Primary hemophagocytic lymphohistiocytosis (HLH), including familial HLH
and some inherited immune deficiency syndromes, is a rare,
life-threating disease. It is caused by mutations of several genes that
impair lymphocytes’ cytotoxic machinery. The mutations mostly generate
defects in perforin- and granzyme-dependent pathway, resulting in the
inability of NK cells and cytotoxic T lymphocytes to down-regulate the
immune response. It is characterized by dysregulated hyperinflammatory
response that results in hypercytokinemia. Hematopoietic stem cell
transplantation (HSCT) is the only curative option for patients
with primary HLH. After the HLH 94-2004 studies conducted by the
Histiocyte Society, the 5 year survival rate is improved by HSCT from
about 50% to 66%.1 HSCT is associated with high
incidence of complications, such as infections, sinusoidal obstructive
syndrome (SOS), respiratory complications and high transplant related
mortality (TRM).
In spite of international collaboration, survival after HSCT has not
changed significantly in the last two decades in primary HLH.
Unavailability of matched donors, susceptibility to conditioning-related
toxicities, and high frequency of mixed chimerism remain challenge for
this hyperinflammatory immune-regulatory disorder. Debates about best
preparative regimens are ongoing without resolution. Recently, the use
of reduced-intensity conditioning (RIC) regimens has shown favorable
outcomes and lower rate of acute complications when compared to
conventional HSCT.2 Prospective RIC national HCT trial
for HLH/primary immunodeficiency resulted in low early mortality and
1-year overall survival (OS) of 80% (HLH only disease 82%), but 66.7%
18-month OS (HLH only disease 68%).1 HLH disease can
recur when donor chimerism declines to less than approximately 20%. RIC
regimens need to be optimized to decrease the mixed chimerism. It is
very interesting that there are two articles publishing in this issue to
address this question in different angle.
In the article by Wustrau et al3, a retrospective
multicenter study in Germany and Austria describes 60 patients with
primary HLH who received transplants between 2009-16. A multivariate
logistic regression model was applied to analyze the five potential risk
factors for substantial mixed chimerism including donor type, graft
source, conditioning alkylating agent, condition serotherapy and
remission status before conditioning. They found that the donor matching
status, whether 10/10 or not, is the only factor with significant impact
on the prevalence of substantial mixed chimerism (defined as while blood
donor Chimerism equal or less than 25% and / or secondary cell therapy
such as donor lymphocyte infusion (DLI), stem cell boost, or secondary
HSCT). The article by Ali et al4 in this issue
describes different preparative regimen associated with mixed chimerism.
Ali’s group studied 36 HLH patients from single institution with 9
patients received reduced-toxicity regimen (RTC) conditioning with the
combination of treosulfan, cyclophosphamide, fludarabine and
thymoglobulin for allogeneic HSCT between 2015-19. They found that RTC
cohort had the best compound event-free survival (EFS) (lack of relapse,
graft failure, second transplant or additional donor cell infusions, or
death) of 89% comparing 73% in conventional myeloablative (Conv MA)
regimen and 42% in RIC regimen while kept similar 2-year OS of 89%
comparing with 73% in Conv MA regimen and 83% with RIC
regimen.4 According to these two groups’ results,
10/10 matching with RTC regimen can result in better outcome for HSCT in
primary HLH.
Optimization of preparative regimen for HLH transplant is the key to get
better donor chimerism and avoid secondary intervention (See summary in
table). Serotherapy is a crucial factor for patient’s survival and the
development of mixed chimerism. Serotherapy is definitely needed for
transplant in this hyperinflammatory disease as shown in Slatter’s study
(50% early mortality).5 Willemsen et
al6 have shown that alemtuzumab was more likely to
result in long-term mixed chimerism than ATG. Interestingly, in
multivariate analysis serotherapy agent was not associated with mixed
chimerism in Wustrau et al’s article in this issue3.
The timing and dosing of alemtuzumab greatly affect HLH patients after
HSCT whether they develop mixed chimerism or GVHD. Both proximal
administration and distal schedule with alemtuzumab more than 2mg/kg
have been shown with increased mixed chimerism with 53% patients
needing more secondary stem cell intervention in Marsh et al’s
study.7 Intermediate alemtuzumab schedule with 1mg/kg
divided by 5 days started on day -14 combined with fludarabine and
melphalan generated better results with less mixed
chimerism.7 Ali’s article concluded that ATG, combined
with treosulfan and second alkylator cyclophosphamide in their RTC
cohort, had the best result with 2-year OS and EFS of
89%.4 In both articles in this issue, treosulfan
combined with other alkylator cyclophosphamide/thiotepa yielded the best
result with least mixed chimerism. Treosulfan is currently available in
Europe – Asia but not in US. Wustrau et al noted that treosulfan versus
melphalan did not change the incidence of mixed chimerism but adding
thiotepa decreased that incidence from 50% to 25%. Similar observation
was made in recently published article by Naik et al.8How active disease status affects patients survival is not widely
studied. As the new IFN-γ targeting therapy-Emapalumab is approved for
primary HLH treatment, it is encouraging that more patients will proceed
to HSCT in remission. Vallurupalli and colleague’s study showed that
65% of the relapsed /refractory HLH patients had overall remission and
proceeded to HSCT with 90.9% post-HSCT survival.9 The
recent phase 2-3 study confirmed that 65% of total of 26 primary HLH
patients had response in 8-week treatment period of Emapalumab and 70%
were able to proceed to transplant with 89.5% estimated 12 months’
survival.10
It is suggested that in primary immunodeficiency disorders, peripheral
blood stem cell transplant (PBSCT) can ensure sustained high-level donor
chimerism in more than 90% patients.11 It is
reasonable to think about PBSCT as a better stem cell source. These two
articles in current issue provide food for thought to conduct
prospective multicenter trial including melphalan/treosulfan with
cyclophosphamide/thiotepa with ATG as serotherapy may be with PBSCT as
stem cell source.
Table. Summary of different conditions and their outcomes in the
transplant of HLH a.