Adult T cell leukaemia/lymphoma (ATL) in pregnancy: A UK case series

Abstract Introduction Chronic infection with human T‐cell lymphotropic virus type‐1 (HTLV‐1) may result in aggressive adult T‐cell leukaemia/lymphoma (ATL) in 4‐6% carriers. The majority of this risk arises in carriers infected during infancy, and so each infant has ∼25% lifetime risk. Other risk factors include a family history of ATL. Antenatal HTLV‐1 screening is not undertaken in the UK. Methods Here we describe four cases of ATL diagnosed during pregnancy and describe strategies to minimise HTLV‐1 transmission to neonates. Results/conclusion These cases highlight undiagnosed HTLV‐1 in pregnancy which allows ongoing mother to child vertical transmission and risk of future ATL. We recommend the UK National Screening Committee incorporate HTLV‐1 serology into antenatal screening.

α is not approved for treatment of ATL in Japan, and so its use in pregnancy to manage ATL has not been previously reported.
Here we describe four cases of ATL presenting during pregnancy in the UK (one acute, one lymphoma, and two chronic unfavourable) including cases managed with ZDV/IFN-α, with a focus on the strategies used to treat the mothers to reduce vertical HTLV-1 transmission, and highlight an undiagnosed HTLV-1 population in a non-endemic country. Cases are summarised in Table 1  (WCC 172 × 10 9 /L). The maternal HTLV-1 proviral load (PVL) (pro-portion of infected mononuclear cells per 100 cells) was unknown, and the mother died shortly after delivery due to sepsis during first CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. The infant was formula-fed and treated with ZDV postexposure prophylaxis for 6 weeks (the first 2 weeks were administered intravenously). At birth and age 7 months, HTLV-1 PVL was not detected but was detected (PVL 0.01%) at 15 months, and she became HTLV-1 seropositive. The child is now aged 13 years old and is clinically well with a stable low PVL 0.01-0.03%.

Case 2
A

Case 3
A 34-year-old female was diagnosed with ATL lymphoma subtype overseas and treated there with chemotherapy (eight cycles of CHOP).
There was not a significant response to therapy despite escalating doses of ZDV to 500 mg twice daily and IFN-α 6mcg/kg, and so an elective caesarean was expedited at 38 weeks' gestation. The infant was formula-fed and completed 6 weeks oral ZDV syrup. At delivery neonatal HTLV PVL was undetectable and remained undetectable at 6 weeks and 3 months. The baby remains well and is under active follow-up with repeat testing planned at 18 months. Following delivery, the mother was treated with mogamulizumab 1 mg/kg due to lack of response to ZDV/IFN-α. Following one dose, haematological remission was achieved, and PVL was reduced to 0.06%. She has received a total of three doses, currently stopped due to mild skin rash and remains in a persistent haematological remission 8 months later.

DISCUSSION/CONCLUSION
Two of these patients were diagnosed with chronic leukaemic ATL in the first trimester of pregnancy following the incidental finding of lymphocytosis (cases 2 and 4). Both mothers were treated with ZDV/IFN-α which are known to be relatively safe in pregnancy, the aim being to induce remission and reduce the risk of vertical HTLV-1 transmission.
In both cases raltegravir, which inhibits HTLV-1 integrase in vitro and readily crosses the placenta, was added in the 3rd trimester to protect foetal mononuclear cells exposed to maternal cells during the perinatal period [17]. Both infants were delivered at term by pre-labour caesarean section, exclusively formula-fed and treated for 6 weeks with ZDV (as per human immunodeficiency virus (HIV) practice) [18]. Both infants were thriving, and their blood remained HTLV DNA polymerase chain reaction (PCR) negative at last follow-up, although one infant is lost to longer term follow up. By contrast, two mothers presented in late 2nd and early 3rd trimester with aggressive ATL, both refractory to chemotherapy and infants requiring emergency delivery. In case 1, where the mother had high WCC and presumably high HTLV PVL, the infant was found to be anti-HTLV-1 antibody positive at 15 months. In case 3, the baby remained blood-HTLV-1 DNA negative at last followup, although long-term outcome is unknown.
The diagnoses of both cases of chronic ATL early in pregnancy, whilst asymptomatic, allowed time to undertake strategies to reduce transmission and reflects the 'tip of the HTLV-1 iceberg' since unscreened pregnant women in the UK with asymptomatic HTLV-1 infection are unknowingly transmitting infection, chiefly through breastfeeding which is promoted by healthcare bodies in the UK. It is notable and reassuring that breastmilk banks do screen their donors for HTLV-1.
In the UK, HIV, hepatitis B and syphilis are the only infectious diseases routinely screened for in pregnancy, and the exclusion of HTLV-1 from this list is difficult to justify given its associated fatal diseases.
Additionally, a recent meta-analysis revealed that asymptomatic HTLV-1 infection results in 57% increased risk of premature death that is independent of ATL and HTLV-1 associated myelopathy, the two diseases commonly associated with HTLV-1 [19].
HTLV-1 remains neglected by health agencies globally, has not been recognised as an oncogenic virus by the National Cancer Institute and only very recently acknowledged by the WHO as a sexually transmitted infection [20]. With all the evidence supporting the benefit of antenatal screening programmes, we urge the national screening committee to reconsider their decision which excludes HTLV-1 in the UK antenatal screening programme. A policy which inevitably fails to offer the HTLV-1 infected mother, her siblings and family members, and her future children appropriate knowledge and clinical interventions to mitigate its preventable serious disease burden.