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Case Report
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in pregnancy
J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214568582 opp.sagepub.com
Candace B Mainor1, Alison P Duffy2, Kristin L Atkins3, Amy S Kimball1,4 and Maria R Baer1,4
Abstract BCR-ABL inhibitors administered in conjunction with chemotherapy have significantly improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia but, for patients diagnosed during pregnancy, data on risks to the fetus are limited. We report a woman treated with chemotherapy and imatinib mesylate who delivered a healthy baby at 30 weeks, and we discuss available data.
Keywords Acute lymphoblastic leukemia, pregnancy, imatinib mesylate
Introduction Acute lymphoblastic leukemia (ALL) represents 20% of adult acute leukemia. The most common cytogenetic abnormality is translocation (9;22), resulting in a derivative chromosome 22 called the Philadelphia chromosome (Ph) that encodes a leukemogenic tyrosine kinase, BCR-ABL. BCR-ABL inhibitors, such as imatinib mesylate (IM), function by binding to the tyrosine kinase and preventing tyrosine autophosphorylation, thereby inhibiting activation of downstream signal transduction pathways. The (9;22) translocation is found in 15%–30% of adult ALL cases.1 Prior to incorporation of BCRABL inhibitors into treatment regimens, Phþ ALL had a lower complete remission (CR) rate than Ph ALL, in the range of 50%–70%,2–5 as well as shorter overall survival, and allogeneic hematopoietic stem cell transplant in first CR was the treatment of choice for eligible patients.6,7 BCR-ABL inhibitors initiated with chemotherapy have significantly improved treatment outcomes in Phþ ALL.8 CR rates are in the range of 90%, and prolonged disease-free survival has been reported in 50%–80% of patients in different series.9,10 BCR-ABL levels are measured by reverse transcription polymerase chain reaction (RT-PCR) every three to six months, as a surrogate for residual
disease, and achieving and maintaining molecular remission is an important treatment endpoint.11 Patients treated with BCR-ABL inhibitors and chemotherapy are still at risk for relapse, and thus this treatment is still often used as a bridge to allogeneic hematopoietic stem cell transplant. Acute leukemia diagnosed during pregnancy is rare. It must be treated promptly and intensively, but teratogenicity of chemotherapeutic agents and, for Phþ ALL, BCR-ABL inhibitors must be considered. We report a woman diagnosed with Phþ ALL at 24 weeks of pregnancy who was treated with chemotherapy and the BCR-ABL inhibitor IM and delivered a healthy baby at 30 weeks.
1
Department of Medicine, University of Maryland School of Medicine, Baltimore, USA 2 Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, USA 3 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, USA 4 Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA Corresponding author: Candace B Mainor, Department of Medicine, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, USA. Email: [email protected]
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Case A 38-year-old woman was diagnosed with Phþ precursor B-ALL at 24 weeks of pregnancy. Multidisciplinary consensus decision was to proceed with therapy and deliver the baby after 30 weeks. The patient was treated with course 1 of the hyperCVAD regimen, as follows: cyclophosphamide 300 mg/m2 intravenously every 12 h for six doses, mesna 1800 mg/m2 by continuous intravenous infusion over 42 h, dexamethasone 40 mg orally on days 1–4 and 11–14, doxorubicin 50 mg/m2 intravenously on day 4, and vincristine 2 mg intravenously on days 4 and 11. Her actual body weight of 140 kg was used for body surface area and dose calculations. She was also treated with IM 400 mg orally daily12 and prophylactic intrathecal cytarabine (100 mg), rather than methotrexate. Fetal heart monitoring was performed daily and middle cerebral artery Doppler monitoring weekly. On day 26, a second identical chemotherapy course was initiated, rather the alternating hyperCVAD regimen, in order to avoid methotrexate. IM was continued. She received filgrastim daily as primary prophylaxis for chemotherapy-induced neutropenia after each chemotherapy course and trimethoprim/sulfamethoxazole for Pneumocystis carinii prophylaxis after course 2. At 30 weeks, the fetus had a biophysical profile of 2, and was delivered by cesarean section. Weight was 1.28 kg and Apgar scores were 5 and 9. Placenta histopathology was normal. Blood counts were normal and neonatal course was uncomplicated. The mother continued chemotherapy. On day 22 of cycle 3, the mother developed severe abdominal pain and a computerized tomography scan of the abdomen and pelvis showed a proximal small bowel obstruction (SBO). A nasogastric tube was placed and surgery consultation was obtained, but she became hemodynamically unstable and had a cardiac arrest. Return of spontaneous circulation was achieved, and she was transferred to the medical intensive care unit. Broadspectrum antibiotics, continuous renal replacement therapy, and vasopressors were initiated, but she developed progressive complications and died of Bacteroides fragilis septicemia seven weeks after delivery. The bacteremia likely resulted from bowel translocation in the setting of the SBO. The cause of the SBO was unknown. The baby was transferred to another hospital in her father’s home town at three months of age. There is no subsequent follow-up information.
Discussion Acute leukemia treatment during pregnancy is challenging.13 With a first trimester diagnosis, therapeutic abortion is recommended because of high risk of fetal death or malformations with chemotherapy given in early pregnancy.14 With a second or third trimester
diagnosis, and especially after 20 weeks, pregnancy can usually be preserved. Chemotherapy drugs administered during the second and third trimesters are associated with increased risk of intrauterine growth retardation and low birth weight, but only rare fetal deaths or long-term complications.15 Current treatment for Phþ ALL consists of chemotherapy and a BCRABL inhibitor, and teratogenicity of BCR-ABL inhibitors as well as chemotherapy must be considered in pregnant patients. Cyclophosphamide, doxorubicin, vincristine, and corticosteroids have been used safely in pregnant ALL patients in the second and third trimesters.15 In an observational study evaluating the long-term effects of prenatal exposure to chemotherapy, Amant et al.16 found that neurocognitive development, growth, hearing, and cardiac function were similar to those of the general population. Aviles et al. analyzed over 80 children exposed to chemotherapy in utero, for a variety of maternal malignancies. None of 29 children whose mothers had acute leukemia had developed a malignancy at a median age of 11.4 years.17 Methotrexate has been designated as pregnancy category X and is teratogenic. The most common abnormalities following methotrexate exposure in utero are skull, hand, and limb deformities.18 Therefore, methotrexate was not used in our patient’s treatment regimen before delivery. We chose IM as the BCR-ABL inhibitor for our patient because of reports of its use in pregnant chronic myeloid leukemia (CML) patients in all three trimesters.19–21 Among 125 women who received IM at various times during pregnancy, 63 delivered normal infants, 18 had spontaneous abortions (similar to the general population), 35 had elective terminations (three with fetal abnormalities), and nine babies had congenital abnormalities, including premature closure of skull sutures, exomphalos, and vertebral abnormalities.21 Mothers of 10 fetuses or babies with abnormalities were exposed to IM during the first trimester. Outcomes in 38 women continuing IM throughout pregnancy included seven spontaneous abortions, six elective terminations with one known fetal abnormality, 18 live births without congenital abnormalities, and seven unknown.21 Among 10 women exposed to IM for four to nine weeks during the first trimester, with IM discontinued when pregnancies were confirmed, two had spontaneous abortions and seven delivered eight babies, including one with congenital hypospadias.20 IM does not appear to cross the placenta late in gestation.21,22 Nevertheless, IM was detected in the blood of the healthy newborn baby of a CML patient started on IM at 21 weeks.19 Additionally, concentrations of IM earlier in pregnancy, when organogenesis is occurring are unknown.
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Little is known about the second-generation BCRABL inhibitors nilotinib and dasatinib in pregnancy. There are two reports of women with CML who were being treated with second-generation tyrosine kinase inhibitors when pregnancy was diagnosed. In both cases, the tyrosine kinase inhibitor was discontinued.23,24 A woman with CML in whom nilotinib was discontinued during the first trimester delivered a healthy baby.23 There are few reports of treatment of Phþ ALL in pregnancy. Two women were treated with chemotherapy and delivered healthy babies, then initiated IM or dasatinib after delivery.25,26 Our patient was treated with hyperCVAD and IM beginning week 24 of pregnancy and delivered a healthy baby at 30 weeks, but unfortunately later died of chemotherapy complications. There are clear data to support initiating IM concurrently with chemotherapy in the treatment of Phþ ALL, but this may be difficult in pregnant patients because of the unknown effects of IM on the fetus. Observational studies have shown limited long-term adverse effects in children exposed to most chemotherapy drugs in utero, but there are no long-term data with IM. Additionally, even when the effects of individual agents in pregnancy are known, unless there are published data on the actual combination being used, unexpected effects are always a possibility. Given scant data on effects of IM on the fetus and no data on long-term effects of exposure in utero, IM use during pregnancy should be based on risk–benefit analysis for both mother and baby. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Mancini M, Nanni M, Sirleto P, et al. Detection of BCR/ ABL rearrangements in adult acute lymphoblastic leukemia using a highly sensitive interphase fluorescence in situ hybridization method (D-FISH). Hematol J 2001; 2: 54–60. 2. Westbrook CA, Hooberman AL, Spino C, et al. Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a cancer and leukemia group B study (8762). Blood 1992; 80: 2983–2990. 3. Preti HA, O’Brien S, Giralt S, et al. Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 1994; 97: 60–65.
4. Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 18: 547–561. 5. Forman SJ, O’Donnell MR, Nademanee AP, et al. Bone marrow transplantation for patients with philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1987; 70: 587–588. 6. Gleissner B, Gokbuget N, Bartram CR, et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 2002; 99: 1536–1543. 7. Nashed AL, Rao KW and Gulley ML. Clinical applications of BCR-ABL molecular testing in acute leukemia. J Mol Diagn 2003; 5: 63–72. 8. Lee HJ, Thompson JE, Wang ES, et al. Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives. Cancer 2011; 117: 1583–1594. 9. Lee KH, Lee JH, Choi SJ, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 2005; 19: 1509–1516. 10. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for philadelphia-positive acute lymphoblastic leukemia (phþ ALL). Blood 2006; 108: 1469–1477. 11. Fielding AK. Current treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia. ASH Educ Program Book 2011; 1: 231–237. 12. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinibmesylate. Blood 2004; 103: 4396–4407. 13. Chelghoum Y, Vey N, Raffoux E, et al. Acute leukemia during pregnancy: a report on 37 patients and a review of the literature. Cancer 2005; 104: 110–117. 14. Shapira T, Pereg D and Lishner M. How I treat acute and chronic leukemia in pregnancy. Blood Rev 2008; 22: 247–259. 15. Cardonick E and Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004; 5: 283–291. 16. Amant F, Van Calsteren K, Halaska MJ, et al. Longterm cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. Lancet Oncol 2012; 13: 256–264. 17. Aviles A and Neri N. Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2001; 2: 173–177. 18. Lloyd ME, Carr M, McElhatton P, et al. The effects of methotrexate on pregnancy, fertility and lactation. QJM 1999; 92: 551–563. 19. Ali R, Ozkalemkas F, Kimya Y, et al. Imatinib use during pregnancy and breast feeding: a case report and review of the literature. Arch Gynecol Obstet 2009; 280: 169–175.
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20. Ault P, Kantarjian H, O’Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with Imatinib. J Clin Oncol 2006; 24: 1204–1208. 21. Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111: 5505–5508. 22. Russell MA, Carpenter MW, Akhtar MS, et al. Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk. J Perinatol 2007; 27: 241–243. 23. Conchon M, Sanabani SS, Bendit I, et al. Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study. J Hematol Oncol 2009; 2: 42.
24. Conchon M, Sanabani S, Serpa M, et al. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol 2010; 2010: 136252. 25. Nakajima Y, Kuwabara H, Hattori Y, et al. Successful treatment of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol 2013; 97: 427–429. 26. Ticku J, Oberoi S, Friend S, et al. Acute lymphoblastic leukemia in pregnancy: a case report with literature review. Ther Adv Hematol 2013; 4: 313–319.
Downloaded from opp.sagepub.com at Bobst Library, New York University on May 20, 2015
(OPP)
[1–4] [INVALID Stage]
Case Report
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in pregnancy
J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214568582 opp.sagepub.com
Candace B Mainor1, Alison P Duffy2, Kristin L Atkins3, Amy S Kimball1,4 and Maria R Baer1,4
Abstract BCR-ABL inhibitors administered in conjunction with chemotherapy have significantly improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia but, for patients diagnosed during pregnancy, data on risks to the fetus are limited. We report a woman treated with chemotherapy and imatinib mesylate who delivered a healthy baby at 30 weeks, and we discuss available data.
Keywords Acute lymphoblastic leukemia, pregnancy, imatinib mesylate
Introduction Acute lymphoblastic leukemia (ALL) represents 20% of adult acute leukemia. The most common cytogenetic abnormality is translocation (9;22), resulting in a derivative chromosome 22 called the Philadelphia chromosome (Ph) that encodes a leukemogenic tyrosine kinase, BCR-ABL. BCR-ABL inhibitors, such as imatinib mesylate (IM), function by binding to the tyrosine kinase and preventing tyrosine autophosphorylation, thereby inhibiting activation of downstream signal transduction pathways. The (9;22) translocation is found in 15%–30% of adult ALL cases.1 Prior to incorporation of BCRABL inhibitors into treatment regimens, Phþ ALL had a lower complete remission (CR) rate than Ph ALL, in the range of 50%–70%,2–5 as well as shorter overall survival, and allogeneic hematopoietic stem cell transplant in first CR was the treatment of choice for eligible patients.6,7 BCR-ABL inhibitors initiated with chemotherapy have significantly improved treatment outcomes in Phþ ALL.8 CR rates are in the range of 90%, and prolonged disease-free survival has been reported in 50%–80% of patients in different series.9,10 BCR-ABL levels are measured by reverse transcription polymerase chain reaction (RT-PCR) every three to six months, as a surrogate for residual
disease, and achieving and maintaining molecular remission is an important treatment endpoint.11 Patients treated with BCR-ABL inhibitors and chemotherapy are still at risk for relapse, and thus this treatment is still often used as a bridge to allogeneic hematopoietic stem cell transplant. Acute leukemia diagnosed during pregnancy is rare. It must be treated promptly and intensively, but teratogenicity of chemotherapeutic agents and, for Phþ ALL, BCR-ABL inhibitors must be considered. We report a woman diagnosed with Phþ ALL at 24 weeks of pregnancy who was treated with chemotherapy and the BCR-ABL inhibitor IM and delivered a healthy baby at 30 weeks.
1
Department of Medicine, University of Maryland School of Medicine, Baltimore, USA 2 Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, USA 3 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, USA 4 Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA Corresponding author: Candace B Mainor, Department of Medicine, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, USA. Email: [email protected]
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Case A 38-year-old woman was diagnosed with Phþ precursor B-ALL at 24 weeks of pregnancy. Multidisciplinary consensus decision was to proceed with therapy and deliver the baby after 30 weeks. The patient was treated with course 1 of the hyperCVAD regimen, as follows: cyclophosphamide 300 mg/m2 intravenously every 12 h for six doses, mesna 1800 mg/m2 by continuous intravenous infusion over 42 h, dexamethasone 40 mg orally on days 1–4 and 11–14, doxorubicin 50 mg/m2 intravenously on day 4, and vincristine 2 mg intravenously on days 4 and 11. Her actual body weight of 140 kg was used for body surface area and dose calculations. She was also treated with IM 400 mg orally daily12 and prophylactic intrathecal cytarabine (100 mg), rather than methotrexate. Fetal heart monitoring was performed daily and middle cerebral artery Doppler monitoring weekly. On day 26, a second identical chemotherapy course was initiated, rather the alternating hyperCVAD regimen, in order to avoid methotrexate. IM was continued. She received filgrastim daily as primary prophylaxis for chemotherapy-induced neutropenia after each chemotherapy course and trimethoprim/sulfamethoxazole for Pneumocystis carinii prophylaxis after course 2. At 30 weeks, the fetus had a biophysical profile of 2, and was delivered by cesarean section. Weight was 1.28 kg and Apgar scores were 5 and 9. Placenta histopathology was normal. Blood counts were normal and neonatal course was uncomplicated. The mother continued chemotherapy. On day 22 of cycle 3, the mother developed severe abdominal pain and a computerized tomography scan of the abdomen and pelvis showed a proximal small bowel obstruction (SBO). A nasogastric tube was placed and surgery consultation was obtained, but she became hemodynamically unstable and had a cardiac arrest. Return of spontaneous circulation was achieved, and she was transferred to the medical intensive care unit. Broadspectrum antibiotics, continuous renal replacement therapy, and vasopressors were initiated, but she developed progressive complications and died of Bacteroides fragilis septicemia seven weeks after delivery. The bacteremia likely resulted from bowel translocation in the setting of the SBO. The cause of the SBO was unknown. The baby was transferred to another hospital in her father’s home town at three months of age. There is no subsequent follow-up information.
Discussion Acute leukemia treatment during pregnancy is challenging.13 With a first trimester diagnosis, therapeutic abortion is recommended because of high risk of fetal death or malformations with chemotherapy given in early pregnancy.14 With a second or third trimester
diagnosis, and especially after 20 weeks, pregnancy can usually be preserved. Chemotherapy drugs administered during the second and third trimesters are associated with increased risk of intrauterine growth retardation and low birth weight, but only rare fetal deaths or long-term complications.15 Current treatment for Phþ ALL consists of chemotherapy and a BCRABL inhibitor, and teratogenicity of BCR-ABL inhibitors as well as chemotherapy must be considered in pregnant patients. Cyclophosphamide, doxorubicin, vincristine, and corticosteroids have been used safely in pregnant ALL patients in the second and third trimesters.15 In an observational study evaluating the long-term effects of prenatal exposure to chemotherapy, Amant et al.16 found that neurocognitive development, growth, hearing, and cardiac function were similar to those of the general population. Aviles et al. analyzed over 80 children exposed to chemotherapy in utero, for a variety of maternal malignancies. None of 29 children whose mothers had acute leukemia had developed a malignancy at a median age of 11.4 years.17 Methotrexate has been designated as pregnancy category X and is teratogenic. The most common abnormalities following methotrexate exposure in utero are skull, hand, and limb deformities.18 Therefore, methotrexate was not used in our patient’s treatment regimen before delivery. We chose IM as the BCR-ABL inhibitor for our patient because of reports of its use in pregnant chronic myeloid leukemia (CML) patients in all three trimesters.19–21 Among 125 women who received IM at various times during pregnancy, 63 delivered normal infants, 18 had spontaneous abortions (similar to the general population), 35 had elective terminations (three with fetal abnormalities), and nine babies had congenital abnormalities, including premature closure of skull sutures, exomphalos, and vertebral abnormalities.21 Mothers of 10 fetuses or babies with abnormalities were exposed to IM during the first trimester. Outcomes in 38 women continuing IM throughout pregnancy included seven spontaneous abortions, six elective terminations with one known fetal abnormality, 18 live births without congenital abnormalities, and seven unknown.21 Among 10 women exposed to IM for four to nine weeks during the first trimester, with IM discontinued when pregnancies were confirmed, two had spontaneous abortions and seven delivered eight babies, including one with congenital hypospadias.20 IM does not appear to cross the placenta late in gestation.21,22 Nevertheless, IM was detected in the blood of the healthy newborn baby of a CML patient started on IM at 21 weeks.19 Additionally, concentrations of IM earlier in pregnancy, when organogenesis is occurring are unknown.
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Little is known about the second-generation BCRABL inhibitors nilotinib and dasatinib in pregnancy. There are two reports of women with CML who were being treated with second-generation tyrosine kinase inhibitors when pregnancy was diagnosed. In both cases, the tyrosine kinase inhibitor was discontinued.23,24 A woman with CML in whom nilotinib was discontinued during the first trimester delivered a healthy baby.23 There are few reports of treatment of Phþ ALL in pregnancy. Two women were treated with chemotherapy and delivered healthy babies, then initiated IM or dasatinib after delivery.25,26 Our patient was treated with hyperCVAD and IM beginning week 24 of pregnancy and delivered a healthy baby at 30 weeks, but unfortunately later died of chemotherapy complications. There are clear data to support initiating IM concurrently with chemotherapy in the treatment of Phþ ALL, but this may be difficult in pregnant patients because of the unknown effects of IM on the fetus. Observational studies have shown limited long-term adverse effects in children exposed to most chemotherapy drugs in utero, but there are no long-term data with IM. Additionally, even when the effects of individual agents in pregnancy are known, unless there are published data on the actual combination being used, unexpected effects are always a possibility. Given scant data on effects of IM on the fetus and no data on long-term effects of exposure in utero, IM use during pregnancy should be based on risk–benefit analysis for both mother and baby. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Mancini M, Nanni M, Sirleto P, et al. Detection of BCR/ ABL rearrangements in adult acute lymphoblastic leukemia using a highly sensitive interphase fluorescence in situ hybridization method (D-FISH). Hematol J 2001; 2: 54–60. 2. Westbrook CA, Hooberman AL, Spino C, et al. Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a cancer and leukemia group B study (8762). Blood 1992; 80: 2983–2990. 3. Preti HA, O’Brien S, Giralt S, et al. Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 1994; 97: 60–65.
4. Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 18: 547–561. 5. Forman SJ, O’Donnell MR, Nademanee AP, et al. Bone marrow transplantation for patients with philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1987; 70: 587–588. 6. Gleissner B, Gokbuget N, Bartram CR, et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 2002; 99: 1536–1543. 7. Nashed AL, Rao KW and Gulley ML. Clinical applications of BCR-ABL molecular testing in acute leukemia. J Mol Diagn 2003; 5: 63–72. 8. Lee HJ, Thompson JE, Wang ES, et al. Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives. Cancer 2011; 117: 1583–1594. 9. Lee KH, Lee JH, Choi SJ, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 2005; 19: 1509–1516. 10. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for philadelphia-positive acute lymphoblastic leukemia (phþ ALL). Blood 2006; 108: 1469–1477. 11. Fielding AK. Current treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia. ASH Educ Program Book 2011; 1: 231–237. 12. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinibmesylate. Blood 2004; 103: 4396–4407. 13. Chelghoum Y, Vey N, Raffoux E, et al. Acute leukemia during pregnancy: a report on 37 patients and a review of the literature. Cancer 2005; 104: 110–117. 14. Shapira T, Pereg D and Lishner M. How I treat acute and chronic leukemia in pregnancy. Blood Rev 2008; 22: 247–259. 15. Cardonick E and Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004; 5: 283–291. 16. Amant F, Van Calsteren K, Halaska MJ, et al. Longterm cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. Lancet Oncol 2012; 13: 256–264. 17. Aviles A and Neri N. Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2001; 2: 173–177. 18. Lloyd ME, Carr M, McElhatton P, et al. The effects of methotrexate on pregnancy, fertility and lactation. QJM 1999; 92: 551–563. 19. Ali R, Ozkalemkas F, Kimya Y, et al. Imatinib use during pregnancy and breast feeding: a case report and review of the literature. Arch Gynecol Obstet 2009; 280: 169–175.
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20. Ault P, Kantarjian H, O’Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with Imatinib. J Clin Oncol 2006; 24: 1204–1208. 21. Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111: 5505–5508. 22. Russell MA, Carpenter MW, Akhtar MS, et al. Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk. J Perinatol 2007; 27: 241–243. 23. Conchon M, Sanabani SS, Bendit I, et al. Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study. J Hematol Oncol 2009; 2: 42.
24. Conchon M, Sanabani S, Serpa M, et al. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol 2010; 2010: 136252. 25. Nakajima Y, Kuwabara H, Hattori Y, et al. Successful treatment of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol 2013; 97: 427–429. 26. Ticku J, Oberoi S, Friend S, et al. Acute lymphoblastic leukemia in pregnancy: a case report with literature review. Ther Adv Hematol 2013; 4: 313–319.
Downloaded from opp.sagepub.com at Bobst Library, New York University on May 20, 2015
