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Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.1 COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.
Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.4 More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.
Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.
Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.5
In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.8 More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.
Additional References
1. Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914
2. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403
3. Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366
4. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5
5. Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501
6. Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
7. Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730
8. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4
Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.1 COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.
Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.4 More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.
Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.
Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.5
In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.8 More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.
Additional References
1. Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914
2. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403
3. Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366
4. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5
5. Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501
6. Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
7. Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730
8. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4
Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.1 COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.
Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.4 More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.
Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.
Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.5
In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.8 More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.
Additional References
1. Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914
2. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403
3. Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366
4. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5
5. Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501
6. Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
7. Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730
8. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4