The most recent approvals for the treatment of FL and MCL have not provided sufficient time yet for real world experience. On the other hand, commercial CAR-T cell products have been commercially available since 2017 and extensive real world data have confirmed their effectiveness with response and survival rates very similar to the original clinical trials.5,27 FDA-approved package inserts, however, do not define any specific eligibility criteria beyond the number of previous treatment lines, although real-world experience has demonstrated that proper patient selection is a crucial step for successful cellular therapy outcomes.

Two separate issues play a critical role in patient selection – organ function and predictive markers of response. Retrospective data of patients treated with commercial products have demonstrated a trend of lower response rates and duration of response for those who did not meet the original eligibility criteria of the clinical trials that led to approval of these products.18 While impressive responses have been seen, even in highly refractory and bulky presentations, poorly controlled lymphoma requiring bridging, high markers of cell turnover or inflammation (such as lactate dehydrogenase-DHL, ferritin, and C-reactive protein), large tumor burden with extensive extranodal involvement or large metabolic tumor volume negatively influence the outcomes of CAR-T cell treatment in B-LNH.19,28,29

While we still try to establish the best sequencing of cellular therapy treatment and the best recently FDA-approved salvage agents, such as the anti-CD19 antibody tafasitamab or the antibody-drug conjugates, polatuzumab and loncastuximab, the progressively expanding option list at the very least allows for more careful selection of the best candidates for CAR-T cell therapy.

This is particularly challenging in the Brazilian healthcare system where many of these agents are still not available and the access to CAR-T cell therapy will, at least at first, be very limited. It will be fundamental that providers consider these features when selecting the patients to be treated with cellular therapy in the R/R B-LNH setting.

Figure 1 proposes an approach for patient selection for the treatment with anti-CD19 CAR-T cell therapy in the current Brazilian setting.30–32 AHSCT remains the standard of care as second-line therapy in the management of R/R DLBCL. Every patient considered eligible for AHSCT should undergo a prior salvage chemoimmunotherapy scheme outside of a clinical trial. Those with CR, particularly those with metabolic CR by PET/CT, should undergo consolidation AHSCT. Those patients with PR could still be considered for AHSCT, but those with disease characteristics associated with high chemorefractoriness, such as high-grade double-hit or triple-hit B-NHL or primarily refractory lymphoma, should be considered for CAR-T cell therapy. Likewise, patients with SD or PD, after salvage therapy, should be preferably considered for cellular therapy.

Figure 1.

Treatment algorithm recommended for R/R DLBCL management.30

Algorithm for management of relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) adapted from Alencar AJ et al.31 Treatment response was based on the LYRIC criteria (Cheson BD et al.32). Allogeneic hematopoietic stem cell transplantation may be considered instead of autologous hematopoietic stem cell transplantation (auto-HSCT) in selected cases of mobilization failure.

CAR, chimeric antigen receptor; CR, complete response; DHL, double-hit lymphoma; LDH, lactate dehydrogenase; PR, partial response; SD/PD, stable/progressive disease; THL, triple-hit lymphoma; ULN, upper limit of normal.

(0.15MB).

In view of failures after CAR-T cell treatment, more frequently observed in patients with fast progressive disease, alternative options, such as second salvage with novel agents or some bridging therapy (BT) in an attempt to achieve better disease control, should be considered prior to CAR-T cell therapy. This proposed approach aims to select the best candidates who may benefit the most from CAR-T cell therapy at least, in an initial phase in Brazil, when product availability will be extremely limited and successful outcomes will be fundamental to its consistent implementation.

Many patients who are candidates to CAR-T cell therapy have symptomatic disease that can be fatal if left untreated during the cell-manufacturing period. Bridging therapy (BT) – therapy administered after apheresis and before CAR-T cell infusion – may include corticosteroids, chemotherapy, targeted therapy, or radiation therapy (RT). According to the “Best practices recommendation of the European Society for Blood and Marrow Transplantation”, the goal of BT is to avoid clinically significant disease progression leading to impaired organ function or any other complications that might prevent the patient proceeding with lymphodepletion and receiving the CAR T-cells.

BT should ideally not induce major complications, such as infections, bleeding, or any organ dysfunction that might interfere with the planned lymphodepleting therapy and CAR T-cell infusion. BT can be omitted if there is stable/low burden disease and/or turn-around time for CAR T cell manufacture is expected to be short. Immunosuppressive drugs with a longer half-life, such as alemtuzumab, daratumumab, checkpoint inhibitors, or brentuximab vedotin, may interfere with the expansion or persistence of the infused CAR T-cells and should be avoided. When choosing BT for lymphoma, patient factors to be considered include prior response to chemo-immunotherapy, overall tumor burden, distribution and sites of tumor involvement. While parenteral agents, such as rituximab, gemcitabine, oxaliplatin, bendamustine or even oral chemotherapy as etoposide, cyclophosfamide and novel targeted agents as lenalidomide and ibrutinib, may be considered; high dose of corticosteroids for four days, repeated as needed, or RT for symptomatic or large masses, tend to be favored as they avoid additional unnecessary myelosuppression in patients that are highly chemorefractory.33

It is still unclear if BT affects the outcome of CAR-T cell therapy.34 The US Lymphoma CAR-T Consortium retrospectively evaluated the influence of BT in 298 R/R DLBCL cases intended to be treated with axi-cel at 17 academic institutions. BT, which was not permitted in the ZUMA-1 trial and led to axi-cel approval, was used in 53% of the patients. Of these, 54% received chemotherapy with or without other therapies, 23% used corticosteroids, 12% received RT with or without corticosteroids, and 10% underwent targeted therapies, such as lenalidomide or ibrutinib alone. BT was associated with worse OS. Patients who received BT were more likely to have poor prognostic features at the time of apheresis, such as ECOG performance status of 2–3, international prognostic index (IPI) ≥ 3, bulky disease, or elevated LDH.11

Preclinical studies have suggested potential synergy between RT and CAR-T cell therapy. Low doses of RT appear to sensitize negative tumor cells to antigen for CAR-T mediated apoptosis by making tumor cells susceptible to cell death mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).35 RT also enhances cytotoxic T-cell migration to irradiated areas, reverses T-cell exhaustion, and diversifies the T-cell receptor repertoire of tumor infiltrating lymphocytes (TIL).36 In addition, complementary immunomodulatory activity, through induction of increased major histocompatibility complex (MHC)-1 expression and release of antigen by irradiated cells, may enhance tumor-specific immunity in irradiated and distant sites.31,37

Retrospective studies have evaluated the role of RT as BT for CAR-T cell therapy. In a retrospective review of 12 patients intended to receive RT as bridging prior to axi-cel therapy, 10 received RT after apheresis and 7 received concurrent systemic treatment. Eleven patients successfully received axi-cel infusion. There was a trend toward the decrease of PFS in 1-year among those who received any type of BT (29% compared to 44% for those who did not receive BT (p = 0.06).38 In a second review of 148 patients, 124 (84%) were successfully treated with CAR-T cell therapy, half required BT. Single modality RT bridging (n = 11, 65%) was associated with higher OR and CR rates, compared to systemic therapy alone (n = 6, 35%) (OR of 100% x 67%, p = 0.03 and CR of 82% x 38%, p = 0.01) and compared to the non-bridging cohort (n = 62) (OR of 100% x 82%, p = 0.13 and CR of 82% x 48%, p = 0.04).34,39

In a third retrospective study of 46 patients with R/R DLBCL treated with commercial anti-CD19 CAR T-cells – axi-cel (n = 21), tisa-cel (n = 25), BT was divided in two groups: high intensity BT (HI), including chemotherapy +/- immunotherapy, and low intensity BT (LI), including the monoclonal antibodies rituximab and brentuximab, lenalidomide and dexamethasone. Thirty patients (65%) received HI and 16 (35%) received LI or no bridging therapy. Patients who received HI had worse prognostic factors. Only 2 of the 46 patients could not receive CAR-T cell infusion as planned. There was no difference in response to cellular therapy between HI and LI groups with 57% progressing during BT. CRS and ICANS rates were higher in the HI group.40

New agents have also been tested as BT. In a retrospective study of 26 German centers, polatuzumab vedotin with bendamustine and rituximab (Pola-BR) was used as BT in 41 patients. In this cohort, 51.2% of patients were successfully bridged to intended CAR T-cell therapy resulting in a 6-month OS of 77.9% from the beginning of BT. Polatuzumab vedotin alone demonstrated ORR of 40% and may be considered a BT option as well.41

Finally, the T-cell modulation effect of ibrutinib may impact CAR-T cell outcomes. In human xenograft models of resistant acute lymphoblastic leukemia (ALL) and CLL, ibrutinib improved CAR T-cell engraftment and tumor clearance. In a phase 1/2 trial of patients with R/R CLL, the introduction of ibrutinib in CAR-T cell therapy decreased incidence of severe CRS and increased the response rate (88% versus 56%, p = 0.06), making ibrutinib an interesting BT strategy in CLL and MCL.42 Ongoing studies are evaluating the clinical significance of these findings. It is also important to note that this effect may not be universal to all agents in the class once newer molecules have more selective BTK inhibition.

Several challenges are expected to the successful implementation of this modality of cellular therapy in emerging countries where public and private health systems coexist, such as Brazil.

The four commercially available anti-CD19 CAR-T cell products in the United States are priced between US$ 373,000 and US$ 475,000 for manufacturing alone.43,44 Separate ancillary, provider, and hospital charges can easily double the cost associated with these interventions. Reimbursement modalities based on outcomes have been implemented in multiple countries including the United States44 and Europe45 and seem to be the best approach to minimize this financial impact. Still, cost-effectiveness studies have demonstrated that CAR-T cell therapy can be cost-effective when compared to multiple consecutive treatment lines, which are also associated with high costs but inferior outcomes when compared to CAR-T cells.44,46

While alternatives to commercial products, such as research protocols with locally manufactured products, may improve the access in a public healthcare system, such initiatives still demand significant financial and intellectual investment.

Structure and quality represent additional expected barriers. Accreditation programs, such as FACT, JACIE and AABB, recommended for CAR-T centers, as well as extensive multi-disciplinary training and infrastructure adjustments for cell processing push up implementation costs.33 Therefore, it has been a natural trend in Europe and the United States to have cellular therapy centers developed in sites with extensive allo-HSCT expertise. Logistics will be another particularly important barrier to the implementation of CAR-T cell therapy in Brazil as patient referral to specialized centers will be challenging in a country with continental dimensions and limited resources.

Despite all challenges, CAR-T cell therapy is expected to be available soon for lymphoma patients in Brazil. Patient registry and post marketing studies must be considered as an important tool for surveillance of outcomes and progressive refinement of the processes involved.33,46