The interpretation of version 3. 2019 of the NCCN guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma_West China Medical Journal

Authors：

FU Xiaoyan ,  NIU Ting

Department of Hematology / Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

NIU Ting, Email: tingniu@sina.com

Keywords：

Chronic lymphocytic leukemia; Small lymphocytic lymphoma; Diagnosis; Therapy

DOI：

10.7507/1002-0179.201904086

Video：

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Chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) is a malignancy of mature B cells characterized by progressive lymphocytosis, lymphadenopathy, and splenomegaly. On February 21st 2019, with the accumulating of new data, the National Comprehensive Cancer Network updated the guideline for CLL/SLL. This article aims at providing a reasonable interpretation of the most important messages conveyed in the guideline.

Citation： FU Xiaoyan, NIU Ting. The interpretation of version 3. 2019 of the NCCN guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma. West China Medical Journal, 2019, 34(4): 355-362. doi: 10.7507/1002-0179.201904086 Copy

1.	The non-Hodgkin’s lymphoma classification project. A clinical evaluation of the international lymphoma study group classification of non-Hodgkin’s lymphoma. Blood, 1997, 89(11): 3909-3918.
2.	Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood, 1975, 46(2): 219-234.
3.	Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer, 1981, 48(1): 198-206.
4.	Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol, 2014, 32(27): 3059-3068.
5.	Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med, 2015, 373: 2425-2437.
6.	Barr P, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: Ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood, 2016, 128(22): Abstract 234. http://hdl.handle.net/1854/LU-8524076.
7.	Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica, 2018, 103(9): 1502-1510.
8.	Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood, 2019, 133(12): 1298-1307.
9.	Byrd JC, Hillmen P, O’Brien SM, et al. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. J Clin Oncol, 2017, 35(15_Suppl): Abstract 7510.
10.	Moreno C, Greil R, Demirkan F. 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.
11.	Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol, 2015, 16(2): 169-176.
12.	Schetelig J, van Biezen A, Brand RA, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European group for blood and marrow transplantation analysis. J Clin Oncol, 2008, 26(31): 5094-5100.
13.	Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia, 2007, 21: 12-17.
14.	Jaglowski SM, Ruppert AS, Heerema NA, et al. Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. Br J Haematol, 2012, 159(1): 82-87.
15.	Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med, 2014, 371(3): 213-223.
16.	Flinn IW, Hillmen P, Montillo M. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood, 2018, 132(23): 2446-2455.
17.	Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med, 2014, 370(11): 997-1007.
18.	Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (Zydelig®) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood, 2014, 124(21): Abstract 330.
19.	Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol, 2017, 18(2): 224-230.
20.	Seymour JF, Kipps TJ, Eichhorst BF, et al. Venetoclax plus rituximab is superior to Bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia-results from pre-planned interim analysis of the randomized phase 3 murano study. Blood, 2017, 130(Suppl 1): Abstract LBA-2.
21.	Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol, 2016, 17(6): 768-778.
22.	Tsimberidou AM, Keating MJ. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer, 2005, 103(2): 216-228.
23.	Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol, 2012, 156(1): 50-66.
24.	Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood, 2011, 117(12): 3391-3401.
25.	Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood, 2013, 122(15): 2673-2682.
26.	Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med, 2013, 210(11): 2273-2288.
27.	Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter’s transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol, 2007, 31(10): 1605-1614.
28.	Tadmor T, Shvidel L, Goldschmidt N, et al. Hodgkin’s variant of Richter transformation in chronic lymphocytic leukemia; a retrospective study from the Israeli CLL study group. Anticancer Res, 2014, 34(2): 785-790.
29.	Giné E, Martinez A, Villamor N, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (" accelerated” chronic lymph ocytic leukemia) with aggressive clinical behavior. Haematologica, 2010, 95(9): 1526-1533.
30.	Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter’s syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol, 2008, 26(2): 196-203.
31.	Tsimberidou AM, Wierda WG, Wen S, et al. Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome. Clin Lymphoma Myeloma Leuk, 2013, 13(5): 568-574.
32.	Tsimberidou AM, Kantarjian HM, Cortes J, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer, 2003, 97(7): 1711-1720.
33.	Dabaja BS. O’Brien SM, Kantarjian HM, et al Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter’s syndrome. Leuk Lymphoma, 2001, 42(3): 329-337.
34.	Langerbeins P, Busch R, Anheier N, et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation. Am J Hematol, 2014, 89(12): E239-E243.
35.	Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol, 2018, 180(2): 259-266.
36.	Ding W, Laplant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, 2017, 129(26): 3419-3427.
37.	Tsimberidou AM, O’Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol, 2006, 24(15): 2343-2351.
38.	Mauro FR, Galieni P, Tedeschi A, et al. Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma. Am J Hematol, 2017, 92(6): 529-535.
39.	Shanafelt T, Wand V, Kay N, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOGACRIN Cancer Research Group (E1912). Blood, 2018, 132: Abstract LBA-4.
40.	Thompson PA, Tam CS, Fludarabine OS, et al. And rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood, 2016, 127(3): 303-309.
41.	Jennifer A, Woyach MD, Amy S. Ibrutinb regimens versus chemmoimmunotherapy in older patients with untreated CLL. N Engl J Med, 2018, 379(26): 2517-2528.
42.	Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic lymphoma. N Engl J Med, 2018, 378(12): 1107-1120.
43.	Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOs study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia, 2019, 33(4): 969-980.

1. The non-Hodgkin’s lymphoma classification project. A clinical evaluation of the international lymphoma study group classification of non-Hodgkin’s lymphoma. Blood, 1997, 89(11): 3909-3918.
2. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood, 1975, 46(2): 219-234.
3. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer, 1981, 48(1): 198-206.
4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol, 2014, 32(27): 3059-3068.
5. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med, 2015, 373: 2425-2437.
6. Barr P, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: Ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood, 2016, 128(22): Abstract 234. http://hdl.handle.net/1854/LU-8524076.
7. Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica, 2018, 103(9): 1502-1510.
8. Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood, 2019, 133(12): 1298-1307.
9. Byrd JC, Hillmen P, O’Brien SM, et al. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. J Clin Oncol, 2017, 35(15_Suppl): Abstract 7510.
10. Moreno C, Greil R, Demirkan F. 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.
11. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol, 2015, 16(2): 169-176.
12. Schetelig J, van Biezen A, Brand RA, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European group for blood and marrow transplantation analysis. J Clin Oncol, 2008, 26(31): 5094-5100.
13. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia, 2007, 21: 12-17.
14. Jaglowski SM, Ruppert AS, Heerema NA, et al. Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. Br J Haematol, 2012, 159(1): 82-87.
15. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med, 2014, 371(3): 213-223.
16. Flinn IW, Hillmen P, Montillo M. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood, 2018, 132(23): 2446-2455.
17. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med, 2014, 370(11): 997-1007.
18. Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (Zydelig®) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood, 2014, 124(21): Abstract 330.
19. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol, 2017, 18(2): 224-230.
20. Seymour JF, Kipps TJ, Eichhorst BF, et al. Venetoclax plus rituximab is superior to Bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia-results from pre-planned interim analysis of the randomized phase 3 murano study. Blood, 2017, 130(Suppl 1): Abstract LBA-2.
21. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol, 2016, 17(6): 768-778.
22. Tsimberidou AM, Keating MJ. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer, 2005, 103(2): 216-228.
23. Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol, 2012, 156(1): 50-66.
24. Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood, 2011, 117(12): 3391-3401.
25. Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood, 2013, 122(15): 2673-2682.
26. Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med, 2013, 210(11): 2273-2288.
27. Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter’s transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol, 2007, 31(10): 1605-1614.
28. Tadmor T, Shvidel L, Goldschmidt N, et al. Hodgkin’s variant of Richter transformation in chronic lymphocytic leukemia; a retrospective study from the Israeli CLL study group. Anticancer Res, 2014, 34(2): 785-790.
29. Giné E, Martinez A, Villamor N, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (" accelerated” chronic lymph ocytic leukemia) with aggressive clinical behavior. Haematologica, 2010, 95(9): 1526-1533.
30. Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter’s syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol, 2008, 26(2): 196-203.
31. Tsimberidou AM, Wierda WG, Wen S, et al. Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome. Clin Lymphoma Myeloma Leuk, 2013, 13(5): 568-574.
32. Tsimberidou AM, Kantarjian HM, Cortes J, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer, 2003, 97(7): 1711-1720.
33. Dabaja BS. O’Brien SM, Kantarjian HM, et al Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter’s syndrome. Leuk Lymphoma, 2001, 42(3): 329-337.
34. Langerbeins P, Busch R, Anheier N, et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation. Am J Hematol, 2014, 89(12): E239-E243.
35. Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol, 2018, 180(2): 259-266.
36. Ding W, Laplant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, 2017, 129(26): 3419-3427.
37. Tsimberidou AM, O’Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol, 2006, 24(15): 2343-2351.
38. Mauro FR, Galieni P, Tedeschi A, et al. Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma. Am J Hematol, 2017, 92(6): 529-535.
39. Shanafelt T, Wand V, Kay N, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOGACRIN Cancer Research Group (E1912). Blood, 2018, 132: Abstract LBA-4.
40. Thompson PA, Tam CS, Fludarabine OS, et al. And rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood, 2016, 127(3): 303-309.
41. Jennifer A, Woyach MD, Amy S. Ibrutinb regimens versus chemmoimmunotherapy in older patients with untreated CLL. N Engl J Med, 2018, 379(26): 2517-2528.
42. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic lymphoma. N Engl J Med, 2018, 378(12): 1107-1120.
43. Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOs study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia, 2019, 33(4): 969-980.

West China Medical Journal

The interpretation of version 3. 2019 of the NCCN guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma

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