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1. Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

Author

Bomken, S, Enshaei, A, Schwalbe, E, Mikulasova, A, Dai, Y, Zaka, M, Fung, K, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, G, Cazzaniga, G, Gohring, G, De Groot-Kruseman, H, Haferlach, C, Nigro, L, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, Van der Velden, V, Rand, V, Hunger, S, Harrison, C, Bacon, C, Van Delft, F, Loh, M, Moppett, J, Vormoor, J, Walker, B, Moorman, A, Russell, L, Bomken, Simon, Enshaei, Amir, Schwalbe, Edward C, Mikulasova, Aneta, Dai, Yunfeng, Zaka, Masood, Fung, Kent Tm, Bashton, Matthew, Lim, Huezin, Jones, Lisa, Karataraki, Nefeli, Winterman, Emily, Ashby, Cody, Attarbaschi, Andishe, Bertrand, Yves, Bradtke, Jutta, Buldini, Barbara, Burke, G. A. Amos, Cazzaniga, Giovanni, Gohring, Gudrun, De Groot-Kruseman, Hesta A, Haferlach, Claudia, Nigro, Luca Lo, Parihar, Mayur, Plesa, Adriana, Seaford, Emma, Sonneveld, Edwin, Strehl, Sabine, Van der Velden, Vincent Hj, Rand, Vikki, Hunger, Stephen P, Harrison, Christine J, Bacon, Chris M, Van Delft, Frederik W, Loh, Mignon L, Moppett, John, Vormoor, Josef, Walker, Brian A, Moorman, Anthony V, Russell, Lisa J, Bomken, S, Enshaei, A, Schwalbe, E, Mikulasova, A, Dai, Y, Zaka, M, Fung, K, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, G, Cazzaniga, G, Gohring, G, De Groot-Kruseman, H, Haferlach, C, Nigro, L, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, Van der Velden, V, Rand, V, Hunger, S, Harrison, C, Bacon, C, Van Delft, F, Loh, M, Moppett, J, Vormoor, J, Walker, B, Moorman, A, Russell, L, Bomken, Simon, Enshaei, Amir, Schwalbe, Edward C, Mikulasova, Aneta, Dai, Yunfeng, Zaka, Masood, Fung, Kent Tm, Bashton, Matthew, Lim, Huezin, Jones, Lisa, Karataraki, Nefeli, Winterman, Emily, Ashby, Cody, Attarbaschi, Andishe, Bertrand, Yves, Bradtke, Jutta, Buldini, Barbara, Burke, G. A. Amos, Cazzaniga, Giovanni, Gohring, Gudrun, De Groot-Kruseman, Hesta A, Haferlach, Claudia, Nigro, Luca Lo, Parihar, Mayur, Plesa, Adriana, Seaford, Emma, Sonneveld, Edwin, Strehl, Sabine, Van der Velden, Vincent Hj, Rand, Vikki, Hunger, Stephen P, Harrison, Christine J, Bacon, Chris M, Van Delft, Frederik W, Loh, Mignon L, Moppett, John, Vormoor, Josef, Walker, Brian A, Moorman, Anthony V, and Russell, Lisa J

Abstract

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.

Published
2023

2. Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

Author

Bomken, S, Enshaei, A, Schwalbe, E, Mikulasova, A, Dai, Y, Zaka, M, Fung, K, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, G, Cazzaniga, G, Gohring, G, De Groot-Kruseman, H, Haferlach, C, Nigro, L, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, Van der Velden, V, Rand, V, Hunger, S, Harrison, C, Bacon, C, Van Delft, F, Loh, M, Moppett, J, Vormoor, J, Walker, B, Moorman, A, Russell, L, Bomken, Simon, Enshaei, Amir, Schwalbe, Edward C, Mikulasova, Aneta, Dai, Yunfeng, Zaka, Masood, Fung, Kent Tm, Bashton, Matthew, Lim, Huezin, Jones, Lisa, Karataraki, Nefeli, Winterman, Emily, Ashby, Cody, Attarbaschi, Andishe, Bertrand, Yves, Bradtke, Jutta, Buldini, Barbara, Burke, G. A. Amos, Cazzaniga, Giovanni, Gohring, Gudrun, De Groot-Kruseman, Hesta A, Haferlach, Claudia, Nigro, Luca Lo, Parihar, Mayur, Plesa, Adriana, Seaford, Emma, Sonneveld, Edwin, Strehl, Sabine, Van der Velden, Vincent Hj, Rand, Vikki, Hunger, Stephen P, Harrison, Christine J, Bacon, Chris M, Van Delft, Frederik W, Loh, Mignon L, Moppett, John, Vormoor, Josef, Walker, Brian A, Moorman, Anthony V, Russell, Lisa J, Bomken, S, Enshaei, A, Schwalbe, E, Mikulasova, A, Dai, Y, Zaka, M, Fung, K, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, G, Cazzaniga, G, Gohring, G, De Groot-Kruseman, H, Haferlach, C, Nigro, L, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, Van der Velden, V, Rand, V, Hunger, S, Harrison, C, Bacon, C, Van Delft, F, Loh, M, Moppett, J, Vormoor, J, Walker, B, Moorman, A, Russell, L, Bomken, Simon, Enshaei, Amir, Schwalbe, Edward C, Mikulasova, Aneta, Dai, Yunfeng, Zaka, Masood, Fung, Kent Tm, Bashton, Matthew, Lim, Huezin, Jones, Lisa, Karataraki, Nefeli, Winterman, Emily, Ashby, Cody, Attarbaschi, Andishe, Bertrand, Yves, Bradtke, Jutta, Buldini, Barbara, Burke, G. A. Amos, Cazzaniga, Giovanni, Gohring, Gudrun, De Groot-Kruseman, Hesta A, Haferlach, Claudia, Nigro, Luca Lo, Parihar, Mayur, Plesa, Adriana, Seaford, Emma, Sonneveld, Edwin, Strehl, Sabine, Van der Velden, Vincent Hj, Rand, Vikki, Hunger, Stephen P, Harrison, Christine J, Bacon, Chris M, Van Delft, Frederik W, Loh, Mignon L, Moppett, John, Vormoor, Josef, Walker, Brian A, Moorman, Anthony V, and Russell, Lisa J

Abstract

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukaemia and use of unproven individualised treatment schedules. Here we contrast the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered on a national BCP-ALL clinical trial/registry. Where present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analysis. Outcome was analysed to define 3-year event free survival (EFS) and overall survival (OS). IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either: established BCP-ALL specific abnormalities (high hyperdiploidy n=3, KMT2A-rearrangement n=6, iAMP21 n=1, BCR-ABL n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J rearranged cases, clearly distinct from Burkitt leukaemia/lymphoma. Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols.

Published
2022

3. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Author

Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, J, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Trka, J, Langerak, A, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht H., Reigl T., Kotrova M., Appelt F., Stewart P., Bystry V., Krejci A., Grioni A., Pal K., Stranska K., Plevova K., Rijntjes J., Songia S., Svaton M., Fronkova E., Bartram J., Scheijen B., Herrmann D., Garcia-Sanz R., Hancock J., Moppett J., van Dongen J. J. M., Cazzaniga G., Davi F., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Trka J., Langerak A. W., Gonzalez D., Pott C., Bruggemann M., Darzentas N., Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, J, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Trka, J, Langerak, A, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht H., Reigl T., Kotrova M., Appelt F., Stewart P., Bystry V., Krejci A., Grioni A., Pal K., Stranska K., Plevova K., Rijntjes J., Songia S., Svaton M., Fronkova E., Bartram J., Scheijen B., Herrmann D., Garcia-Sanz R., Hancock J., Moppett J., van Dongen J. J. M., Cazzaniga G., Davi F., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Trka J., Langerak A. W., Gonzalez D., Pott C., Bruggemann M., and Darzentas N.

Abstract

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

Published
2019

4. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Author

Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Bruggemann M., Kotrova M., Knecht H., Bartram J., Boudjogrha M., Bystry V., Fazio G., Fronkova E., Giraud M., Grioni A., Hancock J., Herrmann D., Jimenez C., Krejci A., Moppett J., Reigl T., Salson M., Scheijen B., Schwarz M., Songia S., Svaton M., van Dongen J. J. M., Villarese P., Wakeman S., Wright G., Cazzaniga G., Davi F., Garcia-Sanz R., Gonzalez D., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Pott C., Trka J., Darzentas N., Langerak A. W., Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Bruggemann M., Kotrova M., Knecht H., Bartram J., Boudjogrha M., Bystry V., Fazio G., Fronkova E., Giraud M., Grioni A., Hancock J., Herrmann D., Jimenez C., Krejci A., Moppett J., Reigl T., Salson M., Scheijen B., Schwarz M., Songia S., Svaton M., van Dongen J. J. M., Villarese P., Wakeman S., Wright G., Cazzaniga G., Davi F., Garcia-Sanz R., Gonzalez D., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Pott C., Trka J., Darzentas N., and Langerak A. W.

Abstract

Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0–14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0–14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies.

Published
2019

5. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Author

Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Bruggemann M., Kotrova M., Knecht H., Bartram J., Boudjogrha M., Bystry V., Fazio G., Fronkova E., Giraud M., Grioni A., Hancock J., Herrmann D., Jimenez C., Krejci A., Moppett J., Reigl T., Salson M., Scheijen B., Schwarz M., Songia S., Svaton M., van Dongen J. J. M., Villarese P., Wakeman S., Wright G., Cazzaniga G., Davi F., Garcia-Sanz R., Gonzalez D., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Pott C., Trka J., Darzentas N., Langerak A. W., Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Bruggemann M., Kotrova M., Knecht H., Bartram J., Boudjogrha M., Bystry V., Fazio G., Fronkova E., Giraud M., Grioni A., Hancock J., Herrmann D., Jimenez C., Krejci A., Moppett J., Reigl T., Salson M., Scheijen B., Schwarz M., Songia S., Svaton M., van Dongen J. J. M., Villarese P., Wakeman S., Wright G., Cazzaniga G., Davi F., Garcia-Sanz R., Gonzalez D., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Pott C., Trka J., Darzentas N., and Langerak A. W.

Abstract

Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0–14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0–14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies.

Published
2019

6. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Author

Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, J, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Trka, J, Langerak, A, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht H., Reigl T., Kotrova M., Appelt F., Stewart P., Bystry V., Krejci A., Grioni A., Pal K., Stranska K., Plevova K., Rijntjes J., Songia S., Svaton M., Fronkova E., Bartram J., Scheijen B., Herrmann D., Garcia-Sanz R., Hancock J., Moppett J., van Dongen J. J. M., Cazzaniga G., Davi F., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Trka J., Langerak A. W., Gonzalez D., Pott C., Bruggemann M., Darzentas N., Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, J, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Trka, J, Langerak, A, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht H., Reigl T., Kotrova M., Appelt F., Stewart P., Bystry V., Krejci A., Grioni A., Pal K., Stranska K., Plevova K., Rijntjes J., Songia S., Svaton M., Fronkova E., Bartram J., Scheijen B., Herrmann D., Garcia-Sanz R., Hancock J., Moppett J., van Dongen J. J. M., Cazzaniga G., Davi F., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Trka J., Langerak A. W., Gonzalez D., Pott C., Bruggemann M., and Darzentas N.

Abstract

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

Published
2019

7. Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia

Author

Shah, N. N., Bhojwani, D., August, K., Baruchel, A., Bertrand, Y., Boklan, J., Dalla-Pozza, L., Dennis, R., Hijiya, N., Locatelli, Franco, Martin, P. L., Mechinaud, F., Moppett, J., Rheingold, S. R., Schmitt, C., Trippett, T. M., Liang, M., Balic, K., Li, X., Vainshtein, I., Yao, N. S., Pastan, I., Wayne, A. S., Locatelli F. (ORCID:0000-0002-7976-3654), Shah, N. N., Bhojwani, D., August, K., Baruchel, A., Bertrand, Y., Boklan, J., Dalla-Pozza, L., Dennis, R., Hijiya, N., Locatelli, Franco, Martin, P. L., Mechinaud, F., Moppett, J., Rheingold, S. R., Schmitt, C., Trippett, T. M., Liang, M., Balic, K., Li, X., Vainshtein, I., Yao, N. S., Pastan, I., Wayne, A. S., and Locatelli F. (ORCID:0000-0002-7976-3654)

Published
2020

8. Pharmacokinetics of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia or acute lymphoblastic leukemia

Author

Hijiya, N, Michel Zwaan, C, Rizzari, C, Foà, R, Abbink, F, Lancaster, D, Landman-Parker, J, Millot, F, Moppett, J, Nelken, B, Putti, M, Xianbin, T, Sinclair, K, Santanastasio, H, Buchbinder, A, Kearns, P, Michel Zwaan,CM, Putti, MC, Hijiya, N, Michel Zwaan, C, Rizzari, C, Foà, R, Abbink, F, Lancaster, D, Landman-Parker, J, Millot, F, Moppett, J, Nelken, B, Putti, M, Xianbin, T, Sinclair, K, Santanastasio, H, Buchbinder, A, Kearns, P, Michel Zwaan,CM, and Putti, MC

Abstract

Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Phþ) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Patients and Methods: Fifteen patients (aged 1–<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n 1⁄4 11) or Phþ ALL relapsed on or refractory to standard therapy (n 1⁄4 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. Results: The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Phþ ALL achieved complete remission. Conclusions: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Phþ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.

Published
2020

9. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Author

Knecht, H., Reigl, T., Kotrova, M, Appelt, F., Stewart, P., Bystry, V., Krejčí, A. (Alena), Grioni, A., Pal, K. (Karin) van der, Stranska, K., Plevova, K. (K.), Rijntjes, J., Songia, S., Svaton, M., Fronkova, E., Bartram, J., Scheijen, B. (Blanca), Herrmann, D., Garcia-Sanz, R. (Ramon), Hancock, J., Moppett, J. (John), van Dongen, JJM, Cazzaniga, G. (Gianni), Davi, F. (Frédéric), Groenen, P., Hummel, M. (Michael), Macintyre, E.A. (Elizabeth), Stamatopoulos, K. (Kostas), Trka, J. (Jan), Langerak, A.W. (Anton), Gonzalez, D., Pott, C. (Christiane), Bruggemann, M, Darzentas, N. (Nikos), Knecht, H., Reigl, T., Kotrova, M, Appelt, F., Stewart, P., Bystry, V., Krejčí, A. (Alena), Grioni, A., Pal, K. (Karin) van der, Stranska, K., Plevova, K. (K.), Rijntjes, J., Songia, S., Svaton, M., Fronkova, E., Bartram, J., Scheijen, B. (Blanca), Herrmann, D., Garcia-Sanz, R. (Ramon), Hancock, J., Moppett, J. (John), van Dongen, JJM, Cazzaniga, G. (Gianni), Davi, F. (Frédéric), Groenen, P., Hummel, M. (Michael), Macintyre, E.A. (Elizabeth), Stamatopoulos, K. (Kostas), Trka, J. (Jan), Langerak, A.W. (Anton), Gonzalez, D., Pott, C. (Christiane), Bruggemann, M, and Darzentas, N. (Nikos)

Abstract

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

Published
2019
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10. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Author

Bruggemann, M, Kotrova, M, Knecht, H., Bartram, J., Boudjogrha, M., Bystry, V., Fazio, G., Fronkova, E., Giraud, M., Grioni, A., Hancock, J., Herrmann, D., Jimenez, C. (Cecilia), Krejčí, A. (Alena), Moppett, J. (John), Reigl, T., Salson, M., Scheijen, B. (Blanca), Schwarz, M. (Michael), Songia, S., Svaton, M., van Dongen, JJM, Villarese, P. (Patrick), Wakeman, S., Wright, G, Cazzaniga, G. (Gianni), Davi, F. (Frédéric), Garcia-Sanz, R. (Ramon), Gonzalez, D., Groenen, P., Hummel, M. (Michael), Macintyre, E.A. (Elizabeth), Stamatopoulos, K. (Kostas), Pott, C. (Christiane), Trka, J. (Jan), Darzentas, N. (Nikos), Langerak, A.W. (Anton), Bruggemann, M, Kotrova, M, Knecht, H., Bartram, J., Boudjogrha, M., Bystry, V., Fazio, G., Fronkova, E., Giraud, M., Grioni, A., Hancock, J., Herrmann, D., Jimenez, C. (Cecilia), Krejčí, A. (Alena), Moppett, J. (John), Reigl, T., Salson, M., Scheijen, B. (Blanca), Schwarz, M. (Michael), Songia, S., Svaton, M., van Dongen, JJM, Villarese, P. (Patrick), Wakeman, S., Wright, G, Cazzaniga, G. (Gianni), Davi, F. (Frédéric), Garcia-Sanz, R. (Ramon), Gonzalez, D., Groenen, P., Hummel, M. (Michael), Macintyre, E.A. (Elizabeth), Stamatopoulos, K. (Kostas), Pott, C. (Christiane), Trka, J. (Jan), Darzentas, N. (Nikos), and Langerak, A.W. (Anton)

Abstract

Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was

Published
2019
Full Text
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11. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Author

Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, JJM, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, EA, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, Ton, Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, JJM, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, EA, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, and Langerak, Ton

Published
2019

12. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Author

Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, van der Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, JJM, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, EA, Stamatopoulos, K, Trka, J, Langerak, Ton, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, van der Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, JJM, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, EA, Stamatopoulos, K, Trka, J, Langerak, Ton, Gonzalez, D, Pott, C, Bruggemann, M, and Darzentas, N

Published
2019

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