investigator: Massimo Breccia, Dr.
  • San Giovanni Rotondo, Italy
    • Recruiting
    • Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
    • Principal Investigator: Nicola Cascavilla, Dr.
    • Contact: Nicola Cascavilla, Dr.
    • Sub-Investigator: Antonietta Pia Falcone, Dr.
  • Sassari, Italy
    • Recruiting
    • Ematologia - Dipartimento di Medicina Clinica e Sperimentale
  • Siena, Italy
    • Recruiting
    • U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
    • Contact: Monica Bocchia, Dr.
    • Principal Investigator: Monica Bocchia, Dr.
    • Sub-Investigator: Lara Aprile, Dr.
  • Taranto, Italy
    • Not yet recruiting
    • U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati
    • Contact: Alessandro Maggi, Dr.
    • Principal Investigator: Alessandro Maggi, Dr.
    • Sub-Investigator: Claudia Ingrosso, Dr.
  • Terni, Italy
    • Not yet recruiting
    • Azienda Ospedaliera S. Maria di Terni
    • Contact: Anna Maria Liberati, Dr.
    • Principal Investigator: Anna Maria Liberati, Dr.
    • Sub-Investigator: Debora Luzi, Dr.
  • Torino, Italy
    • Recruiting
    • SCDO Ematologia 2 AOU S. Giovanni Battista
    • Contact: Patrizia Pregno, Dr.
    • Principal Investigator: Patrizia Pregno, Dr.
    • Sub-Investigator: Paola Riccomagno, Dr.
  • Trento, Italy
    • Not yet recruiting
    • Sezione di Ematologia - Med.II Div. Presidio Ospedaliero S. Chiara di Trento
    • Contact: Paolo Vivaldi, Dr.
    • Principal Investigator: Paolo Vivaldi, Dr.
    • Sub-Investigator: Anna Guella, Dr.
  • Treviso, Italy
    • Recruiting
    • Azienda U.L.S.S.9 - U.O. di Ematologia
    • Contact: Filippo Gherlinzoni, Dr.
    • Principal Investigator: Filippo Gherlinzoni, Dr.
    • Sub-Investigator: Elisabetta Calistri, Dr.
  • Udine, Italy, 33100
    • Recruiting
    • Policlinico Universitario - Clinica Ematologia
    • Contact: Mario Tiribelli, Dr
    • Principal Investigator: Mario Tiribelli, Dr.
    • Sub-Investigator: Luciana Marin, Dr.
  • Verona, Italy
    • Not yet recruiting
    • Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
    • Contact: Massimiliano Bonifacio, Dr.
    • Principal Investigator: Massimiliano Bonifacio, Dr.
  • Vicenza, Italy
    • Recruiting
    • ULSS N.6 Osp. S. Bortolo
    • Contact: Anna D'Emilio, Dr.
    • Principal Investigator: Anna D'Emilio, Dr.
  • Cosenza
    • Rossano, Cosenza, Italy
      • Not yet recruiting
      • Unità Operativa di Oncologia - Presidio Ospedaliero N. Giannetasio - Azienda ASL 3 Rossano (CS)
      • Contact: Francesco Iuliano, Dr.
      • Principal Investigator: Francesco Iuliano, Dr.
      • Sub-Investigator: Stefania Impera, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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.
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Number of spontaneous abortion	Proportion of spontaneous abortion	At 3 years from study entry
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
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
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
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
Number of patients with major molecular remission	Evaluation of Major Molecular Remission (MMR)	At 3 years from study entry

Collaborators and Investigators

• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Investigators: Principal Investigator: Elisabetta Abruzzese, Hematology, S. Eugenio Hospital, Rome

Publications and helpful links

Helpful Links

• GIMEMA Foundation

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2013
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: December 14, 2012
• First Submitted That Met QC Criteria: December 17, 2012
• First Posted (Estimate): December 18, 2012

Study Record Updates

• Last Update Posted (Actual): January 5, 2022
• Last Update Submitted That Met QC Criteria: January 4, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Pregnancy; Chronic Myeloid Leukemia; CML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CML1012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No