Hemophagocytic Lymphohistiocytosis (HLH): A rare cause of primary engraftment failure post autologous stem cell transplant
Pallavi Mehta*; Aakansha Singh; Rohan Halder; Ankit Jain; Narendra Agrawal; Rayaz Ahmed; Dinesh Bhurani
*Department of Hematology and Bone Marrow Transplant Unit, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India.
Received Date: 11/12/2021; Published Date: 31/12/2021
*Corresponding author: Pallavi Mehta, Rajiv Gandhi Cancer Institute and Research Centre Sector-5, Rohini, New Delhi – 110085, Contact: +91- 8837651606.
Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder of uncontrolled immune activation characterized by clinical and laboratory evidence of extreme inflammation, occurring either as a familial or a secondary HLH which is acquired in association with a variety of pathological states . In recent years, HLH has attracted growing attention due to an inexplicable rise in the interest of physicians in recognizing and reporting of the disorder. Clinical features may vary from typical presentation with fever, cytopenia, hepatosplenomegaly to atypical complications such as rash, hepatitis or acute liver failure, coagulopathy and central nervous system (CNS) involvement, which manifest as altered mental status, seizures and focal deficits . Unfortunately, the diagnosis of HLH is often delayed due to the intricacies of the established diagnostic criteria  of this deadly disease, which leads to an irony as HLH needs very fast and accurate diagnosis to prevent the mortality. It is also worthy to be aware of the fact that diagnosis of HLH does not fundamentally depend upon morphological findings of hemophagocytosis as it can be absent in early stages of the disease. Hence, it would be wise to perform serial bone marrow aspirations later in the course of the disease if the clinical suspicion is very high .
HLH post stem cell transplant either autologous and allogeneic, is a very rare complication which involves its own complexities of the diagnosis due to various confounding factors commonly encountered in peri transplant period. In addition to that, it is a known fact that it is associated with high mortality . A separate set of criteria for HLH after SCT has been proposed which requires 2 major criteria, or one major and all four minor criteria. The major criteria are (1) engraftment failure, delayed engraftment or secondary engraftment failure after SCT, and (2) histopathological evidence of hemophagocytosis. The four minor criteria are high-grade fever, hepatosplenomegaly, elevated ferritin and elevated serum LDH . A prospective observational study on 171 post stem cell transplantation (68 allogeneic and 103 autologous) showed 6 cases of secondary HLH in allogeneic transplants whereas only one case was reported in autologous transplant cases which clearly highlights the rarity of this complication . We hereby present the case of a young male recipient of an autologous stem cell transplant for his primary disease of diffuse large B cell lymphoma, leading to primary graft failure secondary to HLH.
We describe the case of a 50 years old male, who was diagnosed with Diffuse Large B cell Lymphoma (DLBCL)- Non Germinal Center type Stage IV in April, 2019, received 6 cycles of RCHOP which showed good response to treatment on PET scan at the end of the therapy. Patient presented again in February, 2021 with progressively enlarging cervical lymph nodes. PET CT confirmed the progression of disease. Bone marrow was not involved. He was salvaged with 4 cycles of RDHAP with which he could achieve partial response. Patient was taken for autologous transplant for further disease control. He received BEAM conditioning regimen at the doses: Carmustine @300mg/sqm on day-6, Cytrabine@200mg/sqm on day-5 to -2, Etoposide @200mg/sqm on day-5 to -2, Melphalan @120mg/sqm on day-1 followed by infusion of autologous stem cells at dose of 5.1x10^6/kg on day 0. On day+4, patient developed oral and abdominal mucositis grade III. Subsequently on day+6, he also had septicemic shock and required antibiotics along with inotropic support. Growth factor support was continued since day+1. In view of deterioration in his clinical condition, granulocyte infusions were also given. Initially around day+16, the patient had a favorable evolution of the white blood cell count reaching 200/cumm on day+18 only to start falling off again on day+21 (to 90/cumm). He remained to be febrile through-out the course and hence work up for secondary HLH was initiated. Although the bone marrow was hypocellular with <5% cellularity with occasional hemophagocytosis ( Figure 1), other parameters like engraftment failure, high grade fever, elevated ferritin( 3660ng/ml)) were fulfilling the criteria of post-transplant secondary HLH as defined by Takagi S et al.  To boost up our diagnosis before taking the decision to start steroids IL-2 R levels were checked and were found to be high(26,638 pg/ml). Viral PCRs for CMV, EBV and respiratory viruses were done to rule out infections related HLH, however, all were negative. He was initiated on dexamethasone along with IvIg (Immunoglobulin)@ 1mg/kg/day for 2 days. Later on, cyclosporine was also added. On day+27, increasing trend in WBC was observed. On day+29, neutrophil engraftment was achieved (ANC>500cumm). Steroid was started to be tapered off thereafter and was stopped as patient developed pseudomonas bacteremia. Patient could not tolerate cyclosporine due to raised creatinine and hyperkalemia, and hence it was stopped on day+40.His platelet count continued to be low and required repeated transfusions. Bone marrow aspiration and biopsy was repeated on day+ 41 which revealed occasional histiocytosis, although the cellularity was still low (<5% cellularity) (Figure 2). In view of persistent severe thrombocytopenia, immunoglobulin administration was repeated every 3 week. At the time of writing this report, patient continued to have low grade fever with no localizing focus for infection. He has been continued on eltromopag for the platelet engraftment.
Figure 1: Significant histiocytes seen in cell trails showing erythrophagocytosis.
Figure 2: Progressive imporvement in cellularity, with few histiocytes showing iron pigment deposition in cytoplasm.
Occurrence of HLH phenomenon post-transplant, although rare, is a well - known entity. It can complicate both allogeneic and autologous transplants leading to high mortality [4,5]. It could be related to infections, mainly viral, or could be independent of any reason . One of the challenging tasks for a clinician is to differentiate HLH from other variety of systemic inflammatory syndromes with including disseminated intravascular coagulation, capillary leak syndrome, engraftment syndrome and infection-associated macrophage activation syndrome . Also, ferritin is a ubiquitously expressed protein and specificity of ferritin for HLH is questionable particularly in transplant settings.
However, primary engraftment failure is a rare complication post autologous transplant; few case reports support this evidently. Fukuno et al reported a case of B-NHL with graft failure post auto SCT . Although patient received high dose methylprednisolone, patient succumbed to multiorgan failure. Similarly, HLH post autologous for multiple myeloma has also been reported . On the other hand, reporting of secondary HLH in allogeneic transplants is relatively common in literature. Abe et al has shared his experience of two cases of secondary HLH post allogeneic transplant for lymphoma . An interesting prospective observational study by Abdelkefi et al reported the incidence of HLH after SCT in a single institution over 18 months. They found 8.8% incidence in alloSCT vs 0.9% in auto SCT. In spite of aggressive treatment, half of the patients with HLH died in their study which emphasize the dreadfulness of this rare complication .
Recently EBMT has reported an estimated rate following allogeneic HSCT of 1.09% and much lower estimate of 0.15% following autologous HSCT. In their report, the median cut-off value of ferritin deemed significant was 3,000 μg/L (1,000–10,000 μg/L). However, EBMT commented that what constitutes significant hyperferritinemia in the post-HSCT setting is still undefined and further study is needed to define appropriate cut-off ranges to inform novel screening and diagnostic criteria  In the experience of Colita A et al, there was only one case of HLH out of the 22 patients receiving auto- SCT in 18 months (incidence 4.5%.) . It was also emphasized that the conditioning regimen like BEAM which contains Etoposide has no protective effect against HLH.
As showed in various studies and case reports, HLH has a poor outcome despite aggressive therapy. Albeit there is no specific recommendation for posttransplant HLH, therapy ranges from corticosteroids, cyclosporine A, low dose etoposide, intravenous immunoglobulins to second transplant in case of refractory cases [3,10]. In this present report, our patient faced primary graft failure secondary to HLH post autologous transplant. He attained neutrophil engraftment post steroids and cyclosporine. Nonetheless, platelet engraftment could not be achieved which prompted us to start thrombopoietin receptor agonist (Eltrombopag). We also encountered renal toxicity due to cyclosporine and hence it could not be continued for a longer duration.
Posttransplant HLH is a rare but possible cause of primary graft failure in autologous stem cell transplants. Whenever sustained fever with cytopenia and hyperferritinemia are observed, differential diagnosis of secondary HLH should be acknowledged. The most important aspect is prompt recognition and initiation of the treatment which could be lifesaving.
All authors have no competing interest.
No financial support was taken.
Patient Consent Statement
Signed Patient Permission to publish the case report has been taken from the patient.
Ethical Approval Statement
The study has been approved by the Institutional Review Board of our Centre.
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