They found that having higher platelet counts at the beginning of Revlimid (lenalidomide) treatment and achieving red blood cell transfusion independence for at least 26 weeks were associated with increased overall survival.

Having high transfusion needs at the beginning of treatment and having additional chromosomal abnormalities were associated with an increased risk of progressing to acute myeloid leukemia (AML).

The researchers presented their findings on June 11 at the 2011 congress of the European Hematology Association (EHA) in London.

According to the researchers, most prior studies that have evaluated the prognoses of myelodysplastic syndromes (MDS) patients have focused on untreated patients with all types of MDS. They pointed out that there is little data available on prognostic factors for specific subgroups of patients.

The researchers therefore analyzed data from a previous Phase 2 and a previous Phase 3 trial to identify factors predictive of overall survival and disease progression that are specific to red blood cell transfusion-dependent, lower-risk MDS patients with the chromosomal abnormality deletion 5q who were treated with Revlimid.

Deletion 5q is a chromosomal abnormality in which part of chromosome 5 is missing. Deletion 5q tends to affect more women than men.

Among the 286 patients included in the analysis, the median age was 69 years, 70 percent were female, 73 percent had lower-risk MDS, and 26 percent had other chromosomal abnormalities in addition to deletion 5q.

The patients were treated with one of three dosing schedules: 5 mg Revlimid every day for 28 days, 10 mg Revlimid daily on days 1 through 21 of a 28-day treatment cycle, or 10 mg Revlimid every day for 28 days.

The median follow-up time was 38.4 months in the Phase 2 study and 36.1 months in the Phase 3 study.

The researchers found that patients who achieved red blood cell transfusion independence for at least 26 weeks had a decreased risk of death (64 percent decrease).  Patients who had high platelet counts at the beginning of treatment also had a decreased risk of death (13 percent decrease for each additional 100×10⁹ platelets/L).

The authors indicated that these results are consistent with findings from previous, smaller-scale studies.

On the other hand, patients had a significantly increased risk of death if they had MDS with refractory anemia and excess immature blood cells or chronic myelomonocytic leukemia (63 percent increase), an increasing need for red blood cell transfusions (6 percent increase per unit of blood per eight weeks), or older age (5 percent increase per year.)

Patients who had high red blood cell transfusion needs at the beginning of treatment and those who had other chromosomal abnormalities in addition to deletion 5q had an increased risk of progressing to AML.

For more information, please see abstract 481 at the EHA 2011 meeting website.

However, the study authors pointed out that further studies are needed to confirm their findings because their study was small and only a few patients had the specific mutation. 

Mutations in the TP53 gene, a gene that is involved in the production of a tumor suppressor protein, are often seen in high-risk MDS patients and are associated with a poor response to therapy and disease progression.

MDS patients with a deletion in chromosome 5 are usually considered low-risk patients, and they respond well to treatment with Revlimid (lenalidomide), with 45 percent of patients achieving a complete response on average.

However, some patients with the deletion in chromosome 5 do not respond to Revlimid to treatment, and approximately 60 percent of these patients progress to acute myeloid leukemia (AML). According to the study authors, it is not clear whether the risk of AML progression is associated with the treatment or with certain patient characteristics.

The researchers recently had an MDS patient with a deletion in chromosome 5 who showed mutations in the TP53 gene at disease progression.

To check if the TP53 mutations may be associated with AML progression, the researchers assessed 55 lower-risk MDS patients with a deletion in chromosome 5. 

They found that out of the 55 patients, 10 (18 percent) had mutations in the TP53 gene, which were detected in the first bone marrow sample (less than four months after diagnosis).  The 45 patients who did not show mutations in the first bone marrow sample did not develop mutations later on; according to the study authors, this may be an indication that TP53 mutations develop in the early phases of the disease.

The researchers also found that patients with TP53 mutations were more likely to progress to acute myeloid leukemia five years after diagnosis (77 percent) compared to patients without the mutation (24 percent). 

The study authors speculated that cells with the TP53 mutations may be less sensitive to Revlimid therapy because patients with the TP53 mutations were less likely to achieve a complete response to the treatment.  None of the patients with the mutation achieved a complete response with Revlimid treatment, compared to 50 percent of patients without the mutation.

The researchers also found that patients with the TP53 mutations had shorter survival times (57 months) than patients without the mutation (73 months). 

For additional information, please see the article in the Journal of Clinical Oncology (abstract).

The study authors therefore suggested that strategies to complement Revlimid therapy should be developed to target the malignant stem cells. 

Myelodysplastic syndromes (MDS) patients who have missing genetic material from the ‘q’ arm of chromosome 5 frequently reach remission in response to treatment with the drug Revlimid (lenalidomide).  Revlimid has been approved for use in lower risk MDS patients with that chromosomal mutation.  However, 50 percent of these patients who reach remission relapse within three years.

Previous research identified a distinct group of malignant stem cells in the bone marrow of MDS patients with deletion 5q.  Researchers hypothesized that these stem cells may be particularly resistant to treatment with Revlimid. 

In this study, researchers investigated this hypothesis by examining the bone marrow from seven low-risk or intermediate-risk MDS patients with deletion 5q. Each patient had been treated with Revlimid and became transfusion-independent. 

Researchers looked for the presence of the distinct stem cells and other cells with deletion 5q in each patient’s bone marrow before and during treatment with Revlimid.

The researchers found that the Revlimid-resistant stem cells were present before treatment, and most of these cells had the deletion 5q mutation.  After the patients achieved transfusion independence, many cells with deletion 5q were reduced or even eliminated. 

However, the researchers also found that despite Revlimid treatment, a small portion of the resistant group of stem cells persisted. 

The researchers noticed that the majority of patients eventually experienced an increase in the portion of treatment-resistant stem cells. Four of the patients progressed from transfusion independence to transfusion dependence. 

The researchers explained that because most of the malignant cells in the marrow are eliminated, normal stem cells can grow following treatment and can restore normal blood cell formation.  However, when the malignant stem cells are allowed to persist, relapse is possible.

For additional information, please see the article in The New England Journal of Medicine (abstract).

“The biggest implication [of our findings] is the confirmation in a large series of cases that cases with deletion 5q and one additional chromosomal abnormality have the same prognosis as patients with deletion 5q as a single anomaly,” said Dr. Francesc Solé from the Hospital del Mar in Barcelona, Spain, and the study’s lead investigator.

“Furthermore, our study reveals that patients with deletion 5q have a risk of transformation to AML [acute myeloid leukemia],” he added.

According to Dr. Solé, this finding is important because the drug Revlimid (lenalidomide), which is approved in the U.S. for the treatment of myelodysplastic syndromes (MDS) patients with deletion 5q, was rejected in Europe because there were concerns that Revlimid would increase the rate of AML transformation in patients with MDS. “Our study reveals that the transformation of patients with deletion 5q is independent of the use of Revlimid,” explained Dr. Solé.

Patients with MDS often have chromosomal abnormalities. Chromosomes contain a cell’s genetic information in the form of DNA. Abnormalities in the chromosomes mean that the DNA can have missing or extra parts or be misshapen.

Deletion 5q is an abnormality in chromosome 5 in which a large part of the chromosome is missing. It is the most common chromosomal abnormality in MDS patients. Ten to 15 percent of MDS patients have deletion 5q. These patients are often younger females who have low-risk MDS with low red blood cell counts.

MDS patients with deletion 5q often survive longer than MDS patients who do not have this chromosomal abnormality. However, they are as susceptible to progression to AML as other MDS patients. Progression to AML is one of the main causes of death for MDS patients.

The risk of progression to AML and the rate of overall survival of MDS patients who have deletion 5q vary widely. The international team of researchers worked to identify factors that predict the prognosis for MDS patients with deletion 5q.

The researchers retrospectively examined case files of 541 MDS patients seen between November 1972 and September 2008.

Of the total number of patients analyzed, 299 only had the deletion 5q chromosomal abnormality, 93 had an additional abnormality, and 149 had two or more additional abnormalities.

The median follow-up time was 17.2 months. At that time, 258 of the 512 patients whose files contained follow-up information were alive. The median overall survival was 36.8 months.

The researcher found that patients with deletion 5q as their sole abnormality and those with one additional chromosomal abnormality showed significantly longer overall survival (63.4 months and 46.0 months, respectively) than those with deletion 5q and two or more additional abnormalities (6.8 months).

Of the 299 patients whose files contained information about progression to AML, 66 patients developed AML. The risk of progressing to AML within five years was 38.8 percent.

Even though patients with deletion 5q as their sole abnormality or patients with deletion 5q and one additional chromosomal abnormality showed similar overall survival, the risk of AML progression varied significantly between the two groups.

MDS patients with deletion 5q as their sole chromosomal abnormality had a significantly lower risk of progressing to AML five years after prognosis (21.1 percent) than those with one additional chromosomal abnormality (57.6 percent).

Other factors that were associated with poorer overall survival and risk of AML transformation were platelet count and the proportion of blasts in the bone marrow.

For more information, please see the study in Leukemia (abstract).

Revlimid is approved for the treatment of lower risk MDS patients with the chromosomal mutation del-5q. This mutation is characterized by a missing ‘q’ arm in chromosome 5.  Revlimid can help these patients become transfusion independent.

The researchers conducted a closer analysis of Revlimid’s side effects found in a previous Phase 3 trial.  The participants were divided into three different groups: the first group received a placebo, the second group received high-dose Revlimid treatment (10 mg/day on days 1 to 21 of a 28 day cycle), and the third group received low-dose Revlimid treatment (5 mg/day on days 1 to 28). Dosage was decreased for patients who experienced severe side effects.

Up to 46 percent of patients in the high-dose Revlimid group experienced severe low white blood cell counts during the first two treatment cycles. The rate of severe low white blood cell counts  decreased to 7 percent over the following four treatment cycles. Severe low platelet counts also decreased from 28 percent to 2 percent during the first six cycles of treatment.

A similar trend during the first six treatment cycles was seen in the low-dose Revlimid group. Severe low white blood cell counts decreased from 46 percent to 15 percent, and severe low platelet counts decreased from 19 percent to 6 percent.

Other severe side effects observed included infection, urosepsis (a urinary tract infection that spreads to the kidneys), and fever.

In the high-dose Revlimid group, the dose of Revlimid had to be reduced in 38 percent of patients due to low white blood cell counts and in 23 percent of patients due to low platelet counts. In the low-dose Revlimid group, the dose of Revlimid had to be reduced in 28 percent of patients due to low white blood cell counts, in 12 percent due to low platelet counts, and in 3 percent due to fever.

The treatment had to be discontinued because of low red blood cells in 1 percent of patients in the high-dose Revlimid group and because of low white blood cell counts in 1 percent of patients in the high-dose group and 6 percent in the low-dose group.

Based on comparable side effect results for both groups but higher response rates in the 10 mg group, the researchers concluded that Revlimid treatment can be started at 10 mg. They recommended supplementing therapy with dose modifications and supportive care to achieve the best outcome.

For more information, please see abstract 6598 at the ASCO meeting website.

The del-5q mutation is a chromosomal abnormality which is characterized by a missing ‘q’ arm of chromosome 5. Although the del-5q sub-type was identified as a specific MDS diagnosis in 2001, few studies have examined the progression of this disease sub-type to AML.  

This study tracked 303 low or intermediate-1 patients with del-5q mutation. The median age of the study participants was 65 years. Patients were identified through MDS registries and followed from diagnosis. The median follow-up time was three years. During the study period, all patients were treated with supportive care. Researchers recorded any changes regarding blood cell count, dependence on red blood cell transfusions, and general disease progression, with progression to AML defined as producing more than 20 percent blasts in the bone marrow. 

Results of the study showed a median survival of nearly six years (71.5 months).  Based on the WPSS score, the median patient survival times were 107 months for very low-risk MDS, 73 months for low-risk MDS, 56 months for intermediate-risk MDS, and 37 months for high-risk MDS.

Del-5q patients with only one chromosomal abnormality achieved median 73 month survival, compared to median survival of 19.3 months for those with more than one chromosomal abnormality. 

The study also revealed that transfusion-independent patients had a significantly higher median survival time (97 months) than transfusion-dependent patients (37 months).

Out of the 303 patients, 44 (15 percent) progressed to AML. Researchers found that patients with intermediate 1 IPSS and high-risk WPSS scores had an increased risk of AML transformation.

In addition, risk for disease progression increased with greater than 5 percent blasts in the bone marrow and red blood-cell transfusion dependence. 

Researchers concluded that the survival of del-5q patients is high.  When compared to other MDS sub-types or diagnoses, del-5q patients were found to have a risk for AML progression comparable with patients who have refractory cytopenia with multilineage dysplasia without the del-5q mutation.

Researchers recommended that further studies be conducted to better identify MDS patients at greatest risk for AML progression.

For more information, see abstract 945 on the 2009 ASH meeting Web site.

Revlimid has already been used with Low- or Intermediate-1 risk MDS subtypes, especially those who require red blood cell transfusions or have del-5q, as it produces a high rate of transfusion independence and improved chromosomal abnormalities.

Patients with del-5q are missing the ‘q’ arm of chromosome 5.

Although the exact mechanism of Revlimid has yet to be fully characterized, it relieves symptoms of MDS by stimulating the immune system, causing cell death, and inhibiting new blood vessel growth.

Twenty High-risk MDS and acute myeloid leukemia (AML) patients, the majority of whom had del-5q, received varying doses of Revlimid over a median of 13 weeks. Doses varied incrementally from 10 mg to 30 mg, and maximum doses were administered for 8 weeks.

Patients’ chromosomal responses were evaluated 8 and 16 weeks after beginning treatments, while bone marrow responses were assessed every four weeks.

Although only seven patients were able to complete the entire 16 weeks of treatment, six achieved greater than 50 percent reduction of chromosomal abnormalities and one patient’s blast count decreased from 9.5 percent to less than 5 percent.

Thirteen patients did not complete the study; ten experienced severe side effects, including hospitalization due to infection or low white blood count, while three encountered disease progression.

Results showed 30 percent of the participating MDS or AML patients achieved at least partial chromosomal response, while 67 percent also reported improvement in blood cell development.

In addition, 15 patients experienced serious adverse events that led to inpatient hospitalization. Although six patients died from these events, cause of death was determined to be unrelated to Revlimid.

These results are similar to a previous study in the journal Blood, which reported 10 mg Revlimid per day for 21 consecutive days every four weeks improved blood cell development in High-risk MDS patients with del-5q.

This Phase 2 study was conducted with 47 patients, 27 percent of whom achieved at least partial response. Seven patients experienced complete remission, and overall median survival was 272 days.

Patients in this study did experience side effects such as low white blood cell or platelet counts; however, researchers were unable to find a correlation to the treatment, due to the high number of patients who presented such symptoms before receiving Revlimid.

In conclusion, Revlimid is promising treatment for High-risk MDS patients with del-5q, despite the frequency of side effects and infection.

Future clinical trials will likely test Revlimid in combination with other agents, including cytostatic or hypomethylating agents, to further improve patient responses.

For more information, please see abstract 115 at the ASH Meeting Web site.

In MDS, Revlimid is typically used as a treatment for Low- or Intermediate-1 risk patients, especially those who require red blood cell transfusions and have del-5q.  A del-5q mutation is a chromosomal abnormality characterized by a missing ‘q’ arm of chromosome 5. 

Revlimid is intended to help MDS patients achieve red blood cell transfusion independence, and is usually given at a standard dose of 10 mg daily during the first 21 days in repeated 28-day cycles.

Recent data indicate that, at its standard dose and for its target patient population, Revlimid can achieve transfusion independence in more than 60 percent of patients.  However, many patients treated with Revlimid also experience drug-related side effects, such as temporarily lowered white blood cell levels (neutropenia) and lowered platelet levels (thrombocytopenia).  In addition, treatment with Revlimid can be expensive.

In the recent Italian study, six transfusion-dependent MDS patients received Revlimid every other day during the first 21 days in repeated 28-day cycles.  Researchers hoped an alternating-day schedule would lower drug-related side effects as well as the overall cost of the treatment, while still maintaining the same level of efficacy.

This was the first study to examine the efficacy and possibly lower side effects of an alternating-day schedule for Revlimid, according to the researchers.

All six patients in the Italian study became independent of red blood cell transfusions, with three patients achieving independence in three months, and the other three in four months.

In terms of drug-related side effects, two patients experienced significant neutropenia, a rate of 33 percent, and one patient experienced significant thrombocytopenia, a rate of 17 percent.  No patients experienced fever or infection.

In comparison, recent data suggest that Revlimid given on a daily schedule produces significant neutropenia in 55 percent of patients, and significant thrombocytopenia in 44 percent of patients.

“I think dose reduction alone is responsible for this lowered toxicity,” Dr. Defina Marzia of the University of Siena in Italy, one of the authors of the report, told the Beacon.

The alternating-day schedule also reduced the cost of the drug by 50 percent.

Previous attempts to reduce Revlimid’s side effects included lowering the daily dose from 10 mg to 5 mg. This did decrease side effects, but it did not substantially reduce the overall price of the drug.

Although all six patients in the Italian study achieved transfusion independence with the alternating-day schedule, achieving independence took longer than with the standard daily schedule. Dr. Marzia pointed out that patients on a daily Revlimid dosing regimen typically achieve transfusion independence in four to six weeks.

The authors also pointed out that, due to the small number of patients and the short follow-up length of less than 14 months, the new alternate-day schedule needs to be explored in a larger study. Results based on at least 15 to 20 additional patients will be needed to confirm the study results, said Dr. Marzia.

For more details, please see the report in the British Journal of Hematology (subscription required).

Revlimid has been used to treat Low- or Intermediate-1 risk MDS subtypes, especially those who require red blood cell transfusions or have del-5q.  The del-5q mutation is a chromosomal abnormality which is characterized by a missing ‘q’ arm of chromosome 5.  Many del-5q MDS patients experience temporarily lowered white blood cell (neutropenia) and platelet (thrombocytopenia) counts. 

Clinical trials have shown that patients taking Revlimid consistently become independent of blood transfusions and show a complete cytogenetic, or chromosomal, response.  A complete cytogenetic response is defined by no abnormal cells present in a specific stage of cell division. 

Although the exact mechanism of Revlimid has yet to be fully characterized, it relieves symptoms of MDS by stimulating the immune system, causing cell death, and inhibiting new blood vessel growth.

The researchers performed a long-term follow-up analysis of 42 Low or Intermediate-1 risk patients with del-5q receiving Revlimid therapy.  Patients received either 10 mg daily or 10 mg for 21 in 28 days.  They were treated until the disease progressed or they relapsed.  

At a median follow-up of 40 months, 58 percent of patients had improved red blood cell production and 48 percent showed a full or partial chromosomal response. 

Thirty-six percent of patients had progressed to AML, and 87 percent of these patients had developed other chromosomal abnormalities in addition to del-5q. 

Results showed del-5q patients who responded to Revlimid treatment with a cytogenetic response had fewer incidents of AML progression.  Three and five years after study entry, 10 and 21 percent of patients who showed a cytogenetic response to Revlimid had progressed to AML, respectively.  In contrast, 46 and 60 percent of patients without cytogenetic response had progressed to AML at three and five year follow-up, respectively.

The study authors conclude that cytogenetic response after Revlimid treatment may be an indicator for a decreased risk of AML progression.  Patients without a cytogenetic response to Revlimid are more likely to progress to AML than those who do show a cytogenetic response.

However, the authors feel their research cannot answer the question of whether or not Revlimid increases the risk of AML transformation.

Dr. Brigitte Schlegelberger, one of the study authors, said in an email to the MDS Beacon “A definite answer cannot be given, since it cannot be excluded that a subpopulation containing genetic lesions that trigger the transformation was present before treatment.” She added, however,”a leukemic transformation rate of more than 60 percent seems quite high.”

The authors suggest regularly monitoring del-5q patients taking Revlimid in order to identity patients who may be at an increased risk for AML progression..

For more information, please see the Annals of Hematology (abstract).

Although the drug was initially perceived to be equally effective across all risk categories and for all deletion 5q patients, recent research has shown that the baseline prognosis of various chromosome 5 abnormalities is different.  This is expected to affect the way Revlimid is prescribed for these conditions, including deletion 5q and monosomy 5.

Patients with deletion 5q syndrome have a significant deletion in the long arm of chromosome 5. This condition most frequently occurs in young female Low-risk MDS patients who need red blood cell transfusions, have anemia (low red blood cells counts), and have normal or average platelet counts. In the condition known as monosomy 5, patients lack one entire chromosome 5. Abnormalities on chromosome 5 are found in 20 percent of all MDS patients.

Revlimid, a structurally similar analog of thalidomide, was first approved by the U.S. Food and Drug Administration after a study showed that MDS patients responded positively.  Although the exact mechanism of Revlimid has yet to be fully characterized, it is believed to affect the genes that direct the cell’s growth and activity, particularly those associated with cytokines, cell death, and metabolism.

Results showed that 66 percent of Revlimid-treated patients became independent of red blood cell transfusions, while 44 percent of patients in the study showed a complete response.  Complete response is defined by the International Working Group as having a blood count of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL.  Patients had a median remission length of 116 weeks.  The drug has been determined as non-curative, but is used to delay or prevent progression to acute myeloid leukemia (AML), a type of blood cancer.

Since the drug was first approved for treating MDS, the potential benefits or effects on the specific subgroups of MDS patients with chromosome 5 abnormalities has not been studied until recently.

Researchers from the M.D. Anderson Cancer Center in Houston investigated the baseline prognoses of MDS patients without Revlimid treatment.  They demonstrated that there are different prognoses even among patients who have abnormalities on chromosome 5.  In addition, results showed that median survival progressively worsened with increased numbers of additional chromosomal abnormalities.

Researchers concluded that those with deletion 5q generally had lower-risk MDS than those with monosomy 5, and that they should not be treated as one group.  This may help oncologists offer Revlimid to patients whose prognoses predict improvement, rather than to those who may not benefit from the treatment.

For more details about the study, please see the related MDS Beacon article or the study in the journal Cancer (abstract).