Initial Case Presentation

A 70-year-old male was referred from his general internist because he was complaining of increasing fatigue and a ten pound weight loss over the preceding three months. A complete blood count revealed him to be pancytopenic, with Hgb 8.7 g/dL, WBC 2300/mm³, ANC 660/mm³ and PLT 53,000/mm³.

Medical History

He has a history of mild hypertension and hypercholesterolemia, which is controlled medically. He does not smoke or use alcohol. The patient has no history of previous surgery other than an appendectomy several years ago. There is a family history of hypertension and heart disease. The patient’s general health appears somewhat frail with an ECOG performance status of 2.

Diagnosis

A bone marrow aspiration and biopsy was performed at referral. This revealed an 80% marrow specimen with dyserythropoiesis, Pelger Huet cells, hypolobated megakaryocytes and 11% bone marrow blasts. The patient is given a diagnosis of refractory anemia with excess of blasts II by WHO criteria. Cytogenetics shows del 7q in 14 of 20 metaphases examined. Vitamin B12 and folic acid levels are normal. Erythropoietin level is 820.

Course of Action

This case presents an elderly individual with newly diagnosed myelodysplastic syndrome (MDS). He has refractory anemia with excess of blasts II by WHO criteria. With trilineage cytopenia, del 7q on cytogenetics and 11% bone marrow blasts, the patient has an International Prognostic Scoring System (IPSS) Score of 3, which puts him in the high risk subgroup with a median survival of 0.4 years.¹ 

Allogeneic transplantation remains the only known curative therapy for patients with MDS. A recent analysis established that for patients with intermediate-2 and high-risk myelodysplastic syndromes that are transplant eligible, allogeneic transplant should be performed as soon as possible after diagnosis.² Allogeneic transplantation results in 5-year disease free survival in 28 % of patients.³ The advent of reduced intensity transplantation strategies (RIC) has reduced the early treatment related mortality and recently, encouraging preliminary results have been reported by the use of reduced intensity allogeneic transplantation for MDS. A recent retrospective comparison of reduced intensity conditioning and standard myeloablative conditioning in MDS showed that long term outcomes were similar. A recent retrospective comparison of reduced intensity conditioning and standard myeloablative conditioning using HLA-identical sibling donors in MDS showed similar 3-year probabilities of progression free (SMC 39% vs. RIC 33%) and overall survival ( SMC 45% vs. RIC 41%). These data are encouraging due to the greater proportion of older patients in the RIC group (> 50 years: 73% vs. 28% for SMC; p < 0.0001).⁴ Unfortunately, at the age of 70 years with a poor performance status the patient is not a candidate for allogeneic transplantation.

The efficacy and safety of lenalidomide has been studied in two phase II trials in lower-risk MDS patients with or without an associated del 5q. Patients with ANC <500 and platelet count < 50K/cumm were excluded from the trial. Red cell transfusion independence occurred in 27% and 67%, respectively.⁵,⁶ No beneficial effects on neutrophil or platelet count improvements were reported. Grade 3 or 4 neutropenia and thrombocytopenia were seen in both the del 5q (59% and 51%) and the non del 5q cohorts (24.1% and 19.5%), respectively. However, our patient has high-risk MDS by IPSS, and there is no data to support the use of lenalidomide in patients with high risk MDS

Azacitidine is a DNA hypo-methylating agent which has been reported to produce trilineage responses. In the pivotal trial comparing azacitidine to best supportive care azacitidine was reported to produce a 60% response rate (RR) (7%CR, 16%PR 37% hematological improvement).⁷ Azacitidine prolonged median time to progression (TTP) to MDS/Acute myeloid leukemia (AML) from 12 months to 21months (p=0.07). The median survival was 14 months versus 20 months, respectively (p=0.1). The latter figure was not statistically significant, most likely due to the crossover design. To eliminate the confounding effect of the crossover, a landmark analysis after 6 months on study showed a significant improvement in overall survival associated with azacitidine (18 months vs. 11 months; p=0.03). In a companion study, azacitidine was shown to significantly improve the quality of life of responding patients.⁸ Therefore, I would favor starting this patient on azacitidine.

Case Evolution

There have been several clinical trials employing a variety of chemotherapy regimen in MDS. Unfortunately, all have produced uniformly poor long-term results.⁹ These regimens have been associated with high rates of treatment related mortality. A retrospective comparison showed that CR rates were fairly similar among patients receiving intensive chemotherapy (45%) vs. a DNA hypomethylating agent (36%). However, mortality in the first 6 weeks was significantly higher for patients receiving intensive chemotherapy (21%) vs. a DNA hypomethylating agent (1%).¹⁰

In the trial that led to the approval of azacitidine the agent was administered at a starting dose of 75 mg/m2 and the trial was designed to administer the drug for a minimum of 4 cycles. If a beneficial effect was not observed after 2 cycles and the drug had been well tolerated the dose of azacitidine was increased to 100 mg/m2 with the third cycle. Those who achieved a CR after 4 cycles were administered another 3 cycles of the drug; those with PR or hematological improvement continued on the drug till CR or disease progression. The median time to initial response and best response were 64 and 93 days, respectively.7 Twenty-five percent of patients had a response to azacitidine after cycle 4 and 10% after cycle 6.¹¹ Therefore, it is premature in our patient to change therapy at this time or switch to supportive care, and at least 4 cycles of therapy would be recommended before considering the patient to have failed azacitidine.

Case follow up: After 4 cycles of azacitidine, the patient has a partial response with elimination of need for transfusions and an improvement in his performance status. He proceeds on to receive another twenty cycles of therapy at which time his disease progresses to acute myeloid leukemia. He is not considered an adequate candidate for aggressive chemotherapy and decides to receive supportive care with transfusion support. He dies two months later, 27 months after initial diagnosis of MDS.

Discussion and Commentary

In the trial comparing azacitidine to best supportive care the median duration of response was 366 days (56-4641+ days) and the median duration of CR was 379 (92-4412+ days).11 Azacitidine improved time to progression to AML by 22.5 months (95% CI 10.4, 34.6) (p=0.002) and death by 9.8 months ( 95% CI 1.3, 18.3) (p=0.03) in the high risk subgroup of MDS.¹²

References

¹ Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079–2088.

² Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004;(104):579-585.

³ Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998;12(suppl 1):S25-29.

⁴ Martino R, Iacobelli S, Brand R, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; (108): 836-846.

⁵ List A, Dewald G, Bennett A, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006;355(14):1456-65.

⁶ List A et al. 10th Congress of European Hematology Association. Stockholm, Sweden. 2005.

⁷ Silverman LR, Demakos EP, Peterson BL, et al. Randomized Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B. Journal of Clinical Oncology 2002; (20):2429-2440.

⁸ Kornblith AB, Herndon, II JE, Silverman LR, et al. Impact of Azacytidine on the Quality of Life of Patients With Myelodysplastic Syndrome Treated in a Randomized Phase III Trial: A Cancer and Leukemia Group B Study Journal of Clinical Oncology 2002;(20)2441-2452.

⁹ Estey E, Thall PE, Cortes JE, et al. Comparison of Idarubicin +ARA-C, Fludarabine +ARA-C, and Topotecan + ARA-C-Based Regimens in the Treatment of Newly Diagnosed AML, Refractory Anemia with Excess Blasts in Transformation, Or Refractory Anemia with Excess Blasts. Blood 2001;98(13):3575-83.

¹⁰ Hagop Kantarjian, Susan O'Brien, Francis Giles, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules. Proceedings of the American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract 2522.

¹¹ Silverman LR, McKenzie DR, Peterson BR et al. Response Rates Using International Working Group (IWG) Criteria in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine. Proceedings of the American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract 2526.

¹² Silverman LR, McKenzie DR, Peterson BL, et al. Analysis of Survival, AML Transformation, and Transfusion Independence in Patients with High-Risk Myelodysplastic Syndromes (MDS) Receiving Azacitidine Determined Using a Prognostic Model. Proceedings of the American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract 2523.