Thyroid dysfunction among long-term survivors of bone marrow transplantation

Thyroid Dysfunction among Long-Term Survivors of Bone Marrow Transplantation

CHARLES A. SKLAR, M.D. TAE H. KIM, M.D. NORMA KC.

RAMSAY,

M.D.

Minneapolis, Minnesota

From the Departments of Pediatrics and Therapeutic Radiology, University of Minnesota Health Sciences Center, Minneapolis, Minnesota. This work was supported in part by a grant (POlCA2 1737) from the National Cancer Institute and a grant (RR-400) from the General Clinical Research Center’s Program of the Division of Research Resources, National Institutes of Health. Requests for reprints should be addressed to Dr. Charles A. Sklar, New York University Medical Center, Department of Pediatrics, 550 First Avenue, New York, New York 10016. Manuscript accepted March 30, 1982.

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Thyroid function studies were followed serially in 27 long-term survivors (median 33 months) of bone marrow transplantation. There were 15 men and 12 women (median age 13& years, range 11/12 to 226/,2 years). Aplastic anemia (14 patients) and acute nonlymphocytic leukemia (eight patients) were the major reasons for bone marrow transplantation. Pretransplant conditioning consisted of single-dose irradiation combined with high-dose, short-term chemotherapy in 23 patients, while four patients received a bone marrow transplantation without any radiation therapy. Thyroid dysfunction occurred in 10 of 23 (43 percent) irradiated patients; compensated hypothyroidism (elevated thyroid-stimulating hormone levels only) developed in eight subjects, and two patients had primary thyroid failure (elevated thyroid-stimulating hormone levels and low Tq index). The abnormal thyroid studies were detected a median of 13 months after bone marrow transplantation. The four subjects who underwent transplantation without radiation therapy have remained euthyroid (median follow-up two years). The only variable that appeared to correlate with the subsequent development of impaired thyroid function was the type of graft-versus-host disease prophylaxis employed; the irradiated subjects treated with methotrexate alone had a higher incidence of thyroid dysfunction compared to those treated with methotrexate combined with antithymocyte globulin and prednisone (eight of 12 versus two of 11, p <0.05). The high incidence and subtle nature of impaired thyroid function following single-dose irradiation for bone marrow transplantation are discussed. Bone marrow transplantation is presently considered the treatment of choice for severe aplastic anemia [ 1,2] and certain hematopoietic malignancies [3-51. Over the past several years there has been a dramatic improvement in the long-term survival of these patients, and many now appear cured of the underlying disorder. Since these patients are exposed to potent cytotoxic chemotherapy usually combined with radiation therapy, we have been concerned about potential late complications resulting from this type of therapy. As a result, we have initiated a prospective study to systematically examine the late effects of this form of treatment on various organ systems. The present report describes our data regarding thyroid function in a group of patients who have successfully undergone bone marrow transplantation at the University of Minnesota. Since hypothyroidism is a well-established sequela of therapeutic radiation when it includes the head and neck region [ 6-91, we anticipated that some degree of thyroid dysfunction would develop in a substantial number of our ir-

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THYROID DYSFUNCTION

TABLE I

I

Group II

Group 111

ET AL.

Patients’ Clinical Data

Patient No. Group

AFTER BONE MARROW TRANSPLANTATION-SKLAR

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Age at BoneMarrow Transplantation Sex F

M F M M

Survivaltotlowing BoneMarrow Transplantation Diagnosis

WI

SCID

11I 12

lO’o/ 12 12’0/,2 l4glI2 WI2

77

AA AA AA

58 43 29 35 21 17 31 50 36 43 39 44 20 17 54 33 33 16 28 69 23 46 12 26 25

2”‘/,2

AA

M F M M M M F F M F M F M M F M F M M F F

3% 2 6%

AA AA AA AA AA AA AA AA AA ANLL ANLL ANLL ANLL ANLL ANLL Lymphoma ANLL Lymphoma ANLL Lymphoma ALL

B2112

11'/12

l3g/1* 14”/12 l77lI2 64/12 l2g/,2 13%~ 14% 14’/12 15’/,2 l6*/12

16”/ 173/,:*

19% 207/,2 22%2

41

AA

F

83/, 2 84/12

(mo)

SCID = severe combined immunodeficiency; AA = aplastic anemia; ANLL = acute nonlymphocytic leukemia; ALL = acute lymphocytic leukemia.

radiated patients. Our results indicate that nearly half the subjects treated with radiation therapy have manifested biochemical evidence of impaired thyroid function. PATIENTS AND METHODS Twenty-seven patients who have successfully undergone allogeneic bone marrow transplantation at the University of Minnesota constituted the study population. The criteria used for patient selection were as follows: survival a minimum of 12 months following bone marrow transplantation and no evidence of recurrence of underlying disease; the absence of significant chronic systemic disease (e.g., liver or kidney disease); follow-up data available a minimum of six months following the discontinuation of all medical therapy. Bone marrow transplantation was performed using sibling donors matched at the major histocompatibility loci. The reasons for bone marrow transplantation were as follows: aplastic anemia (14 patients), acute nonlymphocytic leukemia (eight patients), non-l-todgkin’s lymphoma (three patients), acute lymphocytic leukemia (one patient), and severe combined immunodeficiency (one patient). As of June 1981, all 27 patients were alive, 12 to 77 months (median 33 months) after bone marrow transplantation. There were 15 males and 12 females who were between the ages of “/w and 22% years (median 13 ‘/, 2 years) at the time of bone marrow transplan-

tation (Table I). The patients were divided into three groups based on the type of therapy they received. Group I (No Irradlatlon). This group included jour patients, two men and two women, who had a transplantation for either aplastic anemia (three patients) or severe combined immunodeficiency (one patient). Preparative therapy cMsisted only of chemotherapy (either cyclophosphamide ‘alone or in combination with 6mercaptopurine or procarbazine) for the three patients with aplastic anemia. The patient with severe combined immunodeficiency received a bone marrow transplantation without any preparative treatmbnt. Group II (Irradiated). This group consisted of 1 f patients, seven males and four females, who received a bone marrow transplantation as therapy.for aplastic anemia., Preparative treatment consisted of single-dose irradiation plus high-dose cyclophosphamide (50 mg/kg per day for four days) in all cases [2] ; radiation was given as 750 rads to the midplane of the patient (total lymphoid in 10 patients, total body in one patient). Group 111(Irradiated). All 12 subjects in this gr$wp received a bone marrow transplantation as treatment for leukemia or lymphoma. Preparative therapy included total body irradiation, 750 rads in a single fraction, in ail 12 patients ~[lo]. Those with leukemia received high-dose cyclophoqjhamide (60 mg/kg per day for two days); the patients with lymphoma received a combination of BCNU, cyclophosphamide, and cytosine arabinoside [ 111. The patients in this group had all

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TABLE ii

AFTER BONE MARROW

Thyroid Studies in Bone Marrow Transplant Patients with Thyroid Dysfunction

Palienl No.

Interval to Initial Elevated ThyroidStimulating Hormone

ThyroidStimulating Hormone

(@/ml)*

T4 Index’

Group II

5 7 8 12 13 14

11 11.2 11 12 10 9.6

7.2 7.7 7.8 5.7 5.2 7.1

Group Ill

21 22

30

3.8

21 14 9.2 <6

4.6 5.1 6.9 5-11.5

26 27 Normal

TRANSPLANTATION-SKLAR

For patients with multiple abnormal determinations, abnormal thyroid-stimulating hormone determination multaneous T4 index have been reported. + Time initial thyroid studies were obtained. l

(mo) 6 19 11 6 20 13 19 41+ 13 16 the most and the si-

been brought into remission prior to bone marrow transplantation by the use of various chemotherapeutic protocols. The agents that the patients received included vincristine, prednisone, daunomycin, adriamycin, cytosine arabinoside, %azacytidine, 64hioguanine, cyclophosphamide, methotrexate, 6-mercaptopurine, L-asparaginase, and hydroxyurea. One patient (Patient 27) had received 2,500 rads cranial irradiation as central nervous system prophylaxis for acute lymphocytic leukemia. Total lymphoid irradiation was delivered by a 4 MeV linear accelerator at 26 rads/min, as previously described [ 121. The radiation field was a slight modification of the mantle field plus the inverted Y as is commonly used for the treatment of malignant lymphoma. Total body irradiation was administered by a 10 MeV linear accelerator at 26 rads/min, as previously reported [IO]. The larynx was not shielded during irradiation of any of the patients. The estimated dose of radiation to the thyroid gland was 795 rads for patients who received total lymphoid irradiation and 780 rads for those treated with total body irradiation. Twenty-six of the patients received prophylactic therapy for graft-versus-host disease. The patients were randomly given treatment with either methotrexate alone (13 patients) or a combination of methotrexate, prednisone, and antithymocyte globulin (13 patients), as part of an ongoing prospective study [ 131. Clinical evidence of graft-versus-host disease developed in five patients. Four were treated with topical steroids and one patient received systemic steroids for a period of seven months. Thyroid function studies including determinations of plasma total thyroxine (T,), thyroid-stimulating hormone, T3 uptake (TsU), and T4 index were determined serially at three to sixmonth intervals during the post-transplant period in the majority of patients. Plasma titers of antithyroglobulin and an-

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timicrosomal antibodies were measured in all patients in whom evidence of impaired thyroid function developed. Both T4 and thyroid-stimulating hormone levels were measured by standard radioimmunoassay techniques using reagents supplied by Kaiiestad Laboratories, Inc. (Austin, Texas). The T3U was determined using reagents supplied by NuclearMedical Laboratories, Inc. (Dallas, Texas). Results were normalized to 1.O for a pool of normal serum [ 141. The T4 index was calculated by multiplying the T4 by the T3U. The antithyroglobulin and antimicrosomal antibodies were determined by hemagglutination using kits purchased from Wellcome Reagents, Ltd. The normal values in our laboratory are as follows: T4 5 to 11.5 pg/dl, T$J 0.85 to 1.15, T4 index 5 to 11.5. and thyroid-stimulating hormone less than 6 plJ/ml. Antithyroglobulin antibody titers less than I:10 and antimicrosomal antibody titers less than 1:20 were considered negative. Compensated hypothyroidism was considered present if the T4 index was normal but the thyroid-stimulating hormone level was (1) greater than IO pU/ml on at least one occasion or (2) if there were two thyroid-stimulating hormone values between 7 and 9.9 pU/ml. Primary thyroid failure was defined as a T4 index less than 5.0 combined with an elevated thyroid-stimulating hormone value. Statistical analysis was performed using the unpaired Student t test, chi-square analysis, and the Mann-Whitney test. Life Table was constructed using standard methods [ 151.

RESULTS Function prior to Bone Marrow TransplantaAssessment of thyroid function was obtained before bone marrow transplantation in 12 patients; one patient from Group I, seven from Group II, and four subjects from Group III were tested. Studies included determination of the T4 index in all 12 patients and si-

Thyroid

tion.

multaneous thyroid-stimulating hormone levels in 10 of 12 patients. All studies were within the normal range.

Thyroid Function attqr Bone Marrow Transplantation. Group I: Ail four subjects who did not receive radiation therapy as part of their pretransplant treatment have remained euthyroid. Thyroid function studies, including baseline thyroid-stimulating hormone concentrations, have been within the normal range for a median follow-up of two years (range g/12to S4/12years). Group II: After a median follow-up period of 27/12years (range 13,&*to 4 years), biochemical evidence of abnormal thyroid-function developed in six of the II subjects in Group Ii. Ail six had an elevated thyroidstimulating hormone concentration but a normal T4 index (Table II). The abnormal thyroid values were detected a median of 12 months after bone marrow transplantation (range six to 20 months). Group Ill: Four of the 12 patients in Group ill have

manifested

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impaired thyroid function after a median

THYROID DYSFUNCTION

Months

After

AFTER BONE MARROW TRANSPLANTATION--SKLAR

ET AL.

BMT

F/gum 7. Life Tab188StinW8 Of #I8 proportion Of patients with nOrI?& thyroidstimulating hOftnOn8 (TSH) levels affer bone mat-row transplantation @MT).

follow-up period of 19/12years (range 1 to 58/12years). Primary thyroid failure has developed in two patients, whereas the remaining two patients have had only an elevated thyroid-stimulating hormone level with a normal T4 index (Table II). One patient (Patient 21) with primary thyroid failure had abnormal studies 19 months af’ter bone marrow transplantation; thyroid studies, including a thyroid-stimulating hormone determination, had been normal when measured three months earlier. The second patient with primary thyroid failure (Patient 22) was noted to have compensated hypothyroidism when initially evaluated 41 months after bone marrow transplantation; nine months later his studies were consistent with the diagnosis of primary thyroid failure (Table II). The two patients with compensated hypothyroidism had abnormal thyroid-stimulating hormone concentrations 13 and 16 months after they underwent bone marrow transplantation. Among the 10 patients in whom abnormal thyroid function developed, seven had normal function documented either before bone marrow transplantation (Patients 7, 8, 21, and 26) or in the early post-bone marrow transplantation period (Patients 5, 13, and 27). The remaining three patients (Patients 12, 14, and 22) were noted to have abnormal studies when initially

tested in the post-bone marrow transplantation period. None of the 10 subjects wlth thyroid dysfunction has manifested clinical signs or symptoms of hypothyroidism. Estimates of antithyroglobulin and antimicrosomai antibody titers were negative in all 10 patients. Since the incidence of abnormal thyroid function was similar in the two groups.of patients treated with radiation therapy (Groups II and 111). the groups have been combined for the purpose of further analysis. The overall incidence of abnormal thyroid function among irradiated patients after a median follolw-up of 32 months was 10 of 23 patients (43 percent}, with a median occurrence 13 months after bone m&row transplantation (Flguie l).” The patients with thyroid dysfunction did not differ from those with normal thyroid status in age at treatment, sex ratio, type of radiation, pre-bone mariow transplantation chemotherapy, presence of graft-versus-host disease, or original diagnosis. There was, however, a statistically significantty greater incidence of abnormal thyroid studies &mong Data from Patient 22 are not included in Life Tablg (Figure 1) because thyroid studies were first obtained 41 months after bone marrow transplantation. l

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AFTER BONE MARROW TRANSPLANTATION-SKLAR

the patients given methotrexate alone for graft-versus-host disease prophylaxis when compared to the group who received methotrexate combined with antithymocyte globulin and prednisone (eight of 12 versus two of 11, p <0.05). Age at treatment, sex ratio, type of radiation, pre-bone marrow transplantation chemotherapy, incidence of graft-versus-host disease, original diagnosis, and length of follow-up were similar in the two groups. Longitudinal data are available in six of the eight patients with compensated hypothyroidism; these data deal with the natural history of the abnormal thyroid studies in these patients. Five of the six patients have demonstrated persistently elevated thyroid-stimulating hormone values over a five to 21-month period of time. Thyroid-stimulating hormone concentrations in the sixth patient (Patient 5) have returned to normal 20 months after the initial abnormal studies were detected.

COMMENTS

The present study demonstrates a high incidence of thyroid dysfunction among the survivors of bone marrow transplantation. We were able to document eight cases of compensated and two cases of primary hypothyroidism among the 27 patients evaluated. Although not an unexpected finding, hypothyroidism as a late complication of bone marrow transplantation has not, to our knowledge, been previously reported. Our results strongly suggest that radiation therapy is the major, if not the sole, cause for the subsequent development of thyroid hypofunction in these patients. None of the subjects who received a bone marrow transplantation without radiotherapy (Group I) manifested biochemical evidence of impaired thyroid function. Furthermore, among the irradiated patients the incidence of impaired thyroid function did not differ between those patients previously treated with multiple chemotherapeutic agents (Group Ill) and those who had not received prior chemotherapy (Group II). Since all of the irradiated subjects in the present series were treated with both radiation and short-term, high-dose chemotherapy (primarily cyclophosphamide) in the immediate pretransplant period, we cannot exclude the possibility that the damage to the thyroid resulted from some interaction between these two modalities and not solely from the radiation. The data on thyroid function in patients treated for Hodgkin’s disease and nonHodgkin’s lymphoma lend further support to our contention that thyroid failure as a consequence of combined modality therapy relates primarily to the inclusion of radiotherapy. Radiation alone and radiation plus chemotherapy have been associated with a similar and high incidence of thyroid hypofunction [ 7,9,16- 161,

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whereas those patients with Hodgkin’s disease treated only with cyclic chemotherapy have not had significant thyroid function abnormalities [9]. The radiation conditioning regimen used for bone marrow transplantation in this series of patients differs in several important ways from the type of radiation therapy employed in the conventional treatment of most human malignancies. The effect of this mode of irradiation on the thyroid provides us with new and unique data regarding the radiobiology of the normal human thyroid. The bulk of accumulated data regarding radiation-induced hypothyroidism is derived from studies performed in patients treated for Hodgkin’s disease [ 7,9,16-201. These patients have generally received doses of radiation in the range of 3,000 to 4,000 rads given in multiple fractions over three to four weeks. In contrast, our patients received a single dose of 750 rads, given at 26 rads/min. Despite the large difference in total dose received, the incidence of thyroid dysfunction, the type of abnormalities, and the interval from treatment to appearance of the abnormal studies are remarkably similar in the two radiation regimens. We noted that evidence of impaired thyroid function developed in 43 percent of our irradiated patients after a median follow-up perlod of 32 months (Figure 1). Compensated hypothyroidism was present in 35 percent, while primary thyroid failure developed in an additional 8 percent. The majority of abnormalities appeared to develop during the first two years after bone marrow transplantation, but there was a suggestion of a continued increase over time. The overall incidence of abnormal thyroid function among Hodgkin’s patients has ranged between 31 percent and 9 1 percent [ 7,9,16-201. Compensated hypothyroidism has occurred in 25 percent to 53 percent of patients, while primary thyroid failure is seen in 0 to 58 percent. The majority of abnormalities in the .Hodgkin’s patients have been noted to develop in the first two years after radiation [7], but the percentage of affected patients appear to increase with time, with new cases appearing as late as six years after irradiation [9]. Taking into account the fact that the majority of the latter studies encompassed a much longer period of follow-up than our present study, the incidence of thyroid dysfunction would appear to be nearly identical in the two groups. Thus, single-dose irradiation, when given with highdose, short-term chemotherapy, seems to be equivalent to a total dose of radiation four to five times larger when it is delivered in conventional fractions, at least in terms of toxicity to the normal thyroid. This conclusion corroborates the data from animal experiments and the limited data in human beings that have demonstrated that the biologic effect of radiation on normal tissues is directly related to dose per fraction

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and dose rate, but inversely related to the number of fractions and the overall treatment time [21-231. In analyzing our data, we examined several variables that have been previously noted to affect radiationinduced thyroid dysfunction. We were unable to demonstrate any influence of age at the time of treatment on the subsequent development of hypothyroidism. Although some investigators have shown that younger patients were more susceptible to the damaging effects of radiation [ 7,171, others have not [9,18]. The most striking differences have been noted when one compares patients treated prior to age 20 years to those older than 20 years at the time of irradiation [ 71. Since almost all of the subjects in the present series were less than 20 years of age when exposed to radiation, it is not surprising that we could not find a relationship between age and the development of thyroid abnormalities. An unexpected finding from the present study was the difference noted between the two graft-versus-host disease prophylaxis regimens. The data indicate a significantly lower incidence of thyroid hypofunction among the irradiated patients given antithymocyte globulin and prednisone in addition to methotrexate when compared to the methotrexateonly treated group. Since the groups did not differ in age at treatment, sex ratio, incidence of graft-versus-host disease, type of radiation, underlying disease, or length of follow-up, either antithymocyte globulin or prednisone, or both, would appear in some manner to protect the thyroid from radiation-induced damage. As both these agents have potent immunosuppressive properties [24,25], interference with some immunologically-mediated thyroidotoxic phenomena could explain the differences noted. This explanation, however, seems unlikely in light of the fact that none of the 10 patients with abnormal thyroid studies had detectable titers of either antithyroglobulin or antimicrosomal antibodies in their sera. Furthermore, review of histologic sections of the thyroid obtained at autopsy from a group of 12 patients who died following bone marrow transplantation failed to reveal any evidence of lymphocytic infiltration or inflammatory response, regardless of the type of graftversus-host disease prophylaxis employed (Burke B, Sklar C, Ramsay NKC, unpublished data). The exact mechanism and significance of the putative salutary

AFTER

BONE

MARROW

TRANSPLANTATION--SKLAR

ET AL.

effect of antithymocyte globulin and/or prednisone on thyroid function must await future studies. Our preliminary data regarding the natural history of thyroid dysfunction following bone marrow transplantation deserve further comment. Although the majority of patients have manifested only minor eilevations in thyroid-stimulating hormone levels while maintaining normal circulating levels of thyroxine, these abnormalities seem to persist in most instances. Only one patient has clearly reverted to a normal state. The fact that the one patient who had compensated hypothyroidism at 41 months after bone marrow transplantation and then had primary thyroid failure at 50 months, suggests that the damage sustained is progressive in some cases. Thus, our present data indicate that in the majority of patients, abnormal thyroid studies do not appear to be transient; therefore, institution of thyroid replacement therapy would seem warranted in all patients who manifest elevated thyroid-stimulation hormone values. We wish to emphasize that hypothyroidjsm as a sequela of radiation therapy is often quite subtle and difficult to detect clinically. This fact has been noted by other investigators [ 9,161 and is further supported by the lack of symptoms in our patients, including the two patients with primary thyroid failure. Therefore, we strongly recommend serial screening of thyroid function as part of the routine follow-up of all patients previously treated with radiation therapy for bone marrow transplantation. This is especially critical in the young, since hypothyroidism when undiagnosed and untreated can lead to growth failure and delayed development in children, symptoms that could be mistakenly attributed to the direct effect of radiation therapy on growing bones [26] and the nonspecific deleterious consequence of chronic illness. ACKNOWLEDGMENT

We gratefully acknowledge Mark Nesbit, M.D., for his invaluable help in the preparation of the manuscript, Les Robison, Ph.D., for performing the statistical analyses, Jeffrey Williamson, M.S., for help with the radiation dosimetry, Sharon Roell, R.N., for assistance in data collection, and Ms. Sheryl Frankel for her secretarial assistance.

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