Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy—The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Patient Characteristics
2.2. Treatment Results
3. Discussion
4. Materials and Methods
4.1. Study Group
4.2. Treatment and Supportive Care
4.3. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Stary, J.; Zimmermann, M.; Campbell, M.; Castillo, L.; Dibar, E.; Donska, S.; Gonzalez, A.; Izraeli, S.; Janic, D.; Jazbec, J.; et al. Intensive Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Intercontinental Trial ALL IC-BFM 2002. J. Clin. Oncol. 2014, 32, 174–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Suttorp, M.; Metzler, M.; Millot, F.; Shimada, H.; Bansal, D.; Günes, A.M.; Kalwak, K.; Sedlacek, P.; Baruchel, A.; Biondi, A.; et al. Generic formulations of imatinib for treatment of Philadelphia chromosome-positive leukemia in pediatric patients. Pediatr. Blood Cancer 2018, 65, e27431. [Google Scholar] [CrossRef] [PubMed]
- Ottmann, O.G. Tyrosine kinase inhibitor therapy or transplant in children with Philadelphia chromosome-positive acute lymphoblastic leukaemia: Striking the balance. Lancet Haematol. 2018, 5, e606–e607. [Google Scholar] [CrossRef]
- Schultz, K.R.; Children’s Oncology Group; Carroll, A.J.; A Heerema, N.; Bowman, W.P.; Aledo, A.; Slayton, W.B.; Sather, H.N.; Devidas, M.; Zheng, H.W.; et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group Study AALL0031. Leukemia 2014, 28, 1467–1471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rives, S.; Camós, M.; Estella, J.; Gómez, P.; Moreno, M.J.; Vivanco, J.L.; Melo, M.; Fernández-Delgado, R.; Verdeguer, A.; Fernández-Teijeiro, A.; et al. Longer follow-up confirms major improvement in outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish Cooperati. Br. J. Haematol. 2013, 162, 419–421. [Google Scholar] [CrossRef] [PubMed]
- Biondi, A.; Gandemer, V.; De Lorenzo, P.; Cario, G.; Campbell, M.; Castor, A.; Pieters, R.; Baruchel, A.; Vora, A.J.; Leoni, V.; et al. Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): A prospective, intergroup, open-label, single-arm clinical trial. Lancet Haematol. 2018, 5, e641–e652. [Google Scholar] [CrossRef] [Green Version]
- Xue, Y.J.; Cheng, Y.F.; Lu, A.D.; Wang, Y.; Zuo, Y.X.; Yan, C.H.; Wu, J.; Sun, Y.Q.; Suo, P.; Chen, Y.H.; et al. Allogeneic Hematopoietic Stem Cell Transplantation, Especially Haploidentical, May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era. Biol. Blood Marrow Transplant 2019, 25, 1611–1620. [Google Scholar] [CrossRef] [PubMed]
- Hunger, S.P. Tyrosine Kinase Inhibitor Use in Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Anemia. Hematology 2011, 2011, 361–365. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cario, G.; Leoni, V.; Conter, V.; Attarbaschi, A.; Zaliova, M.; Sramkova, L.; Cazzaniga, G.; Fazio, G.; Sutton, R.; Elitzur, S.; et al. 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. Hematology 2019, 105, 1887–1894. [Google Scholar] [CrossRef] [PubMed]
- Hunger, S.P.; Mullighan, C.G. Redefining ALL classification: Toward detecting high-risk ALL and implementing precision medicine. Blood 2015, 125, 3977–3987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Conter, V.; Bartram, C.R.; Valsecchi, M.G.; Schrauder, A.; Panzer-Grumayer, R.; Moricke, A.; Arico, M.; Zimmermann, M.; Mann, G.; De Rossi, G.; et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: Results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010, 115, 3206–3214. [Google Scholar] [CrossRef] [PubMed]
- Jeha, S.; Coustan-Smith, E.; Pei, D.; Sandlund, J.T.; Rubnitz, J.; Howard, S.C.; Inaba, H.; Bhojwani, D.; Metzger, M.L.; Cheng, C.; et al. Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 2014, 120, 1514–1519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.; Kim, D.-W.; Cho, B.-S.; Yoon, J.-H.; Shin, S.-H.; Yahng, S.-A.; Eom, K.-S.; Kim, Y.-J.; Chung, N.-G.; Kim, H.-J.; et al. Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 2012, 26, 2367–2374. [Google Scholar] [CrossRef] [PubMed]
- Li, S.-Q.; Fan, Q.-Z.; Xu, L.-P.; Wang, Y.; Zhang, X.-H.; Chen, H.; Chen, Y.-H.; Wang, F.-R.; Han, W.; Sun, Y.-Q.; et al. Different Effects of Pre-transplantation Measurable Residual Disease on Outcomes According to Transplant Modality in Patients With Philadelphia Chromosome Positive ALL. Front. Oncol. 2020, 10, 320. [Google Scholar] [CrossRef] [PubMed]
- Cazzaniga, G.; De Lorenzo, P.; Alten, J.; Röttgers, S.; Hancock, J.; Saha, V.; Castor, A.; Madsen, H.O.; Gandemer, V.; Cavé, H.; et al. 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. Hematology 2017, 103, 107–115. [Google Scholar] [CrossRef] [Green Version]
- Mizuta, S.; Matsuo, K.; Maeda, T.; Yujiri, T.; Hatta, Y.; Kimura, Y.; Ueda, Y.; Kanamori, H.; Usui, N.; Akiyama, H.; et al. Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR–ABL-positive ALL. Blood Cancer J. 2012, 2, e72. [Google Scholar] [CrossRef] [PubMed]
- Biondi, A.; Schrappe, M.; De Lorenzo, P.; Castor, A.; Lucchini, G.; Gandemer, V.; Pieters, R.; Stary, J.; Escherich, G.; Campbell, M.; et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): A randomised, open-label, intergroup study. Lancet Oncol. 2012, 13, 936–945. [Google Scholar] [CrossRef]
- Shen, S.; Chen, X.; Cai, J.; Yu, J.; Gao, J.; Hu, S.; Zhai, X.; Liang, C.; Ju, X.; Jiang, H.; et al. Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA Oncol. 2020, 16, 358–366. [Google Scholar] [CrossRef] [PubMed]
- McCafferty, E.H.; Dhillon, S.; Deeks, E.D. Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia. Pediatr. Drugs 2018, 20, 593–600. [Google Scholar] [CrossRef] [PubMed]
- Millot, F.; Suttorp, M.; Versluys, A.B.; Kalwak, K.; Nelken, B.; Ducassou, S.; Bertrand, Y.; Baruchel, A. Ponatinib in childhood Philadelphia chromosome–positive leukaemias: An international registry of childhood chronic myeloid leukaemia study. Eur. J. Cancer 2020, 136, 107–112. [Google Scholar] [CrossRef] [PubMed]
Patients’ Features | n = 31 (%) | p-Value 1 |
---|---|---|
Sex | ||
Female | 13 (42) | |
Male | 18 (58) | 0.37 |
Median age (years) | 9.4 | |
CNS infiltration | ||
Yes | 4 (12.9) | |
No | 27 (87.1) | <0.001 |
Organ infiltration | ||
Testes | 2 (6.5) | <0.001 |
Liver | 19 (61.3) | 0.2 |
Mediastinum | 0 (0) | n/a |
Lymph nodes | 8 (25.8) | 0.01 |
Spleen | 15 (48.4) | 0.86 |
Risk group | ||
Good | 9 (29) | |
Poor | 21 (67.7) | 0.03 |
Immunophenotype | ||
Pre-B | 29 (93.5) | |
T-ALL | 2 (6.5) | <0.001 |
WBC at diagnosis (µL) | ||
<20,000 | 9 (29) | |
≥20,000 | 22 (71) | 0.02 |
Genetic aberration 2 | ||
Karyotype with BCR/ABL1 aberration | 22 (71) | 0.02 |
Karyotype with KMT2A rearrangement | 0 (0) | n/a |
KMT2A/AFF1 (formerly MLL-AF4) | 0 (0) | n/a |
ETV6/RUNX1 | 0 (0) | n/a |
Hypodiploidy | 2 (6.5) | <0.001 |
Hyperdiploidy | 3 (9.7) | <0.001 |
Chromosome 7 aberration (IKZF1) | 4 (12.9) | <0.001 |
Complex karyotype | 10 (32.3) | 0.05 |
Prednisone response | ||
Good | 17 (54.8) | |
Poor | 14 (45.2) | 0.59 |
% blast (BM) day 15 | ||
M1 | 15 (48.4) | |
M2 | 4 (12.9) | |
M3 | 12 (38.7) | 0.04 |
FCM-MRD (%) day 15 | ||
<0.1 | 2 (6.5) | |
≥0.1 and <10 | 12 (38.7) | |
≥10 | 17 (54.8) | 0.004 |
% blast (BM) day 33 | ||
M1 | 29 (93.5) | |
M2 | 1 (3.2) | |
M3 | 1 (3.2) | <0.001 |
TKIs | Toxicity | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Grade I | Grade II | Grade III | Grade IV | ||||||||||||||||||||||
Infection | Hepatotoxicity | Gastrotoxicity | Dermatitis | Neurotoxicity | Nephrotoxicity | Infection | Hepatotoxicity | Gastrotoxicity | Dermatitis | Neurotoxicity | Nephrotoxicity | Infection | Hepatotoxicity | Gastrotoxicity | Dermatitis | Neurotoxicity | Nephrotoxicity | Infection | Hepatotoxicity | Gastrotoxicity | Dermatitis | Neurotoxicity | Nephrotoxicity | Patient | |
Imatinib | 1 | ||||||||||||||||||||||||
2 | |||||||||||||||||||||||||
x | x | x | x | 3 | |||||||||||||||||||||
x | x | x | 4 | ||||||||||||||||||||||
x | x | x | 5 | ||||||||||||||||||||||
x | x | 6 | |||||||||||||||||||||||
x | x | 7 | |||||||||||||||||||||||
x | x | x | 8 | ||||||||||||||||||||||
x | 9 | ||||||||||||||||||||||||
10 | |||||||||||||||||||||||||
11 | |||||||||||||||||||||||||
12 | |||||||||||||||||||||||||
13 | |||||||||||||||||||||||||
x | 14 | ||||||||||||||||||||||||
15 | |||||||||||||||||||||||||
16 | |||||||||||||||||||||||||
x | x | 17 | |||||||||||||||||||||||
18 | |||||||||||||||||||||||||
x | x | x | x | 19 | |||||||||||||||||||||
x | 20 | ||||||||||||||||||||||||
x | x | x | 21 | ||||||||||||||||||||||
x | 22 | ||||||||||||||||||||||||
23 | |||||||||||||||||||||||||
24 | |||||||||||||||||||||||||
x | x | x | 25 | ||||||||||||||||||||||
x | x | x | 26 | ||||||||||||||||||||||
27 | |||||||||||||||||||||||||
Dasatinib | x | x | 28 | ||||||||||||||||||||||
x | x | x | x | 29 | |||||||||||||||||||||
x | x | x | x | 30 | |||||||||||||||||||||
Ponatinib | x | x | x | 31 |
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Zawitkowska, J.; Lejman, M.; Płonowski, M.; Bulsa, J.; Szczepański, T.; Romiszewski, M.; Mizia-Malarz, A.; Derwich, K.; Karolczyk, G.; Ociepa, T.; et al. Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy—The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group. Cancers 2020, 12, 3751. https://doi.org/10.3390/cancers12123751
Zawitkowska J, Lejman M, Płonowski M, Bulsa J, Szczepański T, Romiszewski M, Mizia-Malarz A, Derwich K, Karolczyk G, Ociepa T, et al. Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy—The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group. Cancers. 2020; 12(12):3751. https://doi.org/10.3390/cancers12123751
Chicago/Turabian StyleZawitkowska, Joanna, Monika Lejman, Marcin Płonowski, Joanna Bulsa, Tomasz Szczepański, Michał Romiszewski, Agnieszka Mizia-Malarz, Katarzyna Derwich, Grażyna Karolczyk, Tomasz Ociepa, and et al. 2020. "Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy—The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group" Cancers 12, no. 12: 3751. https://doi.org/10.3390/cancers12123751