Björn Rüter

Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting

We have piloted a low-dose schedule of 5-azacytidine followed by donor lymphocyte infusions (DLIs) in patients with relapse of AML or chronic myelomonocytic leukemia (CMMoL) after allografting. Of the 26 patients (median age 62 years, range 28–75) with relapsed AML (n=24) or CMMoL (n=2), 11 (42%) had poor-risk cytogenetics. Twenty-three patients had received fludarabine-based reduced-toxicity conditioning regimens, and three had received conventional myeloablative conditioning. Patients received 5-azacytidine s.c., at a total daily dose of 100 mg, on days 1–3, to be followed by DLI on day 10, with the next course of treatment to be started on day 22. A total of 60 courses of 5-azacytidine were administered, with a median of 2 courses (range: 1–10). In 44 courses, 5-azacytidine was followed by DLI, and thus 19/26 (73%) patients received at least one course of this combined treatment. Clinically relevant neutropenic infections not associated with progressive disease developed in four patients, one of them succumbing to sepsis. Only two patients developed de novo acute GvHD after the combination of 5-azacytidine and DLI. Overall, 66% of the patients benefited from this treatment, with continued CRs achieved in 4 (16%) patients, lasting a median of 525 days (range: 450+ to 820+), and a 50% rate of temporary disease control with stable mixed chimerism (median duration 72 days). The median survival from the start of 5-azacytidine treatment was 136 days (range: 23 to 873+), with an estimated 2-year survival probability of 16%. In conclusion, this non-intensive outpatient regimen of 5-azacytidine followed by DLI is feasible, with a very low aGVHD rate. Objective responses, including continuous complete donor chimerism, occurred also in patients with poor-risk cytogenetics.

Non-intensive treatment with low-dose 5-aza-2′-deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML patients

Novel, non-intensive treatment options in older MDS/AML patients planned for allografting, with the goal of down-staging the underlying disease and bridging time to transplantation, are presently being developed. 5-azacytidine and decitabine (DAC) are of particular interest, as they can be given repetitively, with very limited non-hematologic toxicity and result in responses both in MDS and AML even at low doses. We describe 15 consecutive patients (median age 69 years, range 60–75 years) with MDS (n=10) or AML (n=5) who all received first-line treatment with DAC and subsequent allografting (from sibling donor in four patients, unrelated donor in 11) after reduced-intensity conditioning with the FBM regimen. Successful engraftment was attained in 14/15 patients, all of whom achieved a CR, with a median duration of 5 months (range 1+ to 51+). Six of these 14 patients are alive (4 with complete donor chimerism), 8 have died either from relapse (n=4) or treatment-related complications while in CR (n=4). We conclude that allografting after low-dose DAC and subsequent conditioning with FBM is feasible, with no unexpected toxicities and appears as a valid alternative to standard chemotherapy (‘InDACtion instead of induction’) in elderly patients with MDS/AML.

DNA methylation as a therapeutic target in hematologic disorders: Recent results in older patients with myelodysplasia and acute myeloid leukemia

DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and developmentspecific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation.Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent.Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.