Elevating the Treatment Standard in Older Patients with AML
The final case in our series on myeloid neoplasms
Sanam Loghavi, Kamran Mirza, Curtis Lachowiez, Courtney D. DiNardo | | Longer Read
72-year-old woman with a history of chronic renal disease and coronary artery disease, referred to our institution with newly diagnosed acute myeloid leukemia.
Complete blood count and differential (reference range)
Bone marrow morphology
Blasts were negative for myeloperoxidase.
Flow cytometry immunophenotyping
Aberrant myeloid blasts (8%) positive for CD13, CD33, CD34, CD38, CD117, and CD123; negative for cytoCD3, CD7, CD19, HLA-DR, and MPO.
Routine cytogenetic studies show an abnormal female karyotype – 47,XX,+8/46,XX
Next-generation sequencing studies showed the following mutations:
Acute myeloid leukemia with minimal differentiation.
The pathologist’s view
In cases of acute myeloid leukemia (AML), the role of the pathologist doesn’t stop at the identification of 20 percent blasts. Gone are the days when morphology and cytochemistry to differentiate myeloid from lymphoid leukemia was considered state-of-the-art diagnostics. An ever-increasing understanding of the pathogenesis of AML, with evolution of therapeutics, requires us to go beyond morphology and phenotype and play a critical role in risk stratification and treatment decisions.
From the diagnostic perspective, before deeming an AML “not otherwise specified,” a panel of phenotypic, cytogenetic, and genetic abnormalities must be queried. Once a diagnosis of acute leukemia is established, we must test for recurrent cytogenetic and molecular abnormalities that inform prognosis and therapeutic strategies. This includes karyotypic analysis for recurrent cytogenetic abnormalities and gene sequencing to assess for recurrent somatic mutations with diagnostic and predictive value. Based on functional status and the presence or absence of mutations, patients are stratified into groups based on their eligibility to receive intensive chemotherapy. The identification of specific gene mutations – including those involving FLT3, IDH1/2, or TP53 – now have clear therapeutic implications and inform selection of targeted therapies, and the list of such mutations continues to grow.
Because morphology, phenotype, and genetics play key roles in the prognostic and therapeutic decision tree, sampling is crucial. Without appropriate sampling, important genetic factors cannot be accurately assessed. In this case, while an adequate differential cell count was performed on the bone marrow touch imprint – allowing us to establish a diagnosis of acute leukemia – a poor-quality aspirate smear was responsible for the underestimation of blast percentage by flow cytometry and of mutation VAFs by next-generation sequencing. As pathologists, our duty to the patient does not stop at diagnosis; it includes incorporation of the results of ancillary studies and rectifying potential discrepancies to enable our clinical colleagues to offer patients the best possible options.
The hematologist’s view
Recent approvals of new and effective targeted AML therapies have provided renewed optimism in a disease where treatment remained stagnant for nearly 30 years – but these advancements in therapy present clinicians with new management challenges.
The initial approach in any patient with newly diagnosed AML requires ascertaining the acuity of the disease and ruling out acute promyelocytic leukemia. Is a proliferative leukocytosis or leukostasis present, necessitating urgent cytoreduction? Is there evidence of an underlying coagulopathy or systemic infection? Outside of these emergent scenarios, data suggest that treatment delays to complete a diagnostic workup are safe (1).
Our 72-year-old patient presented with relatively asymptomatic pancytopenia. Her acute translocation screen was negative, including for the presence of a PML-RARA translocation. A bone marrow examination demonstrated 30 percent myeloblasts, trisomy 8, and somatic mutations in RUNX1 and IDH2 in a background of mild trilineage dysplasia.
After confirming the diagnosis of AML and ruling out the need for urgent intervention, attention should be directed at risk stratification (2,3), selecting induction therapy, and considering consolidative allogeneic stem cell transplantation. Intrinsic factors, such as karyotype and mutations (4), and extrinsic factors, such as comorbidities and performance status (5), inform treatment decisions. Adding to these complexities is the sobering fact that the median age of AML diagnosis is 68, and older patients with even the most favorable risk have inferior outcomes with standard induction.
Due to a history of chronic renal disease and coronary artery disease, the patient was considered ineligible for intensive chemotherapy. Initiation with azacitidine in combination with venetoclax was recommended.
The reduced efficacy (CR rates of 30–45 percent) and increased mortality observed in older patients treated with standard induction is partially attributable to increases in relapse (6,7), frequency of adverse-risk disease, and medical comorbidities (5,8). In adults over 70, intensive chemotherapy resulted in dismal overall survival (5,8). Those deemed ineligible for curative intensive therapy with or without transplantation are often offered single-agent HMA or LDAC therapy with comparatively modest expectations (9,10).
Fortunately, recent therapeutic advancements are changing the natural history of AML. Treatment incorporating the targeted BCL2 inhibitor venetoclax in combination with HMAs (HMA+VEN) has emerged as a safe and strikingly effective therapy for older AML patients across all spectra of disease (11,12).
In the original phase Ib dose escalation and expansion study of HMA+VEN (11) and the recently reported confirmatory international phase III VIALE-A trial comparing HMA+VEN to azacitidine (12), the median age of study subjects was 76 years, with an early mortality rate of 7 percent, CR/CRi rate of 66 percent, and median overall survival of 15 months. Responses to HMA+VEN were rapid, with a median time to CRc of 1.2–1.3 months and median time to best response of 2.1 months. These increased and early responses resulted in a higher portion of patients achieving durable transfusion independence compared to single-agent treatment (12). Patients with MRD-negative CR (as determined using standardized multi-parameter flow cytometry) fare remarkably well, with a two-year survival rate of 73 percent.
Of importance, HMA+VEN is generally well-tolerated. Common non-hematologic adverse events are predominantly gastrointestinal, low-grade, and manageable with supportive care. Infectious complications, particularly febrile neutropenia, are increased, though 30-day mortality does not differ significantly compared to HMA monotherapy (12). Tumor lysis syndrome can rarely occur (~1 percent), but a VEN ramp-up dosing scheme during initiation mitigates this risk.
Our patient’s IDH2 mutation is predictive of a response to HMA+VEN. The patient obtained a complete remission with negative measurable residual disease and remains in remission four years from diagnosis.
Unlike other targeted therapies, venetoclax is not dependent on a specific mutation. In VIALE-A, all genomic subgroups experienced improved responses with HMA+VEN as compared with HMA alone. However improved overall survival was apparent only in particular molecular groups (13). Mutations in IDH1/2 impart leukemic cell dependency on BCL2, increasing susceptibility to apoptosis upon exposure to VEN (14). Patients with IDH1/2 mutations in VIALE-A demonstrated favorable CR rates of 75 percent and a HR for death of 0.34. Other mutations, such as NPM1 and splicing factor mutations, may also provide VEN sensitivity (13,15,16).
Despite improved responses in patients with TP53 mutations treated with HMA+VEN over azacitidine (CRc: 55 percent vs. 0), this group remains at high risk for relapse. Mutations in intracellular signaling genes are additionally recognized as adaptive resistance mechanisms to HMA+VEN, warranting close molecular surveillance on treatment. Mutations in RUNX1 in the absence of co-occurring mutations in NPM1 denote adverse-risk disease (2); however, as our case highlights, certain molecular groups have yet to be validated in large cohorts treated with HMA+VEN. Although RUNX1 mutations may predict resistance to VEN-based therapy, co-mutations in IDH2 appear to abrogate this negative prognostic impact.
The results of VIALE-A usher in a long-awaited treatment standard for older patients with AML and highlight exciting opportunities to harness our understanding of AML biology to exploit molecular vulnerabilities and individualize treatment. Ongoing investigation is needed to define the differential impact of co-occurring mutations on outcomes to HMA+VEN, assess the safety and efficacy of additional targeted agents in combination with HMA+VEN, and develop effective therapies for relapsed patients or those with persistent MRD positivity. In the face of these challenges, VIALE-A confirms that HMA+VEN represents a new foundation of care upon which the future of AML therapy for older patients will be built.
Discover our other myeloid cases...
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