Successful treatment of acute lymphoblastic leukemia (ALL) during pregnancy using a pediatric-based protocol incorporating pegylated asparaginase

Introduction

Malignancy complicates approximately 1/1000 pregnancies and is a leading cause of maternal death in developed countries [1]. Solid tumors are most common, while acute leukemia affects approximately 1/75,000 pregnancies with one third of these being acute lymphoblastic leukemia (ALL) [2].

ALL is rapidly fatal if untreated and minimizing delay in treatment is associated with improved outcomes. Therapeutic challenges unique to pregnancy include the potential teratogenicity of cytotoxic therapy, impact on fetal growth restriction, myocardial toxicity and rates of fetal loss [3]. In addition, there is minimal data on changes in pharmacokinetics and appropriate dosing of cytotoxics during pregnancy. These challenges are further compounded by the psychological and ethical implications of balancing maternal and fetal well-being.

Pregnant patients are usually excluded from clinical trials, highlighting the importance of case reports informing clinical practice in this population. We report a case of ALL diagnosed during the second trimester of pregnancy, managed on the Australasian Leukemia and Lymphoma Group (ALLG) ALLG ALL06 study – an adolescent and young adult (AYA) ALL trial (ACTRN12611000814976). ALLG ALL06 was unique in that pregnancy did not exclude patients from enrollment. ALLG ALL06 was based on a modified BFM2000 protocol incorporating pegylated asparaginase (peg-asp) in induction, reinduction and high-risk block therapy. To our knowledge, this case is only the second case reporting the use of peg-asp in pregnancy and the only case reporting long term maternal and fetal follow-up.

Case presentation

A 27 year old, 27 week pregnant (gravida 1, para 0) female presented to a regional hospital with fatigue, lethargy, and palpitations on exertion. The patient had been previously well. Her pregnancy had been uncomplicated to date. Medications included only an over-the-counter multivitamin. Laboratory results demonstrated pancytopenia with a Hb 46 g/L, platelets 113 × 10⁹/L and WCC 2.0 × 10⁹/L with normal coagulation studies and normal biochemistry. Bone marrow (BM) aspirate demonstrated 75% leukemic blasts (immunophenotype: surface CD45dim to negative, CD19dim/10/22/33, HLA-DR and intracytoplasmic CD79a and TdT+) consistent with precursor-B ALL (Image 1). Cytogenetics demonstrated normal female karyotype. BCR-ABL translocation was not detected by FISH or PCR. Obstetric ultrasound and cardiotocography (CTG) were normal.

Image 1. Bone marrow aspirate and flow cytometry. Bone marrow aspirate at diagnosis demonstrates a markedly hypercellular marrow with a diffuse infiltrate by pleomorphic blasts with open chromatin and inconspicuous nucleoli representing 75% of nucleated cells. There is an associated marked reduction in trilineage hematopoiesis. (A) May Grunwald Giemsa (MGG) stain ×40 magnification. (B) MGG stain ×100 magnification. Flow Cytometry plots from bone marrow aspirate at diagnosis demonstrate a lymphoblast immunophenotype with (C) CD19dim/CD10 co-expression. (D) cyCD79a/nuTdt co-expression.

Management was guided by a multidisciplinary team including hematology, neonatology and maternal-fetal medicine in liaison with a state-based Teratogen Information Service (MotherSafe). The patient was offered and consented to participation in ALLG ALL06.

Day 1 of induction therapy was commenced at 27 + 4 weeks gestation. Induction consisted of intrathecal (IT) methotrexate 12 mg day 1, 15, 33, daunorubicin 30 mg/m² IV and vincristine 1.5 mg/m² IV day 8, 16, 22, 29, peg-asp day 8 and 22 and prednisolone 60 mg/m²/day PO in 2–3 divided doses days 1–28 then tapered to cessation day 29–38 (Table 1). Dosing was based on actual body weight. Standard procedures for IT therapy and BM biopsies were unaltered and procedures were performed without sedation. Monitoring for complications of peg-asp therapy included daily monitoring of liver function, blood glucose and coagulation studies including fibrinogen and second daily monitoring of amylase, lipase and triglycerides. Fetal monitoring involved weekly ultrasounds for growth and Doppler assessment, which were normal. Antimicrobial prophylaxis included sulfamethoxazole/trimethoprim, valaciclovir and liposomal amphotericin. Enoxaparin 40 mg daily was used as thromboprophylaxis during peg-asp therapy. There were no significant infective or thrombotic complications during induction.

Table 1. ALLG ALL06 protocol 1.

Protocol 1 induction (phase I). Duration: 35 days
Drug	Route	Dose	Day
Prednisolone	PO	60 mg/m^2/day	1–28 then taper over 10 days and cease
Methotrexate**	IT	12 mg	1, 15, 33
Daunorubicin	IV	30 mg/m^2	8, 16, 22, 29
Vincristine	IV	1.5 mg/m^2 (cap at 2 mg)	8, 16, 22, 29
Pegasparaginase	IM	1000 Units/m^2	8, 22
Protocol 1 consolidation (phase II). Duration: 29 days
Drug	Route	Dose	Day
Cyclophosphamide	IV	1000 mg/m^2	1 and 29
Mesna	IV	400 mg/m^2 at 0, 4 and 8 h after each cyclophosphamide dose	1 and 29
Mercaptopurine	PO	60 mg/m^2	1–28
Cytarabine	SC	75 mg/m^2	1–4, 8–11, 15–18 and 22–25
Methotrexate	IT	12 mg	8 and 22

** Patients with CNS involvement receive additional intrathecal therapy on day 18 and 27, i.e. a total of 5 intrathecal doses.

Abbreviations. PO: per os (oral); IT: intrathecal; IV: intravenous; IM: intramuscular; SC: subcutaneous.

The patient was discharged at the end of protocol 1 phase I (day 35 of induction treatment) at 32 + 2 weeks gestation. Day 33 BM biopsy demonstrated morphological complete remission (CR). Following steroids for fetal lung maturation, induction of labor was undertaken at 33 + 4 weeks gestation prior to initiation of consolidation therapy. This was mainly due to concerns regarding the safety of an unplanned delivery during a period of neutropenia and/or thrombocytopenia given the predictable myelotoxicity associated with consolidation therapy (protocol 1 phase II). The patient had a normal vaginal delivery of a live female infant weighing 2113 g (70th centile), length 42 cm and normal Apgar score of 9 and 9 and 1 min and 5 min, respectively. There was no evidence of neonatal respiratory distress and noninvasive ventilation was not required. The arterial cord pH was 7.382 and lactate 2.3 mmol/L and full blood count on day 1 post-delivery was normal with Hb 170 g/L, WCC 13.9 × 10⁹/L, platelets 143 × 10⁹/L. The infant was admitted to the neonatal intensive care unit at 15 min of age due to prematurity and need for supplemental enteral feeding. Multiple muscular ventricular septal defects (VSD) were detected on screening cardiac echo. However, there was no evidence of hypoxia or cardiac failure and newborn examination was otherwise unremarkable with no other congenital abnormalities or dysmorphic features. Histopathological examination of the placenta did not demonstrate any evidence of leukemia. The infant was discharged from hospital at 3 weeks of age.

Enoxaparin 40 mg daily was used as post-partum thromboprophylaxis. The patient was advised against breastfeeding and cabergoline was used to suppress lactation.

The patient continued on the ALL06 protocol commencing phase II of protocol 1 (6-mercaptopurine 60 mg/m²/day PO days 36–63, cytarabine 75 mg/m²/day IV or subcutaneously in 4 × 4 day blocks between days 36 and 60, cyclophosphamide 1000 mg/m²/day days 36 and 64 and IT methotrexate (days 43 and 57) 5 days post-delivery (Table 1). The patient was transferred to a regional center to complete treatment and achieved minimal residual disease negativity assessed by ASO-PCR at day 33 and 79 (sensitivity <0.01%) of treatment and remained in CR at completion of maintenance 2 years post-induction. The patient remains well and disease-free almost 8 years post-diagnosis. The child’s VSD closed spontaneously by 18 months of age. There has been no medical or developmental sequelae of intra-uterine chemotherapy exposure or premature delivery.

Discussion

There is increasing evidence to support the use of risk- and response-adapted pediatric ALL protocols in AYA populations. These regimens include L-asparaginase which catalyzes the conversion of L-asparagine to aspartic acid and ammonia depriving ALL cells of circulating asparagine leading to cell death. Historically, native E.coli L-asparaginase was used in ALL regimens. However, peg-asp is now the only commercially available E. Coli asparaginase in most jurisdictions. The use of asparaginase can be associated with significant toxicities including hypertriglyceridemia, pancreatitis and thrombosis with rates of venous thromboembolism (VTE) as high as 34% in adults [4]. Strategies employed to reduce VTE rates associated with asparaginase include chemical VTE prophylaxis and monitoring and replacement of antithrombin III. The VTE risk associated with use of asparaginase is particularly relevant in pregnancy which is associated with a four to five fold increased VTE risk which doubles again following cesarean delivery [5]. As a consequence, asparaginase is often omitted from ALL treatment during pregnancy or administration is delayed until the post-partum period because of concerns regarding additional VTE risk [6,7]. The practice of omitting asparaginase from ALL treatment regimens during pregnancy is illustrated in multiple studies including a recently published series of 15 women with Ph-negative ALL treated during pregnancy on the Russian RALL-2009 clinical trial. This study reported equivalent outcomes in pregnant women when compared to the trial cohort of non-pregnant females; however, the protocol mandated omission of asparaginase and intrathecal methotrexate until after delivery [7]. A further two retrospective case series published in 2021 reporting outcomes of acute leukemia in pregnancy by Wang et al. and Zhu et al. included six and three patients in each respective series with ALL; however, no patient in either series received asparaginase during pregnancy [8,9].

Evidence supporting the use of asparaginase in the treatment of ALL in pregnancy is limited to case reports and small case series. A 2017 series from the Mayo Clinic, reported outcomes of six pregnant patients with ALL. L-asparaginase was used in four patients during the first trimester however three out of four patients underwent elective termination either prior to or within 2 weeks of commencing chemotherapy and one patient had a spontaneous abortion at 22 weeks after commencing therapy at 16 weeks gestation [10]. A limited number of individual case reports document the use of native (non-pegylated) L-asparaginase during the third trimester with positive fetal and maternal outcomes [11–14]. Evidence of the successful use of peg-asp during pregnancy is limited to a single report. Peg-asp was administered in ALL induction in the second trimester with the patient achieving CR and delivering a healthy infant after elective CS at 30 weeks gestation, prior to commencing consolidation therapy [15]. Despite chemical thromboprophylaxis, this patient developed pulmonary embolism post-partum. Long term outcomes were not reported.

Conclusion

The positive outcome in this case provides additional evidence that peg-asp may be used as part of a pediatric-based induction ALL protocol in the third trimester of pregnancy. Further studies are needed to confirm the safety of peg-asp in pregnancy as access to native L-asparaginase is now limited. The challenges of managing maternal and fetal risks during ALL therapy require close collaboration between hematologists, obstetricians and neonatologists in order to maximize feto-maternal outcomes. In addition, we advocate for the inclusion of pregnant patients in clinical trials for haematological malignancies in order to better inform evidence-based care for this challenging cohort of patients.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data was not generated for this case report. Additional information regarding the case can be requested from the corresponding author.

Additional information

Funding

The ALLG ALL06 clinical trial was supported by the Clinical Oncology Society of Australia (COSA) Youth Cancer Networks Program (YCNP), the Barr Family Foundation and Servier.