High-Risk MCL Population Represents Unmet Need in Treatment Landscape

Article

The treatment landscape of mantle cell lymphoma has been enriched with the development of several targeted therapies, but patients considered to have high-risk disease tend to have a worse prognosis, despite the latest development in the field.

The treatment landscape of mantle cell lymphoma (MCL) has been enriched with the development of several targeted therapies, but patients considered to have high-risk disease tend to have a worse prognosis, despite the latest development in the field.

Chemoimmunotherapy was the mainstay of treatment for MCL until the introduction of highly effective targeted therapies, such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica)1 or the BCL-2 inhibitor venetoclax (Venclexta).2 The FDA also recently approved the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (KTE-X19; Tecartus), which has been a landmark advancement in this treatment landscape.3

Most patients will require treatment upon diagnosis of MCL, but some may present with indolent disease. Those with progressive and symptomatic disease require more immediate treatment with early initiation of therapy, which makes risk factor a critical consideration for predicting prognosis and guiding treatment. Use of the simplified MCL International Prognostic Index (MIPI) can identify patients with either low- and intermediate-risk disease, who have a significantly longer survival with a 5-year overall survival (OS) of 83% for low risk and 63% for intermediate risk with chemoimmunotherapy. The prognosis is worse among those with high-risk disease, in which the 5-year OS is 34% with chemoimmunotherapy, with or without autologous stem cell transplant (SCT).4

Overtime, patients with low-risk disease may become high risk overtime. The current understanding of risk factors for MCL progression is based on data collected during the clinical assessment, duration of response to frontline therapy, genetic and molecular determinants of MCL progression, and knowledge about resistance mechanisms of the disease. A major challenge in the field at this time is understanding progression on BTK inhibitors, in particular.

Defining High-Risk Disease to Determine Prognosis

Features of high-risk MCL include poor performance status, elderly age, significant comorbidities, and disease characteristics, including central nervous system (CNS) involvement, disease transformation, and BTK inhibitor-refractoriness. Pathobiologic high-risk disease categories in MCL include blastoid/pleomorphic histology, high-risk simplified and combined MIPI, high Ki-67 (≥ 30%), and TP53 aberrations. These factors are prognostic in newly diagnosed patients, while other factors, such as complex karyotype and disease progression within 12 to 24 months following frontline therapy, are indicators of poor prognosis in patients with relapsed MCL.

Select genetic alterations serve as adverse risk factors, and further validation of their independent prognostic impact is needed during the era of novel therapies, including the presence of MYC rearrangement or overexpression, high-risk 17-gene proliferation signature, complex genomic variants and higher degree of DNA methylation, overexpression of SOX-11, minimal residual disease (MRD)-positivity, unmutated immunoglobulin heavy chair variable region somatic hypermutation status, elevated miR18b, and downregulation of BACH2, as well as somatic mutations in CCND1, NSD2, NOTCH1, NOTCH2, KMT2D, CDKN2A, SMARCA4, and HNRNPH1 genes.

Additionally, overexpression of oxidative phosphorylation pathway genes, cMYC and m-TOR pathways, and non-BTK mutations are predominant factors among patients with ibrutinib-resistant disease, while non-BCL2 mutations, including KMT2DTP53CELSR3, and SMARCA4, have been associated with resistance to venetoclax.

The patients enrolled to clinical trials tend to have a better performance status and comorbidity profile, but a higher number of comorbidities foreshadow poor survival outcomes, according population-based studies. Patients with MCL who are ineligible for SCT also tend to be underrepresented in clinical trials, and patients with aggressive histology, including poor performance status of 3 or 4, is predictive of inferior survival.

CNS involvement is generally uncommon at diagnosis, occurring in 1% of patients. However, a higher frequency of CNS relapses is associated with select baseline high-risk factors, such as blastoid histology, high lactate dehydrogenase (LDH) levels, and high Ki-67. The survival among patients with CNS disease is low, which median survival ranging from 3 to 8 months. According to findings from a recent retrospective comparison, ibrutinib demonstrated superior survival compared with conventional chemotherapy.5

Among 31 patients with CNS relapse MCL, 16 of whom received chemotherapy and 15 the BTK inhibitor, the 1-year progression-free survival (PFS) rate was 49% with ibrutinib versus 6% with chemotherapy (P =.044). The 1-year OS rates also favored ibrutinib but did not reach statistical significance at 57% with ibrutinib versus 37% with chemotherapy (P =.097).

This multicenter series of patient population included high-risk MIPI scores in 73% of the ibrutinib arm and 46% of the chemotherapy arm, while 5 and 6 patients, respectively, had blastoid variant. The study ultimately demonstrated ibrutinib monotherapy could be effective for CNS MCL, despite the limitations of the retrospective analysis.

Although these findings are encouraging, the outcomes for this population remain poor. Ibrutinib appears to have activity against primary CNS disease, but the relapse pattern remains undefined.4

Approximately 10% to 20% of patients with MCL present with blastoid/pleomorphic disease, either as de novo MCL or at relapse as transformed MCL. These patients tend to have poor outcomes, as exhibited in multiple single-arm and randomized clinical trials, such as a study published in Blood that demonstrated aggressive histology patients with transformed MCL have inferior survival compared with de novo patients. The median survival was 14 months in the transformed arm compared with 48 months in de novo patients (P =.001).6

Patients with aggressive histology, transformed MCL had a higher degree of aneuploidy and KMT2D and KMT2B mutations, which is associated with inferior survival compared with patients with de novo disease. This study was the first to report that patients with aggressive histology MCL who harbor high Ki-67 (≥50%) have a distinct mutational profile and very poor survival.

CNS involvement occurs in about 5% to 30% of MCL, which is predominantly leptomeningeal, while the median Ki67 is 70% (range, 10%-100%). Complex karyotypes and tetraploid are also common among this class of MCL, which exhibit a distinct genomic profile compared with the classic presentation of MCL. Some of the most common gene mutations in aggressive MCL include NOTCH2, NOTCH3, UBR5, and CCND1.

Blastoid/pleomorphic MCL is primarily treated with intensive chemoimmunotherapy and consolidation with autologous SCT, but the preferred approach at this time is the offering of clinical trials to these patients. Due to the rarity of this disease, enrollment to prospective clinical trials for aggressive MCL remains a challenge.

Several clinical trials have aimed to evaluate the treatment outcomes of patients with this aggressive histology of MCL. In particular, a pooled analysis of 370 patients with relapsed/refractory MCL demonstrated an overall response rate (ORR) of 66%, which complete responses in 20% and partial responses in 46%, with ibrutinib treatment. The median duration of response was 18.6 months, while the median PFS was 12.8 months and the median OS was 25.0 months. Longer OS findings were observed in patients who received 1 prior line of therapy compared with those who had 2 or more.7

A multivariate analysis in this study demonstrated several factors appeared to affect OS and PFS, and these included the ECOG performance status, simplified MIPI score, bulky disease, and blastoid histology. Having 1 prior line of therapy affected PFS. The time to response was similar among those with blastoid versus non-blastoid histologies, but lower ORR, DOR, PFS, and OS were observed in patients with blastoid histology. The OS and PFS were longer among those with better simplified MIPI scores, those with an ECOG performance status of 0 to 1, non-bulky disease, and non-blastoid histology.

These findings ultimately indicate that outcomes following failure with ibrutinib are associated with the natural biological evolution of the disease, as the proportion of patients with poor prognostic factors had increased as the number of prior lines increased.

Another well-established prognostic indicator for MCL is the MIPI score, which includes prognostic parameters such as age, performance status, serum LDH level, and leukocyte count. Patients with high-risk MIPI scores have been associated with significantly inferior outcomes after frontline lenalidomide (Revlimid) plus rituximab (Rituxan), as well as in the relapsed setting following treatment with either ibrutinib singe agent, ibrutinib plus rituximab, or single-agent acalabrutinib (Calquence). High Ki-67 expression has also been associated with poor survival, independent of blastoid histology, or non-blastoid.

TP53 gene aberrations is known to lead to genomic instability, failure of cell cycle arrest, and loss of tumor growth, and they are also associated with other aggressive disease features, including the blastoid/pleomorphic histology, high Ki-67, complex karyotype, and high-risk MIPI index, which are ultimately predictive of poor outcomes in MCL.

A complex karyotype, defined by the presence of 3 or more unrelated chromosomal abnormalities, not including the driver lesion t(11;14), is another factor associated with a worse prognosis in MCL, which has been demonstrated with inferior OS outcomes on clinical trials compared with non-complex karyotype patients. Older studies evaluating the complex karyotype used treatments besides BTK inhibitors and CAR T-cell therapies, underscoring the need for studies evaluating newer treatment modalities in patients with complex karyotypes.

Understanding Resistance to Therapy

Poor OS can be predicted by failure to achieve a CR following frontline therapy or disease relapse within 12 months of receiving frontline therapies, including treatments such as intensive chemoimmunotherapy with or without consolidative SCT or ibrutinib-based therapies. This type of activity following frontline treatment could also be predictive of an increased frequency of relapses on subsequent lines of therapy.

According to findings from a series of 404 treatment-naïve patients, 70 had early failure to therapy while 133 had late failure, and among these 2 groups, respectively, the median OS was 30 months and 70 months (P<.01). This pattern was observed in evaluation of the survival and CR rates as well, which were impaired with subsequent lines of therapy.8

The median OS and PFS, respectively, following first-line therapy were 9.7 years and 4.0 years compared with 41.1 months and 14.0 months after second-line therapy, and 25.2 months and 6.5 months in the third0line. The OS and PFS medians in the fourth line were 14.4 months and 5.0 months, as well, respectively. This retrospective study demonstrated that early treatment failure after frontline therapy was associated with a worse OS.

The emerging problems with resistance to ibrutinib poses a major challenge to the field, although the evolution of this BTK inhibitor has been an important advancement for the field of MCL. Nevertheless, studies have demonstrated poor survival outcomes among patients who progress following ibrutinib therapy.

A study evaluating the long-term outcomes of patients with MCL who discontinued ibrutinib therapy demonstrated that the median survival after ibrutinib was 10 months for those who discontinued ibrutinib due to disease progression and 6 months for who discontinued due to transformation, compared with 25 months for patients who were ibrutinib-intolerant. It was noted that BTK mutations were observed in 17% of patients after progression and TP53 alterations in 75%.

These findings suggest ibrutinib-resistant MCL is an emerging high-risk subgroup. Venetoclax has demonstrated moderate efficacy in this group of patients with response rates in the range of 40% to 50%. Another promising treatment option in this space includes the CAR T-cell therapy KTE-X19, which has demonstrated promising early results among patients with highly refractory disease. Long-term follow-up on these studies will help determine the durability of responses, while it remains unclear whether patients with disease progression after CAR T-cell therapy are salvageable with the current therapies available.9

Overcoming Resistant in MCL

The single-arm international multicenter phase 2 ZUMA-2 clinical trial evaluated patients who had progressed on a prior BTK inhibitor, including patients with high-risk disease features. The ORR was > 93% among patients with blastoid, TP53-mutated or high Ki-67 MCL, and after a median follow-up of 12.3 months (range, 7.0-32.3), 57% of patients were still in remission. The median DOR, PFS, and OS were not reached in the study.4

The most common grade 3 or higher adverse events (AEs) included cytopenias in 69% and infections in 32%. Cytokine release syndrome (CRS) of grade 3 or higher occurred in 15% of patients, and grade 3 or higher neurologic events occurred in 31%, although none of these were fatal.

KTE-X19 appears to have several major advantages over allogenic SCT, which include reduced morbidity and mortality, preservation of T-cell function, and lower risk of infections, but the data on the durability of response is still needed for its superiority to be established.

Lisocabtagene maraleucel (JCAR-017), another CD19-directed CAR T-cell therapy, is currently under evaluation in clinical trials as well for the treatment of MCL. A phase 1 study has already demonstrated an ORR of 71% with this therapy, with CRs occurring in 53% of patients. Grade ≥3 AEs included CRS in 6% and neurotoxicity in 12%.

Additional studies of cellular therapies are also evaluated CD19-direct CAR natural killer cells, off-the-shelf CAR T cells, allogeneic CAR T cells directed against CD19, and humanized binding domain in CD-10 CAR T cells. Studies are also evaluating combinations with anti-CD19 CAR T cells and BTK inhibitors or lenalidomide. Other targets, such as CD20, CD22, ROR1, BAFF, and CD79b are under investigation in the cellular space as well.

LOXO-305 is a new, reversible BTK inhibit that has also demonstrated potent activity as a selective inhibitor of wild-type BTK as well as BTK harboring the C481S acquired resistance mutation. A phase 1 study has demonstrated promising results for this treatment in BTK inhibitor-refractory MCL and remains under evaluation.

Patients with low- or intermediate-risk disease defined by MIPI can be treated with frontline chemoimmunotherapy, but patients with high risk MIPI scores should be considered for intensive chemoimmunotherapy followed by consolidation SCT followed by rituximab maintenance. However, if it is feasible for the patient to enroll in a clinical trial, that is a recommended course of action, due to the lack of treatment options available and the limited representation of this high-risk population in clinical trials.

References

1. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013. doi: 10.1056/NEJMoa1306220

2. Davids MS, Roberts AW, Seymour JF, et al: Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol 35:826-833, 2017. doi: 10.1200/JCO.2016.70.4320

3. Wang M, Munoz J, Goy A, et al: KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 382:1331-1342, 2020. doi: 10.1056/NEJMoa1914347

4. Jain P, Dreyling M, Seymour JF, and Wang M. High-Risk Mantle Cell Lymphoma: Definition, Current Challenges, and Management. Published Online: October 19, 2020. J Clin Oncol. doi: 10.1200/JCO.20.02287

5. Rusconi C, Tucker D, Bernard S, et al. Ibrutinib compared to standard chemotherapy for central nervous system recurrence of mantle cell lymphoma. Hematol Oncol 37:244-245, 2019. doi:

6. Jain P, Zhang S, Kanagal-Shamanna R, et al: Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL. Blood Adv. 4:1038-1050, 2020 doi: 10.1182/bloodadvances.2019001396

7. 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. Br J Haematol. 179:430-438, 2017. doi: 10.1111/bjh.14870

8. Kumar A, Sha F, Toure A, et al: Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: Progressive shortening in response duration and survival after each relapse. Blood Cancer J. 9:50, 2019. doi: 10.1038/s41408-019-0209-5

9. Wang M, Munoz J, Goy A, et al: KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med 382(14):1331-1342, 2020. doi: 10.1056/NEJMoa1914347

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