Genomic determinants of the blood cancers

A heterogeneous group of blood cancers, leukemia is defined by distinct genetic and molecular anomalies. Genetic and molecular profiling are thus vital to risk stratification and targeted therapeutic strategies in these diseases. In a recent Penn Medicine Physician Interviews segment, Matthew Connor, MD, discussed the genomic determinants of treatment outcomes for the acute leukemias ALL, AML, and MPAL, and how rapid advances in the ability to sub-define types of leukemia based on molecular genetics has contributed to the diagnosis, prognosis, and treatment approaches for the blood cancers at the Abramson Cancer Center.

Background

Acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) have discreet physiological origins and genetic profiles. ALL affects lymphoid progenitor cells and is sub-classified on immunophenotyping into B-cell or T-cell variants. Most patients will have B-cell lineage acute lymphoblastic leukemia, with a smaller proportion having T-cell lineage. Common genetic mutations in ALL include ETV6, RUNX1, IKZF1 deletions, and CRLF2 rearrangements.

AML originates from myeloid precursors and is subtyped on the basis of genetics and morphology. Genetic mutations in AML include TP53, FLT3, NPM1, and IDH1/2.

Mixed phenotype acute leukemia (MPAL), a rare, aggressive form of the disease, possesses the characteristics of both ALL and AML.

Defining the genetic underpinnings of leukemia at Penn Medicine

“The way that we evaluate the cancer genome in patients with blood cancer is strikingly more advanced than even 10 years ago,” says Dr. Connor, who specializes in the blood cancers. “Here at Penn, it’s standard to send targeted next-generation sequencing panels for hundreds of potential oncogenes at the time of diagnosis in any patient with blood cancer.”

Whole genome sequencing and whole exome sequencing, Dr. Connor notes, offer a higher level of complexity, and guided by clinical presentation, are used to search for phenotypic clues in patients in whom the genetic cancer predisposition syndromes are suspected. At this time, he observes, both require higher analytical sensitivity and standardization to ensure equivalence with current targeted panels.

Targeted genetic sequencing has a faster turn-around time by comparison to whole or exome sequencing, Dr. Connor says, an advantage for patients with leukemia for whom early data aids risk stratification and eligibility for beneficial targeted treatments.

Advantages in treatment for ALL and AML

Actionable biomarkers in ALL and AML provide information relevant to high risk for relapse and drive decisions about therapy intensification in transplant and other areas of concern. “Increasingly though, actionable also now means targetable,” Dr. Connor says. “As we understand more about phenotypic markers and genomic drivers of leukemia, new treatments have emerged that really help us tailor therapy based on our testing.”

Acute lymphoblastic leukemia (ALL)

Dr Connor notes that with ALL, the most important determinant of a patient’s treatment course is their initial response to upfront therapy, a characteristic evaluated by testing for measurable residual disease with ultra-sensitive markers.

However, risk stratification for patients with ALL has a genomic component, which can affect considerations for treatment.

“Patients with very high-risk mutations like KMT2As or low hypodiploidy may benefit from consolidative allogeneic transplant if they achieve remission,” Dr. Connor says, noting that patients with standard risk disease generally don’t need such therapy intensification. At Penn Medicine, current approaches include multimodal testing at time of ALL diagnosis, a combination of multi-panel gene fusion testing, next-generation sequencing, FISH, conventional cytogenetics and PCR testing.

The most important genomic determinant in B-ALL is the Philadelphia chromosome, a fusion protein between BCR and ABL1 present in about a quarter of adult patients with the disease. Patients with this subtype are treated in a very different way compared to other forms of ALL, says Dr. Connor, in that their treatment incorporates oral therapies with tyrosine kinase inhibitors upfront and continuing therapy. 

Dr. Connor’s further considerations in ALL concern patients whose genomic profiles place them at higher risk of relapse after standard upfront therapy, as well as those whose oncogenic rearrangements confer a more standard risk, portending more favorable treatment outcomes. Patients with ALL at Penn Medicine receive the targeted tyrosine kinase inhibitors (TKIs), including advanced second and third generation TKIs for Philadelphia chromosome-rearranged ALL.

Acute myeloid leukemia (AML)

In AML, about 50 to 60% of adult patients will have an oncogenic mutation for which targeted therapy options are available. These mutations include FLT3, treated at Penn Medicine with TKI therapy both in the frontline and relapse setting, Dr. Connor says, as well as IDH anomalies, for which effective second-line therapies are available after relapse.

“In patients with high-risk KMT2A rearrangements or NPM1 mutations, we have oral therapy now with the menin inhibitors,” he adds. Approved by the FDA last year as second-line treatment options, the menin inhibitors are actively being studied at Penn and elsewhere in the frontline setting.

Mixed phenotype leukemia (MPAL)

Less than five percent of newly diagnosed patients with acute leukemia are classified as mixed phenotype acute leukemia, or MPAL, a high-risk subtype of leukemia that manifests the phenotypic markers of both AML and ALL. “This means that MPAL expresses both myeloid lineage markers like MPO and CD33 often, as well as either B-cell markers like CD19 or T-cell markers like CD3,” Dr. Connor explains. Historically, the median survival for patients with mixed phenotype leukemias is less than a year, he says, but this is likely improving with modern treatment methods.

Treatment for MPAL at Penn Medicine typically involves standard upfront ALL-style induction therapy involving multi-agent chemotherapy, corticosteroids, and the addition of anti-CD19 therapy with blinatumomab.

“The most important factor in determining the prognosis of MPAL is the ability of patients to undergo allogeneic transplant after achieving remission. And so, therapy that can lead to the highest likelihood of achieving a first complete remission is optimal here.”

Referrals and consultations

To refer a patient to the Penn Medicine Division of Hematology and Oncology, please call 877-937-7366 or refer a patient online.