ASH 2011 Conference Highlights

3 Dec. 2012

The American Society of Hematology (ASH) is the world’s largest professional society concerned with the causes and treatments of blood disorders. The mission of the Society is to further the understanding, diagnosis, treatment, and prevention of disorders affecting the blood, bone marrow, and the immunologic, haemostatic and vascular systems, by promoting research, clinical care, education, training, and advocacy in haematology. ASH attracts about 20,000 attendees every year (physicians, scientists, laboratory staff, pharmaceutical representatives).  Half of them are international visitors.  There the latest research results are presented and it is an opportunity for attendees to discuss and explain their work.

Dr Austin Kulasekararaj, Haematologist Consultant at King’s College Hospital, London kindly agreed to summarise the highlights of ASH 2011 for us.  He covered progress with existing therapies, promising trial data, new molecular mutations, as well as the revised IPSS (International Prognostic Scoring System).

 

MDS therapies

Combination therapy approaches both in low and high risk MDS was the focus of many presentations, building on the remarkable results obtained with 5-azacitidine and lenalidomide monotherapy.

A multicentre trial using combination therapy of 5-azacitidine (75 mg/m2 subcutaneously on days 1-5) plus lenalidomide (10 mg daily orally for 21 days out of 28 day cycle) in ‘high risk’ MDS patients showed response rate of 72%, with complete response seen in 42% and a median response duration of 16 months. The therapy was well tolerated with minimal toxicities (fever and cardiac) and significantly high response rates.

An interesting study from MD Anderson Cancer Centre assessed combination therapy of 5-azacitidine with vorinostat, a histone deactylase (HDAC) inhibitor in MDS and AML patients who were ineligible for another clinical trial or had liver or renal functions or had poor performance status. This combination was well tolerated in this ‘poor risk group’ of MDS patients with complete response rate of 26%.

Several other combination therapies of were studied in Phase 1 and Phase 2 trials, showing good tolerability and clinical activity

eg Panabinostat (HDAC inhibitor) plus 5-azacitidine,

Belinostat (HDAC inhibitor) and bortezomib (Velcade, proteosomal inhibitor)

Ezatiostat hydrochloride (Telintra) and lenalidomide (Revlimid)

Interestingly, studies using oral 5-azacitidine show good tolerability, with no drug accumulation, and promising clinical responses were observed, although these data are preliminary but the encouraging results show promise for oral azacitidine. A Phase 1 study also evaluated the safety of oral decitabine (Dacogen) in MDS patients and found to have a similar safety profile to intravenous decitabine.

A retrospective pooled analysis of MDS patients treated with lenalidomide (Revlimid) did not show a clear evidence that lenalidomide is associated with an increased risk of secondary cancers (second primary malignancies, SPMs) in lower risk MDS patients and the rate of development of SPMs was what would be expected for this age group when compared with US epidemiological database (SEER database). In another retrospective analysis of RBC transfusion-dependent patients with lower-risk MDS and del 5q, lenalidomide treatment was not associated with a higher risk of AML progression but led to a survival benefit.

Romiplostim (thrombopoietin agonists) showed an improvement in platelet count in one third of low risk MDS patients enrolled in a Phase 2 extension study, but unfortunately the trial was terminated early in view of transient increase in blast count which resolved when the drug was discontinued.

A few other selected studies presented included

• Home administration of 5-azacitidine (Vidaza) in France – showed feasibility, higher level of patient satisfaction and safety of administration. The home administration was not associated with increased side-effects or hospitalisation.
• Romiplostim (thrombopoietin agonists) to increase platelet counts after stem cell transplant.
• Role of azacitidine in Lenalidomide failure in del 5q MDS patients.
• Low dose clofarabine (5 mg/m2 vs. 7.5 mg/m2,dose finding study)-standard dose(D1 to D5) or alternate dosing (D1,D3,D5,D8 and D10), in patients failing 5-azacitidine therapy

The increased understanding of the molecular biology in MDS will help in future development of targeted therapies as the currently available therapies, although clinically effective, do not have a well-defined mechanism of action.

MDS pathogenesis

2011 has been an exciting year with the discovery of new class of molecular mutations in patients with myeloid neoplasms. The discovery of recurrent somatic mutations in RNA splicing factors in patients with MDS, especially in those with ring sideroblasts was highlighted in several presentations including the presidential symposium. Although the functional consequences of the altered splicing factors are being elucidated, this is a major breakthrough in the understanding of the pathogenesis of MDS with ring sideroblasts.

SF3B1 mutations are detected in 80-85% of patients with MDS associated with ring sideroblasts and is also present in 30% of patients with MDS overall. The mutations of the RNA splicing factors are the most common MDS-associated mutations yet to be described and these were detected as a result of whole genome/exome sequencing projects undertaken by several groups. Although SF3B1 mutations conferred a better prognosis, the prognostic impact of the other splicing factor mutations is not clear.

Prognostic models

IPSS-R

Recently, the provisional Revised International Prognostic Scoring System (IPSS-R) has been formulated for assessing the prognosis of primary MDS patients by the International working group for prognosis in MDS (IWG-PM). In this new system, as discussed by Dr.Greenberg in the MDS foundation symposium, cytogenetics remains the key stratification parameter and karyotypic abnormalities are classified into five prognostic subgroups with inclusion of more uncommon cytogenetic subsets. The depth of cytopenias was also considered and the information was obtained from 7012 patients who had not received any disease altering therapy. The IPSS-R divided MDS patients into 5 prognostic groups, with median overall survival of 8.7 years for very low risk group versus 0.8 years for the very high risk group. The value of incorporating of molecular abnormalities into the prognostic scoring systems was also debated and various groups also validated the impact of mutations on different prognostic scoring systems in MDS.

We are definitely achieving a better understanding of the mutations associated with MDS and refining risk model, but it is difficult to know just how any of these might translate into new therapies.

 

We thank Austin for his contribution to our scientific news.