Discussion
In this retrospective study, we present our single center long-term
experience of allogeneic HSCT in six patients with MNGIE disease,
including the first patient (patient 1) who underwent HSCT. Despite
obvious statistical limitations of this relatively small cohort and
heterogeneity of pre- and post-HCST characteristics, important lessons
can be learned. Detailed assessment of the long-term follow-up of our
first patient as compared to the other five as well as to previously
reported patients allows us to reinforce previously suggested guidelines
and recent position paper on diagnosis, prognosis and treatment of
MNGIE, when carefully considering selected patients for this procedure.
The first multicenter experience of allogeneic HSCT for MNGIE published
by Halter summarized HSCT in 24 patients with a follow up ranging from
27 months to 8.5 years. The mortality of 15 patients out of a total of
24 was substantial. Overall, they concluded that allogenic HSCT can
alter the natural course of MNGIE and therefore should be considered as
a therapeutic option for carefully selected patients and that the
clinical status of the surviving patients improved significantly over
time, even in patients with very severe disease manifestations. This is
not inline with our experience showing that patients who exhibited
symptoms of progressive disease at the time of transplantation did not
improve to any significant extent following HSCT and their GI-related
symptoms and complications continued to progress. An important parameter
to be followed is weight gain, which occurred very slowly even in
patients who resumed oral feeding and were able to ingest high caloric
nutrients. In fact, only patient 1, who was transplanted early
presumably before the development of nonreversible changes, has started
gaining weight years post-transplant.
Age at diagnosis and timing of transplantation are of paramount
importance. HSCT should be carried out as early as possible, to maximize
the potential for recovery as well as minimizing the risks associated
with HCST. In our cohort, the best outcome was achieved in patient 1 who
was diagnosed early at age 8 years owing to a family history of two
affected cousins (fig. 1A) and had only mild symptoms at the time of
HSCT. Patient 3, who was 27 years of age and had severe GI
manifestations at the time of transplant, died 12 days post-transplant.
This is keeping with the perception that late transplantation is a
significant risk factor for HSCT. It is possible, as was previously
suggested, and as featured by our patient 1, that longer follow-up is
required to evaluate the outcome of these patients. Since patients with
MNGIE are born with this progressive mitochondrial disorder, and age of
HSCT is of paramount importance, including MNGIE in panels of newborn
screening should be considered.
According to the previous consensus proposal for a standardized approach
for allogeneic HSCT, careful donor selection is important, with an
HLA-identical sibling as the first preferred option, with both
non-carriers and heterozygous TYMP mutation carriers as potential
donors. All our patients were transplanted from a fully 10/10
HLA-matched related donor. The family trees of the two kindred, depicted
in Figures 1A and 1B, highlight the role of consanguineous marriages in
the causation of fatal, ultra-rare autosomal recessive disorders such as
MNGIE. On the other hand, the detailed plotting of the consanguineous
pedigrees enabled tracking and identification of 10/10 HLA-matched
donors for all transplanted patients. In general, carrier status of the
HSCT donor in inborn errors of metabolism is considered to be a
significant factor by influencing post-transplant enzyme levels which
appear to be important in determining long-term results, including
neurocognitive outcome in some disorders. In our group, four patients
were transplanted from heterozygous carriers (patients 1,2,5,6). It is
possible that the slow recovery of patient no 1 is related to the fact
that she was transplanted from her heterozygous mother, but on the other
hand her favorable outcome over time could indicate that carrier status
is only one of several factors to be taken into consideration.
Therefore, whilst a fully matched related donor who is not a carrier is
the preferred donor, our experience suggests that in selected patients,
for whom a carrier is the only available fully-matched related donor, it
is acceptable to proceed with HSCT from a carrier.
Furthermore, based on published data regarding matched unrelated donors
(Tables 3 and 4), 10 out of 12 published patients with MNGIE who
underwent matched unrelated donor HSCT engrafted and developed GVHD,
50% of them having grade 3-4 acute GVHD and dying from GVHD or
infections. Another known factor for developing GVHD is the source of
cells. Only patient 1 received peripheral stem cell collection, which
probably contributed to her GVHD, whereas 4/5 patients who received bone
marrow as a source of stem cells (excluding patient 3 who died on day
+12 post HSCT) did not develop GVHD.
Toxicity of the conditioning intensity regimen needs to be balanced
against the risk of secondary engraftment failure while using reduced
intensity and taking into consideration the toxic effect of specific
medications on the mitochondria. Favorable results can be achieved by
careful selection of HLA-matched donors, an adequate number of cells in
the graft and strict monitoring of chimerism to detect graft failure
early and guide therapeutic approaches to prevent graft loss. In our
cohort, four of our patients (patients 3-6) received a reduced to
treosulfan-based conditioning regimen instead of a busulfan-based
regimen to try and minimize GI toxicity for symptomatic patients.
Patient 3 started engraftment with full donor chimerism but died on day
12 post-transplantation from multiple organ failure. Patient 4 had full
donor chimerism 3 years post-HSCT and did not have any significant organ
toxicity. In contrast, our young patients 5 and 6 engrafted with mixed
chimerism and during the first year post-transplant had progressively
decreasing donor cells leading to secondary engraftment failure despite
repeated infusions of donor lymphocytes. Five out of six published
transplanted patients who underwent a non-busulfan-based conditioning
regimen or cord blood source had primary or secondary engraftment
failure (Tables 3 and 4) in contrast to patients who were conditioned
with a busulfan-based regimen. Thus, according to published literature
and our own experience, reduced intensity conditioning is not sufficient
for these patients with normal bone marrow and a healthy immune system.
The conditioning regimen for patients with MNGIE should be
busulfan-based with addition of anti-thymoglobulin to achieve a higher
percentage of donor chimerism. We conclude that the risk of secondary
engraftment failure while using a reduced toxicity conditioning regimen
outweighs the risk of organ toxicity associated with a busulfan-based
regimen, bearing in mind that a second HSCT might not be possible due to
disease progression, as happened with two of our patients (5 and 6).
According to published data, overall survival of transplanted patient
with MNGIE is about 37%, but almost all these patients were older than
16 years of ageand had severe manifestations of their disease (Table 3
and 4). Survival in our cohort was 66%.
Overall, our experience reinforces the significance of HSCT timing with
regard to HSCT-related risks, as well as a prognostic factor for
transplant outcome. We conclude that severe GI symptoms are mostly
irreversible and constitute a poor prognostic indicator both short and
long-term. HSCT should therefore be carefully considered in those
patients.
In conclusion, our present study emphasizes the short and long-term
outcome of allogenic bone marrow transplantation as a curative option
for patients with MNGIE if the following factors are carefully followed:
early diagnosis before irreversible GI symptoms occur, careful selection
of HLA-matched related donor and the use of a busulfan-based
conditioning regimen. Further studies might lead to other promising
therapeutic options and future developments such as newborn screening
may contribute to early diagnosis.
Conflict-of-interest disclosure :
All authors declare no conflict of interest.