Chemotherapy-Free Options Expand the Scope of Treatment in Leukemia and Lymphoma

Partner | Cancer Centers | <b>Karmanos Cancer Institute</b>

Across the paradigms of leukemias and lymphomas, novel therapies—such as BTK inhibitors, PI3K inhibitors, time-limited therapies, and even CAR T-cell therapies—have transformed the treatment of patients and prolonged survival without the need for chemotherapy.

Across the paradigms of leukemias and lymphomas, novel therapies—such as BTK inhibitors, PI3K inhibitors, time-limited therapies, and even CAR T-cell therapies—have transformed the treatment of patients and prolonged survival without the need for chemotherapy, said Dipenkumar Modi, MD, who added that although these advances have been substantial, many of these diseases remain incurable and additional options are needed.

“The therapeutic landscapes for patients with malignant hematologic malignancies are changing. We’ve seen increased efforts, and more novel therapeutic options are being considered. The treatment paradigms are moving toward chemotherapy-free regimens that have shown superior efficacy compared with traditional chemotherapy approaches,” said Modi, a medical oncologist at the Barbara Ann Karmanos Cancer Institute of Wayne State University, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on leukemia and lymphoma.

“[We must] stay tuned to get updated about more agents and, indirectly, to offer the best and most tolerable agents to our patients,” Modi added.

The meeting covered updates in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), follicular lymphoma, and chronic lymphocytic leukemia (CLL), as well as advances with CAR T-cell therapy in hematologic malignancies overall.

In the interview, Modi, chair of the event, discussed key clinical trials in MCL, ALL, follicular lymphoma, and CLL and highlighted potential future directions, particularly with CAR T-cell therapy, that could fulfill remaining unmet needs.

OncLive®: How has the landscape of MCL changed with the introduction of BTK inhibitors and CAR T-cell therapy? What is next for this paradigm?

Modi: The therapeutic landscape of MCL has changed significantly. Previously, we were heavily dependent on chemoimmunotherapy, even in the relapsed/refractory setting. However, the therapeutic approaches are moving toward chemotherapy-free regimens.

In relapsed/refractory MCL, we are utilizing BTK inhibitors heavily. Three trials have shown that BTK inhibitors have good safety profiles. One of these trials compared ibrutinib [Imbruvica] with temsirolimus [Torisel], which was [found to be] clearly inferior [vs ibrutinib] in relapsed/refractory MCL.

Moreover, all BTK inhibitors, namely ibrutinib, acalabrutinib [Calquence], and zanubrutinib [Brukinsa], are similar in efficacy; however, they differ in their [toxicity] profiles. The overall response rates [ORRs] with BTK inhibitors are [around] 70%, with complete remission [CR] rates around 20% to 25%. The median progression-free survival [PFS] with those agents is around 14 to 15 months.

Based on this, BTK inhibitors are considered for the first-line treatment of [patients with] relapsed/refractory MCL. Ibrutinib is a first-in-class, nonselective [BTK inhibitor], but it has more off-target activity against EGFR. Therefore, ibrutinib has a different safety profile and pharmacokinetics [than acalabrutinib and zanubrutinib].

[Ibrutinib] is associated with more atrial fibrillation, diarrhea, and low counts compared with acalabrutinib and zanubrutinib, both of which are second-generation BTK inhibitors that have less off-target activity. [The BTK inhibitors] are somewhat different in terms of safety profile. Regardless, whenever we use BTK inhibitors, we must carefully and frequently monitor patients for adverse effects [AEs].

Oftentimes, patients with relapsed/refractory MCL, particularly those with high-risk features such as TP53 mutations, [high] Ki-67, or blastoid morphology, have poor outcomes even with BTK inhibitors. Patients who have high-risk features do not have [substantial] responses with BTK inhibitors; therefore, these are the patients for which we should have a back-up plan ready, which could be CAR T-cell therapy.

Despite having a high-risk group identified by blastoid morphology, high Ki-67, or TP53 mutations, nearly 93% of patients responded [to CAR T-cell therapy in the ZUMA-2 trial (NCT02601313)], and among them 67% had CRs.

As of now, CAR T-cell therapy is promising and should be utilized in patients who relapse after BTK inhibitors [irrespective of] high-risk features.

Of course, promising agents are also coming and have shown promising activity in MCL. One of the most important [novel classes of agents] are the bispecific T-cell engagers [BiTEs]. We reviewed data on epcoritamab and glofitamab, both of which have shown encouraging activity in relapsed/refractory MCL.

Another agent is pirtobrutinib [LOXO-305], which is the most recent BTK inhibitor that has been shown to have good activity with ORRs of 52% in [patients with] MCL [who were previously treated with covalent BTK inhibitors. Pirtobrutinib is different from ibrutinib, acalabrutinib, and zanubrutinib because it is a noncovalent BTK inhibitor, which means it is not dependent on cysteine-281 activity in the BTK receptors. That is how [pirtobrutinib] works even in patients who did not have responses to prior BTK inhibitors.

What have been some of the most significant advances with novel agents in ALL?

ALL has a bimodal pattern. It is the most common leukemia seen in children and adolescents; however, we also see a fair proportion of adult patients being diagnosed [with the disease].

The treatment landscape of ALL has changed significantly and relies heavily on the novel agents blinatumomab [Blincyto] and inotuzumab ozogamicin [Besponsa] in the relapsed/refractory setting. Blinatumomab is a CD19- and CD3-directed BiTE that has shown impressive results in relapsed/refractory ALL. Therefore, patients who have CD19-positive ALL [should receive] blinatumomab. Moreover, blinatumomab has also been tested in patients with minimal residual disease [MRD]–positive ALL and has shown very good responses in eradicating MRD.

Inotuzumab ozogamicin is a CD22-targeting antibody-drug conjugate that has an active calicheamicin [antibiotic] that goes inside the cells and causes cytotoxic activity. In the phase 3 INO-VATE trial [NCT01564784], inotuzumab ozogamicin showed promising activity compared with the standard of care. Also, up to 78% of those patients also achieved MRD negativity.

Inotuzumab ozogamicin is given once weekly, which is convenient compared with blinatumomab which is given intravenously through a continuous pump. However, inotuzumab ozogamicin is given only in patients who have CD22-positive ALL.

One of the other issues with inotuzumab ozogamicin is veno-occlusive disease. The percentage of veno-occlusive disease with inotuzumab ozogamicin is close to 11% or 12%. Therefore, in patients being considered for stem cell transplantation that can be challenging.

Regardless, blinatumomab and inotuzumab ozogamicin have shown promising activity and are being heavily used in patients with relapsed/refractory ALL.

Given their promising activity, these agents are also being introduced into the frontline setting. Currently, a trial is ongoing comparing blinatumomab with standard chemotherapy in Philadelphia-positive ALL.

Currently, the CAR T-cell therapy tisagenlecleucel [Kymriah] is approved for young adolescent patients up to 25 years [of age with B-cell precursor ALL that is refractory or in second or later relapse]. My guess is that [axi-cel] might soon get approved by the FDA for this indication.

Patients with ALL have some very effective chemotherapy-free regimens [available]; however, it remains to be seen how many of these patients are cured and how many can have durable remissions. We need to see the long-term outcomes of those patients to continue to bring some knowledge to improve outcomes [for these patients].

How have PI3K inhibitors been integrated into the armamentarium of follicular lymphoma and how may cellular therapies expand this space?

Follicular lymphoma is one of the indolent lymphomas that remains incurable. Many advances have been made in the past few years that have improved outcomes for this high-risk population.

In the second-line setting, we often use the lenalidomide [Revlimid] and rituximab [Rituxan]–based combination. In the AUGMENT trial [NCT01938001], [the combination] showed wonderful responses in patients with relapsed/refractory follicular lymphoma. In fact, lenalidomide plus rituximab is also approved in the frontline setting based on the phase 3 [RELEVANCE trial (NCT01476787)], which was a noninferiority study. If I have a patient with relapsed/refractory follicular lymphoma, I usually consider lenalidomide in combination rituximab in the second-line setting.

Patients who progress on this combination are in urgent need for subsequent therapies. One option is a PI3K inhibitor in the third-line setting. Different PI3K inhibitors are approved, namely idelalisib [Zydelig], copanlisib [Aliqopa], and most recently, umbralisib [Ukoniq]. PI3K inhibitors differ in their activity against isoforms. Umbralisib is a PI3K-delta and CD1-epsilon inhibitor that, compared with previous agents such as idelalisib and copanlisib, has significantly less AEs including colitis and pneumonitis. It might be better tolerated [vs idelalisib and copanlisib].

All the PI3K inhibitors have individual ORRs close to 45% to 50% and a median PFS between 11 and 15 months. Therefore, they can often be used temporarily or as a bridge to subsequent therapies. Patients with certain follicular lymphomas, such as those with disease progression within 24 months from first-line therapy, represent an unmet need. These are the highest risk patients who will require treatment soon. Their PFS gets shorter with each line of therapy.

One of the new treatments is CAR T-cell therapy. Most recently, data [from the ZUMA-5 trial (NCT03105336)] were presented at the 2021 ASCO Annual Meeting about axi-cel. The trial showed that the ORR in patients with follicular lymphoma was [over] 90%, and the CR rate was [over] 70%. That treatment has also shown promising results in patients who have progression of disease within 24 months [of starting first-line treatment].

CAR T-cell therapy can be increasingly used in high-risk patients, although it can also replace autologous stem cell transplant in certain instances.

BiTEs or antibodies have shown impressive results [as well]. Those agents are also interesting therapeutic options in the armamentarium of follicular lymphoma. The treatment landscape is increasingly changing, so we might have more agents in the landscape in the next few years.

Could you discuss the utility of BTK inhibitors and other newer therapies in CLL? What factors do you consider during treatment selection?

CLL remains another incurable malignancy in which the therapeutic landscape has changed significantly in the past few years. BTK inhibitors have clearly shown superior results compared with chemoimmunotherapy in the treatment-naive and relapsed/refractory settings.

Currently, 3 [options] are approved in the treatment-naive setting, including ibrutinib, acalabrutinib, and venetoclax [Venclexta] plus obinutuzumab [Gazyva]. The BTK inhibitors have ORRs close to 90% and CR rates around 20% to 30%.

The safety profile of ibrutinib is one of the main challenges we [face] when dealing with [this agent] in this population. About 25% of patients had treatment interruptions or treatment discontinuations [with ibrutinib in the trial], mainly because of AEs. The most common AEs we encounter are diarrhea, arthralgias, myalgias, and bleeding episodes.

At the 2021 ASCO Annual Meeting, the ELEVATE-TN trial [NCT02475681] data were published comparing acalabrutinib vs standard of care, which was chlorambucil/obinutuzumab, in the first-line treatment for patients with CLL. Here, patients were randomized to acalabrutinib, acalabrutinib plus obinutuzumab, or chlorambucil plus obinutuzumab. Acalabrutinib [plus obinutuzumab] was associated with a superior ORR [of 96.1%] compared with chlorambucil/obinutuzumab, [which was 82.5%]. Notably, in patients who received acalabrutinib with obinutuzumab, the CR rate often deepens with time.

Although the BTK inhibitors are good in terms of efficacy, they differ in their AEs. One important study presented at the 2021 ASCO Annual Meeting highlighted these differences. The ELEVATE-RR trial [NCT02477696], which compared ibrutinib vs acalabrutinib in relapsed/refractory CLL, was a noninferiority study. Acalabrutinib was noninferior to ibrutinib with a median PFS of [38.4 months in both arms].

Something important that came out of this study was the difference in the safety profiles [of ibrutinib vs acalabrutinib]. Compared with ibrutinib, acalabrutinib [led to] significantly lower rates of atrial fibrillation, arthralgia, myalgia, hypertension, and other AEs. Based on these data, we can certainly say that both these agents are very efficacious, but agents [associated] with less AEs are preferred. We have a clear winner in this setting [with acalabrutinib]. Based on these data, we can extrapolate [these conclusions to] the treatment-naïve setting, where we can also consider acalabrutinib instead of ibrutinib.

One of the other advances is with umbralisib plus ublituximab, which was tested in [the] phase 3 [UNITY-CLL] trial [NCT02612311] in the relapsed/refractory and treatment-naïve settings of CLL. In both settings, the combination has shown very good activity and has the potential to be used in the future.

The last [emerging strategy] in CLL is CAR T-cell therapy, which is currently under investigation. At the 2020 ASH Annual Meeting and Exposition, data [from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198)] were presented [with lisocabtagene maraleucel (Breyanzi)] in combination with ibrutinib in 19 patients with CLL. The combination was associated with a CR rate of [95%]. About [89%] of patients achieved MRD negativity. CAR T-cell therapies are also currently being considered. Although [this agent] is not FDA approved, it is one of the promising agents we might use in the future.