Study Sheds New Light On The Appropriate Role Of Reduced-Intensity Donor Transplantation In Older MDS Patients
A recent international study provides new insights into the appropriate role of reduced-intensity donor stem cell transplantation in the care of older people with myelodysplastic syndromes.
The study investigates the impact on life expectancy of both transplantation and non-transplantation strategies for the care of these patients.
The study results indicate that older patients with higher-risk myelodysplastic syndromes (MDS) may experience longer life expectancy if their therapy includes reduced-intensity donor transplantation.
Specifically, the study authors found that additional life expectancy for older higher-risk patients was 36 months with transplantation soon after diagnosis, compared to 28 months with treatment that did not include transplantation.
On the other hand, the study indicates that transplantation may negatively impact the life expectancy of older patients with lower-risk MDS, compared to treatment with non-transplant care, such as transfusions and certain drug therapies.
Among older lower-risk MDS patients, additional life expectancy was 77 months with non-transplant care. This was twice as long as the 38 months for lower-risk patients receiving reduced-intensity donor transplants soon after diagnosis.
“We hope that based on our data, older patients with MDS, especially intermediate-2 and high IPSS MDS, would be referred more often for consideration of RIC [reduced-intensity] transplantation,” said the study’s lead investigator Dr. John Koreth from the Dana-Farber Cancer Institute in Boston. “These patients benefit from early RIC transplantation both in terms of length of survival (life expectancy) and quality-adjusted survival (quality-adjusted life expectancy).”
Dr. Koreth explained that potentially curative reduced-intensity donor transplantation is likely underutilized in older patients, in part because of a lack of systematic, objective data regarding its optimal utilization. “While randomized trials of RIC transplantation versus non-transplant therapies would provide the best evidence, in its absence our mathematical decision model offers the next best level of evidence as to the preferred treatment decision,” he said.
Dr. Koreth and his colleagues point out that they classified the patients according to the International Prognostic Scoring System (IPSS), rather than the newer, revised IPSS (IPSS-R), which was not available at the time when the original trials were carried out. They add that it would be beneficial to use genetically-based risk classification schemes in the future.
In an editorial that accompanied the study, Dr. Mikkael Sekeres from the Cleveland Clinic explained that, with a median age of 64 years, the patients included in Dr. Koreth’s study more closely resemble the MDS patients typically seen by physicians, compared to the patients previously included in studies investigating when to use stem cell transplantation for MDS.
Although the new study is an important contribution to understanding the role of reduced-intensity transplantation in older MDS patients, it also raises important questions. It leaves relatively unexplored, for example, the possibility that delayed transplantation in older lower-risk MDS patients may be superior to no transplantation whatsoever.
In addition, the study tends to understate the fact that its own analyses show a substantial majority of older higher-risk MDS patients are likely to experience inferior survival outcomes with transplantation, as compared to non-transplant care.
The IPSS is a tool physicians use to classify MDS patients based on their blood cell counts, percentage of immature cells, and chromosome abnormalities.
For patients classified as low or intermediate-1 IPSS risk, there are several different treatment options, including Revlimid (lenalidomide) for patients with the deletion 5q chromosomal abnormality, anti-anemia medications such as Procrit (epoetin alfa, Eprex) and Aranesp (darbepoietin alfa), and immunosuppressive therapy.
Patients classified as intermediate-2 or high IPSS risk are frequently treated with Vidaza (azacitidine) or Dacogen (decitabine); donor stem cell transplantation may also be considered if a matching stem cell donor is available.
Donor (allogeneic) stem cell transplantation is currently the only possible cure for MDS. During the procedure, the patient receives chemotherapy and/or radiation treatment, which destroys both their diseased stem cells as well as their healthy cells. The patient’s cells are then replaced with stem cells from a healthy donor.
Older patients are typically not considered candidates for donor transplantation with high-intensity chemotherapy because they are often frail and have other diseases that make them more susceptible to the life-threatening side effects of high-dose therapy.
Stem cell transplantation with reduced-intensity chemotherapy is considered an alternative treatment option for older MDS patients. The patient receives lower drug doses, which are associated with lower toxicity. The hope is that any remaining diseased cells that were not destroyed by the chemotherapy will be destroyed by the donor stem cells through a process called the graft-versus-leukemia effect.
A recently published study by Italian researchers showed that higher-risk MDS patients benefit from transplantation soon after diagnosis but that lower-risk MDS patients benefit when transplantation is delayed until the patients progress to intermediate-risk MDS (see related Beacon news).
However, the median age of the patients included in the Italian study was 48 years, and no patients above the age of 65 years were included. In addition, none of the patients in the study were treated with newer MDS treatments such as Vidaza, Dacogen, or Revlimid.
According to the authors of the current study, outcomes of reduced-intensity donor transplantation and non-transplantation therapies have not been directly compared in older MDS patients, so it is not clear what the preferred treatment option for this patient population is.
The researchers therefore retrospectively compared the two treatment approaches to determine if transplantation offers a survival benefit to older patients.
An international group of researchers analyzed data from 514 MDS patients who participated in previous MDS studies conducted at multiple locations around the world. All patients were between the ages of 60 years and 70 years. The previous studies were carried out at various points of time from 1992 to 2010.
The patients were categorized into four different groups based on their IPSS score and the treatment they received.
The first group included 132 patients who underwent reduced-intensity donor stem cell transplantation with matched donors. The median patient age was 64 years, and the median follow-up time was 30 months. Of the 132 patients, 55 percent were classified as low or intermediate-1 IPSS risk and 45 percent were classified as intermediate-2 or high IPSS risk.
The second group of patients included 123 patients with low or intermediate-1 IPSS risk MDS who had normal red blood cell levels and received best supportive care. The median patient age was 66 years, and the median follow-up time was 40 months.
The third group included 94 patients with low or intermediate-1 IPSS risk MDS who had low red blood cell levels or were red blood cell transfusion dependent and who received blood growth factors. The median patient age was 67 years, and the median follow-up time was 38 months.
The fourth group included 165 patients with intermediate-2 or high IPSS risk MDS who received treatment with Vidaza or Dacogen. The median patient age was 66 years, and the median follow-up time was 20 months.
The study did not include MDS patients who have the deletion 5q chromosomal abnormality with no other abnormality, nor did it include patients with what is called “secondary MDS,” which is MDS resulting from previous treatment with chemotherapy drugs or radiation.
Using the data available for all four groups of patients, the researchers used statistical modeling to determine if reduced intensity transplantation provides a life expectancy benefit compared to non-transplantation approaches to MDS patient care.
The researchers made two types of life expectancy comparisons. One was a traditional comparison of life expectancy based on actual calendar time. The other adjusted for the fact that quality of life during and after certain MDS treatments can be considerably reduced. Thus, although a patient’s calendar-based life expectancy might be three years, for example, their quality-adjusted life expectancy might be only two years.
To make the quality-of-life adjustments, the authors used methods regularly employed in similar studies.
The researchers found that for patients with older low or intermediate-1 IPSS risk MDS, additional calendar life expectancy was significantly longer for patients receiving non-transplantation care (77 months) than for patients receiving reduced-intensity donor transplantation within a year of diagnosis (38 months). (See estimated survival curves on the right.)
Quality-adjusted additional life expectancy was also higher for lower-risk patients receiving non-transplantation care (47 months), compared to patients receiving reduced-intensity donor transplantation within a year of diagnosis (35 months).
The authors also investigated whether transplantation therapy might be advantageous in low or intermediate-1 IPSS risk MDS patients if the analysis is broadened to include patients transplanted at any point in time — not just within a year of diagnosis.
However, allowing for more broader transplantation timing still did not yield superior life expectancy for these patients.
Non-transplantation approaches to care in this analysis yielded additional calendar life expectancy of 80 months versus 57 months for transplantation therapy permitted at any time after diagnosis. (The authors did not do a quality-adjusted life-expectancy analysis for this scenario.)
For older patients with intermediate-2 or high IPSS risk MDS, the researchers found results opposite to what they found for low or intermediate-1 IPSS risk patients.
The investigators estimated that additional calendar life expectancy for higher-risk patients was greater in patients receiving reduced-intensity donor transplantation within a year of diagnosis (36 months) than for those who received non-transplantation care (28 months). (See estimated survival curves on the right.)
Quality-adjusted additional life expectancy was also greater for higher-risk patients receiving reduced-intensity donor transplantation (33 months) compared to patients receiving non-transplantation care (15 months).
The life-expectancy benefit of transplantation in higher-risk patients, however, is heavily influenced by the fact that 20 to 25 percent of transplanted patients achieve very long-term survival. The long survival of these patients substantially increases the average life expectancy of the transplantation strategy, making it larger than the average life expectancy of non-transplantation care.
This is illustrated in the accompanying estimated survival curves, which show that, in higher-risk MDS patients, transplantation only begins to show a survival benefit versus non-transplantation after about 40 months of survival.
Although the researchers conclude from their analysis that non-transplantation care is superior to transplantation in the case of older lower-risk MDS patients, one could argue that the authors have left a key question unaddressed.
In particular, a key issue in regard to older lower-risk MDS patients would seem to be whether delayed transplantation is a sensible treatment strategy.
This issue was addressed for a younger set of patients in the Italian study mentioned earlier in this article. It found that transplantation was an advisable strategy in lower-risk MDS patients when it is delayed until the patients progress to intermediate-risk MDS (see related Beacon news).
In the current study, the investigators do not explicitly test treatment strategies that involve different transplantation timing.
However, when they include in their analysis lower-risk patients with transplantations carried out more than a year after diagnosis, the gap in life expectancy between transplantation and non-transplantation narrows noticeably.
This suggests that, for older lower-risk MDS patients, delayed transplantation may also be an attractive strategy compared to a pure, non-transplantation approach to care.
It would also seem fair to ask whether the authors overstate somewhat the finding that transplantation is a superior approach to care for older higher-risk MDS patients.
The survival curves for this group of patients indicate that transplantation is a risky strategy. It provides substantial benefit for a minority of patients, but also a quick demise for many of the other patients.
For more information, please see the study in the Journal of Clinical Oncology (abstract) and a related press release from the Dana-Farber Cancer Institute.
- Long-Term Results Continue To Show Non-Myeloablative Donor Stem Cell Transplantation Is Effective And Safe In Certain MDS Patients
- Pre-Transplant Vidaza May Improve Stem Cell Transplant Outcomes In Higher-Risk MDS Patients
- Large Study Sheds New Light On Tissue-Type Mismatches And Their Impact On Stem Cell Transplant Outcomes
- Protein Biomarkers May Predict Onset Of Acute GVHD After Donor Stem Cell Transplantation
- Beacon NewsFlashes – January 14, 2013