Brentuximab vedotin (BV) is an anti-CD30 ADC carrying the antimicrotubule agent monomethyl auristatin E as a payload. BV has been investigated as a therapy for patients with cHL and NHL in a number of clinical contexts. For example, in the phase III randomized ECHELON-1 trial (NCT01712490), BV was incorporated into a modification of the doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy regimen, which has been the established standard of care for the first-line treatment of all stages of cHL for a number of years.16 17 In this study, 1334 patients with previously untreated stage III or IV cHL were administered ABVD or BV with doxorubicin, vinblastine, and dacarbazine (A-AVD).18 Patients who received A-AVD exhibited a significantly higher progression free survival (PFS) rate of 82.1% versus 77.2% for patients who received ABVD (HR 0.77; 95% CI 0.6 to 0.98; p=0.03) after a median follow-up of 24.9 months.19 Patients in the A-AVD group also exhibited higher overall survival (OS) than those in the ABVD group at 24-month follow-up, at 96.6% versus 94.9% (HR 0.72; 95% CI 0.44 to 1.17; p=0.19), although this difference was not significant.19 In April 2018, these data supported FDA approval for the use of BV in combination with doxorubicin, vinblastine, and dacarbazine for the first-line treatment of stage III–IV cHL.20

BV has also been approved for use as a consolidation therapy of cHL. In the AETHERA trial (NCT01100502), BV-naïve patients who had received autologous stem cell transplant (autoSCT) and were considered to be at high risk for relapse were administered BV or placebo.21 The median PFS with placebo was 15.8 months, while the median PFS with BV was not reached at 5-year follow-up (HR 0.52; 95% CI 0.38 to 0.72).22 Based on the AETHERA trial, in 2015, the FDA approved BV as consolidation therapy for cHL patients who have received autoSCT and are at high risk of relapse.20

Additionally, BV has been approved for the treatment of relapsed or refractory (R/R) cHL patients who had previously received autoSCT based on a single-arm, phase II study (NCT00848926) where 102 participants who received BV as monotherapy after relapse had a median PFS of 9.3 months (95% CI 7.1 to 12.1).23 24 At 3-year follow-up, OS was estimated to be 80% (95% CI 45% to 100%), with an overall response rate (ORR) of 72%.24 These data supported FDA approval in August 2011.20

The checkpoint inhibitor nivolumab, a mAb that blocks programmed cell death protein 1 (PD-1), has been heavily investigated in solid tumor settings and has also been the subject of therapeutic studies in patients with R/R cHL. The phase II, single-arm CheckMate 205 (NCT02181738) and phase I/II, randomized CheckMate 039 (NCT01592370) studies both examined nivolumab monotherapy in patients with R/R cHL who had previously received autoSCT and, in some cases, both autoSCT and BV consolidation.25 26 In a pooled analysis of 243 patients across three cohorts who had disease progression after receiving autoSCT, the ORR for patients treated with nivolumab was 69% (95% CI 63% to 75%), the median duration of response (DOR) was 16.6 months (95% CI 13.2 to 20.3), and the median PFS was 14.7 months (95% CI 11.3 to 18.5). Patients who had previously received both BV and autoSCT (cohort C, n=100) had an ORR of 73% (95% CI 63% to 81%), a median DOR of 14.5 months (95% CI 9.5 to 16.6), and a median PFS of 11.9 months (95% CI 11.1 to 18.4).27 On the basis of data from these two trials, the FDA approved nivolumab monotherapy for the treatment of patients with R/R cHL who have received autoSCT and BV, or who have received three or more prior lines of systemic therapy (including autoSCT) in May 2016.28

A notable phase II trial, NCT02572167, is examining the combination of BV+nivolumab in the second-line treatment of R/R cHL.29 Interim results from this promising study gave an ORR of 83% (95% CI 71.5% to 91.7%) and a complete response (CR) rate of 62% (95% CI 48.2% to 73.9%) and indicate that this regimen is well-tolerated, although this treatment strategy has not received FDA approval and data on secondary endpoints, including DOR and PFS, are still anticipated.30

Another anti-PD-1 checkpoint inhibitor, pembrolizumab, has been evaluated for efficacy in patients with R/R cHL in the non-randomized, phase II KEYNOTE-087 trial (NCT02453594), which enrolled 210 patients with R/R cHL.31 The PFS and OS at 6-month follow-up were 72.4% and 99.5%, respectively.32 The observed ORR was 69.0% (95% CI 62.3% to 75.2%).32 Based on these data, the FDA granted accelerated approval in May 2017 to pembrolizumab for the treatment of patients with cHL that is refractory or that has relapsed after three or more lines of prior therapy.33

Rituximab is a chimeric anti-CD20 anti-CD20 mAb that has been extensively investigated and used for the treatment of patients with B cell NHL. In NHL Studies 1, 2, and 3, patients with R/R, low grade or follicular B cell NHL were administered rituximab as a single agent with ORR of 48%, 57%, and 38%, respectively.34–36 On the basis of data from these trials, in November 1997, the FDA approved the use of rituximab for the treatment of R/R, low grade or follicular CD20+ B cell NHL.37

Rituximab has also been evaluated for the first-line treatment of FL (in combination with cyclophosphamide, vincristine, prednisone (CVP)). NHL Study 4 randomized patients with previously untreated FL to receive CVP or rituximab+CVP (R-CVP).38 Patients receiving rituximab had a PFS of 2.4 years, compared with 1.4 years without rituximab (HR 0.44; 95% CI 0.29 to 0.65; p<0.0001).38 Rituximab was additionally evaluated as a maintenance therapy for patients achieving response following treatment with rituximab-containing chemoimmunotherapy or chemotherapy alone. In NHL Study 5 (PRIMA, NCT00140582), patients with FL who reached response after initial treatment with rituximab-chemotherapy were randomized to rituximab maintenance or no additional therapy.39 Patients who were administered rituximab as maintenance had a higher PFS than patients who received no additional therapy after a median follow-up of 36 months, at 74.9% versus 57.6%, respectively (HR 0.55; 95% CI 0.44 to 0.68; p<0.0001).40 In NHL Study 6 (ECOG 1496), patients with B cell NHL who responded after initial treatment with CVP chemotherapy were randomized to rituximab maintenance or no additional therapy.41 Rituximab maintenance resulted in a longer median PFS, at 4.3 years versus 1.3 years for patients not administered rituximab (HR 0.4; 95% CI 0.3 to 0.5; p=4.4×10⁻¹⁰).41 In September 2006, the results of NHL Studies 4, 5, and 6 formed the basis of FDA approval for the administration of rituximab in patients with FL as combination first-line therapy with chemotherapy and as maintenance therapy following response in patients with FL who received rituximab-containing combination chemotherapy.37 These studies also formed the basis of FDA approval for the use of rituximab as a maintenance therapy for patients with low grade, CD20+ B cell NHL following initial CVP chemotherapy.37

Rituximab has been investigated in the treatment of DLBCL, a specific subtype of B cell NHL. During NHL Studies 7 (ECOG-4494, NCT00003150), 8 (GELA LNH-98.5), and 9 (MInT, NCT00064116), patients with previously untreated DLBCL received either cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab+CHOP (R-CHOP) therapy.42–44 In all three trials, R-CHOP provided increased PFS when compared with CHOP. In Study 7, PFS was 53% for R-CHOP and 46% for CHOP at 3-year follow-up (HR 0.78; 95% CI 0.61 to 0.99; p=0.04).45 In Study 8, event-free survival (EFS) was 57% for R-CHOP and 38% for CHOP at 2 year follow-up (HR 0.58; 95% CI 0.44 to 0.77; p<0.001).43 In Study 9, EFS was 79% for R-CHOP and 59% for CHOP (log-rank p<0.0001).46 On the basis of data from these trials, in February 2006, the FDA approved the use of R-CHOP for the first-line treatment of DLBCL.37 PMBCL, a subtype of DLBCL, has also been successfully treated with rituximab-chemotherapy combination regimens. A phase II clinical trial (NCT00001337) found that patients (n=51) treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-R-EPOCH) experienced an OS rate of 97% (95% CI 81% to 99%) and EFS rate of 93% (95% CI 81% to 98%) at a median follow-up of 63 months.47 A retrospective analysis (n=156) reported an estimated 3-year OS rate of 95.4% (95% CI 91.8% to 99.0%) and EFS rate of 85.9% (95% CI 80.3% to 91.5%).48

Rituximab also plays an important role in the treatment of PTLD. In an analysis of the use of rituximab for the treatment of 58 patients who developed B cell PTLD following solid organ or stem cell transplant, CR occurred in 61% of patients. At a median follow-up of 61 months, OS was 46%.49 Although the FDA has not issued a specific approval for this purpose, rituximab has become an important component in the treatment of B cell PTLD, alongside other treatments for PTLD, including the withdrawal of immunosuppression, chemotherapeutic regimens, antiviral therapies, and, more recently, histone deacetylase (HDAC) inhibitors (in T cell-related PTLD).50–56

In the MCL setting, rituximab has been used in combination with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. A phase II study of 50 patients with R/R MCL (NCT01880567) reported favorable safety profiles with 88% (95% CI 75.7% to 95.5%) of patients achieving an objective response at a median follow-up of 16.5 months.57 58 Rituximab has also been incorporated into first-line regimens with chemotherapy for MCL. In a study of 638 patients treated with a variety of chemotherapy regimens, 2-year OS was 63% and 52%, respectively, for patients treated with rituximab+chemotherapy versus chemotherapy alone (p<0.001).59 Another chemoimmunotherapy regimen involving rituximab has also been examined for the first-line treatment of MCL: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP). During the clinical trial NCT00722137, 487 patients randomly received either R-CHOP or VR-CAP. Patients treated with VR-CAP experienced higher median PFS of 24.7 months (95% CI 19.8 to 31.8) versus 14.4 months (95% CI 12.0 to 16.9; HR=0.63; 95% CI 0.50 to 0.79; p<0.001).60 Rituximab has also been used as a maintenance therapy in patients who have received autoSCT for MCL. During a clinical trial (NCT00921414) including 257 patients who received either maintenance rituximab or observation following autoSCT, the 4-year PFS rate was 83% (95% CI 73% to 88%) versus 64% (95% CI 55% to 73%) for rituximab versus observation, respectively (HR 0.40; 95% CI 0.23 to 0.68; p<0.001). The OS at 4 years was also significantly higher for patients treated with rituximab, at 89% (95% CI 81% to 94%) compared with 80% (95% CI 72% to 88%; HR 0.50; 95% CI 0.26 to 0.99; p=0.04).61

Two rituximab biosimilars (rituximab-abbs and rituximab-pvvr) are also currently approved by the FDA.62 63 Biosimilars can potentially increase patient access to important immunotherapies, and are typically approved following comparative studies that demonstrate no significant clinical difference from the reference agent.64 65 An alternative formulation of rituximab, containing hyaluronidase, is also available for subcutaneous administration after a patient has received at least one dose of intravenous rituximab.66

Obinutuzumab, another anti-CD20 mAb, which is humanized and binds to a different epitope of CD20, is used in the treatment of FL as an alternative to rituximab. During the GADOLIN trial (NCT01059630), patients with R/R indolent B cell NHL that had been previously treated with a rituximab-containing regimen were administered obinutuzumab+bendamustine or standard of care bendamustine.67 68 The majority of these patients had follicular B cell NHL.69 Patients receiving obinutuzumab during treatment also received it as maintenance therapy.67 At the time of follow-up (median 21.9 months for obinutuzumab+bendamustine, 20.3 months for bendamustine), median PFS was not reached for obinutuzumab+bendamustine, and was 13.8 months for bedamustine alone (HR 0.49; 95% CI 0.35 to 0.68; log-rank p<0.0001).69 Based on the results of this trial, in February 2016, the FDA approved the use of obinutuzumab in combination with bendamustine (with obinutuzumab maintenance) for the treatment of R/R FL in patients who have previously received a rituximab-containing regimen.70

In the GALLIUM trial (NCT01332968), obinutuzumab was investigated for the first-line treatment of FL in comparison to rituximab. Patients received a chemotherapy regimen (CHOP, CVP, or bendamustine) in combination with obinutuzumab or rituximab.71 At 3 years maintenance with the assigned antibody, patients who received obinutuzumab exhibited a higher estimated rate of PFS, at 80.0% versus 73.3% (HR 0.66; 95% CI 0.51 to 0.85; p=0.001).72 The FDA approved the use of obinutuzumab in combination with chemotherapy (followed by obinutuzumab maintenance) for the first-line treatment of bulky stage II, stage III, and stage IV FL in November 2017.70 Notably, however, the GALLIUM trial results did not demonstrate statistically significant differences in OS at 3 years for obinutuzumab compared with rituximab (94.0% vs 92.1%; HR 0.75; 95% CI 0.49 to 1.17; p=0.21), despite reported benefits for PFS.72 Obinutuzumab was also investigated as a first-line therapy for DLBCL, in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP), in the GOYA trial (NCT01287741).73 However, when compared with standard of care R-CHOP, G-CHOP did not significantly improve PFS.74

Ibritumomab tiuxetan (IT) is an anti-CD20 antibody, conjugated to the radioisotope ⁹⁰Y. IT was evaluated for the treatment of patients with R/R, low grade or follicular B cell NHL in three clinical trials, IDEC 106-04, IDEC 106-05, and IDEC 106-06.75 In the single-arm IDEC 106-05, the ORR for patients with R/R B cell NHL was 89% (95% CI 70% to 97%).76 In IDEC 106-04, IT was compared with rituximab in the treatment of R/R B cell NHL. The ORR was significantly higher in patients receiving IT, at 83% versus 55% (p<0.001).77 In IDEC 106-06, IT was used as a therapy for patients with R/R B cell NHL who had previously received rituximab. The ORR in this study was 74%.78 These data were the basis for FDA approval of the treatment of R/R low-grade or follicular B cell NHL with IT in February 2002.79

IT has also been approved as a consolidation therapy for FL. In the trial NCT00185393, patients achieving partial response (PR) or CR following first-line chemotherapy were administered either IT or no consolidation therapy.80 The median PFS was significantly higher in the IT arm, at 36.5 months versus 13.3 months in the control arm (HR 0.47; 95% CI 0.36 to 0.61; p<0.0001).81 Based on the results of this trial, in September 2009, the FDA approved the use of IT as consolidation for patients with FL who achieve PR or CR following chemotherapy.79 Tostitumomab, another anti-CD20 antibody conjugated to ¹³¹I, received FDA approval for the treatment of R/R FL in June 2003; however, tositumomab is no longer manufactured or sold.82

In addition to approvals in the cHL setting, BV has also been investigated and approved for the treatment of some subsets of T cell lymphomas (TCL). In the single-arm study NCT00866047, BV was evaluated as a therapy for R/R systemic anaplastic large cell lymphoma (sALCL), a type of peripheral TCL.83 At 5-year follow-up, the median PFS was 20 months, the OS rate was 60% (95% CI 47% to 73%), and the ORR was 86% (95% CI 74.6% to 93.9%).84 In August 2011, the FDA approved the use of BV for the treatment of R/R sALCL after the failure of at least one multi-agent chemotherapy regimen.20

In the ECHELON-2 trial (NCT01777152), patients with CD30+, peripheral T cell lymphoma (PTCL) received CHOP chemotherapy or BV with cyclophosphamide, doxorubicin, prednisone (A+CHP) as first-line therapy.85 Treatment with A+CHP was associated with significantly increased median PFS of 48.2 months versus 20.8 months (HR 0.71; 95% CI 0.53 to 0.94; log-rank p=0.011).86 These data were the basis of FDA approval of BV in combination with CHP for the first-line treatment of CD30+ PTCL, including sALCL, angioimmunoblastic TCL, and PTCL otherwise not specified, in November 2018.20

BV has also been approved for the treatment of two subtypes of cutaneous TCL, mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL). The ALCANZA trial (NCT01578499) compared BV to chemotherapy with methotrexate or bexarotene in patients with R/R MF or pcALCL.87 The ORR in patients receiving BV was significantly higher, at 67% compared with 20% (p<0.0001).86 Median PFS was also higher with BV treatment, at 16.7 months versus 3.5 months (HR 0.27; 95% CI 0.169 to 0.430; p<0.0001).86 In November 2017, the FDA approved the use of BV for the treatment of R/R CD30+ MF and pcALCL.20

In addition to TCL, BV has been examined as a therapy for CD30+ B cell lymphomas (although the FDA has not approved BV for this purpose). A phase II trial (NCT01421667) examined BV monotherapy for patients with R/R DLBCL (n=48). All responding patients had quantifiable CD30 expression, although the level of CD30 expression did not correlate with response. The ORR was 44% (95% CI 27.8% to 60.4%), and median PFS was 4 months.88 A small number of patients (n=9) have been treated with BV for CD30+ PTLD. A systematic review that pooled outcomes from BV-treated patients with CD30+ PTLD (n=9) across clinical trials and case studies found that results were mostly positive, with 56% (n=5) of patients experiencing complete remission.89

Polatuzumab vedotin-piiq is an ADC targeted to CD79b. Study GO29365 (NCT02257567) compared polatuzumab vedotin-piiq with bendamustine+rituximab (BR) to BR alone in patients with R/R DLBCL or FL.90 In patients with DLBCL, those treated with polatuzumab vedotin-piiq exhibited significantly higher median PFS, at 9.5 months versus 3.7 months (HR 0.37; 95% CI 0.21 to 0.66; p<0.001).91 The ORR was also significantly increased, at 45.0% versus 17.5%.91 The FDA approved the use of polatuzumab vedotin-piiq in combination with BR for the treatment of R/R DLBCL after at least two prior therapies in June 2019.92

Mogamulizumab-kpkc is an mAb targeted to CC chemokine receptor 4 (CCR4). Mogamulizumab has been evaluated for the treatment of two types of cutaneous TCL: MF and Sézary syndrome (SS). During the MAVORIC trial (NCT01728805), patients with R/R cutaneous TCL received mogamulizumab or vorinostat.93 The median PFS was 7.7 months for mogamulizumab and 3.1 months for vorinostat (HR 0.53; 95% CI 0.41 to 0.69; log-rank p<0.0001), and ORR for each group was 23% and 4%, respectively (p<0.00001).94 Based on this trial, in August 2018 the FDA approved mogamulizumab for the treatment of R/R MF or SS after at least one prior systemic therapy.95

Pembrolizumab has been approved for the treatment of R/R PMBCL in patients who have received two or more prior lines of therapy, based on the KEYNOTE-170 trial (NCT02576990), which observed an ORR of 45% (95% CI 32% to 60%), median PFS of 5.5 months (95% CI 2.8 months to 12.1 months), and OS at 1-year follow-up estimated at 58%.96 97 The trial formed the basis for FDA approval in June 2018.33

Lenalidomide, an IMiD, has been investigated and approved for a few subtypes of NHL, namely MCL, FL, and MZL. In the single-arm EMERGE trial (NCT00737529), patients with R/R MCL were administered lenalidomide.98 The ORR of this treatment was 30%, and the median PFS was 4.0 months (95% CI 3.7 to 7.2).99 On the basis of data from this trial, the FDA approved lenalidomide for the treatment of patients with R/R MCL who had received two or more prior therapies (one of which was bortezomib) in June 2013.100

In addition to being used as a monotherapy in the treatment of MCL, lenalidomide is commonly administered in combination with rituximab for the treatment of FL and MZL. In the AUGMENT trial (NCT01938001), patients with MZL or FL (grade 1–3a) were administered lenalidomide+rituximab or rituximab+placebo.101 Patients receiving lenalidomide+rituximab exhibited significantly increased median PFS, at 39.4 months versus 14.1 months (HR 0.46; 95% CI 0.34 to 0.62; p<0.0001). The ORR was also significantly increased in the lenalidomide arm, at 78% versus 53% (p<0.0001).102 In the MAGNIFY trial (NCT01996865), patients with R/R FL (grade 1–3b or transformed), MZL, or MCL were administered lenalidomide+rituximab, with either rituximab or lenalidomide+rituximab (R2) administered as maintenance therapy afterward.103 While a comparison between the rituximab and R2 arms has not yet been published, the ORR in patients with MZL was 65%, and the ORR in patients with FL was 74% for patients treated with R2 maintenance.104 Based on data from MAGNIFY and AUGMENT, in May 2019 the FDA approved the use of lenalidomide+rituximab for the treatment of R/R FL and MZL.100 Lenalidomide was also tested as part of a first-line therapy regimen for FL (grade 1–3a) in combination with rituximab as part of the RELEVANCE trial (NCT01476787 and NCT01650701).105 106 In comparison between the R2 regimen and a selection of rituximab-containing chemoimmunotherapy regimens, rates of ORR, PFS, and OS were similar and did not show a clear advantage for either treatment arm. However, the safety profiles of the two treatment arms were different, with R2 resulting in a higher rate of grade ≥3 cutaneous reactions and rituximab+chemotherapy resulting in a higher rate of grade ≥3 neutropenia and febrile neutropenia.107

Lenalidomide has also been investigated as a treatment for DLBCL. Lenalidomide has resulted in similar efficacy to investigator’s choice therapies, as in the phase II/III DLC-001 trial (NCT01197560).108 While lenalidomide did not demonstrate a clear OS advantage over other therapies as a single agent, it is sometimes used clinically in the treatment of DLBCL as an alternative with a different toxicity profile.

At the time of manuscript preparation, three CAR T cell therapies have been approved by the FDA for the treatment of patients with lymphoma. All target cells expressing CD19, but differ in the costimulatory and hinge domains used in the CAR constructs. The single-arm ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel reported an ORR of 83%, a median PFS of 5.9 months (95% CI 3.3 to 15.0), and a DOR of 11.1 months (95% CI 4.2 to not estimable) in patients with large B cell lymphomas. At a median follow-up of 27.1 months, 39% of patients exhibited ongoing remission and median OS was not reached.109 110 Based on this study, in October 2017, the FDA granted approval to axicabtagene ciloleucel for the treatment of R/R large B cell lymphomas (including DLBCL, PMBCL, high-grade B cell lymphoma, and transformed FL) after two or more prior lines of systemic therapy.111

Another CD19-targeting CAR T cell therapy, tisagenlecleucel, is also approved for the treatment of R/R large B cell lymphomas. In the single-arm, phase II JULIET trial (NCT02445248) for R/R DLBCL and transformed FL, tisagenlecleucel therapy resulted in an ORR of 52% (95% CI 41% to 62%). At the data cut-off, the median DOR had not yet been reached, the median OS was 12 months (95% CI 7 to not reached), and the median PFS had not been reached.112 In May 2018, the FDA approved the use of tisagenlecleucel for the treatment of R/R large B cell lymphomas after two or more prior lines of systemic therapy.113

In July 2020, the FDA approved brexucabtagene autoleucel (formerly KTE-X19), an anti-CD19 CAR T cell therapy, for the treatment of R/R MCL.114 This approval was based on the phase II, open-label ZUMA-2 trial (NCT02601313).115 In this trial, 60 patients in the primary efficacy analysis with R/R MCL received brexucabtagene autoleucel, and exhibited an ORR of 93% (95% CI 84% to 98%) and a CR rate of 67% (95% CI 53% to 78%). At 12 months, the estimated OS and PFS were 83% and 61%, respectively.116

During the L-MIND trial (NCT02399085), a phase II, open-label trial, 80 patients received tafasitamab-cxix (an anti-CD19 mAb) with lenalidomide for the treatment of R/R DLBCL.117 The ORR among these patients was 60% (95% CI 48% to 71%), the median DOR was 21.7 months (95% CI 21.7 to not reached), the median PFS was 12.1 months (95% CI 5.7 to not reached), and the median OS was not reached at a median follow-up of 19.6 months.118 On the basis of data from L-MIND, the FDA approved tafasitamab-cxix+lenalidomide for the treatment of R/R DLBCL in patients who are not eligible for autoSCT.119

It is hypothesized that PTLD is often linked to Epstein-Barr virus (EBV) infection or reactivation, and BV represents a potential treatment option for the resulting CD30+ PTLD (as discussed earlier). A recent case study demonstrated the successful combination of BV and EBV-directed allogeneic T lymphocytes to treat CD30+, EBV-associated PTLD, achieving a lasting CR.120 While EBV-directed T lymphocytes have seen clinical use in the treatment of PTLD, no FDA approvals exist for these cellular therapies at the time of publication.

Rituximab has been approved for the treatment of CLL in both first-line and R/R settings, in combination with fludarabine and cyclophosphamide (FC). In the phase III CLL-8 study (NCT00281918), patients received either rituximab+FC or FC for previously untreated CLL.121 Patients receiving rituximab+FC in this study exhibited significantly higher PFS at 5-year follow-up, 56.8 months compared with 32.9 months (HR 0.59; 95% CI 0.50 to 0.69; p<0.001). The ORR with rituximab+FC was also significantly higher, at 90% versus 80% (p<0.001).122 In the REACH trial (NCT00090051), patients with R/R CLL received rituximab+FC or FC alone.123 Patients treated with rituximab+FC had significantly higher median PFS of 27.0 months versus 21.9 months (HR 0.76; 95% CI 0.60 to 0.96; p=0.0218).124 The ORR was also significantly higher in rituximab-treated patients (61% vs 49%; p=0.0048).124 Based on these results, in February 2010, the FDA approved the use of rituximab in combination with FC to treat CLL, with no restrictions related to prior therapy.37

Another combination regimen including the BTK inhibitor ibrutinib with rituximab for the first-line treatment of CLL was approved by the FDA in April, 2020.125 During the phase III E1912 trial (NCT02048813), patients received first-line ibrutinib+rituximab or rituximab+fludarabine+cyclophosphamide.126 The median PFS was not reached for either group, but the percentage of progression-free patients was higher for those treated with ibrutinib at 3 years (89.4% vs 72.9%; HR 0.35; 95% CI 0.22 to 0.58; p<0.001). OS was also significantly higher at 3 years for patients treated with ibrutinib (98.8% vs 91.5%; HR 0.17; 95% CI 0.05 to 0.54; p<0.001).127

Obinutuzumab has been evaluated in the first-line setting for CLL. In CLL11 (NCT01010061), patients received obinutuzumab+chlorambucil, rituximab+chlorambucil, or chlorambucil alone.128 Compared with chlorambucil alone, obtinutuzumab+chlorambucil treatment was associated with a significantly longer median PFS of 31.1 months versus 11.1 months (HR 0.21; 95% CI 0.16 to 0.28; p<0.0001) after median follow-up of 62.5 months. At a median follow-up of 59.4 months, patients treated with obinutuzumab+chlorambucil also exhibited a clear advantage in median PFS over patients treated with rituximab+chlorambucil, at 28.9 months versus 15.7 months (HR 0.49; 95% CI 0.41 to 0.58; p<0.0001).129 On the basis of data from CLL11, the FDA approved the use of obinutuzumab+chlorambucil for the first-line treatment of CLL in November 2013.70

Ofatumumab, an anti-CD20 mAb, has been approved for the treatment of CLL as a first-line, maintenance, or salvage therapy. In the COMPLEMENT 1 trial (NCT00748189), patients with untreated CLL received chlorambucil with or without ofatumumab.130 Treatment with ofatumumab+chlorambucil resulted in a significantly higher median PFS of 22.4 months versus 13.1 months (HR 0.57; 95% CI 0.45 to 0.72; p<0.0001), which led to FDA approval of ofatumumab+chlorambucil for the first-line treatment of CLL in April 2017.131 132

Ofatumumab also demonstrated clinical benefit as a maintenance therapy in the phase IV PROLONG trial (NCT00802737), which enrolled patients with prior response to ofatumumab.133 Patients who received ofatumumab maintenance exhibited longer PFS, with a median of 30.4 months versus 14.8 months (HR 0.55; 95% CI 0.42 to 0.72; p<0.0001).134 In January 2016, the FDA approved the use of ofatumumab as maintenance therapy for patients with CLL in CR or PR following at least two lines of therapy.132

In the setting of R/R CLL, ofatumumab has been the subject of multiple trials. During COMPLEMENT 2 (NCT00824265), patients with R/R CLL were administered FC with or without ofatumumab; patients treated in the ofatumumab arm had significantly longer median PFS, at 28.9 months versus 18.8 months (HR 0.67; 95% CI 0.51 to 0.88; p=0.0032).135 136 The ORR was also significantly higher in the ofatumumab treatment arm—84% versus 68% (p=0.0003).136 In August 2016, the FDA approved ofatumumab+FC for the treatment of relapsed CLL.132During the single-arm NCT00349349 trial, patients with R/R CLL who had previously received fludarabine and alemtuzumab were treated with ofatumumab monotherapy.137 The ORR was 58% (99% CI 40% to 74%) with median PFS of 5.7 months (95% CI 4.5 to 8.0).138 Based on NCT00349349, the FDA approved ofatumumab for the treatment of R/R CLL in patients who have previously been treated with fludarabine and alemtuzumab in October 2009.132

Alemtuzumab, an anti-CD52 mAb, has been approved for the treatment of B cell CLL as a monotherapy. In the phase III CAM307 trial (NCT00046683), alemtuzumab was compared with chlorambucil as first-line therapy for CLL.139 Patients receiving alemtuzumab exhibited prolonged PFS, at a median of 14.6 months versus 11.7 months (HR 0.58; 95% CI 0.43 to 0.77; log-rank p=0.0001).140 Based on the results of CAM307, the FDA approved the use of alemtuzumab for the first-line treatment of CLL in September 2007, expanding the existing indication to include all B cell CLL.141

Alemtuzumab also demonstrated safety and efficacy in the treatment of R/R CLL during three single-arm studies with reported ORRs of 42% (95% CI 23% to 61%), 33%, and 31%.142–144 Based on an analysis of these studies, in May 2001 the FDA approved the use of alemtuzumab for the treatment of R/R CLL.141

Both nivolumab and pembrolizumab, which are currently approved for the treatment of select lymphomas, are typically administered in contexts where patients have already undergone autoSCT. In this setting, ICIs have exhibited promising response rates and tolerable levels of toxicity.27 148 In contrast, little data currently exists regarding the administration of ICIs prior to autoSCT for patients with lymphoma.

AlloSCT, when used in conjunction with ICI therapy, appears to carry some risk of AEs, including GVHD. In a retrospective analysis of 31 cHL patients receiving nivolumab or pembrolizumab following alloSCT, ORR was 77% (95% CI 58% to 90%), but 55% (n=17) of patients developed GVHD (19% acute (n=6), 23% chronic (n=7), and 13% acute/chronic overlap (n=4)).149 Similarly, a retrospective analysis of 107 patients from seven studies who received ICIs prior to alloSCT exhibited an ORR of 68%, but 56% of patients developed acute GVHD and 29% developed chronic GVHD. 60% of patient deaths reported were GVHD-related.150 Another analysis of patients who received anti-PD-(L)1 inhibitors prior to alloSCT demonstrated that patients were at higher risk of acute GVHD if time to transplant was short, and that prophylactic cyclophosphamide improved patient outcomes while reducing the risk of chronic GVHD.151 Generally, the use of ICIs in conjunction with alloSCT may result in improved response rates, but caution must be exercised due to the high likelihood of GVHD. Future studies may also identify ways to integrate these two therapeutic methods while minimizing the risk of GVHD.

Concerning CAR T cell therapies, confirmatory clinical trials resulting in approval of tisagenlecleucel and axicabtagene ciloleucel included patients who had received prior autologous stem cell transplant, and reported consistent efficacy across subgroups.112 152 There is ongoing debate in the field of lymphoma treatment as to the potential for CAR T cell therapy to be used in conjunction with, or to replace, traditional autoSCT.153 154

Little data exists regarding the use of CAR T cell therapy in conjunction with alloSCT for the treatment of lymphoma. In patients with a different hematological malignancy, B cell acute lymphoblastic leukemia, anti-CD19 CAR T cell therapies have been successfully used as a bridge therapy to enable subsequent alloSCT, with promising rates of CR and no reported incidence of GVHD.155 156 This result may serve as a blueprint for future research in the use of alloSCT after CAR T cell therapies.