Two successful deliveries of healthy children by a young woman diagnosed and treated during induction and relapsed therapy for acute promyelocytic leukemia

Abstract

Introduction

Acute promyelocytic leukemia is an oncologic emergency. The limited cases reported in the literature have led to poor understanding of the safety of management of acute promyelocytic leukemia during pregnancy.

Case report

Herein is an acute promyelocytic leukemia case of a 22-year-old young pregnant woman who had various social problems. The patient was diagnosed with acute promyelocytic leukemia in her the second trimester of her first pregnancy.

Management and outcome: She was treated with all-trans-retinoic acid with idarubicin and successfully delivered a healthy baby. She completed induction with idarubicin but defaulted her all-trans-retinoic acid, 6-mercaptopurine and methotrexate maintenance. She relapsed after one year and was salvaged with all-trans-retinoic acid high dose cytarabine and arsenic trioxide. She went into remission and had autologous stem cells collected and was planned for an autologous stem cell transplant but she defaulted. She relapsed when she was pregnant with her second baby during her third trimester (29+weeks) 10 months later. Salvage chemotherapy with arsenic trioxide, all-trans-retinoic acid and idarubicin was given. Patient underwent an emergency lower segment caesarian section at 31 weeks of pregnancy due to abnormal fetal cardiotocography. A healthy baby was delivered.

Discussion

This drug regimen is controversial during pregnancy owing to the teratogenic effects and fatal retinoic acid syndrome especially in early gestation. In this case, patient was started the induction therapy of all-trans-retinoic acid treatment at her second trimester during her first pregnancy.

Conclusion

Our lady demonstrated the possibility of using all-trans-retinoic acid and arsenic trioxide and chemotherapy during second and third trimester with successful pregnancy outcomes.

Keywords

APL arsenic trioxide chemotherapy all-trans-retinoic acid

Introduction

Acute promyelocytic leukemia (APL) arises from the arrest of normal hematopoietic cell maturation in the promyelocyte phase. According to NCCN guidelines, APL is diagnosed by reciprocal chromosomal translocation between chromosomes 15 and 17 [t(15;17)] which represents the promyelocytic leukemia (PML) gene and the retinoic acid receptor-α (RAR-α) gene, respectively.¹ The fusion of these two genes, i.e. PML–RAR-α, leads to the production of an oncoprotein that deregulates the expression of genes in haematopoietic cells during process of maturation. Consequently, it halts differentiation of promyelocytes and causes the accumulation of undifferentiated promyelocytes which gives rise of leukemia.² The prevalence of APL accounts for 10–15% of all AML diagnoses in adults. In fact, there were less than 60 cases of APL in pregnancy described in the literature which indicated that the occurrence is rare.^2–4 However, its prevalence is expected to increase due to the increment of average maternal age of pregnancy in developed countries.⁵

Despite being an aggressive disease, APL is a highly curable subtype of acute myeloid leukemia (AML). All-trans-retinoic acid (ATRA) and chemotherapy are the first-line treatment of APL. While first-line therapy with ATRA and chemotherapy followed by maintenance therapy demonstrates a relatively high response rate,⁶ many patients still relapse. In cases of relapsed or refractory APL, arsenic compounds (e.g. arsenic trioxide (ATO) and arsenic tetrasulfide (ATS)) induce durable remissions. Example of arsenic compounds includes ATO and ATS. Combination treatment regimen of ATRA and ATO can achieve complete remission (CR) in approximately 50–80% APL-relapsed cases.⁷

Though contemporary combined ATRA and arsenic compound therapies are effective in inducing CR in the majority of patients, however, there are only limited cases reported for APL and its relapse during pregnancy. In the pregnant mother, risks and benefits of ATRA plus arsenic compound retreatment in comparison to retreatment with other modalities remain debatable. We report a case of a young female delivering two healthy infants while undergoing treatment for APL.

Case presentation

This was a 22-year-old female who presented with a diagnosis of APL in the mid of her first pregnancy in July 2013 (at 20 gestational weeks). Because her white blood count was >10× 109/L, she was considered to have to high-risk APL. The patient was started on intravenous (IV) idarubicin 12 mg/m² on days 3, 5 and 7 and ATRA 45 mg/m² daily for 12 weeks as induction in her second trimester. The doses were given based on her adjusted body weight, i.e. adjusted body weight = ideal body weight (IBW) +0.4 (actual body weight – IBW). In September 2013, i.e. 32 gestational weeks, she delivered a healthy infant of 1.25 kg via lower segment caesarean section (LCSC) despite completing her induction and consolidation idarubicin chemotherapy. The patient was lost to follow-up during the maintenance phase of her induction therapy.

The patient was admitted to for pneumonia in October 2014. The bone marrow aspiration and trephine showed CR and negative molecular studies. She was re-started on maintenance ATRA therapy, 45 mg/m² daily for 15 days but she was again lost to follow-up.

She presented again in March 2015 with pancytopenia and septic shock. Computerized tomography scan (CT) showed pyelonephritis and splenic lesions. Complete blood count (CBC) and bone marrow aspirate (BMA) showed relapsed APL (70% blast on CBC) and disseminated intravascular coagulation. The patient was treated with ATRA and high-dose Ara-C (HIDAC) regimen with dose of 1500 mg/m².¹ In May 2015, BMA showed CR (molecular negative). The ATRA was continued. In July 2015, two cycles of consolidation treatment on relapse APL were prescribed. In the first cycle, 25 doses of IV ATO (0.15 mg/kg/day, IV infusion over two hours for each dose) five days/week for five weeks was given.⁸ The second cycle of ATO was interrupted for a planned stem cell collection and autologous stem cell transplant in October 2015. However, the patient was successfully collected but she was lost again to follow-up for the planned transplant.

The patient presented after a year in August 2016 with coughing and she was pregnant with a second pregnancy at 13 gestational weeks. Peripheral blood film and counts were still normal then. She lost to follow-up again despite arrangements with the social welfare department for a home. She presented with cough and shortness of breath and then later was diagnosed as relapsed with 42% fusion transcript levels while she was G₂P₁ at 25 weeks period of amenorrhea.

She was started initially on ATRA and dexamethasone, and at 27 weeks gestation, she was given combination ATRA, ATO and idarubicin (12 mg/m²).⁸

BMA evaluation on 8 December 2016 indicated no excess blasts but showed CR (at week 5 of arsenic treatment). Because of an abnormal cardiotocography, an emergency lower segment caesarian section (EMLSCS) was performed two days (10 December 2016) before the scheduled delivery date. The baby of 1.51 kg was successfully delivered with mild neonatal jaundice. At delivery, the patient had already completed 35 doses of her ATO 0.15 mg/kg/day. After delivery, the patient continued her induction therapy and completed a total of 55 doses of ATO 0.15 mg/kg/day for eight weeks on 8 January 2017 without complications. BMA performed on 9 January 2017 was suboptimal where limited spicules were available for assessment. However, no excess blasts were seen. The CBC on 17 January 2017 showed no circulating blasts or abnormal promyelocytes.

The patient underwent an autologous stem cell transplantation, conditioning busulphan and melphalan (oral busulphan 4 mg/kg/day for four days and IV melphalan 140 mg/m² for one day)⁹ on 25 January 2017. Stem cell infusion with a total dose of 6.08 × 10⁶ CD34 cells was given on 1 February 2017. She required only 2 U of apheresis platelet during transplant. She has no other complications except for Grade 3 mucositis which was manageable. Follow-up report showed that the patient was in CR after 12 months post-transplant, and the children were in healthy condition. The summary of the case was presented in Table 1.

Table 1.

Summary of the current presented APL case in her journey of pregnancy.

Event	Date/gestational week	Description/complaints	Remarks/treatment
1st pregnancy	July 2013 / 20 weeks	Diagnosed with APL	Started on idarubicin, ATRA
	September 2013/ 32 weeks	Delivery via LCSC	Completed consolidation
Defaulted treatment
	October 2014	Pneumonia	Started in ATRA maintenance
Defaulted treatment
	March 2015	Relapsed APL	ATRA and HIDAC
	May 2015		ATRA
	July 2015		25 dose IV arsenic
	October 2015	Defaulted on a planned autologous stem cell transplant
Defaulted treatment
2nd pregnancy	May 2016
	August 2016/13 weeks	Coughing	Scheduled for appointment in hematology clinic
Defaulted September 2016
	October 2016/25 weeks	Coughing and shortness of breath	ATRA, Dexamethasone, Arsenic, Idarubicin
	December 2016/32 weeks	EMLSCS	BMA in CR, Completed 35 doses of Arsenic
	January 2017	Continued induction therapy	Completed 55 dose Arsenic
	February 2017	Autologous stem cell transplantation	Completed Treatment
Follow-up
Post 6 months	10 July 2017	Patient did not show up
	20 November 2017	Vital sign stable, 85.3 kg, BP 106/69, no fever	No evidence of relapse, babies in healthy conditionAge of first baby: 4 years 3 months 2 daysAge of second baby: 49 weeks 3 days
Post 12 months	12 February 2018	Vital sign stable, 87.7 kg, BP 113/71, no fever	No evidence of relapse, babies in healthy conditionAge of first baby: 4 years 6 months 2 daysAge of second baby: 61 weeks 3 days

Discussion

Treatment of APL while pregnant is a challenge particularly in patients with limited social support. The risks of APL in pregnancy include sequelae of abortion, perinatal mortality, intrauterine growth retardation, preterm delivery,¹⁰ high risk of bleeding, infection, inflammation, placental abruption, and reduction in oxygen and nutrient delivery.¹¹ The standard treatment of APL in adult with high-risk of relapse is ATRA and anthracycline-based chemotherapy, i.e. idarubicin or daunorubicin. This drug regimen is controversial during pregnancy owing to the teratogenicity and fatal retinoic acid syndrome especially in three to five weeks of gestation.^12,13 Other complications include craniofacial alterations, neural tube defects, cardiovascular malformations, thymic aplasia, psychological impairments and retinoic acid embryopathy (kidney alterations).^12,14 However, recent reviews demonstrate normal fetus outcomes with ATRA usage in the later trimesters. The usage is relatively safe during second and third trimesters in APL pregnancy women. In the current case study, patient was started the induction therapy of ATRA treatment at her second trimester during her first pregnancy.

The patient was given HIDAC for her relapse of APL in 2015. This is a recommended regimen as cytarabine has been reported to significantly reduce the relapse rate. This has brought to her CR status after the induction therapy.¹²

Over the last two decades, single and combination of IV ATO with other agents have been successfully used for the treatment of APL and also some other myeloid neoplasms. In pregnant women, however, this should be avoided due to its teratogenic effect according to a published acute promyelocytic leukemia treatment guideline.¹⁵ In animal studies, arsenic has been reported to cause anencephaly, cranial neural tube defects, that affect embryonic growth by altering the glucocorticoid signaling system during embryonic development and several distinct maternal toxicities.¹⁶ In animals, ATO causes fetal malformations.¹⁷ As there are limited data related to this agent in pregnant women, current case is a special example as it presented the successful usage of ATO in the second to third trimester of pregnancy for the treatment of a relapsed APL.

Conclusion

This patient’s case was unique as her APL happened during pregnancy with two successful births during induction of chemotherapy then later during her relapsed therapy. While receiving ATO, she gave birth to healthy infants with no deformities with no deformities. A post 12 months follow-up revealed a healthy condition of both the patient and her babies.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Siok Yee Chan

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