Kami Maddocks, MD

Mantle cell lymphoma MCL) is a non-Hodgkin lymphoma (NHL) subtype with relapse expected in almost all patients at some point. Thus management of relapsed or refractory (R/R) disease is a highly relevant topic for patients and the clinicians who treat them. The treatment landscape for relapsed MCL has changed rapidly over the past decade, with the development and approval of Bruton tyrosine kinase (BTK) inhibitors at the forefront of the changing treatment paradigm.

“Novel Treatment Approaches in Relapsed/ Refractory Mantle Cell Lymphoma,” presented by Kami Maddocks, MD, at the Society of Hematologic Oncology 2021 Annual Meeting, provided an overview of recent developments in the treatment of R/R MCL with updates outlined by class of therapies. With the approval of chimeric antigen receptor (CAR) T-cell therapy for R/R MCL, referral to an authorized CAR T-cell treatment center is critical when considering options for patients seen in clinical practice. Despite the plethora of emerging treatment options, clinical trial participation should be strongly encouraged for patients with R/R MCL. Results of a number of ongoing clinical trials are expected to lead to new approvals and changes in clinical practice in the near future.

Covalent Irreversible Bruton Tyrosine Kinase (BTK) Inhibitors

Three covalent irreversible BTK inhibitors are approved by the FDA for the treatment of R/R MCL, including first-in-class ibrutinib (Imbruvica) and the more selective acalabrutinib (Calquence) and zanubrutinib (Brukinsa). All 3 drugs are approved as single-agent therapy with overall response rates of 67% to 84% and median progression-free survival (PFS) of 13 to 22 months.

 Improved duration of response to BTK inhibitors is seen when they are used in second line versus in later lines of therapy. Although ibrutinib, acalabrutinib, and zanubrutinib are efficacious and typically well-tolerated options for relapsed MCL, almost all patients eventually will progress on these therapies. Historically, outcomes following progression with prior classes of approved MCL therapies have been poor.4 There is reason for further optimism, however, with multiple emerging novel therapeutic approaches demonstrating promising activity in ongoing and recently completed studies.

Although a growing assortment of combinations incorporating BTK inhibitors are under investigation in phase 1 and 2 studies for patients with relapsed MCL, the one farthest along in development is the combination of ibrutinib with BCL-2 inhibitor venetoclax (Venclexta). The randomized phase 3 SYMPATICO trial (NCT03112174) comparing ibrutinib and venetoclax with ibrutinib alone in R/R MCL has completed accrual, and mature data are awaited to determine whether this combination results in superior efficacy compared with single-agent treatment. Additional triplet combinations incorporating anti-CD20 monoclonal antibodies also are under investigation. When evaluating these combination strategies, differences in treatment toxicity and cost will need to be weighed against possible improvements in efficacy.

Noncovalent reversible BTK inhibitors represent an emerging therapeutic option for patients with B-cell malignancies, offering improved selectivity mitigating off-target toxicities as well as the potential to overcome resistance to irreversible BTK inhibitors. The selective noncovalent reversible BTK inhibitors pirtobrutinib (formerly LOXO- 305) was studied in the recently published phase 1/2 BRUIN study (NCT03740529) and demonstrated impressive clinical efficacy, including in patients with prior BTK inhibitor treatment.5 Of the 56 evaluable patients with R/R MCL enrolled on BRUIN, 52 (93%) had been previously treated with covalent BTK inhibitors, with a median of 3 prior lines of therapy. More than half of patients with MCL achieved an objective response (ORR), with an ORR of 52% among all evaluable patients. Discontinuation due to adverse events (AEs) was infrequent (1.5%), with dose interruptions required in 8% of patients. The majority of AEs were grade 1 or 2. Thus, pirtobrutinib represents a promising potential option for patients with relapsed MCL with progression on irreversible BTK inhibitors or intolerance. A randomized phase 3 study (BRUIN-MCL-321; NCT04662255) is planned to assess for superiority of pirtobrutinib to the currently approved ibrutinib, acalabrutinib, or zanubrutinib in patients with R/R MCL.

Antibody-drug conjugates (ADCs) allow for targeted delivery of chemotherapy drug payload to tumor cells by linking to a monoclonal antibody targeted to a tumor antigen. Although multiple ADCs are approved for other NHL subtypes, there are no currently approved ADCs for the treatment of relapsed MCL. The ADC at the forefront of development is VLS-101, a tyrosine kinase–like orphan receptor 1 antibody conjugated to the monomethyl auristatin E (MMAE) chemotherapy payload. In a phase 1 study, 15 patients with MCL treated across various dose levels had an ORR of 47% including 13% complete response (CR), with 6 of 7 responses ongoing with duration of treatment ranging from 35 to 58 weeks.

 Similar to other MMAE-containing ADCs, VLS-101 was associated with neuropathy (grade 3 in 9% of patients).

Although multiple PI3 kinase inhibitors have shown clinical activity in previously treated MCL, the FDA has not approved any for this indication. Parsaclisib is an investigational selective PI3 kinase δ inhibitor that has been studied in patients with relapsed MCL in recently presented phase 2 studies of patients who are BTK inhibitor–naïve and patients previously treated with a BTK inhibitor. Among 53 patients with R/R MCL previously treated with a BTK inhibitor, the ORR was 25% (2% CR) with a median PFS of 4 months, whereas the ORR was 70% (15% CR) with median PFS of 11 months among 108 patients with MCL enrolled in the BTK inhibitor–naïve study.

One frequently observed adverse effect was diarrhea, which occurred in 31% of BTK inhibitor–naïve patients and 23% of previously BTK inhibitor–treated patients.

Bispecific antibodies allowing for engagement of T cells and other immune subsets with tumor cells are a class of treatment under investigation in multiple NHL subtypes, including R/R MCL. Preliminary data demonstrate clinical activity for this class of treatment in MCL and further data are eagerly anticipated. Preliminary results were recently presented at the 2021 American Society of Clinical Oncology Annual Meeting from the NP30179 study (NCT03075696), a phase I dose expansion study of the CD20/CD3 bispecific antibody glofitamab. Five patients with R/R MCL were enrolled on this study, and notably 4 of 5 patients achieved CR.

Brexucabtagene autoleucel (Tecartus) is a CD19-directed CAR T-cell therapy that is FDA-approved for the treatment of R/R MCL. The approval was based upon results of the pivotal phase 2 ZUMA-2 study (NCT02601313) in which 74 patients with R/R MCL, all previously treated with BTK inhibitors, were enrolled and 68 patients successfully received CAR T-cell infusion following lymphodepletion.

In addition to prior BTK inhibitor treatment, the study population had other high-risk features, including high Ki67 index of 30% or greater in 40 patients and blastoid morphology in 31% of patients. The ORR among the 60 infused patients was 93% with 67% achieving a CR. Even when assessing the entire study population, including patients who did not receive CAR T-cell infusion, the ORR remained 85% with 59% CR. The 1-year estimated PFS among evaluable patients was 61%, with similar response rates and PFS seen among patients with high-risk features, including 

mutation or blastoid morphology. Cytokine release syndrome (CRS) and neurotoxicity of any grade were frequently observed (91% and 63% of patients, respectively), with grade 3 or higher neurotoxicity occurring in 31% of patients. The anti-CD19 CAR T-cell therapy lisocabtagene maraleucel (Breyanzi) also is under investigation for treatment of MCL in the TRANSCEND NHL-001 study (NCT02631044).

 The observed ORR was 84% with 59% CR, with follow-up not yet mature for PFS estimate. CRS of any grade occurred in 59% of patients, whereas neurotoxicity of any grade was observed in 34%, rates that are lower in comparison than those observed with brexucabtagene autoleucel. It also is notable that patients with central nervous system involvement by MCL were eligible for TRANSCEND NHL- 001. Final results will provide further data regarding the efficacy of CAR T-cell therapy in this difficult-to-treat scenario.

The future today is brighter for patients with previously treated MCL, with the approval of both BTK inhibitor and CAR T-cell therapies providing 2 highly effective classes of treatment for patients with R/R disease. Randomized studies are looking at combination treatment options as well as comparing noncovalent reversible BTK inhibitors with the currently approved covalent BTK inhibitors in patients with R/R disease. Despite this progress, further treatment options are needed, but multiple new therapies are on the horizon, including noncovalent BTK inhibitors as well as ADCs.

1. Rule S, Dreyling M, Goy A, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. 

2017;179(3):430-438. doi:10.1111/bjh.14870

2. Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. 

. 2020;26(16):4216-4224. doi:10.1158/1078-0432.CCR-19-3703

3. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. 

2018;391(10121):659-667. doi:10.1016/S0140- 6736(17)33108-2

4. Martin P, Maddocks K, Leonard JP, et al. Post-ibrutinib outcomes in patients with mantle cell lymphoma. 

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5. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. 

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6. Wang ML, Barrientos JC, Furman RR, et al. VLS-101, a ROR1-targeting antibody-drug conjugate, demonstrates a predictable safety profile and clinical efficacy in patients with heavily pretreated mantle cell lymphoma and diffuse large B-cell lymphoma. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; virtual. Accessed 8/20, 2021. https://ash. confex.com/ash/2020/webprogram/Paper136373.html

7. Mehta A, Trněný M, Walewski J, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory MCL not previously treated with a BTK Inhibitor. 

2020;136(suppl 1):22-23. doi:10.1182/blood-2020-134872

8. Zinzani PL, Delwail V, Paneesha S, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory mantle cell lymphoma previously treated with ibrutinib (CITADEL-205). 

2020;136(suppl 1):43-44. doi:10.1182/blood-2020-134609

9. Carlo-Stella C, Hutchings M, Offner FC, et al. Glofitamab step-up dosing (SUD): complete response rates in updated efficacy data in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts). 

2021;39(suppl 15):7519. doi:10.1200/ JCO.2021.39.15_suppl.7519

10. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. 

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11. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. 

. 2020;136(suppl 1):10-11. doi:10.1182/blood-2020-136158

Articles

Management of relapsed or refractory disease is a highly relevant topic for patients with mantle cell lymphoma and the clinicians who treat them.

Novel Treatment Approaches in Relapsed/Refractory Mantle Cell Lymphoma

 I think some of the most important things to recognize when you’re treating patients with follicular lymphoma [LF], number 1, is defining when they present with FL and if they require therapy or not. As I mentioned, treating patients just because they have FL does not improve their survival, but it does expose to them toxicities of therapy. Therefore, making sure that in patients who are asymptomatic with low tumor burden, who do not need treatment, that it’s OK to observe these patients until they meet indications or have symptomatic disease that require treatment. I think ruling out transformed disease is very important in FL, so those patients who present with B symptoms with a very high LDH [lactate dehydrogenase], using the PET [positron emission tomography] scan to determine if there’s an area that has an SUV [standard uptake value] out of proportion to other areas, so that can be biopsied to rule out transformed disease, because these patients, if they have transformed disease, need anthracycline-based therapy.

I think in those patients who do not respond to initial therapy like they should, so not achieving complete remission or they relapse within that 2-year time frame, number 1 again, is reassessing the nature that they don’t have transformation at this time. Because, that has been shown that a certain proportion of those patients will have transformed disease. Then, consideration of referring them for a clinical trial, and just recognizing that those patients have a worse overall survival [OS] than other patients with FL. It’s important to make sure that if there’s a trial available, that they would be able to be treated on thinking about CAR [chimeric antigen receptor] T in some of these early relapse patients and referring them for that. Lastly, as I mentioned that the median OS of FL is over 20 years, so when we’re considering different therapies, it’s also important to think about the toxicities of these therapies in the quality of life for a patient.

Case: A 74-Year-Old Man With Relapsed/Refractory Follicular Lymphoma

A 74-year-old man complains of a 6-month history of fatigue, occasional fevers, decreased appetite, fatigue, and an 8-lb weight loss

PE: palpable right axillary and cervical lymph nodes, palpable ~ 3 cm in both locations; spleen palpable 4.5 cm below left costal margin
 

Labs: ANC 1.6 x 109/L, WBC 11.2 x 109/L, 44% lymphocytes, Hb 9.6 g/dL, plt 98 x 109/L, LDH 315 U/L, B2M 3.5 µg/mL; HBV negative

Excisional biopsy of the axillary lymph node on IHC showed CD 20+, CD 3+, CD5+, CD 10+, BCL2+; follicular lymphoma grade 2

Bone marrow biopsy showed paratrabecular lymphoid aggregates, 4% involvement

PET/CT showed enlargement of right axillary, cervical, and mediastinal lymphadenopathy (3.3 cm, 3.1, cm and 4.6 cm respectively)

He was treated with R-CHOP for 6 cycles, achieved complete response and continued rituximab maintenance

24 months later he complained of increasing weight loss, fever and drenching sweats as well as more enduring fatigue and new onset itching; he was currently taking antibiotics for his 3rd bacterial infection in the past year

Repeat PET/CT revealed progression of disease

He was started on bendamustine + rituximab for 6 cycles and continued on rituximab maintenance

Repeat lymph node biopsy grade 2 follicular lymphoma

12 months later he complained of continued weight loss, increased itching and worsening fatigue; recurrent infections continued

He was started on idelalisib 150 mg PO BID

Videos

Citing clinical pearls from her own experience in working with patients with relapsed/refractory follicular lymphoma, Kami Maddocks, MD, gives advice to colleagues in their efforts to combat follicular lymphoma.

Clinical Pearls in Management of Relapsed/Refractory Follicular Lymphoma

 When we look at the future of follicular lymphoma [FL] and some of the unmet needs, I think 1 of the first things is identifying if we can better decide therapy for patients at initial presentation. As I mentioned, there are prognostic scores, but we don‘t know how to use that to decide treatment. Deciding response and things like maintenance therapies, so minimal residual disease, might be something in the future that we can use to help us to decide if maintenance is appropriate for those patients at high-risk for relapse. Those patients as I mentioned who are at high-risk for death from their FL or have lower overall survival are those patients who relapse within the first 2 years of treatment, and we don‘t know the best treatment for those patients. Although we think maybe using different types of therapy with different mechanism of action in the second-line setting might be more ideal than using chemoimmunotherapy, we don‘t know that and there‘s a large cooperative group trial now trying to see if we can define the best treatment for these high-risk patients.

Chimeric antigen receptor [CAR] T-cell therapy is newly approved for patients with FL after progression after 2 or more prior therapies, but this is also associated with significant toxicities, such as cytokine release and neurotoxicity. I think further defining the right patient population for these, as patients who have gotten very long remissions to their initial 2 therapies probably aren‘t necessarily the most ideal candidates to use this in that setting, but those patients who have done poorly with the initial therapy from the standpoint of not getting into remission or having short time before progression are probably ideal candidates for these therapies. Some of the more promising therapies under development include bispecific therapies, so it‘s targeted CD20 by CD3, these have shown to have good early responses in the B-cell malignancies, including FL, but not the same risk of toxicity with the CRS [cardiorenal syndrome] as the CAR T cells. Other antibody-drug conjugates including those targeting CD [cluster of differentiation]19, and then CD19 antibody therapy is also under investigation for FL.

Kami Maddocks, MD, lists the future directions and unmet needs present in treating relapsed/refractory follicular lymphoma.

Future Directions for Treatment of Relapsed/Refractory Follicular Lymphoma

 The challenges beyond treating patients in the first- and second-line include that patients for every treatment regimen you give them, they typically have less response. So, their remission isn’t as deep, and the treatment doesn’t last as long. Some of the other challenges are what shape the patient’s in, what therapy they’ve had previously, what toxicities of that therapy, and what other comorbidities do they have. I would say that it’s not uncommon to have to give therapies beyond the second-line, so when you see younger patients, even if they get really greater prolonged remissions to their first-line therapy, it’s not uncommon for them to have several relapses. We know that the median overall survival [OS] of a patient with follicular lymphoma [FL] is greater than 20 years, but over that time there are many patients that will require a new treatment off and on. One of the other challenges with treating patients beyond the second-line of therapy is the toxicity. What toxicities have they had with prior therapies and are any of these toxicities lasting? it becomes difficult to retreat with agents that have similar toxicities as prior.

When I’m deciding on a therapy beyond the second-line, I think of the patient’s performance status. How good of shape they are in? What treatments have they had previously? What toxicities have they had to those therapies? What is my goal of treatment? There are several options for therapy beyond the second-line. We know that the options we’ve already discussed such as the different chemoimmunotherapies and lenalidomide can be used if they’ve not been used in the prior 2 lines. PI3K kinase inhibitors are available for third-line and later treatment, or for patients who’ve relapsed after 2 therapies. We have 4 PI3 kinase available, 3 in this setting and then 1 after 3 or more prior therapies. Idelalisib is an oral PI3K kinase inhibitor, duvelisib is another oral PI3K kinase inhibitor, and copanlisib is a BPI3P - PI3 kinase inhibitor all available. Tazemetostat is an EZH2 inhibitor available for relapsed [R/R] FL in this setting, and most recently, we’ve seen the approval of chimeric antigen receptor T-cell or CAR T-cell therapy in this setting. Although, the use of that I think must be thought out regarding which of your patient… because of the toxicities, if a patient is a candidate for that therapy and where that therapy should be used.

When deciding therapy in both second-line and in third-line, I think it’s also important to look at what the patients have had for their other therapies and their responses to those therapies. We know in a patient like this, who had 2 regimens of chemoimmunotherapy and did not have long remission durations to those therapies, that we often think about using a different type of therapy. Therefore, even in this second-line in this patient, this is a patient I might have considered using something different than chemoimmunotherapy, something with a different mechanism of action, so this is when we think about using the immunomodulator, lenalidomide in the second-line, or when we think about using the PI3K inhibitors in the third-line setting because we know that this patient seems like he’ll respond to chemotherapy, but not get prolonged remissions from chemotherapy.

Therefore, using something that targets the disease in a different way is attractive in a patient like this in the second- and third-line setting. When you look at the different PI3K inhibitors, they have similar overall response rates and progression-free survival [PFS]. To me, there’s no right or wrong 1 to choose in any clinical setting. Their toxicities are a little bit different, and again 2 are oral and 1 is IV [intravenous] that are approved in this setting. You must look at a patient and their comorbidities and what your goals are with the patient in deciding which PI3K kinase inhibitor might fit that patient appropriately. There is some data with both the idelalisib and copanlisib, where they evaluated patients who had progressed within that 2-year time frame, which I’ve said is a higher risk FL patient, which we know has a worse overall outcome. Both of those have been evaluated in that patient population and are shown to have similar responses in PFS in those patients who are considered high-risk by short time to relapse, as in those patients who achieve prolonged remissions with their IV therapy.

The challenges faced in treating patients beyond second-line treatment are addressed. Kami Maddocks, MD, reviews the frequency of patients who require third- and fourth-line treatment, in addition to the factors that affect treatment decisions in later lines of therapy.

Treatment Challenges Beyond Second-Line in Relapsed/Refractory Follicular Lymphoma

: When choosing a second-line therapy for patients with follicular lymphoma [FL], there‘s a number of options. Decisions should be based on what therapy did the patient receive in first-line? Did they receive R-CHOP [rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin), prednisolone]? Did they receive BR [bendamustine plus rituximab]? Did the receive single agent rituximab? How did they tolerate that therapy? How long did their response to that therapy last? There‘s always an option to repeat the use of chemoimmunotherapy. So, if somebody had BR or R-CHOP in the front line, and they get a prolonged response to chemotherapy, you could consider using the other chemoimmunotherapy option at relapse.

Again, a lot of times my preference is to save R-CHOP. Therefore, if somebody is going to transform, I have that anthracycline based therapy. But again, with a good response to chemoimmunotherapy, you can use a different chemoimmunotherapy rituximab in combination with lenalidomide is an option for second line therapy, and this is probably my most used second-line treatment. I feel like this is a good option in both patients who‘ve had a good response to first-line therapy and those patients who have a little bit earlier of a relapse changing the antibodies, so obinutuzumab as I mentioned, this can be used in frontline follicular lymphoma. Although, typically this is something I use in combination with either chemotherapy or consider it in combination with lenalidomide therapy when patients relapse. I do not use maintenance therapy in the second-line setting.

Considerations for subsequent treatment options in the second-line setting for patients with follicular lymphoma are reviewed by an expert hematologist.

Options for Second-Line Therapy in Patients With Follicular Lymphoma

: When I treat a patient for follicular lymphoma [FL], if they achieve a complete remission to their initial therapy such as this patient did, I usually follow them every 3 to 4 months. I see them in the clinic, take a good history, do a good physical exam, and then check their labs, CVC [central venous catheter], chemistry panel, LDH [lactate dehydrogenase] for any indications of disease progression. I typically check CT [computed tomography] scans every 6 months for those first 2 years, so monitoring them in the high-risk period. After patients reach that 2 years of follow up standpoint, I usually extend their visits out to 6 months and see them every 6 months through year 5 and then go to yearly. I do CT scans from year 2 to year 5, and sometimes I will do them at most once each year to just get an idea if there’s been any progression.

Otherwise, I just use CT scans if patients call in with symptoms if I detect new lymphadenopathy on exam or if something in their lab is concerning to me. I do not do a routine PET [positron emission tomography] scan for monitoring in FL. I do like to get a PET for their end of therapy, to ensure that they’re negative by PET scan.

Kami Maddocks, MD, highlights what findings may trigger a change in therapy or the introduction of a new agent into a patient’s current treatment.