Brentuximab vedotin is generated by conjugating the anti-CD30 monoclonal antibody, SGN-30, to monomethyl auristatin E (MMAE), a synthetic anti-neoplastic agent that binds tubulin. SGN-30 demonstrated both in vitro and in vivo efficacy in CD30⁺ lymphoma (15), and the potency was increased by linking it to MMAE (16). Brentuximab vedotin binds to the surface antigen CD30, undergoes lysosomal internalization, and releases MMAE into the cytosol, thereby inhibiting microtubule polymerization and inducing apoptosis ( Figure 1 ). Aside from direct tumor cell cytotoxicity by MMAE, preclinical studies suggest that brentuximab vedotin exhibits additional mechanisms of action, including: 1) bystander killing, in which MMAE exerts toxicity on adjacent tumor cells, 2) immunogenic cell death by inducing dendritic cell maturation and activating a cellular immune response and/or by inducing endoplasmic reticulum stress due to the disruption of the microtubule network, and 3) antibody-dependent cellular phagocytosis mediated by macrophages (17–22).

Prior to the development of brentuximab vedotin, unconjugated anti-CD30 monoclonal antibodies demonstrated in vitro activity against ALCL. Incubation of two CD30-expressing ALCL cell lines with two anti-CD30 monoclonal antibodies (M44 or HeFi-1) resulted in significant growth inhibition and decreased cell viability (23). Mice injected with these ALCL cell lines developed various metastases, but treatment with anti-CD30 monoclonal antibodies resulted in improvement in survival.

When conjugating CD30 to MMAE (cAC10-vcMMAE), preclinical studies showed that the conjugated drug was highly potent and selectively more active against CD30⁺ cells in comparison to CD30^- cells (16). The antibody drug conjugate also demonstrated clinical activity against mice xenograft models of ALCL or Hodgkin lymphoma treated with doses of 1 – 30 mg/kg without signs of toxicity. The efficacy of vinblastine in relapsed/refractory ALCL established precedence for the use of tubule inhibition, and preclinical data demonstrated higher potency using brentuximab vedotin versus vinblastine against CD30⁺ cell lines (24–26).

The rarity of systemic ALCL has made effective therapy modalities difficult to study in adults, as this disease is often included with other forms of peripheral T cell lymphomas. Prior to the development of brentuximab vedotin, regimens that included cyclophosphamide, anthracycline, vincristine, and prednisone (CHOP) or CHOP-like regimens were used most frequently. In a systematic review/meta-analysis of anthracycline-based chemotherapy for peripheral T cell lymphoma, the complete remission (CR) rate for ALCL was 65.8% with a 5-year overall survival (OS) of 56.5% (27). The 2-year event-free survival (EFS) was no different between CHOP and another regimen VIP-reinforced-ABVD (etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine) (28). Adding etoposide to CHOP (CHOEP) improved the progression-free survival (PFS) in patients with peripheral T cell lymphoma, especially if ≤60 years old and in those with ALK⁺ ALCL (hazard ratio [HR] for ≤60 years old = 0.49, P=.008) (29, 30). Autologous stem cell transplants were also considered in adults with ALCL, though the lack of randomized clinical trials precluded demonstration of any specific survival advantage (31). Prior to the availability of brentuximab vedotin, the treatment options for adults with systemic ALCL were limited and toxic (29, 32, 33).

Similar to adults, outcomes for children/adolescents with systemic ALCL were suboptimal with a failure rate of 25 – 30% despite multiple attempts to improve upfront therapy. Adding methotrexate and high-dose cytarabine to APO (doxorubicin, prednisone, and vincristine) chemotherapy, compressing the duration of T-cell lineage therapy, or adding vinblastine to APO produced increased toxicities without improving efficacy (34–36). In the largest pediatric clinical trial to date with 353 patients, the ALCL99 study (prophase of dexamethasone and cyclophosphamide followed by 6 alternating courses (Courses 1, 3, 5: dexamethasone, methotrexate, ifosfamide, cytarabine, etoposide, +/- vinblastine and Courses 2, 4, 6: dexamethasone, methotrexate, cyclophosphamide, doxorubicin, +/- vinblastine) given every 21 days) showed no advantage for the use of methotrexate given over 24 hours with intrathecal chemotherapy or for the addition of weekly vinblastine in maintenance (24).

Outcomes for those with relapsed ALCL, and especially for patients who progress on therapy, are also suboptimal. Brugieres et al. performed a retrospective study within a heterogeneous population of patients with relapsed/refractory ALCL who received vinblastine salvage therapy and found that the 5-year EFS was only 30% (37). Chemotherapy followed by hematopoietic stem cell transplant (HSCT) consolidation is another option with one study demonstrating a 5-year EFS of 59% (38). While Gross et al. found no significant difference in 5-year EFS when comparing autologous (35%) versus allogeneic (46%) HSCT, Knorr et al. found that allogeneic HSCTs may be a more effective consolidation for those with early relapse (26, 39). Prior to the availability of brentuximab vedotin and ALK inhibitors, patients who progress on therapy have an EFS of only 25 – 41%, even with HSCT (26, 38, 40, 41). Given the high relapse rate and poor prognosis for those who do relapse or progress on therapy, targeted agents are promising therapeutic options for these patients.

Several studies have evaluated the safety and clinical efficacy of targeting CD30⁺ lymphomas using brentuximab vedotin ( Table 1 ). A phase I dose-escalation study of brentuximab vedotin enrolled heavily pre-treated patients with relapsed/refractory CD30⁺ hematologic malignancies (Hodgkin lymphoma, n=42; systemic ALCL, n=2) (42). The maximum tolerated dose was 1.8 mg/kg administered every three weeks, and the CR rate at this dose was 100% for the two patients with ALCL. Most adverse events (AEs) were mild (grades 1 – 2), and included fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. The only grade 3 AE at the maximum tolerated dose was neutropenia (n=1) and pain (n=2).

In a phase II study, 102 patients with Hodgkin lymphoma who relapsed after autologous HSCT were treated with brentuximab vedotin at 1.8 mg/kg every 3 weeks (49). AEs were similar to the phase I study (peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea). In a phase II study evaluating the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory systemic ALCL, 58 patients were enrolled with a median age of 52 years (range 14 – 76 years) (43, 50). Sixteen were ALK⁺ (28%) while 42 were ALK^- (72%), and 29 (50%) had relapsed disease while the remaining 29 had refractory disease. Fifty of the 58 (86%) patients had an objective response with ALK⁺ and ALK^- disease having similar objective response rates (ALK⁺, 81%; ALK^-, 88%). Thirty-eight (66%) of 58 patients achieved a CR, and these patients had a higher 5-year OS (79%) than those who did not (25%). Sixteen of the patients with a CR went on to either autologous (n = 8) or allogeneic (n =8) HSCT, with similar outcomes for each transplant type at five years. At the time of last follow-up, 16 of the 38 patients who achieved a CR remained in remission after receiving a median of 9 cycles of brentuximab vedotin. While 8 of these patients had received an HSCT (4 autologous, 4 allogeneic), 8 remained in remission without additional therapy. Though 33/58 (57%) of patients experienced peripheral neuropathy, 91% of these patients had resolution or improvement of their neuropathy at time of last assessment. This study demonstrated that brentuximab vedotin monotherapy is tolerable and effective in patients with relapsed/refractory ALCL and led to the FDA approval of brentuximab vedotin for adults with relapsed or refractory ALCL in 2011. Additional studies have demonstrated efficacy of brentuximab vedotin retreatment after initial brentuximab vedotin therapy (45). Eight patients with systemic ALCL had an objective response rate of 88% (63% CR) with toxicities similar to those described in other brentuximab monotherapy trials, though with higher rates of peripheral neuropathy given its cumulative toxic effect.

The clinical success of brentuximab vedotin in patients with relapsed/refractory ALCL led to its use in newly diagnosed patients. A phase I study in patients with newly diagnosed CD30⁺ T-cell lymphoma evaluated brentuximab vedotin’s safety and activity when administered sequentially with CHOP or in combination with CHP (A+CHP) (46). Patients received either brentuximab vedotin monotherapy for two cycles followed by CHOP, or A+CHP for six cycles, with responders receiving an additional 8 – 10 cycles of brentuximab vedotin monotherapy. Thirty-two of the 39 patients studied had systemic ALCL with a median age of 57 years (range 21 – 82 years). For those who received sequential therapy (n=13), 11 (85%) had an objective response with 62% achieving a CR and a 1-year PFS of 77%. The sequential arm was terminated after observing progression of disease on CHOP after an initial response to brentuximab vedotin. Two of 13 (15%) patients experienced grade 3 – 4 peripheral sensory neuropathy. For those who received combination therapy (ALCL, n=19; non-ALCL, n=7), all 26 patients had an objective response with 88% achieving a CR and a 1-year PFS of 71%. After median 21.4 months, 11 (42%) had progressive disease or death. No patient went on to receive an HSCT. Toxicities while receiving combination therapy were manageable with grade 3 or higher AEs to include: febrile neutropenia (31%), neutropenia (23%), anemia (15%), pulmonary embolism (12%) and peripheral sensory neuropathy (8%). This study demonstrated that the combination therapy A+CHP is tolerable and effective in patients with ALCL.

The ECHELON-2 study formally tested the clinical efficacy and safety of A+CHP vs. CHOP. In this global, randomized phase III trial, previously untreated patients with CD30⁺ peripheral T cell lymphoma received either A+CHP or CHOP for 6 – 8 cycles (n=226 in each group) (47). The median age of participants was 58 years (range 18 – 85 years) and 80% had stage III – IV disease. Of the 452 patients, 316 (70%) had systemic ALCL, either ALK⁺ (n= 98) or ALK^- (n=218). Overall, both the OS and PFS were superior for the A+CHP arm (HR for OS=0.66, P=0.0244; HR for PFS=0.71, P=0.0110). The median PFS was 48.2 months (A+CHP) vs. 20.8 months (CHOP), with a 29% reduction in the risk of a PFS event. For those with systemic ALCL, there was a 41% reduction in the risk of a PFS event for those receiving A+CHP. This significant difference in outcomes persisted, with a 5-year PFS of 51.4% with A+CHP vs. 43.0% with CHOP (HR= 0.70; 95% CI: 0.53-0.91, P=0.0077) and a 5-year OS of 70.1% with A+CHP versus 61.0% with CHOP (HR=0.72; 95% CI: 0.53-0.99, P=0.0424) (51). This landmark trial demonstrated the superiority of A+CHP over CHOP and supported A+CHP as the new standard of care for adults with systemic ALCL.

A multi-center phase I/II study evaluating brentuximab vedotin in pediatric patients with relapsed/refractory classical Hodgkin lymphoma or systemic ALCL enrolled 36 patients with a median age of 14 years (range 7 – 18 years) (48). Seventeen had ALCL, either ALK⁺ (n=12) or ALK^- (n=5), and six had already received a HSCT. This study determined the same recommended phase II dose as adults (1.8 mg/kg). Of the 17 patients with ALCL, 9 (53%) had a response and 7 (41%) patients achieved a CR at this dose. Patients with ALCL received a median of 9 cycles of therapy, and a total of 13 patients subsequently underwent an HSCT. The most common ≥ grade 3 AEs included neutropenia, increased γ-glutamyl transpeptidase, and pyrexia. Overall, 3/36 (8%) patients had a drug-related serious AE. While 12 of 36 (33%) patients experienced peripheral neuropathy, only one had severity ≥ grade 3 and 11 of the 12 cases improved or resolved. This trial was the first to demonstrate meaningful tumor response with a manageable safety profile in children/adolescents with CD30⁺ lymphoma receiving brentuximab vedotin monotherapy.

The demonstrated safety and clinical efficacy of brentuximab vedotin provided compelling evidence to study it in newly diagnosed children with ALCL. The Children’s Oncology Group designed a randomized phase II clinical trial (NCT01979536) to determine the tolerability, EFS, and OS of adding either brentuximab vedotin or crizotinib to ALCL99 chemotherapy in children and adolescents with systemic ALK⁺/CD30⁺ ALCL (40, 52). Sixty-eight patients with a median age of 12 years (range 2-21 years) enrolled on the brentuximab vedotin arm of the study. Patients received brentuximab vedotin 1.8 mg/kg on day 1 of each 21-day cycle for a total of 6 cycles. All except three patients (94%) were able to receive the full dose of brentuximab vedotin in all 6 cycles. The 2-year EFS was 79.1% and the 2-year OS was 97.0% with no patient relapsing while receiving therapy. Like prior pediatric studies in ALCL, the major grade 3 – 4 toxicities included hematological events, mucositis, and febrile neutropenia. Importantly, there were no toxic deaths, no case of progressive multifocal leukoencephalopathy, and no case of grade 3 or 4 peripheral neuropathy. The addition of brentuximab vedotin prevented on-therapy relapses which have a poor prognosis. In addition, the EFS and OS compare favorably with all previous clinical trials making this regimen one of the standards of care for pediatric ALCL. For children who relapsed after receiving brentuximab vedotin as part of initial therapy, there are, unfortunately, no specific studies on the efficacy of rechallenging them with brentuximab vedotin.

Specific subtypes of primary cutaneous T cell lymphomas (PCTL) are CD30⁺, including mycosis fungoides (MF), primary cutaneous ALCL (pcALCL), and lymphatoid papulosis (LyP). While these disorders can be more clinically benign and indolent than systemic CD30⁺ lymphomas, those that progress to a higher stage or systemic disease may have poor outcomes (53). Importantly, studies have demonstrated clinical efficacy of brentuximab vedotin in the treatment of CD30⁺ PTCL. A phase II study evaluating the safety and efficacy of brentuximab vedotin in treating 48 patients with CD30⁺ PCTL (28 MF, 2 pc-ALCL, 2 pc-ALCL plus LyP or MF, 9 LyP, and 7 LyP plus MF) at doses of 1.8 mg/kg every 21 days revealed an overall response rate of 73% (95% CI: 60 – 86%) and CR rate of 35% (95% CI: 22 – 49%) (53). In a phase III randomized, multi-center trial, patients with previously treated CD30⁺ mycosis fungoides (n=97) or pcALCL (n=31) were treated with either brentuximab vedotin (MF n=48; pcALCL n=16) or physician’s choice (MF n=49; pcALCL n=15) of either oral methotrexate or oral bexarotene. At median follow-up of 22.9 months, those with an objective global response lasting at least 4 months was 56.3% with brentuximab vedotin vs. 12.5% with physician’s choice (P<0.0001) (54). Response rates were higher for brentuximab vedotin over physician’s choice in MF (50% vs. 10.2%) and pcALCL (75% vs. 20%). These trials suggest clinical benefit in treating cutaneous CD30⁺ diseases with brentuximab vedotin.