correspondence
Pregnancy in acute promyelocytic leukaemia after front-line therapy with arsenic trioxide and all-trans retinoic acid
Arsenic trioxide (ATO) is the most effective agent in acute promyelocytic leukaemia (APL) and is being increasingly used in the management of both relapsed and newly diagnosed patients. We recently reported that a chemotherapyfree regimen including arsenic trioxide ATO and all-trans retinoic acid (ATRA) improved event-free survival and overall survival compared to standard chemotherapy and ATRA in low- and intermediate-risk patients (Lo Coco et al, 2013). While it is known from animal studies that high exposure to arsenic during pregnancy may cause infertility and miscarriages (Golub et al, 1998), no information is available on the effects of arsenic on human fertility for APL patients who received arsenic as front-line therapy and conceived after treatment. We report hereby on 3 APL young women diagnosed with APL and treated with ATO and ATRA frontline at a single Institution who experienced an uneventful pregnancy and gave birth to healthy newborns with no malformations or congenital disorders. The median age of the 3 women was 27 years (range 22– 35 years). Upon confirmation of a diagnosis of APL at the genetic level, they were all enrolled in the APL0406 randomized study. Two patients were categorized as having low risk and one intermediate risk disease according to the Sanz score [median white blood cell (WBC) count of 34 9 109/l and median platelet count of 68 9 109/l]. During induction therapy, one patient had a retinal haemorrhage and leucocytosis (WBC peak 57 9 109/l at day 10) that required concomitant cytoreductive therapy and another patient developed rhagades, accompanied by fever that required intravenous antibiotic therapy and pain management, together with a concomitant moderate leucocytosis (WBC 10 9 109/l at day
4), which resolved spontaneously (Table I). All patients achieved a complete morphological remission (CR) after the first cycle and then received four further cycles of 5 d/week of ATO at a dose of 10 mg as consolidation, alternating with seven ATRA cycles (45 mg/m2). All patients achieved a molecular complete remission (mCR) after the first consolidation cycle. The patients conceived after a median followup of 8 months (range 5–12) from the end of the last consolidation. During gestation, monthly real-time quantitative polymerase chain reaction tests were carried out using peripheral blood samples, which showed a persistent mCR. The course of each gestation and delivery (one caesarean and two vaginal deliveries) were uneventful, with no complications for the mothers or the fetuses. The median weight of the healthy newborns was 35 kg (range 32–38). No pregnancies had been recorded in 35 young women treated with chemotherapy at our Institute during the previous 9 years. Earlier studies have reported the successful delivery of normal infants after ATO treatment for relapsed patients (Ammatuna et al, 2009; Gupta et al, 2012). Preliminary data were reported on 20 patients who successfully conceived after the AIDA (ATRA plus idarubicin) schedule (Carluccio et al, 2010). Data on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenic trioxide (Golub et al, 1998). Animal studies in four species (hamsters, mice, rats, rabbits) have shown that exposure to arsenic can result in malformation, death and growth retardation, which are dose and time-dependent. These studies have not identified an effect of arsenic on fertility in either males or females; however,
Table I. Clinico-biological features of patients with a successful pregnancy arsenic trioxide frontline therapy with arsenic trioxide.
Case
Age (years)
WBC (9109/l)
Plts (9109/l)
Relapse risk
Transcript
1
22
78
69
Intermediate
bcr1
2
33
18
68
Low
bcr1
3
31
08
68
Low
bcr3
Complications during therapy Retinal haemorrhage Leucocytosis No Fever and rhagades, infection
mCR
Delivery
Gender of newborn
Weight of newborn (kg)
Malformations/ Growth retardation
After 1 cycle
Caesarean
Female
38
No
After 2 cycles After 1 cycle
Caesarean
Female
37
No
Vaginal
Female
32
No
mCR, molecular complete remission; Plts, platelet count; WBC, white blood cell count.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
doi:10.1111/bjh.12995
Correspondence animals chronically exposed for periods that included pregnancy had a primary dose-dependent increase in fetal mortality and postnatal growth retardation (Golub et al, 1998). In pregnant mice, arsenic can induce aberrant placenta vasculogenesis and placental insufficiency (He et al, 2007). With regard to humans, data are limited to a few studies conducted in populations exposed to arsenic from drinkable water or from working at or living near smelters; an association with spontaneous abortion and stillbirth has been reported in more than one of these studies (Naujokas et al, 2013). ATO has emerged as the new standard for the frontline treatment of non-high risk APL patients and is the first recommended therapeutic option for relapsed disease. The present report suggests that, in addition to other advantages compared to chemotherapy, ATO may also represent a safe treatment with respect to human fertility.
Acknowledgements
the analysis; RF and FLC critically revised the paper and approved the final version.
Conflict of interest All authors declare no competing financial interests in relation to this work. Massimo Breccia1 Matteo Molica1 Fabio Efficace2 Clara Minotti1 Roberto Latagliata1 Robin Foa1 Francesco Lo Coco3 1
Department of Cellular Biotechnologies and Hematology, Sapienza
University, 2Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), and 3Department of Biopathology, University Tor Vergata, and Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Rome, Italy
No funding or sponsorship for this article.
E-mail: [email protected]
Author contributions
Keywords: acute promyelocytic leukaemia, arsenic trioxide, pregnancy
MB designed the study, analysed data and wrote the manuscript; MM, RL, CM followed patients; FE provided data for
References Ammatuna, E., Cavaliere, A., Divona, M., Amadori, S., Scambia, G. & Lo Coco, F. (2009) Successful pregnancy after arsenic trioxide therapy for relapsed acute promyelocytic leukaemia. British Journal of Haematology, 146, 341. Carluccio, P., Ricco, A., Pastore, D., Breccia, M., Kropp, M.G., Di Bona, E., Fabbiano, F., Ferrara, F., Melillo, L., Lo-Coco, F. & Specchia, G. (2010) Successful pregnancy in APL patients treated according to the AIDA protocol. Blood, 116, abstract 1037. Golub, M.S., Macintosh, M.S. & Baumrind, N. (1998) Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns. Journal of Toxicology and Environmental Health. Part B, Critical Reviews, 1, 199–241.
2
Gupta, S., Bagel, B., Gujral, S., Subramanian, P.G., Khattry, N., Menon, H. & Nair, R. (2012) Parenthood in patients with acute promyelocytic leukemia after treatment with arsenic trioxide: a case series. Leukemia and Lymphoma, 53, 2192– 2194. He, W., Greenwell, R.J., Brooks, D.M., CalderonGarciduenas, L., Beall, H.D. & Coffin, J.D. (2007) Arsenic exposure in pregnant mice disrupts placental vasculogenesis and causes spontaneous abortion. Toxicological Science, 99, 244–253. Lo Coco, F., Avvisati, G., Vignetti, M., Thiede, C., Orlando, S.M., Iacobelli, S., Ferrara, F., Fazi, P., Cicconi, L., Di Bona, E., Specchia, G., Sica, S., Divona, M., Levis, A., Fiedler, W., Cerqui, E., Breccia, M., Fioritoni, G., Salih, H.R., Cazzola, M., Melillo, L., Carella, A.M., Brandts, C.H., Morra, E., von Lilienfeld-Toal, M., Hertenstein,
B., Wattad, M., L€ ubbert, M., H€anel, M., Schmitz, N., Link, H., Kropp, M.G., Rambaldi, A., La Nasa, G., Luppi, M., Ciceri, F., Finizio, O., Venditti, A., Fabbiano, F., D€ ohner, K., Sauer, M., Ganser, A., Amadori, S., Mandelli, F., D€ ohner, H., Ehninger, G., Schlenk, R.F., Platzbecker, U. & Gruppo Italiano Malattie Ematologiche dell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. New England Journal of Medicine, 369, 111–121. Naujokas, M.F., Anderson, B., Ahsan, H., Aposhian, H.V., Graziano, J.H., Thompson, C. & Suk, W.A. (2013) The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environmental Health Perspective, 121, 295–302.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Pregnancy in acute promyelocytic leukaemia after front-line therapy with arsenic trioxide and all-trans retinoic acid
Arsenic trioxide (ATO) is the most effective agent in acute promyelocytic leukaemia (APL) and is being increasingly used in the management of both relapsed and newly diagnosed patients. We recently reported that a chemotherapyfree regimen including arsenic trioxide ATO and all-trans retinoic acid (ATRA) improved event-free survival and overall survival compared to standard chemotherapy and ATRA in low- and intermediate-risk patients (Lo Coco et al, 2013). While it is known from animal studies that high exposure to arsenic during pregnancy may cause infertility and miscarriages (Golub et al, 1998), no information is available on the effects of arsenic on human fertility for APL patients who received arsenic as front-line therapy and conceived after treatment. We report hereby on 3 APL young women diagnosed with APL and treated with ATO and ATRA frontline at a single Institution who experienced an uneventful pregnancy and gave birth to healthy newborns with no malformations or congenital disorders. The median age of the 3 women was 27 years (range 22– 35 years). Upon confirmation of a diagnosis of APL at the genetic level, they were all enrolled in the APL0406 randomized study. Two patients were categorized as having low risk and one intermediate risk disease according to the Sanz score [median white blood cell (WBC) count of 34 9 109/l and median platelet count of 68 9 109/l]. During induction therapy, one patient had a retinal haemorrhage and leucocytosis (WBC peak 57 9 109/l at day 10) that required concomitant cytoreductive therapy and another patient developed rhagades, accompanied by fever that required intravenous antibiotic therapy and pain management, together with a concomitant moderate leucocytosis (WBC 10 9 109/l at day
4), which resolved spontaneously (Table I). All patients achieved a complete morphological remission (CR) after the first cycle and then received four further cycles of 5 d/week of ATO at a dose of 10 mg as consolidation, alternating with seven ATRA cycles (45 mg/m2). All patients achieved a molecular complete remission (mCR) after the first consolidation cycle. The patients conceived after a median followup of 8 months (range 5–12) from the end of the last consolidation. During gestation, monthly real-time quantitative polymerase chain reaction tests were carried out using peripheral blood samples, which showed a persistent mCR. The course of each gestation and delivery (one caesarean and two vaginal deliveries) were uneventful, with no complications for the mothers or the fetuses. The median weight of the healthy newborns was 35 kg (range 32–38). No pregnancies had been recorded in 35 young women treated with chemotherapy at our Institute during the previous 9 years. Earlier studies have reported the successful delivery of normal infants after ATO treatment for relapsed patients (Ammatuna et al, 2009; Gupta et al, 2012). Preliminary data were reported on 20 patients who successfully conceived after the AIDA (ATRA plus idarubicin) schedule (Carluccio et al, 2010). Data on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenic trioxide (Golub et al, 1998). Animal studies in four species (hamsters, mice, rats, rabbits) have shown that exposure to arsenic can result in malformation, death and growth retardation, which are dose and time-dependent. These studies have not identified an effect of arsenic on fertility in either males or females; however,
Table I. Clinico-biological features of patients with a successful pregnancy arsenic trioxide frontline therapy with arsenic trioxide.
Case
Age (years)
WBC (9109/l)
Plts (9109/l)
Relapse risk
Transcript
1
22
78
69
Intermediate
bcr1
2
33
18
68
Low
bcr1
3
31
08
68
Low
bcr3
Complications during therapy Retinal haemorrhage Leucocytosis No Fever and rhagades, infection
mCR
Delivery
Gender of newborn
Weight of newborn (kg)
Malformations/ Growth retardation
After 1 cycle
Caesarean
Female
38
No
After 2 cycles After 1 cycle
Caesarean
Female
37
No
Vaginal
Female
32
No
mCR, molecular complete remission; Plts, platelet count; WBC, white blood cell count.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
doi:10.1111/bjh.12995
Correspondence animals chronically exposed for periods that included pregnancy had a primary dose-dependent increase in fetal mortality and postnatal growth retardation (Golub et al, 1998). In pregnant mice, arsenic can induce aberrant placenta vasculogenesis and placental insufficiency (He et al, 2007). With regard to humans, data are limited to a few studies conducted in populations exposed to arsenic from drinkable water or from working at or living near smelters; an association with spontaneous abortion and stillbirth has been reported in more than one of these studies (Naujokas et al, 2013). ATO has emerged as the new standard for the frontline treatment of non-high risk APL patients and is the first recommended therapeutic option for relapsed disease. The present report suggests that, in addition to other advantages compared to chemotherapy, ATO may also represent a safe treatment with respect to human fertility.
Acknowledgements
the analysis; RF and FLC critically revised the paper and approved the final version.
Conflict of interest All authors declare no competing financial interests in relation to this work. Massimo Breccia1 Matteo Molica1 Fabio Efficace2 Clara Minotti1 Roberto Latagliata1 Robin Foa1 Francesco Lo Coco3 1
Department of Cellular Biotechnologies and Hematology, Sapienza
University, 2Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), and 3Department of Biopathology, University Tor Vergata, and Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Rome, Italy
No funding or sponsorship for this article.
E-mail: [email protected]
Author contributions
Keywords: acute promyelocytic leukaemia, arsenic trioxide, pregnancy
MB designed the study, analysed data and wrote the manuscript; MM, RL, CM followed patients; FE provided data for
References Ammatuna, E., Cavaliere, A., Divona, M., Amadori, S., Scambia, G. & Lo Coco, F. (2009) Successful pregnancy after arsenic trioxide therapy for relapsed acute promyelocytic leukaemia. British Journal of Haematology, 146, 341. Carluccio, P., Ricco, A., Pastore, D., Breccia, M., Kropp, M.G., Di Bona, E., Fabbiano, F., Ferrara, F., Melillo, L., Lo-Coco, F. & Specchia, G. (2010) Successful pregnancy in APL patients treated according to the AIDA protocol. Blood, 116, abstract 1037. Golub, M.S., Macintosh, M.S. & Baumrind, N. (1998) Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns. Journal of Toxicology and Environmental Health. Part B, Critical Reviews, 1, 199–241.
2
Gupta, S., Bagel, B., Gujral, S., Subramanian, P.G., Khattry, N., Menon, H. & Nair, R. (2012) Parenthood in patients with acute promyelocytic leukemia after treatment with arsenic trioxide: a case series. Leukemia and Lymphoma, 53, 2192– 2194. He, W., Greenwell, R.J., Brooks, D.M., CalderonGarciduenas, L., Beall, H.D. & Coffin, J.D. (2007) Arsenic exposure in pregnant mice disrupts placental vasculogenesis and causes spontaneous abortion. Toxicological Science, 99, 244–253. Lo Coco, F., Avvisati, G., Vignetti, M., Thiede, C., Orlando, S.M., Iacobelli, S., Ferrara, F., Fazi, P., Cicconi, L., Di Bona, E., Specchia, G., Sica, S., Divona, M., Levis, A., Fiedler, W., Cerqui, E., Breccia, M., Fioritoni, G., Salih, H.R., Cazzola, M., Melillo, L., Carella, A.M., Brandts, C.H., Morra, E., von Lilienfeld-Toal, M., Hertenstein,
B., Wattad, M., L€ ubbert, M., H€anel, M., Schmitz, N., Link, H., Kropp, M.G., Rambaldi, A., La Nasa, G., Luppi, M., Ciceri, F., Finizio, O., Venditti, A., Fabbiano, F., D€ ohner, K., Sauer, M., Ganser, A., Amadori, S., Mandelli, F., D€ ohner, H., Ehninger, G., Schlenk, R.F., Platzbecker, U. & Gruppo Italiano Malattie Ematologiche dell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. New England Journal of Medicine, 369, 111–121. Naujokas, M.F., Anderson, B., Ahsan, H., Aposhian, H.V., Graziano, J.H., Thompson, C. & Suk, W.A. (2013) The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environmental Health Perspective, 121, 295–302.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
