HAS HEMATOPOIETIC STEM CELL TRANSPLANTATION A ROLE IN THE TREATMENT OF CHILDREN AND ADOLESCENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA? Acute Promyelocytic Leukemia and Hematopoietic Stem Cell Transplantation
Main Article Content
Keywords
Abstract
The past three decades have brought major therapeutic advances in the treatment of acute promyelocytic leukemia (APL) both in adults and children. The current state-of-the-art treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in combination or not with chemotherapy results in long-lasting remission and cure in more than 90% of newly diagnosed patients. These treatments have made relapse a rare event. The detection of PML-RARA transcript by polymerase chain reaction (PCR) during treatment and follow-up can predict a hematological relapse. All studies have suggested a survival benefit in patients with molecular relapse given pre-emptive therapy compared with those treated at the time of overt hematological relapse. ATO-based regimens, seem to be effective for the achievement of a second molecular complete remission (CR). Patients in second molecular CR, are generally considered candidates for autologous hematopoietic stem cell transplant (HSCT), while for those with persistent molecular disease, allogeneic HSCT could be offered if a suitable donor is identified.
Except for sporadic pediatric reports, most of the evidence for the use of HSCT for treatment of relapsed/refractory APL, comes from adult literature. We hereby provide a review of published pediatric data that evaluated the role of HSCT in children with refractory/recurrent APL disease.
KEYWORDS: acute promyelocytic leukemia; relapse; hematopoietic stem cell transplant; children; adolescents
Downloads
Download data is not yet available.
Abstract 575
PDF Downloads 420
HTML Downloads 139
References
1. Testi AM, Biondi A, Lo Coco F, et al. GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood. 2005; 106: 447-453. https://doi: 10.1182/blood-2004-05-1971.
2. Testi AM, Pession A, Diverio D, et al. Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL. Blood. 2018; 132(4): 405-412. https://doi: 10.1182/blood-2018-03-836528.
3. Ortega JJ, Madero L, Martin G, et al. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA group. J Clin Oncol. 2005; 23(30): 7632-7640. https://doi: 10.1200/JCO.2005.01.3359.
4. Kutny MA, Geyer S, Laumann KM, et al. Outcome of pediatric acute promyelocytic leukemia patients at Children’s Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (alliance). Pediatr Blood Cancer. 2019; 66(3): e27542. https://doi: 10.1002/pbc.27542.
5. Creutzig U, Zimmemann M, Dvorzak M, et al. Favourable outcome of patients with childhood acute promyelocytic leukemia after treatment with reduced cumulative anthracycline doses. Br J Haematol. 2010; 143(3): 399-409. https://doi: 10.1111/j.1365-2141.2010.08107.
6. George B, Mathews V, Poonkuzhali B, Shaji RV, Srivastava A, Chandy M. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience. Leukemia. 2004; 18(10): 1587-1590. https://doi: 10.1038/sj.leu.2403480.
7. Zhang L, Zhu X, Zou Y, Chen Y, Chen X. Effect of arsenic trioxide on the treatment of children with newly diagnosed acute promyelocytic leukemia in China. In J Hematol. 2011; 93(2): 199-205. https://doi: 10.1007/s12185-011-0768-0.
8. Creutzig U, Dworzak MN, Bochennek K, et al. First experience of the AML-berlin-Frankfurt-Munster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoic acid. Pediatr Blood Cancer. 2017; 64(8). https://doi: 10.1002/pbc.26461.
9. Strocchio L, Gurnari C, Santoro N, et al. Arsenic trioxide and all-trans retinoic acid treatment for childhood acute promyelocytic leukemia. Br J Haematol. 2019; 185(2): 360-363. https://doi: 10.1111/bjh.15507.
10. Kutny MA, Alonzo TA, Gebing RB, et al. Arsenic trioxide consolidation allows anthracycline dose reduction for pediatric patients with acute promyelocytic leukemia: report from the Children’s Oncology Group Phase III historically controlled trial AAML0631. J Clin Oncol. 2017; 35: 3021-3029. https://doi: 10.1200/JCO.2016.71.6183.
11. Diverio D, Rossi V, Avvisati G, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. GIMEMA-AIEOP Multicent. Blood. 1998; 92: 784-789.
12. Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009; 27: 3650-3658. https://doi: 10.1200/JCO.2008.20.1533.
13. Abla O, Kutney MA, Testi AM, et al. Management of relapsed and refractory childhood acute promyelocytic leukemia: recommendations from an international expert panel. Br J Haematol. 2016; 175: 588-601. https://doi: 10.1111/bjh.14313.
14. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendation fron an expert panel on behalf of the European Leukemia.Net. Blood. 2009; 113(9): 1875-91. https://doi: 10.1182/blood-2008-04-150250.
15. Sanz J, Montesinos P, Sanz AM. Role of hematopoietic stem cell transplant in acute promyelocytic leukemia. Front Oncol. 2021; 11: 614215. https://doi: 10.3389/fonc.2021.614215. eCollection 2021.
16. Sanz J, Labopin M, Sanz MA, et al. Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission. Bone Marrow Transplant. 2021; 56(6): 1272-1280. https://doi: 10.1038/s41409-020-01162-0.
17. Chakrabarty JLH, Rubinger M, Le Rademacher J, et al. Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant. 2014; 20(7): 1021-1025. https://doi: 10.1016/j.bbmt.2014.03.025.
18. Yanada M, Takami A, Mizuno S, et al. Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25 years of experience in Japan. Int J Hematol. 2020; 11(1): 93-102. https://doi: 10.1007/s12185-019-02759-y.
19. Ueki T, Ohashi K, Jinta M, et al. Delayed hematological recovery following autologous transplantation utilizing peripheral blood stem cells harvested after treatment with arsenic trioxide. Pathol Oncol Res. 2008; 14(4): 387-390. https://doi: 10.1007/s12253-008.9049.5.
20. Mannis GN, Logan AC, Leavitt AD, et al. delayed hematopoietic recovery after auto-HSCT in patients receiving arsenic-trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis. Bone Marrow Transplant. 2015; 50(1): 40-44. https://doi: 10.1038/bmt.2014.201.
21. de Botton S, Coiteux V, Chevret S, et al. Outcome of childhood acute promyelocytic leukemia with all-trans retinoic acid and chemotherapy. J Clin Oncol. 2004; 22: 1404-1412. https://doi: 10.1200/JCO.2004.09.008.
22. Termuhlen AM, Klopfenstein K, Olshefski R, et al. Mobilization of PML-RARA negative blood stem cells and salvage with autologous peripheral blood stem cell transplantation in children with relapsed acute promyelocytic leukemia. Pediatric Blood Cancer. 2008; 51: 521-524. https://doi: 10.1002/pbc.21614.
23. Bourquin JP, Thornley I, Neuberg D, et al. Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant. 2004; 34: 795-788. https://doi: 10.1038/sj.bmt.1704676.
24. Baidil’dina DD, Maschan MA, Skorobogatova EV, et al. Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation. Ter Arkh. 2010; 82(7): 20-25.
25. Dvorak CC, Agarwal R, Dahl GV, Gregory JJ, Feusner JH. Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant. 2008; 14: 824-830. https://doi: 10.1016/j.bbmt.2008.04.015.
26. Yamamoto S, Tomizawa D, Kudo K, et al. Hematopoietic stem cell transplantation for pediatric acute promyelocytic leukemia in Japan. Pediatr Blood Cancer. 2020; 67(5): e28181. https://doi: 10.1002/pbc.28181.
27. Testi AM, Mohamed S, Diverio D, et al. Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients – a 25-year Italian Experience. Br J Haematol. 2021; 195(2): 278-283. https://doi: 10.1111/bjh.17637.
28. Fouzia NA, Sharma V, Ganesan S, et al. Management of relapse in acute promyelocytic leukemia treated with upfront arsenic trioxide based regimens. Br J Haematol. 2021: 192(2): 292-299. https://doi: 10.1111/bjh.17221.
29. Marjerrison S, Antillon F, Bonilla M, et al. Outcome of children treated for relapsed acute myeloid leukemia in Central America. Pediatr Blood Cancer. 2014; 61(7): 1222-1226. https://doi: 10.1002/pbc.24942.
30. Lengfelder E, lo Coco F, Ades I, et al. Arsenic trioxide based therapy at relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia. 2015; 29(5): 1084-1091. https:// doi: 10.1038/leu.2015.12.
31. Lou Y, Suo S, Tong V, et al. Outcomes and prognostic factors of first relapse acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy. Annals of Hematology. 2014; 93(6): 941-948. https://doi: 10.1007/s00277-013-2000-1.
32. Breccia M, Cicconi L, Minotti C, et al. Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia. Haematologica. 2011; 96(9); 1390-1391. https://doi: 10.3324/haematol.2011.045500.
33. Douer D, Zickl LN, Schiffer CA, et al. All-trans retinoic acid and late relapsesin acute promyelocyic leukemia: very long-term follow-up of the North American Intergroup Study Io129. Leuk Res. 2013; 37(7): 795-801. https://doi: 10.1016/j.leukres.2013.03.001.
34. Testi AM, Moleti Ml, Canichella M, et al. Very late relapse in a patient with acute promyelocytic leukemia (APL) rescued with a chemotherapy-free protocol. Leuk Lymphoma. 2017; 58(4): 999-1001. https://doi: 10.1080/10428194.2016.1222377.
35. Latagliata R, Carmosino I, Breccia M, et al. Late relapses in acute promyelocytic leukemia. Acta Haematol. 2007; 117(2): 106-108. https://doi: 10.1159/000097385.
36. Chow I, Feusner J, Isolated central nervous system recurrence of acute promyelocytic leukemia in children. Pediatr Blood Cancer. 2009; 52(1): 11-13. https://doi: 10.1002/pbc.21608.
37. de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006; 20(1): 35-41. https://doi: 10.1038/sj.leu.2404006.
38. Helwig A, Klemm M, Schuttig R, et al. Arsenic-induced APL differentiation in cerebrospinal fluid. Leukemia Res. 2007; 31(5): 703-705. doi: 10.1016/j.leukres.2006.06.011.
39. Scheinemann K, Weitzman S, Hitzler J, et al. Isolated central nervous system relapse in childhood acute promyelocytic leukemia. J Pediatr Hematol Oncol. 2008; 30(2): 160-162. https://doi: 10.1097/MPH.0b013e318159a582.
40. Au WY, Tam S, Kwong YL. Entry of elemental arsenic into the central nervous system in patients with acute promyelocytic leukemia during arsenic trioxide treatment. Leuk Res. 2008; 32(2): 357-358. https://doi: 10.1016/j.leukres.2007.06.005.
2. Testi AM, Pession A, Diverio D, et al. Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL. Blood. 2018; 132(4): 405-412. https://doi: 10.1182/blood-2018-03-836528.
3. Ortega JJ, Madero L, Martin G, et al. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA group. J Clin Oncol. 2005; 23(30): 7632-7640. https://doi: 10.1200/JCO.2005.01.3359.
4. Kutny MA, Geyer S, Laumann KM, et al. Outcome of pediatric acute promyelocytic leukemia patients at Children’s Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (alliance). Pediatr Blood Cancer. 2019; 66(3): e27542. https://doi: 10.1002/pbc.27542.
5. Creutzig U, Zimmemann M, Dvorzak M, et al. Favourable outcome of patients with childhood acute promyelocytic leukemia after treatment with reduced cumulative anthracycline doses. Br J Haematol. 2010; 143(3): 399-409. https://doi: 10.1111/j.1365-2141.2010.08107.
6. George B, Mathews V, Poonkuzhali B, Shaji RV, Srivastava A, Chandy M. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience. Leukemia. 2004; 18(10): 1587-1590. https://doi: 10.1038/sj.leu.2403480.
7. Zhang L, Zhu X, Zou Y, Chen Y, Chen X. Effect of arsenic trioxide on the treatment of children with newly diagnosed acute promyelocytic leukemia in China. In J Hematol. 2011; 93(2): 199-205. https://doi: 10.1007/s12185-011-0768-0.
8. Creutzig U, Dworzak MN, Bochennek K, et al. First experience of the AML-berlin-Frankfurt-Munster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoic acid. Pediatr Blood Cancer. 2017; 64(8). https://doi: 10.1002/pbc.26461.
9. Strocchio L, Gurnari C, Santoro N, et al. Arsenic trioxide and all-trans retinoic acid treatment for childhood acute promyelocytic leukemia. Br J Haematol. 2019; 185(2): 360-363. https://doi: 10.1111/bjh.15507.
10. Kutny MA, Alonzo TA, Gebing RB, et al. Arsenic trioxide consolidation allows anthracycline dose reduction for pediatric patients with acute promyelocytic leukemia: report from the Children’s Oncology Group Phase III historically controlled trial AAML0631. J Clin Oncol. 2017; 35: 3021-3029. https://doi: 10.1200/JCO.2016.71.6183.
11. Diverio D, Rossi V, Avvisati G, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. GIMEMA-AIEOP Multicent. Blood. 1998; 92: 784-789.
12. Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009; 27: 3650-3658. https://doi: 10.1200/JCO.2008.20.1533.
13. Abla O, Kutney MA, Testi AM, et al. Management of relapsed and refractory childhood acute promyelocytic leukemia: recommendations from an international expert panel. Br J Haematol. 2016; 175: 588-601. https://doi: 10.1111/bjh.14313.
14. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendation fron an expert panel on behalf of the European Leukemia.Net. Blood. 2009; 113(9): 1875-91. https://doi: 10.1182/blood-2008-04-150250.
15. Sanz J, Montesinos P, Sanz AM. Role of hematopoietic stem cell transplant in acute promyelocytic leukemia. Front Oncol. 2021; 11: 614215. https://doi: 10.3389/fonc.2021.614215. eCollection 2021.
16. Sanz J, Labopin M, Sanz MA, et al. Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission. Bone Marrow Transplant. 2021; 56(6): 1272-1280. https://doi: 10.1038/s41409-020-01162-0.
17. Chakrabarty JLH, Rubinger M, Le Rademacher J, et al. Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant. 2014; 20(7): 1021-1025. https://doi: 10.1016/j.bbmt.2014.03.025.
18. Yanada M, Takami A, Mizuno S, et al. Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25 years of experience in Japan. Int J Hematol. 2020; 11(1): 93-102. https://doi: 10.1007/s12185-019-02759-y.
19. Ueki T, Ohashi K, Jinta M, et al. Delayed hematological recovery following autologous transplantation utilizing peripheral blood stem cells harvested after treatment with arsenic trioxide. Pathol Oncol Res. 2008; 14(4): 387-390. https://doi: 10.1007/s12253-008.9049.5.
20. Mannis GN, Logan AC, Leavitt AD, et al. delayed hematopoietic recovery after auto-HSCT in patients receiving arsenic-trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis. Bone Marrow Transplant. 2015; 50(1): 40-44. https://doi: 10.1038/bmt.2014.201.
21. de Botton S, Coiteux V, Chevret S, et al. Outcome of childhood acute promyelocytic leukemia with all-trans retinoic acid and chemotherapy. J Clin Oncol. 2004; 22: 1404-1412. https://doi: 10.1200/JCO.2004.09.008.
22. Termuhlen AM, Klopfenstein K, Olshefski R, et al. Mobilization of PML-RARA negative blood stem cells and salvage with autologous peripheral blood stem cell transplantation in children with relapsed acute promyelocytic leukemia. Pediatric Blood Cancer. 2008; 51: 521-524. https://doi: 10.1002/pbc.21614.
23. Bourquin JP, Thornley I, Neuberg D, et al. Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant. 2004; 34: 795-788. https://doi: 10.1038/sj.bmt.1704676.
24. Baidil’dina DD, Maschan MA, Skorobogatova EV, et al. Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation. Ter Arkh. 2010; 82(7): 20-25.
25. Dvorak CC, Agarwal R, Dahl GV, Gregory JJ, Feusner JH. Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant. 2008; 14: 824-830. https://doi: 10.1016/j.bbmt.2008.04.015.
26. Yamamoto S, Tomizawa D, Kudo K, et al. Hematopoietic stem cell transplantation for pediatric acute promyelocytic leukemia in Japan. Pediatr Blood Cancer. 2020; 67(5): e28181. https://doi: 10.1002/pbc.28181.
27. Testi AM, Mohamed S, Diverio D, et al. Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients – a 25-year Italian Experience. Br J Haematol. 2021; 195(2): 278-283. https://doi: 10.1111/bjh.17637.
28. Fouzia NA, Sharma V, Ganesan S, et al. Management of relapse in acute promyelocytic leukemia treated with upfront arsenic trioxide based regimens. Br J Haematol. 2021: 192(2): 292-299. https://doi: 10.1111/bjh.17221.
29. Marjerrison S, Antillon F, Bonilla M, et al. Outcome of children treated for relapsed acute myeloid leukemia in Central America. Pediatr Blood Cancer. 2014; 61(7): 1222-1226. https://doi: 10.1002/pbc.24942.
30. Lengfelder E, lo Coco F, Ades I, et al. Arsenic trioxide based therapy at relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia. 2015; 29(5): 1084-1091. https:// doi: 10.1038/leu.2015.12.
31. Lou Y, Suo S, Tong V, et al. Outcomes and prognostic factors of first relapse acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy. Annals of Hematology. 2014; 93(6): 941-948. https://doi: 10.1007/s00277-013-2000-1.
32. Breccia M, Cicconi L, Minotti C, et al. Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia. Haematologica. 2011; 96(9); 1390-1391. https://doi: 10.3324/haematol.2011.045500.
33. Douer D, Zickl LN, Schiffer CA, et al. All-trans retinoic acid and late relapsesin acute promyelocyic leukemia: very long-term follow-up of the North American Intergroup Study Io129. Leuk Res. 2013; 37(7): 795-801. https://doi: 10.1016/j.leukres.2013.03.001.
34. Testi AM, Moleti Ml, Canichella M, et al. Very late relapse in a patient with acute promyelocytic leukemia (APL) rescued with a chemotherapy-free protocol. Leuk Lymphoma. 2017; 58(4): 999-1001. https://doi: 10.1080/10428194.2016.1222377.
35. Latagliata R, Carmosino I, Breccia M, et al. Late relapses in acute promyelocytic leukemia. Acta Haematol. 2007; 117(2): 106-108. https://doi: 10.1159/000097385.
36. Chow I, Feusner J, Isolated central nervous system recurrence of acute promyelocytic leukemia in children. Pediatr Blood Cancer. 2009; 52(1): 11-13. https://doi: 10.1002/pbc.21608.
37. de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006; 20(1): 35-41. https://doi: 10.1038/sj.leu.2404006.
38. Helwig A, Klemm M, Schuttig R, et al. Arsenic-induced APL differentiation in cerebrospinal fluid. Leukemia Res. 2007; 31(5): 703-705. doi: 10.1016/j.leukres.2006.06.011.
39. Scheinemann K, Weitzman S, Hitzler J, et al. Isolated central nervous system relapse in childhood acute promyelocytic leukemia. J Pediatr Hematol Oncol. 2008; 30(2): 160-162. https://doi: 10.1097/MPH.0b013e318159a582.
40. Au WY, Tam S, Kwong YL. Entry of elemental arsenic into the central nervous system in patients with acute promyelocytic leukemia during arsenic trioxide treatment. Leuk Res. 2008; 32(2): 357-358. https://doi: 10.1016/j.leukres.2007.06.005.
Article Sidebar
Published
Apr 28, 2022
Article Details
How to Cite
Testi, A. M. (2022) “HAS HEMATOPOIETIC STEM CELL TRANSPLANTATION A ROLE IN THE TREATMENT OF CHILDREN AND ADOLESCENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA? Acute Promyelocytic Leukemia and Hematopoietic Stem Cell Transplantation”, Mediterranean Journal of Hematology and Infectious Diseases, 14(1), p. e2022038. doi: 10.4084/MJHID.2022.038.
Section
Review Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers. Authors will grant copyright of their articles to the Institute of Hematology, Catholic University, Rome . No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.