Introduction
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.
1
In recent years, HLH has attracted growing attention due to an inexplicable rise in
the interest of physicians in recognizing and reporting the disorder. Clinical features
may vary from a 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 an altered mental
status, seizures, and focal deficits.
2
Unfortunately, the diagnosis of HLH is often delayed due to the intricacies of the
established diagnostic criteria
1
of this deadly disease, which leads to irony as HLH needs a very fast and accurate
diagnosis to prevent 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 the 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.
3
HLH post stem cell transplant, either autologous or allogeneic, is a very rare complication,
which involves the complexities of the diagnosis due to various confounding factors
commonly encountered in the peri-transplant period. In addition to that, it is a known
fact that it is associated with high mortality.
4
A separate set of criteria for HLH after SCT has been proposed requires two 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.
5
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 1 case was reported in autologous transplant cases which clearly highlights the
rarity of this complication.
6
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.
Case Presentation
We describe the case of a 50-year-old male patient, who was diagnosed with diffuse
large B cell lymphoma (DLBCL)-non-germinal center type Stage IV in April 2019, received
6 cycles of RCHOP that showed good response to treatment on PET scan at the end of
the therapy. The patient presented again in February 2021 with progressively enlarging
cervical lymph nodes. PET CT confirmed the progression of the disease. Bone marrow
was not involved. At relapse, the disease was in stage IV as supradiaphragmatic and
infra diaphragmatic nodes were involved along with the liver. He was salvaged with
4 cycles of RDHAP with which he could achieve a partial response. The patient was
taken for an autologous transplant for further disease control. He received BEAM conditioning
regimen at the doses: carmustine @ 300 mg/sqm on day-6, cyatrabine @200 mg/sqm on
day-5 to -2, etoposide @ 200 mg/sqm on day-5 to -2, melphalan @ 120 mg/sqm on day-1
followed by infusion of autologous stem cells (G-CSF and plerixafor mobilized) at
dose of 5.1 × 10
6
/kg on day 0. On day + 4, the patient developed oral and abdominal mucositis grade
III. Subsequently, on day + 6, he also had a septicemic shock and required antibiotics
along with inotropic support. Growth factor support was continued since day + 1. In
view of the 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/mm
3
on day + 18 only to start falling off again on day + 21 (to 90/mm
3
). He remained to be febrile throughout the course and hence workup for secondary
HLH was initiated. Although the bone marrow was hypocellular with <5% cellularity
with occasional hemophagocytosis (
Fig. 1
), other parameters such as engraftment failure, high-grade fever, elevated ferritin
(3,660 ng/mL) were fulfilling the criteria of post-transplant secondary HLH as defined
by Takagi et al in post-HSCT setting, which requires either both major criteria (first
major criterion comprises engraftment failure, delayed engraftment, or secondary engraftment
failure after HSCT and the second is histopathological evidence of hemophagocytosis),
or one major and all four minor criteria (high-grade fever, hepatosplenomegaly, elevated
ferritin, and elevated serum lactate dehydrogenase).
5
With triglyceride levels of 362 mg/dL, fibrinogen 565 mg/dL, and procalcitonin 1.0
ng/mL, his H score was 253. Elevated serum IL2R levels (26,638 pg/mL, normal range:
1,555–10,800 pg/mL) consolidated our diagnosis of HLH, before starting steroids. Viral
PCRs for CMV, EBV, and respiratory viruses were done to rule out infections related
to HLH; however, all were negative. He was initiated on dexamethasone on day + 24
along with IvIg (immunoglobulin) @ 1 mg/kg/day for 2 days. Later on, cyclosporine
was also added on day + 25. On day + 27, an increasing trend in WBC was observed.
On day + 29, neutrophil engraftment was achieved (ANC > 500 mm
3
). The steroid was started to be tapered off thereafter and was stopped as the patient
developed
Pseudomonas
bacteremia. The 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 were
repeated on day+ 41, which revealed occasional histiocytosis although the cellularity
was still low (<5% cellularity) (
Fig. 2
). In view of persistent severe thrombocytopenia, immunoglobulin (Ig) administration
was repeated every 3 weeks. However, IgG levels were not checked before every dose
of Ig administration. At the time of writing this report, the patient continued to
have a low-grade fever with no localizing focus for infection. He has been continued
on eltrombopag (thrombopoietin receptor agonist) since day + 50 for the platelet engraftment
until his last follow-up day (day + 61) (
Fig. 1
).
Fig. 1
This figure depicts the clinical course of the patient post autologous until the last
follow-up (duration between the days is not according to the scale). The patient received
BEAM (carmustine/etoposide/cytarabine/melphalan) conditioning regimen. Day 0 represents
the days of autologous transplant (CD34 dose was 5.1 × 10
6
/kg). From day + 1, G-CSF was started as a part of the protocol. On day + 4, mucositis
started followed by hypotension on day + 6. He was managed with antibiotic support
along with granulocyte infusions. TLC started rising gradually until day + 18 only
to have a failing trend again by day + 21. On day + 23, bone marrow examination showed
hemophagocytosis. The patient received IvIg (immunoglobulin) and steroid from day + 24.
Cyclosporine was added on day + 25. TLC started rising by day + 29 (ANC > 500/mm
3
). On day + 35, the steroid was stopped due to
Pseudomonas
bacteremia. By day + 37, G-CSF was also stopped on day + 41 due to a rise in creatinine
and persistent hyperkalemia. Repeat bone marrow examination on day + 41 showed occasional
hemophagocytic cells. In view of persistent thrombocytopenia, eltrombopag was added
on day + 50. On the last follow-up (day + 61), the patient had TLC 10,540/mm
3
and platelets 32,000/mm
3
without transfusion support.
Fig. 2
Progressive improvement in cellularity, with few histiocytoses showing iron pigment
deposition in the cytoplasm.
Discussion
The occurrence of the 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.
7
One of the challenging tasks for a clinician is to differentiate HLH from other variety
of systemic inflammatory syndromes, including disseminated intravascular coagulation,
capillary leak syndrome, engraftment syndrome, and infection-associated macrophage
activation syndrome.
8
Also, ferritin is a ubiquitously expressed protein, and the specificity of ferritin
for HLH is questionable, particularly in transplant settings.
However, primary engraftment failure is a rare complication post autologous transplant;
a few case reports support this evidently. Fukuno et al reported a case of B-NHL with
graft failure post auto SCT.
9
Although the patient received high-dose methylprednisolone, the patient succumbed
to multiorgan failure. Similarly, HLH post autologous for multiple myeloma has also
been reported.
10
In contrast, reporting of secondary HLH in allogeneic transplants is relatively common
in the literature. Abe et al have shared their experience of two cases of secondary
HLH post allogeneic transplant for lymphoma.
11
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 emphasizes the dreadfulness of this rare complication.
6
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.
12
In the experience of Colita et al, there was only 1 case of HLH out of the 22 patients
receiving auto-SCT in 18 months (incidence: 4.5%.).
3
It was also emphasized that the conditioning regimens such as BEAM that contain etoposide
have no protective effect against HLH.
As shown 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 the 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. This patient had no clinical features of engraftment syndrome
as there were no rashes and weight gain. Also, we ruled out sepsis with low procalcitonin
and repeated negative blood cultures. He attained neutrophil engraftment post steroids
and cyclosporine. Nonetheless, platelet engraftment could not be achieved which prompted
us to start a thrombopoietin receptor agonist (eltrombopag). We also encountered renal
toxicity due to cyclosporine and hence it could not be continued for a longer duration.
Conclusion
Posttransplant HLH is a rare but possible cause of primary graft failure in autologous
stem cell transplants. Whenever sustained fever with cytopenia and hyperferritinemia
is observed, a differential diagnosis of secondary HLH should be acknowledged. The
most important aspect is prompt recognition and initiation of the treatment, which
could be lifesaving. Our patient was mobilized with a GCSF alone peripheral blood
graft. It would be intriguing to explore whether immune-mediated complications differ
between a chemo-mobilized graft versus G-CSF alone graft.