Management of hairy cell leukaemia in pregnancy

Abstract

Background

Hairy cell leukaemia (HCL) represents less 1% of all lymphoid neoplasms with cases rarely reported in pregnancy. Management of HCL requires multidisciplinary care to optimise maternal and neonatal outcomes.

Methods

A literature search of Ovid MEDLINE and EMBASE for ‘hairy cell leukaemia’ and ‘Pregnancy’ was undertaken.

Results

Thirteen cases were reviewed including three within our own institutions. Interferon-alpha was the most prominent treatment at varying doses in n = 3 (23%) patients. Other management included antenatal cladribine and rituximab, post-partum cladribine with and without rituximab, laparoscopic splenectomy and termination of pregnancy. 46.1% (n = 6) of patients birthed vaginally. Due to thrombocytopenia, there was a greater proportion of caesarean delivery under general anaesthetic and half of the cases documented bleeding complications.

Conclusion

Diagnosis and management of HCL in pregnancy is difficult. Women can be managed safely and outcome aims should be the same as non-pregnant patients.

Introduction

Hairy cell leukaemia (HCL) is an uncommon, indolent, mature B cell lymphoproliferative disorder representing less than 1% of all lymphoid neoplasms. ¹ Cases are rarely reported in pregnancy making investigation and management challenging. We reviewed all cases in the literature of HCL in pregnancy to capture investigations undertaken for diagnosis, management of HCL and maternal and neonatal outcomes to help make recommendations for best practice in the future.

Methods

A search of Ovid MEDLINE and EMBASE for the terms ‘Hairy Cell Leukaemia’ and ‘Pregnancy’ was undertaken. Cases were excluded if the full text was not available in English, if they lacked sufficient minimal data to capture patient demographics, investigations undertaken for the diagnosis of HCL, management of HCL in pregnancy and maternal and neonatal outcomes. As the number of cases was small, descriptive statistics of frequency count and percentages were used.

Results and discussion

We found 11 patients across 10 case reports and an additional three cases within our own institutions for a total of 14 cases of HCL in pregnancy between 1986 and 2024. One case was excluded as the patient was treated and in remission prior to becoming pregnant. Table 1 shows patient demographics, presentation and management of HCL in pregnancy and Table 2 describes mode of birth, and maternal and neonatal outcomes of HCL in pregnancy.

Table 1.

Demographics, presentation and treatment of HCL in pregnancy.

Author, Year, Country	Maternal age (Years)	Gestational age at diagnosis/Relapse	Presentation	Splenomegaly (Y/N/ND) (%)	Initial diagnosis correct (Y/N)	Bone marrow biopsy shows HCL (Y/N)	Immunophenotyping, molecular studies	Treatment of HCL	Transfused (Y/N/ND)
Sakri et al., 2021, Malaysia 2	31	10	Pancytopenia, hepatosplenomegaly, fever, dyspnea	Y	Y	Y	ND	Antenatal IFN-a 90 mg weekly	ND
Ainoon et al., 1988, Malaysia 3	22	18	Bicytopenia, petechiae, massive splenomegaly	Y	Y	Y	TRAP positive	Termination of pregnancy	N/A
Shackleton et al., 2019, Ireland 4	37	First trimester	Pancytopenia	N	N - Initially diagnosed as immune thrombocytopenia	Y	Kappa restricted, CD19+, 20+, 11c+, 25+, 103+; BRAFV600E detected	Antenatal observation; Post-partum cladribine	ND
Baer et al., 1991, USA 5	32	14	Bicytopenia (Neutropenia and thrombocytopenia)	ND	Y	Y	ND	Antenatal IFN-a 3.4 million units 3x/week	ND
Baer et al., 1991, USA 5	37	Second trimester	Bicytopenia and splenomegaly	Y	Y	Y	ND	Antenatal IFN-a 2 million units daily	ND
Daver et al., 2013, USA 6	28	23	Pancytopenia	N	N - Initially diagnosed as marginal zone lymphoma	Y	Lambda restricted, CD19+, 20+, 11c+, 25+, 103+	Antenatal rituximab and cladribine	Y - Packed red blood cells and platelets antenatally
Adenji et al., 2010, USA 7	37	23	Pancytopenia, splenomegaly, recurrent epistaxis	Y	Y	Y	CD19+, 20+, 68+, DBA44+	Antenatal Laproascopic splenectomy; Post-partum cladribine	Y - Packed red blood cells and platelets pre-splenectomy
Alothman et al., 1994 Canada 8	23	10	Pancytopenia, splenomegaly	Y	Y	Y	TRAP positive, CD11 and 25	Antenatal laprascopic splenectomy; Post-partum cladribine	ND
Patnser et al., 1993, USA 9	36	15	Bicytopenia recurrence	ND	Y	Y	ND	Termination of pregnanacy	N/A
Williams, 1986, USA 10	34	7	Pancytopenia	ND	Y	Y	ND	Antenatal observation; Post-partum splenectomy	Y - Whole blood and platelets peri-partum
Da Cruz et al., 2017, Australia	42	10	Pancytopenia recurrence	Y	Y	Y	ND	Antenatal observation; Post-partum cladribine	Y - Packed red blood cells and platelets peri-partum
Da Cruz et al., 2020, Australia	36	23	Pancytopenia	N	Y	Y	Kappa restricted, CD19+, 20+, 11c+, 25+, 103+	Antenatal observation; Post-partum rituximab and cladribine	N
Da Cruz et al., 2021, Australia	38	23	Pancytopenia and splenomegaly	Y	Y	Y	Kappa restriced, CD22+, FMC7+, CD11c, CD103+, CD25-; BRAFV600E detected	Antenatal observation; Post-partum rituximab and cladribine	Y - Packed red blood cells peri- and post-partum

BRAFV600E: v-raf murine sarcoma viral oncogene homologue B1 with amino acid valine substituted for glutamic acid at position 600; CD: cell differentiation;

Hb: haemoglobin; IFN: interferon; N/A: not applicable; ND: not documented; N: no; TRAP: tartate-resistant acid phosphatase; USA: United States of America; Y: Yes.

HCL: hairy cell leukaemia.

Table 2.

Mode of birth, maternal and neonatal outcomes of HCL in pregnancy.

Author, Year, Country	Gestation at birth	Induction (Y/N/ND) & reason	Mode of birth	Analgesia	Post-partum haemorrhage (Y/N/ND)	Received post-partum thromboprophylaxis (Y/N/ND)	Breastfeeding (Y/N/ND)	Neonatal birth weight (g)	Apgars
Sakri et al., 2021, Malaysia 2	37	Y - Small gestational age	NVB	ND	N	Y	ND	2490	8/9
Ainoon et al., 1988, Malaysia 3	Termination of pregnancy	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Shackleton et al., 2019, Ireland 4	40	N	NVB	ND	N	ND	ND	ND	ND
Baer et al., 1991, USA 5	30–34	ND	Elective C-section	ND	ND	ND	ND	ND	ND
Baer et al., 1991, USA 5	34	ND	ND	ND	ND	ND	ND	1587	ND
Daver et al., 2013, USA 6	40	N	NVB	ND	ND	ND	ND	ND	ND
Adenji et al., 2010, USA 7	34	Y - Worsening bicytopenia	NVB	ND	ND	ND	ND	2031	8/9
Alothman et al., 1994 Canada 8	40	N	NVB	ND	ND	ND	Y - 6 months	ND	ND
Patnser et al., 1993, USA 9	Termination of pregnancy	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Williams, 1986, USA 10	37	Y - Reduced fetal movements	Emergency C-section	ND	N	ND	Y	2948	7/8
Da Cruz et al., 2017, Australia	37	N	Elective C-section	General anaesthetic	Y (1L)	Y	N	2850	9/9
Da Cruz et al., 2020, Australia	39	N	NVB	Nitric oxide gas	N	N	Y	3200	9/9
Da Cruz et al., 2021, Australia	38	N	Elective C-section	General anaesthetic	Y (3.8L)	Y	N	3040	3/8

C-section: Caesarean section; HCL: hairy cell leukaemia; N/A: not applicable; ND: not documented; N: no; NVB: natural vaginal birth; USA: United States of America; Y: yes.

One patient from our institution had previously been treated for HCL prior to pregnancy but had relapsed in the first trimester of pregnancy. The remaining patients (n = 12) were diagnosed during the first (n = 4) and second (n = 8) trimesters only. The countries of origin for reported cases included USA (n = 6), Canada (n = 1), Ireland (n = 1) and Malaysia (n = 2). The average age of patients was 33.69 years old (range 22–42 years old) and n = 7 patients were nulliparous.

The presenting feature reported in all cases at diagnosis was moderate to severe pancytopenia (mean haemoglobin - 88 g/L (51 −104 g/L); white blood cells −3.4 ×10⁹/L (0.9–8.8 ×10⁹/L); platelets – 57 ×10⁹/L (18–85 × 10⁹/L). Spleen size was documented in 76.9% (n = 10) of cases with splenomegaly described in the majority (70.0%; n = 7). Diagnoses for HCL were confirmed with morphology on bone marrow biopsy in all cases. Immunohistochemistry positivity for cell differentiation (CD) CD10, CD20, CD25, CD72, BCL2 and DBA.44, and flow cytometry with immunophenotyping showing positivity for CD markers CD10, CD11c, CD19, CD20, CD25, CD103 and FMC-7 was documented in n = 7 cases.

Management varied with interferon-alpha the prominent treatment given at varying doses during pregnancy in n = 3 (23.1%) patients. One (n = 1; 7.7%) woman received antenatal cladribine and rituximab and n = 6 (46.1%) women receiving post-partum cladribine (two of which received this in combination with rituximab). Two patients (15.4%) underwent laparoscopic splenectomy at 16 and 23 weeks' gestation respectively due to pain and worsening thrombocytopenia. They were both documented as receiving vaccinations prior to splenectomy. Two patients (15.4%) underwent a termination of pregnancy. The first occurred once a diagnosis was confirmed at 18 weeks' gestation in 1988. The second occurred in 1993 following a confirmation of recurrence of HCL at 6 weeks' gestation after successful treatment of HCL 5 years earlier. Two patients were also initially misdiagnosed including one as marginal zone lymphoma. A subsequent diagnosis of HCL was made in this patient after seeking a second opinion and testing of the v-raf murine sarcoma viral oncogene homologue B1 with amino acid valine substituted for glutamic acid at position 600 (BRAF V600E), the somatic point mutation associated with HCL. One patient received neutropenic prophylaxis due to severe neutropenia (neutrophils <0.5 × 10⁹/L) with sulfamethoxazole and trimethoprim. Survival data was not available on case reports accessed outside our institutions; however, all three patients from our data are still alive today.

Documentation of transfusions of packed red blood cells was noted in n = 6 cases and occurred in the setting of symptomatic anaemia antenatally, peri-partum and post-partum. Platelet transfusion prior to splenectomy was documented in n = 1 case with a platelet count of 46 × 10⁹/L. No cases of febrile neutropenia were documented.

The majority of women underwent fetal growth surveillance by ultrasonography during pregnancy, (76.9%; n = 10), birthed close to term (61.5%; n = 8; range 37–40 weeks gestation) vaginally (46.1%; n = 6). Caesarean section occurred in 30.8% (n = 4) of women and two of these patients received a general anaesthetic rather than neuraxial analgesia due to moderate thrombocytopenia (platelet count: 52 and 71 × 10⁹/L, respectively). Bleeding complications were documented in 46.1. % (n = 6) patients with 15.4% (n = 2) having a post-partum haemorrhage defined as ≥ 1000 mls. Of these, one was 3.8L in volume occurring in a patient who also had significant uterine fibroids. One patient also had a post-partum Mallory-Weiss tear requiring emergency laparotomy reduction for an incarcerated stomach hernia.

Neonatal birth weight was recorded in 53.8% (n = 7) cases and ranged between 1587 and 3200 grams. Apgar scores are documented in 46.1% (n = 6) cases and ranged from 8 to 9 at 1 min and 9 at 5 min. Ten babies had a platelet count undertaken and all were documented within the normal range. It was noted that three babies were breastfed.

Diagnosis of rare haematological malignancies in pregnancy such as HCL can be difficult and misdiagnosis is not uncommon due to presentation often being ascribed to physiological changes of pregnancy. ¹¹ Mild anaemia and mild thrombocytopenia is common in pregnancy, but leukopoenia is rare. ¹² Anaemia is a result of a relative cellular haemodilution compared to increased plasma volume and haemoglobin usually nadirs in the second trimester and improves in the third trimester. ¹³ Thrombocytopenia pathogenesis in pregnancy is less well understood, is mostly gestational and results in a platelet count of < 100 × 10⁹/L in 1% of cases. ¹⁴ White cell counts usually increase and peak to 3–4 fold of non-pregnant levels in the third trimester due to oestrogen and cortisol stimulating bone marrow production. ¹⁵ Persisting cytopenias and pancytopenia in pregnancy is rare and warrant investigation including for bone marrow infiltrative disorders.

All cases underwent bone marrow biopsy which can be undertaken safely with preference for women to be placed in the left lateral position to reduce vena caval compression. Local anaesthetic and light sedatives can be given safely. ¹⁶

In three cases, hairy cells were identified on immunohistochemistry expressing anti-CD 20/DBA-44 and/or tartrate-resistant acid phosphatase stain. Immunophenotyping occurred in five cases expressing strong light chain restricted surface immunoglobulin, B-cell antigens as well as CD103, CD25, CD11c and CD123. A HCL immunological score (where 1 point for each above CD marker is given), of ≥ 3/4 is seen in 98% cases of HCL, with differential disorders scoring lower (0–1). ¹⁷ Pancytopenia from a hypocellular fibrotic bone marrow from hairy cell infiltration can cause a dry tap and low numbers of circulating hairy cells, making diagnosis difficult, as seen in two patients. ¹⁸ One patient was subsequently diagnosed after detecting the BRAF V600E point gene mutation. This mutation is identified in 80–100% of cases with HCL and enables distinction from similar disorders that require different management. ¹⁸

Understanding HCL and safe maternal-fetal management of malignancies in pregnancy has evolved. Consideration of prognosis is important to counsel women. In the non-pregnant population, splenomegaly > 3 cm above the normal range, > 5 × 10⁹/L circulating hairy cells in peripheral blood and a raised beta2-microglobulin or LDH are associated with a worse prognosis and resistance to standard treatment. These investigations can be readily performed in pregnancy. ¹⁹

Women require appropriate counselling regarding management options. Two patients terminated their pregnancies in 1988 and 1993. It is unclear if continuing the pregnancy was discussed. It is likely a lack of safety data for managing HCL during pregnancy was lacking during these decades and this has contributed to the decision for termination as seen in other case series of malignancy in pregnancy. ¹¹ Preference for a non-acute malignancy such as HCL would be observation, with definitive treatment post-partum as observed in five (38.5%) patients.

Triggers to treat HCL in the non-pregnant populations include initial observation with treatment once patients become symptomatic from splenomegaly or declining cytopenias. One in 10 patients with HCL remains asymptomatic for years before requiring treatment. Typically, treatment is considered if the haemoglobin is < 110 g/L, platelet count is < 100 × 10⁹/L or neutrophil count is < 1.0 × 10⁹/L⁹. In pregnancy, commencing treatment in the setting of associated symptoms is key as cytopenias alone may improve post-partum. Indeed, evidence of symptomatic progressive severe cytopenia, symptomatic splenomegaly or infectious or autoimmune complications should serve as indications to consider treatment in the pregnant patient.

The 2024 MBRRACE report emphasises that imaging and interventions, including chemotherapy, should be used in pregnancy unless there is a clear contraindication. ²⁰

For symptomatic HCL in pregnancy, there is relative safety and benefit with standard of care therapy from the second trimester onwards; chemotherapy with risk-adapted purine analogues and rituximab may be used as first line from second trimester, as is recommended in the non-pregnant population.

If treatment for HCL is required in pregnancy, treatment aim is for complete sustained remission with negative minimal residual disease. A summary of medication safety used to treat HCL in pregnancy and breastfeeding can be found in Table 3. Interferon-alpha (IFN-α) was used antenatally as first-line treatment in three patients. Whilst IFN-α is safe in pregnancy as it does not inhibit DNA synthesis, response rates are 75–90%, require ≥ 12 months treatment duration and are associated with negative side effects of depression, flu-like symptoms and fatigue. ⁶ By comparison, in non-pregnant clinical trials, the purine analogue cladribine in combination with rituximab has excellent complete remission rates of 100% at 6 months with minimal residual disease-free rates of 94% at 96 months versus cladribine alone. ¹⁷ If required, rituximab can be given in the second or third trimester of pregnancy without significant concern.^26,27 There is a paucity of data for cladribine in pregnancy. Associated purine analogues such as 6-mercaptopurine have been given for acute lymphoblastic leukaemia in pregnancy without significant concern, and no adverse effects were documented in the baby born to the mother who received rituximab and cladribine in pregnancy.^6,28 Ideally the last dose of cladribine is received 2–3 weeks prior to birth to minimise adverse effects including infective complications. There is limited information available describing the use of BRAF inhibitors during pregnancy. In patients that have BRAF mutations present, BRAF inhibitors such as vemurafenib have been used successfully to treat relapsed or refractory HCL in non-pregnant patients. In pregnancy, a small number of case reports have described normal pregnancy outcomes after vemurafenib use for treatment of metastatic melanoma. Reports of associated intrauterine fetal growth restriction and severe toxic epidermal necrolysis have also been documented.^29–32 Vemurafenib should only be considered in pregnancy in the second or third trimester if benefits outweighs potential risk. Close monitoring and management by a multidisciplinary team would be highly recommended.

Table 3.

A summary of medications used to treat HCL in pregnancy and breastfeeding.

Drug name	Class	Human placental transfer	First trimester	Second trimester	Third trimester	Breastfeeding
Cladribine	Purine Analogue - Purine antimetabolite	Likely	Contraindicated	Consider alternative	Consider alternative	Recommendation – Contraindicated Excreted into milk – Yes Milk to plasma ratio – unknown Relative infant dose – 3.06% (Datta 21 )
Rituximab	Anti-CD20 monoclonal antibody	Yes	Consider alternative	Consider alternative	Consider alternative	Recommendation – Consider alternative Excreted into milk – Yes Milk to plasma ratio – unknown Relative infant dose – 0.08% (0.06 to 0.10%) (Krysko 22 )
IFN - Pegylated interferon alfa-2a	Immunomodulators	Unlikely	Consider alternative	Consider alternative	Consider alternative	Recommendation – Considered safe to use Excreted into milk – Yes Milk to plasma ratio – unknown Relative infant dose – unknown
Vemurafenib	BRAF inhibitors	Yes	Contraindicated	Consider alternative	Consider alternative	Recommendation – Contraindicated Excreted into milk – unknown Milk to plasma ratio – unknown Relative infant dose – unknown
Acyclovir	antiviral medications -synthetic nucleoside analogues	Yes	Considered safe to use	Considered safe to use	Considered safe to use	Recommendation – safe to use Excreted into milk – yes Milk to plasma ratio – 0.6–4.1 (Lau 23 ) Relative infant dose – 1% (Taddio 24 )
PJP prophylaxis Trimethoprim/sulfamethoxazole	sulfonamide antibiotics	Yes	Consider alternative	Considered safe to use. Co-prescribe folic acid 5 mg daily	Considered safe to use. Co-prescribe folic acid 5 mg daily	Recommendation – Considered safe to use Excreted into milk – yes Milk to plasma ratio – 1.25 (trimethoprim), 0.06 (sulfamethoxazole) – (Hale 25 ) Relative infant dose – 4–9% (Hale 25 )

HCL: hairy cell leukaemia; IFN: interferon.

Infectious complications can be a frequent complication of HCL and therapy with purine analogues may increase the risk of myelosuppression and infection with both opportunistic infections and common pathogens. ¹⁷

Only one case in the literature documented an infectious complication which was cellulitis in the setting of progressive cytopenia which was managed with antibiotics, followed by interferon-alpha in the context of worsening cytopenia.

Nevertheless, symptomatic HCL and febrile infection may pose a challenge and infection should be controlled prior to commencement of purine analogues where possible.

Alpha-interferon has been used in the non-pregnant population as bridging therapy in cases where it is not possible to control the infection or in the event of a health crisis such as Sars-Cov-2 (^33,34).

Splenomegaly occurred in over half of patients (n = 7, 53.8%). Two patients underwent splenectomy in second trimester due to symptoms. In non-pregnant patients, splenectomy is considered in relapsed or refractory HCL with symptomatic splenomegaly and minimal bone marrow infiltration. In pregnant patients, if symptomatic splenomegaly is worsening, laparoscopic splenectomy undertaken in the second trimester is reasonable. ⁷ Massive splenomegaly (> 20 cm in length) can cause intrauterine growth restriction and requires close monitoring of fetal growth. ³⁵

Transfusion thresholds include packed red blood cells for symptomatic moderate anaemia (Haemoglobin: 70–90 g/L). Other correctable causes of anaemia including iron and B12 deficiency should be managed with appropriate supplementation. Transfusion for platelets may be necessary if the platelet count is: (i) < 20 × 10⁹/L and there are bleeding concerns, (ii) < 50 × 10⁹/L and birthing or requiring surgery and (iii) < 80 × 10⁹L requiring neuraxial anaesthesia, as seen in two patients. Blood products should be CMV-negative and packed red blood cells should be Rhesus and Kell-matched. If patients are rhesus negative and platelets are < 50 × 10⁹/L, regular intramuscular anti-D prophylaxis should be given intravenously as intramuscular injection may cause muscle haematomas. ³⁶

Maternity care for women with HCL requires multidisciplinary input at a centre with staffing and services for high-risk pregnancies including neonatal, maternal, anaesthetic and transfusion support. Importantly, services should also offer psychological support to the patient and her family. Regular antenatal care, fetal growth monitoring and full blood examinations are required.

Vaginal birth was possible in 46.1% of patients. Mode of birth should be based on obstetric indications and if feasible, go to term. Vaginal births should be actively managed. Chemical thromboprophylaxis with low molecular weight heparin can be given if indicated, providing platelets are ≥ 50 × 10⁹/L. If women are neutropenic (neutrophils < 1.5 × 10⁹/L), antibiotic cover is recommended at birth and avoidance of prolonged rupture of membranes is advised to minimise infection. Fever should prompt management for neutropenic sepsis. Feasibility and preference for breastfeeding should be discussed prior to birth and lactation consultation sought if desired. ³⁷ Post-partum care should ensure ongoing monitoring and definitive treatment instituted if required. There are no contraindications to contraception.

Conclusion

Although rare, women can be managed safely with HCL in pregnancy with outcomes being the same as non-pregnant patients. Optimal management needs to be decided between the woman, family and care team. A malignancy in pregnancy registry would help better inform future management for rare conditions such as these.