Elsevier

Leukemia Research

Volume 25, Issue 9, 1 September 2001, Pages 783-791
Leukemia Research

Poor prognosis acute myelogenous leukemia: 3—biological and molecular biological changes during remission induction therapy

https://doi.org/10.1016/S0145-2126(01)00032-7Get rights and content

Abstract

This is the third paper in a series which describes a new remission induction regimen for patients with ‘poor prognosis’ acute myelogenous leukemia (AML). Twenty-four patients were treated with two one day pulses of chemotherapy separated by 96 h. Each pulse consisted of two doses of cytarabine and a single dose of mitoxantrone. Amifostine was administered three times a week after the second pulse of chemotherapy until treatment outcome became known. The first paper described the outcome of treatment while the second described the relationship of treatment outcome to the pretherapy characteristics of the leukemia. This paper describes the changes in the leukemia cells which occur during remission induction therapy. While only a limited number of specimens were available for each post treatment study, the studies demonstrated a profound fall in blood counts, BM cellularity, and telomerase activity in leukemia cells after pulse #1 of treatment. This fall was usually accompanied by a coordinate rise in IL6, TNFα, and IL1β transcripts within the AML cells which survived chemotherapy. High levels of telomerase activity in the day 5 marrow was correlated with high levels of IL1β transcripts which in turn were associated with treatment failure ascribable to resistant disease.

Introduction

The outcome of remission induction therapy in acute myelogenous leukemia (AML) is determined by, (1) the direct effects of the therapy on the leukemia cells; (2) the behavior of the leukemia cells which survive remission induction therapy; and (3) the ability of the patient to survive the side effects of chemotherapy. Earlier studies by our group demonstrated that significant regrowth of the leukemia cells which survive cytotoxic therapy can result in remission induction failure [1]. This type of resistance has been named ‘regrowth resistance’ and is commonly encountered during the treatment of poor prognosis AML, CML, lymphomas, and solid tumors [2]. The same phenomenon reduces the efficacy of courses of remission consolidation chemotherapy administered to patients with standard prognosis AML resulting in short remissions [3].

The studies described here were designed to assess the behavior of leukemia cells which survived chemotherapy so that the mechanisms responsible for regrowth resistance could be identified. To accomplish this goal bone marrow cells were studied before and 3 days after a single day of chemotherapy was administered. These studies describe the direct effects of chemotherapy on AML cells and in its indirect effects on cytokine transcript levels in the leukemia cells. The percent S phase cells and telomerase activity were also measured.

Section snippets

Patients who participated in the study

To participate in this study a patient had to have a diagnosis of AML and one or more of the following, age 70 years or greater, a history of MDS or MPD prior to the development of AML, and/or a history of toxic exposure. Twenty-five patients were registered onto this study after informed consent was obtained but 24 were treated [4]. Patient ages ranged from 23 to 80 years with 48% of patients being 70 or older. Eleven of the patients who were treated were females and 13 were male. Eighteen

Effects of cytotoxic therapy on the wbc count and on the leukemic cells in the marrow

The administration of two doses of cytarabine and a single dose of mitoxantrone had a profound effect on both the white blood cell count and on the bone marrow. The wbc count fell from 25.4±8.7×103/μl (7.1) to 1.5±0.36×103/μl (1, P<0.001). The mutational status of the p53 gene influenced the effect of chemotherapy on the wbc. For leukemias with wt p53 genes the wbc fell by 25.6±17.6×103/μl (−12.6) while for leukemias with mutant p53 genes the wbc count rose by 7.8±3.6×103/μl (3.6, P=0.002).

The

Discussion

Regrowth resistance is a significant contributor to treatment failure in poor prognosis AML [1], [2]. The biological basis of this phenomenon has been difficult to define when standard remission induction regimens are administered since few leukemia cells can be obtained for study after intensive chemotherapy. In contrast the remission induction regimen described here utilizes 2 one day pulses of chemotherapy administered 96 h apart. The 96 h separation permits the acquisition of cells prior to

Acknowledgements

This work is supported by the National Institute of Health/National Cancer Institute 1 P0-1 CA75606-04 and by a contribution from the Alza Corporation. E. Devemy and B. Li developed the concept, design, analysis of the data, drafting the paper and gave final approval. M. Tao, E. Horvath and H. Chopra assisted with data analysis and gave final approval. L. Fisher assembled the data and gave final approval. J. Nayini provided study materials, technical support and gave final approval. S. Creech

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