Minimally Invasive Blood Sampling for BCR::ABL1 transcript Monitoring

For most chronic phase (CP) chronic myeloid leukemia (CML) patients receiving treatment with tyrosine kinase inhibitors (TKIs), age-matched mortality is similar to patients without CML. However, long-term survival depends on treatment response and monitoring is critical. The National Comprehensive Cancer Network and European LeukemiaNet recommend monitoring BCR::ABL1 IS transcripts every 3 months to ensure that treatment milestones are met and to confirm adherence to therapy. A recent analysis of 1,188 newly diagnosed CML patients on Medicare in the US highlighted that only 32% had optimal monitoring defined as at least 3 tests in the first year. For patients living in remote locations, monitoring can be financially burdensome due to the need for time off from work and the cost of travel. In addition, the COVID-19 pandemic has highlighted that traveling for monitoring can be both challenging to arrange and potentially unsafe, particularly for an individual with vulnerable health.

To address this need, we measured e13a2 and e14a2 BCR::ABL1 transcripts in capillary blood collected using the Tasso-M20 device (Tasso, Inc., Seattle, WA). Using this device patients can collect blood samples at home and mail them to a laboratory. Written informed consent was obtained from 20 CP CML patients undergoing BCR::ABL1 transcript monitoring for clinical indications at our institution. Clinical BCR::ABL1 IS transcript monitoring was performed using Xpert BCR-ABL Ultra (Cepheid, Sunnyvale, CA), which requires 4 ml of venous blood. The research sample was obtained within 10 days of the clinical measurement. Tasso-M20 was applied to the deltoid muscle via adhesive and 70 mcl of blood was collected into 4 absorbent plugs and dried. Tasso-M20 samples were sent to the laboratory, maintained at room temperature, and processed within 2 weeks of collection (mean, 8.8 days and range, 6-13 days) to simulate time for shipment and transportation. BCR::ABL1/ABL1 percent ratios were calculated.

The median patient age was 52.4 years (range, 28-83 years) and 60% were female. We found a strong correlation between the %BCR::ABL1 transcripts in capillary vs venous blood, (r=0.96 between the two log10 transformed measures) (Figure 1A). Figure 1B displays the bias as a function of the average log10 (% BCR::ABL1) with a Bland-Altman plot, where the bias is the difference between the log10 transformed values of the venous and capillary samples. The capillary assay was able to quantify accurately molecular responses associated with survival benefit (BCR::ABL1 transcripts ≤1%) and major molecular response (BCR::ABL1 transcripts ≤ 0.1%), but was less reliable at quantifying BCR::ABL1 transcripts < 0.06% due to assay sensitivity. To improve sensitivity, the device has been modified to collect 300 mcl of blood. All but one patient reported minimal or no pain with the capillary blood extraction.

In conclusion, capillary blood BCR::ABL1 transcript monitoring has the potential to improve CML molecular monitoring adherence by allowing at home patient-initiated sample collection. Home monitoring would limit the exposure risk that accompanies clinic and hospital visits during this, and future, pandemics. Globally, this approach could facilitate CML diagnostic testing for patients, a requirement to obtain therapy, and promote monitoring in geographic locations where conventional PCR testing is not feasible due to labor intensiveness, need for expensive equipment and overall costs. Lastly, TKI discontinuation is an important goal for patients because of long-term chronic adverse side effects, serious toxicities, and cost. However, only ~40-50% of eligible patients succeed at TKI discontinuation and sensitive and frequent monitoring after TKI discontinuation is critical to identify patients who need to restart therapy. At home patient-initiated sample collection could provide a safer opportunity for TKI discontinuation in eligible patients who live in remote locations or where frequent monitoring is logistically challenging.

Figure 1A. Correlation of capillary vs venous BCR::ABL1 %, log scale. R is 0.99 between the two raw measures and 0.96 between the two log10 transformed measures (log10 (x+1) vs log10 (y+1)). Figure 1B. Bland-Altman Plot showing minimal bias between venous and capillary measurements (BCR::ABL1 %). Values are log10 transformed.

Oehler:Novartis: Consultancy; Pfizer, Inc: Consultancy, Research Funding. Welch:Tasso, Inc: Current Employment, Current equity holder in publicly-traded company. Berthier:Tasso, Inc: Current Employment, Current equity holder in publicly-traded company.