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RAPID COMMUNICATION
Increased Incidence of Solid Malignant Tumors After Bone Marrow
Transplantation for Severe Aplastic Anemia
By G. Socie, M. Henry-Amar, J.M. Cosset, A. Devergie, T. Girinsky, and E. Gluckman
From May 1980 to December 1989,107 consecutive patients
with non-constitutional severe aplastic anemia underwent
bone marrow transplantation at our institution using cyclophosphamideand thoraco-abdominal irradiationas conditioning regimen. During the same period, 40 patients with
Fanconi anemia were also grafted after a similar conditioning, giving a total series of 147 patients. With a mean
A
LLOGENEIC BONE MARROW transplantation
(BMT) has been an increasingly world-wide used
therapeutic modality for hematologic malignancies and
other non-malignant hematologic disorders.’
Secondary malignancies have been reported after chemoradiotherapy, and tumors, especially of epidermal tissues
and lymphatic system, have been observed after solid organ
tran~plantation.~,~
Furthermore, studies in canine and nonhuman primate radiation chimeras have shown a significantly increased risk of developing secondary malignan~y.~
Therefore, one would expect that human marrow transplant recipients treated with high dose chemotherapy
and/or radiotherapy and postgrafting immunosuppression
are at high risk of developing secondary malignancies.
However, only few reports have depicted this special issue,
so
PATIENTS AND METHODS
We recently updated (Blood, submitted) our experience using
cyclophosphamide (150 mg/kg)-thoraco-abdominal irradiation
(TAI) (6 Gy) as conditioning regimen’ before BMT for severe
aplastic anemia (SAA). We used large-field irradiation within
conditioning regimens because it was shown to reduce the incidence of graft rejection? From May 1980 to December 1989, 107
consecutive patients with an acquired SAA received this regimen
before BMT with an HLA-identical sibling donor. Graft-versushost disease (GVHD)prophylaxis consisted in methotrexate (MTX)
or cyclosporine A (CSA) or the association. In addition to these
107 patients, 40 patients with Fanconi anemia were grafted from
November 1976 to July 1990; all but five received a modified
conditioning regimen including cyclophosphamide (20 mg/kg)-TAI
(5 Gy), and CSA for GVHD prophylaxis.”
Mean follow-up of these 147 patients (males 87, females 60) was
64 months (range, 3 to 342), and mean follow-up from BMT to last
examination was 36 months (range, 1 to 134). Mean age at
diagnosis was 17 years (range, 5 to 46).
The time at risk for secondary solid tumor was computed from
the date of BMT to the date of solid tumor occurrence, the date of
last examination, or October 1, 1990, whichever came first. The
excess of solid tumor was calculated as the ratio of observed (0)to
expected (E) numbers from the French general population. The
OiE ratio was computed using a cancer incidence rate specific for
age, sex, and calendar year that has been published by the
Bas-Rhin tumor registry in France.” The confidence limits (CL) of
O/E ratio were obtained by assuming a Poisson distribution for the
observed numbers. A one-sided test was used to test the equality of
0 and E (OIE > 1 to be significant).
Blood, Val 78, No 2 (July 15). 1991: pp 277-279
follow-up of 64 months, four male patients developed a solid
malignant tumor, a number that leads to an 8-year cumulative incidence rate of 22% (eg, relative risk to general
population = 41, P < .OOl). These results should be considered as a warning to clinicians who follow these successfully
grafted long-term patients.
0 1991by The American Society of Hematology.
RESULTS
Four male patients developed a solid tumor, all within
the radiation field. Main clinical parameters of these four
patients are summarized in Table 1. Three patients were
grafted for SAA and one patient for Fanconi anemia.
Median age at the time of BMT was 16 years (range, 6 to
24), and median elapsed time from BMT to solid tumor was
7 years. Of the four malignant tumors, three were epidermoid carcinomas (patients unique patient number [UPN]
52, 71, and 83). The fourth one (patient UPN 97) was a
mucoepidermoid carcinoma of the parotid gland. All four
patients were treated by surgery and/or radiotherapy for
their malignancies and three of four are alive with a median
follow-up of less than 1year.
Overall, the O/E ratio was 41 (95% C L 10.9, 102; P <
.001) for a total number of 446 person-years at risk. The
O/E ratio was 80 in males (95% C L 22,205; P < .001). The
8-year cumulative incidence rate was 22% (standard error
11%) overall (Fig. 1).
Among the factors tested were age, sex, previous specific
immunosuppressive therapy (n = 53), type of acute GVHD
prophylaxis (n = 147), acute GVHD treatment (n = 98),
occurrence of chronic GVHD (n = 67) and its treatment;
none correlated with an increased risk of secondary solid
tumor.
DISCUSSION
Late occurrence of solid tumors after BMT has rarely
been reported. To our knowledge, only three groups have
published such a long-term complication after BMT.5-7.’2
It
is noteworthy that only five other secondary solid tumor
From the Bone Marrow Transplant Unit, H6pital Saint-Louis,
Paris, and the Radiotherapy Department and INSERM U247, and the
Department of Biostatistics and Epidemiology, Institut Gustave Roussy,
K l l e j u ~France.
Submitted February 28,1991; acceptedApril 18, 1991.
Address reprint requests to GCrard Socii, MD, Service de Greffe De
Moelle, Hopital Saint Louis, I , Avenue Claude Vellefaux, 75475 Paris
Cedex IO, France.
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 I8 U.S.C.section 1734 solely to
indicate this fact.
0 1991 by The American Society of Hematology.
0006-4971I9117802-0036$3.OOJO
277
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SOCIE ET AL
270
Table 1. Characteristicsof Patients Who Secondarily Developed a Solid Malignant Tumor
Previous
Diagnosis
Age/Sex
IS
52
SAA
Fanconi anemia
24iM
6iM
21iM
12/M
ATG
71
97
UPN
SAA
SAA
03
GVHD
Prophylaxis
CSA
CSA
No
No
No
MTX
MTX
Extensive
Chronic
GVHD
ElapsedTime
From BMT to
Solid Tumor
(mo)
Yes
No
No
Yes
64
74
94
95
Location
Oral cavity
Tongue
Parotid
Lip
Age denotes age at BMT, in years.
Abbreviations: IS, immunosuppressivetherapy; ATG, antithymocyte globulin.
H
.22
.I1
(-
1 SEI
0
0
24
48
72
96
120
Time from 0.M.T. in months
Fig. 1. Eight-year cumulative incidence rate of solid tumors after
BMT for severe aplastic anemia or Fanconi anemia is 22% (standard
error, 11%).
cases have been reported, so far, after BMT in patients with
and only one case in patients with Fanconi anemia.’’
Two of those five patients with S A A have received a
radiation-containing conditioning regimen, while the three
others had only cyclophosphamide.
In a recent report, Storb et a1 specifically analysed the
risk of secondary solid malignant tumor in patients transplanted for SAA at Seattle.” They report a 15-year cumulative incidence rate of 6%, which can be considered not
different with that reported in the present series, ie, 22%,
given the wide standard error. Besides previous chronic
GVHD, which accounted for two of our patients with
secondary solid malignant tumor as compared with four of
four patients from Seattle, the main difference that might
explain the high incidence rate reported is the systematic
use of irradiation within the conditioning regimen in our
patients. Whether the irradiation can totally explain the
difference observed remains unsolved.
As previously emphasized: two of our four patients had
oral chronic GVHD that may predispose to squamous
carcinoma as in oral lichen planus.14 In addition, none of
our patients were smokers nor drinkers. Obviously, with so
limited numbers of patients at risk and so few patients
developing a secondary solid malignant tumor, the search
for risk factors is illusive.
More accurate assessment of incidence risk of solid
tumor and risk factors will ideally come in the future from
multi-institutional study. However, one of our major goals
for the next few years will be to carefully study the late
effects after BMT because, with improvement of long-term
results, the number of patients at risk will increase.
REFERENCES
1. Bortin MM, Rimm AA: Increasing utilization of bone
marrow transplantation. Transplantation 48:453,1989
2. Parker RG: Radiation-induced cancer as a factor in clinical
decision making. Int J Radiat Oncol Biol Phys 18:993,1990
3. Kaldor JM, Day NE, Clarke EA, Van Leeuven FE, HenryAmar M, Fiorentino MV, Bell J, Pedersen D, Band P, Assouline D,
Koch M, Choi W, Prior P, Blair V, Langmark F, Pompe Kirn V,
Neal F, Peters D, Pfeiffer R, Karjalainen S, Cuzick J, Sutcliffe SB,
Somers R, Pellae-Cosset B, Pappagallo GL, Fraser P, Storm H,
Stovall M: Leukemia following Hodgkin’s disease. N Engl J Med
322:7,1990
4. Deeg HJ, Prentice R, Fritz TE, Sale GE, Lombard LS,
Thomas ED, Storb R: Increased cancer risk in canine radiation
chimeras. Blood 55:233,1980
5. Witherspoon RP, Fisher LD, Schoch G, Martin P, Sullivan
KM, Sanders J, Deeg HJ, Doney R, Thomas D, Storb R, Thomas
ED: Secondary cancers after bone marrow transplantation for
leukemia or aplastic anemia. N Engl J Med 321:784, 1989
6. Lishner M, Patterson B, Kandel R, Fyles G, Curtis JE,
Meharchand J, Mindem MD, Messner HA: Cutaneous and mu-
cosal neoplasms in bone marrow transplant recipients. Cancer
65:473,1990
7. McKenzie SE, August CS, Bunin G, Evans A, D’Angio G:
Benign and malignant tumors after bone marrow transplantation in
childhood. Proc Am Assoc Cancer Res 29:184,1988 (abstr)
8. Gluckman E, Devergie A, Benbunan M, Bridier A, Dutreix J:
Bone marrow transplantation in severe aplastic anemia using
cyclophosphamide and thoraco abdominal irradiation, in Young
NS, Levine A, Humphries RK (eds): Aplastic Anemia: Stem Cell
Biology and Advances in Treatment. New York, NY, Liss, 1984,
p 325
9. Champlin RE, Horowitz MM, Van Bekkum DW, Camitta
BM, Effenbein GE, Gale RP, Gluckman E, Good RA, Rimm AA,
Rozman C, Speck B, Bortin MM: Graft failure following bone
marrow transplantation for severe aplastic anemia: Risk factors
and treatment results. Blood 73:606, 1989
10. Gluckman E: Bone marrow transplantation for Fanconi
anemia, in Shahidi NT (ed): Aplastic Anemia and Other Bone
Marrow Failure Syndromes. New York, NY, Springer-Verlag,
1989, p 134
11. Schaffer P, Lavillaureix J: Le Cancer Dans le Bas-Rhin:
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
MALIGNANT TUMORWBONE MARROW TRANSPLANTATION
Incidence Des Nouveaux Cas de 1975 A 1977. Paris, France,
Economica, 1981
12. Flowers MED, Deeg HJ, Sanders J, Doney K, Hansen J,
Storb R: Bone marrow transplantation for Fanconi anemia. Hemato1 18:627,1990 (abstr, suppl l)
13. Storb R, Anasetti C, Appelbaum F, Beatty P, Bensinger W,
Buckner CD, CIift R, Doney K, Hansen J, Loughran T, Martin P,
Pepe M, Petersen F, Sanders J, Singer J, Stewart P, Sullivan K,
279
Witherspoon R, Thomas ED: Allogeneic marrow transplantation
for aplastic anemia: Major issues, in Gale RP, Champlin RE (eds):
New Strategies in Bone Marrow Transplantation. New York, NY,
Wiley-Liss, 1991, p 73
14. Kaplan B, Barnes L Oral lichen planus and squamous
carcinoma: Case report and update of literature. Arch Otolaryngol
111543,1985
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1991 78: 277-279
Increased incidence of solid malignant tumors after bone marrow
transplantation for severe aplastic anemia [see comments]
G Socie, M Henry-Amar, JM Cosset, A Devergie, T Girinsky and E Gluckman
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