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Pregnancy and Acute Lymphoblastic Leukemia: A Case Series and Review of Literature

CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(05): 443-450

DOI: DOI: 10.1055/s-0043-1766129

Author : Sukrita Bhattacharjee, Shouriyo Ghosh, Siddhartha Sankar Ray, Sambit Samanta, Nilanjan Sinha, Sandeep Saha, Maitreyee Bhattacharyya?

Abstract

Acute lymphoblastic leukemia (ALL) diagnosed during pregnancy is rare and causes ethical and therapeutic challenges. We performed a retrospective search of ALL patients (n = 202) treated at our institution from 2015 to 2020 and found five patients diagnosed during pregnancy. In this report, we discuss the individual patients in detail and the challenges faced during their treatment. The use of established lymphoblastic leukemia treatment protocols and the modifications made therein to prevent untoward chemotherapy-related toxicities to the fetus are discussed in this study. We report the second use of rasburicase during pregnancy in literature with favorable maternal and fetal outcomes. We also present an extensive literature review of 41 cases of ALL in pregnancy previously reported. It is important to note that there is a dearth of guidelines for the treatment of these complex situations, and although certain general principles can be established, an individualized approach is needed in most cases of leukemia diagnosed during pregnancy.

Keywords

acute leukemia - ethical considerations - pregnancy - maternal well-being - fetal outcome - chemotherapy

Authors' Contributions

S.B. was involved in conceptualization, data collection, and manuscript drafting. S.G. helped in conceptualization, clinical data curation, and manuscript editing and analysis. S.S.R., S. Samanta, N.S. and S. Saha were involved in Institutional Medical Boards convened for patient management strategies. M.B. was involved in conceptualization, manuscript editing, analysis, and overall supervision.

Ethics Approval

Retrospective study

Consent for Publication

Yes.

Availability of Data and Material

Available for publication/review.

Publication History

Article published online:
17 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

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Abstract

Acute lymphoblastic leukemia (ALL) diagnosed during pregnancy is rare and causes ethical and therapeutic challenges. We performed a retrospective search of ALL patients (n = 202) treated at our institution from 2015 to 2020 and found five patients diagnosed during pregnancy. In this report, we discuss the individual patients in detail and the challenges faced during their treatment. The use of established lymphoblastic leukemia treatment protocols and the modifications made therein to prevent untoward chemotherapy-related toxicities to the fetus are discussed in this study. We report the second use of rasburicase during pregnancy in literature with favorable maternal and fetal outcomes. We also present an extensive literature review of 41 cases of ALL in pregnancy previously reported. It is important to note that there is a dearth of guidelines for the treatment of these complex situations, and although certain general principles can be established, an individualized approach is needed in most cases of leukemia diagnosed during pregnancy.

Keywords

acute leukemia - ethical considerations - pregnancy - maternal well-being - fetal outcome - chemotherapy

Introduction

Acute leukemia is uncommonly encountered during pregnancy, occurring in approximately 1 in 75,000 cases and its management is a challenging task.[1] It requires a multidisciplinary approach to treat this life-threatening condition, keeping in mind the health and well-being of the mother and fetus. Patient management entails a gamut of challenges from treatment decisions to ethical and social considerations. Moreover, there is a dearth of trials in this unique and rare cohort of patients. Data from case reports, case series, and retrospective studies are the only evidence available, thereby emphasizing the need for an individualized approach.

Herein we report five cases of acute lymphoblastic leukemia (ALL) diagnosed during pregnancy at our center and challenges faced in managing these patients. We also reviewed the available literature to summarize the data on the clinical presentation, treatment complications, maternal, and fetal outcomes of these patients.

This is a series of ALL patients presenting during pregnancy who were treated at our institute between January 2015 and July 2020 (5 years). Clinical and laboratory data and outcomes of these patients were retrieved from our archives and reviewed for the purpose of this report. Informed consent was taken from the patients and/or next of kin while reporting these cases. For each patient, an institutional medical board, comprising specialists from hematology, obstetrics, neonatology, anesthesiology, and transfusion medicine, was convened to formulate the management plan. For the management of ALL in the adolescent and young adults age group, our institutional practice is to use pediatric inspired protocols, namely, the Berlin Frankfurt Munster-2002 regimen. Our institute has a state-of-the art neonatal intensive care unit that can manage preterm births as early as 25 weeks of gestational age.

A total of 202 ALL patients were treated during the period 2015 to 2020 at our institution of which five were ALL with pregnancy (B-ALL, n = 4; Philadelphia positive B-ALL, n = 1). All five cases were women aged between 20 and 29 years (median age: 26 years) of whom three were primigravidae. None of the patients were diagnosed in the first trimester (n = 2, third trimester, n = 3, second trimester). The first two patients involving late third trimester mothers with newly diagnosed ALL were relatively stable and therefore could be managed with transfusion support till delivery, after which standard chemotherapy was administered. In the other three patients, chemotherapy had to be started with the fetus in-utero as a life saving measure for the mother. Institutional protocol for ALL induction therapy comprised of prednisolone at 60 mg/m2, vincristine at 1.4 mg/m2, daunorubicin at 30mg/m2, and L-asparaginase at 5000 IU/m2 in accordance with the BFM-2002 protocol in phase IA and 6-mercaptopurine, cyclophosphamide, and cytarabine in phase IB, followed by consolidation, re-induction and maintenance treatment limbs.

Case Series

Patient 1: A 28-year-old third gravida (32 weeks gestation) who presented with anemia was diagnosed with intermediate-risk Philadelphia negative pre-B-ALL. Her pregnancy was supported till 37 weeks with transfusions after which she delivered a healthy male baby by normal vaginal delivery (NVD). Subsequently BFM-2002 protocol was started and the induction was complicated by recurrent episodes of maxillary sinusitis, sepsis (Klebsiella species), and central line associated blood stream infection, which were managed with appropriate antibiotics. Subsequent phases of chemotherapy were administered without any interruptions.

Patient 2: A 24-year-old primigravida at 35 weeks gestation, developed intermittent fever, and generalized weakness of 1 month duration and was diagnosed as intermediate risk pre-B-ALL. Similar to patient 1, she was also kept on supportive care with packed red blood cells and platelets till she delivered a healthy male child by NVD at 37 weeks gestation. Subsequently, she was initiated on BFM-2002 protocol and received chemotherapy without any modifications.

Patient 3: A 29-year-old primigravida at 28 weeks of gestation was diagnosed as Philadelphia negative pre-B-ALL with leucocytosis (50,000/cumm with 80% blasts) and retinal hemorrhage. She received BFM-2002 induction without any modifications. Fetal assessment during leukemia induction revealed no anomalies. At 35 weeks of gestation and at the end of induction IA when her counts had recovered, she underwent planned Cesarean Section (CS) and delivered a healthy baby boy, appropriate for gestational age. Subsequently she received phase IB of BFM-2002. She unfortunately relapsed post-induction, and therapy was switched to rituximab-hyper-CVAD (comprising of hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone). During the second cycle of hyper-CVAD, she developed febrile neutropenia, septic shock, and succumbed to it. The child was healthy at last known follow-up.

Patient 4: A 26-year-old third gravida (26 weeks) presented with fever, generalized lymphadenopathy, and multiple skin nodules and plaques. On evaluation, she had hyperleukocytosis (with 90% blasts), anemia, and thrombocytopenia and was diagnosed as Philadelphia positive (Ph + ) B-ALL with leukemia cutis and central nervous system (CNS) involvement. She developed tumor lysis syndrome (TLS) and was given rasburicase during initial stabilization. She was then started on modified E-WALL protocol which included a tyrosine kinase inhibitor (TKI)—imatinib 600 mg daily along with weekly pulsed dexamethasone and vincristine injections. Intrathecal chemotherapy was given with cytarabine and hydrocortisone, while methotrexate was omitted. Her platelet counts recovered by 31st week of gestation. Her pregnancy was continued till 32 weeks of gestation after which she underwent an elective CS and gave birth to a healthy female child. Post-induction bone marrow on day 52 of E-WALL protocol was in morphological remission and BCR-ABL measurable residual disease (MRD) was negative. She received one cycle of E-WALL consolidation after which she was lost to follow-up.

Patient 5: The last case is that of a 20-year-old primigravida at 24 weeks gestation who presented with progressive weakness, exertional dyspnea, low-grade fever, and was found to have severe anemia and atypical cells in peripheral blood. A diagnosis of Ph negative pre-B-ALL was made. She developed hepatic encephalopathy, TLS, and septic shock that were managed effectively. In this background of deranged liver functions and an early pregnancy, she was started on a modified BFM-2002 protocol, consisting of steroids and vincristine only. Subsequently, she went on to receive a modified phase IB of BFM-2002 protocol where only the cytarabine blocks were administered intravenously and intrathecal cytarabine chemotherapy was given, while omitting methotrexate, 6-mercaptopurine, and cyclophosphamide from the protocol. Her phase IB of induction was completed at 32 weeks of gestation. Pregnancy continued till term and she delivered a healthy male child. Post-induction, bone marrow was in remission and MRD was negative. However, she had persistence of CNS disease and was given high-dose intravenous methotrexate consolidation @ 5gm/m2 along with triple intrathecal chemotherapy. Her reinduction chemotherapy phase was interrupted by coronavirus disease 2019 pandemic. Subsequently on resumption of chemotherapy, she developed febrile neutropenia, macrophage activation syndrome, went into septic shock, and unfortunately succumbed to her illness.

A summary of the patients, course of treatment in hospital, and their outcome are mentioned in [Table 1].

Table 1

Patient characteristics, disease and pregnancy details, protocol and modifications used, issues faced, and fetomaternal outcomes

Abbreviations: ALL, acute lymphoblastic leukemia; BFM, Berlin Frankfurt Munster; CLABSI, central line associated bloodstream infection; COVID-19, coronavirus disease 2019; CNS, central nervous system; CS, cesarean section; EM, extramedullary; IPT, immunophenotype, IRG, HRG, intermediate and high-risk groups respectively; MAS, Macrophage Activation Syndrome; NDC, nondividing cells in cytogenetics; NVD, normal vaginal delivery; POG, Period Of Gestation; RDP, random donor platelets; PN, peripheral neuropathy; TLS, tumor lysis syndrome; IT, Intrathecal Chemotherapy.

Discussion

Among leukemia cases encountered in pregnancy, around 28%- cases of leukemia in pregnancy are ALL, the rest being acute myeloid leukemia (AML) and chronic myeloid leukemia, (CML).[1] The major concern in the management of these cases has been the optimal timing and dosing of chemotherapy so as to prevent harmful effects to the fetus. An extensive search of the literature revealed 41 cases of ALL in pregnancy (summarized in [Table 2])[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] in addition to the 60 cases of ALL during pregnancy described by Cardonick and Iacobucci.[3] Pregnancy leads to physiological changes such as increased plasma volume as well as changes in drug pharmacokinetics due to altered hepatic and renal clearance of drugs. Pregnancy can also change drug metabolism by creation of a third space in the form of the amniotic sac.[13] Estrogen receptors like HL-60 have been found in human myeloblastic leukemia cell lines[14] however, pregnancy alone is not thought to have an adverse effect on leukemia.[13]

Case no.

Patient details (age/obstetric history/POG)

Presenting counts (Hb [g/dl]/total leucocyte count (cumm)/platelets (cumm)/blast [%])

Diagnosis

IPT/CNS status/Ph status/CG/risk group/EM disease

Protocol

Indication for treatment; modification done

Significant Issues faced during treatment

Disease outcome

Pregnancy outcome

Last follow-up

1

28 y

G3P2

32 weeks

9.1/41,500/20,000/

50% blasts

Pre-B-ALL/CNS-1/ Ph- neg/46XX/IRG

BFM-2002

Protocol started post-delivery

No dose adjustments

Induction: Maxillary sinusitis, CLABSI and sepsis

Remission

NVD, male baby@37 weeks gestation

4 years: mother and child doing well

2

24 y

G1P0

35 weeks

9.4/10600/218,000/

30% blasts

Pre-B-ALL/ CNS-1/ Ph- neg/ 46XX/ IRG

BFM-2002

Protocol started post-delivery

Vinblastine given in view of peripheral neuropathy

Induction- CLABSI, genital herpes, pneumonia, vincristine induced PN

Remission

NVD, male baby@ 37 weeks gestation

3 years: mother and child doing well

3

29 y

G1P0

28 weeks, 4 days

8.3/50000/20000/

80% blasts

Pre B-ALL/CNS-1/Ph- neg/NDC/IRG

BFM-2002

Protocol started in third trimester in view of bleeding. No dose modification. Phase IB given post-delivery

Induction- cytopenia

Relapsed prior to consolidation.

Switched to Hyper-CVAD.

Relapse post-induction

2# Hyper-CVAD: death due to septic shock

Elective CS

Male baby @ 35 weeks

Child was healthy at last follow-up

4

26y

G3P2

26 weeks

7/250,000/10,000/

90% blasts

Philadelphia +ve B-ALL/CNS-3/46XX/HRG/

leukemia cutis

Modified E-WALL; Imatinib 600 mg OD

Induction started in late second trimester. Rasburicase given

IT: ARA-C and hydrocortisone. MTX omitted

TLS

Remission

Elective CS, female baby@ 32 weeks

Lost to follow-up after first cycle of consolidation

5

20y

G1P0

24 weeks

6/84,600/25,000/

40% blasts

Pre-B-ALL/CNS-1/BCR- ABL neg/46XX/IRG

BFM 2002 with changes

Induction: second trimester: VCR and steroid only

IB: Only Ara-C; IT ARA-C

Consolidation:

MRC UK-ALL

HD-MTX @ 5gm/m2 and L-ASP 10000 IU/m2 triple IT with MTX, ARA-C and hydrocortisone

Pre-treatment: Hepatic encephalopathy, septic shock, TLS

Consolidation: CNS relapse

Reinduction: therapy interruption due to COVID-19 pandemic

Remission post-induction

Consolidation: Isolated CNS relapse

Re-induction: Death due to septic shock and MAS

Elective CS, male baby@ 37 weeks

Child healthy at the time of her death
Table 2

Synopsis of cases of pregnancy with acute lymphoblastic leukemia reported in literature

Abbreviations: ALL, ALL, acute lymphoblastic leukemia; CR, complete remission; CS, cesarean section; CTX, cyclophosphamide; Cyt, cytarabine; DNR, daunorubicin; G-CSF, granulocyte colony-stimulating factor; HiDAC, high-dose cytarabine; HSCT, hematopoietic stem cell transplant; IT, intrathecal; L-asp, L-asparaginase; LBW, low birth weight; LMWH, low molecular weight heparin; LTFU, lost to follow-up; MTX, methotrexate; MUD, matched-unrelated donor; NVD, normal vaginal delivery; PD, progressive disease; Pred, prednisone; VP-16–Etoposide; WBRT, whole brain radiation therapy.

Management of leukemia in first trimester: In our study, none of the patients presented with leukemia in the first trimester. As per recommendations, the pregnancy should be terminated prior to initiation of chemotherapy (many recommend 20 weeks and earlier).[3] [15] Another approach in precious pregnancies is to give a short course of steroids to carry forward the pregnancy past the period of embryogenesis, after which cytotoxic chemotherapy can be administered.[15] The limited evidence suggests that almost all chemotherapeutic drugs used in ALL induction can be given during pregnancy, albeit, with risks to the fetus including still-births, intrauterine growth restrictions, spontaneous abortions, and congenital malformations, especially in the first trimester.[15] [16] [17] Beyond first trimester, however, almost all chemotherapeutic drugs can be used. Some modifications have also been recommended with regard to L-asparaginase and intrathecal methotrexate in view of risk of thromboembolism and fetal aminopterin syndrome.[18] In our literature search, we found 11 pregnancies in the first trimester with ALL, 8 of whom underwent therapeutic abortion prior to starting chemotherapy and 2 had spontaneous abortion and only 1 pregnancy resulted in a live birth (premature) where induction was with only vincristine and prednisolone.[4] [5] [6] [10] [12]

Management of leukemia in second trimester: In our report, both patients with second-trimester pregnancies presented with complications for which several key modifications were made and the results were favorable. In the fourth patient, presence of a targetable lesion (BCR-ABL) prompted us to use a TKI along with steroids and vincristine as per the E-WALL protocol.[19] [20] Data from CML patients with pregnancy proves that TKIs are teratogenic when used during organogenesis and may also lead to adverse pregnancy outcomes when used in later trimesters. However, other studies have advocated the use of Imatinib safely in second and third trimesters of pregnancy.[21] [22] [23] Data on other second-generation TKIs are scanty with isolated cases of fetal exposure to dasatinib and nilotinib.[24] [25] We, therefore, used imatinib, instead of dasatinib (as per the E-WALL protocol) for our patient.[19] There are six cases of Ph+ ALL described in [Table 2], mostly treated with imatinib as the TKI of choice.[4] [6] [7] [10] In one case, both dasatinib and ponatinib were used due to tyrosine kinase domain mutation. However, as chemotherapy was started post-partum, the effects of these drugs on fetal outcome cannot be commented upon.

The fifth patient in our cohort was also a second-trimester pregnancy, but she had multiple complications at diagnosis itself, precluding the use of full-fledged BFM-2002 protocol.[26] L-asparaginase was added to the consolidation limb of chemotherapy, similar to the UKALL and E-WALL consolidation protocols for the treatment of Ph+ ALL.[19] [27] Of note, there is in vivo antagonism of methotrexate and L-asparaginase due to opposing mechanisms of action. This can be overcome by administration of L-asparaginase after (but, not before) high dose methotrexate. This prompted us to use it 24 hours after completion of methotrexate infusion.[28] [29] Although the patient succumbed to infectious complications later-on during the course of treatment, both maternal and fetal outcomes of pregnancy were favorable.

Management of leukemia in third trimester: Chemotherapy should ideally be withheld 3 weeks prior to childbirth to allow the counts to recover at the time of delivery and also to prevent neonatal myelosuppression.[30] A planned delivery is always essential in these scenarios. Another option for patients presenting near term is to initiate pre-induction with steroids alone and then continue with the full chemotherapy once the child is delivered.[31] A conservative approach with transfusion support till delivery was safely adopted for first two relatively stable patients presenting in late third trimester, while in the third patient, we started chemotherapy ante-partum. In the cited literature, we found two cases of third-trimester pregnancies diagnosed near term, in whom chemotherapy was started post-partum ([Table 2]).

Supportive care: TLS is a common complication in highly proliferative hematological malignancies and is an oncologic emergency. Rasburicase use has not been deemed safe in pregnancy, in view of teratogenicity reports in animal studies. However, it has been used in cases where the benefits outweigh the risk.[32] The Ph+ ALL patient in our cohort presented to us with life-threatening TLS and after due consideration, we gave her rasburicase during induction and did not see any adverse fetal outcomes. To the best of our knowledge, only one earlier case of antepartum use of rasburicase has been published in literature at 35+ weeks of gestation in a case of ALL.[33]

Chemotherapy-induced neutropenia increases the chance of infections in the mother and poses numerous risks during pregnancy, both to the mother and the fetus. This is compounded by the fact that not all antibiotics can be used safely during this period.[13] Recombinant granulocyte colony-stimulating factor has been reported to be safe and can be used to shorten the period of neutropenia.[9] [34] Leukemic patients may also present with thrombocytopenia that can be deleterious at the time of delivery, especially when the required platelet thresholds for vaginal (30,000/cumm) and cesarean delivery (50,000/cumm) are not met.[35] [36]

In all our patients, fetal outcomes were favorable in terms of four babies being born at term either by NVD or elective CS. Only one baby was born prematurely at 32 weeks but is currently doing well. There is an association of intrauterine growth restriction and low birth weight (LBW) babies with exposure to chemotherapeutic agents in the second and third trimester. Preterm deliveries are also common. Prolonged durations of myelosuppression with their inherent complications such as infections have been observed in neonates born to mothers undergoing chemotherapy.[13] Long-term effects on growth and development of these children are also of concern and require follow-up of this rare and unique cohort. Among the 41 cases we reviewed in literature, there were 15 abortions (4 spontaneous, 11 therapeutic), 11 preterm/LBW babies, 1 still born, and 14 normal live births. In 23 cases, the fetuses were exposed to chemotherapy in utero and this resulted in four spontaneous abortions, sixteen LBW/preterm deliveries and fetal deaths. Some of these babies had complications at birth ([Table 2]). Only three live healthy newborns were reported post-chemotherapy exposure in utero.

Post-delivery, due consideration should be given to breast feeding, future fertility, and reproductive health of the patient.[13] In most situations, breastfeeding is not recommended while the mother is on chemotherapy, as these agents can be secreted in breast milk. If at all breastfeeding is essential, it is recommended to commence at least 2 weeks after the last administration of chemotherapy.[15] Complications such as mastalgia and breast abscesses may arise and it is therefore recommended for lactating mothers on chemotherapy to express and discard the milk to prevent such issues. Fertility issues in surviving patients may also arise, and similar to any woman in the reproductive age-group undergoing chemotherapy, it is recommended to give a hiatus of at-least 2 to 3 years after completion of chemotherapy to try to conceive once again.[16]

Saleh et al in their follow-up of 32 patients opined that acute leukemia patients had poorer long-term outcome compared to nonpregnant patients. Given the small number of patients in our cohort, we are unable to comment on this aspect.[2] Our experience shows that those patients who received full dose chemotherapy post-delivery were able to maintain remission and probably reflect the requirement of more aggressive therapy post-delivery to prevent relapse.

The cases described here were unique with respect to several factors including the time of presentation, clinical and leukemia risk profile, and complications. Hence, an individualized approach was undertaken. A proposed algorithm for the management of ALL in pregnancy is described in [Fig. 1].

Sl. no.

Reference

(total cases; ALL cases)

Patient details (age/obstetric history/POG)

Diagnosis

Therapy used; modifications (if any)

Pregnancy and fetal outcome

Disease status

Maternal outcome

1

Krueger et al [1976] (4)

15/-/26

ALL

COAP regimen: cyclophosphamide, vincristine, cytarabine, prednisone

Induction of labor. Normal Infant at 38 weeks

PD

Relapse1-month post-partum

2

O' Donnell et al [1979] (4)

24/-/15

ALL

TAD regimen (thioguanine, cytarabine, daunorubicin)

Pre-eclampsia and intrauterine

fetal death at 30 weeks

CR

Alive

3

Okun et al [1979] (5)

18/-/12

ALL

1st Induction: VCR, Pred, IT MTX. 2nd induction: CTX,

L-Asp, DNR, 6-mercaptopurine; WBRT

CS at 31 weeks; baby with transient pancytopenia, CHF, normal development at 1 year

Relapse

CNS relapse 5 weeks

post-partum

4

Dara et al [1981] (4)

26/-/21

ALL

6-MP, MTX, discontinued when pregnancy confirmed; relapse at 21 weeks, second line initiated with doxorubicin, VCR, Pred, Cyt, MTX

CS at 36 weeks. infant with polycythemia and hyperbilirubinemia

Normal growth and development at 6 months

CR

Alive

5

Sigler et al [1988] (4)

26/-/32

ALL

Pre, DNR, Ctx, Cyt, L-asp

Induction at 35 weeks. Normal infant

CR

Remission followed

by maintenance

6

Avasthi et al [1993] (4)

20/-/22

ALL

Two courses of VCR, Pred

Preterm delivery at 29 weeks to live infant

–

Sudden death 2 days

after delivery

7

Camera et al [1996] (4)

21/-/17

ALL

VCR, Pred, DNR, L-asp

C-section at 29 weeks

Normal male infant

Relapse

Death 9 months later from relapse

8

Tewari et al [1999] (4)

17/-/33

ALL

VCR, Pred for relapse ALL

Induction at 35 weeks

Normal infant

CR

Consolidation s/p allo-

SCT 22 months later

9

Hansen et al [2001] (4)

24/-/26

ALL

Induction CALGB 9111. At 26 weeks: DNR, VCR, Pred, L-asp At 30 & 34 weeks: IT-MTX, Ctx,6-MP, Cyt, VCR, L-asp

Spontaneous delivery at 36 weeks. Normal male infant

–

Unclear

10

Ali et al [2002] (10 cases: 2-ALL) (5)

24/G1/24

21/G2P0/8

B-ALL

Relapsed B-ALL

Not documented

Not documented

Therapeutic abortion

Therapeutic abortion

Remission relapse

Alive

Dead

11

Terek et al 2003] (4)

21/-/31

ALL

VCR, DNR, Pred, L-asp

C-section, newborn respiratory distress (required intubation)

–

Maternal death due to sepsis

12

Chelghoum et al [2005] (n = 37) (6)

6 ALL cases

1. 25/G1/27

2. 34/G2/9

3. 33/G4/26

4. 30/G1/10

5. 21/G1/28

6. 25/G1/9

T-ALL

Pre B-ALL

Pre B-ALL

Ph+ B-ALL

Pre B-ALL

T-ALL

All cases received

VCR + Dauno + CTX + Pred

NVD, premature

Therapeutic abortion

CS; premature

Therapeutic abortion

CS; premature

Therapeutic abortion

PD

CR

CR

CR

CR

CR

13

Molkenboer et al [2005]

2 ALL cases (7)

1. 30/G3P2/6

2. 37/G1/15

Ph+ B-ALL

Ph+ B-ALL

Pred + VCR + Dauno + Asp + ITMTx;

High-dose cytarabine+ imatinib

Same as above

Missed abortion at 11 weeks

Spontaneous delivery at 22 weeks; stillborn

CR

PD post-induction

Death post-HSCT

Imatinib palliation. Death few weeks later

14

Dilek et al [2006] (1/21, ALL) (8)

25/G1/term

ALL

4 drug regimen induction

NVD; LBW

CR post-induction

Alive

15

Matsouka et al [2007] (9)

16/G1/26 + 3d

B-ALL

BFM-95; Recombinant G-CSF use during cytopenic phase. Delivered post-induction

Elective CS at 32.4 weeks; LBW

CR

Alive

16

Papantoniou et al [2008] (4)

16/-/26

ALL

DNR, VCR, L-asp, Pred, IT-Mtx, G-CSF

CS at 32 weeks.

Infant normal at 18 months

CR

Remission at 18-months follow-up

17

Udink Ten Cate et al [2009] (4)

30/-/23

ALL

VCR, Pre, IT-MTX, Ctx, DNR.

VCR, Ctx, DNR. Maintenance 6-MP

PROM at 33 weeks,

NVD baby; pancytopenic, normal development at 2 years

CR

MUD—HSCT

In CR 2 years after transplant

18

Aljurf et al [2009] 2 ALL cases

(4)

37/-/29

27/-/13

ALL

ALL

VCR, dexamethasone, idarubicin

Unknown

Full-term infant; anemia

Spontaneous abortion at 14 weeks during induction

CR

CR

CR with induction

Allo-SCT in CR 1

Alive 4 years later

19

Ticku et al [2013] (4)

22/G1/26

Ph+ B-ALL

Induction: Hyper-CVAD + dasatinib

Ph+ mutation F317L; Ponatinib started 10 days post-partum

Elective CS at 30 weeks; LBW

CR

Alive

20

Nakajima et al [2013] (10)

3 ALL cases

1. 20/G1/37

2. 36/G1/29

3. 29/G1/5

ALL

ALL/ t(9;22)

ALL

Not available

DNR + VCR + , CTX + Pred

Not available

Emergency CS; live birth

Elective CS; live birth

Therapeutic abortion

PD

CR

CR

Dead

Alive

Alive

21

Saleh et al [2014]

(n = 32; 6 ALL cases) (2)

1. 23/G2/38

2. 25/G1/12

3. 26/G3/28

4. 23/G3/13

5. 37/G7/29

6. 21/G1/31

Pre B-ALL

Pre B ALL

Pre B-ALL

Pre B-ALL

Pre B- ALL

T-ALL

None

None

5 drug regime

None

5 drug regime

VCR + Pred

Live birth at term

Spontaneous abortion

Spontaneous abortion

Spontaneous abortion

Live birth at term

Preterm birth at 33+ weeks

PD

PD

CR

PD

LTFU

PD

Death

Death

Alive, post-SCT

Dead, post-SCT

LTFU

Death

22

Farhadfar et al [2016]

(n = 23)

5 ALL cases

(11)

1. 26/-/12

2. 23/-/6

3. 34/-/10

4. 19/-/16

5. 28/-/35

B-ALL

B-ALL

Ph+ ALL

B-ALL

B-ALL

Post-termination induction C10403

Post-termination induction C10403

CALGB9111; Reinduction: Imatinib with ara-C

HSCT: MUD, TBI/VP-16

DNR/VCR/Pred; Consolidation: HiDAC

Post-delivery - DNR/VCR/Pred

Relapse: DNR/VCR/Pred, HiDAC, MTX/L-Asp

Therapeutic abortion

Therapeutic abortion

Fetal loss at 19 weeks

Fetal loss 22 weeks

NVD,38 weeks

-

CR

CR, f/b HSCT

CR

PD

Alive

Alive

Death on D21 of HSCT d/t septic shock

Death

Death

23

Vlijm-Kievit et al [2017] (12)

37/G2P1/36

T-ALL

Pred + VCR + Dauno + Peg-asparaginase

(HOVON 100 protocol)- Asp and MTX delayed till post-delivery

Therapeutic LMWH given upto 6 weeks post-partum

NVD 37 weeks

Remission

Alive

 Fig. 1 Flowchart of management of acute lymphoblastic leukemia in pregnancy. $: L-asparaginase is associated with increased risk of thrombosis during pregnancy and should be combined with low molecular weight heparin (LMWH) prophylaxis or deferred till after delivery.#: Modification of protocol on a case-to-case basis; modification based on co-morbidities/intolerance to specific chemotherapeutics.


Conclusion

Management of leukemia in pregnancy is a challenging task and relies heavily on effort of a multidisciplinary team, from treating hematologists to obstetricians. Individualized approach to manage these patients is essential, considering the gestational timing of presentation of ALL, cytogenetics, clinical profile, and active medical issues at diagnosis. Novel approaches used in our patients such as the use of modified BFM and E-WALL protocols, modifications with regard to timing of L-asparaginase administration, and antepartum use of rasburicase were met with favorable pregnancy outcomes.

Conflict of interest

None declared.

Authors' Contributions

S.B. was involved in conceptualization, data collection, and manuscript drafting. S.G. helped in conceptualization, clinical data curation, and manuscript editing and analysis. S.S.R., S. Samanta, N.S. and S. Saha were involved in Institutional Medical Boards convened for patient management strategies. M.B. was involved in conceptualization, manuscript editing, analysis, and overall supervision.

Ethics Approval

Retrospective study

Consent for Publication

Yes.

Availability of Data and Material

Available for publication/review.

References

  1.  Acute leukemia in pregnancy with ovarian metastasis: a case report and review of the literature - PubMed [Internet]. [cited 2020 Sep 8]. Accessed February 21, 2023 at:  https://pubmed.ncbi.nlm.nih.gov/14675333/
  2.  Saleh AJM, Alhejazi A, Ahmed SO. et al. Leukemia during pregnancy: long term follow up of 32 cases from a single institution. Hematol Oncol Stem Cell Ther 2014; 7 (02) 63-68
    Crossref PubMed Google Scholar
  3.  Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004; 5 (05) 283-291
    Crossref PubMed Google Scholar
  4.  Ticku J, Oberoi S, Friend S, Busowski J, Langenstroer M, Baidas S. Acute lymphoblastic leukemia in pregnancy: a case report with literature review. Ther Adv Hematol 2013; 4 (05) 313-319
    Crossref PubMed Google Scholar
  5.  Ali R, Ozkalemkaş F, Ozçelik T. et al. Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a single institutional experience with 10 pregnancies at 16 years. Leuk Res 2003; 27 (05) 381-385
    Crossref PubMed Google Scholar
  6.  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 (01) 110-117
    Crossref PubMed Google Scholar
  7.  Molkenboer JFM, Vos AH, Schouten HC, Vos MC. Acute lymphoblastic leukaemia in pregnancy. Neth J Med 2005; 63 (09) 361-363
    PubMed Google Scholar
  8.  Dilek I, Topcu N, Demir C. et al. Hematological malignancy and pregnancy: a single-institution experience of 21 cases. Clin Lab Haematol 2006; 28 (03) 170-176
    Crossref PubMed Google Scholar
  9.  Matsouka C, Marinopoulos S, Barbaroussi D, Antsaklis A. Acute lymphoblastic leukemia during gestation. Med Oncol 2008; 25 (02) 190-193
    Crossref PubMed Google Scholar
  10.  Nakajima Y, Hattori Y, Ito S. et al. Acute leukemia during pregnancy: an investigative survey of the past 11 years. Int J Lab Hematol 2015; 37 (02) 174-180
    Crossref PubMed Google Scholar
  11.  Farhadfar N, Cerquozzi S, Hessenauer MR. et al. Acute leukemia in pregnancy: a single institution experience with 23 patients. Leuk Lymphoma 2017; 58 (05) 1052-1060
    Crossref PubMed Google Scholar
  12.  Vlijm-Kievit A, Jorna NGE, Moll E. et al. Acute lymphoblastic leukemia during the third trimester of pregnancy. Leuk Lymphoma 2018; 59 (05) 1274-1276
    Crossref PubMed Google Scholar
  13.  Santiago-López CJ, Cuan-Baltazar Y, Pérez-Partida AM, Muñoz-Pérez MJ, Soto-Vega E. Leukemia during pregnancy. Obstet Gynecol Int J 2017; 6 (06) 00225
    Google Scholar
  14.  Kauss MA, Reiterer G, Bunaciu RP, Yen A. Human myeloblastic leukemia cells (HL-60) express a membrane receptor for estrogen that signals and modulates retinoic acid-induced cell differentiation. Exp Cell Res 2008; 314 (16) 2999-3006  https://pubmed.ncbi.nlm.nih.gov/18692045/ cited 2020Oct23 [Internet]
    Crossref PubMed Google Scholar
  15.  Milojkovic D, Apperley JF. How I treat leukemia during pregnancy. Blood 2014; 123 (07) 974-984
    Crossref PubMed Google Scholar
  16.  Brenner B, Avivi I, Lishner M. Haematological cancers in pregnancy. Vol. 379, The Lancet. Lancet Publishing Group; 2012: 580-7
    Google Scholar
  17.  Yarbro CH, Wujcik D, Gobel BH. Cancer Nursing. Jones & Bartlett Learning; 2016. Available at:  https://books.google.co.in/books?id=mGt7jgEACAAJ
    Google Scholar
  18.  Zaidi A, Johnson L-M, Church CL. et al. Management of concurrent pregnancy and acute lymphoblastic malignancy in teenaged patients: two illustrative cases and review of the literature. J Adolesc Young Adult Oncol 2014; 3 (04) 160-175
    Crossref PubMed Google Scholar
  19.  Rousselot P, Coudé MM, Gokbuget N. et al; European Working Group on Adult ALL (EWALL) group. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood 2016; 128 (06) 774-782
    Crossref PubMed Google Scholar
  20.  Gökbuget N. Treatment of older patients with acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 573-579
    Crossref PubMed Google Scholar
  21.  Pye SM, Cortes J, Ault P. et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111 (12) 5505-5508
    Crossref PubMed Google Scholar
  22.  Mukhopadhyay A, Dasgupta S, Kanti Ray U, Gharami F, Bose CK, Mukhopadhyay S. Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy. Ir J Med Sci 2015; 184 (01) 183-188
    Crossref PubMed Google Scholar
  23.  Cole S, Kantarjian H, Ault P, Cortés JE. Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: a case report and review of the literature. Clin Lymphoma Myeloma 2009; 9 (04) 324-327
    Crossref PubMed Google Scholar
  24.  Conchon M, Sanabani SS, Serpa M. et al. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol 2010; 2010: 136252-136252
    Crossref PubMed Google Scholar
  25.  Conchon M, Sanabani SS, Bendit I, Santos FM, Serpa M, Dorliac-Llacer PE. 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 (01) 42
    Crossref PubMed Google Scholar
  26.  Stary J, Zimmermann M, Campbell M. et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol 2014; 32 (03) 174-184
    Crossref PubMed Google Scholar
  27.  Rowe JM, Buck G, Burnett AK. et al; ECOG, MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106 (12) 3760-3767
    Crossref PubMed Google Scholar
  28.  Gilis L, Lebras L, Bouafia-Sauvy F. et al. Sequential combination of high dose methotrexate and L-asparaginase followed by allogeneic transplant: a first-line strategy for CD4+/CD56+ hematodermic neoplasm. Leuk Lymphoma 2012; 53 (08) 1633-1637
    Crossref PubMed Google Scholar
  29.  Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy: Principles and Practice. Wolters Kluwer Health; 2011. Available at:  https://books.google.co.in/books?id=0U4aj4GZWCIC
    Google Scholar
  30.  Fernández Fernández C, Pérez Prieto B, Argüelles Álvarez S, García González C, González García C. Leucemia aguda mieloblástica en gestante de 28 semanas. [Acute myeloblastic leukemia in a 28-week pregnant woman] Clin Invest Ginecol Obstet 2008; 35 (05) 184-186
    Google Scholar
  31.  Shapira T, Pereg D, Lishner M. How I treat acute and chronic leukemia in pregnancy. Blood Rev 2008; 22 (05) 247-259
    Crossref PubMed Google Scholar
  32.  Middeke JM, Bruck N, Parmentier S, Bornhäuser M, Schetelig J. Use of rasburicase in a pregnant woman with acute lymphoblastic leukaemia and imminent tumour lysis syndrome. Ann Hematol 2014; 93 (03) 531-532
    Crossref PubMed Google Scholar
  33.  Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N Engl J Med 2011; 364 (19) 1844-1854
    Crossref PubMed Google Scholar
  34.  Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins; 2011. Available at:  https://books.google.co.id/books?id=OIgTE4aynrMC
    Google Scholar
  35.  Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood 2003; 102 (13) 4306-4311
    Crossref PubMed Google Scholar
  36.  Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115 (02) 168-186
    Crossref PubMed Google Scholar

Address for correspondence

Maitreyee Bhattacharyya, MBBS, MD, DM
Institute of Hematology and Transfusion Medicine, Medical College Hospital
88, College Street, Kolkata 700073, West Bengal
India   


Publication History

Article published online:
17 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

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 Fig. 1 Flowchart of management of acute lymphoblastic leukemia in pregnancy. $: L-asparaginase is associated with increased risk of thrombosis during pregnancy and should be combined with low molecular weight heparin (LMWH) prophylaxis or deferred till after delivery.#: Modification of protocol on a case-to-case basis; modification based on co-morbidities/intolerance to specific chemotherapeutics.

References

  1.  Acute leukemia in pregnancy with ovarian metastasis: a case report and review of the literature - PubMed [Internet]. [cited 2020 Sep 8]. Accessed February 21, 2023 at:  https://pubmed.ncbi.nlm.nih.gov/14675333/
  2.  Saleh AJM, Alhejazi A, Ahmed SO. et al. Leukemia during pregnancy: long term follow up of 32 cases from a single institution. Hematol Oncol Stem Cell Ther 2014; 7 (02) 63-68
    Crossref PubMed Google Scholar
  3.  Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004; 5 (05) 283-291
    Crossref PubMed Google Scholar
  4.  Ticku J, Oberoi S, Friend S, Busowski J, Langenstroer M, Baidas S. Acute lymphoblastic leukemia in pregnancy: a case report with literature review. Ther Adv Hematol 2013; 4 (05) 313-319
    Crossref PubMed Google Scholar
  5.  Ali R, Ozkalemkaş F, Ozçelik T. et al. Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a single institutional experience with 10 pregnancies at 16 years. Leuk Res 2003; 27 (05) 381-385
    Crossref PubMed Google Scholar
  6.  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 (01) 110-117
    Crossref PubMed Google Scholar
  7.  Molkenboer JFM, Vos AH, Schouten HC, Vos MC. Acute lymphoblastic leukaemia in pregnancy. Neth J Med 2005; 63 (09) 361-363
    PubMed Google Scholar
  8.  Dilek I, Topcu N, Demir C. et al. Hematological malignancy and pregnancy: a single-institution experience of 21 cases. Clin Lab Haematol 2006; 28 (03) 170-176
    Crossref PubMed Google Scholar
  9.  Matsouka C, Marinopoulos S, Barbaroussi D, Antsaklis A. Acute lymphoblastic leukemia during gestation. Med Oncol 2008; 25 (02) 190-193
    Crossref PubMed Google Scholar
  10.  Nakajima Y, Hattori Y, Ito S. et al. Acute leukemia during pregnancy: an investigative survey of the past 11 years. Int J Lab Hematol 2015; 37 (02) 174-180
    Crossref PubMed Google Scholar
  11.  Farhadfar N, Cerquozzi S, Hessenauer MR. et al. Acute leukemia in pregnancy: a single institution experience with 23 patients. Leuk Lymphoma 2017; 58 (05) 1052-1060
    Crossref PubMed Google Scholar
  12.  Vlijm-Kievit A, Jorna NGE, Moll E. et al. Acute lymphoblastic leukemia during the third trimester of pregnancy. Leuk Lymphoma 2018; 59 (05) 1274-1276
    Crossref PubMed Google Scholar
  13.  Santiago-López CJ, Cuan-Baltazar Y, Pérez-Partida AM, Muñoz-Pérez MJ, Soto-Vega E. Leukemia during pregnancy. Obstet Gynecol Int J 2017; 6 (06) 00225
    Google Scholar
  14.  Kauss MA, Reiterer G, Bunaciu RP, Yen A. Human myeloblastic leukemia cells (HL-60) express a membrane receptor for estrogen that signals and modulates retinoic acid-induced cell differentiation. Exp Cell Res 2008; 314 (16) 2999-3006  https://pubmed.ncbi.nlm.nih.gov/18692045/ cited 2020Oct23 [Internet]
    Crossref PubMed Google Scholar
  15.  Milojkovic D, Apperley JF. How I treat leukemia during pregnancy. Blood 2014; 123 (07) 974-984
    Crossref PubMed Google Scholar
  16.  Brenner B, Avivi I, Lishner M. Haematological cancers in pregnancy. Vol. 379, The Lancet. Lancet Publishing Group; 2012: 580-7
    Google Scholar
  17.  Yarbro CH, Wujcik D, Gobel BH. Cancer Nursing. Jones & Bartlett Learning; 2016. Available at:  https://books.google.co.in/books?id=mGt7jgEACAAJ
    Google Scholar
  18.  Zaidi A, Johnson L-M, Church CL. et al. Management of concurrent pregnancy and acute lymphoblastic malignancy in teenaged patients: two illustrative cases and review of the literature. J Adolesc Young Adult Oncol 2014; 3 (04) 160-175
    Crossref PubMed Google Scholar
  19.  Rousselot P, Coudé MM, Gokbuget N. et al; European Working Group on Adult ALL (EWALL) group. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood 2016; 128 (06) 774-782
    Crossref PubMed Google Scholar
  20.  Gökbuget N. Treatment of older patients with acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 573-579
    Crossref PubMed Google Scholar
  21.  Pye SM, Cortes J, Ault P. et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111 (12) 5505-5508
    Crossref PubMed Google Scholar
  22.  Mukhopadhyay A, Dasgupta S, Kanti Ray U, Gharami F, Bose CK, Mukhopadhyay S. Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy. Ir J Med Sci 2015; 184 (01) 183-188
    Crossref PubMed Google Scholar
  23.  Cole S, Kantarjian H, Ault P, Cortés JE. Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: a case report and review of the literature. Clin Lymphoma Myeloma 2009; 9 (04) 324-327
    Crossref PubMed Google Scholar
  24.  Conchon M, Sanabani SS, Serpa M. et al. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol 2010; 2010: 136252-136252
    Crossref PubMed Google Scholar
  25.  Conchon M, Sanabani SS, Bendit I, Santos FM, Serpa M, Dorliac-Llacer PE. 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 (01) 42
    Crossref PubMed Google Scholar
  26.  Stary J, Zimmermann M, Campbell M. et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol 2014; 32 (03) 174-184
    Crossref PubMed Google Scholar
  27.  Rowe JM, Buck G, Burnett AK. et al; ECOG, MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106 (12) 3760-3767
    Crossref PubMed Google Scholar
  28.  Gilis L, Lebras L, Bouafia-Sauvy F. et al. Sequential combination of high dose methotrexate and L-asparaginase followed by allogeneic transplant: a first-line strategy for CD4+/CD56+ hematodermic neoplasm. Leuk Lymphoma 2012; 53 (08) 1633-1637
    Crossref PubMed Google Scholar
  29.  Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy: Principles and Practice. Wolters Kluwer Health; 2011. Available at:  https://books.google.co.in/books?id=0U4aj4GZWCIC
    Google Scholar
  30.  Fernández Fernández C, Pérez Prieto B, Argüelles Álvarez S, García González C, González García C. Leucemia aguda mieloblástica en gestante de 28 semanas. [Acute myeloblastic leukemia in a 28-week pregnant woman] Clin Invest Ginecol Obstet 2008; 35 (05) 184-186
    Google Scholar
  31.  Shapira T, Pereg D, Lishner M. How I treat acute and chronic leukemia in pregnancy. Blood Rev 2008; 22 (05) 247-259
    Crossref PubMed Google Scholar
  32.  Middeke JM, Bruck N, Parmentier S, Bornhäuser M, Schetelig J. Use of rasburicase in a pregnant woman with acute lymphoblastic leukaemia and imminent tumour lysis syndrome. Ann Hematol 2014; 93 (03) 531-532
    Crossref PubMed Google Scholar
  33.  Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N Engl J Med 2011; 364 (19) 1844-1854
    Crossref PubMed Google Scholar
  34.  Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins; 2011. Available at:  https://books.google.co.id/books?id=OIgTE4aynrMC
    Google Scholar
  35.  Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood 2003; 102 (13) 4306-4311
    Crossref PubMed Google Scholar
  36.  Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115 (02) 168-186
    Crossref PubMed Google Scholar

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