Physicians Consider Loncastuximab for Older Patients With R/R DLBCL

Paolo Strati, MD

Assistant Professor

Department of Lymphoma/Myeloma

The University of Texas MD Anderson Cancer Center

Houston, TX

CASE SUMMARY:

A 73-year-old woman presented with fever, headaches, and 7-lb unintentional weight loss​. She was married with 2 grown children who live in other states and the primary caretaker for her mother who has advanced dementia, with no family history of cancer. She had hyperlipidemia, well controlled with simvastatin. Physical examination showed palpable bilateral cervical lymphadenopathy​. Laboratory results included lactate dehydrogenase of 300 U/L (280 U/L upper limit); hemoglobin of 10.8 g/dL; bilirubin 1.3 mg/dL (1.2 mg/dL upper limit); and creatinine 1.7 mg/dL (1.2 mg/dL upper limit); with all others within normal limits. She was negative for hepatitis B, C, and HIV. A lymph node biopsy with immunohistochemistry panel showed she had CD10+, CD20+ confirmed diffuse large B-cell lymphoma (DLBCL); fluorescence in situ hybridization was negative for rearrangements of BCL6, BCL2 and C-MYC.

A whole-body PET/CT scan showed diffuse adenopathy, largest node 3.9 cm, and MRI of the brain showed no evidence of lesions. Her ECOG performance status was 1. Her DLBCL was ​stage III, International Prognostic Index low-intermediate risk​. ​

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The patient received 6 cycles of R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone, which was well-tolerated​ and led to a complete response at the end of treatment. One year later, the patient presented with diffuse lymphadenopathy, confirmed by PET CT scan​. A biopsy showed relapse of the same DLBCL. She received 6 cycles of pola-BR​ [polatuzumab vedotin (Polivy), bendamustine (Bendeka), and rituximab], and had stable disease for 6 to 8 months before progression​. She was not able to travel because she is the primary caretaker for her mother who has dementia​. She received loncastuximab tesirine (Zynlonta) as third-line therapy. ​

DISCUSSION QUESTIONS

• Do you agree with the treatment choice for this patient? ​
• Have you used loncastuximab before?​
• What other therapeutic options could be considered?

PAOLO STRATI, MD: Do you agree with the treatment choice? Have you used loncastuximab before…and what other therapeutic options would you have considered in this specific patient, someone who is older, primary chemo-refractory, and then both [stem cell] transplant and chimeric antigen receptor [CAR] T-cell therapy ineligible.

SREENI CHITTOOR, MD: I think it’s perfectly reasonable. This patient...wasn’t willing to have a transplant or CAR T-cell therapy. Our options are moving on to antibody-drug conjugates or bispecifics, and I don’t see anything wrong with giving her loncastuximab.

STRATI: Yes, I completely agree. As you said, CAR T-cell therapy or transplant will not be an option, either based on age or logistical challenges. Somebody may argue that we could have used tafasitamab [Monjuvi] plus lenalidomide [Revlimid] in the second line, but let’s not forget tafasitamab’s schedule is not easy. There are more [frequent] infusions the first [3 cycles]; they even have to come back on day 4.¹ Administering loncastuximab or polatuzumab is much easier. They’re given every 3 weeks. I can see how [it would be hard for] somebody who is unable to travel for frequent infusions—even if we have nice long-term data for tafasitamab/lenalidomide in the second line, including in primary refractory patients. Logistically, I agree with you. I think I would have done the same. I would have tried polatuzumab first and loncastuximab second.

Does anybody have a different opinion? Do you have experience prescribing loncastuximab?

RYAN GRIFFIN, MD: The short answer is I have not prescribed it yet.

STRATI: Has anyone prescribed it and wants to share how they went? I do prescribe it a lot for non-trial eligible patients.

SHAN GO, MD: I have a patient who is on it right now. He’s been on loncastuximab for 4 months. He’s [being treated in the] fourth or fifth line; the patient had refractory or relapsed lymphoma, progressed on CAR T-cell therapy, and they received pretty much every [option]. The only thing we haven’t had is a second CAR T-cell therapy and bispecifics. He’s on loncastuximab right now; he’s doing fine. The adverse events [AEs] he experienced include fatigue, nausea, some minor gastrointestinal AEs, cytopenia. Otherwise, it’s already done reasonably well for someone who has been heavily treated.

STRATI: You were running out of options.

GO: Yes. I did have to dose reduce, which decreased the AEs. The treatment is much more tolerable for the patient.

STRATI: After how many cycles did you dose reduce and how much did you decrease the dose?

GO: [I did so] after 3 cycles. The patient also had many other issues. He had multiple bouts of COVID-19, 1 episode of Clostridioides difficile, and 2 episodes of Pseudomonas bacteremia, but every time he bounced back. Then...several weeks later he was [better] again, so we restarted treatment. We did have multiple interruptions of treatment because of hospitalizations. I had to space out the interval because he had a prolonged neutropenia, or [give it] in between as long as he didn’t have disease progression. We’re trying to find a balance [using] the granulocyte colony–stimulating factor for neutropenia without disease progression, because the next step is a bispecific. He was being evaluated for the natural killer–cell CAR T-cell therapy, but his platelet count was too low. Now with loncastuximab, he has pancytopenia but is not too critical.... His quality of life is still pretty decent, but not high enough for more intensive treatment. He’s 74, and he’s been on treatment for lymphoma for 4 and a half years.

STRATI: I think this is so interesting. You touched on some very important aspects of the utilization of loncastuximab, such as progression and dose reduction.

DISCUSSION QUESTION

• How does the approval of loncastuximab address an unmet need in the treatment of patients with R/R DLBCL? ​
• How do you plan to use loncastuximab in the context of other available therapies?

STRATI: How would you sequence loncastuximab now that there are so many agents that are available in third line? Do you use it before or after CAR T-cell therapy and before or after bispecifics? There are no data to support an answer one way or the other; I would just like to hear your experience and your suggestions.

ANDY DALOVISIO, MD: I think the every-3-weeks dosing schedule is very convenient for our patients who are far away. It’s nice that it’s 1 drug rather than a combination. It’s a little easier to sort through and counsel patients. Having data in patients exposed to CAR T-cell therapy is reassuring, particularly in that patient population. Third line and beyond is typically where I’d [use it].

STRATI: Yes, I agree. The label is in third line, and as you mentioned, we have some data about its efficacy after CAR T-cell therapy. The CR rate was [15%].²

If you look into LOTIS-2 [NCT03589469], there were also some patients who received loncastuximab before CAR T-cell therapy.³ One concern with agents that target CD19 like tafasitamab or loncastuximab is that they may downregulate CD19 expression, it may hamper the efficacy of your subsequent anti-CD19 CAR T-cell therapy…. In the LOTIS-2 trial, there was a small fraction of patients who received loncastuximab but then they...proceeded with CAR T-cell therapy and one possible explanation is...the half-life. Tafasitamab has a very long half-life. The concern is if you utilize tafasitamab as a bridging [therapy] before CAR T-cell therapy, by the time those 8 weeks are gone and your patient is ready for CAR T-cell infusion, there could still be measurable tafasitamab in peripheral blood that may induce downregulation of CD19.

Loncastuximab’s half-life is relatively short; it’s about a week. So most patients, by the time they’re ready for CAR T-cell infusion, have been off treatment for about 3 weeks, which is 1 cycle. Usually, the CD19 expression is preserved. [When] we have to use an agent in third line and have to pick between tafasitamab and loncastuximab, I would be nervous to use tafasitamab, and a little bit less [nervous] to use loncastuximab.

_References:

_{1. Monjuvi (tafasitamab). Prescribing information. MorphoSys US Inc; 2020. Accessed November 30, 2023. https://bit.ly/2S38ZW7} 

_{2. Caimi PF, Ardeshna KM, Reid E, et al. The antiCD19 antibody drug immunoconjugate loncastuximab achieves responses in DLBCL relapsing after antiCD19 CAR-T Cell therapy. Clin Lymphoma Myeloma Leuk. 2022;22(5):e335-e339. doi:10.1016/j.clml.2021.11.005}

_{3. Kahl BS, Hamadani M, Caimi PF, et al. ABCL-022: LOTIS-2 follow-up analysis: updated results from a phase 2 study of loncastuximab tesirine (lonca) in relapsed or refractory diffuse large b-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2021;21(suppl_1):S377-S378. doi:10.1016/S2152-2650(21)01861-9}