Considering Tolerability of Regimens for Third-Line DLBCL Therapy

Targeted Oncology Staff;

A woman aged 73 years presented with fever, headaches, and 7-lb unintentional weight loss. She is married with 2 grown children who live in other states; she is the primary caretaker for her mother, who has advanced dementia; there is no family history of cancer. She had hyperlipidemia, which was well controlled with simvastatin. Physical examination showed palpable bilateral cervical lymphadenopathy.

Laboratory results included lactate dehydrogenase level of 300 U/L (280 U/L upper limit), hemoglobin level of 10.8 g/dL, bilirubin level of 1.3 mg/dL (1.2 mg/dL upper limit), and creatinine level of 1.7 mg/dL (1.2 mg/dL upper limit), with all other levels within normal limits. She had negative results for hepatitis B, hepatitis C, and HIV. A lymph node biopsy result with immunohistochemistry panel showed she had CD10-positive and CD20-positive confirmed diffuse large B-cell lymphoma (DLBCL); fluorescence in situ hybridization result was negative for rearrangements of BCL6, BCL2, and cellular MYC.

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

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 remission at the end of treatment. One year later, the patient presented with diffuse lymphadenopathy, confirmed by PET-CT scan. A biopsy result 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. She received loncastuximab tesirine (Zynlonta) as third-line therapy.

BALA: I’ve heard of [loncastuximab] and I’ve read a summary of the [LOTIS-2 (NCT03589469)] study, but not had an opportunity to use it. I would probably think of using multiagent chemotherapy, like R-GemOx [rituximab, gemcitabine, and oxaliplatin] or one of those regimens traditionally used in the relapse setting.

TIAN: The drug is easy to use. I have used it once or twice. A bispecific antibody would be another option. The patient should tolerate it well.

MEHTA: Yes, you’re right. Bispecifics are also approved in the third line.

ASHRAF: Once we get comfortable using [bispecifics]—the initial couple of treatments are still a little complicated—in a year or so, once we have a system in place, we might use it more often.

MEHTA: Yes, what you’re highlighting is the cytokine release syndrome [CRS] risk and hospital admission for observation.

MODERATOR SIDEBAR

Q:What did the LOTIS-2 study (NCT03589469) suggest in terms of the dosing and adverse event (AE) management of loncastuximab?

MEHTA: Loncastuximab was approved based on the LOTIS-2 study. [Enrolled patients were] adult patients with relapsed/refractory DLBCL who had seen more than 2 lines of therapy, who were CD19 positive if they had received prior CD19 therapy. Otherwise, they didn’t have to test. [They had] ECOG performance status of 0 to 2, and they also allowed patients who are high risk.

In the first 2 cycles, the dosing is a little bit higher, 0.15 mg/kg [every 3 weeks], and then after 2 cycles, for the third cycle onward, that dose is halved [0.075 mg/kg], and you can continue up to 1 year. This was how the study was designed.¹

The most important toxicities [were] GGT [γ-glutamyl transferase] increase, [which] was tested because of the payload, [as well as] the cytopenias. These were the 2 major [AEs]. The other AE that you might see in clinical practice is peripheral edema, as you can see that in 20% of patients, but in [most] patients, the top 3 or 4 AEs are cytopenias, [fatigue], as well as GGT increase.

GGT increase in 41% [of patients], neutropenia in 40%, thrombocytopenia [in 33%], fatigue [in 28%], anemia in [26%] were the major AEs of interest [Table²]. Those who have used it may have seen patients who get peripheral edema or fluid retention. That is an AE of the PBD [pyrrolobenzodiazepine] payload, tesirine, that is attached, like the neuropathy we see in brentuximab vedotin [Adcetris]. You see it more as a fluid retention, pleural effusions, that sort of thing, and there is a way to deal with it. [In] the study, they gave those patients dexamethasone before and after, and you can also use a diuretic. [In] the study, they used spironolactone for the fluid retention as well as pleural effusion.

Dexamethasone is given [at 4 mg orally or intravenously for 3 days, starting on the day] before the loncastuximab.³ There are many reasons. One of the reasons is pleural effusion and fluid retention. [Another is] the photosensitivity. The dexamethasone is useful in that setting, so keep that in mind.

MEHTA: This is a potentially good drug in this setting without any CRS and ICANS [immune effector cell–associated neurotoxicity syndrome]. Mind you that LOTIS-2 had an aggressive relapsed/refractory patient population. The reason I say that there is no CRS and no ICANS [is that] we are using loncastuximab in the post CAR [chimeric antigen receptor] T-cell therapy setting and I have [seen] responses in that setting, even in heavily pretreated patients.

TIAN: I think for this…patient, it is probably easy, it is [given] every 3 weeks...and schedule-wise is much easier than some of the bispecifics because they require the addition of inpatient observation. It at least might be an easy option for this patient, who has a mother with dementia.

MEHTA: I agree; there is no CRS, and the patient doesn’t have to go to the hospital, and it’s an every-3-week infusion. Does anyone else who has used loncastuximab want to share their experience?

KUMARAN: Yes, one of the adverse events [AEs] I noticed was the photosensitivity. They should be aware of it and take necessary precautions to avoid direct sunlight with the loncastuximab.

MEHTA: Yes, you’re right, and you must counsel patients that they have to come in. The photosensitivity can be serious in some patients, [in the form of] the skin rash.

KUMARAN: Correct, and…the [γ-glutamyl transferase [GGT)] was not significant. It [was not a] clinically meaningful end point, [to the point that] the physician should not be stopping the drug because of the [GGT] elevation. It is more of a laboratory finding.

MEHTA: Yes, you’re right. But still the dose adjustment criteria are listed…some of the grade 3 or higher GGT elevation could be scary for some patients, but you’re right, in most situations it’s [only] a laboratory abnormality.

HEMPHILL: Is there any worry [because] obviously there weren’t a lot of patients who had CAR T-cell therapy prior? We are seeing a lot more patients who would have been exposed to it ahead of time. I am curious about that subset… [as well as] post treatment when they inevitably relapse, if CAR T-cell therapy is considered at that point. Is there any concern as far as [T cell] mobilization, because with [other regimens] there was potentially an issue with that.

MEHTA: In LOTIS-2, they looked at both…before and after: CAR T-cell therapy first and loncastuximab second; loncastuximab first and CAR T-cell therapy second.^4,5 There was not much impact on the response rate; it was not that post loncastuximab they did not respond at all, or vice versa. There was no correlation between CD19 expression and responses to either CAR T-cell therapy or loncastuximab. I think [the investigators] are satisfied that those patients would respond post loncastuximab or [before] loncastuximab with CAR T-cell therapy.

Technically, patients did [undergo] collection post loncastuximab and there were no issues with collection, so [it appears] the PBD [pyrrolobenzodiazepine] has no impact on collection.⁵ There is always a risk when they have been through multiple lines of therapy before collection, but typically I have not faced that situation. The warning in that situation is immediately before collection, be cautious with bendamustine; that can impact the collection.

SCHAEFER: Do some centers sometimes recommend this as a bridge to CAR T-cell therapy?

MEHTA: I have not used it in bridging. Based on the data that we have, you could use it, but if you’re using some of the products now, they’re getting ready so quickly. In those situations, I will not take a chance; I will probably use just 1 cycle of any sort of chemotherapy just to get them to CAR T-cell therapy. Some physicians consider that, and they have used it, and there were no issues, but I do not personally use it.

MEHTA: There are 2 bottom lines of [using] tafasitamab plus lenalidomide. One is to use it in an earlier line of therapy; there you see the maximum benefit of tafasitamab/lenalidomide.⁶ For patients who have 1 prior line of therapy, if they’re frail and they’re not eligible for stem cell transplant [or] eligible for T-cell therapy, tafasitamab/lenalidomide is your go-to combination. The [second] bottom line is that the combination has more AEs, but once these patients go on single-agent tafasitamab [after 1 year], the AEs [occur] less and less [From the Data⁶]. Most of the patients with single-agent tafasitamab have relatively no AEs in that setting.

Be careful with lenalidomide dosing, as the majority of the first combined therapy AEs are cytopenias. If you don’t pick the right lenalidomide dose, the patient will have a lot of AEs: fatigue, cytopenias, skin rash, I’ve seen all of them. I have 1 [older] patient who absolutely did not want to go for CAR T-cell therapy, and I started her on tafasitamab/lenalidomide. I started on 10 mg of lenalidomide because she was 83 years old. She couldn’t handle 10 mg, and right now she’s on a 5-mg lenalidomide dose and handling it well. If I put her on 25 mg, she would have a lot of AEs, so pick your lenalidomide dose very carefully in this patient population.

SCHAEFER: I’ve used it once before; I started at 15 mg of lenalidomide for fear of cytopenias because [the] patient was older and had been through a lot of therapies. They tolerated therapy well. I didn’t make it past a year, though; they relapsed before that. I didn’t get to use tafasitamab by itself. I thought it was tolerated well.

ASHRAF: I used it in 1 patient. It was a Hail Mary as it was very advanced disease. She had response to treatment, but she died from other causes.

MEHTA: Is there any special patient for whom you would consider using tafasitamab/lenalidomide? To me, it would be the person who’s either not eligible or has already gone through CAR T-cell therapy and stem cell transplant.

_{1. 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}

_{2. Zinzani PL, Caimi PF, Carlo-Stella C, et al. LOTIS 2 follow-up analysis: updated results from a phase 2 study of loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma. Hematol Oncol. 2021;39(suppl 2):252-254. doi:10.1002/hon.89_2880}

_{3. Zynlonta. Prescribing information. ADC Therapeutics; 2021. Accessed November 7, 2023. https://tinyurl.com/yeytwndh}

_{4. 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}

_{5. Thapa B, Caimi PF, Ardeshna KM, et al. CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy. Blood Adv. 2020;4(16):3850-3852. doi:10.1182/bloodadvances.2020002587}

_{6. Duell J, Abrisqueta P, Andre M, et al. Abstract CT022: five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: final results from the phase II L-MIND study. Cancer Res. 2023;83(suppl 8):CT022. doi:10.1158/1538-7445.AM2023-CT022}