Management and controversies of classical Hodgkin lymphoma in pregnancy Toby A. Eyre,1 I-Jun Lau,1 Lucy Mackillop2 and Graham P. Collins1 1

Department of Haematology, Oxford University Hospitals NHS Trust, and 2Department of Obstetrics & Gynaecology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK

Summary The goal of managing classical Hodgkin lymphoma (cHL) in pregnancy is to obtain good long-term outcomes for both the mother and fetus. Given the excellent outcomes outside of pregnancy, the goal of treatment should remain curative. There remains a tension and debate regarding the timing of chemotherapy, the curative nature of such treatment and the timing of delivery. Moreover, the aim during pregnancy should be to minimize fetal toxicity and optimize perinatal outcomes. The management of cHL within pregnancy was covered within the excellent recent British Committee for Standards in Haematology guidelines, but with necessary brevity. By reviewing the literature over the last 30 years, herein we discuss the options for management during each trimester. Critical organogenesis occurs between 2 and 8 weeks post-conception; during which time the immature fetus is vulnerable to cytotoxic exposure. We discuss the evidence for using ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and single agent vinblastine in the first trimester. cHL presenting in pregnancy raises complex and difficult ethical dilemmas that can cause anxiety for patients, families and physicians. Decision-making must be multi-disciplinary and holistic, taking into account the patient’s wishes, psycho-social and religious beliefs and personal circumstances. Clear communication between the haemato-oncologist, medical obstetrician, nurse specialists, midwives and neonatologists is paramount to a successful outcome. Keywords: Hodgkin lymphoma, doxorubicin, bleomycin, vinblastine and dacarbazine, vinblastine, pregnancy, teratogenicity.

Diagnostic approach to Hodgkin lymphoma in pregnancy In 2011, there were 459 new cases of classical Hodgkin lymphoma (cHL) in females aged between 15 and 50 years in the

Correspondence: Graham P. Collins, Department of Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK. E-mail: [email protected]

ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 613–630

UK ( types/hodgkinslymphoma/incidence/uk-hodgkins-lymphomaincidence-statistics). From this data, it is logical to surmize that a small proportion of these cases will present in pregnancy each year in the UK. The fundamental principle of the diagnostic evaluation of cHL in pregnancy requires balancing disease assessment and staging investigations with the risks to maternal and fetal wellbeing. Initial evaluation is similar to that of a non-pregnant patient with cHL. Histological confirmation should be obtained by excision or core biopsy of involved tissue, procedures that are generally safe in pregnancy. Laboratory investigations should include a full blood count, erythrocyte sedimentation rate (ESR), liver and renal function, bone profile, lactate dehydrogenase (LDH), albumin, serum protein electrophoresis and human immunodeficiency virus (HIV) testing. Physiological changes that accompany increasing gestational age can result in a raised ESR, low haemoglobin and raised alkaline phosphatase (ALP) (due to placentally-derived ALP). Results therefore should be interpreted in the context of the gestation (Broek & Letsky, 2001).

Staging and imaging modalities in pregnancy 18

F fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT)

Outside of pregnancy, the management of cHL follows wellestablished guidelines based on initial staging assessment and prognostic criteria using FDG-PET/CT. Accurate radiological staging is the basis for the selection of an appropriate therapeutic approach to maximize survival and minimize treatment-related morbidity (Nisce et al, 1986). Outside of pregnancy, there is also growing consensus that interim PET-based responses are predictive of outcome. Interim PET [usually after two cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine)] has been shown to be a clear prognostic indicator of disease-free survival (Cerci et al, 2010; Gallamini et al, 2007; Hutchings et al, 2006) and, as such, testing of PET response-adapted treatment pathways have been described in recent retrospective and non-randomized analyses (Avigdor et al, 2010; Gallamini et al, 2011) and are the subject of ongoing clinical trials.

First published online 13 February 2015 doi: 10.1111/bjh.13327

Review Bone marrow involvement carries a worse prognosis and occurs in 4–16% of cHL (El-Galaly et al, 2012). It is generally accepted that FDG-PET/CT can accurately detect marrow involvement, which has abrogated the need for biopsy in most cases (El-Galaly et al, 2012). However, due to the paucity of safety data in pregnancy, FDG-PET/CT has generally been avoided. In a small number of case series, the total fetal dose from FDG-PET/CT has been estimated by taking into account the fetal FDG self-dose, dose coming from the maternal tissues and CT dose (Takalkar et al, 2011; ZanottiFregonara et al, 2010, 2012). This ranges from 111 to 218 mGy for various trimesters in pregnancy with no documented adverse pregnancy outcomes described. The advice remains to avoid ionizing radiation during pregnancy and therefore PET CT imaging is contraindicated. It is likely that PET-based, risk-adapted therapy outside of pregnancy will become a standard of care, but such an approach should be discouraged in pregnant patients.

Standard CT Scanning The current accepted cumulative dose of ionizing radiation to the fetus is unclear. Although the incidence of gross congenital malformations is not increased at doses 3 (EORTC) or >2 (GHSG) lymph node sites ESR >50 or >30 if B symptoms present

4 ABVD and IFRT 30 Gy HD11 study (Eich et al, 2010)

EORTC, European Organization for Research and Treatment of Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte sedimentation rate; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; IFRT, involved field radiotherapy.

therapy as consolidation and autologous stem cell transplantation (ASCT) at relapse was permissive within the trial. The 7-year progression-free survival (PFS) was 85% after BEACOPP and 73% after ABVD (P = 0004). More patients required salvage therapy and an ASCT post-ABVD but higher initial toxicity was observed with BEACOPPESCALATED. Due to the efficacy and curative potential of second line treatment, the 7-year overall survival (OS) was not significantly different [89% (BEACOPP) vs. 84% (ABVD) P = 039] although OS was not the primary endpoint. Standard therapy outside of clinical trials in most UK centres remains six cycles of ABVD.

Pharmacology of chemotherapy in pregnancy Data collected over recent decades describes the use of many chemotherapeutics at different time points during pregnancy in solid tumours, haematological malignancies and non-malignant conditions. ABVD combines an anthracycline, a vinca alkaloid, an alkylating agent and a glycopeptide antibiotic. When considering the potential drug effects on the embryo or fetus, the fetal gestation, the gestation of proposed treatment, the drug and the dose of drug need to be considered. Teratogenicity refers to the potential for congenital malformations due to disruption of organogenesis, which largely occurs between weeks 2 and 8 after conception. Fetotoxicity refers to the potential for alternations in the structure or function of an organ system that is normally 615

Review formed. This can occur from the time of organogenesis until term. Any drug of high lipid solubility, i.e., loosely bound to plasma protein, and of low molecular weight will cross the placenta more effectively (Doll et al, 1989). It is not fully understood why two fetuses exposed to the same medication at the same gestation may experience different outcomes.

Alkylating agents in pregnancy Alkylating agents are key components in multi-agent chemotherapy and have been used in pregnancy in all three trimesters. Fetal malformations have been described following cyclophosphamide in the first trimester. These include toe atresia, ocular anomalies, low-set ears, cleft palate, oesophageal atresia, arm deformity and abnormal inferior vena cava development. However, data is mixed, with other reports describing how 16 other fetuses were exposed during the first trimester with no anomalies noted (Doll et al, 1989; Reynoso et al, 1987; Toledo, 1971). In two series of 15 cases of exposure to busulphan, one developed pyloric stenosis and the other unilateral renal agenesis. None of eight fetuses exposed in the first trimester developed abnormalities (Boros & Reynolds, 1977; Earll & May, 1965). Historical cases of fetal mortality or malformations have often been exposed to alkylators in combination with radiotherapy or other chemotherapy. Despite this, there is some evidence of safety in the second and third trimesters, with only a small proportion of fetal fatalities (Cantini & Yanes, 1984; Warkany et al, 1959).

Anthracyclines in pregnancy Anthracyclines are typically large molecular weight chemotherapeutics. It is postulated that they are less liable to cross the placenta due to their size, their hydrophilic molecular properties, and that they are substrates for placental P-glycoprotein (Smit et al, 1999). The lipid structure of doxorubicin, epirubicin and idarubicin differ and so do their relative safety profiles in pregnancy. Idarubicin and epirubicin exposure in pregnancy has been limited given the concerning outcomes in fetuses exposed. For example, in 17 historical cases exposed to either of these anthracyclines, there were four fetal/neonatal deaths, and two cases of fetal cardiomyopathy (Achtari & Hohlfeld, 2000; Giacalone et al, 1999; Peres et al, 2001; Siu et al, 2002). This concern has been challenged recently by data from breast cancer patients treated in pregnancy and from pre-clinical animal models suggesting that epirubicin may have a similar toxicity and pharmacological placental transfer profile to doxorubicin in the second and third trimester, although use in the first trimester remains associated with poor fetal outcomes (Mir et al, 2008a). In contrast, case series published demonstrate the relative safety of daunorubicin (O’Donnell et al, 1979; Reynoso & Huerta, 1994; Reynoso et al, 1987; Volkenandt, 1988) and doxorubicin, with the latter the preferred agent given the 616

more extensive safety data published in pregnancy. Doxorubicin use has been described in well over 200 fetal exposures (Germann, 2004). There are rare examples of fetal anomalies, although concurrent radiotherapy and chemotherapy were typically also used in these cases. Other complications described include IUGR, intrauterine death (IUD) and second trimester miscarriage; (Ebert et al, 1997; Karp et al, 1983; Murray, 1984; Toledo, 1971; Zemlickis et al, 1992) although again, multi-agent therapy was given, including anti-metabolites that are now considered strictly contraindicated in pregnancy (Brenner et al, 2012).

Vinca alkaloids in pregnancy Vinca alkaloids display high protein binding properties in the plasma, and as such have a lower placental transfer compared to other agents (Doll et al, 1989). A case series of vinca alkaloid exposure in pregnancy bears this out, with little teratogenicity displayed. In one case series of 29 exposures, a single neonate had an atrial septal defect and absent radii and fifth finger digits following multiagent chemotherapy (including cytarabine and doxorubicin) (Ebert et al, 1997). Over 100 cases of vinca alkaloid exposures are reported in pregnancy, with malformations typically only noted following first trimester exposure. Examples of fetal or neonatal deaths typically involve exposure to multiagent chemo-radiotherapy (radiotherapy, doxorubicin and prednisolone in case one; prednisolone and epirubicin in case two, ifosfamidine and dactinomycin in case three and 6-mercaptopurine, methotrexate, cytarabine and prednisolone in case four) (Cantini & Yanes, 1984; Fernandez et al, 1989; Karp et al, 1983; Peres et al, 2001).

Searches The authors performed searches of Medline, Current Contents, PubMed, and references from relevant articles using the search terms ‘Hodgkin(s) lymphoma’ ‘Hodgkin(s)’ ‘pregnancy’ and ‘haematological malignancy’, or ‘lymphoma’. Abstracts and reports from meetings were included only when they related to previously published work. Table II summarizes the fetal and maternal outcomes of the all the key reported data of cHL case series and individual case reports within the published literature over the last 30 years. Understandably, there have been no randomized studies performed, and most case series are retrospective.

Treatment options for cHL in pregnancy cHL is one of the commonest cancers presenting in pregnancy, occurring in approximately 1 in 1000 to 1 in 6000 deliveries (Pentheroudakis & Pavlidis, 2006). Up to 3% of new presentations occur in pregnancy (Bachanova & Connors, 2013; Lishner et al, 1992) and as such there is a limited evidence base from which to guide decision-making, although new data has ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 613–630

ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 613–630

b. 1 ABV c. 1 AVD d. 1 Single agent vincristine Mean gestation first chemotherapy 187 weeks 1 HL; Etoposide, vinblastine and doxorubicin 13 HL; Regimen details not given

10 HL; 1 Spontaneous Abortion, 1 TOP (conceived on ABVD) a. 2 deferral b. 1 R-CHOP/AVD c. 5 ABVD/AVD (most in TM2-3) 23 Primary HL, 2 recurrent HL Majority Stage II. 1 TOP, 2 deferred treatment a. 19 ABVD

Not stated

‘remission’ at 17 months F/up

Not stated

‘excellent outcomes’, no specific data stated

a. Normal development, no complications, F/up 0–10 years. 1 syndactyly correction, considered unrelated to chemotherapy. 1 Plagiocephaly b. Normal development aged 66 years c. Reduced birth weight 15%, N otherwise at birth d. IUGR, Normal otherwise at birth Mean 41 months F/up: 15 HL; mean height 69% weight 67%. 1 chronic bronchiolitis, 1 recurrent otitis media, 1 asthma The child had normal psychomotor development and no secondary cancers were noted at 17 months F/up  Two infants had a birth weight below the 10th percentile (one received surgery and RT)  Pectus excavatum noted in one infant exposed to MOPP/ABV (39) in TM2-3  Bilateral partial syndactyly in one infant exposed to Mantle RT in TM2 and MOPP/ABV in TM2-3

No spontaneous abortions, Mean birth weight 2587 kg, delivery mean gestation 359 weeks

19 babies, median birth weight 3125 kg (range 28–365 kg), all alive, median F/up 253 years. No congenital abnormalities. Physical, psychological, educational and neurological developments were normal. Cardiac function and chromosomal examination normal. No secondary cancer observed 1 mother treated with ABVD in TM2 had stillborn twins at 26 weeks. 1 symptomatic HL started ABVD at 11/40 weeks (TM1) with normal infant. Others treated with chemotherapy delivered at c. 37 weeks with no fetal malformations

14 of 18 long term DFS

89% CR and 89% 20-year DFS

b. 4 RT (25–30 Gy for stage I–IIA); 3 in TM2, 1 in TM3 c. 3 AVD; 1 in TM2, 2 in TM3 17 HL; a. 11 deferral b. 6 single agent vinblastine 19 HL treated in TM1; 12 ABVD, 5 MOPP/ABVD, 2 MOPP

Induction of labour in 35% (antenatal treatment) vs. 45% (deferred treatment), preterm delivery 39% (antenatal treatment) vs. 38% (deferred treatment), LSCS 20% (antenatal treatment) vs. 18% (deferred treatment),

Management and controversies of classical Hodgkin lymphoma in pregnancy.

The goal of managing classical Hodgkin lymphoma (cHL) in pregnancy is to obtain good long-term outcomes for both the mother and fetus. Given the excel...
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