Discussion
We describe our ten-year institutional experience in CAYA patients with
myeloid malignancies undergoing allo-HCT on our pediatric service. This
includes twenty-three consecutive patients of all risk categories who
were conditioned with BU-FLU-MEL and received grafts from a variety of
donor and stem cell sources. Thirty-nine percent of our patients were
young adults (19 to 27 years). At a median follow-up of greater than 37
months, we have a remarkable OS of 100% and PFS of 95.5%. Irrespective
of age, risk index, or treatment related disease, our OS and PFS is
noticeably higher that previous reports of AML/MDS in CAYA undergoing
allo-HCT.
There are several indications for allo-HCT in AML, including poor
cytogenetics such as the presence of high allelic FLT3/ITD ratio,
monosomy 5, monosomy 7, or an MLL/KMT2A rearrangement. A
pediatric DRI has been developed to risk stratify children and
adolescents with leukemia prior to transplant21. For
AML, stratification into low, intermediate, high, and very high-risk
groups is based upon cytogenetic risk, but also age and disease status
complete remission (CR) and MRD. Using this stratification, 5-year
leukemia free survival (LFS) was 78%, 53%, 40%, and 25% respectively
with OS of 80%, 64%, 50%, and 33%21. Applying this
DRI to our AML/MDS patient cohort, we had 2 low risk patients, 15
intermediate risk, 3 high, and 1 very high for which we would anticipate
OS and PFS of 64% and 54% respectively at 36 months. Four of our
patients had treatment related MDS/AML. A multicenter study of 273
pediatric patients with treatment-related MDS/AML undergoing MAC
allo-HCT found the 5-year OS and EFS to be 49.9% and
41.2%25. A retrospective review of pediatric patients
with poor cytogenetics who underwent allo-HCT (55 MSD and 55 unrelated
donor [URD]), demonstrated a 5-year OS of 46% with MSD, 50% with
URD26. These results are in line with what would be
predicted based on the DRI. In a review of Center for International
Blood and Bone Marrow Transplant Research (CIBMTR) data comparing
allo-HCT outcomes of pediatric (<15 years) and adolescent and
young adult (AYA) patients (15-40 years), similar survivals were
noted27. For patients receiving MSD allo-HCT in first
complete remission (CR1) the 5-year OS was 69% for pediatric patients
compared to 52% for AYAs. The PFS was 65% and 51% respectively. For
those receiving URD allo-HCT, decreased OS was seen with 34% for
pediatric patients and 41% for AYAs. More recent CIBMTR data have shown
improvement in 3-year probabilities of OS at 70% for AML patients
<18 years receiving MSD in CR1 and 67% in those in CR2 or
greater and 61% following MUD allo-HCT.
As there is still no consensus on optimal conditioning regimen for
allo-HCT in CAYA with myeloid malignancies there have been several
reports examining various regimens. A large multicenter study by
Pediatric Disease Working Party of the European Group for Blood and
Marrow Transplantation reported on pediatric patients with AML receiving
TBI-CY (n=109), BU-CY (n=389) or BU-CY-MEL (n=133)10.
The addition of MEL to BU-CY resulted in a reduced incidence of relapse
of 14.7% when compared to 31.5% with BU-CY and 30% with TBI-CY as
well as improved OS, 76.6% vs 64% with BU-CY, and 64.5% with TBI-CY
as well as PFS 74.5 vs 58% vs 61.9% respectively with comparable NRM.
There have been limited studies applying BU-FLU-MEL as conditioning in
pediatric transplantation. We have previously reported on six patients
receiving alternative donor allo-HCT conditioned with BU-FLU-MEL that
was found to be safe and effective11. No grade 4
toxicities were seen, with grade 3 mucositis being the most common
adverse effect. In a single institution study, pediatric (n=17) and
adult patients with AML/MDS received BU-MEL-FLU and ATG followed by a
T-depleted PBSC graft. The dose of BU and MEL was lower, 8-9.6 mg/kg and
140 mg/m2 when compared to our regimen of 12.8 mg/kg
and 180 mg/m2 respectively for MSD and URD
transplants28. The PFS was only 47.2% for pediatric
patients. The incidence of grade III-IV aGvHD and cGvHD was low as one
would expect from a T-cell depleted graft at 3.9% and 5.9%
respectively with a relapse rate of 28%28. In a large
multicenter retrospective report of 846 adult patients compared FLU-BU
to FLU-BU-MEL conditioning in myeloid and lymphoid malignancies and
found a significant improvement in the 5-year OS of 34.2% vs 30.1% and
a decrease in relapse 30.8% vs 38%9. Similarly, a
retrospective single-center review of 39 adult patients reported on
their use of FLU-BU-MEL in myeloid and lymphoid malignancies with BM, PB
and UCB as stem cell sources, with a 2-year OS of 62% for their entire
cohort and 44% in their high risk to very high-risk subset. The authors
concluded that this was a safe and successful regimen considering the
highest risk group included many chemo-resistant patients with active
disease at the time of transplant29.
We observed a significantly higher incidence of grades II-IV aGvHD in
MSD and MUD PBSCT compared to patients undergoing haplo-BMT(Figure 1B). As expected with PBSC grafts, we saw a
significantly increased cumulative incidence of cGvHD (1 mild, 2
moderate and 1 severe) and MUD allo-HCT (1 moderate, 1 severe) when
compared to the anticipated lower occurrence in haplo-BMT with PT-CY,
with none of the haplo-BMT patients developing cGvHD (Figure
1D) . Similarly, none of the three unrelated UCB transplant patients
showed signs of cGvHD. Consequently, GRFS was superior in haplo-BMT
patients when compared to our MSD/MUD PBSCT recipients (Figure
1F) . While aGvHD, and especially cGvHD, is well-known to occur more
frequently with the use of PBSC grafts, the addition of MEL has also
been associated with increased aGvHD when compared to non-MEL containing
conditioning regimens. In an adult report in patients with hematologic
malignancies receiving MUD or MSD PBSC, BM, or UCB grafts and either
tacrolimus or cyclosporine GvHD prophylaxis, an increase in grade II-IV
aGvHD was seen with BU-FLU-MEL compared to FLU-BU (52.6% vs40.8%) with a analogous protection from relapse (30.8% vs
39%)9. Moreover, pediatric AML patients receiving
BU-CY-MEL had a higher incidence of grade III-IV aGvHD (17.6%) compared
to those conditioned BU-CY alone (9.6%) with a parallel reduction in
relapse of 14.7% and 31.5% respectively. Chronic GvHD was higher in
PBSCs (34.9%) vs BM recipients (25.6%) as was observed in our series.
Our OS and PFS were similar, regardless of donor and stem cell source.
In a recent single institution retrospective pediatric study, the
outcomes of patients with hematologic malignancies (40% AML/MDS)
undergoing MSD BMT (n=31) and MUD BMT (n-47) where compared to their
haplo-PBSCT with PT-CY (n=26) recipients30. The OS
(80.9%, 83.3% and 80.7%), PFS (66.5%, 70.2% and 73.8%) and the
GRFS (62.1%, 44.6% and 61%) were not different between MSD, MUD and
haplo respectively. However, cGvHD was significantly higher in MUD BMT
recipients 31.7% compared to MSD BM 10% and haplo 9.2% despite use of
PBSC grafts in the latter group. We have recently updated our experience
of 31 CAYA patients with hematologic malignancies receiving haplo-BMT,
which compares favorably to the above study with OS 85.6%, PFS 76.1%
and GRFS 58.2% with our median follow-up of 32 months compared to only
12 months in the above study13.
Our current study along with our previous reports and those of others
confirm that haplo-BMT in CAYA is a viable alternative to MSD and MUD
allo-HCT12-15, 30, 31. This study expands our
experience with myeloablative BU-FLU-MEL in allo-HCT for myeloid
malignancies. As we are a smaller pediatric HCT center, this report is
limited by the relatively small number of patients, their heterogeneous
transplant characteristics in terms of stem cell source, type of donor
and GvHD prophylaxis regimen used and the retrospective nature of our
study. Nonetheless, the favorable outcomes remain striking considering
the disease risk in this ethnically and racially diverse population with
myeloid malignancies undergoing allo-HCT. Of caution is the unacceptably
high aGvHD and cGvHD seen in patients receiving MSD and MUD PBSC
transplants with MTX + CSA GvHD prophylaxis. It remains to be determined
whether the evolving application of PT-CY in the non-haplo setting will
offer better control of GvHD in CAYA PBSCT recipients following
BU-FLU-MEL without increasing their risk of relapse.