Conference Coverage

MDS genetic analysis identifies allogeneic HSCT candidates


 

– Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).

Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.

Dr. Amer M. Zeidan Mitchel L. Zoler/Frontline Medical News

Dr. Amer M. Zeidan

When patients have markers for poor outcomes, “consider alternatives to allogeneic HSCT,” such as enrolling them in a trial, Amer M. Zeidan, MBBS, advised at a conference held by Imedex. “For other patients, allogeneic HSCT is reasonable, especially [for] younger patients,” those less than 40 years old, said Dr. Zeidan, a hematologist/oncologist at Yale University in New Haven, Conn.

Allogeneic HSCT is the only potentially curative procedure for patients with MDS or MDN. Although an increasing number of these patients undergo transplantation, clinicians need to choose the patients they select for the treatment carefully. “Molecular testing is playing an increasing role in selecting the best candidates,” Dr. Zeidan said.

The largest reported genetic study of allogeneic HSCT in MDS patients involved 1,514 patients entered into a U.S.-based dataset during 2005-2015. Testing identified at least one mutation in 1,196 (79%) of these patients.

Analysis of data from these patients found a disparate pattern of posttransplant survival that appeared to link with gene mutations and other risk factors. The highest risk patients were those with a mutation in their TP53 gene, found in 289 patients (19% of the 1,514 tested) who had a median overall survival (OS) of 0.7 years and a 3-year OS of 20% (New Engl J Med. 2017 Feb 9;376[6]:536-47).

Among patients without a TP53 mutation, OS depended on age, with the best survival seen among patients less than 40 years old. Patients in this subgroup who also had no other high-risk features – no therapy-related MDS, a platelet level of at least 30 x 109 at the time of transplantation, and bone marrow blasts less than 15% at diagnosis – had the best OS, 82% at 3-years of follow-up. The studied cohort included 116 patients (8%) who fell into this low-risk, best-outcome category, the optimal population for receiving an allogeneic HSCT, Dr. Zeidan said. Another 98 patients (6%) who had at least one of these high risk feature had a median OS of 2.6 years and a 3-year OS of 49%.

Additional gene mutations further subdivided the older patients in the study, those at least 40 years old, into various risk subgroups. Older patients with a mutation in a ras-pathway gene had a 0.9 year median OS and a 3-year OS of 30%. This subgroup included 129 patients (9%). Among older patients with no mutation in the ras-pathway gene, mutations in the JAK2 gene also linked with worse survival, a median OS of 0.5 years and a 3-year OS of 28% of a subgroup with 28 patients (2%). The largest subgroup in the study was older patients with no mutations in the TP53, JAK2, or ras-pathway genes, a subgroup with 854 patients (56%), who had a median OS of 2.3 years and a 3-year OS of 46%.

The second recent report was a Japanese study of 797 MDS patients who underwent genetic testing and received an allogeneic HSCT through the Japan Marrow Donor Program. The investigators found identifiable mutations in 617 patients (77%) and documented that patients with a TP53 or ras-pathway mutation had a “dismal prognosis” when associated with a complex karyotype and myelodysplastic or myeloproliferative neoplasms. However, among patients with a mutated TP53 gene or complex karyotype alone, long-term survival following transplantation appeared possible (Blood. 2017. doi: org/10.1182/blood-2016-12-754796.

Two smaller, earlier studies (J Clin Oncol. 2014 Sept 1;32[25]:2691-8; J Clin Oncol. 2016 Oct 20;34[30]:2627-37) also implicated mutations in the TET2, DNMT3A, ASXL1, and RUNX1 genes as identifying MDS patients with worse OS following allogeneic HSCT, Dr. Zeidan noted, but the combination of a TP53 gene mutation and a complex karyotype appears to confer the worst prognosis of all. Patients with mutations in more than one of these genes fared much worse than those with single mutations.

Dr. Zeidan had no relevant disclosures.

On Twitter @mitchelzoler

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