Tafasitamab for the treatment of patients with diffuse large B-cell lymphoma

ABSTRACT

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) require additional treatments, especially those not eligible or not responding to high dose cytotoxic chemotherapy and stem cell transplantation. Over the last few years, several new treatments have been developed and approved for these patients, among them of particular relevance are those targeting CD19. Tafasitamab is a humanized monoclonal antibody targeting CD19, composed of a modified fragment crystallizable (Fc) region engineered with higher affinity for Fc gamma receptors (FcγR) receptors, leading to increased cytotoxicity through natural killer cells and macrophages (antibody-dependent cellular cytotoxicity and antibody-dependent cell-mediated phagocytosis). In this product review, we will discuss its mechanism of action, safety profile and efficacy results from clinical trials that led to its approval in combination with lenalidomide for patients with R/R DLBCL ineligible for high-dose chemotherapy and autologous transplantation.

KEYWORDS:

• DLBCL
• relapsed-refractory disease; monoclonal antibodies
• Anti CD-19 agent
• Tafasitamab

Introduction

Diffuse large B-cell lymphoma is the most common subtype accounting for 30–40% of non-Hodgkin’s lymphoma (NHL) cases in the Western countries.¹

It is an heterogeneous disease presenting subtypes with distinct molecular features, clinical behavior and outcome.^2,3 The most common first-line therapy is represented by the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), which has been the backbone of first-line therapy of DLBCL for more than 20 years. Despite several efforts and many clinical trials, no new regimen has been able to replace R-CHOP as the standard first-line treatment for all patients with DLBCL so far.⁴ Recently the combination of the antibody drug conjugate polatuzumab vedotin to R-CHP (R-CHOP with omission of vincristine) showed a significant improvement in progression free survival (PFS) over R-CHOP in DLBCL patients however without improvement in overall survival (OS).⁵

Unfortunately, 35–40% of patients relapse after initial treatment with an estimated 12-month survival of less than 30%.⁶ The management of relapsed and refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) has long represented an unmet medical need.

Until a few years ago, the standard treatment for patients with R/R DLBCL was represented by salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) in young and fit patients with chemotherapy-sensitive relapse.

However, only a minority of patients could be treated with ASCT because most of them were not eligible due to advanced age, comorbidities, or failure to achieve a good response to salvage chemotherapy.⁷ However, even among those patients who are able to receive ASCT, relapses can occur, and additional therapies are needed. The prognosis of patients who are ineligible for ASCT or relapse after ASCT is dismal.

Over the last years several new therapeutic strategies have been developed and some of them introduced in the standard care of patients with R/R disease. The most significant achievement has been the introduction of chimeric antigen receptor T-cell (CAR-T) therapy. Three CD19 directed CAR-T constructs have been approved for the treatment of patients with DLBCL relapsed after at least two prior lines of treatment. More recently, randomized studies have shown significant superiority of two products (axicabtagene ciloleucel and lisocabtagene maraleucel) over the standard second-line therapy represented by ASCT in patients with primary refractory disease or relapse within 12 months of first-line chemoimmunotherapy showing a potential curative effect and leading to their approval also in this setting.⁸

Although CAR-T cell therapies may offer durable responses, there are some important limitations to consider, including adverse events (in particular neurological toxicity and cytokine release syndrome), manufacturing time limiting treatment opportunities in patients with rapidly progressing disease, and finally very high costs.^9,10 Consequently, it is possible that only selected patients may benefit from CAR-T therapy. Furthermore updated follow-up from clinical trials shows that while patients achieving complete remission after CAR-T cells may maintain this remission for long time, those patients achieving partial response or not responding to CAR-T therapy will need additional therapies.

In addition to CAR T cell therapy, various salvage treatments based on novel therapeutic agents have been made available in recent years for patients with R/R DLBCL, while others are in clinical development. These new therapies comprise antibody-drug conjugates (ADCs), small molecules and bispecific antibodies and can be used based on state of approval and patient and disease characteristics.

Polatuzumab vedotin, an anti‐CD79b antibody‐drug conjugate (ADC), was approved in 2019 in combination with bendamustine and rituximab for the treatment of adult patients with R/R DLBCL, not otherwise specified, after at least two prior therapies. In the phase II trial thaat led to its approval a high complete remission rate was observed (40%) but over half of the responders progressed in the first year. In addition, treatment was associated with significant neurological toxicity (peripheral neuropathy in 40%) and serious infections (grade 3 or higher pneumonia in 16% and or sepsis in 7%).¹¹ Another ADC, loncastuximab tesirine, a CD19-directed antibody – drug conjugate, has been approved for patients with R/R DLBCL based on the results of a phase II trial showing overall response rate (ORR) of 48·3% and an acceptable safety profile.¹² In addition to these ADCs, an oral selective inhibitor of nuclear export, selinexor, was approved based on the results of a phase II study which showed an ORR of 28% and CR rate of 12% in patients with R/R DLBCL.¹³

Other treatments, such as ibrutinib and the combination of lenalidomide with rituximab, have demonstrated activity in non-GCB DLBCL but they are not currently approved.¹⁴

Finally, bispecific CD20-CD3 targeting monoclonal antibodies like glofitamab and epcoritamab which link and activate T cells on tumor targets demonstrated very high overall and complete remission rates in patients with R/R disease, including patients previously failing CAR-T and are being successfully introduced as monotherapy in the management of patients with R/R DLBCL.^15,16 A third T-cell engager CD20×CD3 bispecific antibody, mosunetuzumab, which is approved for patients with R/R Follicular Lymphoma (FL), showed also efficacy and a manageable safety profile in patients with R/R DLBCL, including those failing CAR-T cells.¹⁷

Another combination that has recently gained approval for patients with relapsed or refractory disease is represented by the anti-CD19 monoclonal antibody tafasitamab with lenalidomide. Here we will review the main efficacy and safety results of tafasitamab in patients with R/R DLBCL.

Tafasitamab

Tafasitamab (MOR00208/MOR208/XmAb5574/tafasitamab-cxix) is an Fc-modified, humanized monoclonal antibody (mAb) directed against the pan B-cell antigen CD19.

CD19 is a B-cell surface glycoprotein expressed throughout B-cell development in most B-cell lymphomas, including DLBCL^18,19 and plays a critical role in B-cell signaling, antigen-induced responses, and tolerance induction.²⁰ The interaction between Fc antibody chain and FcγR on immune effector cells such as natural killer (NK) cells, macrophages and γδ T cells is responsible for antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) respectively. For this reason, the development of tafasitamab in hematological malignances is based on the modification of human Fc.²¹ Fc modification resulted in increased binding affinity to Fc receptors on effector cells, enhancing ADCC, ADCP and direct cytotoxic effects.²² Compared with the binding affinity of a comparative humanized Ab monoclonal, XENP5603, the binding affinity of tafasitamab for FcγRIIIa was found to be 37-fold increased and 137-fold for the 158 V and 158F alleles, respectively. The superiority of the binding affinity of tafasitamab was also shown in the comparison of binding to FcγRIIa, which showed that the affinity of tafasitamab increased 11-fold and 6-fold for the 131 R and 131 H alleles, respectively. Based on these properties, tafasitamab showed an average increase efficacy of 2–3 log10 in ADCC assays, depending on the target cell type, and approximately 10-fold increase in ADCP activity compared with XENP5603. Ab-mediated complement dependent cytotoxicity was not observed for either tafasitamab or XENP5603. Of note, binding of CD19 with tafasitamab was associated with minimal internalization of the receptor, which could have an impact on the antibody effector function.^22,23

Pharmacodynamics

In vitro, tafasitamab has shown potential to induce a more effective ADCC activity than a non-engineered anti-CD19 antibody for killing of cancer cells from patients with acute lymphoblastic leukemia (ALL) and mantle cell lymphoma²² and also a 10-fold increase in ADCP compared with the IgG1 analog in monocyte-derived macrophages and two ALL cell lines.²³

Results of the open-label phase I/IIa trial in 27 patients with R/R chronic lymphocytic leukemia (CLL) showed that tafasitamab treatment does not induce loss of CD19 expression on CLL cells before and after cessation of drug treatment. After tafasitamab treatment, mean CD19 expression levels were evaluable from 14/27 patients. Relative median CD19 expression level was 109% (range 71–166%) when compared to baseline CD19 expression levels.²⁴

Tafasitamab and MG4101 allogeneic NK cells were co-administered in Raji and Ramos NHL xenograft models resulted in survival benefit over monotherapy with tafasitamab or MG4101, showing that adoptive cell transfer of ex vivo expanded allogeneic NK cells or autologous γδ T cells in combination with tafasitamab treatment may enhance the antitumor effect of tafasitamab.²⁵

In a Burkitt lymphoma (BL) model, the combination of tafasitamab and CD47/SIRPα checkpoint blockade enhanced ADCP activity of primary M2 macrophages on BL-derived Ramos cells, compared with the anti-CD47 mAb or tafasitamab single agents. The in vivo combination of tafasitamab and anti-CD47 mAb was associated with significant increase in anti-tumor activity. In the Ramos disseminated survival model, the combination showed an increased life span (ILS) of >182% compared with tafasitamab monotherapy and an overall survival of all animals treated with the combination (15/15) until the end of the study (Day 99 post-cell injection). In the Ramos subcutaneous tumor model, the combination resulted in a significant delay in tumor growth compared with the tafasitamab or anti-CD47 mAb single agent (ILS >175% tafasitamab and ILS >72% anti-CD47 mAb vs tafasitamab + B6H12).²⁶

Furthermore, important lines of preclinical evidence have supported the combination of tafasitamab with the immunomodulatory agent lenalidomide.

XmAb5574 mediates strong ADCC, modest direct cytotoxicity, and antibody-dependent cellular phagocytosis but not complement-mediated cytotoxicity against CLL cells. The XmAb5574- dependent ADCC is mediated by natural killer (NK) cells through a granzyme B – dependent mechanism. The NK cell-mediated cytolytic and secretory function with XmAb5574 is characterized by enhanced NK-cell activation, interferon production, extracellular signal- regulated kinase phosphorylation down- stream of Fc receptor, and no increased NK-cell apoptosis. Notably, enhanced NK cell-mediated ADCC with XmAb5574 was enhanced further by lenalidomide providing strong support for the clinical development of XmAb5574 in combination with lenalidomide for CD19 B-cell malignancies.²⁷

Results of an in vitro study showed that pre-treatment of macrophages with lenalidomide enhanced tafasitamab-associated cytotoxicity by 3–5 fold in lymphoma cell lines and autologous lymphoma cells, in comparison with lenalidomide alone or target-cell modification of CD19 expression.²⁸

Efficacy results

Phase I trials

A first in human phase 1 trial evaluated tafasitamab in patients with R/RCLL. Twenty-seven patients were enrolled over 6 escalating dose levels, with expansion at the highest dose level of 12 mg/kg. Treatment was well tolerated, with no maximum tolerated dose and the recommended phase II dose (RP2D) was established at 12 mg/kg weekly. Preliminary activity was observed with clinical and laboratory responses in 18 patients (66.7%) and radiological responses in 8 patients (29.6%).²⁹

More recently, results of the Phase 1b First-MIND study were reported. This trial assessed the safety and preliminary efficacy of tafasitamab in combination with R-CHOP ± lenalidomide in patients with newly-diagnosed DLBCL. Primary endpoint was safety, while ORR and complete response rate were secondary endpoints. The study enrolled 66 patients and randomized 33 patients in each arm. The most common treatment emergent adverse events were hematologic. With regards to efficacy, at the end of treatment ORR was 75.8% (CR 72.7%) in the arm without lenalidomide and 81.8% (CR 66.7%) in the arm containing also lenalidomide. Progression-free survival (PFS) and OS at 24 months were 72.7% and 90.3% in the R-CHOP with tafasitamab arm, and 76.8% and 93.8% in the R-CHOP-tafasitamab and lenalidomide arm respectively³⁰ (Table 1). Despite these preliminary results, no solid efficacy conclusions can be made from this phase I trial and in particular this trial was not designed to compare the efficacy of the two treatment arms.³¹

Table 1. Main results of tafasitamab trials in DLBCL.

Trial	NCT	Phase	Setting	Regimen	ORR	PFS
First-MIND^Citation28	NCT04134936	Ib	1 L DLBCL	6 × q21 tafa +R-CHOP ± lenalidomide (25 mg/day, days 1–10)	75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L;
MOR208C201^Citation29	NCT01685008	II	R/R NHL	Tafa weekly C1–3; extended treatment available for responding patients	26% in DLBCL cohort	median PFS 2.7 months (95% CI 2.1–15.4)
L-MIND^Citation32	NCT02399085	II	R/R DLBCL	12 × q28 cycles of tafa + lenalidomide (25 mg/day, Days 1–21), then tafa monotherapy	ORR was 57.5%, with CR of 41.3%	Median PFS 11.6 months (95% CI, 5.7–45.7)

Legend: DLBCL: diffuse large B cell Lymphoma, R/R: relapsed and refractory; NHL: non Hodgkin lymphoma; ORR: objective response rate, PFS: progression free survival.

Other phase I trials are ongoing including a trial evaluating tafasitamab and lenalidomide with maplirpacept (PF-07901801), an anti-CD47 soluble recombinant fusion protein, in patients with R/R DLBCL not eligible for ASCT or unable to receive approved chimeric antigen receptor T-cell (CAR-T) therapy (Table 2).

Table 2. Ongoing trial tafasitamab-based in DLBCL.

NCT	Phase	Setting	Regimen	Status (Sep 2023)
NCT05626322	Ib, II	R/R DLBCL	Maplirpacept (anti CD47) weekly C1-C3 then every 2 weeks. Tafa weekly C1-C3 and then every 2 weeks. Lenalidomide d1-d21, q28 up to C12	Recruiting
NCT04661007	Ib, II	R/R DLBCL	Tafa alone, tafa + lenalidomide, tafa + parsaclisib and tafa + lenalidomide in combination with R-CHOP in Japanese participants	Recruiting
NCT04974216	II	1 L DLBCL elderly pts	12 cycles q28. From C1 to C6: rituximab + tafa + lenalidomide and from C7 to C12: tafa and lenalidomide	Recruiting
NCT04824092	II	1 L DLBCL (high, intermediate risk)	6 × q21 R-CHOP ± lenalidomide (25 mg/day, days 1–10) + tafa weekly	Active, not recruiting
NCT02763319	II/III	R/R DLBCL	Tafa + bendamustine vs R-Bendamustine	Active, not recruiting
NCT04978584	II	1 L non-GCB DLBCL	4 × q21 R (D1)+lenalidomide (d1–10) + acalabrutinib (d1-d21) + tafa weekly vs 6 × q21 R-CHOP (D1) + lenalidomide (d1–10)+acalabrutinib (d1-d21) + tafa weekly	Recruiting

Legend: DLBCL: diffuse large B cell Lymphoma, Non-GCB: non germinal center B, R/R: relapsed and refractory; pts: patients.

J-MIND is another ongoing phase 1b/2 trial that is evaluating tafasitamab alone, tafasitamab plus lenalidomide, tafasitamab plus parsaclisib and tafasitamab plus lenalidomide in combination with R-CHOP in Japanese participants with NHL. This is an open-label, multicenter, clinical trial designed to assess the safety and tolerability, determine the RP2Ds, and assess the pharmacokinetic (PK) profile of tafasitamab single agent and in various combinations in Japanese subjects with NHL, and to assess preliminary efficacy in patients with R/R DLBCL. The study recruitment is open (Table 2).

Phase II trials

The MOR208C201 phase II trial evaluated the activity of tafasitamab monotherapy in relapsed/refractory patients with different types of NHL after at least one prior therapy. A total of 92 patients were enrolled; among them 35 had DLBCL, 12 mantle cell lymphoma (MCL), 34 follicular lymphoma and 11 other indolent NHLs. Patients received tafasitamb 12 mg/kg weekly for the first three 28-days cycles; at the end of the third cycle, responding patients proceeded treatment with tafasitamab (either monthly or every second week) until disease progression. In the DLBCL cohort, the response rate was 26% and median DoR was 20.1 months; median PFS was 2.7 months (95% confidence interval [CI] 2.1–13.2 months). Similar PFS was observed in rituximab-refractory as well as non-refractory patients. Subjects with a baseline peripheral natural killer cell count (NKCC) above 100 cells/μL had longer PFS compared to subjects with fewer than 100 NK cells/μL³² (Table 1).

MOR208C203 (L-MIND) is a phase II trial which evaluated the safety and efficacy of tafasitamb in combination with lenalidomide in patients with R/R DLBCL, excluding double- or triple-hit DLBCLs. The study enrolled patients that had relapsed after at least one but no more than three prior systemic therapies and who were not candidates for high-dose chemotherapy (HDC) and ASCT. Treatment consisted of tafasitamab (12 mg/kg once weekly for the first 3 cycles, bi-weekly after the 4^th cycle) and lenalidomide (25 mg/day orally, days 1–21) for up to twelve 28-day cycles, followed by tafasitamab monotherapy until disease progression in responding patients. The primary endpoint was centrally assessed objective response rate.³³ Eighty-one patients were enrolled. Among them, 49% (n = 40/81) received one previous therapy and 19% had primary refractory disease (defined as progression within 6 months after completing first line of therapy). The primary analysis with a median follow-up of 13.2 months, showed an objective response rate (ORR) of 60%, with 43% of patients achieving CR and a median duration of response (DoR) of 21.7 months. Notably, ORR was 70% in patients who had received only one prior line of therapy, 50% in patients with ≥ 2 prior lines and 60% in patients with primary refractory disease. Median PFS was 12.1 months (95% CI 2.3–NR).³³

Main limitations of this trial derive from its design as single-arm phase II trial, making it difficult to make any comparisons with other treatment options for patients with R/R disease and the inclusion of relatively few patients with high-risk features (primary refractory disease and double-triple hit lymphomas represented 19% and 2% respectively of the patient population). In addition, patients with low-intermediated International Prognostic Index (IPI) showed an improved response rate in comparison to patients with intermediate – high or high-risk IPI score suggesting that the benefit of the combination may be different among different groups of patients with DLBCL and additional trials would be needed to further clarify.³³

Based on these results, tafasitamab was approved in combination with lenalidomide followed by tafasitamab monotherapy for the treatment of adult patients with R/R DLBCL ineligible for ASCT,under accelerated approval by FDA in July 2020 and conditional marketing authorization in Europe in August 2021.

Follow-up results of this study at 3 years confirmed durable responses with ORR of 57.5%, CR rate of 40% and median DoR of 43.9 month,³⁴ results that were confirmed also subsequently with the final 5 years follow up analysis which showed a persistent benefit and durable efficacy. At the data cutoff on November 14, 2022, ORR was 57.5%, CR 41.3%. With median follow-up of 44.0 months, median DoR was not reached. Median PFS was 11.6 months [95% CI, 5.7–45.7], and median OS was 33.5 months [95% CI, 18.3–NR]³⁵ (Table 1).

Several phase II trials with tafasitamab are currently ongoing (Table 2). A phase II trial evaluating tafasitamab and lenalidomide in combination with plamotamab, an anti-CD20 × CD3 bispecific antibody, in patients with R/R DLBCL unfortunately has been terminated early by the sponsor due to business decision.

Phase III trials

Following results of phase I and II trials, tafasitamab has entered clinical evaluation in phase III trials in different lymphoma subtypes and results are awaited. Among them a phase III trial in patients with R/R FL comparing rituximab-lenalidomide-tafasitamab versus rituximab-lenalidomide and the phase III frontMIND trial which is comparing R-CHOP to R-CHOP plus tafasitamab-lenalidomide in patients with newly diagnosed high-risk DLBCL³⁶ (Table 2).

Evidence from real-world studies

In addition to prospective clinical trials, important information regarding the use of tafasitamab has derived also from real-world studies. RE-MIND (NCT04150328) is an observational, real-world, retrospective cohort study of lenalidomide monotherapy in R/R DLBCL ineligible for ASCT in comparison with tafasitamab lenalidomide – treated patients. Patients enrolled in the study met the same eligibility criteria as those in the L-MIND study. The primary endpoint was investigator-assessed ORR and secondary endpoints included CR rate, PFS and OS. Among collected data from 490 patients treated with lenalidomide single agent, 140 matched the L-MIND study criteria. For the primary analysis 76 patients (receiving lenalidomide 25 mg/day) from each cohort were considered. An ORR of 67% (95% confidence interval, 55.4–77.5) in the combination arm in comparison to the ORR of 34.2% (23.7–46.0) for lenalidomide alone (p < .0001) were reported. In addition, the CR rate was significantly higher in tafasitamab-lenalidoide treated patients 39.5% versus 13.2% in lenalidomide only treated patients. Progression-free survival and OS were also significantly improved with the combination therapy (PFS: HR 0.463 [95% CI 0.307–0.698], p = .0002; OS: HR 0.499 [95% CI 0.317–0.785], p = .0026).³⁷ The outcome of patients who received lenalidomide monotherapy were similar to previously published data.^37–40

A second large observational, retrospective study RE-MIND2 (NCT04697160) compared outcomes of patients treated with tafasitamab and lenalidomide in the L-MIND (NCT02399085) trial with those of patients receiving other therapies for R/R DLBCL (receiving ≥2 systemic therapies), ineligible for ASCT. This study reported outcomes for three pre-specified treatments not assessed in the RE-MIND study which included treatment with polatuzumab vedotin in combination with bendamustine and rituximab (pola-BR), rituximab in combination with lenalidomide (R²), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The OS was the primary endpoint. A total of 3454 patients were enrolled. After applying the eligibility and matching criteria, 44 patients treated with pola-BR, 47 with R² and 71 patients receiving CAR-T, were eligible for matching from the observational cohort. Tafasitamab in combination with lenalidomide appeared to improve survival outcomes versus pola-BR and R² (HR: 0.441; p = .034; (HR: 0.435; p = .012, respectively), and had superimposable outcomes when compared to CAR-T cohort (HR: 0.953, p = .892).⁴¹

A more recently published paper showed the results of another multicentric real-world study which evaluated the efficacy of tafasitamab-lenalidomide in R/R LBCL. In this retrospective study, patients treated with Tafasitamab-Lenalidomide had higher rates of comorbidities showing a lower progression-free survival and overall survival, compared to the L-MIND registration clinical trial.⁴²

Safety

The tafasitamab good safety profile was initially shown in the first phase I trial in patients with CLL. As mentioned above, no maximum tolerated dose was identified and the drug was well tolerated with infusion reactions of grade 1–2 as the most common adverse events.⁴³ Similar results were reported in the phase II single-agent trial in patients with different types of R/RNHL; among 92 patients enrolled, most common adverse events of any grade were infusion-related reactions (12%) and neutropenia (12%). A grade 4 infusion-related reaction was experienced by only one patient while eight patients (9%) experienced grade 3/4 neutropenia. Of note, no treatment-related deaths were reported.³²

In the registration L-MIND trial, 81 patients received at least one dose of either drug and were evaluated for safety. All patients experienced treatment-emergent adverse events of any grade. The most common adverse event (AE) of all grades was neutropenia occurring in 48% of patients (N = 39), that was well managed with G-CSF administration. Other grade 3 or higher AEs thrombocytopenia, febrile neutropenia, leukopenia, anemia, and pneumonia. Non-hematologic AEs were mainly mild to moderate and included diarrhea and rash. Serious adverse events occurred in 51% (41/81) of patients and the most frequently reported were pneumonia (five [6%]), febrile neutropenia (five [6%]), pulmonary embolism (three [4%]), bronchitis (two [2%]), atrial fibrillation (two [2%]), and congestive cardiac failure (two [2%]). Drug related serious adverse occurred in 15 (19%) patients.

The rate and severity of AEs decreased following lenalidomide discontinuation (as per protocol or earlier in case of toxicities) in patients receiving only tafasitamab as evidenced by the fact that grade 3–4 AEs occurred in 70% of patients during the combination therapy versus 29% after lenalidomide discontinuation.³³

In trials reporting more mature follow-up data no further emergent safety signals were observed, where AEs were consistent with the previous analysis and showing a decreased frequency during tafasitamab monotherapy as mentioned above.⁴¹

Approval status and conclusion

In July 2020, the Food and Drug Administration granted accelerated approval to tafasitamab in combination with lenalidomide for adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, not eligible for ASCT. The approval was based on the results of L-MIND study. The European Medicines Agency approved with conditional authorization tafasitamab with lenalidomide, followed by tafasitamab monotherapy, for adult patients with R/R DLBCL who are not candidates for ASCT.

For patients with R/R DLBCL salvage chemotherapy followed by high-dose chemotherapy and ASCT has been the standard of care for many years. Unfortunately this approach was able to cure only a minority of patients failing first line therapy. Over the last years, new treatment approaches have emerged for these patients. In particular CAR-T cells have shown significant activity and at least two products were shown superior to ASCT in second line. Furthermore, other treatment options including ADCs and bispecific antibodies have shown activity in patients failing prior therapies including more recently also patients failing CARTs.

Tafasitamab in combination with lenalidomide has shown a favorable safety profile and efficacy in patients with R/R DLBCL. The combination is recommended by international treatment guidelines for patients with R/R DLBCL ineligible for ASCT. Given the increased accessibility to CAR-T therapy in this setting, these different salvage treatments are not mutually exclusive. However, the optimal treatment sequencing strategy remains still to be established.

Author contributions

MCP, AS, EZ wrote and revised the manuscript.

Disclosure statement

MCP: travel grant from BeiGene, Institutional funding for clinical trial Incyte; AS: Institutional funding for clinical trials: Abbvie; ADC Therapeutics; Amgen, Astra Zeneca; Bayer; Cellestia; Incyte, Loxo Oncology; Merck MSD; Novartis; Pfizer; Philogen; Roche; Consultant/expert testimony/advisory board: Debiopharm, Janssen, AstraZeneca, Incyte, Eli Lilly, Novartis, Roche, Loxo Oncology. Travel grant: Incyte; Astra Zeneca; EZ: honoraria from AstraZeneca, BeiGene, Celgene, Incyte, Janssen, Merck, Roche AbbVie, Miltenyi Biomedicine, Celltrion HealthCare, Kite, A Gilead Company.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.