Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes
Yogen Saunthararajah, … , Matt Kalaycio, Jaroslaw Maciejewski
Yogen Saunthararajah, … , Matt Kalaycio, Jaroslaw Maciejewski
Published January 26, 2015
Citation Information: J Clin Invest. 2015;125(3):1043-1055. https://doi.org/10.1172/JCI78789.
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Clinical Medicine Clinical trials

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Abstract

BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells.

METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m2/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion.

RESULTS. The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased.

CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01165996.

FUNDING. NIH (R01CA138858, CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program).

Authors

Yogen Saunthararajah, Mikkael Sekeres, Anjali Advani, Reda Mahfouz, Lisa Durkin, Tomas Radivoyevitch, Ricki Englehaupt, Joy Juersivich, Kathleen Cooper, Holleh Husseinzadeh, Bartlomiej Przychodzen, Matthew Rump, Sean Hobson, Marc Earl, Ronald Sobecks, Robert Dean, Frederic Reu, Ramon Tiu, Betty Hamilton, Edward Copelan, Alan Lichtin, Eric Hsi, Matt Kalaycio, Jaroslaw Maciejewski

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Figure 6

Functional hematopoietic capacity.

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Functional hematopoietic capacity. (A) Shorter ATLs in MDS subjects comp...
(A) Shorter ATLs in MDS subjects compared with those observed in age-categorized normal controls and especially in nonresponders compared with responders. Shorter telomere length implies greater replications by fewer hematopoietic clones. Telomere length was measured by qRT-PCR. The standard curve is shown in Supplemental Figure 10. Error bars represent the median ± IQR. P values were determined by the Mann-Whitney U test. (B) Pretreatment BM cellularity was especially decreased in subjects with short telomere lengths, including in a young subject with a previous diagnosis of aplastic anemia and cytogenetic response without hematologic response on this protocol. Orange pyramids denote responders; purple diamonds denote nonresponders. (C) Pretreatment ANCs were significantly decreased in subjects previously treated with 5-azacytidine (Aza) and/or lenalidomide (Len). Error bars represent the median ± IQR. P values were determined by the Mann-Whitney U test. (D) Lower pretreatment neutrophil counts in nonresponders resulted in fewer decitabine administrations during the induction period (weeks 0–6). Error bars represent the IQR. P values were determined by the Mann-Whitney U test.