Haematological malignancy in pregnancy

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1 Haematological malignancy in pregnancy Dr Kylie Mason Haematologist Royal Melbourne Hospital / Peter MacCallum Cancer Centre NHMRC Fellow, University of Melbourne Senior Research Fellow, University of Sydney

2 Blood cancers are relatively rare

3 But are overrepresented in young people

4 Young people tend to more aggressive blood cancer Annual crude rates per : Haematological Malignancy Research Network (HMRN),

5 Haematologic malignancy in pregnancy is rare Incidence has been variably estimated from 1:1000 to 1:10,000 new cancer diagnoses in age by top 5 tumour type, Australia, 2014 Hodgkin Lymphoma % pregnancies Non Hodgkin Lymphoma: 0.016% Leukaemia 0.001% AIHW 2015

6 Lymphoma Non-Hodgkin Lymphoma 6th Most Common Cancer 4.1% of cancers in Australia 5500 new cases / year Incidence increases with age >60 subtypes can be roughly divided into indolent, intermediate and aggressive - which determine treatment strategy More aggressive lymphomas generally have higher cure rates treatment is with multi-agent chemotherapy +/- radiotherapy with variable outcomes Hodgkin Lymphoma Much less common 0.5% of cancers 400 new cases / year Dual peak incidence - Adolescence and young adults and >50yo good prognosis in most however outcomes for relapsed / refractory disease are very poor treatment is with multi-agent chemotherapy +/- radiotherapy with the goal of minimizing toxicity PET scans guide therapy with patients that are PET negative post 2 nd cycle of treatment having an excellent prognosis and ability to possibly reduce treatment

7 Leukaemia Myeloid vs Lymphoid Acute vs Chronic All present with signs and symptoms of bone marrow failure Can present with a hyper-leucostasis particularly AML Chronic Lymphocytic Leukaemia - disease of elderly, rare in younger women. Unlikely to need immediate treatment. Chronic Myeloid Leukaemia - now treated with tyrosine kinase inhibitors with excellent long term outcomes Acute Myeloid Leukaemia - most common acute leukaemia, can present with bleeding, gum infiltration, cutaneous disease Acute Lymphoblastic Leukaemia - can also present with mediastinal masses and lymphadenopathy

8 The path to cure is often more complex in pregnancy diagnosis staging treatment social support

9 Case 1 - diagnosis 32yo woman, G2P1, post partum depression with 1st child, history of anxiety shortness of breath, increased fatigue, loss of 3kg over pregnancy. investigated with increased fetal monitoring, regular ultrasounds confirmed normal fetal growth NVD at 39/40. no complications 3/52 post partum presented to A&E with stridor and hypoxia 1/52 night sweats cough since late pregnancy shortness of breath, fatigue and weight loss continued since birth

10 Case 1

11 Case 1 - PET

12 Classical Hodgkin Lymphoma Diagnosis

13 Diagnosis of haematological malignancy in pregnancy Many of the symptoms / signs of lymphoma and leukaemia are often seen in normal pregnancy, and dismissed as being normal for pregnancy fatigue shortness of breath itch anaemia, thrombocytopenia Occasionally increased monitoring during pregnancy can lead to incidental diagnosis - particularly with leukemia's that are diagnosed on a routine FBE.

14 Pregnancy should never preclude an adequate diagnostic biopsy critical to obtain a tissue diagnosis allows treatment stratification and prognostication critical in pregnancy as it may be that treatment can be delayed / minimised until post delivery Lymphoma: adequate biopsy (a core or excisional biopsy, never a FNA) Leukaemia: Bone Marrow Aspirate and Trephine An adequate first biopsy is essential to avoid delay and further complications. Always consult a haematologist early if there is a suspicion of a haematological malignancy

15 Case 2 - staging 27yo G1P0 18/40 presents with rapidly enlarging cervical lymph node no prior medical history, uncomplicated pregnancy to date clinical examination: well looking, no other palpable lymphadenopathy or hepatosplenomegaly. good air entry bilaterally CXR: normal Biopsy - Classical Hodgkin Lymphoma Preferred staging is PET / CT scan - alternatives in pregnancy?

16 Choice of imaging depends on gestation American College of Obstetricians and Gynecologists committee - I maging in pregnancy

17 Staging should be completed if possible Lymphoma FBE, UEC, LDH, HepB,C, HIV, SPEP, Ca/Mg/Po4 Imaging tests (X-ray, CT, MRI, PET scan) Bone marrow biopsy Lumbar puncture (in aggressive disease) 24-hour urine collection whilst purpose of staging is to establish extent of disease, investigations to establish safety / baseline for treatment are also does - e.g.: RFT s, cardiac assessment with GBPS or echo, viral serology Leukaemia lymphoid leukaemia, particularly T-ALL, require imaging of mediastinum cytogenetic and molecular markers - greatest prognostic tool lumbar puncture blood tests

18 Staging in pregnancy avoidance of fetal irradiation if possible MRI is scan of choice PET scan is relatively safe in pregnancy: fetal radiation dose is below 2.4mGy (below threshold dose for deterministic fetal events) recommend give vigorous hydration and diuresis to minimise fetal exposure to irradiation

19 MRI for lymphoma staging

20 Case 3 - early pregnancy 24yo woman undergoing treatment of primary CNS lymphoma completed 6 cycles of high dose methotrexate chemotherapy and commenced high dose cranial irradiation presents for routine MRI scan and announces that she is approximately 8 weeks pregnant. conception likely to have occurred prior to admission for high dose methotrexate. High Dose methotrexate and Cranial Irradiation given whilst (unknowingly) pregnant.

21 Chemotherapy in first trimester Chemotherapy during the first trimester is associated with the risk of spontaneous abortions, fetal death and major malformations Overall the rate of major malformations is 10 20%. If a diagnosis of malignancy is made in first trimester - termination of pregnancy should be considered and treatment proceeds as per standard protocol. options for non-chemotherapy base treatment should be considered and discussed, however best practice maternal treatment should be the goal The risk of fetal complications increases with combination chemotherapy vs single agent chemotherapy, and is less if anti-metabolites are excluded.

22 Case 4 - treatment 32yo married mother of 2 working part time G3P2, 2 prior NVD s with uncomplicated pregnancies 24 weeks: routine FBE at obstetric review: Hb 85g/dL total WCC 1.3x19^9/L Platelets 21 x 10^9/L Film: immature blasts on film Diagnosis:Acute Lymphoblastic Leukaemia

23 2nd and 3rd Trimesters: Principles of treatment The priority is appropriate delivery of life-saving maternal treatment with harm minimization to fetus Survival rates of haematologic malignancy in pregnancy are the same as age / stage matched non-pregnant controls Greatest risk to fetal health is premature delivery - aim for delivery as close to term as practical Outcome of children exposed in utero (2 nd and 3 rd trimesters) to chemotherapy is the same as peers for intellectual physical, neurological and social development, as are grandchildren of mothers exposed to chemotherapy during pregnancy.

24 Hodgkin Lymphoma Early stage disease Advanced disease Novel agents standard treatment ABVD combination therapy BEACOPP, MOPP or Stanford V combination therapies Brentuximab modification in pregnancy good evidence that standard treatment is well tolerated with no adverse outcome to foetus or mother no evidence. Aim to give ABVD and intensify treatment post delivery No evidence. monoclonal antibody to CD30

25 Non-Hodgkin Lymphoma Standard treatment Modification in pregnancy Indolent disease (ie: Follicular Lymphoma) watch and wait or Bendamustine / Rituximab chemotherapy watch and wait advised with careful monitoring. treat post-partum Intermediate (ie Diffuse Large B cell Lymphoma) R-CHOP (rituximab - monoclonal anti-cd20, plus anthracycline base combination chemotherapy) R-CHOP is well tolerated with good maternal and fetal outcomes Aggressive (ie: Burkitt Lyphoma, Mantle cell lymphoma) high dose, highly intensive multiagent regimes i.e.: CODOX-M/IVAC high maternal mortality if not treated promptly. termination of pregnancy highly recommended high dose methotrexate is important part of treatment - severe fetal myelosuppression Can treat with IVAC then deliver if delivery not viable at diagnosis / termination not desirable Specific Ie Primary CNS Lymphoma, T cell lymphomas, Treatments are increasingly specific not only to disease subtype but molecular stratification Individualize therapy with principles of trying to achieve as close to standard treatment of malignancy with minimal fetal harm

26 Acute Lymphoblastic leukaemia standard treatment is stratified by age, and risk factors <30 yo - paediatric protocol with high intensity multiagent chemotherapy based on a backbone of vinca alkaloids, methotrexate, anthracyclines Well tolerated in pregnancy with the exception of methotrexate and L Aspinaginase >30yo - standard is HyperCVAD - poorly tolerated in pregnancy - use paediatric protocol until post delivery then individualize approach to catch up on doses required.

27 Acute Myeloid Leukaemia Fetal loss is highly likely in first trimester and spontaneous abortion is risky. Elective termination should be considered Greater than 32 weeks gestation, early delivery should be considered Early initiation of treatment should be a priority Standard treatment is with high dose anthracycline and Cytarabine (7&3) and whilst associated with risks of fetal exposure to chemotherapy are best option to reduce risks of early delivery and prematurity Plan delivery at 3 weeks post chemotherapy to minimize chance of cytopenias and sequale such as infection and bleeding Exception is Acute pro-myelocytic leukaemia - excellent prognosis with ATRA (vit A derivative). Responses with single agent ATRA therapy should be closely monitored (molecular testing) and give chemotherapy only when complications arise or post delivery).

28 Supportive care in the pregnant patient delivery of chemotherapy successfully requires multiple prophylactic and supportive medications in pregnancy - risk is high to both mother and baby with a septic episode literature from HIV population studies are most helpful anti-fungal - Voriconazole is preferred anti-fungal prophylaxis, however relatively contraindicated in pregnancy non-liposomal amphotericin has safest profile in pregnancy, with Ambisome being used in case studies with no adverse effect. Currently recommended anti-fungal in pregnancy Ambisome can cross the placenta and can contribute to fetal renal dysfunction. Azoles and caspofungin are teratogenic up to 23 weeks. anti-viral - Valaciclovir - safe in pregnancy anti-pcp - Bactrim DS - considered relatively safe anti-emetics - well documented in pregnancy tumour lysis prophylaxis - Allopurinol - avoid in fist trimester, otherwise proceed with caution. GIT protection - Rantidine is standard and is well tolerated in pregnancy

29 Timing of delivery Where possible delivery should be planned to avoid higher risks associated with complications of chemotherapy Caesarian section should only be recommended for obstetric indications common side effects of chemotherapy peak at 7-10 days post commencement of chemotherapy thrombocytopenia - often profound nadir depends on chemotherapy protocol, but generally is around 10 days with recovery by day 20 neutropenia - often absolute with nadir around 7-10 days with faster recovery than platelets. GIT - nausea, vomiting, ileus, enterocolitis, timing parallels neutropenia critical to have a multidisciplinary team and close liaison between obstetric and haematology teams, to monitor pregnancy and time delivery Avoid epidural when platelets <80 x 10^9/L or neutrophils <1 x 10^9/L Post-partum - potential high risk of thrombosis - discuss anticoagulation aim for recommencement of chemotherapy as soon as is practical, depending on stage of disease, chemotherapy already given and complications of delivery

30 Breast feeding Whilst breast feeding is often desired by the mother and medial team, it is often not practical mother and child are often separated for long periods of time physical, social and practical issues In general avoid breast feeding for a period of two weeks following chemotherapy administration If the anti-cancer treatment is acceptable in breast milk - often the supportive / prophylactic medications are not. Breastfeeding should be avoided for 24 hours after a PET scan. (restaging is often done post - partum to re-assess and plan for ongoing treatment) Important to engage team from obstetrics for management of weaning and reduce the risk of mastitis Specific drugs: ATRA & Arsenic avoid cardiac toxicity in infant IFN-a excreted in breast milk, avoid breast feeding TKI s excreted in breast milk, recommend to avoid breast feeding however some case reports with good outcomes Many of the novel agents there is little to no information available

31 Impact of cancer in pregnancy is long-lasting Impact of cancer diagnosis on young family restructure of family roles (especially with regards to primary childcare roles) poor bonding with baby, often unable to room in once moved to nonmaternity hospital delivery often stressful, culmination of weeks / months planning, but also signals start of more intensive treatment treatment may be ongoing for months or years, or include other modalities such as bone marrow transplantation Financial issues - sick leave may not available as maternity leave planned Income replacing insurance may be denied as planned maternity leave

32 Cancer in pregnancy be aware of the presentations of leukaemia and lymphoma in pregnancy transfer to a high risk obstetric unit with close links to a haematology unit experienced in obstetric medicine close liaison with obstetricians, midwives and haematologists, with a strong back up with social work obstetric support needs to continue post partum - management of lactation, regular mother - baby follow up support for the whole family with recognition of secondary carers

33 The outcomes Case 1-post partum dx of Hodgkin lymphoma Initially achieved good response with chemotherapy Never achieved CR Despite allograft and novel therapy disease progressed. Died 2 years post diagnosis. Case 2 - Hodgkin lymphoma at 24 weeks managed with a combination of dexamethasone and cyclophosphamide until delivery at 34 weeks completed 6 cycles of ABVD chemotherapy post partum remains in CR1 7 years later and has had another child naturally Case 3 - conception post high dose methotrexate / radiotherapy elected to proceed with pregnancy monitored closely for fetal malformations and relapse of CNS lymphoma delivered healthy boy at term presented for next MRI - 4 months post partum - was pregnant again!! Case 4 - ALL at 24 weeks treated with paediatric protocol and at time of delivery was in morphologic CR. went on to have 6 months of intensive chemotherapy but never achieved a molecular remission. bone marrow transplant from unrelated donor relapsed 3 months post transplant Remains in CR 3 years later. Eldest child being investigated for developmental delay received immunomodulatory therapy and remains in remission 5 years post transplant 6 years post diagnosis has returned to work, and formed a strong bond with her son who started school this year