Treating Double-Hit Lymphoma With CAR T-Cell Therapy and Other Drugs

Haifaa Abdulhaq, MD

During a Targeted Oncology Case-Based Peer Perspectives event, Haifaa Abdulhaq, MD, director, Hematology, and associate clinical professor of Medicine at UCSF Fresno discussed the case of a 63-year-old patient with lymphoma with concurrent MYC and BCL2 rearrangements.

Targeted Oncology^TM: Would you offer this patient central nervous system (CNS) prophylaxis? How would your treatment differ for this patient if she had double expressor lymphoma?

ABDULHAQ: You have to do CNS prophylaxis, either with intrathecal [IT] chemotherapy or a combination of IT chemotherapy followed by intravenous [IV] high-dose methotrexate.

[Treating] a patient who is a double expressor is a controversial point, and it’s institution dependent. Some people would treat with R-EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] and some people would treat with R-CHOP. The data for using R-EPOCH are not as strong as [those for patients with] double-hit lymphoma. If I have a young healthy patient, I consider R-EPOCH. In older patients, I use R-CHOP. But with a patient who is a double expressor, there is nothing wrong with using R-CHOP because we don’t have strong data to support R-EPOCH. CNS prophylaxis is indicated for all patients who are double expressors.

At the conclusion of therapy for double-hit lymphoma, would you consider a transplant, or would you use chemotherapy?

That was a big question several years ago, but since then there have been 2 studies that reported no improvement in progression-free survival [PFS] or overall survival [OS] with autologous stem cell transplant [ASCT] in [patients who achieved their first] complete remission [CR] for double-hit lymphoma. It has fallen out of favor. At some point, probably 5 or 6 years ago, we used to consider it, but trials have not shown improvement in outcome. They were retrospective trials, so these were not strong data, but I would say most [cancer] centers at this point do not offer transplant [for patients with their] first CR.

What therapeutic options would you consider for patients with recurrent or relapsed disease?

If we can get this patient to chimeric antigen receptor [CAR] T-cell therapy, especially on a clinical trial, that would be probably my preferred approach. ASCT in patients who have relapsed double-hit lymphoma [generally leads to poor outcomes], and this is a patient who is much less likely to respond to salvage chemotherapy.

I think the clear answer in this situation is CAR T; this is where I would advocate for using CAR T therapy in this patient, and that’s what I would recommend.

Can you discuss the data for CAR T-cell therapy in relapsed and refractory DLBCL?

The ZUMA-1 study [NCT02348216] led to the FDA approval of axicabtagene ciloleucel [axi-cel; Yescarta] in patients who [have] relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma.¹ There were 2 cohorts of patients in this trial, and patients were eligible if they did not respond to their last chemotherapy or relapsed within 12 months post ASCT. A conditioning regimen of cyclophosphamide and fludarabine was used prior to the infusion of the CAR T cells. Ninety-nine percent of the patients who underwent the procedure were successful and 91% were dosed.

The updated analysis from ZUMA-1, with 27.1 months median follow-up, [showed the] overall response rate [ORR] was 83% with a CR of 58% and a partial response [PR] of 25%.² The median OS was not reached [95% CI, 12.8 months-not estimable]. The median PFS was 5.9 months [95% CI, 3.3-15.0].

The other [data] were from the JULIET study [NCT02445248], which was the phase 2 study that led to the FDA approval of the other CAR T product, tisagenlecleucel [tisa-cel; Kymriah], and patients on this trial were allowed bridging chemotherapy between the collection of the T cells and infusion.³

The updated analysis from the JULIET trial, with 14 months median follow-up, [had an] ORR of 52% [95% CI, 41%-62%] with a CR of 40% and a PR of 12%. Twelve months relapse-free survival was 65%, and the median OS was 12 months for the infused patients.

How do these CAR T therapies compare?

ORRs varied between [axi-cel, tisa-cel, and lisocabtagene maraleucel (liso-cel)], with higher response rates with axi-cel and liso-cel and less ORR with tisa-cel.2-4 However, when we look at the CR rates, we see the CRs are close but still less with the tisa-cel. Median PFS was 5.9 months with axi-cel, 6.8 months with liso-cel, and it was not reached for patients who achieved CR on tisa-cel. The median OS was not reached with axi-cel, [and was] 12 months with tisa-cel and 21.1 months with liso-cel.

In terms of the adverse effect [AE] profile of the CAR T [therapies], the 2 main AEs that we look at are cytokine release syndrome [CRS] and neurotoxicity. There was more grade 3/4 neurotoxicity [with axi-cel] at 32% and less grade 3/4 CRS [than the other therapies] at 11%.2 With tisa-cel, there was more grade 3/4 CRS at 23% and less grade 3/4 neurotoxicity at 11%.3 With liso-cel, there was way less CRS and neurotoxicity, and that’s one of the distinguishing factors of this product—the CRS was 2% and the neurotoxicity was 10%.⁴

What do you think about the use of CAR T cells for patients with relapsed and refractory DLBCL, and how would that compare with stem cell transplant?

In many of the patients who relapsed, we see that an important reason for this is the sustainability of these T cells in the peripheral blood. Basically, they are being lost after a certain period of time. I would say, though, patients who obtain CR with CAR T therapy tend to have a much better chance of maintaining their response. It’s patients who get a PR [who] don’t maintain that response…those are the patients who relapse within a few months.

I think it is early to comment on CAR T versus ASCT. We are going to wait for the phase 3 trials that are looking at those data.

How does the neurotoxicity seen with CAR T-cell therapy affect patients long term?

Typically speaking, the neurotoxicity is reversible, but it can be also quite serious. If patients get seizures and it is not controlled, patients can have permanent damage neurologically. The chance of having that is small and, typically, the treatments that we do for CRS are not quite efficacious for neurotoxicity. Right now, we don’t have a lot of effective treatments other than using steroids and supportive care for neurotoxicity.

In terms of tocilizumab [Actemra], which we use for CRS, it’s not effective for neurotoxicity, and there are other drugs like anakinra [Kineret], an interleukin 1 inhibitor, that are being looked at for neurotoxicity. Theoretically, it can be permanent. The chance of that happening is very small.

What other drugs are approved in this setting, and what were the data behind them?

The trial that led to the approval of polatuzumab vedotin [Polivy] plus bendamustine and rituximab [Rituxan] was a phase 2 trial, and it included patients with relapsed/refractory follicular lymphoma, as well as DLBCL.⁵ Patients were stratified based on the duration of response to prior line of treatment, whether it was less than 12 months or more than 12 months, and whether they had high versus low disease burden.

There were some older patients [in the control] arm with a median age of 71, and there were, in general, more male patients on the trial. There were about 40% of patients [in each arm] with germinal center-B [GCB] subtype.

The ORR was 45% with the combination of polatuzumab, bendamustine, and rituximab compared with 17.5% with bendamustine and rituximab. The median PFS [by the independent review committee] was 9.5 months with the combination compared with 3.7 months with the bendamustine and rituximab alone.

The improvement in outcome with the addition of polatuzumab among different subsets of groups [was seen] regardless of the age and GCB versus non-GCB subtype.

Most of the AEs [were] hematologic. When we look at the febrile neutropenia, however, it wasn’t different between the 2 arms. The main AE of polatuzumab was peripheral neuropathy, which was seen in 7.7% of patients with the combination.

Have you used selinexor (Xpovio) for relapsed/refractory DLBCL?

Selinexor was recently approved for treatment of DLBCL. I personally have not used it yet in this setting. I have used it in multiple myeloma, but not for DLBCL. The FDA approval was on June 22, 2020.⁶

The phase 2b trial that led to the FDA approval was the SADAL trial [NCT02227251].⁷ The dose of selinexor is significantly less than the dose that was approved for multiple myeloma [80 mg twice a week]. The dose here was 60 mg twice a week, and that drug was continued until progression of disease or unacceptable toxicity, and the primary end point of the trial was ORR.

The ORR was 28% with 12% CR and 17% PR. The median PFS was 2.6 months and the median OS was 9.1 months.

In general, the drug was better tolerated with this dose compared with [the dose] in multiple myeloma. There was some nausea, especially grade 1/2, but not a lot of grade 3 nausea. In terms of the grade 1/2 diarrhea, it was about 32%, and 3% for grade 3. There was some thrombocytopenia with the drug, at 31% for grade 3. Treatment discontinuation because of AEs was [seen] in 17% of the patients.

_References:

_{1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447}

_{2. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a singlearm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7}

_{3. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980}

_{4. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0}

_{5. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172}

_{6. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. FDA. June 22, 2020. Accessed November 30, 2020. https://bit.ly/3eWDPGW}

_{7. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4}