Article
VA National Precision Oncology Program
The VA National Precision Oncology Program is one of the largest clinical DNA sequencing programs in the US with integrated consultation services...
Ryan Chiang is a Resident at Stanford University Medical Center, Department of Medicine in Stanford, California. Daphne Friedman is a Staff Physician and Sendhilnathan Ramalingam is a Fellow, both at Durham Veterans Affairs Medical Center in North Carolina. Kelsey McHugh is a Staff Pathologist at Cleveland Clinic Foundation, Department of Pathology in Cleveland, Ohio. Vishal Vashistha is a Staff Physician at Raymond G. Murphy New Mexico Veterans Affairs Medical Center, Section of Hematology and Oncology in Albuquerque, New Mexico. Daphne Friedman is an Associate Professor of Medicine and Sendhilnathan Ramalingam is a Fellow, both at Duke University Medical Center in Durham, North Carolina.
Correspondence: Vishal Vashistha (vishal.vashistha@va.gov)
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.
Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.
We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.11,12 As of now, there are no treatments specifically targeting BCOR mutations.
Although there are novel targeting agents with proven efficacy for both FLT3 and IDH1 mutations (Figure), it is difficult to determine which pathogenic mutation drives disease onset. No evidence suggests that these drugs could be administered in tandem. At the present time, interest is directed towards targeting all AML subclones simultaneously, which could reduce the likelihood of evolution among founder clones.7,10,13 In their comparison between molecular profiles and outcomes of patients with AML, Papaemmanuil and colleagues observed that > 80% of patients with AML harbor ≥ 2 driver mutations concurrently.14 Moreover, FLT3-ITD and IDH1 mutations tend to co-occur in approximately 9 to 27% of AML cases.15-18 Available targeted agents for AML are relatively new and hematologists’ familiarity with these drugs is continuing to grow. As the number of novel agents increases, investigations directed toward assessing the safety profile and efficacy of combining targeted agents will be beneficial for patients with AML with ≥ 1 driver mutation.
For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.
The VA National Precision Oncology Program is one of the largest clinical DNA sequencing programs in the US with integrated consultation services...
The VHA is uniquely positioned to address the integration of germline genetic testing into precision oncology practice due to its outsized role in...
CLL incidence by race and location