Haemophagocytic Lymphohistiocytosis Following Fludarabine/Cyclophosphamide Chemotherapy for Chronic Lymphocytic Leukaemia
Authors: Jayakody Arachchillage Deepa Ranjani , Moses Samuel , O'Brien Stephen , Menne Tobias , Carey Peter , Keenan Fiona , Wallis Jonathan 
Published: October 2019

Abstract
Abstract 4617
We report 3 patients who developed Haemophagocytic Lymphohistiocytosis (HLH) following treatment with Fludarabine/Cyclophosphamide (FC) chemotherapy for Chronic Lymphocytic Leukaemia (CLL).
Acquired (secondary) HLH is more frequent than primary (familial) HLH and usually described in patients with an underlying immune disorder. Acquired HLH in association with haematological malignancies is well recognised. The most commonly reported associations in adults are NK/T and peripheral T cell lymphomas. There is only one previous published case report of HLH in association with CLL as a direct trigger for development of HLH where the patient developed HLH one month after FC therapy and died in spite of treatment with the HLH 2004 protocol. Our 3 patients were diagnosed with HLH using standard diagnostic criteria, fulfilling at least 5 out of 8 clinical/laboratory criteria (Table 1). There was no evidence of haemophagocytosis in the bone marrow of any of these patients prior to treatment with FC. Two patients are still alive while the other died one month after diagnosis.Table 1Patient 1Patient 2Patient 3Fever+++Splenomegaly (cm)181719Haemoglobin (g/dl)10.39.07.3Platelets (× 109/l)116319Neutrophils (× 109/l)0.81.020.6Haemophagocytosis in bone marrow+++Ferritin (ug/l)165009342>100000Triglycerides (0.5–1.7 mmol/l)1.7 mmol/l1.9 mmol/l1.8 mmo/lFibrinogen level(2.1–4.8 g/l)0.6 g/l2.0 g/l1.0 g/lDecreased/absent NK cell activityNot assessedNot assessedNot assessedSoluble CD25Not assessedNot assessedNot assessed
Each had been treated with FC before they developed HLH and 2 of them had received previous treatment with chlorambucil. All 3 patients were extensively investigated for infective causes that may be associated with HLH. Multiple blood, urine and sputum cultures were negative for bacteria, fungi, mycobacteria and parasites. Polymerase chain reaction (PCR) studies for cytomegalovirus, Epstein Barr virus, herpes simplex virus, human herpes virus-6 and parvovirus B19 were all negative initially in all 3 patients. Patient 2 developed immunosuppression related HHV-6 reactivation while he was undergoing treatment with HLH 2004. This responded to brief treatment with Foscarnet. All 3 patients were treated with empirical intravenous antibiotics for neutropenic sepsis and subsequently administered antifungal therapy due to prolonged fever not responding to antibiotics. All had whole body Computerised Tomography (CT) scans looking for any evidence of infection. CT scans in each case showed splenomegaly and minor adenopathy in the abdomen and chest with no evidence of infection. Bone marrow biopsies from all 3 patients showed appearances of haemophagocytosis but no significant residual infiltration with CLL.
The time interval from treatment with FC to the development of HLH ranged from 1 month to 6 months (Table 2). Patient 1 died 4 weeks following the diagnosis of HLH in spite of treatment according to HLH 2004. The remaining 2 patients are still alive and undergoing treatment as per HLH 2004. Patient 2 has been worked up for allogenic bone marrow transplant (alloBMT) as part of HLH 2004. The other patient is being treated with chemotherapy alone due to age and other co morbidity factors precluding consideration for alloBMT.Table 2:Patient 1Patient 2Patient 3Age655774SexmalemalefemaleDate of first diagnosis of CLL09/05/200931/07/200605/06/2001Previous treatmentChlorambucilNoneChlorambucilTime of treatment with FC15/09/2009 To 28/06/201003/01/2009 to 09/10/2009 and 04/04/201104/03/2010 To 10/11/2010Number of FC cycles88 and 1(FC +Rituximab)6Date of diagnosis of HLH05/01/201115/05/201106/05/2011Current statusDied on 05/02/2011Undergoing treatment with HLH2004 and awaiting alloBMTUndergoing treatment with HLH2004
To our knowledge, this is the first case series of CLL patients who developed HLH in direct association with FC treatment without evidence of an underlying infective aetiology. Therefore in CLL patients presenting with cytopenias and fever, HLH should be considered early and diagnostic tests performed. This complication of treated CLL may be more common with FC than treatment with Chlorambucil alone, with which it had not previously been reported.

Disclosures:
No relevant conflicts of interest to declare.