The findings were presented at the 2011 American Society of Hematology (ASH) meeting held in December.

The results need to be considered carefully, however, because the analysis compares the rate of second cancers among Revlimid-treated MDS patients in clinical trials with the rate of cancer in the general public.

A more relevant comparison would be to look only at patients within the same controlled clinical trials, and compare cancer rates for patients treated with Revlimid with rates for patients not treated with Revlimid.

Similar to the current MDS study, an analysis involving multiple myeloma patients showed that cancer rates among patients treated with Revlimid were much the same as those in the general public (see related Myeloma Beacon news).

However, other studies showed that myeloma patients treated for long periods with Revlimid in controlled clinical trials were at significantly higher risk of developing a second cancer compared to myeloma patients in the same trials who were not treated with Revlimid (see additional Myeloma Beacon news).

Revlimid (lenalidomide) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of lower-risk myelodysplastic syndromes (MDS) patients who have the deletion 5q chromosomal abnormality and are dependent on red blood cell transfusions.

In April 2011, the FDA began investigating the possibility that Revlimid may cause additional, or secondary, cancers  (see related Beacon news).  The investigation was started based on the results from clinical trials in patients with the blood cancer multiple myeloma.

The trial results suggested that Revlimid may increase the risk of developing new types of cancers in patients taking the drug for extended periods of time.  However, despite its investigation, the FDA advised patients currently taking Revlimid to continue treatment.

In the current study, European and American researchers retrospectively analyzed five clinical trials involving lower-risk MDS patients to determine if Revlimid use was associated with an increased risk of additional cancers in MDS patients.

The analysis included data from 557 lower-risk MDS patients who had received Revlimid treatment. The median patient age was 71 years; 72 percent of patients were 65 years or older.

Of the 557 patients included in the analysis, 16 percent had previously had cancer including skin, brain, breast, and lung cancer.

The researchers found that 5 percent of patients developed at least one secondary cancer after a median of 13.5 months of therapy; of these patients, 18 percent had a prior history of cancer.

The researchers also determined that 2.6 percent of patients developed a secondary cancer each year.

They then compared this rate of cancer development to the rate of new cancer cases in the general public, which are reported to the Surveillance, Epidemiology, and End Results cancer registry, to determine if Revlimid-treated MDS patients were more likely to develop secondary cancers.

The cancer registry shows that 2.1 percent of people who are at least 65 years old develop cancer every year.

For more information, please see abstract 1704 at the ASH 2011 meeting website.

Based on their findings, the researchers concluded that tobacco use may influence the biology of the disease and suggested that lower-risk myelodysplastic syndromes (MDS) patients may improve their outcomes if they discontinue any tobacco use.

The study results were presented during a poster session at the 2011 American Society of Hematology meeting last month.

Previous studies have linked tobacco use to the development of MDS. Other studies have shown that smoking decreases survival in certain MDS patients (see related Beacon news).

In the current study, researchers retrospectively compared the outcomes of MDS patients treated at the Moffitt Cancer Center who had a history of tobacco use (487 patients) to patients who had never used tobacco products (256 patients).

Tobacco use included cigarettes, cigars, pipes, snuff, and chew tobacco.

The researchers found that there were no statistically significant differences in age, type of MDS, presence of chromosomal abnormalities, red blood cell transfusion dependence, blood ferritin levels, or Vidaza (azacitidine) or Dacogen (decitabine) use between the tobacco users and the patients with no history of tobacco use.

However, the researchers found that among lower-risk MDS patients, the share of patients who had a history of tobacco use were significantly more likely to have chromosomal abnormalities that increased their risk of progressing to acute myeloid leukemia (9 percent of patients) than lower-risk MDS patients who had never used tobacco (2 percent).

Likewise, a higher percentage of lower-risk MDS patients who had a history of tobacco use progressed to acute myeloid leukemia (18 percent) than lower-risk MDS patients who did not have a history of tobacco use (10 percent). 

Tobacco usage did not affect the rate of disease progression for patients with higher-risk MDS.

After a median follow-up time of 55 months, the median overall survival for lower-risk MDS patients who had never used tobacco was significantly longer (69 months) than for lower-risk MDS patients who had used tobacco (48 months).

When the researchers compared data from lower-risk MDS patients who had formerly used tobacco to those of current tobacco users, they found that those who had given up tobacco had a median overall survival of 50 months, compared to 38 months for those still using tobacco.

Overall survival was similar among higher-risk MDS patients who had never used tobacco (22 months) and those who were tobacco users (18 months).

For more information, please see abstract 3790 at the ASH 2011 meeting website.

Specifically, the patients benefited from donor stem cell transplants without T-cells, a type of white blood cell.

Over 60 percent of patients experienced survival times greater than five years, and the rate of graft-versus-host disease, a common transplant-related complication, was low.

According to the researchers, these findings support the use of transplantation without T-cells in lower-risk myelodysplastic syndromes (MDS) patients.

The findings were presented at the 2011 American Society of Hematology (ASH) meeting last month.

Donor stem cell transplantation, also called allogeneic stem cell transplantation, is the only curative treatment for patients with MDS. However, this treatment is typically not considered early in the treatment plan for patients with lower-risk MDS due to the high risk of transplant-related complications.

Graft-versus-host disease is a common transplant-related complication, in which the donated stem cells attack the body’s cells. The rate of graft-versus-host disease decreases if mature T cells are removed from the donor cells before they are transplanted. T cells are a type of white blood cell that helps fight infections and tumor cells. They have also been identified as a cause of transplant rejection.

In the present study, researchers evaluated survival outcomes of 44 lower-risk MDS patients who underwent T cell-depleted stem cell transplantation early in their treatment plan. The median patient age was 37 years, and the median time from diagnosis to transplant was 0.6 years.

Prior to transplantation, patients received chemotherapy, with or without high-dose total body irradiation. Most of the patients also received anti-thymocyte globulin as preventative treatment for graft rejection. For 55 percent of patients, the transplant donor was a sibling, whereas 45 percent underwent transplantation with an unrelated donor.

The researchers found that the donated stem cells started producing white blood cells, a sign of a successful transplant, a median of 11 days after the transplant.

Five patients experienced graft failure, in which the body does not accept the donated cells. Four of these patients received second transplants, the common treatment for this complication.

The two-year and five-year survival rates were 70.1 percent and 63.3 percent, respectively.

Of the 44 patients included in the study, 14 percent developed graft-versus-host disease; half of the cases developed within the first 100 days after the transplant, the other half developed more than 100 days after the transplant.

As of May 2011, 36 percent of patients had died. Their causes of death included graft-versus-host disease (11 percent of patients), infections (11 percent), graft failure or poor graft function (7 percent), side effects of the preparative therapy prior to transplantation (5 percent), and lung cancer (2 percent).

For more information, please see abstract 3831 at the ASH 2011 meeting website.

These results were presented during a poster session at the 2011 American Society of Hematology (ASH) meeting last month.

Velcade (bortezomib) is currently approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma and mantle cell lymphoma.

Belinostat (PXD 101), which is being developed jointly by the American company Spectrum Pharmaceuticals (NASDAQ: SPPI) and the Danish company TopoTarget, belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors.  HDAC inhibitors work by increasing the production of proteins that slow cell division and cause cell death.

Zolinza (vorinostat), which is also being investigated as a potential treatment for myelodysplastic syndromes (MDS), belongs to the same class of drugs as belinostat and has shown promising results in combination with Vidaza (azacitine) in MDS patients with poor health (see related Beacon news).

Previous clinical trials have shown that treatment with Velcade or belinostat alone is not effective against MDS.

However, proteasome inhibitors such as Velcade and HDAC inhibitors such as belinostat have been shown to act synergistically, prompting the researchers to investigate whether a Velcade-belinostat combination may be effective for patients with blood cancers.

The primary goal of this Phase 1 trial was to determine the maximum safe dose of Velcade and belinostat for use in future Phase 2 trials.

So far, 13 patients with acute myeloid leukemia, chronic myelogenous leukemia, or MDS with a median age of 59 years have enrolled in the study.  The participants had received a median of two prior treatments.

During a 21-day treatment cycle, the patients received 1.0 mg/m² to 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 followed by 500 mg/m² to 650 mg/m² of belinostat on days 1 through 5 and days 8 through 12.

Of the 12 patients who were evaluated for response to the combination treatment,  8 percent achieved a complete response and 33 percent maintained stable disease.

Side effects included low white blood cell counts, low platelet counts, and nerve damage in the limbs.  The researchers did not observe any dose-limiting side effects.

For more information, please see abstract 2598 at the ASH 2011 meeting website.

The findings were presented at the 2011 American Society of Hematology (ASH) meeting in San Diego last month.

In France, chemotherapy is typically administered in a hospital. However, the French National Health Service allows home administration of some chemo­therapy treatments after the first treatment cycle.

A group of French researchers, therefore, sought to investigate if Vidaza (azacitidine) could be safely administered at home.

Sixty-eight patients, including 51 with myelodysplastic syndromes (MDS), volunteered for this study after receiving their first cycle of chemotherapy in the hospital. Forty-eight of the study patients were treated with Vidaza.

The study participants were divided into two groups. One group continued to receive all doses of Vidaza administered at a hospital.  The other group received Vidaza at a hospital the first day of every treatment cycle, but all other doses of Vidaza in the treatment cycle were administered at home.

The researchers compared the number of treatment cycles the patients were able to complete, the dosage patients were able to tolerate, and problems with administration for both patient groups.

Results showed that over the 18-month study period, both groups received a similar median number of treatment cycles.

The two groups also experienced similar side effects, delays between treatment cycles, and hospitalizations between cycles.

The researchers also observed a high level of patient satisfaction in the home administration group.

They reported that all patients in the home administration group agreed to continue at-home treatment.

In some cases, home administration of Vidaza was not possible because of infection, low blood cell counts, or drug availability.

According to the researchers, further randomized studies are planned to compare the quality of life between patients receiving chemotherapy in the hospital or at home.

For more information, please see abstract 1719 at the ASH 2011 meeting website.

The study authors found that 50 percent of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) progressed to leukemia.

However, the results also showed that patients who responded or maintained stable disease survived significantly longer than those who did not respond.  The study investigators suggested that Sprycel could be a reasonable treatment option for MDS, CMML, and acute myeloid leukemia (AML) if researchers are able to develop a test that would predict which patients are likely to respond.

The findings were presented at the 2011 American Society of Hematology (ASH) conference in San Diego last month.

Sprycel (dasatinib), which is marketed by Bristol-Myers Squibb (NYSE: BMY),  is approved in the United States to treat patients with certain types of leukemia.   It is also being investigated by Bristol-Myers as a treatment for MDS and a number of other types of cancer.

Sprycel belongs to a class of drugs called kinase inhibitors, which may possess anti-cancer activity by stopping abnormal proteins from signaling for cancer cells to multiply.

In the present study, researchers evaluated the activity of Sprycel in 18 patients with higher-risk MDS, AML, and CMML.

The median patient age was 73.5 years, 72 percent of the participants had MDS, and all participants had previously failed Vidaza (azacitidine) or Dacogen (decitabine) therapy.

All patients received 100 mg of oral Sprycel daily; however, the dosage was increased to 150 mg daily for patients who tolerated the treatment but did not achieve at least a partial response.

Of the 18 patients included in the study, 17 percent responded to treatment and achieved a complete response without improvement in blood cell counts, 22 percent maintained stable disease, and 59 percent progressed.

The median overall survival time was 7.6 months, and the one-year survival rate was 38 percent. Among the patients with MDS or CMML (but not AML), half progressed to AML during the study, and the median time to progression for these patients was 4.4 months.

Patients who responded or maintained stable disease survived significantly longer (28.5 months) than those who did not respond (four months).

Eighty-three percent of patients discontinued treatment, primarily due to a lack of response or disease progression. The most common severe side effects were fatigue, infection, low blood cell counts, and low platelet counts.

For more information, please see abstract 1727 at the ASH 2011 meeting website.

Dr. Rami Komrokji of the Moffitt Cancer Center and Research Institute in Tampa, Florida, presented these results at the 2011 American Society of Hematology (ASH) meeting last month.

ARRY-614 is an oral drug that is being developed by Array BioPharma. It works by preventing the death of precursor blood cells, the cells that give rise to mature blood cells.  Maintaining more precursor blood cells may increase the number of healthy blood cells a patient has.

According to the study authors, death of precursor blood cells is common in lower-risk myelodysplastic syndromes (MDS) patients.

The goals of this Phase 1 study were to get preliminary results on whether ARRY-614 may be an effective MDS treatment and to identify the highest dose of ARRY-614 that is safe.

The study included 45 lower-risk MDS patients with a median age of 72 years and who had received a median of three prior therapies. Previous treatments included Vidaza (azacitidine) (58 percent of patients), red blood cell-stimulating agents (49 percent), Dacogen (decitabine) (42 percent), and Revlimid (lenalidomide) (40 percent). Eighty percent of patients required red blood cell transfusions.

The patients received one of the following three treatment schedules: 400 mg to 1,200 mg of ARRY-614 daily on an empty stomach, 200 mg to 300 mg twice a day on an empty stomach, or 400 mg daily after eating. Patients received treatment for a median of 20 weeks.

Of the 44 patients who could be evaluated for response, 30 percent experienced improved blood counts. Patients who received the highest dose of ARRY-614 (1,200 mg daily) had the highest response rate (38 percent).

The most common side effects were rash (31 percent), diarrhea (20 percent), dry skin (13 percent), and anorexia (11 percent).

The maximum tolerated dose was not reached at the once-daily oral doses studied.

Patients who received 300 mg twice a day on an empty stomach  experienced dose-limiting side effects.  As a result, the researchers discontinued use of the twice-daily dosing schedule.

Eighteen percent of patients required dose reductions and 18 percent discontinued treatment due to side effects.

For more information, please see abstract 118 at the ASH 2011 meeting website or Dr. Komrokji’s slide deck, which has been made publicly available by Array Biopharma.

The study authors also found that patients with mutations in the FLT-3 gene responded particularly well to the drug combination, yielding an overall response rate of 100 percent.

Dr. Guillermo Garcia-Manero of the MD Anderson Cancer Center in Houston presented these findings at the 2011 American Society of Hematology (ASH) conference in San Diego last month.

Zolinza (vorinostat), which is marketed by the U.S. pharmaceutical company Merck, is an oral drug already approved in the United States for a certain type of lymphoma. It also is approved for a similar use in Canada and Australia, but not in Europe.

Zolinza belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, which work by increasing the production of proteins that slow cell division, repair DNA mistakes, and control cell death. The drug panobinostat, which has been investigated as a potential treatment for myelodysplastic syndromes (MDS), belongs to the same class of drugs.

Zolinza is currently being investigated in combination with various other drugs as a potential treatment for MDS and another blood cancer called multiple myeloma. Recent results have shown that MDS patients in poor health may benefit from treatment with Zolinza in combination with Vidaza (azacitine) (see related Beacon news).

In preclinical studies, Zolinza showed anti-leukemia activity when combined with idarubicin (Idamycin) or cytarabine (Cytosar-U).

In the present study, the researchers evaluated the safety and activity of Zolinza, followed by idarubicin and cytarabine, as first-line treatment in 75 patients with acute myeloid leukemia and higher-risk MDS.

The median patient age was 52 years. In addition, 39 percent of patients had a normal number of chromosomes; 15 percent had mutations in the gene coding for the protein FLT-3. Mutations in the FLT-3 gene can lead to cancer.

Patients received 500 mg of oral Zolinza three times daily (on days 1 to 3 of the treatment cycle), 12 mg/m² of intravenous idarubicin three times daily (on days 4 to 6 of the treatment cycle), and 1.5 gm/m² of intravenous cytarabine continuously (on days 4 to 7 of the treatment cycle).

The overall response rate was 85 percent, with 76 percent achieving complete remission. For patients with FLT-3 gene mutations, the overall response rate was 100 percent.

At a median follow-up of 82 weeks, the median overall survival and event-free survival times for the overall patient population were 82 weeks and 47 weeks, respectively. Patients with FLT-3 gene mutations had better overall survival (91 weeks) and event-free survival (66 weeks) than the overall patient population. Patients with normal chromosomal numbers also had higher overall survival and event-free survival times (105 weeks and 68 weeks, respectively).

The most common side effects were diarrhea (73 percent), nausea and vomiting (65 percent), and skin reactions (38 percent). Four percent of patients died from treatment.

For more information, please see abstract 763 at the ASH 2011 meeting website.

Treatment with a combination of Vidaza (azacitidine) and Revlimid (lenalidomide) has previously been shown to be effective in higher-risk myelodysplastic syndromes (MDS) patients with or without chromosomal abnormalities.

The two new studies on the combined use of Vidaza and Revlimid were presented at the 2011 American Society of Hematology (ASH) meeting last month.

Phase 2 Trial: Simultaneous Treatment With Vidaza And Revlimid

Dr. Mikkael Sekeres of the Cleveland Clinic presented results from a Phase 2 trial showing high efficacy of the Vidaza-Revlimid combination therapy in higher-risk MDS patients who had not been previously treated with either drug.

The study included 36 patients with a median age of 68 years. They had been diagnosed a median of eight weeks before signing up for the trial.

The patients were treated with 75 mg/m² of Vidaza daily for the first five days of a 28-day treatment cycle.  They also received 10 mg of Revlimid daily for the first 21 days of the treatment cycle.

Patients could receive a maximum of seven cycles of combination therapy, after which they could choose to continue treatment with Vidaza alone.  The study participants received a median of five treatment cycles.

Overall, 72 percent of patients responded to the Vidaza-Revlimid combination treatment after a median of three months: 42 percent of patients achieved a complete response lasting for a median of 16 months, plus 28 percent of patients showed improved blood cell counts.

The patients who experienced a complete response had a median overall survival of 27 months; 50 percent of these patients progressed to acute myeloid leukemia at a median of 20 months.

The most common severe side effects included low white blood cell counts with fever (31 percent), heart problems (11 percent), lung problems (11 percent), infections (8 percent), blood clots (6 percent), and central nervous system bleeding (6 percent).

Three patients (8 percent) died during the trial.

Phase 1 Trial: Vidaza Treatment Immediately Followed By Revlimid Treatment

Results of a recent Phase 1 study of Vidza followed by high-dose Revlimid were summarized in a poster presentation. The results show that the combination may be effective and safe in certain higher-risk MDS patients.

This study included 28 patients with MDS, chronic myelomonocytic leukemia, or acute myeloid leukemia.

Study participants could be any age if they were unresponsive to their previous treatment (22 patients).  Patients were also accepted if they were older than 60 years and had not received prior treatment for their condition (six patients).  The median age of the study participants was 65 years.

The patients received 75 mg/m² Vidaza intravenously (in the vein) for the first five days of a 28-day treatment cycle.

They then received 10 mg to 75 mg of Revlimid starting on the sixth day of the treatment cycle for five consecutive days or 75 mg of Revlimid for ten consecutive days

The study participants completed a median of 1.5 treatment cycles.

The researchers were able to evaluate five of the six patients who had not received prior treatment; 60 percent of these patients achieved a complete response.  They were treated with 25 mg or 50 mg of Revlimid for five consecutive days following Vidaza treatment.

None of the previously treated patients responded to the sequential treatment; 47 percent maintained stable disease.

The most common side effects included fatigue, loss of appetite, constipation, rash, fever, and weight loss.

No dose-limiting side effects were observed, so the maximum tolerable Revlimid dose was not determined.

One of the patients who received 75 mg of Revlimid for ten days after Vidaza treatment died.  The remaining six patients in this treatment group continued treatment without any severe side effects.

A Phase 2 trial is currently under way to study the effects of 50 mg of Revlimid for ten consecutive days after Vidaza treatment in 40 newly diagnosed patients.

For more information, please see abstract 607 and abstract 2613 at the ASH 2011 meeting website.

The findings were presented during a poster session at the 2011 meeting of the American Society of Hematology (ASH) in December.

AR-67 is a drug being developed by the biopharmaceutical company Arno Therapeutics for the treatment of various forms of cancer.  It causes cell death by inhibiting the cell’s DNA repair mechanisms.

In this study, the researchers wanted to evaluate the efficacy and safety of AR-67 in myelodysplastic syndromes (MDS) patients and chronic myelomonocytic leukemia (CMML) patients who previously failed other treatments.

The study included eight MDS patients and two CMML patients, who had  a median age of 69 years. The participants had failed a median of two prior treatments, including Vidaza (azacitidine), Dacogen (decitabine), and Clolar (clofarabine).

Nine of the ten patients received 7.5 mg/m² of AR-67 by intravenous infusion on five consecutive days every four weeks. One patient withdrew from the study before receiving treatment.

The patients completed a median of two treatment cycles.  However, two patients needed their dosage of AR-67 reduced to 6.3 mg/m² due to serious fatigue or low platelet counts.

Of the nine patients who received AR-67, 11 percent (one patient) responded to treatment for 170 days, and 22 percent (two patients) maintained stable disease for at least two months.

The most common side effects were low platelet counts (56 percent), low white blood cell counts (56 percent), and low red blood cell counts (56 percent).

Other side effects included diarrhea (44 percent), nausea (22 percent), swelling of the mucus membranes (11 percent), and fatigue (11 percent).

For more information, please see abstract 3820 at the ASH 2011 meeting website.