Keywords
CLL, Treatment, History
How to Cite
Bezares, R., Borge, M., & Giordano, M. (2021). Treatment of chronic lymphocytic leukemia. History repeats itself. Journal of Hematology, 25(2), 56–62. Retrieved from https://revistahematologia.com.ar/index.php/Revista/article/view/375
Abstract
Treatment in chronic lymphocytic leukemia (CLL) represents the paradigm of advances in the therapy for hematological malignancies. In the last 10 years, the increased knowledge on the mechanisms of tumor progression, crosstalk with the microenvironment, molecular biology and cytogenetic breakthroughs became the fundamental pieces of these advances.
However, therapeutic strategies seem to follow the same pattern. Whereas early therapy used single drugs, they were gradually combined in duplets and triplets leading to successful results that had never been achieved and envisioning for the first time a future full of hope for this incurable disease.
The development of ibrutinib has been probably the milestone that definitely highlighted the importance of signaling pathways in CLL progression and opens the investigation of novel target agents which constitute the current treatment of this disease. Today, we have a plethora of new drugs that, as in their early stages, went from being used as monotherapy to being tested in combinations with optimal results, even in high-risk patients. It shows us that history repeats itself.
References
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5. Catovsky D, Richards S, Matutes E y col. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 trial): a randomised controlled trial. Lancet. 2007; 370(9583):230-9.
6. Keating MJ, O’Brien S, Albitar M y col. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-88.
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8. Ozegowski W, Krebs D. IMET 3393, -[1-methyl5-bis(chloroethyl)-amino-benzimidazolyl-2]-butyric acid hydrochloride, a new cytostatic agent from among the series of benzimidazole mustard compounds. ZblPharma. 1971; 110:1013-9.
9. Eichhorst B, Fink AM, Bahlo J y col. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928-942
10. Ahmadi T and Schuster SJ. Variations on the Fludarabine, Cyclophosphamide, and Rituximab Combination in Chronic Lymphocytic Leukemia Therapy: What Have We Learned? J Clin Oncol. 2009;27:491-497.
11. Appleby N, O'Brien D, Quinn FM y col. Risk adjusted therapy in chronic lymphocytic leukemia: a phase
II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL. Leuk Lymphoma. 2018;59(6):1338-47.
12. Cramer P, Eichhorst B, Reinhardt HC, Hallek M. Current strategies to create tailored and risk-adapted therapies for CLL patients. Best Prac Res Clin Haematol. 2016;29(1):111-21.
13. Burger JA, Tedeschi A, Barr PM y col. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
14. Burger JA, Barr PM, Robak T y col. Long-term efficacy and safety of first line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-upfrom the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
15. Sharman JP, Egyed M, Jurczak W y col. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
16. NCCN Clinical practice guidelines in oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 4.2021. NCCN website. http://www.nccn.org/.
17. Woyach JA, Ruppert AS, Heerema NA y col. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
18. Moreno C, Greil R, Demirkan F y col. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised,
open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-
56.
19. Shanafelt TD, Wang XV, Kay NE y col. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
20. Seymour JF, Ma S, Brander DM y col. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230-240.
21. Al-Sawaf O, Zhang C, Tandon M y col. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreatedchronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
22. Rogers KA, Huang Y, Ruppert AS y col. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic
lymphocytic leukemia. Blood. 2018;132(suppl 1):693.
23. Lampson BL, Tyekucheva S, Crombie JL y col. Preliminary safety and efficacy results from a phase 2 study of
acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):32.
24. Tam C, Trotman J, Roberts A y col. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019; 134(11): 851–859
25. Burris HA 3rd, Flinn IW, Patel MR y col. Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486– 496.
26. Chanan-Khan A, Cramer P, Demirkan F y col. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small
lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016; 17:200–11.
27. de Rooij MF, Kuil A, Geest CR y col. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-4.
28. Herman SE, Mustafa RZ, Jones J, Wong DH, Farooqui M, Wiestner A. Treatment with Ibrutinib Inhibits
BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo. Clin Cancer 2015;21(20):4642-51.
29. Patrussi L, Capitani N, Martini V y col. Enhanced Chemokine Receptor Recycling and Impaired S1P1 Expression Promote Leukemic Cell Infiltration of Lymph Nodes in Chronic Lymphocytic Leukemia. Cancer Res. 2015;75(19):4153-63.
30. Kohrt HE, Sagiv-Barfi I, Rafiq S y col. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123(12):1957-60.
31. Bojarczuk K, Siernicka M, Dwojak M, y col. B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. Leukemia. 2014;28(5):1163-7.
32. Da Roit F, Engelberts PJ, Taylor RP y col. Ibrutinib interferes with the cell-mediated anti-tumor activities of
therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100(1):77-86.
33. Borge M, Belen Almejun M, Podaza E y col. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica. 2015;100(4):e140- 2.
34. Colado A, Marin Franco JL, Elias EE y col. Second
generation BTK inhibitors impair the anti-fungal response of macrophages and neutrophils. Am J Hematol. 2020;95(7):E174-E8.
35. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica. 2017;102(10):e400-e3.
36. Flinsenberg TWH, Tromedjo CC, Hu N y col. Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma. Haematologica. 2020;105(2):e76-e9.
37. VanDerMeid KR, Elliott MR, Baran AM, Barr PM, Chu CC, Zent CS. Cellular Cytotoxicity of Next-Generation CD20 Monoclonal Antibodies. Cancer Immunol Res. 2018;6(10):1150-60.
38. Bojarczuk K, Sasi BK, Gobessi S y col. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127(25):3192-201.
39. Pavlasova G, Borsky M, Seda V y col. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood. 2016;128(12):1609-13.
40. Skarzynski M, Niemann CU, Lee YS y col. Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy. Clin Cancer Res 2016;22(1):86-95.
41. Burger JA, Sivina M, Jain N y col. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011-9.
2. Keating MJ. Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Sem Oncol. 1990;17(5 Suppl 8):49-62.
3. Kay NE, Wu W, Kabat B y col. Pentostatin and rituximab therapy for previously untreated patients with B-cell chronic lymphocytic leukemia. Cancer. 2010;116(9):2180-7.
4. Robak T, Smolewski P, Cebula B, Grzybowska-Izydorczyk O, Blonski JZ. Rituximab plus cladribine with or without cyclophosphamide in patients with relapsed or refractory chronic lymphocytic leukemia. Eur J Haematol. 2007;79(2):107-13.
5. Catovsky D, Richards S, Matutes E y col. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 trial): a randomised controlled trial. Lancet. 2007; 370(9583):230-9.
6. Keating MJ, O’Brien S, Albitar M y col. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-88.
7. Hallek M, Fischer K, Fingerle-Rowson G y col. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376:1164-74.
8. Ozegowski W, Krebs D. IMET 3393, -[1-methyl5-bis(chloroethyl)-amino-benzimidazolyl-2]-butyric acid hydrochloride, a new cytostatic agent from among the series of benzimidazole mustard compounds. ZblPharma. 1971; 110:1013-9.
9. Eichhorst B, Fink AM, Bahlo J y col. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928-942
10. Ahmadi T and Schuster SJ. Variations on the Fludarabine, Cyclophosphamide, and Rituximab Combination in Chronic Lymphocytic Leukemia Therapy: What Have We Learned? J Clin Oncol. 2009;27:491-497.
11. Appleby N, O'Brien D, Quinn FM y col. Risk adjusted therapy in chronic lymphocytic leukemia: a phase
II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL. Leuk Lymphoma. 2018;59(6):1338-47.
12. Cramer P, Eichhorst B, Reinhardt HC, Hallek M. Current strategies to create tailored and risk-adapted therapies for CLL patients. Best Prac Res Clin Haematol. 2016;29(1):111-21.
13. Burger JA, Tedeschi A, Barr PM y col. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
14. Burger JA, Barr PM, Robak T y col. Long-term efficacy and safety of first line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-upfrom the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
15. Sharman JP, Egyed M, Jurczak W y col. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
16. NCCN Clinical practice guidelines in oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 4.2021. NCCN website. http://www.nccn.org/.
17. Woyach JA, Ruppert AS, Heerema NA y col. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
18. Moreno C, Greil R, Demirkan F y col. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised,
open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-
56.
19. Shanafelt TD, Wang XV, Kay NE y col. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
20. Seymour JF, Ma S, Brander DM y col. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230-240.
21. Al-Sawaf O, Zhang C, Tandon M y col. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreatedchronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
22. Rogers KA, Huang Y, Ruppert AS y col. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic
lymphocytic leukemia. Blood. 2018;132(suppl 1):693.
23. Lampson BL, Tyekucheva S, Crombie JL y col. Preliminary safety and efficacy results from a phase 2 study of
acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):32.
24. Tam C, Trotman J, Roberts A y col. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019; 134(11): 851–859
25. Burris HA 3rd, Flinn IW, Patel MR y col. Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486– 496.
26. Chanan-Khan A, Cramer P, Demirkan F y col. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small
lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016; 17:200–11.
27. de Rooij MF, Kuil A, Geest CR y col. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-4.
28. Herman SE, Mustafa RZ, Jones J, Wong DH, Farooqui M, Wiestner A. Treatment with Ibrutinib Inhibits
BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo. Clin Cancer 2015;21(20):4642-51.
29. Patrussi L, Capitani N, Martini V y col. Enhanced Chemokine Receptor Recycling and Impaired S1P1 Expression Promote Leukemic Cell Infiltration of Lymph Nodes in Chronic Lymphocytic Leukemia. Cancer Res. 2015;75(19):4153-63.
30. Kohrt HE, Sagiv-Barfi I, Rafiq S y col. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123(12):1957-60.
31. Bojarczuk K, Siernicka M, Dwojak M, y col. B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. Leukemia. 2014;28(5):1163-7.
32. Da Roit F, Engelberts PJ, Taylor RP y col. Ibrutinib interferes with the cell-mediated anti-tumor activities of
therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100(1):77-86.
33. Borge M, Belen Almejun M, Podaza E y col. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica. 2015;100(4):e140- 2.
34. Colado A, Marin Franco JL, Elias EE y col. Second
generation BTK inhibitors impair the anti-fungal response of macrophages and neutrophils. Am J Hematol. 2020;95(7):E174-E8.
35. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica. 2017;102(10):e400-e3.
36. Flinsenberg TWH, Tromedjo CC, Hu N y col. Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma. Haematologica. 2020;105(2):e76-e9.
37. VanDerMeid KR, Elliott MR, Baran AM, Barr PM, Chu CC, Zent CS. Cellular Cytotoxicity of Next-Generation CD20 Monoclonal Antibodies. Cancer Immunol Res. 2018;6(10):1150-60.
38. Bojarczuk K, Sasi BK, Gobessi S y col. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127(25):3192-201.
39. Pavlasova G, Borsky M, Seda V y col. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood. 2016;128(12):1609-13.
40. Skarzynski M, Niemann CU, Lee YS y col. Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy. Clin Cancer Res 2016;22(1):86-95.
41. Burger JA, Sivina M, Jain N y col. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011-9.
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