Leukemia following chemotherapy for breast cancer.

Leukemia following chemotherapy for breast cancer was studied among patients diagnosed during 1973-1985 within the population-based tumor registries in the Surveillance, Epidemiology, and End Results Program. Among 13,734 women given initial chemotherapy, 24 developed acute nonlymphocytic leukemia (ANLL) compared to 2.1 expected based on general population rates (observed/expected = 11.5; 95% confidence interval = 7.4-17.1). Overall, 58 excess ANLL occurred per 100,000 women-years at risk for patients treated with chemotherapy. The cumulative incidence was 0.7% at 10 years. Risk remained high over all periods of observation up to 9 years after treatment. Among 7974 women treated only with surgery during 1973 and 1974, a period before the widespread use of adjuvant chemotherapy for breast cancer, ANLL was not significantly increased (observed = 7, expected = 5.1). A case-control study was then conducted in Connecticut to evaluate in more detail the risk associated with adjuvant chemotherapy in the general population. Among 20 cases (17 incident leukemias and 3 deaths due to preleukemia) and 60 matched controls, alkylating agents were linked to an 11.9-fold risk of ANLL and preleukemia (95% confidence interval = 2.6-55). Chemotherapy regimens including melphalan were related to a higher risk of leukemic conditions than those including cyclophosphamide. These data suggest that women in the general population treated with adjuvant chemotherapy for breast cancer are at an increased risk of leukemia, that the risk remains high among long-term survivors, and that risk differs by type of alkylating agent administered.

Cytochrome P4501B1 mediates induction of bone marrow cytotoxicity and preleukemia cells in mice treated with 7,12-dimethylbenz[a]anthracene.

Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) through many environmental pollutants, especially cigarette smoke. These chemicals cause a variety of tumors and immunotoxic effects, as a consequence of bioactivation by P-450 cytochromes to dihydrodiol epoxides. The recently identified cytochrome P4501B1 (CYP1B1) bioactivates PAHs but is also a physiological regulator, as evidenced by linkage of CYP1B1 deficiency to congenital human glaucoma. This investigation demonstrates that CYP1B1 null mice are almost completely protected from the acute bone marrow cytotoxic and preleukemic effects of the prototypic PAH 7,12-dimethylbenz[a]anthracene (DMBA). CYP1B1 null mice did not produce the appreciable amounts of bone marrow DMBA dihydrodiol epoxide DNA adducts present in wild-type mice, despite comparable hepatic inductions of the prominent PAH-metabolizing P-450 cytochrome, CYP1A1. Wild-type mice constitutively expressed low levels of bone marrow CYP1B1. These findings suggest that CYP1B1 is responsible for the formation of DMBA dihydrodiol epoxides in the bone marrow. Furthermore, this study substantiates the importance of DMBA dihydrodiol epoxide generation at the site of cancer initiation and suggests that tissue-specific constitutive CYP1B1 expression may contribute to cancer susceptibility in the human population.

Myelodysplasia, chemical exposure, and other environmental factors.

This paper describes a case-control study of the occupational and environmental exposures of patients with myelodysplasia. The methodology, first described in Canada for solid tumors, estimates lifetime exposures to a number of potential toxic hazards or carcinogens. This pilot study confirms that the methodology, with the use of questionnaires and interviews, can estimate exposures to specific chemicals and shows some significant associations with myelodysplasia, including exposure to petrol or diesel compounds.

Myeloproliferative disorders in patients with rheumatoid arthritis treated with total body irradiation.

Four patients with refractory rheumatoid arthritis were treated with total body irradiation administered in two sittings, 300 to 400 rads to each half of the body. All four patients had taken antimetabolites prior to receiving total body irradiation, and two continued to use them after total body irradiation. Two patients had taken alkylating agents before, and one had used them after total body irradiation. All patients showed clinical improvement. However, in two patients myeloproliferative disorders developed: a myelodysplastic preleukemia at 40 months after total body irradiation in one and acute myelogenous leukemia at 25 months in the other. Total body irradiation differs from total nodal irradiation in the total dose of irradiation (300 to 400 rads versus 2,000 to 3,000), and in the duration of the therapy (two sittings versus treatment over several weeks to months). Furthermore, the patients in the total body irradiation study frequently used cytotoxic drugs before and/or after irradiation, whereas in one total nodal irradiation study, azathioprine (2 mg/kg per day or less) was permitted, but no other cytotoxic agents were allowed. Rheumatologists may therefore face a binding decision when deciding to treat a patient with rheumatoid arthritis with either a cytotoxic drug or irradiation.

Preleukemic proliferative changes in murine bone marrow after single and multiple 7,12-dimethylbenz(a)anthracene (DMBA)-applications.

The effect of a leukemia-inducing treatment on early changes in kinetic parameters of murine bone marrow cells were investigated. Mice were treated i.p. one, four and eight times at biweekly intervals with 1 mg DMBA. Up to nine weeks after the last injection, CFU-S number, proliferation ability of bone marrow cells (PF), cell doubling time (td) and the compartment ratio (CR) were measured. Following multiple DMBA injections, CFU-S number and PF were decreased whereas CR and td increased, thus indicating persisting stem cell injury and proliferative compensation in the hemopoietic amplification compartment. A single DMBA injection had no effect. It is concluded that a first DMBA injection induces cytotoxic (and genotoxic) damage in the bone marrow leading simultaneously to a strong proliferation stimulus and a hindered proliferation ability of HSC, some of which will be predisposed for further mutagenic treatment. The following DMBA injections meet strongly proliferating HSCs, thus enhancing the probability for the loss of proliferation control/terminal differentiation.

On the pathogenesis of preleukemic myelodysplastic syndromes: development of a dysplastic hemopoietic proliferation in the rat after a single pulse dose of dimethylbenz(a)anthracene (DMBA).

After a single pulse dose of DMBA, rats develop bone-marrow hypoplasia, which is almost compensated for by regeneration after 16 weeks. Subsequently, dysplastic signs of hemopoiesis appear in all experimental animals as massive extrusion of normoblasts into the peripheral blood, red-cell aniso- and poikilocytosis, nuclear deformities, atypical mitoses, and PAS-positivity, as well as megaloblastoid maturation dissociation of erythroblasts and nuclear and granulation anomalies of neutrophilic granulocytes and monocytes, comparable to human "pseudo-Pelger cells" and "paraneutrophils". At the time of death (112-497 days after DMBA pulse) experimental animals showed hyperplastic bone marrow with increased granulopoietic/erythropoietic ratios and an augmented, mainly erythropoietic, hemopoiesis in the spleen, with splenomegaly in six rats. Splenic hemopoiesis is accompanied by white pulp atrophia. The cause of death was septicopyemia in three rats, anemia in three, and bleeding in one rat. None of the animals developed a leukemic blast phase. Myelodysplastic changes in this experiment are the same as have been shown to precede leukemia in rats treated with five DMBA pulses (Fohlmeister et al. 1981). Possible relations of myelodysplasia and leukemia are discussed.

Preleukemia and leukemia with 12p- and 19q+ chromosome alterations following Alkeran therapy.

Among 20 patients with acute nonlymphocytic leukemia or dysmyelopoietic preleukemia secondary to Alkeran therapy for another tumor, four had a del(12)(p11-p12) and four had a translocation to 19q13 among multiple karyotypic alterations in their neoplastic hematopoetic clones. It is suggested that these two cytogenetic abnormalities may occur nonrandomly in such hemic disorders and may play a limited role in their pathogenesis.

Cytogenetic abnormalities and leukemic transformation in hydroxyurea-treated patients with Philadelphia chromosome negative chronic myeloproliferative disease.

Eighty-one consecutive hydroxyurea-treated patients with Philadelphia (Ph) chromosome negative chronic myeloproliferative disease were followed prospectively from 1981 to 1989; 35 of them had polycythemia vera, 32 had essential thrombocythemia, 12 had myelofibrosis, and 2 had myeloproliferative syndromes. The 81 patients were treated with hydroxyurea for a total of 3,804 months during the observation time. Only three patients had been treated with alkylating agents or 32P before start of hydroxyurea treatment. Four patients transformed into acute myeloid leukemia or myelodysplastic syndromes; three of these patients had essential thrombocythemia, and one had a myeloproliferative syndrome. Two patients died of solid cancers. Five out of 53 evaluable patients (9%) had pretreatment clonal cytogenetic abnormalities involving chromosomes 1, 9, 20, and 21. At follow-up, during or after hydroxyurea treatment, 15% had cytogenetic abnormalities, an unexpectedly low frequency compared to the previously reported frequency in patients with polycythemia vera treated with alkylating agents. None of our patients who developed cytogenetic clonal changes during hydroxyurea therapy had polycythemia vera. However, follow-up is too short to draw any conclusions about the mutagenic potential of hydroxyurea compared to alkylating agents.

Translocations and deletions with breakpoint on 21q are nonrandomly associated with treatment-related acute nonlymphocytic leukemia and preleukemia.

Six of 70 (8.6%) consecutive cases with therapy-related acute nonlymphocytic leukemia (ANLL) or preleukemia had a translocation or deletion with a breakpoint on 21q. Such aberrations were seen in only one of 200 (0.5%) consecutive cases of de novo ANLL examined at our laboratory. The figures reflect a 17.1-fold increased incidence of 21q aberrations in therapy-related ANLL or preleukemia, compared with ANLL de novo. The difference is highly significant (p = 0.003). The increased incidence of 21q aberrations in therapy-related myelodysplastic syndromes was confirmed by literature studies. Band 21q22 was most often involved. Cases with t(8;21), which is strongly associated with the M2 variant of ANLL, or cases with i(21q), which is supposedly due to a centromeric misdivision, were not included in the count. It is concluded that the 21q aberrations are associated with treatment-related ANLL or preleukemia with at least the same degree of specificity as aberrations of #5 and #7.

[Karyotype of peripheral blood lymphocytes in patients treated for Hodgkin disease]. / Le caryotype des lymphocytes sanguins périphériques des hodgkiniens traités.

Peripheral lymphocyte chromosomes were analyzed in 55 consecutive patients with complete remission after treatment for Hodgkin's disease. In 8 patients, observed metaphases were too few in number. The other 47 patients, 29 men and 18 women, had been off all therapy for 53 months (median 41, ext. 1 to 250 months). The mean interval since the diagnosis was 78 months (median: 73 months) and the mean age at the time of chromosome analysis was 38 years (median: 34, ext. 10-78 years). No patient had either a preleukemic syndrome or leukemia. In contrast to karyotypes in normal controls and previously untreated patients, abnormal cells, hypodiploid, hyperdiploid and tetradiploid cells were more frequent. But neither monosomy 5 or 7 nor trisomy 8 were observed. Intrachromosomal rearrangements (gaps, breaks...) were significantly more frequent (12% vs 5% in untreated patients) particularly on chromosomes 1 and 2. Interchromosomal rearrangements were also numerous (1,25%) but no cells showed any specific translocation for malignant hemopathy. Chromosomal aberrations do not seem closely associated with treatments but influenced by the post-diagnosis interval and the factors present at the time of primary treatment.

[Acute leukemia secondary to the treatment of multiple sclerosis with chlorambucil]. / Leucémie aiguë secondaire au traitement de la sclérose en plaque par le chlorambucil.

A new case is reported here of acute myeloid leukemia after chlorambucil therapy for multiple sclerosis. This is the sixth case seen at our institution during the period 1978 to 1984. The leukemogenic potential of the immunosuppressive cytotoxic drugs in patients with multiple sclerosis is emphasized.

[The significance of beta 2-microglobulin for the diagnosis of preleukemic states in workers of the chemical industry]. / Znachenie beta 2-mikroglobulina dlia diagnostiki predleikoznykh sostoianii u rabochikh khimicheskoi promyshlennosti.

A study is presented of 89 workers contacting with benzene and its derivatives and 98 workers without contacts with chemical substances. Radioimmunological assay of peripheral blood B2-microglobulin was carried out. Persons with a length of work over 10 years contacting with anilin and its derivatives showed a marked increase of B2-microglobulin in the blood serum as well a marked reduction of leucocyte number. It is considered that leucopenia with granulocytopenia and marked increase of B2-microglobulin is regarded as a preleucosis state.