Bone marrow transplantation for Fanconi anemia

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1995 86: 2856-2862
Bone marrow transplantation for Fanconi anemia
E Gluckman, AD Auerbach, MM Horowitz, KA Sobocinski, RC Ash, MM Bortin, A Butturini, BM
Camitta, RE Champlin and W Friedrich
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Bone Marrow Transplantation for Fanconi Anemia
By Eliane Gluckrnan, Arleen D. Auerbach, Mary M. Horowitz, Kathleen A. Sobocinski, Robert C. Ash,
Mortimer M . Bortin, Anna Butturini, Bruce M . Carnitta, Richard E. Charnplin, Wilhelrn Friedrich, Robert A. Good,
Edward C. Gordon-Smith, Richard E. Harris, John P. Klein, Juan J. Ortega, Ricardo Pasquini, Norma K.C. Rarnsay,
Bruno Speck, Marcus R. Vowels, Mei-Jie Zhang, and Robert Peter Gale
Fanconi anemia is a genetic disorder associated
with diverse
congenital abnormalities, progressivebone marrow failure,
and increased risk of leukemia and other cancers. Affected
persons often die before 30 years of age. Bonemarrow transplantation is an effective treatment, but there are few data
regarding factors associated with transplant outcome. We
analyzed outcomesof HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow
transplantsforFanconianemiaperformed
between 1978
and 1994 and reported to the International Bone Marrow
Transplant Registry. Fanconi anemia was documented by
cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabil-
From theInternational Bone Marrow Transplant Registry, Health
Policy Institute, Medical College of Wisconsin, Milwaukee, Wl: the
Hdpital St Louis, Paris, France; Rockefeller University, New York,
NY; the Methodist Hospital of Indiana. Indianapolis, IN; the Midwest
Children’s Cancer Center, Medical College of Wisconsin, Milwaukee, Wl: the M.D. Anderson Cancer Center, Houston, TX; the Universitat Kinderklinik, UldDonau, Germany; the All Children’s Hospital, St Petersburg, FL; the St George’s Hospital Medical School,
London, UK; the Children’s Hospital Medical Center, Cincinnati,
OH; the Hospital lnfantil Val1 d’Hebron, Barcelona, Spain; rhe
Hospital de Clinicas, Curitiba. PR, Brazil; the University of Minnesota Hospital and Clinic, Minneapolis, MN; the
Kantonsspital Basel,
Basel, Switzerland; the Prince of Wales Children’s Hospital, Rundwick, Australia; Salick Health Care, L o s Angeles, CA.
Submitted August 19, 1994; accepted June 6, 1995.
Supported by Public Health Service Grant No. POI-CA-40053
from the National Cancer Institute, the National Institute of Allergy
and Infectious Diseases, and the National Heart, Lung and Blood
Institute of the US Department of Health and Human Services; and
by grants from Alpha Therapeutic Corp, Armour Pharmaceutical
CO, Astra Pharmaceutical, Bawter Healthcare Corp, Biogen. Lvnde
and H a r p Bradley Foundation, Bristol-Myers Squibb CO, Frank
G. Brotz Family Foundation, Burroughs- Wellcome Co. Center jbr
Advanced Studies in Lrukemia, Charfes E. Culpeper Foundation,
Eleanor Naylor Dana Charirable Trust, Epple)) Foundation for Research, Immunex Corp. Kettering Family Foundation. Kirin Brewery
CO, Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Herbert H.Kohl Charities, Inc, Eli Lilly Company Foundation, Nuda
and Herbert P. Mahler Charities, Marion Merrell Dow, Inc,Milstein
Family Foundation, Milwaukee FoundatiodElsa Schoeneich Research Fund, Samuel RobertsNoble Foundation, Orrho Biotech
Corp, John Oster Family Foundation, Elsa U. Pardee Foundation,
Jane and Lloyd Pettit Foundution. Pharmacia, RGK Foundation,
Roerig/Pfzer Pharmaceuticals, Sandoz Pharmuceuticuls, Walter
Schroeder Foundation, Stackner Family Foundation, Sturr Foundation, Joan and Jack Stein Charities, and Wyeth-Ayerst Laboratories.
Address reprint requests to M a y M . Horowitz, MD, MS, International Bone Marrow Transplant Registr?: Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
The publicationcosts of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordunce with I8 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8607-0042$3.00/0
2856
ities (95% confidence interval) of survival were 66% (58% to
73%) after HLA-identical siblings transplants and29% (18%
to 43%) after alternative donor transplants. Youngerpatient
age ( P .0001),higherpretransplant platelet counts ( P =
.04), use of antithymocyte globulin ( P = .005), and useof
low-dose (15 to 25 mgfkg) cyclophosphamide plus limited
for pretransplant conditioning and
field irradiation ( P = .OW)
cyclosporine for graft-versus-host disease prophylaxis( P =
.002) were associated with increased survival. Bone
marrow
transplants are effective therapy for Fanconi anemia. The
adverse impact of increasing age and lower pretransplant
platelet count on transplant outcome favors earlier intervention, especiallywhen there is an HLA-identical sibling donor.
0 1995 by The American Society of Hematology.
F
ANCON1 ANEMIA is an autosomal recessive disorder
characterized by diverse congenitalabnormalities, progressive bone marrow failure, and
increased risk of acute
cancer^."^ The Fanconi
myelogenousleukemiaandother
anemia phenotype is variable; diagnosis based on clinical
features is difficult and often unreliable.’ Hypersensitivity
of Fanconi anemia cells to DNA cross-linking agents is a
morereliable markerforthe
Fanconi anemia genotype.‘
Lymphocytes from persons with Fanconi anemia haveincreasedchromosomebreaks eitherspontaneously or after
incubationwith alkylatingagents such asdiepoxybutane
(DEB) or nitrogen mustard.“’*
Bone marrow transplantation is an effective therapy for
Fanconianemia. Thereareseveral
reports of successful
transplants for Fanconi anemia, although most include few
patients.”-15 Patient and disease factors affecting transplant
outcome and optimal transplant approach are not well-defined. In particular, because Fanconi anemia patientsmay
have increased sensitivity to cyclophosphamide and
radiation
in doses commonly used for pretransplant conditioning,“”’
some centers use lower doses to decrease transplant-related
mortality.’x-21 Whether
this strategy is effective is controversia~,l“.?’
This report from the International Bone Marrow TransplantRegistry (IBMTR) analyzes the outcome of 199 patients receiving bone marrowtransplants for Fanconi anemia
from HLA-identical sibling (n = 15 1 ) or alternative related
or unrelated donors (n = 48). We identify several patient,
disease, andtreatment factors associated with transplant outcome.
MATERIALS AND METHODS
Patients. Forty-two teams reported detailed information to the
IBMTR for 228 patients receiving a bone marrow transplant for
Fanconi anemia between 1978 and 1992. This study includes 199
patients whose lymphocytes showed increased chromosome breaks
spontaneously or after exposure to cross-linking agents. Fifteen cases
were excluded because cytogenetic analyses were not performed
and 14 cases were excluded because no chromosome breaks were
reported. One hundred fifty-one patients received transplants from
Blood, Vol 86,No 7 (October l ) , 1995: pp 2856-2862
From www.bloodjournal.org by guest on November 14, 2014. For personal use only.
2857
BMT FOR FANCONI ANEMIA
Table 1. Donor-Recipient Histocompatibilii and Relationship
Donor
~
_ _ ~ ~ ~
HLA-identical sibling
l-Antigen-mismatched sibling
2-Antigen-mismatched sibling
HLA-identical parent
l-Antigen-mismatched parent
2-Antigen-mismatched parent
3-Antigen-mismatched parent
HLA-identical other relative
l-Antigen-mismatched other relative
3-Antigen-mismatched other relative
HLA-identical unrelated donor
l-Antigen-mismatched unrelated donor
Total patients
No.
~
151
3*
11
11
3
5*
25
1
2”
1
15
4
199
*One donor-recipient pair mismatched in rejection direction only
(donor homozygous).
t Two-antigen mismatch in rejection direction; l-antigen mismatch
in GVHD direction.
$ Two donor-recipient pairs mismatched in rejection direction only:
1 donor-recipient pair, 2-antigen mismatch in rejection direction, and
l-antigen mismatch in GVHD direction; 1 donor-recipient pair, l-antigen mismatch in rejection direction, and 2-antigen mismatch in GVHD
direction.
§ One donor-recipient pair mismatched in rejection direction only;
1 pair, 3-antigen mismatch in rejection direction, 2-antigen mismatch
in GVHD direction.
HLA identical sibling donors, 29 from other related donors, and 19
from unrelated donors (Table 1).
Patient, disease, and treatment variables studied are shown in
Table 2. The median age at transplant was 10 years (range, 1 to 36
years). The median pretransplant level of granulocytes was 0.5 X
109L (range, < l to 4 X 109L) and median level of platelets was
26 X 109L (range, 2 to 305 X 109/L).At transplant, 8% of patients
were untransfused, 50% had received fewer than 20 transfusions,
and 42% had received 20 or more transfusions. Clinically important
infections were present in 22% of patients in the week before transplant.
Pretransplant conditioning regimens were divided into three main
categories according to cyclophosphamide dose and radiation schedule. Forty-nine percent received limited field irradiation (LFI) plus
low-dose (15 to 25 mg/kg) cyclophosphamide with or without antithymocyte globulin (ATG). The median LFI dose was 5 Gy (range,
4 to15Gy). Fifteen percent received totalbody irradiation (TBI)
plus low-dose cyclophosphamide. The median TB1 dose was 6 Gy
(range, 3 to 8 Gy). Fourteen percent of patients received high-dose
( 2 100 m a g ) cyclophosphamide with or without ATG andno radiation. The remainder (22%) received a variety of other conditioning
regimens.
Prophylaxis of graft-versus-host disease (GVHD) was with posttransplant methotrexate in 1l%, cyclosporine in 59%, methotrexate
plus cyclosporine in 20%, T-cell depletion of donor bone marrow
in 9%, and other regimens in 1% of patients.
End points. The end points analyzed were graft failure, acute
and chronic GVHD, interstitial pneumonia, and survival. Graft failurewas analyzed in patients surviving z 2 1 days after transplant
using published riter ria^'.^^; persons who never engrafted as well as
those with transient engraftment were considered to have graft failure. Acute GVHD was defined as moderate to severe (grade If-IV)
disease using published ~ r i t e r i a ~patients
~ ~ * ~ ;surviving more than 21
days with engraftment were considered to be at risk. Chronic GVHD
was determined by clinical criteria in patients survivinj more than
90 days with engraftment.” Interstitial pneumonia was defined as
nonbacterial pneumonia characterized by bilateral diffuse interstitial
Statistical methods. Probabilities of graft failure, acute and
chronic GVHD, interstitial pneumonia, and survival were calculated
using the Kaplan-Meier method. The difference in survival between
HLA-identical sibling and alternative donors was tested with the
log-rank statistic.
Associations between patient, disease, and treatment variables
(Table 2) and survival were tested in multivariate analysis using
Cox proportional hazards regression, with time-to-death as the outcome.29 A stepwise backward elimination procedure was used.
Briefly, all covariates tobe considered were entered in an initial
regression model. Factors not statistically significant ( P > .05) were
removed from the model one at a time, with re-estimation of all
model variables after each step. Variable elimination (or reinsertion)
was stopped when all remaining factors were significant at a P value
less than .05. The proportionality assumption was tested using a
time-dependent covariate. Interactions were tested and none was
significant.
Potential center effects were tested using a center-specific frailty
model.30In this approach, patients within a center share a common
random effect that represents the shared unmeasured covariates for
the center’s patients. This random effects model induces an association among individuals with a center. A Gamma frailty model including the covariates found significant in the final Cox model was fit
tothe data. A testof the hypothesis of no shared random effect
within centers was performed and found to be insignificant ( P = .9).
This analysis strongly suggests that the simple Cox model provides a
reasonable fit to the data and that there is no need for further adjustment for center effects once risk factors are accounted for.
All P values are two-sided andbased on multivariate analysis,
unless otherwise specified. Because of the large number of comparisons made, we considered only P values less than .O1 to be statistically significant.” P values between .01 and .05 are presented to
show trends but should be interpreted with caution. This maybe
overly conservative because the study includes 280% of the target
population of patients receiving transplants for Fanconi anemia during the study period.
RESULTS
Table 3 shows outcomes after HLA-identical sibling and
alternative donor bone marrow transplants for Fanconi anemia. Two-year probabilities of survival (95% confidence interval) were 66% (58% to 73%) after HLA-identical sibling
transplants and 29% (18% to 43%) after alternative donor
transplants (Fig 1). A total of 109 of 199 patients are alive
at a median of 33 months (range, 4 to 162 months) after
transplantation. Ninety-nine of the 109 survivors (91%) have
normal hematologic parameters and require no transfusions,
6 (6%) are improved compared with pretransplant hematologic values and require no or fewer transfusions, 3 (2%)
are unchanged or worse, and hematologic parameters were
not reported for 1 patient. At last follow-up, 91 % of survivors
had Kamofsky performance scores 290%. Four patients developed cancers after transplantation. One patient developed
acute myelogenous leukemia 4 months after transplantation,
2 patients developed squamous cell carcinoma of the tongue
6 and 7 years after transplantation, and 1 patient developed
squamous cell carcinoma of the larynx 8 years after transplantation.
Table 4 presents the results of a multivariate analysis of
factors correlated with survival after HLA-identical sibling
transplants after Fanconi anemia. Our main objective was
From www.bloodjournal.org by guest on November 14, 2014. For personal use only.
2858
GLUCKMAN ET AL
Table 2. Patient, Disease, and Treatment Charactoristicsfor 199 Patients Receiving
Bone Marrow Transplantsfor Fanconi Anemia, Accordingto Donor Type
~~
~
HLA-identical Sibling Donors (n = 151)
No. of Patients
Evaluable
Variable
at
(29)
Age
diagnosis of Fanconi anemia (yr)
151
Family history of Fanconi anemia
45
137
No
(67)
Yes
13
Suspected
(3)
Age at 1st hematologic abnormality
(yr)
6
(<1-35)
40
6
1 43
Interval between diagnosis of Fanconi anemia and
1st hematologic abnormality 47
143
Diagnosis before hematologic
(28) abnormality 13
(29)
<l mo after first abnormality
(38)
18
(35)
>l mo after first abnormality
(34)
16
(36)
Treatment for aplastic anemia before transplantation
48
151
None
(27)
13
(38)
Corticosteroids ? other
(6)
3
(9)
Androgens f other
(31)
15
(301
Androgens corticosteroids 2 other
Other
(8)
4
No. of transfusions pretransplantation
45
144
None
4 0
+
d o
Interval between 1st hematologic abnormality and
(<1-292)28
transplantation (mol
WBC pretransplantation (x109/L)
.5
Granulocytes pretransplantation (x109/L)
(2-305) 26
Platelets pretransplantation (~10%)
Patient age at transplantation (yr)
(1-36) 10
Male sex
(56)
84
Infection in week before transplantation
(21)
31
Performance score 190%
(24)
36
Donor age at transplantation (yr1
10
Donor-recipient ABO-matched
(64)
95
Donor-recipient sex-match
Male to male
(19)
9
Male to female
Female to male
(36)
17
Female to female
Conditioning 48
8
TB1 15-25mg/kg Cy (17)
TB1 + 15-25mg/kg Cy f ATG
(27)
13
LFI + 15-25m g k g Cy
LFI + 15-25mg/kg Cy + ATG
2100 m g k g Cy
=l00 mg/kg Cy + ATG
Other
GVHD prophylaxis
(8) MTX 2 other
4
(12)
CsA c other
(17) MTX + CsA
8
(21)
T-cell depletion
9
(5)
Other
Year of transplantation
48
+
1978-1985
1986-1992
(81)
39
143
147
140
149
151
151
150
148
151
149
151
(32)
(23)
(23)
151
(13)
(43)
(11)
(15)
151
Alternative
Donors
Median (range)*
N {%)t
7
No. of Patients
Evaluable
(<1-35)(1-27)6
Median (range)'
N I%)t
48
92
41 (30)
4
1
(2)
12-27)
41
50
52
57
14
45
30 (20)
5 (3)
(27)
13 (9)
74 (51)
57 (40)
2
13
2
21
22
(3-1771
(<1-8)
(<1-41
(<l-3)
(3-103)
(4-31)
.5
24
9
(27)
(37)
(3-52)
(<1-39)
(55)
13
17
35
26
39
49
33 (22)
35
34
47
45
43
41
48
48
48
46
45
47
47
(21)
19
1 (1)
65
17 (11)
17
8 (5)
24
2
(4)
(47)
(49)
(41-8)
20 (42)
10
1 1 (23)
1
(2)
2
(4)
1
1
(21
(2)
22
(461
48
18
93 (62)
32
8
(52)
151
(24)
(76)
In = 48)
36
115
Abbreviations: WBC, white blood cells; Cy, cyclophosphamide; MTX, methotrexate; CsA, cyclosporine.
* For continuous variables.
t For categorical variables.
25
2
(4)
9 (19)
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2859
BMT FOR FANCONIANEMIA
Table 3. Probabiiiiiesof Graft Failure, Grade Il-IV Acute GVHD,
Chronic GVHD, Interstitial Pneumonia, and Survival After Bone
Marrow Transplantation for Fanconi Anemia
Table 4. Results of Multivariate A n a m Examining Risk Factors
Associated With Death Among 120 Recipients of HIA-Identical
Sibling Bone Marrow Transplants for Fanconi Anemia
HLA-Identical
Sibling
Donors
Alternative
Donors
No. at
Risk
Time
Point
End
Graft failure*
Grade Il-IV acute GVHDt
Chronic GVHDS
Interstitial pneumonia
Survival
2 yr
100 d
2 yr
2 yr
2 yr
Variable
Probability No. at Probability
(95% Cl)
Risk
(95% Cl)
146
(5-14)
8
135
42
(34-50)
116 44 (34-53)
151
12
(8-19)
151
66
(58-73)
41
24
(13-40)
37 51 (36-67)
18 46 (24-70)
48 25
(13-43)
48 29
(18-43)
Among patients surviving 221 days.
t Among patients surviving 221 days with evidence of engraftment.
*Among patients surviving 290 days with evidence of engraftment.
to compare transplant regimens (conditioning and GVHD
prophylaxis). Consequently, we included only patients
treated with regimens for which there were sufficient cases
for analysis. Conditioning regimens studied were (1) LFI
and low-dose (15 to 25 mgkg) cyclophosphamide with or
without ATG (N = 75), (2) TB1 and low-dose cyclophosphamide (N = 20), and (3) high-dose ( 2100 mgkg) cyclophosphamide with or without ATG (N = 25). GVHD prophylaxis
regimens studied included (1) methotrexate (N = lo), (2)
cyclosporine (N = 82), and (3) cyclosporine combined with
methotrexate (N = 28).
Younger age (P< .OO01), use of ATG in the conditioning
regimen (P = .005), use of cyclosporine with or without
methotrexate to prevent GVHD (P= .002), and conditioning
with LFI and low-dose cyclophosphamide versus 2 100 mg/
kg cyclophosphamide and no radiation ( P = .009) were significantly associated with decreased posttransplantation mortality. A marginally significant association (P = .01) with
pretransplantation platelet count (P = .M) was observed
Fig 1. Pmbability of survivel after
bone
marrow
HLA-idenusing
anemia
Fenconi
transplantation
for
ng
tical
donors. or alternative
Relative Risk
of Death
N
Age at transplant* <.0001 1.18"
120
Platelets pretransplantt
0.98m
120
Conditioning included ATG
No
95
.005
0.15
25
Yes
Conditioning (other than ATG)
25
No radiation, Cy =l00 mgkg
20
TBI, Cy 15-25 m g k g 0.55
,0095
75
LFI, Cy 15-25 m g k g
GVHD prophylaxis
10
MTX 2 other
,0022 other 0.18
110
CsA 2 MTX
P
c.04
-
1.oo
.03$
1.oo
.34§
0.27
-
1.oo
Only non-T-cell-depleted cases with the conditioning regimens
shown are included.
Abbreviations: CsA, cyclosporine; MTX, methotrexate; Cy, cyclophosphamide.
n = age increment in years.
t m = platelet increment in 10s/L.
P value for overall effect of conditioning regimen.
5 P value for pairwise comparison with no radiation, Cy 2100 mgl
*
kg.
with lower mortality in persons having higher pretransplant
platelet counts. Variables not significantly associated (P 2
.05) with treatment failure included age at diagnosis of Fanconi anemia, age at detection of first hematologic abnormality, and interval from diagnosis to transplant, although these
three variables are correlated with age at transplant. Year
of transplantation was also not significantly associated with
treatment failure and inclusion of year of transplantation in
the model or restricting the analysis to patients receiving
transplants after 1985 did not alter results. Table 5 shows
probabilities (with 95% confidenceintervals) of graft failure,
"P
094
0
n
a4
88
MONTES
4a
ca
n
From www.bloodjournal.org by guest on November 14, 2014. For personal use only.
2860
GLUCKMANET AL
acute and chronic GVHD, interstitial pneumonia, and survival for patients with favorable and unfavorable prognostic
factors.
DISCUSSION
Most patients withFanconi anemia die of hematologic
causes including bone marrow failure, myelodysplastic syndromes, and acute myelogenous l e ~ k e m i a . ~ , Prior
~ . ~ *stud,~~
ies indicate that bone marrow transplants are effective treatment for Fanconi anemia. However, many issues remain
unresolved.
We found 5-year survival rates of about 65% after transplants from HLA-identical siblings. The 5-year survival rate
after transplants from alternative donors was about 30%.The
latter group of 48 patients (with 11 different donor-recipient
histocompatibility relationships) was too small and heterogeneous for a more detailed analysis of risk factors. There
were also substantial differences in patient-, disease-, and
treatment-related variables between recipients of HLA-identical sibling transplants and alternative donor transplants.
Because of small numbers of patients, we could not adjust
outcome for these differences and, consequently, we cannot
comment onwhat role, if any, HLA-matching and donor
relationship play in transplant outcome in Fanconi anemia.
Multivariate analysis identified several factors correlated
with survival after HLA-identical sibling transplants: age at
transplant, pretransplant platelet count, conditioning regimen, andGVHD prophylaxis. As in other transplant settings,
older patients had a lower rate of ~ u r v i v a l . ~Lower
~ - ~ ' platelet
counts before transplantation were also associated with a
lower survival probability ( P = .04), mostly because of increased graft failure and chronic GVHD (P = .03; Table 5).
The reason for this correlation is unclear, but may reflect
more severe or long-standing Fanconi anemia. The platelet
count was inversely correlated with the number of pretransplant transfusions.
Transplant regimen had an important impact on outcome.
Use of ATGfor conditioning had a favorable effect, with less
acute GVHD and less chronic GVHD in univariate analyses
(Table 5) and lower mortality in multivariate analyses ( P =
,005, Table 4). There was no statistically significant association with other end points such as graft failure or interstitial
pneumonia. One important issue we tried to address was the
impact of cyclophosphamide dose and radiation schedule on
transplant outcome. S ~ r n e ' ~but
. ~ ' not all'4,22previous studies
suggest better survival with low-dose cyclophosphamide and
LFI, possibly because of increased in vivo sensitivity of
Fanconi anemia cells to alkylating agents similar to observed
sensitivity of Fanconi anemia cells to agents such as DEB
in vitro. Our data indicate that persons receiving this regimen
had a lower risk of treatment failure (relative risk = .27) than
did persons receiving conventional dose cyclophosphamide
without radiation ( P = ,009).
Graft failure rates were low with all three
conditioning
regimens. This finding suggests that low-dose cyclophosphamide, combined with LFI or TBI, provides adequate immune
suppression for stable engraftment in Fanconi anemia. This
finding is consistent with those of a prior report.2' We could
not address whether it is necessary to add radiation to lowdose cyclophosphamide. This issue is important because
some reports suggest an increased risk of cancers after transplantation for aplastic anemia in patients receiving radiation
for c~nditioning.~~
The risk might be even higher in patients
with Fanconi anemia, because the disease itself is associated
with an increased cancer risk. A recent analysis from the
International Fanconi AnemiaRegistry
reports approximately a 50% actuarial risk of developing a myelodysplastic
syndrome or acute myelogenous leukemia by 40 years of
age in patients with Fanconi anemia who do not receive a
tran~plant.~
In our study, with a median follow-up of survivors of 33 months (range, 4 to 162 months), there was 1
patient whodeveloped acute myelogenous leukemia in recip-
Table 5. Probabilities (95% ConfidenceIntervals) of Graft Failure, Acute and Chronic GVHD, Interstitial Pneumonia, and Survival After
HLA-Identical Sibling Bone Marrow Transplantationfor Fanconi Anemia for Patients With Favorable and Unfavorable Risk Factors
Risk Factors
N
2-yr Probability
of Survival
(95% Cl)
2-yr Probability
of Ipn
(95% Cl)
34 (23-46)
53 (39-66)
29 (19-42)
66 (49-80)
8 (3-17)
10 (4-24)
89 (80-95)
54 (40-67)
4 (1-9)
0
41 (32-50)
53 (23-82)
42 (32-53)
38 (11-75)
7 (3-14)
29 (8-64)
78 (69-85)
30 (11-60)
4 (2-11)
0
49 (38-58)
20 (9-39)
50 (38-61)
18 (7-38)
11 (6-19)
0
70 (60-78)
91 (73-98)
41 (29-54)
42 (31-55)
45 (31-60)
40 (27-54)
6 (2-16)
11 (5-21)
68 (55-78)
80 (68-89)
38 (27-49)
54 (32-74)
45 (27-65)
39 (28-511
54 (31-76)
45 (24-69)
9 (4-18)
11 (3-31)
6 (1-26)
82 (71-89)
70 (48-85)
55 (36-73)
2-yr Probability
of Graft Failure
100-d Probability
of Acute GVHD
2-yr Probability
of Chronic GVHD
(95% Cl)
(95% Cl)
(95% Cl)
Age at transplant
68
5 1 0 yr
52
> l 0 yr
GVHD prophylaxis
CSA 2 MTX 2 other
110
10
MTX t other
Conditioning included ATG
No
95
Yes
25
Platelets pretransplant
s26.5 X 109/~
60
>26.5 X 109/~
60
Conditioning (other than ATG)
(1-14 75
LFI,Cy 15-25 mg/kg
20
TBI, Cy 15-25 mglkg
25
No radiation, Cy 2100 mg/kg
0
(3-18) 8
(2-14) 5
2 (1-9)
1)
0
4 ( 1-24)
Only non-T-cell-depleted cases with the conditioning regimens shown are included. Values are percentages.
Abbreviations: Cl, confidence interval: IPn, interstitial pneumonia; CsA, cyclosporine: MTX, methotrexate; Cy, cyclophosphamide.
From www.bloodjournal.org by guest on November 14, 2014. For personal use only.
BMT FOR FANCONI ANEMIA
ient cells 4 months after transplantation. It is possible that
this patient had leukemia or myelodysplasia before transplantation. Three other patients developed squamous cell
carcinomas. All 4 patients received L H for conditioning and
the cancers occurred outside the radiation field. Posttransplantation tumors are also reported in another series among
patients not receiving radiati~n.’~
Much longer follow-up is
required to determine the risk of posttransplantation cancers
and whether radiation increases risk.
The use of cyclosporine with or without methotrexate for
GVHD prophylaxis was also associated with a higher rate
of survival, a finding similar to one observed in a recent
IBMTR study of transplants for leukemia.39
Our data indicate that bone marrow transplants are effective in Fanconi anemia. An important question is when they
should be performed. This issue is best addressed in a prospective study. However, the adverse impact of increasing
age and lower pretransplantation platelet counts favors earlier intervention, especially when there is an HLA-identical
sibling donor.
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