Melphalan) Still an Option for the Treatment of Myelodysplastic Syndromes?

Comprehensive Review Is Traditional Low-Dose Chemotherapy (Cytarabine/Melphalan) Still an Option for the Treatment of Myelodysplastic Syndromes? Annika M. Whittle, David T. Bowen Abstract In the United Kingdom, low-dose cytarabine (Ara-C) is now considered the standard of care for nonintensive therapy of myelodysplastic syndromes (MDS) with > 10% blasts and acute myeloid leukemia (AML). It remains an inexpensive and effective therapy in older patients with AML or MDS who are not fit for intensive chemotherapy. Low-dose Ara-C is ineffective for adverse-risk karyotype, and the early death rate is high (9%). The incidence of grade 3/4 infection and hemorrhage is as high as 17% and 9%, respectively. A more favorable outcome is linked to the administration of ≥ 4 courses and to the achievement of complete remission (CR). The largest published series showed an overall response rate of 44% in 180 patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation and a progression-free survival time of 9 months. Low-dose melphalan cannot be routinely recommended but should be considered in a subgroup of elderly patients with MDS with > 10% blasts or AML, normal karyotype, and hypocellular bone marrow, where durable CR rates of 30% are reported with minimal side effects. Preliminary phase III trial data suggest that demethylating agents produce superior overall survival compared with other low-dose options. Clinical Leukemia, Vol. 2, No. 3, 187-192, 2008; DOI: 10.3816/CLK.2008.n.023 Keywords: Arsenic trioxide, Azacytidine, Decitabine, Hypomethylating agents, Lenalidomide

Introduction Myelodysplastic syndromes (MDS) are clonal bone marrow disorders with a significant risk of leukemic transformation. They are more common in elderly patients. With the increasing size of the older population in the Western world, the incidence of MDS will increase over the next few decades. Treatment so far is unsatisfactory in all but a minority of patients, eg, those who achieve prolonged red blood cell transfusion independence after interventional therapy. Cure is only possible in patients fit for allogeneic transplantation. A major clinical challenge is the age and comorbidity of most patients, which limits the intensity of treatment that can be given. Emphasis is therefore often placed on optimizing quality of life (QOL). Hence, several schedules have been investigated that attempt to meet these requirements in the majority population of patients with MDS.

Low-Dose Cytarabine Background Cytarabine (Ara-C; cytosine arabinoside) is one of the major active chemotherapeutic agents and is used in myelosuppressive doses for the treatment of acute myeloid leukemia (AML). It is an antimetabolite whose mechanism of action is the competitive inhibition of DNA polymerase, an enzyme involved in the conversion of cytidine to deoxycytidine and also inhibition of DNA repair. In vitro studies suggest that Ara-C also had a differentiating action that remains active in doses too low to have a significant myelosuppressive effect.1 Case series have supported this observation in vivo.2-4 Department of Haematology, Leeds Teaching Hospitals NHS Trust, St. James’s Institute of Oncology, Bexley Wing, St. James’s University Hospital, Leeds, United Kingdom Submitted: Jan 9, 2008; Revised: Mar 15, 2008; Accepted: Mar 28, 2008 Address for correspondence: David T. Bowen, MD, Department of Haematology, Leeds Teaching Hospitals NHS Trust, St. James’s Institute of Oncology, Bexley Wing, St. James’s University Hospital, Beckett St, Leeds, LS9 7DF, United Kingdom Fax: 44-113-206-7716; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

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Low-Dose Chemotherapy for MDS

Table 1

Juneja et al treated 5 patients with classical deletion 5q of chromosome (del[5q]) syndrome with low-dose Study (Year) N CR (%) PR (%) Overall Survival, Months Ara-C 7.5-20 mg/m2 twice a day or 79 MDS Significantly higher in patients with Hellstrom-Lindberg biweekly for 10 days to 39 weeks.11 Two 16.7* 12.7* 23 MDS/AML high response rates (P = .018) et al (1992)9 patients continued in their first hemato17 RARS logic response at the time of reporting in No difference between supportive 52 RAEB Miller et al † † care (5.1) and LDAC (6.8) 11 21 1994 (29 months and 30 months). Two 6 13 CMML (1992) in median months (no P value) patients were reinduced on 2 and 3 occa20 RAEB-t sions, respectively. A total of 9 complete ‡ 107 RAEB Median, 17.2; no difference Zwierzina et al PR, 12.8 17.8‡ 73 RAEB-t between arms (P = .27) and 1 partial hematologic response were (2005)7 MR, 8.9‡ achieved in the 5 patients (BM assess29 RAEB-t Significantly better in LDAC arm Burnett et al 18§ NA 183 AML (P = .0009) (2007)8 ment was not part of the criteria). Two admissions with neutropenic fever were Significantly better with LDAC Di Febo et al 28 AML plus ATRA (15.4) vs. LDAC alone 21|| – the only complications attributed to low10 (2007) (8.6; P = .019) dose Ara-C. *CR = Hb > 10 g/dL, platelets > 100 × 109/L, ANC > 1.5 × 109/L, and < 5% BM blasts; PR = Hb > 10 g/dL (with increment Several randomized studies of lowq 2 g/dL) and q 1 additional criterion (ANC increase q 1 × 109/L, platelet increase q 50 × 109/L, or BM blasts < 5%). dose Ara-C in MDS followed. In 1992, †CR = hematocrit > 30 vol%, platelets > 100 × 109/L, ANC > 1.5 × 109/L, and BM normal morphology and cellularity and Miller et al compared low-dose Ara-C < 5% blasts. PR = q 1 of the following sustained for 2 months: 50% fewer transfusions, increase in Hb > 2 g/dL, platelets > 30 × 109/L, and/or ANC > 0.5 × 109/L, decrease of blasts by 50%. with supportive therapy.6 A total of ‡CR = Hb > 10 g/dL, platelets > 100 × 109/L, and < 5% BM blasts for q 4 weeks. PR = 3 of the following: increase in Hb 9 9 102 patients (17 with refractory anemia > 4 g/dL, increase in ANC q 1 × 10 /L, or in platelets of q 50 × 10 /L or decrease in BM blasts by q 50%; MR = achievement of 1 PR criterion. with ring sideroblasts [RARS], 52 with §CR = platelets > 100 × 109/L; ANC > 1.0 × 109/L; and BM > 50% normal cellularity, trilineage maturation, < 5% blasts. ||CR = normal peripheral count and < 5% BM blasts. RAEB, 13 with CMML, and 20 with Abbreviations: ANC = absolute neutrophil count; Hb = hemoglobin; LDAC = low-dose Ara-C; MR = minor RAEB in transformation (RAEB-t) were response; NA = not available evaluable. Only 1 course of low-dose Ara-C (10 mg/m2 twice daily for 21 days) was given. Patients in the supportive arm crossed over to the This has been exploited in subcutaneous schedules that allow most low-dose Ara-C arm at 3 months. Both of these factors will have patients to stay at home and avoid the hazards of indwelling cathcontributed to the apparently negative results, with no difference in eters. The drug cost is low at £4.00 for 100 mg (nonproprietary).5 overall survival between the 2 arms. Schedules In 2005, Zwierzina et al compared low-dose Ara-C with low-dose There is no recognized standard schedule for low-dose Ara-C Ara-C plus granulocyte-macrophage colony-stimulating factor (GMtherapy. Reported regimens have varied from 10 mg/m2 every CSF) and a third arm of low-dose Ara-C plus interleukin (IL)-3 in a 312 hours for 14-21 days,6,7 20 mg every 12 hours for 10-14 days,8 way randomization.7 A total of 180 evaluable patients (RAEB, 59.4%, 2 to 15 mg/m daily in 2 divided doses until response or for 8 weeks RAEB-t, 40.5%) were monitored for a median of 3.7 years. Low-dose with an increase to 25 mg/m2 daily for an additional 8 weeks if Ara-C 10 mg/m2 was given twice daily for 14 days, with a planned 9 there is no response at the lower dose. Results from larger studies length of treatment of 6 cycles. Overall response rate was highest in the are summarized in Table 1.6-10 low-dose Ara-C arm (44.1%), followed by the IL-3 arm (40.3%) and the GM-CSF arm (33.9%). However, overall, disease-free and progresClinical Efficacy sion-free survival were not significantly different in the 3 groups (17.2, Between 1984 and 1989, the Nordic MDS groups treated 15.4, and 9.1 months, respectively). It is important to note that 67 of 102 patients (79 with MDS and 23 with MDS/AML) with 71 (94%) responding patients received ≥ 3 cycles, and 26 of 32 (82%) Ara-C 15 mg/m2 daily in 2 divided doses for 8 weeks, increased to complete responders received all 6 cycles. 25 mg/ m2 daily for an additional 8 weeks if no response had been Very (ultra) low-dose Ara-C was given to 8 patients (5 with seen.8 Response rates (complete response [CR] and partial response AML and 3 with RAEB according to World Health Organization [PR]) varied from 28.6% in refractory anemia and refractory classification) by Worsley et al with a schedule of Ara-C 5 mg (3 mg/m2) twice a day for 21 days.12 Three patients had a CR anemia with excess blasts (RAEB) to 40% in chronic myelomono(normalization of blood count and < 5% marrow blasts), 3 had a cytic leukemia (CMML). Responses lasted between 4 months and good response (sustained improvement in blood count), and only 15 months. Predictors of response were low bone marrow (BM) 2 had no response. cellularity, absence of ring sideroblasts, and < 2 chromosomal A small Italian study investigated the previously demonstrated abnormalities. On the basis of these 3 factors and the platelet count synergistic in vitro activity with low-dose Ara-C combined with at presentation, a predictive model was drawn up with 4 distinctive all-trans retinoic acid (ATRA) in a clinical trial of 28 patients with subgroups (4% responses with none of the above factors and low AML, of which 10 had antecedent MDS.10 Low-dose Ara-C 15 mg platelet count, 55% responses with platelet count in the normal was administered twice daily for 14 days, and half of the patients range). Survival was significantly better in responders compared also received ATRA 45 mg/m2. Eleven patients had an intermediwith nonresponders (P = .018).

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Large Series of Patients Treated with Low-Dose Cytarabine

Clinical Leukemia • August 2008

Annika M. Whittle, David T. Bowen ate and 1 patient an adverse karyotype. A median of 3 courses was needed to reach CR, and the overall CR rate of 36% was comparable with those of the other studies. Complete remission rates were not significantly different in the 2 arms (21% vs. 50%), but patients receiving ATRA had a longer survival time (37 weeks vs. 66 weeks; P = .019). The authors state that no serious complication occurred, and courses did not need to be delayed. The Medical Research Council (National Cancer Research Institute [NCRI]) AML14 study compared low-dose Ara-C 10 mg/m2 twice daily for 14 days with hydroxycarbamide to control the white blood cell count; ≥ 3 courses were recommended.8 A total of 202 patients were enrolled. Seventy-nine percent were aged > 70 years, 29 had RAEB-t, 57 had secondary AML, and 126 had de novo AML. The CR rate was 18% in the low-dose Ara-C arm versus 1% in the hydroxycarbamide arm (P < .00006). Survival in the low-dose Ara-C arm was significantly longer (P = .0009). Longer survival was linked to achievement of CR (80 weeks if in CR, 10 weeks if not in CR). Most responders needed 2 or 3 courses of low-dose Ara-C to have a response, which confirms the findings of Zwierzina et al.7 Of the 91% of patients randomized to receive low-dose Ara-C who actually received the drug, 36% received 1 course, 15% 2 courses, 9% 3 courses, and 31% ≥ 4 courses. Lowdose Ara-C is currently considered the UK standard of care for nonintensive therapy of MDS with > 10% blasts and AML. The nonintensive arm of the current UK NCRI study for AML/MDS (> 10% blasts) in a population aged > 60 years (AML16) contains a 4-way randomization between low-dose Ara-C, low-dose Ara-C plus gemtuzumab, low-dose Ara-C plus arsenic trioxide (As2O3), and low-dose clofarabine. From 1984 to 1987, of 126 patients aged > 65 years with AML entered into a French trial, 39 were excluded mainly because of comorbidities, clearly demonstrating the problems of delivering chemotherapy in this population. Eighty-seven were randomized between low-dose Ara-C 10 mg/m2 twice a day for 21 days and intensive chemotherapy (zorubicin 100 mg/m2 for 4 days and Ara-C 200 mg/m² continuous infusion for 7 days). While significantly fewer patients in the low-dose Ara-C arm had a CR (32% vs. 52%), deaths from early complications were significantly lower (10% vs. 31%). Significantly less transfusion support was needed in the lowdose Ara-C group, and patients spent significantly less time in the hospital (low-dose Ara-C. 27.5 days vs. 33.6 days for the intensive arm; P = .01). There was no significant survival difference between the 2 groups (low-dose Ara-C, 8.8 months vs. 12.8 months for the intensive arm; P = .12).13

Toxicity Zwierzina et al reported a 24% infection rate (grade 3/4, 2%) and a 41% hemorrhage rate (grade 3/4, 3.4%).7 Ten percent of patients stopped treatment early because of excessive toxicity. Toxicities were higher in the arms given growth factor support. There was no supportive care arm for comparison in this study. The authors emphasize that most patients were treated as outpatients. The Nordic group reported that side effects were most significant in patients who did not show a response to low-dose Ara-C; risk factors included chromosomal aberrations, thrombocytopenia, and high BM cellularity. Side effects in the favorable group were negligible.9

In AML14, patients required a median of 19 nights in the hospital and 8 days of case visits.8 Toxicity in the first 8 weeks included infections in 19% and hemorrhage in 2% of patients; these were not significantly higher than in the hydroxycarbamide arm. Other toxicities included stroke (1%), renal disease (2%), and resistant/progressive disease (14%). These numbers were very similar in both arms. Induction deaths were exactly the same with hydroxycarbamide and low-dose Ara-C (26% in each group). The overall conclusion was that the data did not support any excess toxicity or increased supportive care requirements with low-dose Ara-C over hydroxycarbamide. Worsley et al saw 2 infections and 3 patients needing platelet support in their 8 patients on the ultra low-dose schedule.12 Miller et al described a 22.5% rate of grade 3/4 infectious complications over a total of 102 courses of lowdose Ara-C, which was significantly higher than in the supportive care arm.6 Transfusion requirements were lower in the low-dose Ara-C arm at 3 months, but this was not significant. Other side effects included gastrointestinal symptoms (31% with low-dose Ara-C vs. 3% with supportive care) and hemorrhage (29% vs. 19%). Overall, the most frequent side effects were infectious or hemorrhagic complications, both of which are also a feature of the underlying disease.

Summary Low-dose Ara-C is an effective therapy in high-risk MDS and AML in elderly patients but does carry a risk of clinically significant adverse effects of around 20%. A minimum of 4 courses is recommended for optimal response. In patients with an adverse karyotype, hypercellular RARS, and those with MDS < 10% blasts, low-dose Ara-C therapy is probably not indicated (Nordic group/ AML14), although high response rates in patients with del5q syndrome might be worthy of further study.

Low-Dose Melphalan There is considerably less literature on low-dose melphalan, although easy administration, good side effect profile, and low cost (melphalan tablets 2 mg, proprietary, net price 25 = £11.46)5 makes it an attractive option. Melphalan is a cytotoxic alkylating agent, although its mechanism of action in MDS/AML remains unclear. Responses are preceded by mild worsening of baseline cytopenias, but the pharmacodynamics are not typical for conventional chemotherapeutic agents in these disorders. All studies described used a schedule of 2 mg daily of oral melphalan. The favorable side effect profile was confirmed in all studies, with Omoto et al14 describing no serious complications and Denzlinger et al15 no hospitalization and no infectious or hemorrhagic complications. Results are summarized in Table 2.14-16 In 1995, Omoto et al observed CR in 7 and PR in 4 of 21 patients (5 with RAEB and 16 with RAEB-t) with a median total dose of 140 mg of melphalan.14 Median CR duration was 14 months. Responders tended to have a normal karyotype and hypocellular marrow. In 2000, Denzlinger et al treated 21 patients (5 with RAEB-t, 8 with RAEB, 1 with CMML, and 7 with AML) and achieved a CR in 7 and a PR in 2 patients, for an overall response rate of 42.5%. Complete response lasted from 12 weeks to 55 weeks.15 Patients with normal karyotypes and hypocellular marrow had a 75% response rate. Of 23 patients with RAEB and AML with multilineage dysplasia who received oral melphalan 2 mg daily, 4 had a CR, and 3 a PR,

Clinical Leukemia • August 2008

189

Low-Dose Chemotherapy for MDS

Table 2

Studies of Low-Dose Melphalan

Study (Year)

N

Omoto et al (1995)14

5 RAEB 16 RAEB-t

33*

Denzlinger et al (2000)15

14 MDS 7 AML

33†

Robak et al (2002)16

8 RAEB 15 AML

Studies of Demethylating Agents

Median Overall Survival, Months

Study (Year)

N

CR (%)

PR (%)

Median Overall Survival, Months

19*

Responders, 27 vs. 6.5 for nonresponders (no P value)

Silverman et al (2002)19

150 MDS

7*

16*

Aza C, 20 vs. 14 for control arm (not significant; P = .1)

9.5†

NA

Kaminskas et al (2005)20

270

5.9†

9.3 PR† 19 MR†

No survival benefit shown

Silverman et al (2006)21

206 MDS 103 AML

10-17‡

23-36‡

19.3 in AML with response (no P value given)

Kantarjian et al (2006)24

89 MDS

9§

8§

12.3 (Not significant; P = .6)

Jabbour et al (2006)22

19 CMML

58

11 HI

NA

Wijermans et al (2006)23

28 CMML

14

11 PR 11 MR

NA

Kantarjian et al (2007)18

34||; 77 MDS Marrow CR, 18 CMML 25

1||

19

Fenaux et al (2007)25

358 Highrisk MDS

–

Aza C, 24.4 vs. 15 (P = .0001)

CR (%) PR (%)

17‡

Table 3

13 PR‡ 13 SD‡

Responders, 10 vs. 4 (P = .008)

*CR = Hb > 10 g/dL, platelets > 100 × 109/L, ANC > 1.5 × 109/L, and < 5% BM blasts for q 4 weeks. †CR = Hb > 12 g/dL, platelets > 100 × 109/L, ANC > 1.5 × 109/L, and absence of blasts; PR = increase in ANC/platelets and reduction/elimination of blasts. ‡CR = Hb > 11 g/dL, platelets > 100 × 109/L, ANC > 1.5 × 109/L, and < 5% BM blasts and no dysplasia; PR = normal blood counts and blast decrease by 50%; SD = no progression for 2 months. Abbreviations: ANC = absolute neutrophil count; Hb = hemoglobin; NA = not available; SD = stable disease

with 3 achieving stability of their counts. Survival in responders was significantly longer (10 months vs. 4 months).16 Kerr et al described 2 patients with AML with trilineage dysplasia and normal karyotype at diagnosis who were treated to CR with oral melphalan 2 mg daily on 2 occasions each and became melphalan-resistant on their third relapse, at which point both had abnormalities of chromosome 17.17 Deletion of 17p (del[17p]) is a feature of therapy related with MDS and AML, and previous melphalan therapy was described in 4 of 25 cases of MDS/AML and del(17p).12 This observation should perhaps restrict the use of melphalan to elderly patients with AML whose treatment emphasis is on improved QOL.

Not given

*CR = Hb > 13 g/dL in men, Hb > 11.7 g/dL in women, platelets > 140 × 109/L, ANC > 1.8 × 109/L, and < 5% BM; PR = improvement of > 50% in all 3 cell lines and decrease in BM blasts by > 50%. †CR = normalization of blood count and BM blast percentage for q 4 weeks; PR = improvement in blood counts > 50%, absence of peripheral blood blasts, and decrease in BM blasts > 50% for q 4 weeks. ‡As for * and †. §CR = Hb > 11 g/dL in men, platelets > 100 × 109/L, ANC > 1.5 × 109/L, and < 5% BM for q 8 weeks; PR = same hematologic parameters and decrease in BM blasts by > 50%. ||CR = platelets > 100 × 109/L, ANC > 1 × 109/L, and < 5% BM for q 4 weeks; PR = same but BM blasts reduced by 50% only; marrow CR = normalization of BM without hematologic normalization. Abbreviations: ANC = absolute neutrophil count; Hb = hemoglobin; NA = not available

New Agents Hypomethylating Agents Background. DNA methylation is an important epigenetic regulator of gene expression. DNA hypermethylation is thought to contribute to the pathogenesis of MDS by silencing tumor suppressor genes. The hypomethylating agents 5-azacytidine (Aza C) and decitabine have demonstrated activity in MDS, and more recently, epigenetic therapy has been considered the standard of care for patients with high-risk MDS.18 The results of recent studies are summarized in Table 3.18-25 5-Azacytidine. In 2002, Silverman et al randomized 191 patients between Aza C and supportive care.19 The median time to transformation to AML or death was significantly longer in patients on Aza C (P = .007), but the survival curves converged at 4 years. This might have partly been a result of the crossover from the supportive care arm into the treatment arm. Interestingly, the median survival time on the Aza C arm (20 months) is not greatly different than that of the lowdose Ara-C study by Zwierzina et al (17.2 months).7 Kornblith et al reported significantly improved fatigue and psychologic well-being in those of the 191 patients in the treatment arm who were prepared and able to complete in the QOL questionnaire.26 These improvements were most pronounced in patients who received ≥ 4 cycles of Aza C. Preliminary data from the global AZA-001 randomized phase

190

III trial of Aza C versus conventional care regimens (including best supportive care, low-dose Ara-C, or intensive chemotherapy) show a strong survival advantage for Aza C.25 Decitabine. Kantarjian et al reported a randomized phase III study comparing decitabine (15 mg/m2 for 8 hours for 3 days, n = 89) with supportive care (n = 81) in 170 patients with MDS according to French-American-British criteria.24 The CR rate in the treatment group was 9%, with an overall response rate of 17%. Median duration of response was 10.3 months. Patients receiving decitabine had a “trend” to longer survival or progression to AML compared with those on supportive care only (12.1 months vs. 7.8 months), with a statistically significant survival advantage in the high-risk MDS subgroup only. The study design required treatment to be stopped at 2 cycles after achievement of CR, and significant interruptions because of myelosuppression occurred, which might explain the lower CR rate compared with some later studies. The median number of cycles was 3 (range, 0-9 cycles). Kantarjian et al also compared the above patient group with a historical group who received a standard intensive chemotherapy regimen for higher-risk MDS.27 The CR rate was 43% in the 115 patients who received decitabine; 46% in a group of 118 historical patients who were matched to the decitabine group by International

Clinical Leukemia • August 2008

Annika M. Whittle, David T. Bowen Prognostic Scoring System (IPSS) score, age, and cytogenetics; and 52% in all 376 historical patients available for analysis. Survival was significantly better in the decitabine group compared with their matched historical group. There could be some bias in this comparison because it is difficult to ascertain the contribution made by improved supportive care over time. Toxicities. The main toxicities of demethylating therapy were myelosuppression, gastrointestinal toxicity, and irritation at the injection site (Aza C only). The incidence of infection and bleeding was not increased in the treatment group compared with supportive care in the phase III trials, but worsening cytopenia was observed in 78% of patients receiving Aza C in the largest trial.

Lenalidomide Lenalidomide alone produced a high rate of complete cytogenetic response and durable hematologic improvement (median, 2.2 years) in MDS with del5q.28 Of 214 patients with MDS (IPSS low or intermediate-1) without 5q abnormalities who were transfusion dependent, 56 (26%) achieved transfusion independence for a median duration of 41 weeks, and a further 37 patients experienced a ≥ 50% reduction in transfusion requirement.29 Toxicities included 20%-25% grade 3/4 myelosuppression and mild/moderate nonhematologic toxicities in around one third of patients. Several case reports are now published of CRs in high-risk MDS (similar to AML) with del5q30 and AML with del5q.31 Such patients may then proceed successfully to allograft.32 Neutropenia and thrombocytopenia were the most common toxicities, occurring in about half of patients.

Arsenic Trioxide In vitro studies have suggested that As2O3 could be beneficial in MDS through its proapoptotic activity, inhibition of angiogenesis, and suppression of proliferation. However, only 19% of 115 enrolled patients on a phase II study showed hematologic improvement, while toxicities included arrhythmias in 18% and gastrointestinal side effects in 40% of patients.33

Conclusion Low-dose Ara-C and low-dose melphalan are 2 agents that have proven efficacy in selected patients with MDS. They are considerably better tolerated than intensive chemotherapy in the mostly elderly MDS population and still produce some remissions. However, neither demonstrates significant response in the patients with MDS and AML who have abnormal karyotypes. Moreover, low-dose Ara-C also produces significant toxicity, and melphalan is only really suitable for patients whose age or concomitant illness makes the emergence of 17p mutations an acceptable risk. The hypomethylating agents are promising alternatives because they produce significant cytogenetic responses in patients with adverse-risk karyotypes.34 Although hematologic responses occur in a sizeable proportion of patients, CR rates are low. In most health care systems in the world, cost-effectiveness is an important component of drug availability, and the new agents have to show results that justify the use of much larger resources compared with traditional agents. For the time being, low-dose Ara-C and low-dose melphalan remain readily available, reasonably

tolerated, and effective treatments for selected older patients with high-risk MDS and AML.

References 1. Sachs L. The differentiation of myeloid leukemia cells: new possibilities for therapy. Br J Haematol 1978; 40:509-17. 2. Housset M, Daniel MT, Degos L. Small doses of Ara-C in the treatment of acute myeloid leukemia: differentiation of myeloid leukemia cells? Br J Haematol 1982; 51:125-9. 3. Baccarani M, Tura S. Differentiation of myeloid leukaemic cells: new possibilities for therapy. Br J Haematol 1979; 42:485-90. 4. Castaigne S, Daniel MT, Tilly H, et al. Does treatment with Ara-C in low dosage cause differentiation in leukaemic cells? Blood 1983; 62:85-6. 5. British National Formulary [Web site]. Available at: http://www.bnf.org. Accessed: July 15, 2008. 6. Miller KB, Kyungmann M, Morrison FS, et al. The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study. Ann Hematol 1992; 65:162-8. 7. Zwierzina H, Suciu S, Loeffler-Ragg J, et al. Low-dose cytosine arabinoside (LDAraC) vs LD-Ara C plus granulocyte/macrophage stimulating factor vs LD-AraC plus interleukin-3 for myelodysplastic syndrome patients with a high risk of developing acute leukemia: final results of a randomized phase III study (06903) of the EORTC leukemia Cooperative Group. Leukemia 2005; 19:1929-34. 8. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007; 109:1114-24. 9. Hellstrom-Lindberg E, Robert KH, Gahrton G, et al. A predictive model for the clinical response to low dose Ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukemia. Br J Haematol 1992; 81:503-11. 10. Di Febo A, Laurenti L, Falcucci P, et al. All-trans retinoic acid in association with low dose cytosine arabinoside in the treatment of acute myeloid leukemia in elderly patients. Am J Ther 2007; 14:351-5. 11. Juneja HS, Jodhani M, Gardner FH, et al. Low-dose ARA-C consistently induces hematologic responses in the clinical 5q-syndrome. Am J Hematol 1994; 46:338-42. 12. Worsley A, Mufti GJ, Copplestone JA, et al. Very low dose cytarabine for myelodysplastic syndromes and acute myeloid leukemia in the elderly. Lancet 1986; 26:966. 13. Tilly H, Castaigne S, Bordessoule D, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990; 8:272-9. 14. Omoto E, Deguchi S, Takaba S, et al. Low dose melphalan for treatment of highrisk myelodysplastic syndromes. Leukemia 1996; 10:609-14. 15. Denzlinger C, Bowen D, Benz D, et al. 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