ASH Clinical News October 2016 | Page 27

CLINICAL NEWS

The TP53 mutation , a common molecular abnormality in myeloid malignancies such as myelodysplastic syndromes ( MDS ), is associated with poor outcomes ; however , it is unclear whether specific characteristics of the mutation can affect prognosis .

At the 2016 ASH Meeting on Hematologic Malignancies , Karam Al-Issa , MD , of the Leukemia Program at the Cleveland Clinic in Cleveland , Ohio , presented results of a DNA sequencing study that confirmed the poor prognosis associated with TP53 mutations and that outcomes varied depending on the type of mutation and variant allele frequency ( VAF ).

Dr . Al-Issa and colleagues sequenced DNA samples from 732 patients with MDS and related myeloid malignancies ( median age = 70 years ; range = 24-89 years ) to detect the presence of TP53 mutations , as well as 61 other genes that have been described as recurrently mutated in MDS .

A total of 80 mutations were detected in 73 patients ( 10 %): 66 were missense ( 88 %), seven were nonsense ( 9 %), and seven were frame shift deletions / insertions ( 9 %).

Compared with a control group of 659 patients with wild-type TP53 , patients with mutated TP53 had higher :

• white blood cell count ( 3.9x10 9 / L vs . 4.6x10 9 / L ; p = 0.04 )

• bone marrow blast percentage ( median = 3 vs . 9 ; p = 0.1 )

• risk category by revised International Prognostic Scoring System ( 27 % vs . 56 %; p = 0.01 )

TP53 mutations were identified as driver mutations in 20 percent of samples , as passengers in 40 percent , and as mosaic in the remaining 40 percent .

Mutation positions included : 19 ( 24 %) in the DNA binding domain , two in the transactivation domain ( 3 %), one in the tetramerization domain ( 1 %), and 58 in an “ other ” locations ( 72 %).

The authors also found that the TP53 mutation commonly occurred with the following genes :

• TET2 ( 16 %)

• PRPF8 ( 13 %)

• ASL1 ( 11 %)

• DDX54 ( 8 %)

• DNMT3A ( 8 %)

• IDH2 ( 8 %)

TABLE 2 . Overall Survival , According to VAF of TP53 Mutation

After a median follow-up of 16.4 months , the median overall survival ( OS ), measured from the time of MDS diagnosis to time of death or last follow-up , was 8.24 months in the entire patient group .

The type of mutation ( passenger or driver ) affected the length of OS : Patients with TP53 as driver mutations had a shorter OS compared with those with TP53 as passenger mutations ( median = 2.2 vs . 13 months ; p = 0.02 ). Similarly , lower TP53 VAF was associated with longer OS ( TABLE 2 ).

Among the 54 patients with available therapy data , 34 were treated with the hypomethylating agents ( HMAs ) azacitidine or decitabine as first-line therapies . Eight of these patients responded ( 7 complete remissions and 1 partial remission ), and 19 had stable disease . Overall , rates of OS were similar among patients treated with HMAs and other therapies ( including chemotherapy ). The investigators observed that patients who received hematopoietic cell transplantation ( HCT ) had superior OS , compared with patients who did not receive HCT ( median OS = 14.9 vs . 8.9 months ; p = 0.05 ).

“ HCT remains the best available option , but the outcome remains poor ,” Dr . Al-Issa said . “ Treatment with HCT remains a valid treatment option in a subset of patients , but novel treatment strategies are desperately needed .” He also noted that a larger study is required to confirm these results .

REFERENCE

Al-Issa K , Sekeres MA , Nielsen A , et al . TP53 mutations and outcome in patients with myelodysplastic syndromes ( MDS ). Abstract # 89258 . Presented at the ASH Meeting on Hematologic Malignancies , September 16-17 , 2016 ; Chicago , IL .

Adolescent and young adult ( AYA ) patients , defined as those between the ages of 15 and 29 years , and non-white patients are often under-represented in clinical trials of novel agents in hematologic malignancies , meaning that these patients might not benefit from the therapeutic advances gained through these trials . In two studies presented at the 2016 ASH Meeting on Hematologic Malignancies , researchers assessed efforts to increase clinical trial participation in these under-represented patient populations : the first in AYA patients with non-Hodgkin lymphoma ( NHL ) 1 and the second in AYA patients with acute lymphocytic leukemia ( ALL ) and acute myeloid leukemia ( AML ). 2

Adolescents and Young Adults With Non-Hodgkin Lymphoma Over the past 25 years , the incidence of NHL in AYAs has increased , with diffuse large B-cell lymphoma ( DLBCL ), Burkitt lymphoma , anaplastic large cell lymphoma , lymphocytic lymphoma , and primary mediastinal B-cell lymphoma as the most common subtypes in those 15 to 19 years old .

AYA patients with NHL also have increased relapsed rates and mortality , compared with pediatric and adult NHL patients .

Melissa A . Crawley , MD , of the Department of Hematology and Oncology at the University of Tennessee Health Sciences Center / West Cancer Center in Memphis , Tennessee , and colleagues questioned whether being treated at adult centers could increase the availability of clinical trials for AYA patients with NHL and , subsequently , their outcomes .

Dr . Crawley and investigators conducted a keyword search of “ NHL ” in the Clinical Trials . gov database to identify trials of novel agents in hematologic malignancies and collected data about the included age groups , sample size , investigational agents , and lymphoma subtypes . They also assessed whether the study sites were members of the Children ’ s Oncology Group ( COG ) – a clinical trials group supported by the National Cancer Institute that is devoted exclusively to pediatric cancer research .

Trials were excluded from the analysis if the study regimen did not contain a novel pharmacologic agent or if a study focused solely on a transplant conditioning regimen .

A total of 404 trials were included in the analysis , 61 of which ( 15 %) were studies of novel agents that were open to those younger than 18 years . The most commonly studied drug classes included :

• cellular therapy ( chimeric antigen receptor-T cells , donor lymphocytes , and cytotoxic T lymphocytes ; n = 7 )

• tyrosine kinase inhibitors ( n = 7 )

• novel small molecules ( n = 7 )

• monoclonal antibodies ( n = 5 )

See TABLE 3 ( on page 26 ) for clinical trial enrollment analysis .

Of the 343 trials that were limited to adult patients at least 18 years old , twothirds ( 227 ) allowed the enrollment of patients with DLBCL , Burkitt lymphoma , anaplastic large cell lymphoma , lymphocytic lymphoma , follicular lymphoma , and primary mediastinal B-cell lymphoma – the most common lymphoma diagnoses in AYA patients .

“ All agent classes were represented in trials open to patients who were at least 18 years old ,” Dr . Crawley and authors noted . “ However , three agent classes were excluded from clinical trials in the under-18 subset : BiTE immunotherapy , PI3K inhibitors , and pleiomorphic pathway modifiers .”

Notably , more than half of these trials ( n = 178 ; 51 %) had at least one study site that was a member of COG . “ While this suggests that AYAs treated at COG member sites may have access to trials studying novel agents , the extent to which AYAs are being enrolled in these trials requires further study ,” the authors concluded .

Under-Representation of Minorities in Acute Lymphocytic and Acute Myeloid Leukemias Compared with white and Asian children with ALL and AML , patients in underserved populations ( including African- American and Hispanic children , Hispanic females , and AYA patients 15 to 39 years old ) have worse survival outcomes . In the second study , Nupur Mittal , MD , and colleagues compared clinical trial enrollment rates among these populations before and after implementation of a focused initiative to enhance trial enrollment among these patients and , potentially , address disparities in survival .

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