|
|
Over the past few years, progress has been made toward improving management of myelodysplastic syndromes (MDS). Several drugs have recently been approved by the US Food and Drug Administration (FDA) for treating specific subtypes of MDS: lenalidomide (Revlimid) for patients with chromosome 5q deletions, azacitidine (Vidaza) and decitabine (Dacogen) for nonresponsive patients, and deferoxamine and deferasirox (Exjade) for iron-overloaded patients. However, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines on MDS state that clinical trials remain the mainstay of managing this disease; “That’s how we got this far in MDS in the past 10 years,” concurred Steven D. Gore, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.
A key component in planning therapeutic options for patients
with MDS is the International Prognostic Scoring System (IPSS), which provides
a risk-based evaluation of the patient’s condition. In terms of risk-stratified
treatment, the four IPSS groups are actually referred to as low/intermediate-1 versus
intermediate-2/high. “Although the system works well, it tends to overweight
the percent blasts and underweight the cytopenias,” declared Stephen D. Nimer,
MD, of Memorial Sloan-Kettering Cancer Center in New York.
Lenalidomide has produced “remarkable” results in low-risk patients with del(5q) abnormalities, Dr. Gore stated. In the multicenter MDS-003 phase II study (List AF et al. J Clin Oncol 2006;24[18S]:5), 148 patients with low-risk disease, fairly good baseline counts, and deletions of chromosome 5 achieved an erythroid response rate (transfusion independence) of 66% with lenalidomide, with a median time to response of 4.4 weeks and a median rise in hemoglobin of 5.3 g/dL. “These are really ‘knock your socks off’ clinical data,” Dr. Gore pronounced. However, in addition to this unprecedented hematologic and cytogenetic activity, lenalidomide resulted in profound cytopenias, so for patients with these chromosomal abnormalities taking this oral drug, he recommended close monitoring (usually twice a week) during the first month or so.
For low-risk patients with symptomatic anemia, equine anti-thymocyte globulin (ATG, Atgam) has undergone extensive investigation Dr. Gore said. Four phase II studies have reported a 29% response rate to ATG, while one phase II study was discontinued after there was no response seen in 8 patients. Candidates for anti-thymocyte globulin are a select population of patients younger than age 70; those with a brief transfusion history; and individuals who are positive for HLA-DR15, perhaps the most common HLA genotype in patients with aplastic anemia, according to Dr. Gore. In this select population, durable remissions are possible with this palliative immunosuppressive agent, he concluded.
 |
| Dr. Gore |
Since aberrant DNA methylation is common in patients with MDS and sometimes is the earliest mark of the cancer, it has become a target for pharmacologic therapy Methyltransferase inhibitors, such as azacitidine, have been recommended by the NCCN clinical practice guidelines for low-risk patients who do not respond to other therapies, as well as for patients with serum erythropoietin (EPO) levels > 500 mU/mL who are negative for HLA-DR15.
The Cancer and Leukemia Group B (CALGB) 9223 trial, conducted by Silverman and colleagues (J Clin Oncol 2002;20:2429–2440), demonstrated a 60% hematologic improvement overall in the azacitidine group and a 47% rate in the group that started with observation and then crossed over to azacitidine. “This definitively showed the activity of this class of agents in the treatment of MDS,” Dr. Gore said. In a similar trial comparing decitabine with observation in 170 patients with MDS (Kantarjian H et al. Cancer 2006;106:1794–1803), there was a lower overall improvement rate of 30%. However, Dr. Gore pointed out that patients were only given two cycles of decitabine, and thus these patients may have been undertreated. “Both these drugs require four cycles to expect to see hematologic improvement,” Dr. Gore asserted.
Another interesting statistic in these two studies was the time to progression to AML and death. In the CALGB 9223 study, in the group that was randomized to receive initial azacitidine, the median time to AML or death was increased by about a year. In the trial of decitabine, a similar difference was found. These data suggest that these agents may change the natural history of the disease, said Dr. Gore.
Because transplant-related complications may hamper long-term survival, hematopoietic stem cell transplantation (HSCT) is not indicated for low-risk patients with MDS. Moreover, the survival of these patients does not appear to be negatively impacted by withholding transplants until their condition worsens, Dr. Gore revealed. “It is reassuring that low-risk patients are not being compromised by waiting, especially now that we have some disease natural history-impacting drugs,” he concluded.
Therapy for higher-risk patients with MDS is contingent on whether they are considered candidates for intensive therapies, such as allogeneic HSCT or chemotherapy. According to the NCCN clinical practice guidelines, age, performance status, and major comorbid conditions may preclude consideration of allogeneic transplant. Obviously, the patient’s personal preference for therapy of this type should be a primary consideration. “Although we have some very active drugs, none of them is curative, and the only curative therapy remains allogeneic transplantation,” Dr. Gore reported.
Treatment algorithm for myelodysplastic syndromes
Risk designations based on IPSS scores have an impact on outcome from allogeneic transplant, according to Dr. Gore. For instance, in a retrospective study of patients who underwent allogeneic transplantation from an HLA-matched sibling (Deeg J et al. Blood 2002;100:1201–1207), low-risk patients had better disease-free and relapse-free survival than high-risk patients. Azacitidine and decitabine, as well as supportive care, can be considered for certain high-risk patients, such as those who are not candidates for intensive therapy or who require a decrease in tumor burden prior to bone marrow transplantation.
Another investigational option for high-risk patients is the combined use of azacitidine and MS-275, an oral histone deacetylase (HDAC) with a long half-life. In an ongoing randomized phase II trial (Eastern Cooperative Oncology Group study E1905), Dr. Gore and colleagues are evaluating the use of a 10-day schedule of azacitidine alone or with MS-275 in patients with MDS, chronic myelomonocytic leukemia, or AML with trilineage dysplasia. Six cycles will be given before clinical response is assessed. Dr. Gore shared an anecdotal case report of a 37-year-old man with high-risk MDS based on “awful” cytogenetics who received this regimen as part of a phase I trial; after the fourth cycle of treatment, he experienced a pathologic/cytogenetic complete response, which was maintained for 2 years.
The selection of treatment for low-risk patients should not be based solely on age or risk status, according to Dr. Nimer, but ought to include the presence of symptomatic anemia. Transfusion, EPO, azacitidine, decitabine, and anti-thymocyte globulin are all appropriate treatments for patients with anemia.
 |
| Dr. Nimer |
Hematopoietic growth factor therapy includes the use of EPO, granulocyte colony-stimulating factor (G-CSF; Neupogen), and darbepoetin alfa (Aranesp). EPO has a response rate of between 15% and 20% in patients with MDS, which actually is lower than that in patients with cancer-related anemia, reported Dr. Nimer; the highest rates have been seen in those with low serum EPO levels (£ 500 mU/mL). “If the patient is anemic and has never been transfused, the chance of responding to EPO is high. On the other hand, if the patient’s EPO level is higher than 500 mU/mL and two units of blood are required per month, the chance of responding to EPO is about 7%,” Dr. Nimer stated. Although G-CSF alone seems to be an ineffective long-term option, he added, the combination of G-CSF and EPO, which is synergistic on the production of red blood cells, has achieved a response rate nearly double that of EPO alone. Studies of darbepoetin alfa suggest that the response rates appear to be higher than those for EPO, for reasons that are unclear.
What is the risk of simply transfusing anemic patients forever? “If you are fortunate enough to have MDS and to live a long time and receive transfusions, you may develop iron overload,” answered Dr. Nimer. Patients who require chronic transfusions have an iron excess of approximately 0.4–0.5 mg/kg per day, he explained, and the asymptomatic accumulation of iron can result in serious complications, including cardiac failure, cirrhosis, diabetes mellitus, infertility, and growth failure. Therefore, it is crucial to monitor such patients, particularly their serum ferritin concentration and liver iron content, Dr. Nimer advised.
Deferoxamine, an FDA-approved treatment for transfusional iron overload, has been shown to reduce the incidence and development of fatal iron overload, according to Dr. Nimer. Although it is an effective option, there is a high degree of noncompliance with this therapy. The major challenges associated with using deferoxamine center on quality-of-life difficulties. The subcutaneous slow (at least 12 hours) infusion required for 5–7 nights a week represents a serious commitment to care and disruption of normal activities, especially for children, he explained.
Complications of iron overload
Oral iron chelators have become an alternative means of treatment. Deferasirox, the only such oral agent approved by the FDA in the United States, has been primarily investigated in trials of thalassemia in both adults and children. Although no data have yet been published on this agent in patients with MDS, “There is no reason a priori to think that iron overload in MDS is not the same as in thalassemia,” Dr. Nimer asserted.
One randomized phase III study compared deferasirox with deferoxamine in beta-thalassemia patients with transfusional hemosiderosis. At 1 year of treatment, the reduction in liver iron content with daily oral deferasirox was both statistically and clinically significant, said Dr. Nimer, and adequate chelation was equivalent to that obtainable with the subcutaneous drug. Moreover, deferasirox appeared to be a convenient, well-tolerated therapy.