Three men with primary mediastinal germ-cell tumors subsequently developed a malignant hematologic disorder characterized by pancytopenia and marrow infiltration with hematopoietic blast cells. Two of these patients were classified as having acute megakaryocytic leukemia and the third was believed to have a myelodysplastic syndrome with a prominent megakaryocytic component. Analysis of clinical characteristics of these patients and review of the literature suggest that the proximate association of mediastinal germ-cell tumors with malignant hematologic disorders is neither a coincidence nor a consequence of chemotherapy given for the germ-cell tumor. We believe this association represents the evolution of a neoplastic disorder that initially involves a totipotent germ cell. These germ cells, when located in the mediastinum, apparently acquire hematologic phenotypes and are manifested clinically as a hematologic malignancy.

Hematologic malignancies associated with primary mediastinal germ-cell tumors.

We evaluated the occurrence of second cancers among 517 patients with non-Hodgkin's lymphoma (NHL) treated at the National Cancer Institute. Nine cases of acute nonlymphocytic leukemia (ANL) were observed compared to 0.08 cases expected (ratio of observed to expected cases, 105; 95% confidence limits, 48; 199). The excess risk of ANL was 4.1 cases per 1000 patients per year; the cumulative risk of ANL at 10 years was 7.9 ± 3.2% (S.E.). A case-control study within the NHL cohort revealed that patients treated with both radiation and chemotherapy were at greater risk of ANL than were patients who received single-modality therapy (relative risk, 6.0; p < 0.05), especially if the therapy included total-body or hemibody radiation.

A positive correlation between cumulative radiation dose to the bone marrow and risk of ANL was demonstrated, independent of chemotherapy duration. A similar correlation between chemotherapy dose and risk of ANL was suggested but could not be proven with the available data. An apparent association between ANL risk and indolent NHL histological subtypes was due to the significantly larger amounts of potentially leukemogenic therapy to which these patients were repeatedly exposed. Only one case of ANL occurred among NHL patients whose initial therapy produced a durable complete remission. Our data are compatible with a multistep model of leukemogenesis and also underscore the need for curative NHL treatment regimens which minimize the duration and quantity of therapy required for optimum patient management.

https://cancerres.aacrjournals.org/content/canres/43/4/1891.full.pdf

Evidence of a Treatment Dose Response in Acute Nonlymphocytic Leukemias Which Occur after Therapy of Non-Hodgkin's Lymphoma

Risk factors were analyzed and searched for possible predictive parameters for the development of acute myeloid leukemia in 216 reported patients previously treated for Hodgkin's disease. The distribution of histologic subtypes and the stage at diagnosis were similar to that of all patients with Hodgkin's disease. Seventy-five percent of the 216 patients in whom acute myeloid leukemia developed had received both radiotherapy and chemotherapy, 15% chemotherapy only, and 10% radiotherapy only. Of those receiving radiotherapy, 66% were given multiple courses or total nodal irradiation. Of the patients receiving chemotherapy, 77% had received more than eight months of single or combination drug therapy; only 4% had not been exposed to alkylating agents. When acute leukemia developed, 68% of the patients showed no clinical or pathologic evidence of residual Hodgkin's disease. A period of pancytopenia preceded the onset of overt leukemia in at least one-third of the patients. Complete or partial remission of the acute leukemia was achieved in 25% of the patients treated with antileukemic chemotherapy. On the basis of these findings, it is deemed advisable to reexamine the intensity of treatment presently being administered to achieve cure of Hodgkin's disease. Unnecessary or unproved programs of combined radiation therapy and chemotherapy should be avoided. An optimal balance between the risks and benefits of treatment needs to be applied.

Acute myeloid leukemia following treatment of hodgkin's disease. A review

Chromosomes and causation of human cancer and leukemia. L. Cytogenetics of leukemias complicating other diseases

The literature is replete with reports of the putative relationship of aggressive treatment of malignant, and even benign, disease and the development of acute myelogenous leukemia. Do these reports reflect an increased risk of developing acute leukemia? If so, is this simply a part of the natural history of the primary neoplasm, or benign disease, which is more recently becoming manifest because of improvement in treatment and concomitant improvement in survival? On the other hand, is this risk of leukemia due to the more aggressive treatment programs themselves? The characteristic clinical picture and the refractory nature of the leukemia which occurs in the setting is clearly different from the spontaneous acute leukemia seen in otherwise normal patients and makes unlikely the alternative possibility of spontaneous leukemia occurring in long term survivors.

Richard Bakemeier

Papers

Leukemia in radiation-treated patients: cytogenetic studies in eight cases.