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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3546-3556
Bone Marrow Transplantation for Children Less Than 2 Years of Age
With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
By
Ann E. Woolfrey,
Ted A. Gooley,
Eric L. Sievers,
Laurie A. Milner,
Robert G. Andrews,
Mark Walters,
Paul Hoffmeister,
John A. Hansen,
Claudio Anasetti,
Eileen Bryant,
Frederick R. Appelbaum, and
Jean
E. Sanders
From the Fred Hutchinson Cancer Research Center and University of
Washington Departments of Pediatrics and Medicine, Seattle, WA.
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ABSTRACT |
We analyzed results of 40 infants less than 2 years of age who
received bone marrow transplants (BMT) between May 1974 and January
1995 for treatment of acute myelogenous leukemia (AML; N = 34) or
myelodysplastic syndrome (MDS; N = 6) to determine outcome and
survival performance. Among the AML patients, 13 were in first
remission, 9 were in untreated first relapse or second remission, and
12 were in refractory relapse. Patients were conditioned with
cyclophosphamide in combination with either total body irradiation (TBI; N = 29) or busulfan (N = 11). Source of stem cells included 6 autologous donors, 15 HLA genotypically identical siblings, 14 haploidentical family members, and 5 unrelated donors.
Graft-versus-host disease (GVHD) prophylaxis was methotrexate (MTX) for
17, MTX plus cyclosporine (CSP) for 14, or CSP plus prednisone for 3. Incidence of severe (grade 3-4) regimen-related toxicity was 10% and
transplant-related mortality was 10%. Acute GVHD (grades II-III) occurred in 39% of allogeneic patients, and chronic GVHD developed in
40%. Relapse, the most significant problem for patients in this study,
occurred in 1 MDS patient and 23 AML patients and was the cause of
death for 19 patients. The 2-year probabilities of relapse are 46%,
67%, and 92%, respectively, for patients transplanted in first
remission, untreated first relapse or second remission, and relapse.
One MDS and 8 AML patients received second marrow transplants for
treatment of relapse, and 5 of these survive disease-free for more than
1.5 years. All 6 MDS patients and 11 of 34 AML patients survive more
than 1.5 years later. The 5-year probabilities of survival and
disease-free survival are 54% and 38% for patients transplanted in
first remission and 33% and 22% for untreated first relapse or second
remission. None of the patients transplanted with refractory relapse
survive disease-free. Outcome was significantly associated with phase
of disease at transplantation and pretransplant diagnosis of
extramedullary disease. Long-term sequelae included growth failure and
hormonal deficiencies. Survival performance was a median of 100% (80%
to 100%) and neurologic development for all survivors was appropriate
for age. This study indicates that infants with AML have similar
outcome after BMT compared with older children and that BMT should be
performed in first remission whenever possible. In addition, allogeneic
BMT provides effective therapy for the majority of infants with MDS.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
ALLOGENEIC BONE marrow transplantation
(BMT) plays an important role in the primary therapy for children with
acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Recent cooperative group studies have demonstrated superior outcome for
patients with AML transplanted from matched related donors compared
with those treated with chemotherapy alone.1,2 For children
who relapse after chemotherapy, BMT also offers a second chance for
curative therapy.3 Studies have also demonstrated favorable
outcome for younger patients with MDS treated with allogeneic BMT.4
Outcome after marrow transplantation, tolerance of high-dose therapy,
and risks for long-term sequelae may be different for very young
children, who have distinct biologic and developmental characteristics
to consider. We have previously reported outcome for a group of 11 children less than 2 years of age with AML transplanted in first
complete remission.5 These infants had favorable outcome with few early transplant-related problems, but follow-up was limited.
In the present study, we update these results and expand our analysis
to include 29 additional infants less than 2 years of age transplanted
for AML or MDS referred to the Fred Hutchinson Cancer Research Center
(FHCRC; Seattle, WA) for BMT.
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PATIENTS AND METHODS |
Between May 1974 and January 1995, 40 consecutive children less than 2 years of age with a diagnosis of AML or MDS received BMT at FHCRC or
Children's Hospital and Medical Center (CHMC; Seattle, WA) and were
analyzed as of December 1997. Diagnosis was made at the referring
institution and confirmed by review of diagnostic bone marrow. Patient
characteristics at diagnosis are shown in
Table 1. The French-American-British (FAB)
classification was used for assignment of disease subtypes M0 through
M7 or refractory anemia with excess blasts (RAEB) and refractory anemia
with excess blasts in transformation
(RAEB/T).6 Records of diagnostic cytogenetic analysis performed at referring institutions were available for 27 patients, with abnormalities reported for 21 AML patients and all MDS
patients, 5 of whom had monosomy 7. Primary and secondary therapies for
AML varied according to referring institution practice. Remission
status was determined within 2 weeks before BMT by histopathologic analysis of bone marrow and cerebral spinal fluid (CSF) and cytogenetic analysis. Patients considered in untreated first relapse had
histopathologic evidence for bone marrow relapse and were transplanted
without further effort at remission induction.7 Patients
who received therapy for first relapse and achieved complete response
in bone marrow (<5% blasts) and extramedullary sites of leukemia
were considered to be in second remission, and those with greater than 5% marrow blasts or evidence of extramedullary disease despite remission induction were considered in refractory relapse.
Preparative regimens used for infants with AML or MDS depended on
protocols in use at the time of transplant and were determined by phase
of disease and type of donor (Table 2).
From 1974 to 1982, total body irradiation (TBI) was delivered in a
single setting of 9.2 to 10.0 Gy from opposing Co sources, and from
1982 onward 12.0 to 15.75 Gy TBI was delivered in fractionated or
hyperfractionated doses as previously described.5,8,9
Eleven infants were prepared with busulfan (Bu) plus cyclophosphamide
(Cy) and did not receive TBI. Intrathecal methotrexate (MTX) was
administered during the preparative phase to 25 patients who had either
history or presence of central nervous system (CNS) disease. Four
patients with CNS leukemia at the time of transplant received 6.0 to
23.0 Gy irradiation to the CNS and 2 patients with testicular leukemia received 5.0 and 10.0 Gy testicular irradiation immediately before the
start of conditioning. Beginning in 1990, 5 patients received posttransplant consolidation with interleukin-2
(IL-2).10,11 Transplant protocols and consent
forms were approved by the Institutional Review Board (IRB) at FHCRC or
CHMC, and informed consent was obtained from parents or guardians
according to IRB policies.
Histocompatibility testing was performed by the Clinical Immunogenetics
Laboratory at FHCRC for all patients and donors. The standard National
Institute of Health (NIH) two-stage microtoxicity assay9
was used for typing of HLA-A and -B antigens, assigned as defined by
the World Health Organization (WHO) HLA nomenclature committee.12 HLA-DR typing was performed using nylon
wool-purified B lymphocytes in a modified microtoxicity assay, and
compatibility of HLA-D region was defined by determining Dw phenotype
using HLA-D homozygous typing cells (HTC).9,12 From 1990, HLA-D region compatibility was determined by identification of DRB1 alleles through hybridization of sequence-specific oligonucleotide probes (SSOP).13 Patient-donor compatibility was further
tested by lymphocyte cross-match (patient serum v donor T and B
cells) before transplantation.14 Mismatched related donors
were matched for HLA-A, -B, and -DR/ DRB1 on one haplotype and could be
mismatched for one to three HLA-A, -B, or -DR/DRB1 antigens on the
second haplotype. Unrelated donors were either matched for HLA-A, -B, and -DR/DRB1 or had incompatibility of a single HLA locus, defined as a
disparity within a cross-reactive group for the HLA-A or -B loci or
within the same serologically defined DR specificity, for HLA-Dw
antigens or DRB1 alleles.
All allogeneic transplant recipients received unmanipulated bone marrow
cells collected according to established methods.8,15 One
patient also received allogeneic peripheral blood stem cells (PBSC)
mobilized with a 6-day course of granulocyte colony-stimulating factor
(G-CSF; 10 mg/kg).16 Among the autologous patients, 3 received marrow purged with 4-hydroperoxycyclophosphamide (4HC), 2 received nonpurged marrow plus PBSC, and 1 received PBSC alone. Stem
cell products were infused through a central venous catheter on day 0, at least 36 hours after last dose of preparative chemotherapy or within
24 hours after the last dose of irradiation. Recipients of allogeneic
marrow received prophylaxis for graft-versus-host disease (GVHD)
depending on type of donor and protocol in use at time of BMT, as shown
in Table 2.8,17
All patients had indwelling central venous catheters. Nutritional
support was provided by hyperalimentation. Measures to prevent infection varied according to the standard of practice at the time of
BMT, including prophylactic fluconazole18 and ganciclovir for cytomegalovirus (CMV) prophylaxis,19,20 as
well as use of single conventional or laminar airflow rooms, growth
factors, and intravenous Ig.
Engraftment was defined by achievement of peripheral granulocyte count
of greater than 500/µL for 3 consecutive days and by donor
cytogenetics. Patients were not considered evaluable for engraftment if
they died and did not achieve a granulocyte count greater than 500/µL
before day 28. For allogeneic recipients, donor engraftment was
determined by in situ DNA hybridization with Y-body-specific
probe21 (sex-mismatched transplants), by restriction
fragment length polymorphism (RFLP) analysis,22 or by
polymerase chain reaction (PCR) assay of genomic DNA for variable
number of tandem repeats (VNTR).23 Regimen-related toxicity
(RRT), including veno-occlusive disease (VOD), was scored using the
method of Bearman et al.24 Criteria for skin toxicity were
modified to include perianal skin toxicity (dermatitis) defined as
grade 1 for a rash and grade 2 for epidermal erosion. Acute and chronic
GVHD were diagnosed according to conventional criteria and treated as
previously described.8,25,26 Patients were not considered
evaluable for acute GVHD if they died before engraftment. Patients were
not considered evaluable for chronic GVHD if they died before day 80. Quality of life was evaluated by using the Lansky Play Performance
Scale (LPPS) results reported by parent/guardians or physicians on an
annual basis.27 Growth was evaluated by annual reports of
height measurements and height standard deviation (SD) scores,
calculated as the difference between the 90th and 10th percentiles for
a given age and gender, divided by 2.5628 (GrowTrak;
Genetech, Inc, South San Francisco, CA). Annual evaluation for hormonal deficiency included measurement of growth hormone (GH),
thyroxine (T4), thyroid stimulating hormone (TSH), luteinizing hormone
(LH), and follicle stimulating hormone (FSH). Neuropsychologic development was evaluated using Full Scale Intelligence Quotient (FSIQ)
tests appropriate for age at testing.29,30
Statistical methods.
Proportional hazards regression models were fit for the endpoints
overall survival, relapse, and disease-free survival (DFS; death or
relapse, whichever occurs first, is considered an event). For each of
these endpoints, data from all 40 patients were used when examining
explanatory variables relevant to patients with AML or MDS. When
variables relevant only to patients with AML were examined, regression
models were restricted to data from the 34 patients with this
diagnosis. Explanatory variables examined included donor age, patient
gender, extramedullary disease (EMD; defined as diagnosis of EMD at any
time before transplantation), cytogenetic abnormalities (examined in
two ways: normal v abnormal and normal v abnormal
involving chromosome 11q23 v abnormal not involving chromosome
11q23), white blood cell count (WBC) at diagnosis (WBC >20.0
v <20.0), phase of disease at transplant (early phase AML
[defined as first remission] v intermediate stage AML
[defined as untreated first relapse or second remission] v
advanced stage AML [defined as relapse] v diagnosis of MDS),
type of transplant (autologous v matched related v
mismatched or unrelated), patient and donor CMV serostatus, use of TBI,
and GVHD prophylaxis (autologous v CSP + MTX v others).
Estimates of overall survival and DFS were calculated using the method
of Kaplan and Meier,31 and cumulative incidence estimates
were used to describe relapse rates.32 For the endpoint of
relapse, death without relapse was regarded as a competing risk. In the
regression models, patients not reaching the appropriate endpoint were
censored at last contact or failure from a competing risk, whichever
occurred first. All P values associated with the regression
models were derived from the Wald test and are two-sided.
Comparisons between proportions of patients with a specific
characteristic were made using the Fischer's exact two-sided test. No
adjustments were made for multiple comparisons.
| |
RESULTS |
Patient characteristics.
Patient characteristics at time of transplant are shown in Table 2.
Twenty-one of the 34 patients with AML had disease phase beyond first
remission at time of transplant. Of the 13 patients transplanted in
first remission, 9 had one or more poor prognostic factors, including
WBC greater than 20.0 × 109/L at diagnosis in 5, history of extramedullary disease in 3, or 11q23 cytogenetic
abnormality in 2. EMD was diagnosed in 15 AML patients before
transplantation, 6 of whom had more than one site involved. Sites of
EMD included CNS in 14 patients, skin in 4, testes in 2, mastoid bone
in 1, and orbit in 1. Four patients who developed EMD before BMT did
not have EMD at diagnosis of AML. Of the 11 patients with EMD at
diagnosis, 4 had no recurrence before BMT and 7 had recurrence of EMD
at the same site. Six AML patients and 2 MDS patients were less than 1 year of age at BMT, and 6 of these 8 patients were conditioned with
TBI. Fourteen donors were genotypically HLA-identical siblings.
Haploidentical family donors included 1 phenotypically HLA-identical, 6 mismatched for one antigen, 4 mismatched for two antigens, and 4 mismatched for three antigens. Of the 5 unrelated donors, 3 were
determined to have mismatch for one antigen.
Survival and DFS.
All 6 infants with MDS survive greater than 1.5 years after BMT. One of
these relapsed with AML and survives after second BMT, and the rest
survive continuously disease-free. Eleven of the 34 infants with AML
are surviving more than 1.5 years after BMT. Nineteen patients died
from recurrent leukemia and 4 patients died of causes other than
relapse. Overall survival and DFS are shown in Table 2.
Results from univariable regression models are contained in
Table 3. Diagnosis and stage of disease
were statistically significantly associated with the hazard of
mortality (survival) as well as the hazard of death or relapse (DFS).
The association of stage of disease with survival among patients with
AML is shown in Fig 1. None of the 6 patients with MDS has died as of last contact; thus, the relative risk
of death cannot be determined. History of EMD was also significantly
associated with survival and DFS (Table 3 and
Fig 2). Only 2 of the 15 patients who
developed EMD before BMT survive long term (10 of these died of relapse and 3 died of other causes), whereas 9 of 19 AML patients without EMD
survive long term.
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| Fig 1.
Kaplan-Meier estimates of survival (left panel) and
cumulative incidence estimates of relapse (right panel) for 34 patients
with AML stratified for phase of disease at BMT. Statistical
significance was determined by log-rank test.
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| Fig 2.
Kaplan-Meier estimates of survival (left panel) and DFS
(right panel) for 34 patients with AML stratified for history of EMD
before BMT. Statistical significance was determined by log-rank test.
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No other variables were significantly associated with the survival or
DFS, although the relatively small number of patients prevents
definitive conclusions. Six of the 11 patients conditioned with BuCy
survive long-term (3 of these without recurrent disease), and 11 of 29 patients conditioned with TBI survive long-term (9 of these without
recurrent disease). Both autologous patients transplanted in first
remission survive, whereas none of the 4 autologous patients
transplanted in untreated first relapse or second remission survive.
When attempting to fit a multivariable model for survival and DFS for
all patients, no variables were significantly associated with the
appropriate hazard once stage of disease was considered. However, among
AML patients, the same was true of EMD. Because the number of patients
in this study is relatively small, it is not possible to determine
whether these variables act independently, synergistically, or
interchangeably.
Relapse.
Relapse occurred in 24 patients: 23 with AML and 1 with MDS. Results
from univariable regression analyses are provided in Table 3. Stage of
disease was significantly associated with relapse, and history of EMD
was suggestive of being associated with relapse.
Preparative regimen was not found to be significantly associated with
relapse. This may be misleading, because phase of disease was not
equivalent between the BuCy- and TBI-treated groups. Among AML patients
transplanted in first or second remission or untreated first relapse,
relapse occurred in 7 of 10 conditioned with BuCy and 5 of 12 conditioned with TBI. All 12 patients with refractory relapse were
conditioned with TBI, and relapse occurred in 11. Type of donor also
was not found to be significantly associated with relapse; however,
again, phase of disease was not evenly distributed between the
autologous and allogeneic patients. Among the group of patients
transplanted in first or second remission or untreated first relapse,
relapse occurred in 4 of 6 patients receiving autologous marrow and 8 of 16 receiving allogeneic marrow. None of the 12 patients with
refractory relapse received autologous marrow.
If stage of disease alone is included in a regression model, no other
variable provides a statistically significant improvement to this
model. In particular, the likelihood ratio test for addition of EMD
yields P = .43. On the other hand, addition of stage of disease
to the model already containing EMD yields P = .05, suggesting that the impact of relapse on outcome is not entirely accounted for by
the impact of having EMD. However, similar to survival and DFS, the
small number of patients limits the power to detect anything but
relatively large differences.
Engraftment.
Thirty-six patients achieved sustained engraftment. Two patients died
before engraftment could be evaluated, 1 from disseminated fungal
infection on day 5 and 1 from cardiac arrhythmia on day 12. Graft
failure occurred in 2 patients. One patient with M1 AML in first
remission received 6.5 × 108 mononuclear cells
(MNC)/kg marrow from his father, who was mismatched for
one antigen at the DR locus. Patient serum did not react with donor
lymphocytes pretransplant; however, after transplant, antibodies against donor B cells were demonstrated. Engraftment was achieved after
a second marrow infusion from the same donor after a preparative regimen using Cy/ATG, but the patient died from relapse on day 165. One
patient with M7 AML in first remission received 2.3 × 108 MNC/kg from a phenotypically matched unrelated donor
after BuCy conditioning, but died from infection with persistent graft
failure 21 days after a second marrow transplant from a different
matched unrelated donor after a CyTBI conditioning regimen.
RRT.
Information regarding toxicities resulting from the conditioning
regimen was available for 37 infants (Table
4). Two infants died of noninfectious causes during the first 30 days
after transplant, 1 from cardiac arrhythmia and 1 from a medication
error. The fatal cardiac event occurred in an infant with a previous
history of cardiomyopathy and a pretransplant ejection fraction of
32%. Grade 3 toxicities included mucositis resulting in temporary
intubation for airway obstruction in 2 patients and reversible renal
failure in 1 patient who required transient dialysis. Grade 1-2 mucositis and dermatitis were the most frequently observed toxicities.
Perianal skin breakdown (diaper dermatitis) accounted for 8 of 15 cases of skin toxicity, occurred in association with diarrhea, and generally persisted until granulocyte recovery. Hepatic toxicity (VOD) was limited in severity (grades 1-2) with maximum bilirubin of 0.8 to 6.0 mg/dL and weight gain of 5% to 11% over baseline. All cases of
hemorrhagic cystitis resolved within 10 days without intervention other
than platelet support. Two patients developed transient episodes of
congestive heart failure treated with diuretics. Three patients
required temporary supplemental oxygen for pulmonary toxicity that
could not be explained by infection.
RRT were analyzed according to conditioning regimen and diagnosis.
Comparing available data for 11 patients who received BuCy to 26 TBI
patients, the incidence and severity of mucositis, VOD, and pulmonary
toxicity were similar. Recipients of BuCy had an apparent decrease in
incidence of diarrhea (8% v 42%, P = .02) and
perianal skin breakdown (0% v 27%, P = .08). No grade
III or IV toxicities or cardiopulmonary complications were observed in
the MDS patients.
GVHD.
Acute GVHD developed in 17 of the 31 evaluable allogeneic patients.
Grades II-III acute GVHD occurred in 9 patients with AML and 3 patients
with MDS, for an overall incidence of 39%. Of the 4 patients who
developed grade III GVHD, 1 received marrow from a matched sibling
donor and 3 received marrow from unrelated or mismatched related
donors. No patient developed grade IV acute GVHD and there were no
deaths resulting from acute GVHD. Eight of 20 infants who survived more
than 80 days after allogeneic BMT developed chronic GVHD. GVHD resolved
in 6 patients after a single 9-month course of immunosuppresive
therapy, and 2 patients required further treatment of 3 and 18 months'
duration. No patient died from opportunistic infection, bleeding, or
other condition associated with chronic GVHD, and no patient has
ongoing chronic GVHD requiring therapy.
Long-term side effects.
Information regarding growth and development was available for all 17 long-term survivors, including 4 patients who survive into puberty. For
the first 2 years after BMT, growth velocity and height SD scores were
within normal ranges for all patients (Fig
3). Growth rate and height SD scores for the 3 patients who received
BuCy continued to remain within the normal range, with follow-up of 3 to 6 years. In contrast, the 14 patients who received TBI developed
growth failure beginning approximately 3 years after BMT, at which time
height SD scores decreased to less than  2.0. Although small
numbers of patients prevent definitive conclusions, there were no
apparent differences in height SD scores related to age at BMT (<13
[N = 5] v >13 months [N = 9]), type of irradiation (single [N = 3] v fractionated dose TBI [N = 11]), number
of transplants (1 [N = 10] v 2 [N = 4]), or history of
cranial irradiation (N = 2). Information regarding hormonal status was
available for 14 long-term survivors
(Table 5). Growth hormone deficiency
developed in 6 of 7 patients tested at least 3 years after BMT, all
within the group who received TBI. Five of these patients were treated with recombinant growth hormone that resulted in improved height SD
scores for 3 patients who received therapy before onset of puberty.
Height SD scores for 2 patients treated with growth hormone after
puberty did not improve. Thyroid hormone production was evaluated
annually in 13 patients and 2 patients have developed thyroid hormone
deficiency at 10 and 13 years after transplant. Both patients received
a single 10.0 Gy dose of TBI. Among the 4 patients who reached more
than 12 years of age, 2 have developed primary gonadal failure with
elevated LH and FSH and deficient sex hormone production and 2 have not
been evaluated.
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| Fig 3.
Mean height SD scores plotted for each year after
transplantation, grouped separately according to whether patients were
conditioned with TBI ( ) or BuCy ( ). The number of patients tested
at each time point is given next to the error bar. Patients were
censored after initiation of exogenous growth hormone therapy.
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Fourteen long-term survivors, including 4 patients less than 1 year of
age at BMT, had LPPS scores of 100%, a measurement of survival
performance after BMT. Two patients had LPPS scores of 90%, 1 of whom
was 9 and 13 months of age, respectively, at first and second BMT. One
patient who received a second transplant and developed chronic GVHD had
an LPPS score of 80%. Eleven patients have reached school age, and all
have progressed in school at appropriate grade levels. FSIQ was
measured for 5 AML patients between 3 and 12 years of age. FSIQ scores
were 117 and 78, respectively, for 1 patient conditioned with
fractionated TBI at age 12 months and 1 patient conditioned with
single-dose TBI at age 18 months. FSIQ scores for 3 patients who
received second BMTs were 81, 89, and 101, respectively, with the last
two scores reflecting patients also treated with cranial irradiation.
Three patients developed other long-term sequelae. One patient
developed asymptomatic cataracts at 4 years of age. A second patient
developed congestive heart failure (stable with digoxin therapy) and
hepatitis C virus hepatitis at 7 and 8 years after BMT, respectively.
The third patient developed a bipolar disorder 16 years after BMT,
requiring psychiatric hospitalization.
Second marrow transplant.
Eight of the 23 AML patients who relapsed after first transplant were
treated with a second marrow transplant and 1 of these also received a
third. One MDS relapsed with AML 82 days and received a second BMT at
another institution while in remission after chemotherapy. Conditioning
regimen, donor, and outcome are shown for second transplant patients in
Table 6. Four of the 8 patients who
received a second BMT for recurrent leukemia remain alive without
disease more than 2.5 years after first BMT, 3 died of relapse, and 1 died of toxicities associated with second BMT. None of the 15 patients
who did not receive a second BMT survives.
| |
DISCUSSION |
Despite intensive chemotherapy less than half of all children with AML
will survive.33,34 Infants with AML are more likely than
older children to have aggressive disease associated with inferior
outcomes.35 The current study found phase of disease at
time of transplant to be an important prognostic factor for survival
and relapse. Infants who received BMT in first remission had
significantly better overall survival and a significantly lower rate of
relapse compared with infants transplanted in more advanced phases of
disease. Prospective cooperative group studies in newly diagnosed AML
patients have consistently shown better outcome for patients receiving
allogeneic transplants in first remission compared with those receiving
chemotherapy alone, with DFS of 50% to 60% verus 30% to
40%.1,2,36 However, none of these studies specifically
addresses comparative outcome for infants. Our series of infants
transplanted in first complete remission shows similar overall survival
of 54% but an apparent lower DFS of 38%, which may reflect the
aggressive nature of infant AML and/or inclusion of a high
proportion of patients with poor prognostic factors. For infants with
disease beyond first remission, BMT was successful only if performed in
untreated first relapse or second complete remission. Of this group, 4 of 9 infants survive long term, 1 after second BMT. Results in the
current study are comparable to larger series of older children
transplanted in second remission, in which DFS of 37% DFS and relapse
risk of 48% have been reported.37 Other studies have
reported DFS of 61% to 75% for second remission patients treated with
allogeneic3 or autologous BMT38 using
preparative regimens similar to those in the current study. The small
numbers of patients in these studies preclude comparison; however, the
fact that these outcomes were not observed in the current study may
reflect the difficulty of erradicating recurrent leukemia in infants.
Correspondingly, outcome for infants with disease beyond second
remission was extremely poor. Despite lower transplant-related
mortality, infants with advanced disease did not have a better outcome
than older patients.39,40 Thus, the current study supports
allogeneic marrow transplant for treatment of infants in first
remission.
EMD was the only other factor statistically significantly associated
with poor outcome in our series. Among the 44% of AML patients with a
history of EMD before transplantation, DFS was 7%, compared with 32%
for infants without EMD. Outcome for infants is comparable to that
observed for older children with EMD, for whom a DFS of less than 15%
after either conventional chemotherapy or BMT has been
reported.33 EMD should be considered as a prognostic factor
in addition to phase of disease at transplant, even though our small
number of patients precludes definitive determination of whether these
variables act independently to influence outcome. Poor outcome for
infants with EMD was due to relapse; thus, efforts to improve DFS for
this group of patients should be directed toward decreasing recurrent
leukemia.
The primary cause of treatment failure for infants in this study was
relapse. To improve outcome our results suggest, first, that the
optimum time to transplant infants is in first remission, based on the
significantly smaller risk for relapse. Secondly, for patients
transplanted after first remission, the primary strategy for improving
survival should be directed toward decreasing incidence of
posttransplant relapse. Methods to reduce disease recurrence include
use of more intensive transplant preparative regimens41 or
posttransplant immune modulation, such as IL-2.11
Additionally, aggressive pretransplant induction therapy has been shown
to improve outcome after BMT for first remission patients, probably by
minimizing leukemic burden before the transplant preparative
regimen.42 However, further intensification of the
induction regimen appears to be limited by toxicity-related deaths,
reported to be at least 10% in current investigations, precluding
marrow transplantation for a significant number of
patients.42 We have previously demonstrated that
intensification of the transplant regimen results in fewer relapse-related deaths for patients with acute leukemia.41
However, in most studies, the benefit of an intensified regimen is
offset by the increased incidence of toxic deaths.41,43,44
In the current study, the incidence of regimen-related mortality was relatively low, suggesting that infants may be a group of patients who
will better tolerate more aggressive preparative regimens. Novel
methods to deliver increased doses of therapy while avoiding additional
toxicity, such as dosing Bu based on therapeutic blood levels45 or use of radiolabeled monoclonal antibody
targeted to hematopoietic cells,46 are currently being
developed in our institution for use in young children.
Posttransplant immune modulation might also improve outcome for infants
at risk of relapse. Graft-versus-leukemia (GVL) has been implicated in
reduction of relapse rates observed in larger series of patients with
AML receiving marrow from mismatched or unrelated
donors.47,48 Because infants have a low risk of
complications from GVHD and a high risk of relapse, we are currently
exploring strategies to increase GVL effects. Outcome of mismatched
related or unrelated donor grafts is similar to that of genotypically identical donors in the study presented here; thus, alternative donors
should be considered for infants at high risk of relapse without an
HLA-identical sibling who would otherwise benefit from transplantation
in first remission. Reducing the strength of GVHD prophylaxis also may
enhance GVL, an approach that appears to benefit patients in first
relapse being grafted from HLA-identical siblings.44,49
Thus, we consider MTX alone to be sufficient GVHD prophylaxis for
infants, particularly for those with genotypically identical donors.
Furthermore, we are currently exploring strategies for induction of GVL
in infants who do not develop GVHD. Phase I studies of posttransplant
IL-2 immunotherapy have demonstrated that it can be given safely to
children and may decrease the relapse rate if administered early after
BMT.10,11 The effect of donor lymphocyte infusions in
patients without significant GVH who develop cytogenetic relapse is
also being investigated.50
Infants who relapsed after transplant died from their recurrent
leukemia, except for some infants receiving a second BMT. Second marrow
transplants resulted in long-term survival for 50% of patients, an
outcome comparable to that reported previously for children less than
10 years of age.51 Infants initially conditioned with
either BuCy or TBI had similar outcomes after second BMT, although
small numbers make comparison difficult. Infants initially conditioned
with BuCy tolerated their second transplant as early as 3 months after
the first. Significant toxicity was not observed for second transplants
after initial TBI-conditioned BMT, a situation that is benefited by a
longer interval between transplants.51 Relapse continued to
be the major cause of death after second transplant.
This study demonstrates that risk for regimen-related mortality after
transplant is low (<10%). Half of the regimen-related deaths
occurred in infants with pre-existing conditions, ie, cardiac death in
a patient with cardiomyopathy and infectious death in a patient with
pre-existing infection. Growth failure associated with growth hormone
deficiency was the most frequent long-term sequelae observed in
patients conditioned with irradiation.52-54 The pattern of
growth rate showed a significant decrease beginning 3 years after BMT,
the same pattern observed for older prepubertal children receiving
TBI.55 Exogenous growth hormone resulted in improved height
outcome for patients treated before puberty. Although most long-term
survivors developed sequelae of irradiation, survival performance did
not appear to be impaired in the majority of these patients. These
patients attend school and participate in activities with a normal
level of function. Thus, devastating long-term complications should not
be viewed as the natural consequence of TBI as therapy for infant AML.
Several studies have established that MDS can be cured with allogeneic
BMT.4,56-58 Age has been shown to be an important factor,
such that patients less than 20 years of age are reported to achieve a
DFS of 50% to 65%4,56; however, outcome for infants has
not been specifically addressed. We demonstrate long-term DFS for 5 of
6 patients, with minimal regimen-related toxicity or long-term sequelae
observed in the current study. These findings are encouraging, because
young children with MDS tend to have aggressive disease with early
transformation to leukemia, poor response to chemotherapy, and poor
long-term survival without marrow transplantation.59,60
Although numbers are small, our preliminary results suggest that
transplantation with alternative donors should be considered for
patients without genotypically identical donors, because marrow from
matched related, mismatched related, and unrelated donors was used with
apparently equal success. Results from a larger series of MDS patients
demonstrate superior outcome for children transplanted before leukemic
transformation (<25% marrow blasts; unpublished data);
thus, our current approach is proceeding to BMT as soon as a suitable
donor is identified.
The current study demonstrates that results of marrow transplantation
for infants with AML are similar to those for older patients. We show
that outcome for infants is primarily determined by relapse as opposed
to transplant-related complications. Because infants have a low risk of
regimen-related mortality, we recommend proceeding with allogeneic BMT
for very young patients with MDS or AML in first remission. Alternative
donor grafts appear to be well tolerated by infants and should be
sought to permit BMT in the early phase of the disease. To improve DFS
for infants transplanted after first remission, efforts should be
directed toward reducing the risk of relapse, including the use of
intensified preparative regimens or strategies to increase GVL effects.
Second transplants may also be required to achieve long-term survival. Long-term sequelae for patients transplanted as infants are not substantially different from those observed in children transplanted at
an older age and thus should not be considered a reason to defer BMT.
| |
ACKNOWLEDGMENT |
The authors thank Francis Kemp for his assistance in preparation of the
manuscript.
| |
FOOTNOTES |
Submitted February 17, 1998;
accepted June 29, 1998.
Supported in part by National Institutes of Health Grants No. DK02431,
CA-18029, CA-18221, and CA-47748.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Ann E. Woolfrey, MD, Pediatric
Transplantation, Fred Hutchinson Cancer Research Center, M185, 1100 Fairview Ave N, Seattle, WA 98109; e-mail: awoolfre{at}fhcrc.org.
| |
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Abstract
Introduction