XPERT BCR-ABL ULTRA
Report
- Report Number
- 3004530258-2024-00024
- Event Type
- Malfunction
- Date Received
- December 17, 2024
- Date of Event
- July 1, 2024
- Report Date
- February 14, 2025
- Manufacturer
- CEPHEID
- Product Code
- OYX
- PMA / PMN Number
- K190076
- Product Problem
- Yes
- Report Source
- Manufacturer report
- Reporter Location
- FR
- Reporter Occupation
- OTHER HEALTH CARE PROFESSIONAL
- Health Professional
- Yes
Narratives
AS OF (B)(6) 2025, THE MUTATION ANALYSIS IS STILL ONGOING AT CUSTOMER LEVEL. BASED ON COLLECTED INFORMATION, THE MOST LIKELY ROOT CAUSE FOR THE DISCREPANCY IS THE EAC RT-QPCR ASSAY UNDER QUANTIFICATION BECAUSE OF THE IDENTIFIED SEQUENCE VARIANT THAT AFFECTS THE FORWARD PRIMER BINDING IN THE EAC ASSAY. DETAIL OF THE ACTIONS PERFORMED: THE CUSTOMER HAS CONFIRMED THE SEQUENCE OF THE EAC FORWARD PRIMER (BELOW) THAT DIRECTLY OVERLAPS WITH THE IDENTIFIED SEQUENCE VARIANT (PORTION TAAG BELOW). EAC FW PRIMER (P210 ENF501): TCCGCTGACCATCAATAAGGA (P210_ENF501) NONE OF THE P210 PRIMERS USED IN THE XPERT BCR-ABL ULTRA TEST OVERLAP WITH THE BCR MUTATION (NM_004327.4: C.3152_3155DELINSCAAA: P.V1051_F1052DELINSAN) ON EXON 13 DETECTED IN THIS PATIENT. THE CUSTOMER DOES NOT INTEND TO TEST THE FOLLOWING PATIENT MONITORING SPECIMEN WITH A THIRD INDEPENDENT RT-QPCR METHOD AS THEY SEEM CONVINCED THE EAC METHOD IS UNDERESTIMATING BCR::ABL1 TRANSCRIPT LEVEL AND PLAN TO CONTINUE BCR::ABL1 MONITORING WITH THE XPERT BCR-ABL ULTRA TEST ONLY. NO ACTIONS ARE IMPLEMENTED SINCE THE MOST LIKELY ROOT CAUSE IS NOT RELATED TO THE GXBCRABL-10.THE TKD MUTATION RESEARCH IS ONGOING. THE INVESTIGATION IS ONGOING. ADDITIONAL INFORMATION WILL BE PROVIDED IN A FOLLOW UP REPORT ONCE THE INVESTIGATION HAS BEEN COMPLETED.
BCR-ABL1 P210 TRANSCRIPT WAS MONITORED BY XPERT BCR-ABL ULTRA TEST IN THE CONFIRMED PH+ (PHILADELPHIA POSITIVE) CML (CHRONIC MYELOID LEUKAEMIA) (B2A2) PAEDIATRIC PATIENT ON THE FIRST GENERATION TKI (TYROSINE KINASE INHIBITOR) (IMATINIB). INITIAL DIAGNOSIS WAS DONE USING EAC RT-QPCR (EUROPE AGAINST CANCER REVERSE TRANSCRIPTION QUANTITATIVE POLYMERASE CHAIN REACTION) METHOD, FISH (FLUORESCENCE IN SITU HYBRIDIZATION) AND RNASEQ (RNA SEQUENCING). PATIENT WAS DIAGNOSED ON (B)(6) 2023. INITIAL EAC RESULT AT DIAGNOSIS WAS 5% AND 100% RESULT OBTAINED WITH FISH. FURTHER FOLLOW UP WAS DONE BY XPERT BCR-ABL ULTRA. THE PATIENT HAS NOT BEEN ABLE TO REACH MMR (MAJOR MOLECULAR RESPONSE) FOR MORE THAN A YEAR NOW (AROUND 0.15% ON THREE CONSECUTIVE MONITORING TIME POINTS). RNA EXTRACTION WAS DONE AND SAMPLE WAS SENT FOR EAC RT-QPCR AND FOR BCR: ABL1 KD MUTATION ANALYSIS. RT-QPCR RESULTS SHOWED OPTIMAL RESPONSE (<0.01% IS). SAMPLE WAS ALSO SENT FOR BCR: ABL1 KINASE DOMAIN (KD) MUTATION ANALYSIS, AND ONE MUTATION WAS DISCOVERED, BUT IT WAS NOT INTERPRETABLE. SAMPLE WAS SENT FOR RNASEQ (RNA SEQUENCING) TO UNDERSTAND DISCREPANCY BETWEEN THE TWO METHODS AND SHOWED MUTATION (DELETION/INSERTION) IN THE FORWARD PRIMER SEQUENCE FOR EAC METHOD. SIMULTANEOUSLY, THE SAMPLE WAS SENT FOR REPEAT ABL1 KD (KINASE DOMAIN) MUTATION ANALYSIS. CUSTOMER STILL WAITS FOR RESULTS. PATIENT WAS SWITCHED TO THE SECOND GENERATION TKI (TYROSINE KINASE INHIBITOR) (BOSUTINIB) DUE TO LACK OF RESPONSE. THE RESULTS OF THE XPERT BCR: ABL ULTRA P210 TESTING IS CONSISTENT OVER THREE TIMEPOINTS. THERE IS NO EVIDENCE TO SUGGEST THAT THE ASSAY IS INCORRECTLY QUANTIFYING THE TRANSCRIPT LEVEL BASED ON INTERNAL PERFORMANCE DATA INVOLVING THE RELEVANT LOT. SINCE THIS IS A B2A2 TRANSCRIPT, THERE IS A KNOWN AND WELL DESCRIBED IN THE LITERATURE PROPENSITY FOR ASSAYS LIKE OURS THAT USE A B3A2 CONTROL TO SLIGHTLY OVER-QUANTIFY B2A2 TRANSCRIPT LEVELS, BUT THIS IS SMALL AND NOT CONSIDERED TO BE CLINICALLY SIGNIFICANT. FURTHERMORE, EAC ASSAY IS ALSO BASED ON B3A2 REFERENCE MATERIAL, THEREFORE, THIS IS UNLIKELY RELATED TO OBSERVED DIFFERENCE IN QUANTIFICATION. ON THE OTHER HAND, RNASEQ ANALYSIS REVEALED AN IN/DEL MUTATION AT THE SITE WHERE THE FORWARD EAC PRIMER BINDS. THIS MUTATION DOES NOT INTERFERE WITH THE BINDING OF ANY OF THE XPERT BCR-ABL ULTRA TEST PRIMERS OR PROBE. THIS PROVIDES A SECOND POTENTIAL EXPLANATION FOR THE DISCREPANCY, IN BOTH CASES SUGGESTING THAT THE CORRECT XPERT BCR-ABL ULTRA QUANTIFICATION. AS OF 10-JAN-2025, THE MUTATION ANALYSIS IS STILL ONGOING AT CUSTOMER LEVEL. BASED ON COLLECTED INFORMATION, THE MOST LIKELY ROOT CAUSE FOR THE DISCREPANCY IS THE EAC RT-QPCR ASSAY UNDER QUANTIFICATION BECAUSE OF THE IDENTIFIED SEQUENCE VARIANT THAT AFFECTS THE FORWARD PRIMER BINDING IN THE EAC ASSAY. DETAIL OF THE ACTIONS PERFORMED: THE CUSTOMER HAS CONFIRMED THE SEQUENCE OF THE EAC FORWARD PRIMER (BELOW) THAT DIRECTLY OVERLAPS WITH THE IDENTIFIED SEQUENCE VARIANT (PORTION TAAG BELOW). EAC FW PRIMER (P210 ENF501): TCCGCTGACCATCAATAAGGA (P210_ENF501) NONE OF THE P210 PRIMERS USED IN THE XPERT BCR-ABL ULTRA TEST OVERLAP WITH THE BCR MUTATION (NM_004327.4: C.3152_3155DELINSCAAA: P.V1051_F1052DELINSAN) ON EXON 13 DETECTED IN THIS PATIENT. CEPHEID REACHED OUT TO THE CUSTOMER TO OBTAIN THE RESULTS OF THE TKD MUTATION ANALYSIS PERFORMED BUT THE CUSTOMER WAS UNRESPONSIVE. THE MOST LIKELY ROOT CAUSE FOR THE DISCREPANCY IS THE EAC RT-QPCR ASSAY UNDER QUANTIFICATION BECAUSE OF THE IDENTIFIED SEQUENCE VARIANT THAT AFFECTS THE FORWARD PRIMER BINDING IN THE EAC ASSAY. A CORRECT QUANTIFICATION OF THE XPERT BCR-ABL ULTRA LOT: 40701 WAS CARRIED OUT, AND NO MALFUNCTION WAS DETECTED. THEREFORE, THIS CASE IS DEEMED NOT REPORTABLE.
BCR-ABL1 P210 TRANSCRIPT WAS MONITORED BY XPERT BCR-ABL ULTRA TEST IN THE CONFIRMED PH+ (PHILADELPHIA POSITIVE) CML (CHRONIC MYELOID LEUKAEMIA) (B2A2) PAEDIATRIC PATIENT ON THE FIRST GENERATION TKI (TYROSINE KINASE INHIBITOR) (IMATINIB). INITIAL DIAGNOSIS WAS DONE USING EAC RT-QPCR (EUROPE AGAINST CANCER REVERSE TRANSCRIPTION QUANTITATIVE POLYMERASE CHAIN REACTION) METHOD, FISH (FLUORESCENCE IN SITU HYBRIDIZATION) AND RNASEQ (RNA SEQUENCING). PATIENT WAS DIAGNOSED IN (B)(6) 2023. INITIAL EAC RESULT AT DIAGNOSIS WAS 5% AND 100% RESULT OBTAINED WITH FISH. FURTHER FOLLOW UP WAS DONE BY XPERT BCR-ABL ULTRA. THE PATIENT HAS NOT BEEN ABLE TO REACH MMR (MAJOR MOLECULAR RESPONSE) FOR MORE THAN A YEAR NOW (AROUND 0.15% ON TWO CONSECUTIVE MONITORING TIME POINTS). RNA EXTRACTION WAS DONE AND SAMPLE WAS SENT TO EAC RT-QPCR AND FOR BCR: ABL1 KD MUTATION ANALYSIS AND RT-QPCR RESULTS SHOWED OPTIMAL RESPONSE (<0.01%). SAMPLE WAS ALSO SENT FOR BCR: ABL1 KINASE DOMAIN (KD) MUTATION ANALYSIS, AND ONE MUTATION WAS DISCOVERED, BUT IT WAS NOT INTERPRETABLE. SAMPLE WAS SENT FOR RNASEQ (RNA SEQUENCING) TO UNDERSTAND DISCREPANCY BETWEEN THE TWO METHODS AND SHOWED MUTATION (DELETION/INSERTION) IN THE TARGET SEQUENCE FOR EAC METHOD. SIMULTANEOUSLY, THE SAMPLE WAS SENT FOR REPEAT ABL1 KD (KINASE DOMAIN) MUTATION ANALYSIS. CUSTOMER STILL WAITS FOR RESULTS. PATIENT WAS SWITCHED TO THE SECOND GENERATION TKI (TYROSINE KINASE INHIBITOR) (BOSUTINIB) DUE TO LACK OF RESPONSE. THE RESULTS OF THE XPERT BCR::ABL ULTRA P210 TESTING IS CONSISTENT OVER THREE TIMEPOINTS. THERE IS NO EVIDENCE TO SUGGEST THAT THE ASSAY IS INCORRECTLY QUANTIFYING THE TRANSCRIPT LEVEL BASED ON INTERNAL PERFORMANCE DATA INVOLVING THE RELEVANT LOTS. SINCE THIS IS A B2A2 TRANSCRIPT, THERE IS A KNOWN AND WELL DESCRIBED IN THE LITERATURE PROPENSITY FOR ASSAYS LIKE OURS THAT USE A B3A2 CONTROL TO SLIGHTLY OVER-QUANTIFY B2A2 TRANSCRIPT LEVELS, BUT THIS IS SMALL AND NOT CONSIDERED TO BE CLINICALLY SIGNIFICANT. IN ADDITION, THERE APPEARS TO BE A MUTATION THAT OCCURS AT THE SITE WHERE A PRIMER BINDS IN THE EAC ASSAY, BUT DOES NOT INTERFERE WITH THE BINDING OF ANY OF THE XPERT ASSAY PRIMERS OR PROBE. THIS PROVIDES A SECOND POTENTIAL EXPLANATION FOR THE DISCREPANCY, IN BOTH CASES SUGGESTING THAT THE XPERT ASSAY IS LIKELY TO BE CORRECT. AT THIS POINT, THE INVESTIGATION IS STILL ONGOING. SAMPLE IS PENDING RETURN AND IN-HOUSE INVESTIGATION. AT THIS TIME, NO PATIENT HARM HAS BEEN REPORTED, HOWEVER MORE INFORMATION TO BE OBTAINED. A SUPPLEMENTAL REPORT WILL BE SUBMITTED ONCE ADDITIONAL INFORMATION IS RECEIVED. IN SECTION B1 'PRODUCT PROBLEM' AND SECTION H3 'MALFUNCTION' WERE SELECTED AS THESE SECTIONS ARE REQUIRED FOR SUBMISSION. HOWEVER, THERE IS NOT ENOUGH INFORMATION AT THIS TIME TO MAKE A DETERMINATION. NOTE FOR SECTION H3 DEVICE EVALUATED BY MANUFACTURER - ANSWER OF NO IS DUE TO THE SINGLE USE OF THE XPERT BCR-ABL ULTRA TEST AND THE UNAVAILABILITY OF THAT PRODUCT LOT TO BE RETURNED TO CEPHEID.
ON (B)(6) 2024, A CUSTOMER CONTACTED CEPHEID TO REPORT A QUESTIONABLE QUANTITATIVE RESULT ON XPERT BCR-ABL ULTRA (LOT 40701), AFTER TESTING CONSECUTIVE SAMPLES FROM THE SAME PATIENT, COMPARED TO THE EAC RT-QPCR BASED METHOD. THE CUSTOMER NOTICED A 1 LOG DIFFERENCE BETWEEN EUROPE AGAINST CANCER (EAC) BCR: ABL DETECTION METHOD AND XPERT BCR-ABL ULTRA TESTING WITH XPERT BCR-ABL ULTRA SHOWING THE HIGHEST LEVEL OF QUANTIFICATION. THE PEDIATRIC PATIENT WAS DIAGNOSED WITH PH+ (B2A2 P210) CHRONIC MYELOID LEUKEMIA (CML) IN (B)(6) 2023 BY EAC RT-QPCR, RNASEQ AND FISH (FLURORESCENT IN-SITU HYBRIDIZATION). THE PATIENT WAS THEN MONITORED WITH XPERT BCR-ABL ULTRA. INITIAL RESULTS AT DIAGNOSIS WERE 5% FOR EAC RT-QPCR, AND 100% FOR FISH. THE PATIENT WAS CONFIRMED AS PH+ CML AND STARTED ON IMATINIB (GLEEVEC) THERAPY. DESPITE THE THERAPY, THE PATIENT DID NOT REACH MAJOR MOLECULAR RESPONSE (MMR) (0.1% IS) FOR ABOUT A YEAR. CHRONOLOGY OF EVENTS: ON (B)(6) 2024, A WHOLE BLOOD SAMPLE WAS COLLECTED AND TESTED ON XPERT BCR-ABL ULTRA LOT 40701. TEST RESULT REPORTED: POSITIVE [0.15% (IS) AND MR2.82 (MOLECULAR RESPONSE)]. THE SAME SAMPLE WAS USED FOR RNA EXTRACTION THAT WAS SENT FOR RT-QPCR WITH EAC BCR-ABL DETECTION METHOD. TEST RESULT REPORTED: 0.0098 BCR: ABL1 % IS (INTERNATIONAL SCALE) ON (B)(6) 2024, 2 WHOLE BLOOD SAMPLES (IN EDTA) WERE COLLECTED. THE FIRST SAMPLE WAS TESTED ON XPERT BCR-ABL ULTRA, LOT 40701. TEST RESULT REPORTED: POSITIVE [0.14% (IS) AND MR2.85] THEN THE OTHER BLOOD SAMPLE WAS TESTED ON EAC BCR-ABL DETECTION METHOD. TEST RESULT REPORTED: 0.0093 % IS. RNA SEQUENCING PERFORMED ON THE PATIENT SAMPLE BY THE CUSTOMER SHOWED A MUTATION (DELETION/ADDITION: NM_004327.4: C.3152_3155DELINSCAAA: P.V1051_F1052DELINSAN) ON THE FORWARD PRIMER FOR THE EAC BCR::ABL1 DETECTION METHOD, WHICH MAY EXPLAIN THE 1 LOG DIFFERENCE. THE PATIENT WAS SWITCHED TO SECOND-GENERATION TYROSINE KINASE INHIBITORS (TKI), BOSUTINIB, BASED ON THE HIGHER RESULTS FROM THE XPERT BCR-ABL ULTRA TEST, DESPITE THE BCR-ABL TRANSCRIPT LEVEL BEING STABLE OVER THREE CONSECUTIVE MONITORING TIME POINTS AND NO ADDITIONAL REPORTED SIGNS OF RELAPSE. THE CUSTOMER NOTED NO SIGNIFICANT IMPROVEMENT IN RESPONSE AFTER THE THERAPY SWITCH. THE CUSTOMER IS STILL AWAITING RESULTS FROM A REPEAT BCR::ABL1 KINASE DOMAIN (KD) MUTATION ANALYSIS TO CONFIRM A POTENTIAL MUTATION THAT COULD EXPLAIN THE LACK OF AN OPTIMAL RESPONSE. THE INITIAL MUTATION ANALYSIS RESULTS WERE NOT INTERPRETABLE, AND THE REPEAT ANALYSIS RESULTS ARE EXPECTED BY THE END OF THE YEAR. THE CUSTOMER ALSO SEEKS FURTHER DETAILS ON WHETHER IDENTIFIED MUTATION COULD AFFECT THE XPERT BCR-ABL ULTRA TEST RESULTS. IDENTIFIED MUTATION DOES NOT OVERLAP WITH THE PRIMERS OR PROBE USED IN THE XPERT BCR-ABL ULTRA TEST. CONCLUSION: THE CONTEXT OF THE TEST WAS FOLLOW-UP ON THE PATIENT'S TREATMENT FOR BCR-ABL MUTATION IN PAEDIATRICS. THE HIGHER RESULTS ON XPERT BCR-ABL ULTRA HAVE RAISED CONCERNS ABOUT THE EFFECTIVENESS OF THE TREATMENT GIVEN TO THE PATIENT. THE LIKELY ROOT CAUSE OF THE DISCREPANCY IS STILL INCONCLUSIVE, AND A THIRD INDEPENDENT TEST RESULT IS PENDING.
Devices
| Seq | Brand | Generic | Product Code | Manufacturer | Model | Lot | UDI-DI |
|---|---|---|---|---|---|---|---|
| 1487303 | XPERT BCR-ABL ULTRA | XPERT BCR-ABL ULTRA | OYX | CEPHEID | 1001424700 |
Patients
| Seq | Age | Sex | Outcome | Treatment |
|---|---|---|---|---|
| 1 | NA | Unknown |