Drug induced leukemia
Citations

TOXIC OVERLOAD: BLOOD DISORDERS AND CANCERS RESULTING FROM EXPOSURE TO DRUGS, CHEMICALS AND RADIATION by Edward Priestley That drugs may cause leukaemia and other cancers without first causing a blood disorder serious enough to be diagnosed has been touched upon in some books but it seems there is a hesitancy to discuss this problem. That a chemical can cause leukaemia and other cancers without first causing a diagnosed blood disorder is shown very clearly in the case of the chemical Lindane, an organochlorine pesticide. Blood disorders like aplastic anaemia, leukaemia and other cancers are very well documented to be caused by this chemical and compensation has been paid to victims. Letters we have from the Health and Safety Executive and answers we have from questions to Government experts in questions in Parliament all confirm that this is so. This is evidence again that all the drugs, chemicals and radiation that are documented to cause blood disorders are also capable of causing leukaemia and other cancers

Atichartakarn V, Punyammalee B, Nitiyanant P. Therapy related acute non-lymphocytic leukemia: report of 4 cases.Southeast Asian J Trop Med Public Health. 1985 Sep;16(3):421-30.PMID: 4095607 [PubMed - indexed for MEDLINE]

Advani SH, Doval DC, Gopal R, Nair CN, Kutty PM.  Therapy-related leukemia. A report of five patients and a review of the literature.Oncology. 1983;40(4):268-72. Review.PMID: 6346196 [PubMed - indexed for MEDLINE]
5 patients developed acute nonlymphocytic leukemia (ANLL) 2-4 years following the use of various cytotoxic agents for other primary disease. Alkylating agents were responsible for development of ANLL in 3 patients while mitomycin-C and methotrexate appear to be linked with leukemia transformation in the remaining 2 patients. 3 patients had a prolonged preleukemic phase preceding ANLL. Pancytopenia observed in 4 of 5 patients favors drug-induced stem cell damage leading to relatively resistant leukemia. Although the incidence of secondary leukemia is not very high, careful use of cytotoxic agents is needed to minimize therapy-linked neoplasms.

Bell DR, Woods RL, Levi JA.  Acute leukaemia after alkylating-agent therapy of ovarian cancer.Med J Aust. 1982 Sep 4;2(5):243-4. No abstract available.PMID: 7132879 [PubMed - indexed for MEDLINE]

Brenner B, Carter A, Sharon R, Tatarsky I. Acute leukemia following chemotherapy and radiation therapy--a report of 15 cases.Oncology. 1984;41(2):83-7.PMID: 6584810 [PubMed - indexed for MEDLINE]

14 patients developed acute nonlymphocytic leukemia and 1 patient developed Burkitt's leukemia following longterm chemotherapy and/or radiotherapy for other disorders. The main primary disorders included multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma and breast carcinoma. Acute leukemia developed earlier in patients treated by chemotherapy with or without radiotherapy than in patients treated by radiotherapy alone (63 months, range 24-132 months; 201 months, range 48 months to 30 years, respectively). 13 patients presented without organomegaly and 8 were pancytopenic. Abnormalities of myeloid and erythroid cell lines were observed in the majority of the patients. A high rate of acute erythroleukemia (5 out of 14) was found. Increased reticulin fibers were found in 3 patients. The leukemia was invariably refractory to treatment with a median survival of 4 months. The possible role of preexisting abnormal marrow structure in the development of therapy-related leukemia is discussed.

Curtis RE, Hankey BF, Myers MH, Young JL Jr. Risk of leukemia associated with the first course of cancer treatment: an analysis of the Surveillance, Epidemiology, and End Results Program experience.J Natl Cancer Inst. 1984 Mar;72(3):531-44.PMID: 6583439 [PubMed - indexed for MEDLINE]

Curtis RE, Boice JD Jr, Moloney WC, Ries LG, Flannery JT.Leukemia following chemotherapy for breast cancer.Cancer Res. 1990 May 1;50(9):2741-6.PMID: 2328500 [PubMed - indexed for MEDLINE]

Casoli P, Tumiati B.  Acute myelogenous leukemia in a rheumatoid arthritis patient under cyclosporine A therapy.Clin Rheumatol. 1994 Dec;13(4):646-7. No abstract available.PMID: 7697973 [PubMed - indexed for MEDLINE]

Dubin Kerr L, Troy K, Isola L.Temporal association between the use of methotrexate and development of leukemia in 2 patients with rheumatoid arthritis.J Rheumatol. 1995 Dec;22(12):2356-8.PMID: 8835576 [PubMed - indexed for MEDLINE]

To date only a single case of leukemia coincident with the use of methotrexate (MTX) in rheumatoid arthritis (RA) has been reported. We report 2 additional patients with RA, each of whom developed leukemia after receiving short term low dose MTX. Whether these cases represent an adverse effect of MTX treatment has yet to be determined.

Fiere D, Felman P, Vu Van H, Coiffier B.[Acute myeloid leukemia following chlorambucil administration. 2 observations]Nouv Presse Med. 1978 Mar 4;7(3):756. French. No abstract available.PMID: 273887 [PubMed - indexed for MEDLINE]

Iqbal MP, Ali AA, Alvi AA [corrected to Ali AA].  Severe bone marrow suppression in a patient with rheumatoid arthritis on methotrexate.J Pak Med Assoc. 1993 Dec;43(12):262-3. No abstract available.PMID: 8133640 [PubMed - indexed for MEDLINE]

Kapadia SB, Kaplan SS.  Acute myelogenous leukemia following immunosuppressive therapy for rheumatoid arthritis.Am J Clin Pathol. 1978 Aug;70(2):301-2.PMID: 279231 [PubMed - indexed for MEDLINE]

A 51-year-old woman had acute myelogenous leukemia following log-term cyclophosphamide therapy for rheumatoid arthritis. After standard methods of management had failed, the rheumatoid arthritis showed considerable improvement in response to approximately 25 mg cyclophosphamide per day over a four-year period. At the end of this period, pancytopenia developed, and cyclophosphamide was discontinued. A bone-marrow aspirate showed nonspecific changes. However, four months later because of severe progressive pancytopenia, another bone-marrow examination was performed; it showed acute myelogenous leukemia. Therapy failed to induce a remission, and two months after diagnosis the patient died of aspergillosis. Autopsy confirmed the presence of leukemic infiltration of bone marrow, lymph nodes, liver and spleen. These findings suggest a possible leukemogenic role of cyclophosphamide in this case and suggest that caution should be exercised in treating non-fatal diseases with antitumor drugs.

Krauss JS, Rodriguez AR, Milner PF. Erythroleukemia with high fetal hemoglobin after therapy for ovarian carcinoma.Am J Clin Pathol. 1981 Nov;76(5):721-2.PMID: 6170223 [PubMed - indexed for MEDLINE]

Kolte B, Baer AN, Sait SN, O'Loughlin KL, Stewart CC, Barcos M, Wetzler M, Baer MR.   Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis.Leuk Lymphoma. 2001 Jul;42(3):371-8.PMID: 11699401 [PubMed - indexed for MEDLINE]

Methotrexate is in widespread use as second-line therapy for rheumatoid arthritis. Treatment with methotrexate in this and other settings has not been associated with the development of therapy-related leukemias. Four patients with rheumatoid arthritis are reported who developed acute myeloid leukemia (AML) while receiving low dose weekly methotrexate therapy in the absence of previous or concomitant treatment with known leukemogenic agents. AML in these four patients was of different morphologic subtypes and was associated with heterogeneous cytogenetic abnormalities, cell surface marker expression and multidrug resistance protein expression. None of the recognized features of therapy-related leukemia were present in these four nor in five previously-reported patients. It is likely that the occurrence of AML in patients with rheumatoid arthritis in the setting of methotrexate therapy represents the coincidence of these two diseases, and does not reflect a causal relationship.

Littleton RE, Homesley HD, Richards F 2nd. Leukemogenesis related to chemotherapy of ovarian carcinoma: a review with three new case reports.Gynecol Oncol. 1984 Nov;19(3):268-77. Review.PMID: 6389274 [PubMed - indexed for MEDLINE]

A review of the literature of 68 case reports of acute leukemia following ovarian cancer is presented and 3 new cases are reported. Review of the literature revealed 34 patients received chemotherapy and radiotherapy, 32 patients received chemotherapy alone, 1 patient had only surgery, and the radiation status of the remaining patient is unclear. Chemotherapy usually consisted of alkylating agents often given in high dose and for long durations. The reported risk for developing acute leukemia after treatment of ovarian cancer ranges from 21 to 175 times that of the general population with a prevalence range in treated patients of 0.8 to 2.7%. The median interval from initiation of therapy to the development of leukemia is shortened from 54.2 to 41.1 months if radiation therapy is used in addition to chemotherapy. The patients typically exhibit a brief preleukemic phase and poor survival with death occurring 3 to 5 months after diagnosis of leukemia. Proposed mechanisms for leukemogenesis are presented.

Marce S, Bannwarth B, Schaeverbeke T, Dehais J.[Neutropenia after the first administration of methotrexate in rheumatoid arthritis]Rev Rhum Ed Fr. 1993 Nov 30;60(11):843-4. French. No abstract available.PMID: 8054935 [PubMed - indexed for MEDLINE]

Meirow D, Nugent D.The effects of radiotherapy and chemotherapy on female reproduction.Hum Reprod Update. 2001 Nov-Dec;7(6):535-43.PMID: 11727861 [PubMed - in process]
High dose chemotherapy and radiotherapy have radically increased long-term survival of young cancer patients, but major side effects of these treatments are ovarian failure and infertility. Knowledge of the risks and probabilities of ovarian failure caused by treatment is crucial for patients and physicians in order to make informed choices that will best serve patients' interests. This review presents data on ovarian damage and failure following exposure to radiotherapy, chemotherapy and ablative therapy. The risk is evaluated from the published literature according to patient's age, treatment protocol and also according to the diagnosis of some common malignancies. Many of these patients will not be sterilized immediately following treatment, but will suffer from premature menopause. In order to prevent sterilization, ovarian transposition before pelvic irradiation is mandatory. Besides cryopreservation of ovarian tissue and embryos before administration of chemotherapy, the possible protective effect of pituitary-ovarian down-regulation is discussed. The mechanism of primordial follicles damage induced by radio/chemotherapy is presented as well as the role of apoptosis signalling pathways underlying destruction. Increased knowledge of these mechanisms could help to identify potential effective inhibitors that can block the path of primordial follicles destruction and reduce ovarian failure rate.

Murohashi I.  Leukemia in patients following radiotherapy for malignant neoplasms in the pelvic region.Leuk Res. 1985;9(9):1201-8.PMID: 4068751 [PubMed - indexed for MEDLINE]

Mok CC, Kwong YL, Lau CS.  Secondary acute myeloid leukaemia with 7q- complicating azathioprine treatment for rheumatoid arthritis.Ann Rheum Dis. 1995 Feb;54(2):155-6. No abstract available.PMID: 7702408 [PubMed - indexed for MEDLINE]

Meytes D, Ramot B. Chemotherapy related leukemogenesis.Arch Toxicol Suppl. 1983;6:13-20.PMID: 6578712 [PubMed - indexed for MEDLINE]

Administration of aggressive chemotherapy to patients with cancer has considerably improved their outlook for effective palliation or cure. However, a hitherto unappreciated complication consisting of a secondary malignancy, in particular acute leukemia, has emerged. Prolonged therapy with alkylating agents and chemotherapy plus radiotherapy are associated with an increased risk of this complication. The disease evolves through a preleukemic phase of pancytopenia and sideroblastic refractory anemia. The median onset from the initiation of chemotherapy is about 5 years with an increasing incidence with time. Myelomonocytic, monocytic and erythroleukemia with atypical features and resistance to conventional therapy predominate. Hyploidy and aberrations involving chromosomes 5 and 7 are frequent. Alkylating agents are carcinogenic in laboratory animals. Although the pathway to leukemogenesis in humans is unknown, a multistep evolution is envisaged. This involves: 1) initiation through induction of errors in DNA, 2) promotion related to stem cell replication following chemotherapy-induced aplasia and 3) propagation related to immunosuppression. It is possible that, as in myeloproliferative disorders, an underlying tendency for leukemia is present in patients with cancer. This may be accentuated by chemotherapy, and more frequently observed due to the longer survival of such patients. The crucial role of chemotherapy in leukemogenesis is evident from data accumulated in non-malignant conditions such as rheumatoid arthritis.

Najean Y. The iatrogenic leukaemias induced by radio- and/or chemotherapy.Med Oncol Tumor Pharmacother. 1987;4(3-4):245-57. Review.PMID: 3326987 [PubMed - indexed for MEDLINE]
A short review, limited to recently published series of data, has been compiled on the 'therapy-induced' secondary malignancies. Their frequency, peak of incidence, haematological and clinical criteria, the influence of age, treated primary disease, choice of drug(s) and modality of prescription and the role of genetic and environmental factors are analyzed. The risk varies between 0.6 and 20.5% after different treatment forms. Some suggestions for the choice of treatment of chronic malignant disorders, and for the design of future epidemiological studies are given.

Parker LM.  Leukemia after treatment of ovarian cancer with alkylating agents.N Engl J Med. 1983 Jun 9;308(23):1422. No abstract available.PMID: 6843637 [PubMed - indexed for MEDLINE]

Pointud P, Prudat M, Peron JM.Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis.J Rheumatol. 1993 Jul;20(7):1215-6.PMID: 8371222 [PubMed - indexed for MEDLINE]

An 83-year-old woman with seropositive rheumatoid arthritis (RA) developed acute myeloid leukemia after receiving weekly methotrexate (MTX) for 33 months (total dose 690 mg). Although cytogenetic abnormalities typical of damage by cytotoxic agents were not documented, our case may be the first report of acute myeloid leukemia in RA with MTX. We estimate that 6 similar cases should have been observed in France by chance alone. The absence of other reports suggests either that MTX possesses a paradoxical protective effect or that it is not considered a risk factor for malignancy by rheumatologists. Since the number of patients with RA taking MTX can be estimated with reasonable accuracy, the reporting of all suspected cases could help to assess the safety of the drug in rheumatology.

Rosner F, Grunwald HW. Acute leukemia associated with chemotherapy.Arch Intern Med. 1983 Jul;143(7):1322-3. No abstract available.PMID: 6870402 [PubMed - indexed for MEDLINE]

Treves R, Kabta H, Bonnet C, Arnaud M, Bertin P, Desproges-Gotteron R.[Acute leukosis after immunosuppressive treatment in rheumatoid polyarthritis]Rev Rhum Mal Osteoartic. 1990 Dec;57(12):907. French. No abstract available.PMID: 2080405 [PubMed - indexed for MEDLINE]

Touboul E, Merle-Beral H, Nizri D, Guerin RA. [Acute leukemia and cancer induced by the combination of radiotherapy and chemotherapy]Nouv Presse Med. 1982 May 29;11(25):1948-9. French. No abstract available.PMID: 7110948 [PubMed - indexed for MEDLINE]

Zarrabi MH, Rosner F. Acute myeloblastic leukemia following treatment for non-hematopoietic cancers: report of 19 cases and review of the literature.Am J Hematol. 1979;7(4):357-67.PMID: 296652 [PubMed - indexed for MEDLINE]