The cell surface receptor encoded by the proto-oncogene KIT and its ligand.
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Animals↗
Biomedical subjects
M D Minden
Publications and source records attributed to M D Minden.
Differential sensitivity of human myeloma cell lines and normal bone marrow colony forming cells to a recombinant diphtheria toxin-interleukin 6 fusion protein.
The cytotoxicity of a recombinant interleukin 6 (IL-6)-diphtheria toxin (DT) fusion protein towards human myeloma cell lines was investigated. DAB389-IL-6 inhibited protein synthesis and methylcellulose colony formation by U266 myeloma cells. In the clonogenic assay, the fusion protein approached the level of cytotoxicity achieved by native DT. The specificity of killing by DAB389-IL-6 was demonstrated by inhibition of cytotoxicity by a molar excess of free rhIL-6. The effect of DAB389-IL-6 on colony formation by six OCI-My cell lines was assessed. Similar to U266 cells, colony growth by the OCI-My 5 and -My 2 cell lines was inhibited in a simple dose dependent manner. However, a biphasic effect was observed for the IL-6 dependent OCI-My 4 cells; DAB389-IL-6 stimulated colony formation at low (< or = 10(-11) M) concentrations, yet was inhibitory at higher doses. Three other cell lines whose growth was not altered by IL-6 were relatively unaffected by DAB389-IL-6, despite their sensitivity to native DT. Flow cytometric analysis for IL-6 receptor expression using phycoerythrin-conjugated IL-6 demonstrated specific binding sites on both DAB389-IL-6 sensitive and certain insensitive cell lines, suggesting that other factors in addition to the expression of IL-6 receptors are involved in killing by the fusion toxin. Despite evidence for a role of IL-6 in myeloid cell development, normal bone marrow was insensitive to the IL-6 fusion toxin. In cultures containing both normal bone marrow and U266 cells DAB389-IL-6 effectively inhibited the growth of U266 myeloma colonies but had little effect on normal bone marrow erythroid, granulocyte and mixed erythroid/granulocyte colony growth. From these experiments we conclude that DAB389-IL-6 is specifically cytotoxic towards a subset of IL-6-responsive human myeloma cell lines and may be useful, in some cases, in the selective elimination of tumour cells from mixed populations of normal and malignant cells.
Cells, Cultured↗
Cytotoxicity of a recombinant diphtheria toxin-granulocyte colony-stimulating factor fusion protein on human leukemic blast cells.
Granulocyte colony-stimulating factor (G-CSF) is a potent stimulator of the growth of normal and malignant hematopoietic cells and synergizes with other factors such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The action of G-CSF is mediated through a specific membrane receptor, however it is not clear if all of the effects of G-CSF are direct or indirect. As a step towards addressing this problem, a recombinant diphtheria toxin (DT)-related human G-CSF fusion protein has been constructed and purified from E. coli. The 70,000 dalton chimeric protein has immunologic determinants characteristic of both DT and G-CSF. At high concentrations, DAB486-G-CSF is cytotoxic towards G-CSF-dependent OCI/AML1 cells, but not factor independent OCI/AML3 cells; colony formation by G-CSF-responsive leukemic blasts from a patient with acute myeloblastic leukemia (AML) was also inhibited. The G-CSF fusion toxin displayed ADP-ribosyltransferase activity in a cell-free system. Genetic conjugation of G-CSF to an enzymatically inactive DT mutant, CRM197, resulted in a 200-fold reduction in the ability of G-CSF to stimulate normal bone marrow colony formation. These results suggest that fusion of G-CSF to DT sequences interferes with some of the activity but not the specificity of the ligand binding domain of the molecule. Nevertheless, DAB486-G-CSF may be included with the increasing number of other toxin-hormone fusion proteins whose toxicity is directed towards specific receptor-bearing cells, and may represent a novel approach towards the study and treatment of leukemia.
ADP Ribose Transferases↗
Influence of schedule on regulated sensitivity of AML blasts to cytosine arabinoside.
Regulatory molecules that affect the growth culture of blast cells from acute myeloblastic leukemia (AML) may also alter drug sensitivity, a phenomenon that may be called regulated drug sensitivity. Previous studies have shown: (i) blast cells exposed to retinoic acid before cytosine arabinoside (Ara-C) usually show increased sensitivity, but after some retinoic acid exposure times, sensitivity may be decreased; (ii) factor-sensitive or responsive blasts cultured with granulocyte colony-stimulating factor (G-CSF) are regularly more Ara-C-sensitive than when cultured with granulocyte-macrophage CSF (GM-CSF). This paper is concerned with the effects of schedule on drug sensitivity as regulated by either retinoic acid or the myelopoietic growth factors, G-CSF and GM-CSF. We measured the effects of retinoic acid on the sensitivity of blasts cells from the two continuous AML lines to Ara-C or arabinofuranosyl 5-azacytosine (Ara-AC). Cells from seven patients with AML were tested for Ara-C sensitivity in conjunction with retinoic acid. The cells were treated with retinoic acid before or after administration of the drug. Both increases and decreases in Ara-C sensitivity were seen for both schedules. Consistent increases in Ara-C sensitivity were obtained when retinoic acid was included in the methylcellulose cultures used to determine clonogenic cell recovery at each drug dose. In studies of growth factors, a single factor-dependent cell line (OCI/AML-5) was used to compare the effects of G-CSF and GM-CSF on Ara-C sensitivity. An experimental design was used that permitted factors to present in culture for 24 h before Ara-C, during the next 24 h period with the drug, for a subsequent day in suspension without drug, and during the 5-7 days required for colony formation in methylcellulose cultures. G-CSF and GM-CSF were most effective in increasing or decreasing Ara-C, respectively, when the factor under test was included in the methylcellulose cultures. Thus, like retinoic acid, growth factors influenced drug sensitivity when they were present after the drug had been removed. These data, therefore, are compatible with the hypothesis that repair mechanism may contribute to regulated drug sensitivity.
Acute Disease↗
Treatment of adults with severe aplastic anemia: primary therapy with antithymocyte globulin (ATG) and rescue of ATG failures with bone marrow transplantation.
PURPOSE: To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. PATIENTS AND METHODS: Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. RESULTS: Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. CONCLUSIONS: This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy.
Adolescent↗
A human lymphoma cell line with multiple immunoglobulin rearrangements.
The development of a cell culture system efficient in the establishment of lymphoma cell lines has made it possible to dissect basic biological and molecular aspects of lymphoma cells. We have established a lymphoma cell line from a patient with B cell lymphoma. The cell line has a complex karyotype with translocations involving bands 8q24, 14q32, and 18q21. Molecular analysis revealed that the Myc gene was rearranged; we were unable to demonstrate rearrangement of the Bcl-2 gene. Evaluation of the structure of the heavy chain Ig genes revealed that the cell line carried the same rearrangements as the cells from which the cell line was derived. The pattern of rearrangement, however, was unusual in that there were at least four rearranged bands when DNA cut with HindIII was probed with a fragment of the heavy chain joining region. To further characterize the cell line, subclones were derived. Individual subclones had the same pattern of rearrangement as the parent cell line. The results of these studies provide evidence that multiple rearranged Ig genes may be present in a single clone of cells.
Gene Rearrangement↗
Constitutive production of the interleukins IL-5 and IL-6 by the lymphoma cell line OCI-Ly 17 derived from a patient with malignant lymphoma and hypereosinophilia.
Peripheral blood cells of a patient with diffuse large cell non-Hodgkin's lymphoma presenting with hypereosinophilia were used to establish an EBV negative lymphoma cell line termed OCI-Ly17. Cells of the line stained positive for CD2 and CD5 determinants and demonstrated rearrangement of the T-cell receptor beta chain. The immunoglobulin heavy chain gene was found to be in germ line configuration. Northern blot studies using probes for IL-1 alpha, IL-3, IL-4, IL-5, IL-6, and GM-CSF showed message for IL-5 and IL-6. Supernatants of the cell line were evaluated on normal non-adherent, E-rosette depleted bone marrow cells to determine the presence of growth promoting activities for clonogenic eosinophilic progenitors. Eosinophilic colonies were observed. Their frequency depended upon the amount of supernatant added to the cultures. The growth promoting activity in the supernatant was reduced in a dose dependent manner by preincubation with increasing concentrations of anti-IL-5 antibodies. The supernatants of the cell line were also tested on the IL-6 sensitive human myeloma line OCI-My4 and myeloma colonies grew in response. This stimulatory activity within the supernatant was neutralized by addition of increasing concentrations of anti-IL-6 antibodies. Although producing IL-5 and IL-6 constitutively, the lymphoma line did not increase proliferation in response to either interleukin, nor did it show a reduced proliferative rate when antibodies to IL-5 or IL-6 were added to the cultures.
Aged↗
Growth of human lymphoma cells in SCID mice.
Two EBV-negative human lymphoma cell lines raised in this laboratory and peripheral blood cells of a patient with large cell lymphoma in leukemic phase were injected intravenously or intraperitoneally into C.B.17 SCID mice. One line (OCI-LY18) was derived from the pleural fluid of a patient with a large cell, immunoblastic malignant lymphoma. Cells of this line are of B cell origin and characterized by multiple rearrangements of the JH locus. The second line (OCI-LY17) was grown from the peripheral blood of a patient with a large cell lymphoma of T-cell phenotype which has characteristic rearrangement of the T-cell receptor beta chain. The cells directly obtained from a patient with large cell non-cleaved malignant lymphoma were of B-cell origin. Animals carrying OCI-LY18 developed large tumor masses within 6-8 weeks of inoculation. The tumors were detected in the intestine, mesentery, retroperitoneum, lymph nodes, spleen, lung and kidney. The masses resembled the primary tumor with respect to histological appearance and immunological phenotype. It was possible to generate secondary cell lines from the tumors found in the inoculated SCID mice. Injection of one of these secondary cell lines into SCID mice resulted in the rapid development of lymphoma and as few as 10 cells were sufficient to establish the disease in the inoculated animals. In contrast cells of OCI-LY17 produced small tumor aggregates that did not appear to progress over time and did not cause death of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Interleukin-6 levels in the plasma of patients with lymphoma.
We have suggested a growth stimulatory role of lymphoma cells in culture by interleukin 6. To test the hypothesis that IL-6 may have a role in vivo, the plasma of lymphoma patients was assayed for the presence of IL-6 bioactivity. A significantly greater proportion of lymphoma patients had elevated IL-6 levels (23 of 40) compared to controls (3 of 35). In follow-up, eight of 15 patients with previously elevated levels returned with decreased or undetectable levels of IL-6 post radio- or chemotherapy. This response was seen primarily in those with intermediate or high grade lymphomas. In contrast no change in IL-6 levels was seen in patients with low grade lymphoma despite measurable reductions in tumor size in both groups.
Biological Assay↗
High-dose cytosine arabinoside remission induction for acute myelogenous leukemia: comparison of two regimens of remission maintenance.
We report a single institution sequential trial of two maintenance treatment regimens for patients with acute myelogenous leukemia (AML). A total of 175 consecutive patients with AML received initial remission induction therapy with high-dose cytosine arabinoside (ara-C) and glucocorticoids. For the initial 63 patients (group A), the control population, planned maintenance treatment was with conventional-dose ara-C given over 4 days for up to 18 months. The subsequent 107 patients (group B) had planned maintenance therapy of up to 6 courses of daunorubicin, ara-C and prednisone and daily cis-retinoic acid for up to two years. The presenting features of group A and B patients were similar as were the response to remission induction, 60 and 52%, respectively. Severe neurological toxicity was encountered once after high-dose ara-C; no drug-related deaths occurred during maintenance treatment. Median duration of remission for group B patients was 9.9 months compared with 5.5 for group A (p = 0.0685). Median survival duration for the two groups was similar, 9.1 months for group A and 10.4 for group B. Survival of patients in group B who attained a complete remission was significantly better than that of patients in group A (p = 0.0439). The studies confirm our initial experience with remission induction using single agent high-dose ara-C and suggest a positive role for maintenance therapy in AML.
Acute Disease↗
Comparison of the effects of all-trans and cis-retinoic acid on the blast stem cells of acute myeloblastic leukemia in culture.
Recent work has shown that acute promyelocytic leukemia (APL) cells have a characteristic translocation involving the retinoic acid receptor on chromosome 17 and the myl protein on chromosome 15. Patients with APL respond to the administration of all-trans-retinoic acid. A cell line with t15;17 (NB4) has recently been reported; this line responds to all-trans-retinoic acid with differentiation. There is also a recent report showing that all-trans-retinoic acid is more active than cis-retinoic acid in inducing differentiation in freshly obtained APL cells. All-trans-retinoic and cis-retinoic acid are compared for their effects on growth in culture of freshly obtained AML cells, cell lines without t15;17, and NB4 cells. While all of these AML populations responded to both forms of retinoic acid, NB4 cells only were much more sensitive to all-trans-retinoic acid compared to cis-retinoic acid. The difference was seen when the NB4 cells were exposed in suspension and not when colony-formation in methylcellulose was used as an end point. Both forms of retinoic acid increased the sensitivity of blast cells to cytosine arabinoside; for NB4 cells, the sensitization was much greater when all-trans-retinoic acid was used rather than cis-retinoic acid. We conclude that the increased effects of all-trans-retinoic acid are specific for APL cells, and that a major effect of retinoic acid is on blast stem cell self-renewal.
Cell Survival↗
Role of interleukin-6 in the proliferation of human multiple myeloma cell lines OCI-My 1 to 7 established from patients with advanced stage of the disease.
Interleukin-6 (IL-6) has been shown to stimulate the proliferation of multiple myeloma cells purified to a high degree from human bone marrow. IL-6 production in multiple myeloma has been attributed to cells belonging to the myeloma clone, thus supporting a mechanism of autostimulation. In addition, it has been shown that IL-6 may be produced by auxiliary cell populations of the bone marrow that are not part of the myeloma clone. A definitive separation of both putative sources for IL-6 may be difficult to achieve in fresh patient IL-6 growth requirement and production by pure myeloma cell populations using seven human myeloma cell lines (OCI-My 1 to 7) that were established from patients with advanced disease. The proliferative response of each line to recombinant IL-6 was measured in a clonogenic assay providing human plasma and methylcellulose as a viscous support and by 3H-thymidine uptake in liquid suspension culture. We observed marked heterogeneity, ranging from IL-6-dependent colony formation by OCI-My 4, to IL-6-independent growth. All lines expressed mRNA for the IL-6 receptor. Expression of IL-6 mRNA was analyzed after amplification by polymerase chain reaction and was present in five of seven lines. IL-6 protein was detected by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants of two lines (OCI-My 3 and 2). Its functional activity was confirmed in a bioassay using the IL-6-dependent murine hybridoma line B 13.29. This activity was neutralized by anti-IL-6 antibody. Two lines did not express mRNA for IL-6. The remaining three lines expressed mRNA for IL-6, but did not secrete IL-6 protein. Immunoprecipitation experiments with lysates of one of these three lines did not detect the presence of IL-6 protein. These results suggest that autocrine stimulation by IL-6 may occur in some cell lines derived from patients with multiple myeloma. However, it does not represent a universal mechanism in myeloma cell growth.
Cell Division↗
Mutation of the p53 gene in human acute myelogenous leukemia.
Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.
Base Sequence↗
Hydrocortisone in culture protects the blast cells in acute myeloblastic leukemia from the lethal effects of cytosine arabinoside.
The blast cells in acute myeloblastic leukemia (AML) respond to many of the same regulatory mechanisms that control normal hemopoiesis. These include the growth factors that bind to membrane receptors and steroid hormones or vitamins that have intracellular receptors. We report the effects in culture of the steroid glucocorticoid hydrocortisone on freshly explanted AML blasts from patients and on two continuous AML cell lines. Only small changes in clonogenic cell numbers in suspension cultures were seen in the presence of hydrocortisone. The most striking effect of the hormone was on the sensitivity of blasts cells to cytosine arabinoside (ara-C). In contrast to the response of AML blast cells to retinoic acid, a ligand for intracellular steroid receptors that sensitizes some blast populations to ara-C, hydrocortisone reduced the toxic effects of the drug. The protective action of hydrocortisone was not mediated through the cell cycle since exposure of blasts to hydrocortisone did not affect the percentage of cells in DNA synthesis as measured with the tritiated thymidine (3HTdR) "suicide" technique. The hydrocortisone effect could be demonstrated using a pulse (20 min) exposure protocol. Blasts pulsed with increasing specific activities of 3HTdR showed the usual response pattern with an initial loss in plating efficiency to about 50% of control, followed by a plateau, regardless of whether the cells had been exposed to hydrocortisone. Control blasts exposed to increasing ara-C concentrations gave very similar dose-response curves; in striking contrast, blast cells cultured in hydrocortisone, then pulsed with ara-C did not lose colony-forming ability even though the same population was sensitive to 3HTdR. The hydrocortisone effect was dose and time related; protection from ara-C increased from 10(-8) to 10(-5) M and was seen after 4 hr exposure but required 8 hr to reach a maximum. We conclude that hydrocortisone can protect blasts from the lethal effects of ara-C even while the cells are in active DNA synthesis.
Blast Crisis↗
Regulation of interleukin-6 expression in the lymphoma cell line OCI-LY3.
Previously we described a cell line OCI-LY3 derived from a patient with non-Hodgkin's lymphoma. The cell line produced interleukin-6 (IL-6) mRNA and protein and demonstrated an autocrine pattern of growth for IL-6. Southern blot analysis of the IL-6 gene did not reveal any rearrangement. To determine whether the production of IL-6 by OCI-LY3 was due to subtle changes in the promoter of IL-6 or due to the expression of trans-acting factors chloramphenicol acetyltransferase (CAT) reporter constructs containing from -1,180 to +13 to -112 to +13 of a normal IL-6 gene were electroporated into the cell line. When these constructs are transferred into unstimulated fibroblasts, no CAT activity is seen; however, CAT activity is induced when the cells are stimulated with either IL-1 alpha, lipopolysaccharide (LPS), or cyclic adenosine monophosphate (cAMP) analogues. When the cell line OCI-LY3 was transfected with these constructs, CAT activity was observed; it was not necessary to stimulate the cells with exogenous factors to observe this activity. No CAT activity was observed in a second lymphoma cell line, OCI-LY13.1, that does not produce IL-6. These results suggest that the constitutive production of IL-6 by the cell line OCI-LY3 is due to the presence of trans-acting factors that stimulate the expression of IL-6 and not due to a cis-acting mutation of the IL-6 promoter.
Blotting, Southern↗
Mast cell growth factor, a ligand for the receptor encoded by c-kit, affects the growth in culture of the blast cells of acute myeloblastic leukemia.
The c-kit proto-oncogene encodes a transmembrane receptor with a tyrosine kinase internal domain. C-kit has been mapped to the W locus in the mouse, and the gene encoding the ligand has been shown to be the product of the murine SI locus. Previous genetic studies have shown that the murine W and SI loci play important roles in the normal function of hemopoietic stem cells. As these stem cells have been identified as the origins of abnormal clones in acute myeloblastic leukemia (AML), a study was begun of c-kit in AML. By Northern blot analysis, it was shown that all of 21 blast populations from AML patients were kit expression positive, but some AML cell lines did not transcribe detectable c-kit mRNA. This study is now extended to the responses of freshly obtained AML cells and cell lines to the ligand, mast-cell growth factor (MGF). In culture, fresh cells usually responded to added ligand with increases in both self-renewal and terminal divisions. The most obvious effects were seen when MGF was combined with either IL-3 or G-CSF. The response of cell lines to MGF mirrored their expression of c-kit; expression positive lines responded in culture with patterns similar to those seen for fresh cells. C-kit expression negative cells did not respond to MGF. RNA prepared from the cells giving rise to one such line, OCI/AML-5, was available for study. mRNA for c-kit could not be detected in this RNA sample by Northern blot analysis or the polymerase chain reaction. Thus the heterogeneity found in AML blast populations extends to the involvement of c-kit and its ligand in growth regulation, although blast populations without this regulatory apparatus appear to be rare.
Cell Division↗
OCI/AML-4 an acute myeloblastic leukemia cell line: regulation and response to cytosine arabinoside.
This paper describes the properties of a continuous cell line derived from the blast cells of a patient with acute myeloblastic leukemia (AML), secondary to the treatment of Hodgkin's disease. The line grows slowly without stimulation but responds to interleukin-3 (IL-3), GM-CSF and mast cell growth factor (MGF), a ligand for the receptor encoded by the c-kit oncogene. When OCI/AML-4 cells are exposed to MGF with IL-3 or GM-CSF, additive or synergistic effects are seen. Combinations of MGF and G-CSF, IL-6 or CSF-1 give less growth than MGF alone. OCI/AML-4 cells are sensitive to retinoic acid; a dose related decrease in clonogenic cells is observed when OCI/AML-4 cells are exposed to retinoic acid in suspension culture. OCI/AML-4 cells are sensitive to cytosine arabinoside (ara-C), but the ara-C dose-response curve can be changed by altering the regulatory milieu in suspension culture. The cells are more ara-C sensitive in MGF or G-CSF than in IL-3 or GM-CSF. Following a 24 h exposure to retinoic acid, the ara-C sensitivity increases; in contrast, after a similar exposure to hydrocortisone, the cells become less ara-C sensitive. These changes in ara-C sensitivity occur in cells that are actively making DNA, as indicated by the reduction in colony formation after exposure to tritiated thymidine. Since OCI/AML-4 cells respond to many of the regulators that affect the growth of freshly obtained AML blast cells, it is proposed that this cell line may be useful for the study of regulation on AML in general and the interaction between different regulators in particular.
Antigens, CD↗
Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate.
One hundred and sixty-six patients between the ages of 12 and 48 years with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation following single fraction total body irradiation (TBI) of 500 cGy from a cobalt source. Patients also received one of three chemotherapeutic regimens according to their diagnosis or disease status at time of transplant. The median follow-up was 67 months with a range of 33-120 months. The actuarial 5-year event-free survival (EFS) for the subgroup of patients with good risk disease (first complete remission AML and ALL or first chronic phase CML) was 43% with an actuarial relapse rate at 5 years of 26%. Patients with poor risk disease (other than first remission AML and ALL or other than first chronic phase CML) had an EFS at 5 years of 15% with a relapse rate of 62%. Disease status at the time of transplantation was the most important factor predicting outcome in this patient population. We conclude that preparation of good risk patients with chemotherapy and single fraction TBI of 500 cGy at a dose rate of 42-91 cGy/min resulted in EFS and relapse rates similar to those observed by centers using fractionated radiotherapy schedules, without a concomitant increase in toxicity, in particular interstitial pneumonitis and cataracts.
Adolescent↗