#ASH09 meeting report: Myelodysplastic Syndromes (MDS)

This is my second to last report on the interesting new data coming out from the American Society of Hematology (ASH) meeting in New Orleans, LA earlier this month. They've taken a little long than I expected to get through due to our current workload and client reports, so sincere apologies for the backlog.

The final update will be a comprehensive one on chronic myeloid leukemia (CML), but today I wanted to focus on myelodysplastic syndromes or MDS for short.  Let's start with a basic question: what are they?

According to the NCI:

"The myelodysplastic syndromes (MDS) are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction.  MDS are diagnosed in slightly more than 10,000 people in the United States yearly for an annual age-adjusted incidence of 3.4/100,000 people."

MDS can arise naturally or as a result of chemotherapy given to treat acute myeloid leukemia (AML). Unfortunately, secondary MDS has a much poorer prognosis than de novo.

Standard treatment options include:

• myeloablative allogeneic stem cell transplantation
• azacitadine or decitabine
• lenalidomide for patients with deletions of chromosome 5q31.

A few years ago I remember sitting in a packed plenary session and getting goosebumps hearing about the lenalidomide data in patients with 5q31 deletions, or maybe it was the freezing hangar where the presentations were being held, but the science behind the concept was fascinating.  

The question is, what was hot this year at ASH in MDS?  Here's a roundup of some of the interesting data I thought was interesting and relevant to this disease:

1. Bortezomib (Velcade): This study suggested that Millennium's drug, currently approved for the treatment of myeloma and mantle cell lymphoma, may be effective in MDS. The study included 10 MDS patients with a median age of 64 years. Bortezomib was given at a dose of 1.3 mg/m² on days 1, 4, 8 and 11 every 28 days for a maximum of eight cycles. 6 patients completed all eight cycles. Of the 6 evaluable patients, 3 patients (50%) achieved a minor red blood cell response, and three patients (50%) achieved stable disease. 7 out of 10 patients survived to the median follow-up of 24 months.
   Four patients experienced severe neutropenia (low white blood cell count), and six patients experienced severe thrombocytopenia (low platelet count). 7 patients experienced other non-blood cell-related side effects including diarrhea, fever, skin rash, and pneumonia. 
   It was concluded that single agent bortezomib has some initial efficacy in achieving hematological improvement in MDS patients but a larger sample of MDS patients is needed to confirm these results.

2. Lenalidomide (Revlimid): Some German researchers looked at gene expression profiles to try and predict responses to therapy in MDS.  They found that single sample prediction could discriminate 3 out of 8 patients as possible responders to lenalidomide, but this was not correlated with the clinical course of those patients while on treatment with the drug.  In addition, it appeared that none of the MDS-patients receiving lenalidomide showed significant clinical response as defined by reduction of transfusion requirement by 50% or transfusion independence.  The researchers concluded that prediction of response to treatment with lenalidomide in patients with Non-Del 5q myelodysplastic syndrome by gene expression profiling remains difficult.
   A phase III trial looked at the optimal dosing for lenalidomide in 205 patients wo were randomised to receive either 5mg or 10mg of lenalidomide versus placebo.  Previous phase II trials have shown that lenalidomide resulted in transfusion-dependence (RBC-TI) in 67% of patients and complete cytogenetic response (CyR) in 45% of patients with RBC transfusion-dependent low or intermediate risk MDS with del5q.
   The researchers concluded that both doses of lenalidomide were generally well tolerated and achieved significant transfusion dependence and CyR. Lenalidomide 10 mg was associated with better RBC-TI and CyR than 5 mg, while maintaining a comparable safety profile.  The data supported the use of 10 mg as a starting dose, with dose reductions or discontinuations, if needed.

3. Arsenic trioxide (Trisenox):  A phase II study investigated the combination of ATO and ascorbic acid is tolerable.  The drug was administrated intravenously over 1 hour at the loading dose of 0.30mg/kg/day for 5 consecutive days, followed by 0.25mg/kg/day twice weekly for 15 weeks. Ascorbic acid 1000mg was given by IV within 30 minutes after each arsenic trioxide infusion.
   44 patients were enrolled in the study and 10 obtained a response (23%), including 1 complete remission. In 8 out of 10 responders, the response was evident within the first 8 weeks of treatment. 52% patients discontinued treatment because of various factors including disease progression (11%), severe adverse events (32%), drug unrelated adverse events (5%) and withdrawal of consent (5%).  Severe neutropenia and thrombocytopenia were observed respectively in 45% and 23% patients. 
Overall, the researchers concluded that the combination of ATO and ascorbic acid was tolerable and active in about 25% of MDS patients. The addition of ascorbic acid to ATO does not increase neither the toxicity nor the response rate to ATO.  The tolerability of this regimen is reduced in elderly and high risk patients.
4. Vorinostat (Zolinza): Merck's HDAC was initially approved for CTCL, a rare form of NHL, but we have seen little dramatic data from other clinical trials since.  There is, however, significant logic in testing epigenetic therapy in MDS.
   
   This phase I study looked at the combination of vorinostat with decitabine in the treatment of newly diagnosed AML or MDS using 6 different dosing schedules including concurrent and sequential therapy.  72 patients were entered into the study with a median age of 68 years and 58% were male. To date, 69 patients have discontinued. Of the 70 patients evaluable for safety, 69 experienced AEs, the majority of which were relatively mild ie grade 1/2 in severity and included nausea, diarrhea, fatigue, constipation, and vomiting.  In MDS patients receiving concurrent therapy, complete remission (CR) was achieved in 2 out of 5 patients, stable disease (SD) in 1 patient, partial remission (PR) in 1 patient, and hematologic improvement in 1 patient; all 6 of the patients who received sequential treatment experienced SD.
   Overall, although preliminary, the data is promising and indicates that the combination of vorinostat and decitabine, either concurrently or sequentially, is possible without significant toxicity.

In all, while MDS is a particular difficult to treat disease, the initial results suggest that further investigation of drugs such as bortezomib, lenalidomide, arsenic trioxide and vorinostat is warranted and if further studies show more durable and repeatable responses, we may potentially see some new treatment options for MDS in the near future.