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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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3. Hypersensitivity Reactions to Native E. coli L-asparaginase in Children with Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction

Author

Moricke, A, Rizzari, C, Alten, J, Attarbaschi, A, Beier, R, Biondi, A, Burkhardt, B, Bodmer, N, Boos, J, Cario, G, Conter, V, Flotho, C, Kulozik, A, Lanvers-Kaminsky, C, Mann, G, Niggli, F, Silvestri, D, Von Stackelberg, A, Stanulla, M, Valsecchi, M, Schrappe, M, Zimmermann, M, Moricke A., Rizzari C., Alten J., Attarbaschi A., Beier R., Biondi A., Burkhardt B., Bodmer N., Boos J., Cario G., Conter V., Flotho C., Kulozik A., Lanvers-Kaminsky C., Mann G., Niggli F., Silvestri D., Von Stackelberg A., Stanulla M., Valsecchi MG., Schrappe M., Zimmermann M., Moricke, A, Rizzari, C, Alten, J, Attarbaschi, A, Beier, R, Biondi, A, Burkhardt, B, Bodmer, N, Boos, J, Cario, G, Conter, V, Flotho, C, Kulozik, A, Lanvers-Kaminsky, C, Mann, G, Niggli, F, Silvestri, D, Von Stackelberg, A, Stanulla, M, Valsecchi, M, Schrappe, M, Zimmermann, M, Moricke A., Rizzari C., Alten J., Attarbaschi A., Beier R., Biondi A., Burkhardt B., Bodmer N., Boos J., Cario G., Conter V., Flotho C., Kulozik A., Lanvers-Kaminsky C., Mann G., Niggli F., Silvestri D., Von Stackelberg A., Stanulla M., Valsecchi MG., Schrappe M., and Zimmermann M.

Published
2023

4. Hypersensitivity Reactions to Native E. coli L-asparaginase in Children with Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction

Author

Moricke A., Rizzari C., Alten J., Attarbaschi A., Beier R., Biondi A., Burkhardt B., Bodmer N., Boos J., Cario G., Conter V., Flotho C., Kulozik A., Lanvers-Kaminsky C., Mann G., Niggli F., Silvestri D., Von Stackelberg A., Stanulla M., Valsecchi MG., Schrappe M., Zimmermann M., Moricke, A, Rizzari, C, Alten, J, Attarbaschi, A, Beier, R, Biondi, A, Burkhardt, B, Bodmer, N, Boos, J, Cario, G, Conter, V, Flotho, C, Kulozik, A, Lanvers-Kaminsky, C, Mann, G, Niggli, F, Silvestri, D, Von Stackelberg, A, Stanulla, M, Valsecchi, M, Schrappe, M, and Zimmermann, M

Subjects
acute lymphoblastic leukemia, immunotherapy, MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, chemotherapy, childhood
Published
2023

5. The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia

Author

Kulp, M, Siemund, A, Larghero, P, Dietz, A, Alten, J, Cario, G, Eckert, C, Caye-Eude, A, Cave, H, Bardini, M, Cazzaniga, G, De Lorenzo, P, Valsecchi, M, Diehl, L, Bonig, H, Meyer, C, Marschalek, R, Kulp M., Siemund A. L., Larghero P., Dietz A., Alten J., Cario G., Eckert C., Caye-Eude A., Cave H., Bardini M., Cazzaniga G., De Lorenzo P., Valsecchi M. G., Diehl L., Bonig H., Meyer C., Marschalek R., Kulp, M, Siemund, A, Larghero, P, Dietz, A, Alten, J, Cario, G, Eckert, C, Caye-Eude, A, Cave, H, Bardini, M, Cazzaniga, G, De Lorenzo, P, Valsecchi, M, Diehl, L, Bonig, H, Meyer, C, Marschalek, R, Kulp M., Siemund A. L., Larghero P., Dietz A., Alten J., Cario G., Eckert C., Caye-Eude A., Cave H., Bardini M., Cazzaniga G., De Lorenzo P., Valsecchi M. G., Diehl L., Bonig H., Meyer C., and Marschalek R.

Abstract

The most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A:AFF1 and AFF1:KMT2A, respectively. KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without the accumulation of secondary mutations. A rational explanation for the observed chemo-resistance and satisfactory treatment options remain to be elucidated. We found that elevated ICOSLG expression level at diagnosis was associated with inferior event free survival (EFS) in a cohort of 43 patients with t(4;-11) iALL and that a cohort of 18 patients with iALL at relapse displayed strongly increased ICOSLG expression. Furthermore, co-culturing t(4;11) ALL cells (ICOSLGhi) with primary T-cells resulted in the development of Tregs. This was impaired through treatment with a neutralizing ICOSLG antibody. These findings imply ICOSLG (1) as a relapse-predicting biomarker, and (2) as a therapeutic target involved in a potential immune evasion relapse-mechanism of infant t(4;11) ALL.

Published
2022

6. Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach

Author

Siebel, C, Lanvers-Kaminsky, C, Alten, J, Smisek, P, Nath, C, Rizzari, C, Boos, J, Wurthwein, G, Siebel C., Lanvers-Kaminsky C., Alten J., Smisek P., Nath C. E., Rizzari C., Boos J., Wurthwein G., Siebel, C, Lanvers-Kaminsky, C, Alten, J, Smisek, P, Nath, C, Rizzari, C, Boos, J, Wurthwein, G, Siebel C., Lanvers-Kaminsky C., Alten J., Smisek P., Nath C. E., Rizzari C., Boos J., and Wurthwein G.

Abstract

Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.)

Published
2022

7. 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

8. P305: COMPREHENSIVE TRANSCRIPTIONAL AND CYTOGENETIC PROFILING IMPROVES CLASSIFICATION AND DETECTION OF RISK-STRATIFYING MARKERS IN THE B-OTHER PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA

Author

Antić, Ž., primary, Chouvarine, P., additional, Lentes, J., additional, Schröder, C., additional, Alten, J., additional, Möricke, A., additional, Brüggemann, M., additional, Carrillo-de Santa Pau, E., additional, Illig, T., additional, Laguna, T., additional, Schewe, D. M., additional, Stanulla, M., additional, Tang, M., additional, Zimmermann, M., additional, Schrappe, M., additional, Schlegelberger, B., additional, Cario, G., additional, and Bergmann, A. K., additional

Published
2022
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9. Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia

Author

Schieck, M, Lentes, J, Thomay, K, Hofmann, W, Behrens, Y, Hagedorn, M, Ebersold, J, Davenport, C, Fazio, G, Moricke, A, Buchmann, S, Alten, J, Cario, G, Schrappe, M, Bergmann, A, Stanulla, M, Steinemann, D, Schlegelberger, B, Cazzaniga, G, Gohring, G, Schieck M., Lentes J., Thomay K., Hofmann W., Behrens Y. L., Hagedorn M., Ebersold J., Davenport C. F., Fazio G., Moricke A., Buchmann S., Alten J., Cario G., Schrappe M., Bergmann A. K., Stanulla M., Steinemann D., Schlegelberger B., Cazzaniga G., Gohring G., Schieck, M, Lentes, J, Thomay, K, Hofmann, W, Behrens, Y, Hagedorn, M, Ebersold, J, Davenport, C, Fazio, G, Moricke, A, Buchmann, S, Alten, J, Cario, G, Schrappe, M, Bergmann, A, Stanulla, M, Steinemann, D, Schlegelberger, B, Cazzaniga, G, Gohring, G, Schieck M., Lentes J., Thomay K., Hofmann W., Behrens Y. L., Hagedorn M., Ebersold J., Davenport C. F., Fazio G., Moricke A., Buchmann S., Alten J., Cario G., Schrappe M., Bergmann A. K., Stanulla M., Steinemann D., Schlegelberger B., Cazzaniga G., and Gohring G.

Abstract

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1plus profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1plus (n = 6/12) and B-other (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.

Published
2020

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

15. 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. 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

17. 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

18. 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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19. 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

22. 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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23. 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

24. 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

25. The Minnesota Daily.

Author

von Alten, J. Walthers and Engstrom, Paul

Abstract

Presents a series of brief articles discussing the school newspaper at the University of Minnesota. Includes information about publishing, staff disagreements, differences between this newspaper and those at several other universities, how an issue is put together, the use of special sections, and the future use of computers. (TJ)

Published
1980

26. Abstract P-420

Author

Nuñez, M.J., primary, Diaz, F., additional, Pino, P., additional, and Alten, J., additional

Published
2018
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27. Acute Decompensated Heart Failure in the Pediatric Population: A Report from the Pediatric Cardiac Critical Care Consortium (PC 4 )

Author

Lasa, J.J., primary, Gaies, M., additional, Rossano, J., additional, Retzloff, L., additional, Zhang, W., additional, Banerjee, M., additional, Elhoff, J., additional, Lorts, A., additional, Schumacher, K., additional, Butts, R., additional, Cabrera, A., additional, Alten, J., additional, and Price, J., additional

Published
2018
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28. 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

29. The MLL recombinome of acute leukemias in 2017

Author

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

Published
2017
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34. Incidence and genetic characterization of childhood acute lymphoblastic leukemia with CRLF2 overexpression treated according to the AIEOP-BFM ALL 2009 protocol

Author

Schmäh, J, primary, Fedders, B, additional, Zimmermann, M, additional, Dagdan, E, additional, Dörge, P, additional, Bens, S, additional, Moericke, A, additional, Alten, J, additional, Bleckmann, K, additional, Siebert, R, additional, Schrappe, M, additional, Stanulla, M, additional, and Cario, G, additional

Published
2015
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35. A Case of Concordant Twins with Infant ALL and Discordant Clinical Outcome – Part II: highlights on an immunoescape phenotype as a potential mechanism of disease persistence

Author

Alsadeq, A, primary, Fedders, H, additional, Petersen, BS, additional, Kellner, C, additional, Peipp, M, additional, Bulduk, M, additional, Valerius, T, additional, Häsler, R, additional, Alten, J, additional, Möricke, A, additional, Strube, S, additional, Wiesel, T, additional, Cario, G, additional, Schrappe, M, additional, Franke, A, additional, Stanulla, M, additional, and Schewe, DM, additional

Published
2015
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36. A Case of Concordant Twins with Infant ALL and Discordant Clinical Outcome – Part I: the genetic basis – identification of DSC2 as a gene with prognostic impact in infant MLL-rearranged ALL

Author

Fedders, H, primary, Petersen, BS, additional, Alsadeq, A, additional, Kellner, C, additional, Peipp, M, additional, Bulduk, M, additional, Valerius, T, additional, Häsler, R, additional, Alten, J, additional, Möricke, A, additional, Strube, S, additional, Wiesel, T, additional, Cario, G, additional, Schrappe, M, additional, Franke, A, additional, Stanulla, M, additional, and Schewe, DM, additional

Published
2015
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38. Concurrent deIetions of IKZF1 and PAX5, CDKN2A, CDKN2B or PAR1 (IKZF1plus) confer a very poor prognosis in pediatric acute lymphoblastic leukemia

Author

Dagdan, E, primary, Zaliova, M, additional, Zimmermann, M, additional, Dörge, P, additional, Möricke, A, additional, Teigler-Schlegel, A, additional, Koehler, R, additional, Bartram, CR, additional, Alten, J, additional, Schewe, D, additional, Kratz, C, additional, Houlston, RS, additional, Schrappe, M, additional, Cario, G, additional, and Stanulla, M, additional

Published
2014
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46. Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease

Author

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

Subjects
BCR::ABL1-positive acute lymphoblastic leukemia (ALL), minimal residual disease (MRD), Cancer Research, Neoplasm, Residual, Oncology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Acute Disease, Fusion Proteins, bcr-abl, Humans, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Child, Retrospective Studies
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

47. Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach

Author

Christian Siebel, Claudia Lanvers-Kaminsky, Julia Alten, Petr Smisek, Christa E. Nath, Carmelo Rizzari, Joachim Boos, Gudrun Würthwein, Siebel, C, Lanvers-Kaminsky, C, Alten, J, Smisek, P, Nath, C, Rizzari, C, Boos, J, and Wurthwein, G

Subjects
Antineoplastic Agent, Pharmacology, Humans, Asparaginase, Antineoplastic Agents, Pharmacology (medical), MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Child, Polyethylene Glycol, Polyethylene Glycols, Human
Abstract

Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.)

Published
2021

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

Author

Tomasz Szczepański, Claus Meyer, Maria Grazia Valsecchi, Jan Stary, Birgitte Lausen, Alina Ferster, Gabriele Escherich, Inge M. van der Sluis, Martin Schrappe, Myriam Campbell, Vincent H.J. van der Velden, Giovanni Cazzaniga, Rishi S. Kotecha, Luca Lo Nigro, Julia Alten, Andishe Attarbaschi, Franco Locatelli, Andrea Biondi, Ajay Vora, Rolf Marschalek, Chi Kong Li, Jan Zuna, Benoit Brethon, Rob Pieters, Paola De Lorenzo, Philip Ancliffe, Janine Stutterheim, 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, and Immunology

Subjects
Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, KMT2A gene, Lymphoblastic Leukemia, Incidence (epidemiology), medicine.disease, Minimal residual disease, Infant Acute Lymphoblastic Leukemia, Minimal Residual Disease, Infant Acute Lymphoblastic Leukemia, KMT2A, KMT2A, MRD, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, SDG 3 - Good Health and Well-being, Internal medicine, biology.protein, Medicine, Neoplasm, business, ALL
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 benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Published
2021

49. The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia

Author

Marius Külp, Anna Lena Siemund, Patrizia Larghero, Alissa Dietz, Julia Alten, Gunnar Cario, Cornelia Eckert, Aurelie Caye-Eude, Helene Cavé, Michela Bardini, Giovanni Cazzaniga, Paola De Lorenzo, Maria Grazia Valsecchi, Laura Diehl, Bonig Halvard, Claus Meyer, Rolf Marschalek, Kulp, M, Siemund, A, Larghero, P, Dietz, A, Alten, J, Cario, G, Eckert, C, Caye-Eude, A, Cave, H, Bardini, M, Cazzaniga, G, De Lorenzo, P, Valsecchi, M, Diehl, L, Bonig, H, Meyer, C, and Marschalek, R

Subjects
History, Polymers and Plastics, Health science, Immunology, Business and International Management, Industrial and Manufacturing Engineering, Cancer
Abstract

The most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A:AFF1 and AFF1:KMT2A, respectively. KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without the accumulation of secondary mutations. A rational explanation for the observed chemo-resistance and satisfactory treatment options remain to be elucidated. We found that elevated ICOSLG expression level at diagnosis was associated with inferior event free survival (EFS) in a cohort of 43 patients with t(4;-11) iALL and that a cohort of 18 patients with iALL at relapse displayed strongly increased ICOSLG expression. Furthermore, co-culturing t(4;11) ALL cells (ICOSLGhi) with primary T-cells resulted in the development of Tregs. This was impaired through treatment with a neutralizing ICOSLG antibody. These findings imply ICOSLG (1) as a relapse-predicting biomarker, and (2) as a therapeutic target involved in a potential immune evasion relapse-mechanism of infant t(4;11) ALL.

Published
2022

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

Author

Lewis B. Silverman, G Escherich, J. Stary, I M van der Sluin, Benoit Brethon, Franco Locatelli, Ajay Vora, Martin Schrappe, Judith M. Boer, Maria Grazia Valsecchi, V H J van der Velden, Rishi S. Kotecha, Birgitte Lausen, Alina Ferster, P De Lorenzo, Andishe Attarbaschi, Philip Ancliffe, Jan Zuna, Janine Stutterheim, P Diaz, Alex Wk Leung, Luis Aversa, Andrea Biondi, Tomasz Szczepański, Julia Alten, Gianni Cazzaniga, Rob Pieters, Immunology, 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, and Pieters, R

Subjects
Male, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, Prognosi, Immunology, Gastroenterology, Biochemistry, SDG 3 - Good Health and Well-being, Internal medicine, White blood cell, hemic and lymphatic diseases, Medicine, Humans, Univariate analysis, biology, KMT2A-germline, business.industry, Infant, Cell Biology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Minimal residual disease, Survival Analysis, Clinical trial, KMT2A, Standard error, medicine.anatomical_structure, Germ Cells, Treatment Outcome, MRD, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, biology.protein, Prednisolone, Female, Bone marrow, business, ALL, medicine.drug
Abstract

Background The outcome of infants with KMT2A-germline ALL is much better than of infants with KMT2A-rearranged ALL, but still worse than of non-infant ALL patients. Here, we describe the outcome and prognostic factors for infants with KMT2A-germline ALL treated on Interfant-06 protocol. Methods 167 infants with KMT2A-germline ALL were enrolled in Interfant-06. Univariate analysis on prognostic factors (age, WBC 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 PCR of immunoglobulin genes and/or T-cell receptor genes, at various time points (EOI, n= 68, end of consolidation (EOC) n= 56, and before OCTADAD (n=57)). MRD results were classified as negative, intermediate (< 5*10 -4), and high (≥5*10 -4). Genetic data on NUTM1 rearrangements and MRD were available in 53 patients. Results The 6-year event free survival [SE] and overall survival [ SE] was 73.9% (3,6) and 87.2% (2.7). 28 of 31 (90%) relapses occurred early, within 2 years of diagnosis. Treatment related mortality was 3.6%. Age 6 months of age (p=0.04). Of the MRD timepoints, MRD at end of induction (EOI) was most prognostic for outcome. At EOI, 76.5% (n=52/68) of patients were either MRD negative (41.2%, n=28) or intermediate MRD (35.3%, n=24). 23.5% (n=16) had high EOI MRD, which was associated with significantly lower 6-year DFS (SE), compared to patients with intermediate or negative EOI MRD (61.4% (12.4), 76.4% (11.3) and 87.9% (6.6), respectively; p=0.02, Figure 1a). At EOC, 55.4% (n=31/56) of patients were MRD negative. Outcome by MRD levels at EOC was not significantly different (p=0.24); the 6-year DFS (SE) of negative and intermediate EOC MRD patients was 89.0% (6.0) and 72.7 % (10.6), respectively, while only one of the 5 patients with high EOC MRD relapsed in BM and CNS (Figure 1b). MRD data for both EOI and EOC were available for 55 patients. Of these patients, 18 were MRD negative at EOI and EOC, with a 6-year DFS 93.3% (SE, 6.4). Five patients had negative EOI MRD, but showed intermediate EOC MRD levels; none of these patients relapsed. There were 12 of 55 patients who were MRD positive at EOI and became MRD negative at EOC. These patients had a 6-year DFS of 82.5 % (SE, 11.3). Patients with detectable disease at both timepoints had a 6-year DFS of 68.3% (SE,10.8) (n=20, Figure 1c). At the end of MARMA (TP5), 77.2% (n=44/57) of patients were MRD negative. MRD at TP5 was significantly related to DFS (Figure 1d); the 6-year DFS was 89.6% (SE, 5.0) for MRD negative patients, compared to 65.6% (SE, 14.0) for patients with intermediate MRD levels (p= 0.039). In the current study, NUTM1 status was known in 53 patients with MRD data. Of them, 13 harbored a NUTM1-rearrangement. Seven out of 11 (63.6%) were aged< 6 months and 6 out of 42 (14.3%) were older. None of them relapsed, despite positive EOI MRD detected in 8 cases. Conclusion We conclude that young age at diagnosis and low EOI MRD are favorable prognostic factors in infants with KMT2A-germline ALL. However, the prognostic value of MRD is not as strong as in infants with KMT2A-rearranged ALL or older children with ALL. This can partly be explained by the differences in genetic makeup of infants with KMT2A-germline ALL, thus supporting the hypothesis that in the future a combined MRD- and genetic-based stratification of KMT2A-g infants might be considered Figure 1 Figure 1. Disclosures Biondi: Colmmune: Honoraria; Bluebird: Other: Advisory Board; Novartis: Honoraria; Incyte: Consultancy, Other: Advisory Board; Amgen: Honoraria. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Schrappe: Novartis: Honoraria, Other: research support; SigmaTau: Other: research support; Amgen: Other: research support; Servier: Honoraria; Novartis: Honoraria; JazzPharma: Honoraria; JazzPharma: Honoraria, Other: research support; SHIRE: Other: research support; Servier: Honoraria, Other: research support.

Published
2022

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