Mantle Cell Lymphoma is a rare B-cell malignancy that can invade almost any structure in the body and recur after short-lived clinical responses.
The pathogenesis and clinical features are well defined, but management has not yet been optimized.
Induction with traditional immune-chemotherapy regimens that are used in other non- Hodgkin lymphomas rarely generate durable remissions.
Mantle cell lymphoma (MCL) is an uncommon but aggressive lymphoma, comprising about 6% of all non-Hodgkin lymphomas, with a typical median survival of 5-7 years
Patients are much more commonly male and elderly with a median age of onset of 68 years.
The disease is less frequent in Asian countries.
Most cases are advanced at presentation and often exhibit complete responses to initial treatment followed by frequent relapses
This neoplasm is characterized by mature B-lymphocytes that infiltrate the lymph nodes, bone marrow, peripheral blood, and extranodal sites.
Histologically it appears homogenous with a background of pink histiocytes that stain positively for cyclin D1, surface immunoglobulin B-cell markers, and CD5
The t (11;14) (q13;q32) translocation is present in over 90% of MCL, and other translocations have been reported.
Disease heterogeneity features: a blastoid variant with a high Kiel 67 (Ki67) proliferation index, as well as a more indolent variant that can be appropriately managed with a watch and wait approach until symptomatic.
Younger, fit patients can be managed with intensive cytarabine-containing chemotherapy alternating with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with rituximab (R-HyperCVAD) with or without autologous stem cell transplantation for consolidation.
Other patients receive CHOP-like (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy plus rituximab.
Substitution of vincristine with the proteasome inhibitor bortezomib has emerged as a validated treatment for both relapsed and untreated disease.
Awareness of prognostic factors through the validated MIPI score, identification of potential transplant candidates, and careful assessment of response to and tolerance of immunochemotherapies, are all crucial determinants of both survival and quality of life.
MCL can be distinguished by immunohistochemistry (IHC) with a profile usually showing positivity for B-cell markers as well as CD5, FMC7, CD43, and cyclin D1.
Most cases are negative for CD10 and CD23.
The reciprocal translocation t (11;14) results in the overexpression of cyclin D1,
In less than 5% of cases, cyclin D1 and t (11;14) may be negative in MCL if there is an otherwise typical IHC profile, with over half of these cases revealing rearranged CCND2 and consequent overexpression of cyclin D2 mRNA,
Most pathologic findings and clinical features of cyclin D1-negative MCL appear similar to those of cyclin D1-positive cases and are managed the same.
The pathogenesis of mantle cell lymphoma (MCL) occurs through two major events that cause a gain and loss of function.
Chromosome 11q13 holds the proto-oncogene CCND1, which encodes cyclin D1, and its translocation to chromosome 14q32, the locus of the immunoglobulin heavy chain complex (IGH), deregulates the cell cycle at the G1/S phase transition and makes cyclin D1 constitutively overexpressed in otherwise normal B lymphocytes.
Gain of function occurs via t (11;14) translocation, causing BCL-1 over-transcription.
Loss of function occurs via 11q22-23 deletion, alters the DNA damage pathway response.
Cyclin D1 protein has a major oncogenic effect through two different mechanisms.
MCL carries a high degree of genomic instability, with secondary chromosomal alterations.
MCL is thought to derive from naïve B-cells in the pre-germinal center (mantle zone) since the initial translocation event t (11;14) occurs during recombination of the V(D)J segments of the IGH variable region (IGHV) in the bone marrow.
Antigen selection is now thought to play an important role in pathogenesis for the 15-40% of MCLs that carry IGHV hypermutations similar to those in chronic lymphocytic leukemia.
Cyclin D1 binds to CDK4 and CDK6, which phosphorylates retinoblastoma 1 (RB1), thereby activating the transcription factor E2F while promoting cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle.
The round cell variant has a CLL-like clinical presentation that tends to behave more like an indolent lymphoma, usually showing a rather low cell proliferation (Ki-67 roughly 10%).
A blastoid variant occurring 5% of the time shows a much more aggressive clinical course.
Biological factors like high cell proliferation (determined by Ki-67 staining) or p53 mutations and p16 deletions are closely related to this MCL subtype.
More than 80% of MCL still presents with somewhat intermediate characteristics.
Prognostic marker system categorize MCL patients:
relative survival probability by grading the following risk factors: age, performance status, lactate dehydrogenase (LDH) level, and white blood cell (WBC) count.
A MIPI combined biologic index (MIPIb) score of less than 5.7 classifies patients into a low-risk group comprising 44% of patients with a median overall survival (OS) not reached; a score of 5.7 to less than 6.2 yields an intermediate-risk group comprising 35% of patients with median OS of 51 months; and a score of 6.2 or greater falls into the high-risk group with 21% of the patients and median OS of 29 months.
The number of extranodal sites is not an independent prognostic factor in the MIPI score.
Tumor cell proliferation, assessed on by Ki-67, showed a median value of 14.5% (range 1.2–91%).
Ki-67 value is prognostically significant using a cutoff point of 10%, and is independent of the MIPI.
Ki-67 of 30% has been proposed by the NCCN as a cutoff for determining the aggressiveness of the disease.
MIPIb Index Score Risk and overall survival:
<5.7 Low risk 44% Not reached
5.7 to 6.2 Intermediate risk 35% 51 months
6.2 High risk 21% 29 months
Localized presentation, which is extremely rare, can be managed with observation, radiation therapy, or a combination of radiation and chemotherapy.
The use of radiotherapy with or without chemotherapy engendered significantly better progression-free survival (PFS) at 5 years (73% vs. 13%) with a trend towards overall survival benefit, when compared to patients who did not receive radiation.
Radiotherapy as a primary treatment for stage 1-2 MCL patients analyzed retrospectively showed curative results for 3.6% of patients, with 3-year OS of 93%.
Bulky Stage II, Stage III, and Stage IV
In highly select cases in which the patient is asymptomatic, advanced disease can also be managed with a watch and wait approach.
R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) is considered a preferred aggressive regimen in patients who can tolerate considerable toxicity
A phase II study of 97 treatment-naïve patients with advanced MCL showed failure-free survival of 64% and overall survival of 82% at 3 years, and median overall survival not yet reached at 10 years follow-up
Newly diagnosed patients under the age of 70 who received R-HyperCVAD yielded PFS of 4.8 years and OS of 6.8 years, with 2-year PFS of 63% and OS of 76%.
In a phase III randomized trial of the German Low Grade Lymphoma study group that evaluated the addition of rituximab to CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) in treatment-naïve patients with advanced MCL aged 65 and younger.
R-CHOP showed significantly better overall response rate (94% vs. 75%), complete remission rate (34% vs. 7%) and median time to treatment failure (21 months vs. 14 months) than CHOP.
However, PFS and OS outcomes were not superior. R-CHOP can also be alternated with R-DHAP (rituximab, dexamethasone, cisplatin, cytarabine) or R-ICE (rituximab, ifosfamide, carboplatin, etoposide) in sequence.
For elderly patients or those with poor performance status, bendamustine plus rituximab (BR) has shown superior PFS than R-CHOP (35 months vs. 22 months.
Another less aggressive induction regimen to gain FDA approval is VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone): When compared to R-CHOP in patients who underwent front-line VR-CAP showed superior PFS (24.7 vs. 14.4 months, p<0.001) and CR rate (48% vs. 41%) with a trend towards OS benefit (64% vs. 54%) in a phase III randomized study.
Following successful induction with R-HyperCVAD or CHOP-like immunochemotherapy, high-dose therapy (HDT) with one cycle of etoposide, cytarabine, and rituximab and one cycle of carmustine, etoposide, and cyclophosphamide has been effectively followed by autologous stem cell rescue.
Thirty-three patients treated after achieving first remission with HyperCVAD with or without rituximab achieved 5-year disease-free survival of 42% and OS of 77%with 100% OS rate in those patients with a low serum beta-2 microglobulin level.
Long-term follow-up showed a median PFS of 42 months and OS of 93 months.
There is improved PFS in transplanted patients who were induced with HyperCVAD (with or without rituximab) rather than CHOP (with or without rituximab).
Post-induction maintenance therapy with rituximab has been shown to provide extended disease control for patients who cannot undergo high-dose therapy and stem cell transplantation.
Additionally studies have also shown promising data for rituximab maintenance after R-CHOP induction.
It remains unclear whether first-line consolidation with high-dose chemotherapy with autologous stem cell rescue (HDT/ASCR) provides an advantage over rituximab maintenance in patients of any age.
Second-line consolidation therapy can be pursued with autologous or allogeneic stem cell transplantation (SCT) following non-myeloablative or myeloablative conditioning regimens.
Graft-versus-host disease (GVHD) prophylaxis consisted of a combination of cyclosporin or tacrolimus with mini-dose methotrexate and/or methylprednisolone.
Allo-SCT in 44 patients resulted in lower recurrence rates but higher treatment-related mortality rates than the 68 patients who underwent high-dose therapy with autologous stem cell transplantation.
The improved OS among the allogeneic SCT group was not statistically significant but the improved DFS was significant.
Regimens suitable for use in first relapse include: bendamustine with or without rituximab, . Cladibrine, FC (fludarabine plus cyclophosphamide) with or without rituximab, FCMR (fludarabine, cyclosphamide, mitoxantrone, and rituximab), FMR (fludarabine, mitoxantrone, and rituximab), PCR (pentostatin, cyclophosphamide, and rituximab) and PEPC (prednisone, etoposide, procarbazine, cyclophosphamide with or without rituximab.
Bortezomib is approved for relapsed or refractory MCL based on the phase II PINNACLE trial, in which bortezomib induced an overall response rate of 33% (CR in 8%), with a median duration of response of 9 months and median time to progression of 6 months.
Bortezomib combined with rituximab has shown activity in heavily pre-treated patients with relapsed/refractory disease.
The immunomodulating agent, lenalidomide, has shown efficacy in relapsed or refractory aggressive non-Hodgkin lymphoma, with subset analysis of MCL patients showing an ORR of 35% and CR rate of 12% at a median follow-up of 12 months in a phase II trial.
In this study the duration of response was 16 months, and the median PFS was approximately 9 months.
The small-molecule Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has shown promising activity in several B-cell malignancies.
A multicenter phase II trial of 111 patients who had been previously treated with bortezomib and/or rituximab-containing regimens, 72% of whom had advanced disease and 42% of whom had high-risk MIPI scores, showed an ORR of 68% with CR rate of 21% after 15 months of ibrutinib.
The median duration of response was 17.5 months, median PFS was 14 months, and estimated OS rate at 18 months was 58%.
The response rates appeared to increase with longer duration of therapy.
The most common adverse event rated grade ≥3 were neutropenia (16%), thrombocytopenia (11%), anemia (10%), pneumonia (6%), diarrhea (6%), fatigue (5%) and dyspnea (5%).
The use of ibrutinib causes a transient lymphocytosis that resolves after an average of 8 weeks, and caused grade ≥3 bleeding events in 5% of patients.
Ibrutinib can extend the lives of heavily treated, relapsed, or refractory patients with mantle cell lymphoma (MCL), many become resistant to the drug.
30% of the patients who developed resistance to ibrutinib expressed high levels of activated phosphatidylinositol-3 kinase (PI3K-AKT) and cyclin-dependent kinase 4 (CDK4).
Analysis of longitudinal functional genomics in MCL showed that 30% of the patients who developed resistance to ibrutinib expressed high levels of activated phosphatidylinositol-3 kinase (PI3K-AKT) and cyclin-dependent kinase 4 (CDK4): PI3K-AKT proteins promote survival; CDK4 drives MCL cells through the cell cycle.
These two mechanisms appeared to override ibrutinib’s inhibitory action in resistant cells.
Stepwise treatment with palbociclib followed by ibrutinib, or palbociclib followed by the PI3K pathway inhibitor, idelalisib, which is FDA-approved to treat CLL, might treat MCL patients who initially do not respond to ibrutinib.
Idelalasib evaluated in patients with relapsed or refractory mantle cell lymphoma patients who had received a median of four prior therapies.
Overall, nine (18%) patients discontinued therapy due to adverse effects including diarrhea, transaminase elevations, pneumonia, and acute renal failure.
Thirty-three (84.6%) patients had some reduction in lymph node size, with CR in two (5%) patients, PR in 14 (35%) patients, and stable disease in nineteen (47.5%) patients.
Bortezomib Phase II PINNACLE trial with 33% response rate and median duration of response of 9 months, with a median time to progression of 6 months .
Lenalidomide Phase II Multicenter Study with 35% response rate and duration of response was 16 months.
Mantle cell lymphoma is an incurable but increasingly well characterized clinicopathologic entity that unfortunately poses persistent obstacles in achieving durable responses with available treatment regimens.
Early stage disease is rare, but limited available data suggests that radiation with or without chemotherapy can effectively manage limited, non-bulky distribution.
For advanced disease can be managed up-front with either observation, R-HyperCVAD, CHOP-like chemotherapy, or less aggressive induction regimens including bendamustine and rituximab.
Relapsed and refractory disease carries a poorer prognosis, but novel agents including bortezomib, lenalidomide, and ibrutinib have shown promising efficacy and tolerability.
Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous.
Risk stratification at the time of diagnosis is critical.
One of the most powerful prognostic indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical factors.
In addition, the presence of TP53 mutation is associated with suboptimal response to intensive chemoimmunotherapy and particularly dismal survival outcomes.
Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics—such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax—are being incorporated into chemotherapy-free regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma.
After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib.
Comprehensive biologic characterization of mantle cell lymphoma leads to optimal disease risk stratification and should include an estimate of proliferation (Ki67 index) and targeted genomic sequencing to assess for TP53 mutation.
Presence of TP53 mutation is associated with a poor response to standard chemoimmunotherapy, and clinical trial participation is strongly encouraged for this high-risk subset in the frontline and relapsed/refractory setting.
In patients with high-risk mantle cell lymphoma, early referral for consideration of CAR T-cell therapy is advisable, as similar efficacy has been observed with CAR T-cell therapy across subgroups, including patients with a high-risk Mantle Cell Lymphoma International Prognostic Index score, blastoid morphology, high Ki67 index, and TP53 mutation.
Mantle cell lymphoma is characterized by the presence of t(11;14), which juxtaposes the CCDN1 gene with the immunoglobin heavy chain locus, leading to overexpression of cyclin D1.
Mantle cell lymphoma is clinically and biologically heterogeneous, ranging from the indolent non-nodal leukemic variant to the highly proliferative blastoid variant.
The Mantle Cell Lymphoma International Prognostic Index (MIPI) was initially devised in 2008 from data from over 400 pooled patients.
The MIPI score is calculated as a weighted summation of pretreatment values of age, ECOG Performance Status, lactate dehydrogenase level, and white cell count.
A simplified version of MIPI (s-MIPI) has been devised for routine clinical practice, as has the biologic MIPI (MIPI-b), in which tumor cell proliferation measured by the Ki67 index is added to the MIPI score.
The MIPI-b integrates the Ki67 index, this index effectively divides patients into only two groups, as very few patients are in the low-risk group and these patients have similar outcomes to intermediate-risk MIPI-b cohorts.
Validation of the MIPI was performed using a large European Mantle Cell Lymphoma Network cohort of patients from two frontline clinical trials (958 patients; median age, 65; age range, 32–87).
Five-year overall survival (OS) rates of low-, intermediate-, and high-risk MIPI groups were 83%, 63%, and 34%, respectively, and the MIPI was similarly prognostic for time-to-treatment failure.
The four individual factors comprising the MIPI were independently prognostic for OS and time-to-treatment failure.
Although the MIPI has been shown to be prognostic and reproducible, an additional modification has been shown to have even more discriminatory prognostic power:Ki-67.
The integration of Ki67 index levels and the MIPI score to devise the combination MIPI (MIPI-c): according to Ki67 index status that modified combination separated patients into four groups: low, low-intermediate, high-intermediate, and high risk.
Five-year OS rates were 85%, 72%, 43%, and 17%, respectively,
demonstrating greater discrimination than the MIPI alone.
High TP53 expression was strongly prognostic for both inferior time-to-treatment failure and OS compared with low TP53 expression after adjusting for MIPI score and Ki67 index.
TP53 mutations are observed in 11%, del17p in 16%, NOTCH1 mutations in 4%, and CDKN2A mutations in 20%.
All these genetic subgroups, together with the MIPI, MIPI-c, blastoid morphology, and Ki67 index greater than 30%, were each associated with inferior survival.
Patients with disease harboring a TP53 mutation were enriched for Ki67 index greater than 30%, blastoid morphology, and a high-risk MIPI, and had a short median OS of 1.8 years.
TP53 mutation was a stronger negative prognostic marker than presence of del17p.
Interestingly, when patients without TP53 mutations were analyzed, the MIPI score was no longer prognostic.
MIPI-c provides a robust and reproducible prognostic scoring in the immunochemotherapy era and is a useful tool for risk stratification.
The single strongest negative prognostic marker is presence of a TP53 mutation.
Widespread usage of mutational testing by next-generation sequencing or other techniques such as RT-PCR remains limited but should be encouraged given its prognostic value.
A calculation of the MIPI-c, histopathological subtyping, and assessment of Ki67 index should be performed in all cases.
If available, TP53 mutational analysis should also be performed prior to initiation of treatment and with each subsequent line of therapy, as it provides valuable prognostic information.
The impact of relapse was greatest for patients whose disease relapsed within 6 months (5-year OS, 45% for relapsed vs. 71% for not relapsed disease) 12 months (35% for relapsed vs. 74% for not relapsed disease; HR, 6.68), and 18 months (38% for relapsed vs. 75% for not relapsed disease.
Undetectable MRD following immunochemotherapy in patients with mantle cell lymphoma predicts superior survival outcomes.
Techniques used to measure MRD, including real-time quantitative polymerase chain reaction, nested–polymerase chain reaction, double-droplet polymerase chain reaction, and next-generation sequencing.
Routine testing outside of clinical trials is not considered standard practice.
Covalent BTK (cBTK) inhibitors are a cornerstone of treatment for patients with relapsed/refractory mantle cell lymphoma.
Many patients treated with ibrutinib, acalabrutinib, or zanubrutinib have deep and durable remissions.
CAR T-cell therapy, which is currently most often used in the post-BTK inhibitor space.
Outcomes with ibrutinib monotherapy overall response rates (ORR) were 55%, 50%, and 55%, respectively, with complete responses (CRs) uncommon.
The median progression-free survival (PFS) rates were 6.5 months, 5 months, and 4 months, respectively.
Approximately one-third of patients with relapsed/refractory mantle cell lymphoma receiving ibrutinib monotherapy have a poor prognostic feature (high-risk s-MIPI, blastoid morphology, or TP53 mutation) and have an ORR of approximately 55% and a median PFS of only 6 months.
Ki67 index has also been shown to be a poor prognostic marker in a cohort of 50 patients with relapsed/refractory mantle cell lymphoma treated with ibrutinib/rituximab.
Patients with a Ki67 index greater than or equal to 50% had an inferior ORR (50% vs. 100%), PFS (median, 5.9 months vs. not reached), and OS (13.6 months vs. not reached) compared with patients with a Ki67 index less than or equal to 50%.
Adverse clinical factors in this series were progression of disease within 24 months, increased age, and poor performance status.
Factors such as high-risk MIPI, blastoid morphology, high Ki67 index, and TP53 mutation are consistently associated with inferior survival following frontline immunochemotherapy and targeted inhibitors in relapsed/refractory mantle cell lymphoma, in contrast, outcomes for high-risk patients treated with brexucabtagene autoleucel provide some encouragement.
Brexucabtagene autoleucel in the ZUMA-2 trial equivalent ORRs for patients with and without blastoid morphology 93%, TP53 mutation 100%, Ki67 index greater than or equal to 50% (ORR 94%), and intermediate- or high-risk s-MIPI (ORR 94%).
It is suggested that allogeneic haematopoietic stem cell transplantation may have similar activity in patients with relapsed/refractory mantle cell lymphoma with or without TP53 aberration.
Although a subset of patients with indolent disease may undergo observation, most patients ultimately require therapy.
For young, fit, transplant-eligible patients, an accepted standard of care is induction chemotherapy incorporating cytarabine and rituximab followed by consolidation with an autologous stem cell transplantation and rituximab maintenance.
For older patients or those who are transplant ineligible, chemoimmunotherapy regimens such as bendamustine/rituximab are recognized as standard approaches in addition to R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) and VR-CAP (bortezomib/rituximab/cyclophosphamide/doxorubicin/prednisone).
In recent years, advances in our understanding of mantle cell lymphoma biology and drug development have led investigators to examine chemotherapy-free treatment paradigms.
Targeted agents, including the cBTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib, showed unprecedented clinical activity in patients with relapsed/refractory disease and are now second-line options for patients following chemoimmunotherapy.
The incorporation of ibrutinib improves response rates, duration of response, and survival.
A chemotherapy-free regimen was a multicenter, phase II study of lenalidomide/rituximab.
This trial included patients with mantle cell lymphoma with either low- or intermediate-risk disease or high-risk disease (MIPI ≥ 6.2) with a contraindication to intensive chemotherapy.
Lenalidomide/rituximab induction for 12 months was followed by indefinite lenalidomide/rituximab maintenance.
The ORR was 92%,64% CR; 36 evaluable patients; median follow-up, 30 months)
With a longer median follow-up of 64 months, the 3-year PFS was 80% and the estimated 5-year PFS was 64% with an estimated 5-year OS of 77%.
Attempts to improve upon the lenalidomide/rituximab regimen by examining the triplet of venetoclax/lenalidomide/rituximab in patients with treatment-naïve mantle cell lymphoma regardless of age or disease characteristics.
At a median treatment duration of 278 days, the triplet had an ORR of 96%, and 71% patients had undetectable MRD.
Multiple studies are attempting to incorporate BTK inhibitors into the frontline setting without the use of chemotherapy: findings from a phase II study of ibrutinib and rituximab for 2 years with continuation of ibrutinib in patients age 65 or older with treatment-naive mantle cell lymphoma without a Ki67 index greater than or equal to 50% or blastoid morphology.
The ORR was 96%, and median PFS and OS have not been reached (median follow-up, 45 months).
A common clinical trial design for frontline chemotherapy-treatment is a triplet combination of a BTK inhibitor, venetoclax, and an anti-CD20 antibody.
Synergy of ibrutinib and venetoclax has been seen in relapsed mantle cell lymphoma cells in the preclinical setting and in a phase II trial of the combination in relapsed mantle cell lymphoma.
Triplet combinations observed in patients with chronic lymphocytic leukemia,provide a rationale to study BTK inhibitors, venetoclax, and anti-CD20 antibody combinations for treatment-naïve mantle cell lymphoma.
The OASIS trial was a phase I/II study of the triplet ibrutinib/obinutuzumab/venetoclax in patients with relapsed and treatment-naïve mantle cell lymphoma.
The ORR after six cycles was 86%, with 73% and 67% of patients attaining undetectable MRD in the peripheral blood and bone marrow by allele-specific oligonucleotide polymerase chain reaction, respectively.
With a median follow-up of 14 months, 1-year PFS for the cohort was 93.3% with a 1-year OS of 100%.52
The combination of acalabrutinib/venetoclax/rituximab has also shown preliminary safety and efficacy in treatment-naïve patients.
The triplet had an ORR of 100% at the end of cycle 6, with a median duration of response of 19 months and a 1-year estimated PFS rate of 89%.
At cycle 6, 75% of patients had undetectable MRD in the peripheral blood.
Given the heterogeneity of mantle cell lymphoma biology, a single approach is likely to overtreat or undertreat certain patient subgroups.
After 12 months, the ORR was 84% with 80% CR.
Sixty-nine percent of patients discontinued ibrutinib per protocol because of undetectable MRD.
In the patients who discontinued ibrutinib, somhave experienced MRD-positive relapse (peripheral blood; range to detectable MRD, 3–20 months).57 Longer follow-up is needed to determine the durability of responses.
Using MRD status to guide consolidation therapy is also an area of ongoing study.
BTK inhibitors have become a mainstay of therapy for patients with relapsed/refractory mantle cell lymphoma.
Although BTK inhibitors have improved the prognosis of relapsed/refractory mantle cell lymphoma, therapeutic options for patients who experience progression during or following BTK inhibitors remain limited.
Anti-CD19 CAR T-Cell Therapy
The development of anti-CD19 CAR T-cell therapy represents a major advance in the treatment of patients with chemorefractory B-cell malignancies.
Axicabtagene ciloleucel, an anti-CD19 CAR T-cell product, for treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma.
Brexucabtagene autoleucel (KTE-X19) is an anti-CD19 autologous CAR T-cell product with similar construct to axicabtagene ciloleucel, including the CD28 costimulatory domain, but with an additional manufacturing step to promote T-cell selection and remove circulating malignant B cells.
In the ZUMA-2 study, patients with mantle cell lymphoma were treated with lymphodepleting chemotherapy followed by a single infusion of brexucabtagene autoleucel.
Eligible patients had received three or more prior lines of therapy, including a cBTK inhibitor and 88% had prior exposure to at least one cBTK inhibitor.
ORR was 93%, with CR of 67%.
With longer follow-up of 17.5 months, 70% of patients in CR maintained their response.
Grade 3 or higher cytokine release syndrome, neurotoxicity, and infections occurred in 15%, 31%, and 32% of patients, respectively, including two deaths secondary to infection.
In a retrospective study of patients treated with brexucabtagene autoleucel across 14 U.S. centers the ORR in 81 patients with efficacy-evaluable disease was 86%, with a CR rate of 64%.
In a study of brexucabtagene autoleucel across seven European centers, ORR for all patients was 61% (CR 46%) and was 89% for reinfused patients (CR 68%).
Bbrexucabtagene autoleucel remains effective and deliverable to patients with mantle cell lymphoma outside of a clinical trial setting.
TRANSCEND NHL001 study (NCT02631044) patients with relapsed/refractory B-cell non-Hodgkin lymphoma receive lymphodepleting chemotherapy followed by one to two infusions of lisocabtagene maraleucel which is an anti-CD19 autologous CAR T-cell product with a 4-1BB costimulatory domain.
The ORR was 84%, with a CR rate of 59%.
In both ZUMA-2 and TRANSCEND NHL001, efficacy was observed in patients with high-risk biologic features, including TP53 mutation and blastoid morphology, and in patients with a previous progression of disease within 24 months event.
Anti-CD19 CAR T-cell therapy is emerging as an effective therapy for patients with relapsed/refractory mantle cell lymphoma, including those with high-risk disease.
A number of bispecific antibodies,especially targeting CD20/CD3, are in development for treatment of B-cell malignancies.
The reported safety and efficacy data in the small numbers of patients with mantle cell lymphoma, an early-phase trials for these agents are encouraging.
Glofitamab is an intravenously administered anti-CD20/CD3 bispecific T-cell–engaging antibody, engineered with a 2:1 configuration of CD20:CD3 to increase potency72 and administered in fixed duration of 12 or fewer cycles.
In a phase I clinical trial glofitamab was administered as monotherapy, and in combination with obinutuzumab to patients with B-cell non-Hodgkin lymphoma, including patients with mantle cell lymphoma.
The ORR was 81%, with a CR of 67%, with similar efficacy irrespective of prior exposure to a BTK inhibitor.
Epcoritamab is a subcutaneously administered bispecific CD20/CD3 antibody, administered until disease progression or unacceptable toxicity.
For patients with mantle cell lymphoma, the ORR was 50% with CR in 25%.
Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 0% and 4% of patients, respectively, with resolution of neurotoxicity in less than 24 hours.
Injection site reactions occurred in 47% patients, all grade 1–2, and one patient experienced grade 3 tumor lysis syndrome.
The majority of patients will eventually experience disease progression or treatment intolerance within BTK inhibitors.
The most frequent causes of BTK inhibitor resistance in mantle cell lymphoma are mutations in ATM, TP53, and NSD2,76,77 observed in up to 75% of patients who progress on ibrutinib.
Mutations in BTK are less frequent at approximately 17%, in contrast to chronic lymphocytic leukemia, where BTK mutations are the dominant cause of resistance.
Pirtobrutinib is a potent and selective first-in-class non-cBTK inhibitor, designed to overcome resistance mutations associated with cBTK inhibitor use, such as mutations in the C481S BTK binding site.
Pirtobrutinibwith mantle cell lymphoma, with a median follow-up of 6 months, the ORR was 52% (CR 25%).
The ORR was 51%, with a CR of 25%, and ORR was higher among the patients who were cBTK inhibitor–naïve (ORR 83%; CR 18%).
Activity was observed among six patients who had experienced CAR T-cell failure (ORR 50%):
Adverse events associated with pirtobrutinib were uncommon, with lower rates of atrial fibrillation (2%), rash (11%), arthralgia (11%), and hypertension (7%) than those observed with cBTK inhibitors use.
Parsaclisib is a potent, highly selective, next-generation inhibitor of PI3Kδ.
The ORR in patients with mantle cell lymphoma was 67%.