The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of MDS will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of MDS include the following:
Improving High-Dose Chemotherapy with Stem Cell Transplant
Autologous Stem Cell Transplant: An autologous stem cell transplant utilizes the patients own stem cells, while allogeneic transplants involve the collection of stem cells from a donor. High-dose chemotherapy and autologous stem cell transplant had not been widely used to treat myelodysplastic syndrome because stem cells collected from the patient with myelodysplasia were thought to be abnormal. However, many patients are not able to undergo an allogeneic stem cell transplant due to side effects of the procedure or the absence of an matched donor.
Results of a clinical trial have shown that autologous stem cell transplants may provide long-term survival for patients with MDS or AML secondary to MDS. Patients involved in this trial were first treated with initial moderate-dose chemotherapy followed by one round of high-dose chemotherapy. After high-dose chemotherapy, patients with a matched donor were treated with an allogeneic transplant and those with no matched donor were treated with an autologous transplant.
The number of patients who were cancer-free four years after transplant was similar for both types of transplant—27% for autologous and 31% for allogeneic. Patients who experienced a complete remission during therapy and received their transplant while in remission had slightly better outcomes, but there was still little difference autologous and allogeneic transplant. 1
“Mini transplants”: A mini transplant involves lower doses of therapy prior to stem cell transplant using donor cells. Mini-transplants have been associated with a lower treatment-related mortality than high-dose allogeneic stem cell transplants, while still providing the benefit of donor stem cells that can attack the patient’s cancer cells. Mini-transplants are still being investigated in clinical trials involving various cancers and may prove to be hopeful strategies for elderly patients, who may not be able to tolerate the potential complications of a conventional allogeneic stem cell transplantation.
Researchers from Germany have reported that “mini” allogeneic stem cell transplants may provide a chance for cure for patients over 60 years of age with poor-prognosis blood cancers, including MDS. Of the 19 patients involved in this study, 17 experienced a complete disappearance (complete remission) of their cancer. Also, 13 patients lived nearly two and a half years after treatment. 2
Umbilical cord transplantation: Results from a clinical trial conducted in Japan suggests that an umbilical cord transplant may be an effective option for patients with myelodysplastic syndrome who are eligible for an allogeneic stem cell transplant but cannot find a suitable donor. However, the major disadvantage of using umbilical cord blood is the low number of stem cells collected, which has limited the use of this technique, particularly in larger patients who require more stem cells. 3
Advances in Chemotherapy without Stem Cell Transplant
Dacogen™ (decitabine): A clinical trial has shown that patients treated with Dacogen experienced significantly higher response rates and longer time to disease progression—defined as transformation AML or death—compared to patients who received supportive care. Patients who had not received prior treatment and those with intermediate 2 to high-risk disease received the most benefit from Dacogen. 4
Patients in this study only received three courses of Dacogen. More recent findings, however, suggest that a better response may be possible with multiple courses of therapy.
Topotecan/cytarabine may be more tolerable than standard idarubicin/cytarabine: A clinical study that involved 510 patients and compared four different chemotherapy combinations has revealed that anticancer responses and duration of survival were the same for all four treatments. However, treatment with topotecan/cytarabine resulted in fewer deaths than other regimens and may be considered an alternative to the standard idarubicin/cytarabine combination for the treatment of patients with progressive or high-risk MDS. 5
New Targeted Therapies
Antithymocyte globulin (ATG): Administering a drug that suppresses the immune system—a technique called immunosuppression—appears to provide some benefit in the treatment of MDS. ATG is the best immunosuppressive agent for the treatment of patients with severe aplastic anemia (a type of bone marrow disease) and produces results rivaling those of stem cell transplantation. This drug has also demonstrated activity in the treatment of patients with MDS.
Clinical trial results suggest that over 43% of patients with MDS respond to immunosuppression with ATG. This response lasted nearly two and a half years (29 months) on average.6 Research has also demonstrated that after 8 months of treatment with ATG, 34% of patients no longer required red blood cell transfusions, 48% no longer required platelet transfusions, and over 50% had improvement in levels of white blood cells. 7
Gleevec® (imitanib methylate): Gleevec slows or stops the uncontrolled growth of cancer cells caused by a specific genetic abnormality that is the hallmark of chronic myeloid leukemia. Gleevec is the first treatment of its kind to be FDA-approved and is widely used in the treatment of chronic myeloid leukemia. Clinical trials are ongoing to determine whether Gleevec may be effective in the treatment of other cancers, including myelodysplastic syndrome.
Zarnestra™ (tipifarnib): Zarnestra blocks a key enzyme (protein) called farnesyl transferase that is involved in stimulating a cell to grow and replicate in an uncontrolled manner. In this way, Zarnestra slows down or stops the excessive replication of cancer cells.
Zarnestra appears to be an active treatment with limited side effects in the treatment of patients with intermediate or high-risk MDS. On average, patients survived approximately one year after treatment with Zarnestra. 8
de Witte T, Suciu A, Verhoef S, et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood
2 Bertz H, Potthoff K, Finke J. Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. Journal of Clinical Oncology. 2003;21:1480-1484.
3 Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood. 2003 Jun 15;101(12):4711-3.
4 Saba H, Rosenfeld C, Issa JP, et al. Clinical benefit and survival endpoints from a phase III trial comparing decitabine (DAC) vs supportive care (SC) in patients with advanced myelodysplastic syndromes (MDS). Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando FL. 2005; Abstract #6543.
5 Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer. 2006;106: 1099–1109.
6 Lim Z, Killick S, Cavenagh J, et al. European Multi-Centre Study on the Use of Anti-Thymocyte Globulin in the Treatment of Myelodysplastic Syndromes [abstract]. Blood. 2005;106:707a.
7 Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Annals of Internal Medicine. 2002;137:156-163.
8 Kurzrock R, Fenaux P, Raza A, et al. High-Risk Myelodysplastic Syndrome (MDS): First results of international phase 2 study with oral farnesyltransferase inhibitor R115777 (ZARNESTRA™). Blood. 2004;104(suppl 1):Abstract #68.