A phase-II trial of all trans retinoic acid and low-dose cytosine arabinoside for the treatment of high-risk myelodysplastic syndromes

Abstract

Twenty-two patients with high-risk myelodysplastic syndrome (HRMDS) were treated with a 10-day course of oral all trans retinoic acid (45 mg/m2) and s.c. low-dose cytosine arabinoside (LDARAc) given at the dose of 20 mg twice per day. The courses were repeated monthly until response or progression, in the case of response, the therapy was administered until relapse. Morphologic diagnoses were refractory anemia with excess blasts (RAEB) in nine, RAEB in transformation (RAEB-t) in nine, and chronic myelomonocytic leukemia (CMMoL) in four patients; in all cases, bone-marrow blast infiltration was greater than 10% (median 20%, range 12-30%). When the international prognostic scoring system was applied, all the cases qualified as intermediate/high-risk categories. Nineteen patients were males and three were females; the median age was 69 years (range 25-90 years); three patients had previously been treated with conventional chemotherapy, and one of them had also undergone autologous bone-marrow transplantation. The criteria of response were defined as follows: (1) complete response: normalization of blood counts and bone-marrow blasts (<5%), and (2) partial response: decrease in bone-marrow blast infiltration by 50%, and two of the following parameters - improvement in hemoglobin level by 1.5 g/dl or decrease by 50% in transfusional requirement, increase by 50% in absolute neutrophil count, and increase by 50% in platelet count. Overall, 7 (32%) of 22 patients achieved a response, with 5 (23%) being classified as complete responders and 2 (9%) as partial responders. Fifteen (68%) patients did not achieve any response, and 14 died of progressive disease or infectious disease. The overall median survival was 8 months (range 1-27 months), whereas the median survival of responders was 16 months (range 8-27 months); the median duration of response was 11 months (range 2-21 months). Moderate to severe hematological toxicity and infections were the most common side effects. In conclusion, it seems that the association of ATRA and LDARA-C may be effective in approximately 30% of HRMDS patients. Optimizing this approach might be pursued by selecting, on a biological basis, those cases more likely to respond or by incorporating other differentiating agents or growth factors.

Ham-Wasserman Lecture

“…78 When ATRA was used in conjunction with low-dose Ara-C in the treatment of "poor prognosis" AML, 48% (16/33) of the patients entered CR, and the CR rate was 88% in 17 patients with < 50% blasts in bone marrow. 79 It is noteworthy that a cytotoxic adverse effect cannot be excluded when low-dose chemotherapeutic drugs are used as differentiation-inducing agents.…”

The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA

“…[7][8][9] The clinical results of ATRA in non-APL AML have been variable. Venditti et al found that the combination of low-dose Ara-C and ATRA resulted in a remarkably high complete remission (CR) rate in a poor-prognosis AML patient population, particularly those with a lower marrow blast count, 10 but in a randomized phase 2 trial Estey et al found no benefit from the addition of ATRA to a fludarabine and cytarabine regimen in newly diagnosed poor prognosis AML and myelodysplastic syndrome. 11 Similarly, in a United Kingdom Medical Research Council (MRC) trial, we failed to demonstrate an overall advantage of adding ATRA to standard chemotherapy in patients who were deemed to have high risk AML or who had relapsed, 12 or to low-dose cytarabine or hydroxycarbamide as first-line treatment of older patients not considered fit for intensive therapy.…”

Mechanisms of resistance to apoptosis in human AML blasts: the role of differentiation-induced perturbations of cell-cycle checkpoints

“…44,47,48 We were unable to show a relationship between bcl-2 expression and the degree of protection from apoptosis in our previous study, and furthermore Del Bino et al demonstrated that DMSO-induced reductions in apoptosis preceded changes in bcl-2 expression, which only occurred after 72 h incubation with DMSO. 16,17 Previous studies which have examined the effect of diffentiating agents on apoptosis have shown the crucial importance of the relative timings of the two treatment modalities: preincubation of AML cells with ATRA, 1,25(OH) 2 D3 or DMSO is associated with cytoprotection on exposure to chemotherapy, whilst treatment with these differentiating agents after chemotherapy potentiates drug-induced DNA damage and cell death.…”

“…43 The current United Kingdom Medical Research Council AML trials, AML-12 and AML-14, include randomisations for the treatment of non-M3 AML cases with ATRA. [44][45][46] The cited rationale for the use of ATRA in such patients includes the down-regulation of bcl-2 by differentiation with retinoic acid, thus removing a powerful anti-apoptotic influence.…”