Initial Case Presentation

A 75-year-old male was referred from his primary care physician because he was complaining of mild fatigue for several months and a complete blood count revealed him to have anemia. His CBC was significant: Hgb 8.5 g/dL, WBC 2300/mm3, ANC 830/mm3 and PLT 12,000/mm3.

Medical History

The patient’s general health has been good; he has a history of mild hypertension which is controlled medically and has no other major medical problems. He does not smoke, drinks alcohol socially, and takes one aspirin per day in addition to his blood pressure medicine. The patient has no history of previous surgery, and no family history of cancer, heart disease or diabetes.

Diagnosis

The patient was referred to a hematologist for work-up. A bone marrow aspiration and biopsy was performed at referral. This revealed an 80% marrow specimen with trilineage dysplasia and 2% bone marrow blasts. No ringed sideroblasts were seen. The patient is given a diagnosis of Refractory Anemia with Multilineage Dysplasia by WHO criteria. Cytogenetics shows a normal male karyotype. Vitamin B12 and folic acid levels are normal. Erythropoietin level is 620.

Course of Action

This case presents an elderly individual with newly diagnosed myelodysplastic syndrome (MDS). He has Refractory Anemia with Multilineage Dysplasia by WHO criteria. With trilineage cytopenia, normal cytogenetics and no increase in bone marrow blasts, the patient has an International Prognostic Scoring System (IPSS) Score of 0.5, which puts him in the Intermediate-1 (In-1) risk subgroup with a median survival of 3.5 years.¹ 

Allogeneic transplantation remains the only known curative therapy for patients with MDS. The best results for allogeneic transplantation are obtained in patients with low risk myelodysplastic syndromes with 5-year disease free survival being reported in up to 60% of patients.² However, conventional standard myeloablative conditioning (SMC) allogeneic transplantation is associated with a high rate of treatment related mortality, especially in the first year. Therefore, in patients with a potential median survival of several years the appropriate timing for transplantation has been an issue. A recent analysis established that for patients with low- and intermediate-1-risk myelodysplastic syndromes allogeneic transplant should be delayed for some years but performed prior to the development of acute myeloid leukemia.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 low risk MDS. 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 75, the patient is not a candidate for allogeneic transplantation.

Erythropoietic growth factors have relatively modest efficacy in the treatment of anemia in patients with MDS. The lack of standardized criteria to define hematological improvement, as well as the heterogeneity of the cohorts make it difficult to carry out a comparative evaluation of most of the clinical trials published to date. A meta-analysis of studies reported a response rate of 16% in patients with MDS.⁵ However, in selected patients with with low endogenous erythropoietin levels <500 and low transfusion needs response rates of above 70% may be observed.⁶ The use of a myeloid growth factor in combination with an erythropoietic agent has been reported to augment the responses observed with erythropoietic agents alone with responses in 38-52% of patients.⁷ However, with a high endogenous erythropoietin level this patient is unlikely to benefit with the use of an erythropoietic growth factor. Also, an erythropoietic growth factor will not help improve his thrombocytopenia.

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).⁸ Azacitidine prolonged median time to progression (TTP) to MDS/Acute myeloid leukemia (AML) from 12months to 21 months (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 of 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.⁹ In addition, azacitidine has been reported to produce red cell and platelet transfusion independence in 45% and 53% of patients, respectively.¹⁰ Therefore, I would favor starting this patient on azacitidine.

Case Evolution

The results of an open-label, single-center trial evaluating lenalidomide in MDS with red cell transfusion dependence or symptomatic anemia were first reported by List et al. in 2005.¹¹ Of the transfusion dependent patients, 63% achieved independence from red cell transfusions. The response rate was highest among patients with the del 5q. These encouraging results let to two additional phase II trials investigating possible differences in the safety and efficacy of lenalidomide 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.¹²,¹³ 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. In our patient with neutropenia and severe thrombocytopenia, we need an agent capable of producing trilineage responses, and lenalidomide is likely not a good choice as it produces predominantly red cell responses. In fact, we may observe a worsening of his neutropenia and thrombocytopenia.

In the trial that led to the approval of azacitidine the agent was administered at a starting dose of 75mg/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 100mg/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 until CR or disease progression. The median time to initial response and best response were 64 and 93 days, respectively.8 Twenty-five percent of patients had a response to azacitidine after cycle four and 10% after cycle six.10 Therefore, it is premature in our patient to change therapy at this time or switch to supportive care and at least four cycles of therapy would be recommended before considering the patient to have failed azacitidine.

Case follow up: After six cycles of azacitidine the patient normalizes his peripheral blood counts. A repeat BM biopsy confirms that he has attained a complete response with resolution of dysplasia. He proceeds on to receive another three cycles of therapy at which time azacitidine is discontinued. He remains in remission for the next year. Thereafter, his hemoglobin drops to 9.5g/dl and platelet count slowly declines to 60K/cumm, ANC is 1300. Therapy with azacitidine is resumed at this point.

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).10 The patient seems to have had the average duration of response and retreating with the same agent to which he responded in the past is perfectly reasonable.

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

³ 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.

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 Hellstrom-lindberg, E. Efficacy of erythropoietin in myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. British Journal of Haematology 1995; 89:67-7.

⁶ Mannone L, Gardin C, Quarre MC, et al. High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. British Journal of Haematology 2006;(133): 513-519.

⁸ 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.

¹⁰ 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. American Society of Hematology 2005; Abstract 2526.

¹¹ List A, Kurtin S, Roe DJ et al. Efficacy of Lenalidomide in Myelodysplastic Syndromes. N Engl J Med 2005;352(6):11-19.

¹² 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.

¹³ List A et al. 10th Congress of European Hematology Association. Stockholm, Sweden 2005.