Fitting Loncastuximab Into the Current Landscape of R/R DLBCL

CASE

• A 73-year-old woman presented with fever, headaches, and 7-lb unintentional weight loss​.
• Medical history: no family history of cancer, and hyperlipidemia that was well controlled with simvastatin.
• Physical examination: palpable bilateral cervical lymphadenopathy​
• Laboratory results: lactate dehydrogenase (LDH) s265 U/L (280 U/L upper limit); Hemoglobin 10.8 g/dL; bilirubin 1.3 mg/dL (1.2 mg/dL upper limit); creatinine 1.7 mg/dL (1.2 mg/dL upper limit); all others within normal limit​
• Hepatitis B, C and HIV negative​
• Lymph node biopsy; immunohistochemistry panel: CD 10+, CD 20+, which confirmed diffuse large B-cell lymphoma (DLBCL).
• Fluorescence in situ hybridization: negative for rearrangements of BCL6, BCL2 and C-MYC​
• Whole body PET/CT scan showed diffuse adenopathy, largest node 3.9 cm.
• MRI of the brain showed no evidence of lesions​.
• ECOG performance status: 1​
• Stage III disease; International Prognostic Index (IPI) score 2: low-intermediate risk​
• Patient received 6 cycles of R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin)], and vincristine sulfate (Oncovin), which was well tolerated​.
• She had a complete response (CR) at the end of treatment, but 1 year later the patient presented with diffuse lymphadenopathy, confirmed by PET CT scan​.
• Biopsy showed relapse of the same DLBCL​.
• Patient received 6 cycles of polatuzumab vedotin (Polivy), bendamustine (Bendeka), and rituximab (Pola-BR).
• Had stable disease for 6 to 8 months before progression​.
• Current treatment:​ loncastuximab tesirine-lpyl (Zynlonta)

Targeted Oncology: What is the current landscape for the treatment of patients with DLBCL?

EMILY AYERS, MD​: In the first-line setting, patients who are transplant eligible should be treated with chemoimmunotherapy.1 Some of the recommended regimens [for these patients] include R-CHOP, rituximab, cyclophosphamide, doxorubicin, and prednisone [R-CHP], and polatuzumab vedotin [plus] R-CHP. Then in the second-line setting, the major branch point is the [patient’s] time to relapse, so whether the patient relapses early, within a year of their first-line therapy or late. In addition to that, whether they are transplant eligible or ineligible.

Emily Ayers, MD​

Assistant Professor

Emily Couric Clinical Cancer Center

University of Virginia Health​

Charlottesville, VA

For those patients who had a late relapse and are transplant eligible, they often get second-line salvage immunochemotherapy. For those patients with chemotherapy-sensitive disease, they end up with stem cell transplant. For those patients with early relapse disease, some of the new data from a couple years ago demonstrates that chimeric antigen receptor [CAR] T-cell therapy for patients who are eligible, and have access [to it], should be the standard of care.²

How do these treatment considerations change if the patient is transplant ineligible?

For those patients who are transplant ineligible, there is a CAR T-cell product they can get, but a lot of these patients end up either getting rituximab with chemotherapy in the second-line setting, or additional non-chemotherapy based options that are approved in this setting.1 In the third-line setting and beyond, some of the recent advances over the last few years include CAR T-cell therapy, tafasitamab-cxix [Monjuvi]/lenalidomide [Revlimid], polatuzumab vedotin-piiq plus or minus bendamustine/rituximab, loncastuximab, selinexor [Xpovio], which is an oral therapy, and pembrolizumab [Keytruda] for patients with primary mediastinal large B-cell lymphoma.1 Ibrutinib [Imbruvica] is used in some select cases, and 2 different bispecific antibodies that were recently approved [are used in some cases] as well.^3,4

How does the IPI and other risk stratification measures factor into treatment decisions?

There are several different IPI scores, as this is how we risk stratify patients [with DLBCL] in the first-line setting.¹ The IPI scores date back many decades at this point to the early 1990s, and the standard IPI has 5 different factors to it including, age, LDH, performance status, disease stage, and extra nodal involvement at more than 1 site.¹ Then, you can risk stratify patients, according to the number of risk factors that they have into low, low-intermediate, high-intermediate, or high [risk categories].¹

What other risk stratification methods are there to consider?

Over the last few decades, there have been several different ways that this has been changed. There's an age-adjusted IPI for patients younger than the age of 60;⁵ there’s also a stage modified IPI score,⁶ and then there is the NCCN IPI score that...further subdivides age and LDH into 3 different categories instead of just 2 categories, and you have a risk score from 0 to 6 in this setting.⁷ The Pola-R-CHP [regimen] has the approval for IPI 2 and beyond, so I sometimes calculate [risk] in that setting, but I have not adopted the updated IPIs for whatever reason. I think that we can do a lot better in terms of risk stratifying patients up front with molecular data.

What led to the FDA approval of loncastuximab in DLBCL?

Loncastuximab was approved following the...phase 2 LOTIS-2 study [NCT03589469], which included patients with relapsed and refractory DLBCL in the third-line setting and beyond.^8,9 [To be eligible for the trial], patients had to have at least 2 prior lines of therapy.⁹ Patients who had prior CD19-directed therapy did have to have a biopsy to prove CD19 positivity prior to treatment on the study; they also had to have a good performance status and patients were allowed [on the study] if they were either transplant eligible or ineligible. [Patients were enrolled on the study] at least a month after their transplant, or 60 days after allogeneic transplant.⁹

Of note, they allowed patients with primary refractory disease as well, which is different compared with the L-MIND study [NCT02399085].10 Loncastuximab was given every 3 weeks for up to a year. It is a finite treatment and is not given until disease progression.9 [Patients were given] a dose of 0.15 mg/kg for the first 2 cycles, and then the dose droped down [to 0.075 mg/kg] for all subsequent cycles. The primary end point [of the study] was overall response rate with secondary end points including duration of response, complete response rates, and then survival and safety data.⁹

References:

1. National Comprehensive Cancer Network. B-cell lymphomas; version 1.2024. https://tinyurl.com/nvndmfnc
2. Boardman AP, Salles G. CAR T-cell therapy in large B cell lymphoma. Hematol Oncol. 2023;41:(suppl 1):112-118. doi:10.1002/hon.3153
3. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. News release. FDA. May 19, 2023. Accessed March 21, 2024. http://tinyurl.com/mrrfzf7j
4. FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refractory large B-cell lymphomas. News release. FDA. June 16, 2023. Accessed March 21, 2024. http://tinyurl.com/446mnbr3
5. International Non-Hodgkin's Lymphoma Prognostic Factors Project; A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329(14):987-94. doi:10.1056/NEJM199309303291402
6. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998;339(1):6-21. doi:10.1056/NEJM199807023390104
7. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837-42. doi:10.1182/blood-2013-09-524108
8. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. News release. FDA. April 23, 2021. Accessed March 21, 2024. http://tinyurl.com/2mh48j2r
9. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X
10. Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study. Haematologica. 2024;109(2):553-566. doi:10.3324/haematol.2023.283480