Radiotherapy and Oncology, Suppl. 1 (1990) 82-87 Elsevier
Late effects in children receiving total body irradiation for bone marrow transplantation Jean E. Sanders Fred Hutchinson Cancer Research Center, Children’s Hospital and Medical Center, Departments of Medicine and Pediatrics, Universityof WashingtonSchool of Medicine, Seattle, Washington, U.S.A.
Keywords: Marrow transplant; Late effects; Delayed growth and development; Second malignancies
Summary Bone marrow transplantation is a life-saving procedure for an increasing number of children and young adults. As greater number of patients continue to receive this procedure and are cured of their underlying hematologic disorder, greater attention must be given to the delayed effects, especially those which do not appear until years after the transplant procedure. Children who are cured of their underlying disease continue to visit the hematologist/oncologist, but with decreasing frequency as time increases following the curative therapy, and at the same time increase the relative frequency of visits to their pediatrician. Thus, it is imperative that the primary care pediatrician be aware of the details of the patient’s previous medical history, especially of chemotherapy and irradiation therapy which may have been given, in order to anticipate the delayed effects. Early diagnosis of thyroid and GH deficiencies with institution of appropriate hormone therapy may prevent subsequent development of thyroid malignancy and may improve the child’s growth and development. Recognition of cataracts and dry eye syndrome is necessary to prevent visual difficulties. Careful oral examination and attention to the child’s general neurological presentation and inquiry regarding school performance is important in recognising dental difficulties, learning difficulties and early recognition of development of tumors of the head and neck. Attention to details, early recognition of problems and early therapy of the problems is needed to improve the quality of life for these unique patients.
Introduction During the past two decades, advances in immunobiology, histocompatibility testing, immunosuppressive therapy and supportive care have resulted in improvements in the survival of bone marrow transplant recipients. As a result this technique is being incorporated into the therapeutic management plan for an ever increasing number of children with hematologic malignancies, selected solid tumors and some non-malignant hematologic disorders [l]. For some patients, marrow transplantation offers improved disease-free survival compared to conventional therapy, and represents the only possible cure for patients who have failed conventional treatment [20]. As the use of autologous marrow increases and the pool of suitable marrow donors expands to include partially HLA matched related individuals and fully matched 0167-8140/90/$03.50
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
83
or partially matched unrelated individuals, the application of this procedure will include an even larger number of patients. Thus, there will continue to be increasing numbers of long-term survivors. Marrow transplant preparatory regimens are associated with both acute and delayed toxicities. The regimens are designed to suppress the patient’s immune system and to eradicate the underlying hematologic and/or malignant disorder [21]. The most frequently used regimen for patients with malignancy includes high-dose chemotherapy, usually cyclophosphamide (CY), which may be given with other chemotherapy agents and/or in combination with total body irradiation (TBI). Patients with non-malignant hematologic disorders usually receive CY alone or combination with busulphan (BU) [9,14]. Since all patients are given an infusion of marrow, the doses of the agents administered are not limited by marrow toxicity. The transplant preparative regimens, however, are associated with other non-marrow toxicities which may occur early or late. This article will discuss the major late effects which may occur months to years after the transplant procedure. These late effects may be related to the transplant procedure itself, to the patient’s original disease, or to the transplant preparative regimen. Only those late effects which may be related to the transplant preparative regimen will be discussed.
Neuroendocrine
function
Thyroid function
Children who received a transplant preparative regimen of chemotherapy only have an incidence of thyroid function abnormalities which is not greater than normally observed among non-transplant children [ 151. However, an increased incidence of decreased thyroid function has been observed among children evaluated after a preparative regimen containing TBI [ 15,161. Among those who receive 10.0 Gy single exposure TBI, 28-56% had compensated hypothyroidism (elevated TSH and normal T4) and 13% had overt hypothyroidism. Patients who received fractionated TBI had 12-21% with compensated hypothyroidism and 3% with overt hypothyroidism. Longer follow-up is needed to determine if these differences are real since those who received single exposure TBI have been observed for a median time of 9 years and those who received fractionated TBI have been followed for a median of 5 years. Growth
Children who have received transplant preparative regimens containing CY only have normal growth rates, but young patients who received regimens containing TBI have decreased growth velocity rates [15]. Subnormal growth hormone (GH) levels have been noted in 87% who received both previous cranial irradiation and TBI whereas only 42% had low GH levels when only TBI had been given [16]. Treatment with GH supplementation has resulted in some improvement in height, but the amount of height velocity increase has been less than the response usually seen in non-irradiated GH deficient children. Puberty
In general, all patients who received CY only preparative regimen have normal development through puberty with appearance of secondary sexual characteristics at a normal age [15]. Their gonadotropin levels and sex hormone levels were also normal. Nearly all patients who received a preparative regimen containing 1.0 Gy single exposure TBI had delayed onset of puberty and gonadotropin levels reflected primary gonadal failure. These patients required the addition of appropriate sex hormone supplements to
84 promote pubertal development. Among the children who received preparative regimens containing fractionated TBI, nearly half have normal pubertal development and normal gonadotropin levels. Fertility
All women who were post-pubertal at time of transplant developed amenorrhea for some time after transplant 1171. Women who were less than 26 years of age and who received a preparative regimen of CY only had ovarian function recovery between 3 and 42 months (median 6 months), but the majority of women older than 26 years developed primary ovarian failure. Those who have ovarian function recovery may be fertile and 10 women have had 13 pregnancies which resulted in the birth of 9 normal children. In contrast, after preparative regimens containing TBI, the majority of women have developed primary ovarian failure. Most have symptoms of menopause which respond to treatment with cyclic hormones. A rare woman (5 of 139) has had ovarian function recovery occur between 3 and 7 years after TBI. Four of these 5 have become pregnant, but only one has delivered a normal child. After preparative regimens of CY only, most men recover normal testicular function. They have normal gonadotropin and testosterone levels and spermatogenesis [ 181. Recovery does not appear to be related to patient age. The men who have normal testicular function after CY are also fertile, with 10 known to have fathered 11 normal children. Most adult male patients prepared with TBI containing regimens have preservation of Leydig cell function with normal testosterone and normal serum luteinizing hormone. Sertoli cell function is usually abnormal and spermatogenesis is absent. A rare patient has recovered sperm production after 6 years, and only one man has fathered 3 children.
Ophthalmologic
abnormalities
Cataracts are a recognised complication of exposure to long-term steroid therapy as well as to ionizing irradiation. Following 10.0 Gy single exposure TBI, posterior subcapsular cataracts have occurred in 80% of patients, but after 12.0-15.75 Gy fractionated exposure TBI cataracts have occurred in only 20% [5]. Nearly all patients who develop cataracts after single exposure TBI will need to have the cataracts removed, whereas after fractionated TBI only 20% have required cataract removal. All patients who have received TBI should be evaluated for development of dry eye syndrome [7]. While the majority of patients with this problem have chronic GVHD, some do not. The development of mild to severe comeal stippling and ulcers can be prevented with use of artificial tears or other ocular lubricants.
Dental abnormalities Irradiation given to growing bones results in epiphyseal, metaphyseal and diaphyseal injury which effects subsequent bone growth [12]. The severity of the effect increases with greater irradiation doses, lengthening time after irradiation and younger age at irradiation. Dental abnormalities have been described in children who received 18.0-65.0 Gy maxillofacial irradiation for treatment of lymphoma, leukemia or solid tumors [8]. These abnormalities included foreshortening and blunting of the roots, incomplete calcification, premature closure of the apices, delayed or arrested tooth development and caries. Other problems observed have included hismus, abnormal occlusal relationships, bimaxillary micrognathia and hypoplastic mandible. Children given 10.0 Gy TBI for marrow transplantation have developed similar disturbances in dental development and facial growth [4]. Those who were less than 6
85 years of age at time of TBI all had arrested root development, premature apical closure, enamel hypoplasia and microdontia. Children over 7 years of age usually had only arrested root development. Vertical development of the lower third of the face was the most severely affected area of facial growth.
Central nervous system abnormalities Following cranial irradiation and/or intrathecal medications, central nervous system (CNS) structural changes and functional disturbances have been noted [l]. The structural CNS changes, such as ventricular dilatation, calcifications and focal white matter hypodensity, have been seen on both CT and MRI scans. The significance of many of these changes has not yet been defined, but ventricular dilatation has been correlated with deficits in verbal fluency, hypothalamic-pituitary dysfunction and memory loss [2]. Neuropsychological deficits have been observed among children surviving long-term after treatment for acute leukemia [ 10,131. CNS irradiation has been implicated as the most likely causative agent, with the age of the patient at time of treatment and the length of time after treatment also being important factors. Children who were less than 8 years of age at time of irradiation had lower I.Q. scores, performed less well with visual-motor, fine motor, abstract thinking and spatial processing tasks. To date, no studies have been reported from the marrow transplant population, but it may be anticipated that these children are at risk for development of neuropsychologic deficits.
Secondary malignancies Multiple factors most likely contribute to the development of secondary malignancies. Following curative therapy for childhood acute leukemias and lymphomas both multiagent chemotherapy and irradiation have been implicated [l 11.Studies in allogeneic transplant murine models suggest that GVHD may also be a causative factor [6]. Secondary malignancies have been observed in man after marrow transplantation. A recent analysis of more than 2,000 marrow transplant recipients demonstrated that among the 35 patients who developed secondary malignancies, the major risk factors were related to GVHD immunosuppressive therapy and TBI [22].
Pulmonary
dysfunction
Late interstitial pneumonia has been observed in patients with chronic GVHD [19]. These episodes, occurring in 15% of patients, were either of viral or pneumocystis etiology or were idiopathic. Use of prophylactic trimethoprim-sulfamethoxazole decreased the overall incidence of these pneumonias. Sequential pulmonary function studies in long term survivors more than 8 years of age and more than one year after TBI, has demonstrated the development of both restrictive and obstructive changes [3]. The obstructive lung disease often becomes clinically manifested from 6-12 months after transplant. The major risk factor for this in adult patients was presence of chronic GVHD and was not related to type of TBI administered.
86 Acknowledgemenb This investigation was supported by PHS grant Numbers HL 36444 awarded by the National Heart, Lung and Blood Institute, CA 18029, CA 15704 and CA 18221 awarded by the National Cancer Institute, DHHS.
References 1. Bortin, M.M. and Rimm, A. Increasing utilization of bone marrow transplantation. Transplantation, 42,229-234, 1986. 2. Brouwers, P., Riccatdi, K., Poplack, D.G. and Ferdo, P; Additional deficits in long-term survivors of childhood acute lymphoblastic leukemia. J. Clin. Neurophysiol., 6, 235-336, 1984. 3. Clark, J.G., Crawford, SW., Madtes, D.K. and Sullivan, K.M. Obstructive lung disease after allogeneic marrow transplantation: Clinical presentation and course. Ann. Intern. Med., 111, 368-376, 1989. 4. Dahlltif, G., Barr, M., Bolme, P., Modeer, T., LXinnqvist, B., Ringden, 0. and Heimdahl. A. Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral. Surg. Oral Med. Oral Pathol., 65, 41-44, 1988. 5. Deeg, H.J., Floumoy, N., Sullivan, K.M., Sheehan, K., Buckner, C.D., Sanders, J.E., Storb, R., Witherspoon, R.P. and Thomas, E.D. Cataracts after total body irradiation and marrow transplantation: A sparing effect of dose fractionation. Int. J. Radiat. Oncol. Biol. Phys., 10, 957-964, 1984. 6. Gleichmann, E., Gleichmamr, H., Schwartz, R.S. Immunologic induction of malignant lymphoma. Identification of donor and host tumors in the graft-versus-host model. J. Natl. Cancer Inst., 54, 107-116, 1975. 7. Jack, M.J. and Hicks, J.D. Ocular complications in high-dose chemoradiotherapy and marrow transplantation. Ann. Ophthalmol., 13, 6,709-711, 1981. 8. Jaffe, N., Toth, B.B., Hoar, R.E., Ried, H.L., Sullivan, M.P. and McNeese, M.D. Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: Effects of treatment with chemotherapy and radiation to the head and neck. Pediatrics, 73, 816-823, 1984. 9. Lucatelli, G., Polchi, P., Izxi, T., Manna, M., Agostinelii, F., Delfini, C., Porcellini, A., Galimberti, M., Motetti, L., Manna, A., Sparaventi, G., Baronciani, D., Proietti, A. and Bucker, C.D. Allogeneic marrow transplantation for thalassemia. Exp. Hematol., 12, 676-681, 1984. 10. Mulhem, R.K., Wasserman, A.L.. Fairclough, D. and Ochs, J. Memory function in disease-free survivors of childhood acute lymphocyte leukemia given CNS prophylaxis with or without 1,800 cGy cranial irradiation. J. Clin. Oncol., 6, 315-320, 1988. 11. Ochs, J. and Mulhem, R.K. Late effects of antileukemic treatment. Pediatr. Clin. North Am., 35, 815-833, 1988. 12. Probert, J.C. and Parker, B.R. The effects of radiation therapy on bone growth. Radiology, 114, 155-162, 1975. 13. Robinson, L.L., Nesbit Jr, M.E., Sather, H.N., Meadows, A.T., Ortega, J.A. and Hammond, G.D. Factors associated with IQ scores in long-term survivors of childhood acute lymphoblastic leukemia. Am. J. Pediatr. Hematol. Oncol., 6, 115-121, 1984. 14. Sanders, J.E., Whitehead, J,., Storb, R., Buckner, C.D., Clift, R.A., Mickelson, E., Appelbaum, F.R., Bensinger, W.I., Stewart, P.S., Doney, K., Sullivan, K., Deeg, H.J., Witherspoon, R.P. and Thomas, E.D. Bone marrow transplantation experience for children with aplastic anemia. Pediatrics, 77, 179-186, 1986. 15. Sanders, J.E., Buckner, C.D., Sullivan, K.M., Doney, K., Apppelbaum, F., Witherspoon, R., Anasetti, C., Storb, R. and Thomas, E.D. Growth and development after bone marrow transplantation. In: C.D. Buckner, R.P. Gale and G. Lucarelli teds.), Advances and Controversies in Thalassemia Therapy: Bone Marrow Transplantation and Other Approaches. New York, Alan R. Liss, Inc., pp. 375-382, 1989. 16. Sanders, J.E., Pritchard, S., Mahoney, P., Amos, D., Buckner, CD., Witherspoon, R.P., Deeg, H.J., Doney, K.C., Sullivan, K.M., Appelbaum, F.R., Storb. R. and Thomas, E.D. Growth and development following marrow transplantation for leukemia. Blood, 68, 1129-1135, 1986. 17. Sanders, J.E., Buckner, C.D., Amos, D., Levy, W., Appelbaum, F.R., Doney, K., Storb, R., Sullivan, K.M., Witherspoon, R.P. and Thomas, E.D. Ovarian function following marrow transplantation for aplastic anemia or leukemia. J. Clin. Oncol., 6, 813-818, 1988. 18. Sanders, J.E., Buckner, C.D., Leonard, J.M., Sullivan, K.M., Witherspoon, R.P., Deeg, H.J., Storb, R. and Thomas, E.D. Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation. Transplantation, 36, 252-255, 1983. 19. Sullivan, K.M. and Shulman, H.M. Chronic graft-versus-host disease, obliterative bronchiolitis, and graft-versus-leukemia effect: Case histories. Transpl. Proc., 21, 51-62, 1989. 20. Thomas, E.D. Bone marrow transplantation: Past, present and future. Seminars in Hematol., in press.
87 21. Thomas, E.D., Storb, R., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Lemer, K.G., Glucksberg, H. and Buckner, CD. Bone-marrow transplantation. N. Engl. J. Med., 292, 832-843 & 895-902, 1975. 22. Witherspoon, R.P., Fisher, L.D., Schoch, G., Martin, P., Sullivan, K.M., Sanders, J., Deeg, H.J., Doney, K., Thomas, D., Storb, R. and Thomas, E.D. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N. Engl. J. Med., 321, 784-789, 1989. For: Proceedings of the International Meeting on Physical, Biological and Clinical Aspects of Total Body Irradiation, The Hague, Netherlands. September 7-9, 1988.
Late effects in children receiving total body irradiation for bone marrow transplantation Jean E. Sanders Fred Hutchinson Cancer Research Center, Children’s Hospital and Medical Center, Departments of Medicine and Pediatrics, Universityof WashingtonSchool of Medicine, Seattle, Washington, U.S.A.
Keywords: Marrow transplant; Late effects; Delayed growth and development; Second malignancies
Summary Bone marrow transplantation is a life-saving procedure for an increasing number of children and young adults. As greater number of patients continue to receive this procedure and are cured of their underlying hematologic disorder, greater attention must be given to the delayed effects, especially those which do not appear until years after the transplant procedure. Children who are cured of their underlying disease continue to visit the hematologist/oncologist, but with decreasing frequency as time increases following the curative therapy, and at the same time increase the relative frequency of visits to their pediatrician. Thus, it is imperative that the primary care pediatrician be aware of the details of the patient’s previous medical history, especially of chemotherapy and irradiation therapy which may have been given, in order to anticipate the delayed effects. Early diagnosis of thyroid and GH deficiencies with institution of appropriate hormone therapy may prevent subsequent development of thyroid malignancy and may improve the child’s growth and development. Recognition of cataracts and dry eye syndrome is necessary to prevent visual difficulties. Careful oral examination and attention to the child’s general neurological presentation and inquiry regarding school performance is important in recognising dental difficulties, learning difficulties and early recognition of development of tumors of the head and neck. Attention to details, early recognition of problems and early therapy of the problems is needed to improve the quality of life for these unique patients.
Introduction During the past two decades, advances in immunobiology, histocompatibility testing, immunosuppressive therapy and supportive care have resulted in improvements in the survival of bone marrow transplant recipients. As a result this technique is being incorporated into the therapeutic management plan for an ever increasing number of children with hematologic malignancies, selected solid tumors and some non-malignant hematologic disorders [l]. For some patients, marrow transplantation offers improved disease-free survival compared to conventional therapy, and represents the only possible cure for patients who have failed conventional treatment [20]. As the use of autologous marrow increases and the pool of suitable marrow donors expands to include partially HLA matched related individuals and fully matched 0167-8140/90/$03.50
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
83
or partially matched unrelated individuals, the application of this procedure will include an even larger number of patients. Thus, there will continue to be increasing numbers of long-term survivors. Marrow transplant preparatory regimens are associated with both acute and delayed toxicities. The regimens are designed to suppress the patient’s immune system and to eradicate the underlying hematologic and/or malignant disorder [21]. The most frequently used regimen for patients with malignancy includes high-dose chemotherapy, usually cyclophosphamide (CY), which may be given with other chemotherapy agents and/or in combination with total body irradiation (TBI). Patients with non-malignant hematologic disorders usually receive CY alone or combination with busulphan (BU) [9,14]. Since all patients are given an infusion of marrow, the doses of the agents administered are not limited by marrow toxicity. The transplant preparative regimens, however, are associated with other non-marrow toxicities which may occur early or late. This article will discuss the major late effects which may occur months to years after the transplant procedure. These late effects may be related to the transplant procedure itself, to the patient’s original disease, or to the transplant preparative regimen. Only those late effects which may be related to the transplant preparative regimen will be discussed.
Neuroendocrine
function
Thyroid function
Children who received a transplant preparative regimen of chemotherapy only have an incidence of thyroid function abnormalities which is not greater than normally observed among non-transplant children [ 151. However, an increased incidence of decreased thyroid function has been observed among children evaluated after a preparative regimen containing TBI [ 15,161. Among those who receive 10.0 Gy single exposure TBI, 28-56% had compensated hypothyroidism (elevated TSH and normal T4) and 13% had overt hypothyroidism. Patients who received fractionated TBI had 12-21% with compensated hypothyroidism and 3% with overt hypothyroidism. Longer follow-up is needed to determine if these differences are real since those who received single exposure TBI have been observed for a median time of 9 years and those who received fractionated TBI have been followed for a median of 5 years. Growth
Children who have received transplant preparative regimens containing CY only have normal growth rates, but young patients who received regimens containing TBI have decreased growth velocity rates [15]. Subnormal growth hormone (GH) levels have been noted in 87% who received both previous cranial irradiation and TBI whereas only 42% had low GH levels when only TBI had been given [16]. Treatment with GH supplementation has resulted in some improvement in height, but the amount of height velocity increase has been less than the response usually seen in non-irradiated GH deficient children. Puberty
In general, all patients who received CY only preparative regimen have normal development through puberty with appearance of secondary sexual characteristics at a normal age [15]. Their gonadotropin levels and sex hormone levels were also normal. Nearly all patients who received a preparative regimen containing 1.0 Gy single exposure TBI had delayed onset of puberty and gonadotropin levels reflected primary gonadal failure. These patients required the addition of appropriate sex hormone supplements to
84 promote pubertal development. Among the children who received preparative regimens containing fractionated TBI, nearly half have normal pubertal development and normal gonadotropin levels. Fertility
All women who were post-pubertal at time of transplant developed amenorrhea for some time after transplant 1171. Women who were less than 26 years of age and who received a preparative regimen of CY only had ovarian function recovery between 3 and 42 months (median 6 months), but the majority of women older than 26 years developed primary ovarian failure. Those who have ovarian function recovery may be fertile and 10 women have had 13 pregnancies which resulted in the birth of 9 normal children. In contrast, after preparative regimens containing TBI, the majority of women have developed primary ovarian failure. Most have symptoms of menopause which respond to treatment with cyclic hormones. A rare woman (5 of 139) has had ovarian function recovery occur between 3 and 7 years after TBI. Four of these 5 have become pregnant, but only one has delivered a normal child. After preparative regimens of CY only, most men recover normal testicular function. They have normal gonadotropin and testosterone levels and spermatogenesis [ 181. Recovery does not appear to be related to patient age. The men who have normal testicular function after CY are also fertile, with 10 known to have fathered 11 normal children. Most adult male patients prepared with TBI containing regimens have preservation of Leydig cell function with normal testosterone and normal serum luteinizing hormone. Sertoli cell function is usually abnormal and spermatogenesis is absent. A rare patient has recovered sperm production after 6 years, and only one man has fathered 3 children.
Ophthalmologic
abnormalities
Cataracts are a recognised complication of exposure to long-term steroid therapy as well as to ionizing irradiation. Following 10.0 Gy single exposure TBI, posterior subcapsular cataracts have occurred in 80% of patients, but after 12.0-15.75 Gy fractionated exposure TBI cataracts have occurred in only 20% [5]. Nearly all patients who develop cataracts after single exposure TBI will need to have the cataracts removed, whereas after fractionated TBI only 20% have required cataract removal. All patients who have received TBI should be evaluated for development of dry eye syndrome [7]. While the majority of patients with this problem have chronic GVHD, some do not. The development of mild to severe comeal stippling and ulcers can be prevented with use of artificial tears or other ocular lubricants.
Dental abnormalities Irradiation given to growing bones results in epiphyseal, metaphyseal and diaphyseal injury which effects subsequent bone growth [12]. The severity of the effect increases with greater irradiation doses, lengthening time after irradiation and younger age at irradiation. Dental abnormalities have been described in children who received 18.0-65.0 Gy maxillofacial irradiation for treatment of lymphoma, leukemia or solid tumors [8]. These abnormalities included foreshortening and blunting of the roots, incomplete calcification, premature closure of the apices, delayed or arrested tooth development and caries. Other problems observed have included hismus, abnormal occlusal relationships, bimaxillary micrognathia and hypoplastic mandible. Children given 10.0 Gy TBI for marrow transplantation have developed similar disturbances in dental development and facial growth [4]. Those who were less than 6
85 years of age at time of TBI all had arrested root development, premature apical closure, enamel hypoplasia and microdontia. Children over 7 years of age usually had only arrested root development. Vertical development of the lower third of the face was the most severely affected area of facial growth.
Central nervous system abnormalities Following cranial irradiation and/or intrathecal medications, central nervous system (CNS) structural changes and functional disturbances have been noted [l]. The structural CNS changes, such as ventricular dilatation, calcifications and focal white matter hypodensity, have been seen on both CT and MRI scans. The significance of many of these changes has not yet been defined, but ventricular dilatation has been correlated with deficits in verbal fluency, hypothalamic-pituitary dysfunction and memory loss [2]. Neuropsychological deficits have been observed among children surviving long-term after treatment for acute leukemia [ 10,131. CNS irradiation has been implicated as the most likely causative agent, with the age of the patient at time of treatment and the length of time after treatment also being important factors. Children who were less than 8 years of age at time of irradiation had lower I.Q. scores, performed less well with visual-motor, fine motor, abstract thinking and spatial processing tasks. To date, no studies have been reported from the marrow transplant population, but it may be anticipated that these children are at risk for development of neuropsychologic deficits.
Secondary malignancies Multiple factors most likely contribute to the development of secondary malignancies. Following curative therapy for childhood acute leukemias and lymphomas both multiagent chemotherapy and irradiation have been implicated [l 11.Studies in allogeneic transplant murine models suggest that GVHD may also be a causative factor [6]. Secondary malignancies have been observed in man after marrow transplantation. A recent analysis of more than 2,000 marrow transplant recipients demonstrated that among the 35 patients who developed secondary malignancies, the major risk factors were related to GVHD immunosuppressive therapy and TBI [22].
Pulmonary
dysfunction
Late interstitial pneumonia has been observed in patients with chronic GVHD [19]. These episodes, occurring in 15% of patients, were either of viral or pneumocystis etiology or were idiopathic. Use of prophylactic trimethoprim-sulfamethoxazole decreased the overall incidence of these pneumonias. Sequential pulmonary function studies in long term survivors more than 8 years of age and more than one year after TBI, has demonstrated the development of both restrictive and obstructive changes [3]. The obstructive lung disease often becomes clinically manifested from 6-12 months after transplant. The major risk factor for this in adult patients was presence of chronic GVHD and was not related to type of TBI administered.
86 Acknowledgemenb This investigation was supported by PHS grant Numbers HL 36444 awarded by the National Heart, Lung and Blood Institute, CA 18029, CA 15704 and CA 18221 awarded by the National Cancer Institute, DHHS.
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