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Study Sheds New Light On The Appropriate Role Of Reduced-Intensity Donor Transplantation In Older MDS Patients

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Published: Sep 18, 2013 4:08 pm
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.

Background

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.

Study Design

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.

Results


Click on image to view a larger version of it.

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.


Click on image to view a larger version of it.

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.

Open Questions

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.

Photo by Michal Osmenda on Flickr – some rights reserved.
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