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1. The KMT2A recombinome of acute leukemias in 2023

Author

Meyer, C., Larghero, P., Almeida Lopes, B., Burmeister, T., Gröger, D., Sutton, R., Venn, N. C., Cazzaniga, G., Corral Abascal, L., Tsaur, G., Fechina, L., Emerenciano, M., Pombo-de-Oliveira, M. S., Lund-Aho, T., Lundán, T., Montonen, M., Juvonen, V., Zuna, J., Trka, J., Ballerini, P., Lapillonne, H., Van der Velden, V. H. J., Sonneveld, E., Delabesse, E., de Matos, R. R. C., Silva, M. L. M., Bomken, S., Katsibardi, K., Keernik, M., Grardel, N., Mason, J., Price, R., Kim, J., Eckert, C., Lo Nigro, L., Bueno, C., Menendez, P., zur Stadt, U., Gameiro, P., Sedék, L., Szczepański, T., Bidet, A., Marcu, V., Shichrur, K., Izraeli, S., Madsen, H. O., Schäfer, B. W., Kubetzko, S., Kim, R., Clappier, E., Trautmann, H., Brüggemann, M., Archer, P., Hancock, J., Alten, J., Möricke, A., Stanulla, M., Lentes, J., Bergmann, A. K., Strehl, S., Köhrer, S., Nebral, K., Dworzak, M. N., Haas, O. A., Arfeuille, C., Caye-Eude, A., Cavé, H., and Marschalek, R.

Published
2023
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2. The KMT2A recombinome of acute leukemias in 2023

Author

C. Meyer, P. Larghero, B. Almeida Lopes, T. Burmeister, D. Gröger, R. Sutton, N. C. Venn, G. Cazzaniga, L. Corral Abascal, G. Tsaur, L. Fechina, M. Emerenciano, M. S. Pombo-de-Oliveira, T. Lund-Aho, T. Lundán, M. Montonen, V. Juvonen, J. Zuna, J. Trka, P. Ballerini, H. Lapillonne, V. H. J. Van der Velden, E. Sonneveld, E. Delabesse, R. R. C. de Matos, M. L. M. Silva, S. Bomken, K. Katsibardi, M. Keernik, N. Grardel, J. Mason, R. Price, J. Kim, C. Eckert, L. Lo Nigro, C. Bueno, P. Menendez, U. zur Stadt, P. Gameiro, L. Sedék, T. Szczepański, A. Bidet, V. Marcu, K. Shichrur, S. Izraeli, H. O. Madsen, B. W. Schäfer, S. Kubetzko, R. Kim, E. Clappier, H. Trautmann, M. Brüggemann, P. Archer, J. Hancock, J. Alten, A. Möricke, M. Stanulla, J. Lentes, A. K. Bergmann, S. Strehl, S. Köhrer, K. Nebral, M. N. Dworzak, O. A. Haas, C. Arfeuille, A. Caye-Eude, H. Cavé, R. Marschalek, and Immunology

Subjects
Cancer Research, Oncology, SDG 3 - Good Health and Well-being, Hematology
Abstract

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Published
2023

3. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1

Author

Pfeifer, H., Cazzaniga, G., van der Velden, V. H. J., Cayuela, J. M., Schäfer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I., Borg, K., Cavé, H., Elia, L., Reshmi, S. C., Gerrard, G., Hayette, S., Hermanson, M., Juh, A., Jurcek, T., Chillón, M. C., Homburg, C., Martinelli, G., Kairisto, V., Lange, T., Lion, T., Mueller, M. C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Serve, H., Herrmann, E., Markovic, S., Dongen, J. J. M. van, and Ottmann, O. G.

Published
2019
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4. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Stutterheim, J, de Lorenzo, P, van der Sluin, I, Alten, J, Ancliffe, P, Attarbaschi, A, Aversa, L, Boer, J, Biondi, A, Brethon, B, Diaz, P, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Leung, A, Locatelli, F, Silverman, L, Stary, J, Szczepanski, T, van der Velden, V, Vora, A, Zuna, J, Schrappe, M, Valsecchi, M, Pieters, R, Stutterheim J., de Lorenzo P., van der Sluin I. M., Alten J., Ancliffe P., Attarbaschi A., Aversa L., Boer J. M., Biondi A., Brethon B., Diaz P., Cazzaniga G., Escherich G., Ferster A., Kotecha R. S., Lausen B., Leung A. W., Locatelli F., Silverman L., Stary J., Szczepanski T., van der Velden V. H. J., Vora A., Zuna J., Schrappe M., Valsecchi M. G., Pieters R., Stutterheim, J, de Lorenzo, P, van der Sluin, I, Alten, J, Ancliffe, P, Attarbaschi, A, Aversa, L, Boer, J, Biondi, A, Brethon, B, Diaz, P, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Leung, A, Locatelli, F, Silverman, L, Stary, J, Szczepanski, T, van der Velden, V, Vora, A, Zuna, J, Schrappe, M, Valsecchi, M, Pieters, R, Stutterheim J., de Lorenzo P., van der Sluin I. M., Alten J., Ancliffe P., Attarbaschi A., Aversa L., Boer J. M., Biondi A., Brethon B., Diaz P., Cazzaniga G., Escherich G., Ferster A., Kotecha R. S., Lausen B., Leung A. W., Locatelli F., Silverman L., Stary J., Szczepanski T., van der Velden V. H. J., Vora A., Zuna J., Schrappe M., Valsecchi M. G., and Pieters R.

Abstract

Background: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. Methods: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10−4), and high (≥5∗10−4). Results: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10−4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10−4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). Conclusion: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

Published
2022

5. The KMT2A recombinome of acute leukemias in 2023

Author

Meyer, C, Larghero, P, Almeida Lopes, B; https://orcid.org/0000-0003-1072-470X, Burmeister, T; https://orcid.org/0000-0003-4843-2876, Gröger, D, Sutton, R; https://orcid.org/0000-0002-0188-6005, Venn, N C, Cazzaniga, G, Corral Abascal, L, Tsaur, G, Fechina, L, Emerenciano, M; https://orcid.org/0000-0003-2337-8420, Pombo-de-Oliveira, M S; https://orcid.org/0000-0002-1507-004X, Lund-Aho, T, Lundán, T, Montonen, M, Juvonen, V, Zuna, J; https://orcid.org/0000-0002-0887-3709, Trka, J, Ballerini, P, Lapillonne, H, Van der Velden, V H J; https://orcid.org/0000-0001-9457-3763, Sonneveld, E, Delabesse, E, de Matos, R R C; https://orcid.org/0000-0002-8737-1669, Silva, M L M; https://orcid.org/0000-0003-2549-1320, Bomken, S; https://orcid.org/0000-0001-9163-5738, Katsibardi, K, Keernik, M, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, et al, Meyer, C, Larghero, P, Almeida Lopes, B; https://orcid.org/0000-0003-1072-470X, Burmeister, T; https://orcid.org/0000-0003-4843-2876, Gröger, D, Sutton, R; https://orcid.org/0000-0002-0188-6005, Venn, N C, Cazzaniga, G, Corral Abascal, L, Tsaur, G, Fechina, L, Emerenciano, M; https://orcid.org/0000-0003-2337-8420, Pombo-de-Oliveira, M S; https://orcid.org/0000-0002-1507-004X, Lund-Aho, T, Lundán, T, Montonen, M, Juvonen, V, Zuna, J; https://orcid.org/0000-0002-0887-3709, Trka, J, Ballerini, P, Lapillonne, H, Van der Velden, V H J; https://orcid.org/0000-0001-9457-3763, Sonneveld, E, Delabesse, E, de Matos, R R C; https://orcid.org/0000-0002-8737-1669, Silva, M L M; https://orcid.org/0000-0003-2549-1320, Bomken, S; https://orcid.org/0000-0001-9163-5738, Katsibardi, K, Keernik, M, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, and et al

Abstract

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Published
2023

7. Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1

Author

Pfeifer, H., Cazzaniga, G., van der Velden, V. H. J., Cayuela, J. M., Schäfer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I., Borg, K., Cavé, H., Elia, L., Reshmi, S. C., Gerrard, G., Hayette, S., Hermanson, M., Juh, A., Jurcek, T., Chillón, M. C., Homburg, C., Martinelli, G., Kairisto, V., Lange, T., Lion, T., Mueller, M. C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Serve, H., Herrmann, E., Markovic, S., van Dongen, J. J. M., and Ottmann, O. G.

Published
2020
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8. Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1 (Leukemia, (2019), 33, 8, (1910-1922), 10.1038/s41375-019-0413-0)

Author

Pfeifer H., Pfeifer, H, Cazzaniga, G, van der Velden, V, Cayuela, J, Schafer, B, Spinelli, O, Akiki, S, Avigad, S, Bendit, I, Borg, K, Cave, H, Elia, L, Reshmi, S, Gerrard, G, Hayette, S, Hermanson, M, Juh, A, Jurcek, T, Chillon, M, Homburg, C, Martinelli, G, Kairisto, V, Lange, T, Lion, T, Mueller, M, Pane, F, Rai, L, Damm-Welk, C, Sacha, T, Schnittger, S, Touloumenidou, T, Valerhaugen, H, Vandenberghe, P, Zuna, J, Serve, H, Herrmann, E, Markovic, S, van Dongen, J, Ottmann, O, Pfeifer H., Cazzaniga G., van der Velden V. H. J., Cayuela J. M., Schafer B., Spinelli O., Akiki S., Avigad S., Bendit I., Borg K., Cave H., Elia L., Reshmi S. C., Gerrard G., Hayette S., Hermanson M., Juh A., Jurcek T., Chillon M. C., Homburg C., Martinelli G., Kairisto V., Lange T., Lion T., Mueller M. C., Pane F., Rai L., Damm-Welk C., Sacha T., Schnittger S., Touloumenidou T., Valerhaugen H., Vandenberghe P., Zuna J., Serve H., Herrmann E., Markovic S., van Dongen J. J. M., Ottmann O. G., Pfeifer H., Pfeifer, H, Cazzaniga, G, van der Velden, V, Cayuela, J, Schafer, B, Spinelli, O, Akiki, S, Avigad, S, Bendit, I, Borg, K, Cave, H, Elia, L, Reshmi, S, Gerrard, G, Hayette, S, Hermanson, M, Juh, A, Jurcek, T, Chillon, M, Homburg, C, Martinelli, G, Kairisto, V, Lange, T, Lion, T, Mueller, M, Pane, F, Rai, L, Damm-Welk, C, Sacha, T, Schnittger, S, Touloumenidou, T, Valerhaugen, H, Vandenberghe, P, Zuna, J, Serve, H, Herrmann, E, Markovic, S, van Dongen, J, Ottmann, O, Pfeifer H., Cazzaniga G., van der Velden V. H. J., Cayuela J. M., Schafer B., Spinelli O., Akiki S., Avigad S., Bendit I., Borg K., Cave H., Elia L., Reshmi S. C., Gerrard G., Hayette S., Hermanson M., Juh A., Jurcek T., Chillon M. C., Homburg C., Martinelli G., Kairisto V., Lange T., Lion T., Mueller M. C., Pane F., Rai L., Damm-Welk C., Sacha T., Schnittger S., Touloumenidou T., Valerhaugen H., Vandenberghe P., Zuna J., Serve H., Herrmann E., Markovic S., van Dongen J. J. M., and Ottmann O. G.

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

9. Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.

Author

Venn, NC, Huang, L, Hovorková, L, Muskovic, W, Wong, M, Law, T, Heatley, SL, Khaw, SL, Revesz, T, Dalla Pozza, L, Shaw, PJ, Fraser, C, Moore, AS, Cross, S, Bendak, K, Norris, MD, Henderson, MJ, White, DL, Cowley, MJ, Trahair, TN, Zuna, J, Sutton, R, Venn, NC, Huang, L, Hovorková, L, Muskovic, W, Wong, M, Law, T, Heatley, SL, Khaw, SL, Revesz, T, Dalla Pozza, L, Shaw, PJ, Fraser, C, Moore, AS, Cross, S, Bendak, K, Norris, MD, Henderson, MJ, White, DL, Cowley, MJ, Trahair, TN, Zuna, J, and Sutton, R

Abstract

BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.

Published
2022

10. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Stutterheim, J., de Lorenzo, P., van der Sluis, I. M., Alten, J., Ancliffe, P., Attarbaschi, A., Aversa, L., Boer, J. M., Biondi, A., Brethon, B., Diaz, P., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Leung, A. W., Locatelli, Franco, Silverman, L., Stary, J., Szczepanski, T., van der Velden, V. H. J., Vora, A., Zuna, J., Schrappe, M., Valsecchi, M. G., Pieters, R., Locatelli F. (ORCID:0000-0002-7976-3654), Stutterheim, J., de Lorenzo, P., van der Sluis, I. M., Alten, J., Ancliffe, P., Attarbaschi, A., Aversa, L., Boer, J. M., Biondi, A., Brethon, B., Diaz, P., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Leung, A. W., Locatelli, Franco, Silverman, L., Stary, J., Szczepanski, T., van der Velden, V. H. J., Vora, A., Zuna, J., Schrappe, M., Valsecchi, M. G., Pieters, R., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. Methods: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10−4), and high (≥5∗10−4). Results: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10−4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10−4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). Conclusion: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

Published
2022

11. Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease

Author

Zuna, J, Hovorkova, L, Krotka, J, Koehrmann, A, Bardini, M, Winkowska, L, Fronkova, E, Alten, J, Koehler, R, Eckert, C, Brizzolara, L, Trkova, M, Stuchly, J, Zimmermann, M, De Lorenzo, P, Valsecchi, M, Conter, V, Stary, J, Schrappe, M, Biondi, A, Trka, J, Zaliova, M, Cazzaniga, G, Cario, G, Zuna, Jan, Hovorkova, Lenka, Krotka, Justina, Koehrmann, Amelie, Bardini, Michela, Winkowska, Lucie, Fronkova, Eva, Alten, Julia, Koehler, Rolf, Eckert, Cornelia, Brizzolara, Lisa, Trkova, Marie, Stuchly, Jan, Zimmermann, Martin, De Lorenzo, Paola, Valsecchi, Maria Grazia, Conter, Valentino, Stary, Jan, Schrappe, Martin, Biondi, Andrea, Trka, Jan, Zaliova, Marketa, Cazzaniga, Giovanni, Cario, Gunnar, Zuna, J, Hovorkova, L, Krotka, J, Koehrmann, A, Bardini, M, Winkowska, L, Fronkova, E, Alten, J, Koehler, R, Eckert, C, Brizzolara, L, Trkova, M, Stuchly, J, Zimmermann, M, De Lorenzo, P, Valsecchi, M, Conter, V, Stary, J, Schrappe, M, Biondi, A, Trka, J, Zaliova, M, Cazzaniga, G, Cario, G, Zuna, Jan, Hovorkova, Lenka, Krotka, Justina, Koehrmann, Amelie, Bardini, Michela, Winkowska, Lucie, Fronkova, Eva, Alten, Julia, Koehler, Rolf, Eckert, Cornelia, Brizzolara, Lisa, Trkova, Marie, Stuchly, Jan, Zimmermann, Martin, De Lorenzo, Paola, Valsecchi, Maria Grazia, Conter, Valentino, Stary, Jan, Schrappe, Martin, Biondi, Andrea, Trka, Jan, Zaliova, Marketa, Cazzaniga, Giovanni, and Cario, Gunnar

Abstract

Recently, we defined “CML-like” subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000–IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.

Published
2022

12. RT-PCR-Based Detection of TEL/AML1 Fusion Transcript in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia — a Czech Childhood Leukemia Working Group Experience

Author

Childhood Leukemia Working Group, Trka, J., Zuna, J., Kalinova, M., Hrusak, O., Paukertova, R., Eckschlager, T., Stary, J., Hiddemann, W., editor, Büchner, T., editor, Wörmann, B., editor, Ritter, J., editor, Creutzig, U., editor, Keating, M., editor, and Plunkett, W., editor

Published
1998
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13. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Stutterheim, J., primary, de Lorenzo, P., additional, van der Sluis, I.M., additional, Alten, J., additional, Ancliffe, P., additional, Attarbaschi, A., additional, Aversa, L., additional, Boer, J.M., additional, Biondi, A., additional, Brethon, B., additional, Diaz, P., additional, Cazzaniga, G., additional, Escherich, G., additional, Ferster, A., additional, Kotecha, R.S., additional, Lausen, B., additional, Leung, Alex WK., additional, Locatelli, F., additional, Silverman, L., additional, Stary, J., additional, Szczepanski, T., additional, van der Velden, V.H.J., additional, Vora, A., additional, Zuna, J., additional, Schrappe, M., additional, Valsecchi, M.G., additional, and Pieters, R., additional

Published
2022
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16. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1

Author

Pfeifer, H, Cazzaniga, G, van der Velden, V, Cayuela, J, Schäfer, B, Spinelli, O, Akiki, S, Avigad, S, Bendit, I, Borg, K, Cavé, H, Elia, L, Reshmi, S, Gerrard, G, Hayette, S, Hermanson, M, Juh, A, Jurcek, T, Chillón, M, Homburg, C, Martinelli, G, Kairisto, V, Lange, T, Lion, T, Mueller, M, Pane, F, Rai, L, Damm-Welk, C, Sacha, T, Schnittger, S, Touloumenidou, T, Valerhaugen, H, Vandenberghe, P, Zuna, J, Serve, H, Herrmann, E, Markovic, S, Dongen, J, Ottmann, O, Pfeifer, H., Cazzaniga, G., van der Velden, V. H. J., Cayuela, J. M., Schäfer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I., Borg, K., Cavé, H., Elia, L., Reshmi, S. C., Gerrard, G., Hayette, S., Hermanson, M., Juh, A., Jurcek, T., Chillón, M. C., Homburg, C., Martinelli, G., Kairisto, V., Lange, T., Lion, T., Mueller, M. C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Serve, H., Herrmann, E., Markovic, S., Dongen, J. J. M. van, Ottmann, O. G., Pfeifer, H, Cazzaniga, G, van der Velden, V, Cayuela, J, Schäfer, B, Spinelli, O, Akiki, S, Avigad, S, Bendit, I, Borg, K, Cavé, H, Elia, L, Reshmi, S, Gerrard, G, Hayette, S, Hermanson, M, Juh, A, Jurcek, T, Chillón, M, Homburg, C, Martinelli, G, Kairisto, V, Lange, T, Lion, T, Mueller, M, Pane, F, Rai, L, Damm-Welk, C, Sacha, T, Schnittger, S, Touloumenidou, T, Valerhaugen, H, Vandenberghe, P, Zuna, J, Serve, H, Herrmann, E, Markovic, S, Dongen, J, Ottmann, O, Pfeifer, H., Cazzaniga, G., van der Velden, V. H. J., Cayuela, J. M., Schäfer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I., Borg, K., Cavé, H., Elia, L., Reshmi, S. C., Gerrard, G., Hayette, S., Hermanson, M., Juh, A., Jurcek, T., Chillón, M. C., Homburg, C., Martinelli, G., Kairisto, V., Lange, T., Lion, T., Mueller, M. C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Serve, H., Herrmann, E., Markovic, S., Dongen, J. J. M. van, and Ottmann, O. G.

Abstract

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10 −3 and 36/67 (53%) and 53/67 (79%) at 10 −4 BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

Published
2019

19. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Author

Stutterheim, J., van der Sluis, I. M., de Lorenzo, P., Alten, J., Ancliffe, P., Attarbaschi, A., Brethon, B., Biondi, A., Campbell, M., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Li, C. K., Lo Nigro, L., Locatelli, Franco, Marschalek, R., Meyer, C., Schrappe, M., Stary, J., Vora, A., Zuna, J., van der Velden, V. H. J., Szczepanski, T., Valsecchi, M. G., Pieters, R., Locatelli F. (ORCID:0000-0002-7976-3654), Stutterheim, J., van der Sluis, I. M., de Lorenzo, P., Alten, J., Ancliffe, P., Attarbaschi, A., Brethon, B., Biondi, A., Campbell, M., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Li, C. K., Lo Nigro, L., Locatelli, Franco, Marschalek, R., Meyer, C., Schrappe, M., Stary, J., Vora, A., Zuna, J., van der Velden, V. H. J., Szczepanski, T., Valsecchi, M. G., Pieters, R., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). RESULTS: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may bene

Published
2021

20. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Author

Stutterheim, J, van der Sluis, I, de Lorenzo, P, Alten, J, Ancliffe, P, Attarbaschi, A, Brethon, B, Biondi, A, Campbell, M, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Li, C, Lo Nigro, L, Locatelli, F, Marschalek, R, Meyer, C, Schrappe, M, Stary, J, Vora, A, Zuna, J, van der Velden, V, Szczepanski, T, Valsecchi, M, Pieters, R, Stutterheim, Janine, van der Sluis, Inge M, de Lorenzo, Paola, Alten, Julia, Ancliffe, Philip, Attarbaschi, Andishe, Brethon, Benoit, Biondi, Andrea, Campbell, Myriam, Cazzaniga, Giovanni, Escherich, Gabriele, Ferster, Alina, Kotecha, Rishi S, Lausen, Birgitte, Li, Chi Kong, Lo Nigro, Luca, Locatelli, Franco, Marschalek, Rolf, Meyer, Claus, Schrappe, Martin, Stary, Jan, Vora, Ajay, Zuna, Jan, van der Velden, Vincent H J, Szczepanski, Tomasz, Valsecchi, Maria Grazia, Pieters, Rob, Stutterheim, J, van der Sluis, I, de Lorenzo, P, Alten, J, Ancliffe, P, Attarbaschi, A, Brethon, B, Biondi, A, Campbell, M, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Li, C, Lo Nigro, L, Locatelli, F, Marschalek, R, Meyer, C, Schrappe, M, Stary, J, Vora, A, Zuna, J, van der Velden, V, Szczepanski, T, Valsecchi, M, Pieters, R, Stutterheim, Janine, van der Sluis, Inge M, de Lorenzo, Paola, Alten, Julia, Ancliffe, Philip, Attarbaschi, Andishe, Brethon, Benoit, Biondi, Andrea, Campbell, Myriam, Cazzaniga, Giovanni, Escherich, Gabriele, Ferster, Alina, Kotecha, Rishi S, Lausen, Birgitte, Li, Chi Kong, Lo Nigro, Luca, Locatelli, Franco, Marschalek, Rolf, Meyer, Claus, Schrappe, Martin, Stary, Jan, Vora, Ajay, Zuna, Jan, van der Velden, Vincent H J, Szczepanski, Tomasz, Valsecchi, Maria Grazia, and Pieters, Rob

Abstract

Purpose: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). Materials and methods: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). Results: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). Conclusion: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may bene

Published
2021

21. History of treatment and long-term outcome in children with acute lymphoblastic leukemia in the Czech Republic

Author

Starý, J., Mihál, V., Smíšek, P., Blažek, B., Jabali, Y., Hrstková, H., Hak, J., Procházková, D., Černá, Z., Štěrba, J., Trka, J., Hrušák, O., Zuna, J., Mejstříková, E., Janotová, I., Sedláček, P., Ptoszková, H., Pospíšilová, D., Toušovská, K., Timr, P., Vávra, V., Zdráhalová, K., Šrámková, L., Zemanová, Z., Jarošová, M., Gajdoš, P., and Hrodek, O.

Published
2011
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22. New insights to the MLL recombinome of acute leukemias

Author

Meyer, C, Kowarz, E, Hofmann, J, Renneville, A, Zuna, J, Trka, J, Ben Abdelali, R, Macintyre, E, De Braekeleer, E, De Braekeleer, M, Delabesse, E, de Oliveira, M P, Cavé, H, Clappier, E, van Dongen, J J M, Balgobind, B V, van den Heuvel-Eibrink, M M, Beverloo, H B, Panzer-Grümayer, R, Teigler-Schlegel, A, Harbott, J, Kjeldsen, E, Schnittger, S, Koehl, U, Gruhn, B, Heidenreich, O, Chan, L C, Yip, S F, Krzywinski, M, Eckert, C, Möricke, A, Schrappe, M, Alonso, C N, Schäfer, B W, Krauter, J, Lee, D A, zur Stadt, U, Te Kronnie, G, Sutton, R, Izraeli, S, Trakhtenbrot, L, Lo Nigro, L, Tsaur, G, Fechina, L, Szczepanski, T, Strehl, S, Ilencikova, D, Molkentin, M, Burmeister, T, Dingermann, T, Klingebiel, T, and Marschalek, R

Published
2009
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24. The KMT2Arecombinome of acute leukemias in 2023

Author

Meyer, C., Larghero, P., Almeida Lopes, B., Burmeister, T., Gröger, D., Sutton, R., Venn, N. C., Cazzaniga, G., Corral Abascal, L., Tsaur, G., Fechina, L., Emerenciano, M., Pombo-de-Oliveira, M. S., Lund-Aho, T., Lundán, T., Montonen, M., Juvonen, V., Zuna, J., Trka, J., Ballerini, P., Lapillonne, H., Van der Velden, V. H. J., Sonneveld, E., Delabesse, E., de Matos, R. R. C., Silva, M. L. M., Bomken, S., Katsibardi, K., Keernik, M., Grardel, N., Mason, J., Price, R., Kim, J., Eckert, C., Lo Nigro, L., Bueno, C., Menendez, P., zur Stadt, U., Gameiro, P., Sedék, L., Szczepański, T., Bidet, A., Marcu, V., Shichrur, K., Izraeli, S., Madsen, H. O., Schäfer, B. W., Kubetzko, S., Kim, R., Clappier, E., Trautmann, H., Brüggemann, M., Archer, P., Hancock, J., Alten, J., Möricke, A., Stanulla, M., Lentes, J., Bergmann, A. K., Strehl, S., Köhrer, S., Nebral, K., Dworzak, M. N., Haas, O. A., Arfeuille, C., Caye-Eude, A., Cavé, H., and Marschalek, R.

Abstract

Chromosomal rearrangements of the human KMT2A/MLLgene are associated with de novoas well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2Agene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2Agene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2Adeletion, and one ETV6::RUNX1patient had an KMT2Ainsertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2Arecombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Published
2023
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26. The MLL recombinome of acute leukemias in 2013

Author

Meyer, C, Hofmann, J, Burmeister, T, Gröger, D, Park, T S, Emerenciano, M, Pombo de Oliveira, M, Renneville, A, Villarese, P, Macintyre, E, Cavé, H, Clappier, E, Mass-Malo, K, Zuna, J, Trka, J, De Braekeleer, E, De Braekeleer, M, Oh, S H, Tsaur, G, Fechina, L, van der Velden, V HJ, van Dongen, J JM, Delabesse, E, Binato, R, Silva, M LM, Kustanovich, A, Aleinikova, O, Harris, M H, Lund-Aho, T, Juvonen, V, Heidenreich, O, Vormoor, J, Choi, W WL, Jarosova, M, Kolenova, A, Bueno, C, Menendez, P, Wehner, S, Eckert, C, Talmant, P, Tondeur, S, Lippert, E, Launay, E, Henry, C, Ballerini, P, Lapillone, H, Callanan, M B, Cayuela, J M, Herbaux, C, Cazzaniga, G, Kakadiya, P M, Bohlander, S, Ahlmann, M, Choi, J R, Gameiro, P, Lee, D S, Krauter, J, Cornillet-Lefebvre, P, Te Kronnie, G, Schäfer, B W, Kubetzko, S, Alonso, C N, zur Stadt, U, Sutton, R, Venn, N C, Izraeli, S, Trakhtenbrot, L, Madsen, H O, Archer, P, Hancock, J, Cerveira, N, Teixeira, M R, Lo Nigro, L, Möricke, A, Stanulla, M, Schrappe, M, Sedék, L, Szczepański, T, Zwaan, C M, Coenen, E A, van den Heuvel-Eibrink, M M, Strehl, S, Dworzak, M, Panzer-Grümayer, R, Dingermann, T, Klingebiel, T, and Marschalek, R

Published
2013
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27. The MLL recombinome of acute leukemias in 2017

Author

Meyer, C, Burmeister, T, Gröger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, N, Emerenciano, M, Pombo-De-Oliveira, M, Barbieri Blunck, C, Almeida Lopes, B, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Corral Abascal, L, Van Der Velden, V, Delabesse, E, Park, T, Oh, S, Silva, M, Lund-Aho, T, Juvonen, V, Moore, A, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, Zur Stadt, U, Lentes, J, Göhring, G, Kustanovich, A, Aleinikova, O, Schäfer, B, Kubetzko, S, Madsen, H, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, J, Clappier, E, Alonso, C, Zwaan, C, Van Den Heuvel-Eibrink, M, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Möricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, O, Panzer-Grümayer, R, Sedék, L, Szczepa, T, Caye, A, Suarez, L, Cavé, H, Marschalek, R, Meyer, C., Burmeister, T., Gröger, D., Tsaur, G., Fechina, L., Renneville, A., Sutton, R., Venn, N. C., Emerenciano, M., Pombo-De-Oliveira, M. S., Barbieri Blunck, C., Almeida Lopes, B., Zuna, J., Trka, J., Ballerini, P., Lapillonne, H., De Braekeleer, M., Cazzaniga, G., Corral Abascal, L., Van Der Velden, V. H. J., Delabesse, E., Park, T. S., Oh, S. H., Silva, M. L. M., Lund-Aho, T., Juvonen, V., Moore, A. S., Heidenreich, O., Vormoor, J., Zerkalenkova, E., Olshanskaya, Y., Bueno, C., Menendez, P., Teigler-Schlegel, A., Zur Stadt, U., Lentes, J., Göhring, G., Kustanovich, A., Aleinikova, O., Schäfer, B. W., Kubetzko, S., Madsen, H. O., Gruhn, B., Duarte, X., Gameiro, P., Lippert, E., Bidet, A., Cayuela, J. M., Clappier, E., Alonso, C. N., Zwaan, C. M., Van Den Heuvel-Eibrink, M. M., Izraeli, S., Trakhtenbrot, L., Archer, P., Hancock, J., Möricke, A., Alten, J., Schrappe, M., Stanulla, M., Strehl, S., Attarbaschi, A., Dworzak, M., Haas, O. A., Panzer-Grümayer, R., Sedék, L., Szczepa, T., Caye, A., Suarez, L., Cavé, H., Marschalek, R., Meyer, C, Burmeister, T, Gröger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, N, Emerenciano, M, Pombo-De-Oliveira, M, Barbieri Blunck, C, Almeida Lopes, B, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Corral Abascal, L, Van Der Velden, V, Delabesse, E, Park, T, Oh, S, Silva, M, Lund-Aho, T, Juvonen, V, Moore, A, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, Zur Stadt, U, Lentes, J, Göhring, G, Kustanovich, A, Aleinikova, O, Schäfer, B, Kubetzko, S, Madsen, H, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, J, Clappier, E, Alonso, C, Zwaan, C, Van Den Heuvel-Eibrink, M, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Möricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, O, Panzer-Grümayer, R, Sedék, L, Szczepa, T, Caye, A, Suarez, L, Cavé, H, Marschalek, R, Meyer, C., Burmeister, T., Gröger, D., Tsaur, G., Fechina, L., Renneville, A., Sutton, R., Venn, N. C., Emerenciano, M., Pombo-De-Oliveira, M. S., Barbieri Blunck, C., Almeida Lopes, B., Zuna, J., Trka, J., Ballerini, P., Lapillonne, H., De Braekeleer, M., Cazzaniga, G., Corral Abascal, L., Van Der Velden, V. H. J., Delabesse, E., Park, T. S., Oh, S. H., Silva, M. L. M., Lund-Aho, T., Juvonen, V., Moore, A. S., Heidenreich, O., Vormoor, J., Zerkalenkova, E., Olshanskaya, Y., Bueno, C., Menendez, P., Teigler-Schlegel, A., Zur Stadt, U., Lentes, J., Göhring, G., Kustanovich, A., Aleinikova, O., Schäfer, B. W., Kubetzko, S., Madsen, H. O., Gruhn, B., Duarte, X., Gameiro, P., Lippert, E., Bidet, A., Cayuela, J. M., Clappier, E., Alonso, C. N., Zwaan, C. M., Van Den Heuvel-Eibrink, M. M., Izraeli, S., Trakhtenbrot, L., Archer, P., Hancock, J., Möricke, A., Alten, J., Schrappe, M., Stanulla, M., Strehl, S., Attarbaschi, A., Dworzak, M., Haas, O. A., Panzer-Grümayer, R., Sedék, L., Szczepa, T., Caye, A., Suarez, L., Cavé, H., and Marschalek, R.

Abstract

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients

Published
2018

28. Childhood secondary ALL after ALL treatment

Author

Zuna, J, Cavé, H, Eckert, C, Szczepanski, T, Meyer, C, Mejstrikova, E, Fronkova, E, Muzikova, K, Clappier, E, Mendelova, D, Boutard, P, Schrauder, A, Sterba, J, Marschalek, R, van Dongen, J J M, Hrusak, O, Stary, J, and Trka, J

Published
2007
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29. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1 (vol 32, pg 345, 2019)

Author

Pfeifer, H., Cazzaniga, G., Velden, V.H.J. van der, Cayuela, J.M., Schafer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I., Borg, K., Cave, H., Elia, L., Reshmi, S.C., Gerrard, G., Hayette, S., Hermanson, M., Juh, A., Jurcek, T., Chillon, M.C., Homburg, C., Martinelli, G., Kairisto, V., Lange, T., Lion, T., Mueller, M.C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Serve, H., Herrmann, E., Markovic, S., Dongen, J.J.M. van, and Ottmann, O.G.

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

30. The MLL recombinome of acute leukemias

Author

Meyer, C, Schneider, B, Jakob, S, Strehl, S, Attarbaschi, A, Schnittger, S, Schoch, C, Jansen, M W J C, van Dongen, J J M, den Boer, M L, Pieters, R, Ennas, M-G, Angelucci, E, Koehl, U, Greil, J, Griesinger, F, zur Stadt, U, Eckert, C, Szczepański, T, Niggli, F K, Schäfer, B W, Kempski, H, Brady, H J M, Zuna, J, Trka, J, Nigro, L L, Biondi, A, Delabesse, E, Macintyre, E, Stanulla, M, Schrappe, M, Haas, O A, Burmeister, T, Dingermann, T, Klingebiel, T, and Marschalek, R

Published
2006
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31. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols

Author

Cario, G, Leoni, V, Conter, V, Attarbaschi, A, Zaliova, M, Sramkova, L, Cazzaniga, G, Fazio, G, Sutton, R, Elitzur, S, Izraeli, S, Lauten, M, Locatelli, F, Basso, G, Buldini, B, Bergmann, AK, Lentes, J, Steinemann, D, Göhring, G, Schlegelberger, B, Haas, OA, Schewe, D, Buchmann, S, Moericke, A, White, D, Revesz, T, Stanulla, M, Mann, G, Bodmer, N, Arad-Cohen, N, Zuna, J, Valsecchi, MG, Zimmermann, M, Schrappe, M, Biondi, A, Cario, G, Leoni, V, Conter, V, Attarbaschi, A, Zaliova, M, Sramkova, L, Cazzaniga, G, Fazio, G, Sutton, R, Elitzur, S, Izraeli, S, Lauten, M, Locatelli, F, Basso, G, Buldini, B, Bergmann, AK, Lentes, J, Steinemann, D, Göhring, G, Schlegelberger, B, Haas, OA, Schewe, D, Buchmann, S, Moericke, A, White, D, Revesz, T, Stanulla, M, Mann, G, Bodmer, N, Arad-Cohen, N, Zuna, J, Valsecchi, MG, Zimmermann, M, Schrappe, M, and Biondi, A

Abstract

ABL-class fusions other than BCR-ABL1 characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5x10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

Published
2020

32. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols

Author

Cario, G., Leoni, V., Conter, V., Attarbaschi, A., Zaliova, M., Sramkova, L., Cazzaniga, G., Fazio, G., Sutton, R., Elitzur, S., Izraeli, S., Lauten, M., Locatelli, Franco, Basso, G., Buldini, B., Bergmann, A. K., Lentes, J., Steinemann, D., Gohring, G., Schlegelberger, B., Haas, O. A., Schewe, D., Buchmann, S., Moericke, A., White, D., Revesz, T., Stanulla, M., Mann, G., Bodmer, N., Arad-Cohen, N., Zuna, J., Valsecchi, M. G., Zimmermann, M., Schrappe, M., Biondi, A., Locatelli F. (ORCID:0000-0002-7976-3654), Cario, G., Leoni, V., Conter, V., Attarbaschi, A., Zaliova, M., Sramkova, L., Cazzaniga, G., Fazio, G., Sutton, R., Elitzur, S., Izraeli, S., Lauten, M., Locatelli, Franco, Basso, G., Buldini, B., Bergmann, A. K., Lentes, J., Steinemann, D., Gohring, G., Schlegelberger, B., Haas, O. A., Schewe, D., Buchmann, S., Moericke, A., White, D., Revesz, T., Stanulla, M., Mann, G., Bodmer, N., Arad-Cohen, N., Zuna, J., Valsecchi, M. G., Zimmermann, M., Schrappe, M., Biondi, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

ABL-class fusions other than BCR-ABL1 characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5x10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

Published
2020

36. An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia

Author

Zimmermannova, O, Doktorova, E, Stuchly, J, Kanderova, V, Kuzilkova, D, Strnad, H, Starkova, J, Alberich-Jorda, M, Falkenburg, J H F, Trka, J, Petrak, J, Zuna, J, and Zaliova, M

Subjects
Leukemia, Oncogene Proteins, Fusion, GTP-Binding Protein beta Subunits, Protein-Tyrosine Kinases, respiratory tract diseases, Drug Resistance, Neoplasm, hemic and lymphatic diseases, Cell Line, Tumor, Mutation, Imatinib Mesylate, Humans, Original Article, RNA, Small Interfering, Protein Kinase Inhibitors, Signal Transduction
Abstract

Leukemias harboring the ETV6-ABL1 fusion represent a rare subset of hematological malignancies with unfavorable outcomes. The constitutively active chimeric Etv6-Abl1 tyrosine kinase can be specifically inhibited by tyrosine kinase inhibitors (TKIs). Although TKIs represent an important therapeutic tool, so far, the mechanism underlying the potential TKI resistance in ETV6-ABL1-positive malignancies has not been studied in detail. To address this issue, we established a TKI-resistant ETV6-ABL1-positive leukemic cell line through long-term exposure to imatinib. ETV6-ABL1-dependent mechanisms (including fusion gene/protein mutation, amplification, enhanced expression or phosphorylation) and increased TKI efflux were excluded as potential causes of resistance. We showed that TKI effectively inhibited the Etv6-Abl1 kinase activity in resistant cells, and using short hairpin RNA (shRNA)-mediated silencing, we confirmed that the resistant cells became independent from the ETV6-ABL1 oncogene. Through analysis of the genomic and proteomic profiles of resistant cells, we identified an acquired mutation in the GNB1 gene, K89M, as the most likely cause of the resistance. We showed that cells harboring mutated GNB1 were capable of restoring signaling through the phosphoinositide-3-kinase (PI3K)/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, whose activation is inhibited by TKI. This alternative GNB1K89M-mediated pro-survival signaling rendered ETV6-ABL1-positive leukemic cells resistant to TKI therapy. The mechanism of TKI resistance is independent of the targeted chimeric kinase and thus is potentially relevant not only to ETV6-ABL1-positive leukemias but also to a wider spectrum of malignancies treated by kinase inhibitors.

Published
2017

38. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph plus ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1

Author

Pfeifer, H., Cazzaniga, G., van der Velden, V. H. J., Cayuele, J. M., Schafer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I, Borg, K., Cave, H., Elia, L., Reshmi, S. C., Gerrard, G., Hayette, S., Hermansson, Monica, Juh, A., Jurcek, T., Chillon, M. C., Homburg, C., Martinelli, G., Kairisto, V, Langen, T., Lion, T., Mueller, M. C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Server, H., Herrmann, E., Markovic, S., van Dongen, J. J. M., Ottmann, O. G., Pfeifer, H., Cazzaniga, G., van der Velden, V. H. J., Cayuele, J. M., Schafer, B., Spinelli, O., Akiki, S., Avigad, S., Bendit, I, Borg, K., Cave, H., Elia, L., Reshmi, S. C., Gerrard, G., Hayette, S., Hermansson, Monica, Juh, A., Jurcek, T., Chillon, M. C., Homburg, C., Martinelli, G., Kairisto, V, Langen, T., Lion, T., Mueller, M. C., Pane, F., Rai, L., Damm-Welk, C., Sacha, T., Schnittger, S., Touloumenidou, T., Valerhaugen, H., Vandenberghe, P., Zuna, J., Server, H., Herrmann, E., Markovic, S., van Dongen, J. J. M., and Ottmann, O. G.

Abstract

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10(-3) and 36/67 (53%) and 53/67 (79%) at 10(-4)BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

Published
2019
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39. Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions

Author

Meyer, C, Lopes, BA, Caye-Eude, A, Cavé, H, Arfeuille, C, Cuccuini, W, Sutton, R, Venn, NC, Oh, SH, Tsaur, G, Escherich, G, Feuchtinger, T, Kosasih, HJ, Khaw, SL, Ekert, PG, Pombo-de-Oliveira, MS, Bidet, A, Djahanschiri, B, Ebersberger, I, Zaliova, M, Zuna, J, Zermanova, Z, Juvonen, V, Grümayer, RP, Fazio, G, Cazzaniga, G, Larghero, P, Emerenciano, M, Marschalek, R, Meyer, C, Lopes, BA, Caye-Eude, A, Cavé, H, Arfeuille, C, Cuccuini, W, Sutton, R, Venn, NC, Oh, SH, Tsaur, G, Escherich, G, Feuchtinger, T, Kosasih, HJ, Khaw, SL, Ekert, PG, Pombo-de-Oliveira, MS, Bidet, A, Djahanschiri, B, Ebersberger, I, Zaliova, M, Zuna, J, Zermanova, Z, Juvonen, V, Grümayer, RP, Fazio, G, Cazzaniga, G, Larghero, P, Emerenciano, M, and Marschalek, R

Published
2019

40. Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions

Author

Meyer, C., Lopes, B. A., Caye-Eude, A., Cavé, H., Arfeuille, C., Cuccuini, W., Sutton, R., Venn, N. C., Oh, S. H., Tsaur, G., Escherich, G., Feuchtinger, T., Kosasih, H. J., Khaw, S. L., Ekert, P. G., Pombo-de-Oliveira, M. S., Bidet, A., Djahanschiri, B., Ebersberger, I., Zaliova, M., Zuna, J., Zermanova, Z., Juvonen, V., Grümayer, R. P., Fazio, G., Cazzaniga, G., Larghero, P., Emerenciano, M., Marschalek, R., Meyer, C., Lopes, B. A., Caye-Eude, A., Cavé, H., Arfeuille, C., Cuccuini, W., Sutton, R., Venn, N. C., Oh, S. H., Tsaur, G., Escherich, G., Feuchtinger, T., Kosasih, H. J., Khaw, S. L., Ekert, P. G., Pombo-de-Oliveira, M. S., Bidet, A., Djahanschiri, B., Ebersberger, I., Zaliova, M., Zuna, J., Zermanova, Z., Juvonen, V., Grümayer, R. P., Fazio, G., Cazzaniga, G., Larghero, P., Emerenciano, M., and Marschalek, R.

Published
2019

43. PF162 FREQUENCY AND PROGNOSTIC IMPACT OF ZEB2 H1038/Q1072 MUTATIONS IN CHILDHOOD B-OTHER ACUTE LYMPHOBLASTIC LEUKEMIA

Author

Zaliova, M., primary, Potuckova, E., additional, Lukes, J., additional, Winkowska, L., additional, Starkova, J., additional, Janotova, I., additional, Sramkova, L., additional, Stary, J., additional, Zuna, J., additional, Stanulla, M., additional, Zimmermann, M., additional, Bourquin, J.-P., additional, Eckert, C., additional, Cario, G., additional, and Trka, J., additional

Published
2019
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44. PF237 THE PROGNOSTIC IMPACT OF LYMPHOCYTE REPERTOIRE RECOVERY AFTER INDUCTION TREATMENT OF CHILDHOOD AML

Author

Svaton, M., primary, Novakova, M., additional, Reznickova, L., additional, Darzentas, N., additional, Stuchly, J., additional, Svenkrtova, A., additional, Zaliova, M., additional, Zuna, J., additional, Mejstrikova, E., additional, Kotrova, M., additional, Reigl, T., additional, Hrusak, O., additional, Stary, J., additional, Trka, J., additional, and Fronkova, E., additional

Published
2019
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45. PF414 DNA-BASED BCR-ABL1 ANALYSIS PROVIDES A “TRAFFIC LIGHT” STRATIFICATION MODEL FOR CHRONIC MYELOID LEUKEMIA WITH IMPLICATIONS FOR TREATMENT FREE REMISSION

Author

Machova Polakova, K., primary, Zizkova, H., additional, Zuna, J., additional, Motlova, E., additional, Hovorkova, L., additional, Pecherkova, P., additional, Klamova, H., additional, Stastna Markova, M., additional, Srbova, D., additional, Koblihova, J., additional, Benesova, A., additional, Polivkova, V., additional, Jurcek, T., additional, Zackova, D., additional, Mayer, J., additional, Ernst, T., additional, Mahon, F.X., additional, Saussele, S., additional, Cross, N.C., additional, and Hochhaus, A., additional

Published
2019
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46. The MLL recombinome of acute leukemias in 2017

Author

Meyer, C., Burmeister, T., Gröger, D. (D.), Tsaur, G., Fechina, L., Renneville, A., Sutton, R., Venn, N., Emerenciano, M. (M.), Pombo-De-Oliveira, M.S. (M. S.), Barbieri Blunck, C. (C.), Almeida Lopes, B. (B.), Zuna, J., Trka, J. (Jan), Ballerini, P. (P.), Lapillonne, H. (H.), Braekeleer, E. de, Cazzaniga, G. (Gianni), Corral Abascal, L. (L.), Velden, V.H.J. (Vincent) van der, Delabesse, E., Park, T.S. (T. S.), Oh, S.H. (S.), Silva, M.L.M. (M. L M), Lund-Aho, T. (T.), Juvonen, V. (V.), Moore, A.S. (A.), Heidenreich, O., Vormoor, J. (J.), Zerkalenkova, E. (E.), Olshanskaya, Y. (Y.), Bueno, C. (C.), Menéndez, P. (Pablo), Teigler-Schlegel, A., zur Stadt, U., Lentes, J. (J.), Göhring, G. (Gudrun), Kustanovich, A. (A.), Aleinikova, O. (O.), Schäfer, B.W. (B. W.), Kubetzko, S. (S.), Madsen, H.O., Gruhn, B. (B.), Duarte, X. (X.), Gameiro, P., Lippert, E. (Eric), Bidet, A. (A.), Cayuela, J.-M. (Jean-Michel), Clappier, E., Alonso, C.N. (Cristina), Zwaan, C.M. (Michel), Heuvel-Eibrink, M.M. (Marry) van den, Izraeli, S. (Shai), Trakhtenbrot, L., Archer, P. (P.), Hancock, J., Möricke, A., Alten, J. (J.), Schrappe, M. (Martin), Stanulla, M. (Martin), Strehl, S., Attarbaschi, A. (Andishe), Dworzak, M.N. (Michael), Haas, O.A. (O. A.), Panzer-Grümayer, R. (Renate), Sedek, L. (Lukasz), Szczepa, T. (T.), Caye, A. (Aurélie), Suarez, L. (L.), Cavé, H. (Helene), Marschalek, R. (Rolf), Meyer, C., Burmeister, T., Gröger, D. (D.), Tsaur, G., Fechina, L., Renneville, A., Sutton, R., Venn, N., Emerenciano, M. (M.), Pombo-De-Oliveira, M.S. (M. S.), Barbieri Blunck, C. (C.), Almeida Lopes, B. (B.), Zuna, J., Trka, J. (Jan), Ballerini, P. (P.), Lapillonne, H. (H.), Braekeleer, E. de, Cazzaniga, G. (Gianni), Corral Abascal, L. (L.), Velden, V.H.J. (Vincent) van der, Delabesse, E., Park, T.S. (T. S.), Oh, S.H. (S.), Silva, M.L.M. (M. L M), Lund-Aho, T. (T.), Juvonen, V. (V.), Moore, A.S. (A.), Heidenreich, O., Vormoor, J. (J.), Zerkalenkova, E. (E.), Olshanskaya, Y. (Y.), Bueno, C. (C.), Menéndez, P. (Pablo), Teigler-Schlegel, A., zur Stadt, U., Lentes, J. (J.), Göhring, G. (Gudrun), Kustanovich, A. (A.), Aleinikova, O. (O.), Schäfer, B.W. (B. W.), Kubetzko, S. (S.), Madsen, H.O., Gruhn, B. (B.), Duarte, X. (X.), Gameiro, P., Lippert, E. (Eric), Bidet, A. (A.), Cayuela, J.-M. (Jean-Michel), Clappier, E., Alonso, C.N. (Cristina), Zwaan, C.M. (Michel), Heuvel-Eibrink, M.M. (Marry) van den, Izraeli, S. (Shai), Trakhtenbrot, L., Archer, P. (P.), Hancock, J., Möricke, A., Alten, J. (J.), Schrappe, M. (Martin), Stanulla, M. (Martin), Strehl, S., Attarbaschi, A. (Andishe), Dworzak, M.N. (Michael), Haas, O.A. (O. A.), Panzer-Grümayer, R. (Renate), Sedek, L. (Lukasz), Szczepa, T. (T.), Caye, A. (Aurélie), Suarez, L. (L.), Cavé, H. (Helene), and Marschalek, R. (Rolf)

Abstract

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

Published
2018
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47. Predictive value of minimal residual disease in philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies

Author

Cazzaniga, G, De Lorenzo, P, Alten, J, Röttgers, S, Hancock, J, Saha, V, Castor, A, Madsen, H, Gandemer, V, Cavé, H, Leoni, V, Köhler, R, Ferrari, G, Bleckmann, K, Pieters, R, Van Der Velden, V, Stary, J, Zuna, J, Escherich, G, Stadt, U, Aricò, M, Conter, V, Schrappe, M, Valsecchi, M, Biondi, A, Röttgers, Si, Madsen, HO, Ferrari, GM, Stadt, UZ, Conter, Valentino, Valsecchi, MG, Cazzaniga, G, De Lorenzo, P, Alten, J, Röttgers, S, Hancock, J, Saha, V, Castor, A, Madsen, H, Gandemer, V, Cavé, H, Leoni, V, Köhler, R, Ferrari, G, Bleckmann, K, Pieters, R, Van Der Velden, V, Stary, J, Zuna, J, Escherich, G, Stadt, U, Aricò, M, Conter, V, Schrappe, M, Valsecchi, M, Biondi, A, Röttgers, Si, Madsen, HO, Ferrari, GM, Stadt, UZ, Conter, Valentino, and Valsecchi, MG

Abstract

The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-MÃ1⁄4nster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10−4and 70 with MRD≥5×10−4had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis.

Published
2018

48. The MLL recombinome of acute leukemias in 2017

Author

Hubrecht Institute with UMC, Meyer, C, Burmeister, T, Gröger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, N C, Emerenciano, M, Pombo-de-Oliveira, M S, Barbieri Blunck, C, Almeida Lopes, B, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Corral Abascal, L, van der Velden, V H J, Delabesse, E, Park, T S, Oh, S H, Silva, M L M, Lund-Aho, T, Juvonen, V, Moore, A S, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, Zur Stadt, U, Lentes, J, Göhring, G, Kustanovich, A, Aleinikova, O, Schäfer, B W, Kubetzko, S, Madsen, H O, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, J M, Clappier, E, Alonso, C N, Zwaan, C M, van den Heuvel-Eibrink, M M, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Möricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, O A, Panzer-Grümayer, R, Sedék, L, Szczepański, T, Caye, A, Suarez, L, Cavé, H, Marschalek, R, Hubrecht Institute with UMC, Meyer, C, Burmeister, T, Gröger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, N C, Emerenciano, M, Pombo-de-Oliveira, M S, Barbieri Blunck, C, Almeida Lopes, B, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Corral Abascal, L, van der Velden, V H J, Delabesse, E, Park, T S, Oh, S H, Silva, M L M, Lund-Aho, T, Juvonen, V, Moore, A S, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, Zur Stadt, U, Lentes, J, Göhring, G, Kustanovich, A, Aleinikova, O, Schäfer, B W, Kubetzko, S, Madsen, H O, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, J M, Clappier, E, Alonso, C N, Zwaan, C M, van den Heuvel-Eibrink, M M, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Möricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, O A, Panzer-Grümayer, R, Sedék, L, Szczepański, T, Caye, A, Suarez, L, Cavé, H, and Marschalek, R

Published
2018

50. PREDICTIVE VALUE OF IG/TR AND BCR/ABL1 PCR-BASED MINIMAL RESIDUAL DISEASE MONITORING IN PH plus PEDIATRIC ALL TREATED WITH IMATINIB IN THE ESPHALL STUDY

Author

Cazzaniga, G., Lorenzo, P., Alten, J., Roettgers, S., Hancock, J., Saha, V., Castor, A., Madsen, H., Gandemer, V., Cave, H., Leoni, V., Ferrari, G., Pieters, R., Velden, V., Stary, J., Zuna, J., Escherich, G., Zur Stadt, U., Maurizio Arico', Conter, V., Schrappe, M., Valsecchi, M. G., Biondi, A., Centre Hospitalier Universitaire [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, education, [SDV.GEN] Life Sciences [q-bio]/Genetics, social sciences, humanities, geographic locations, health care economics and organizations
Abstract

International audience; 21st Congress of the European-Hematology-Association

Published
2016

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