【JCO】Tumor case study: first-line treatment of mantle cell lymphoma

The abundance of first-line treatment options for mantle cell lymphoma (MCL) makes treatment choice one of
the challenges for clinicians.
The Journal of Clinical Oncology recently published a case study describing current diagnostic and treatment challenges following the MCL case presentation, reviewing the literature (prospective phase 2 and 3 clinical trials and real-world studies), and summarizing the authors' recommended first-line treatment strategies
for MCL.
The authors suggest that in some cases, real-world evidence may be inconsistent with data from prospective clinical trials, such as on the role of
rituximab maintenance therapy after BR induction.
The authors place these important new real-world data in the context of the changing treatment landscape, hoping to help clinicians choose first-line treatment
for MCL patients.

Introduction to the condition

The patient, a 73-year-old woman with only a history of hypertension, sought medical attention
for left lower quadrant pain.
CT scan of the abdomen and pelvis shows left iliac, groin, and femoral lymphadenopathy, and patients complain of fatigue and intermittent night sweats for several weeks
.
Neoplastic lymphatic invasion was shown by resection of lymph node biopsy for femoral lymphadenopathy, positive for tumor cells CD20, cyclin D1, and SOX-11 by immunohistochemistry, 70% for Ki-67 staining, positive flow cytometry CD5, CD19, CD20, CD10-negative kappa light chain restriction cell population, and (11;14) translocation confirmed by FISH; There are no obvious abnormalities on complete blood count, differential count, and comprehensive metabolic studies, and lactate dehydrogenase is in the normal range
.
Diagnosis of mantle cell lymphoma (MCL).

Staging of 18F-FDG PET/CT scan shows 18F-FDG high-uptake lymphadenopathy in the right axilla, left iliac, and left groin/femoral region (Figure 1).

Bone marrow biopsy shows low MCL involvement (10%), classified as stage IV-B, and assessed as intermediate-risk
by MIPI.
Taking into account the proliferation index, the MIPI-c score is high/intermediately risky
.
Due to persistent intermittent lower abdominal pain, night sweats, and fatigue, the patient was treated with 6 cycles of bendamustine and rituximab, with repeat examination of 18F-FDG PET/CT (Figure 1) and bone marrow biopsy confirming complete remission, followed by referral to discuss treatment options
after remission.

Diagnostic and treatment challenges

If appropriate diagnostic tissue is present, based on typical histopathology, immunohistochemistry (CD51, CD201, cyclin D11, CD102, and CD232), and cytogenetics (presence t(11; 14) (q13; q32)), the diagnosis of MCL is usually relatively simple
.

Based on validated diagnostic criteria, retrospective studies have shown a median OS of MCL to be between 3 and 5 years, establishing outcome benchmarks
for a range of prospective studies.
Different scholars around the world have developed a variety of first-line treatment options at the same time, extending the median survival of MCL to > 10 years, but it has also brought about the reality
of chaos in first-line treatment options.
This gives treating oncologists multiple options
.
First, does the patient need treatment? Asymptomatic patients with low volume can often be observed
.
Secondly, if treatment is required, which induction regimen to choose? Third, should patients receive autologous hematopoietic cell transplantation (auto-HCT) consolidation therapy? Fourth, should patients receive rituximab maintenance (RM)?

First, MCL is a highly heterogeneous disease, further complicating
its decision-making.
At one end of the disease is an indolent form of MCL that may not require treatment for years; MCL, on the other hand, with blast-like histological and/or high-risk molecular features such as TP53 mutations, has a very aggressive clinical course
.
Second, MCLs have a large number of prognostic factors, including MIPI scores, proliferation index, complex karyotypes, gene expression profiles, KMT2D mutations, other molecular aberrations, and minimal residual disease (MRD), but they rarely prove useful
in the choice of specific treatments.
Finally, patients with MCL vary widely in age and comorbidities, which have a significant impact on
treatment choice.

Literature summary

Selection of induction protocol

First-line treatment of MCL has a number of induction regimens available (Table 1) and is divided into intensive (containing high-dose cytarabine [araC] and/or auto-HCT) and non-intensive regimens
.

Intensive induction protocols

MD Anderson's group published the outcomes of the R-HCVAD/R-MA intensive induction regimen in MCL, which enrolled 97 patients from 1999 to 2002 with a median failure-free survival of 4.
8 years; however, the protocol was quite toxic, with 5.
2% of patients dying of acute toxicity and another 6.
2% subsequently developing AML or MDS
。 Professor Wang Luhua et al.
recently published the results of Window-1 study on the addition of ibrutinib to R-HCVAD/R-MA, 131 patients aged ≤ 60 years received ibrutinib + rituximab for up to 12 cycles until maximum remission was achieved, and then continued to receive R-HCVAD/R-MA therapy for 4-8 cycles, and the result was a 3-year PFS rate of 79%.

The CALGB/ALLIANCE working group evaluated a methotrexate-fortified RCHOP-like regimen in 78 patients in study 59909, followed by etoposide/araC and auto-HCT, resulting in a median PFS of 5 years
for transplant patients.
Their follow-up study 50403 added bortezomib to the 59909 platform for consolidation or maintenance, resulting in a median PFS of 8.
5 years
for transplant patients.

The Nordic MCL2 regimen (R-maxiCHO alternating with R-araC, followed by auto-HCT consolidation therapy) had a 6-year PFS of 66% and lower acute and long-term toxicity than R-HCVAD/R-MA
.
Patients who have completed auto-HCT have median PFS for 11 years
.
The European MCL Network compared RCHOP alternating RDHAP and RCHOP and all patients were expected to undergo auto-HCT, resulting in a better median to treatment failure (9.
1 years versus 3.
9 years) in the RCHOP/RDHAP group, but at the cost of significantly higher
haematological and nephrotoxicity 。 SWOG compared simplified R-HCVAD/R-MA with BR induction in the S1106 randomized study, and autoHCT was proposed in all patients; Both groups had excellent 5-year PFS (62%-66%), but the study was closed
early due to increased failure rates of stem cell collection in the R-HCVAD/R-MA group.
A study of alternating R-araC therapy with BR showed that 88 patients who were suitable for transplantation had very good 3-year PFS (83%)
.

A particularly difficult condition in MCL is the TP53 mutation, and these patients have a particularly poor prognosis, even in intensive induction therapy including auto-HCT
.
Although successful alternative first-line strategies have not been established, studies suggest that allogeneic HCT may overcome the poor prognosis
of TP53 mutations.
In the largest published study of CD19 CAR T cell therapy for MCL, only 6 patients are known to have TP53 mutations, and as of June 2022, 2 of these 6 patients are still in remission
.
Enrollment of patients with TP53 mutations in clinical trials of novel first-line therapies and consideration of early use of allogeneic HCT
are strongly encouraged.

Non-intensive induction protocol

There are also a variety of non-intensive induction regimens
.
The European MCL Network compared R-FC with R-CHOP, and although R-FC was initially expected to be a good group, the efficacy was actually not good: survival was actually poor
due to increased toxic deaths.
The StiL study compared BR with R-CHOP, and BR showed superior efficacy and less toxicity
.
The BRIGHT study, a phase 3 non-inferiority trial comparing BR with R-CHOP (or R-CVP), resulted in non-inferiority of BR, with fewer neuropathy, alopecia, and neutropenia, but more lymphopenia; Of the 74 MCL patients studied, the BR group had better
5-year PFS.
One study compared VR-CAP (bortezomib substituted vincristine in RCHOP) with RCHOP and found that the median PFS of VR-CAP was better than RCHOP (25 months vs.
14 months).

In an ECOG-ACRIN study comparing BR with BR+ bortezomib induction, the addition of bortezomib did not improve PFS at 5 years (64% in both groups), but BR+ bortezomib increased neutropenia and peripheral neuropathy
.
The 5-year PFS in a phase 2 study of rituximab plus lenalidomide was 64%, and although generally well tolerated, treatment in this study is still unclear
.

The RBAC500 regimen (rituximab, bendamustine, and low-dose araC) from an Italian phase 2 study showed high activity with a 3-year PFS of 76%.

Till et al.
evaluated RCHOP + bortezomib with a CR rate of 45% and a 5-year PFS of 28%.

The E1405 study treated 75 patients with bortezomib in addition to modified R-HCVAD (VcR-CVAD) resulted in a CR rate of 68% and a 4-year PFS of 46%.

In the recently published SHINE study, older MCL patients who added ibrutinib to BR resulted in a significant improvement in median PFS (81 months vs.
53 months) in favor of the BR + ibrutinib group; However, an increase in toxicity was also found, and there was no benefit
of OS even after 7 years of follow-up.

Although rare, patients with localized disease at diagnosis may also achieve better outcomes
with low-intensity induction (e.
g.
, radiation therapy to the affected area) or induction of non-intensive immunochemotherapy (with or without radiation therapy to the affected area).

It is important to remember that some patients with MCL can be initially observed
without treatment.
Patients with non-large lymphadenopathy, no cytopenias, and no symptoms due to lymphoma are indicated for delayed treatment
.
For some patients, induction therapy can be safely postponed for
years.

Latest trends in induction therapy

In recent years, there has been a trend of protocol shift in patients aged < 65 years to avoid R-HCVAD/R-MA and to prefer Nordic MCL2 (R-CHOP alternating R-araC, post-auto-HCT) and European MCL networks (R-CHOP alternating R-DHAP, post-auto-HCT) regimens, >while there is also a trend
from RCHOP to BR in patients aged 65 years.
In a recent analysis, 49% of patients > 65 years of age received BR
between 2010 and 2015.
However, there are still wide variations
in the practice of community oncologists and lymphoma specialists.

To transplant or not to transplant?

Clinical Research Data: After choosing an induction regimen, clinicians face the next decision about whether patients will benefit from auto-HCT, an issue that has challenged clinicians for years
.
On the one hand, multiple prospective studies have shown excellent outcomes in patients with MCL who have undergone intensive induction (including auto-HCT), with a median PFS of 8 to 11 years; However, all patients in these studies were scheduled to receive auto-HCT, so it is unclear to what extent auto-HCT components contributed to the beneficial outcomes of
these studies.
Patient selection was also an excellent factor in the outcomes of such studies, as only young, transplant-appropriate MCL patients
were enrolled.

A randomised prospective study comparing auto-HCT consolidation therapy with non-transplant regimens was randomised to receive whole-body irradiation pretreatment + auto-HCT versus interferon maintenance therapy
following CHOP induction.
Studies were subsequently revised to allow R-CHOP induction
.
Originally reported in this study showed PFS benefits but no OS benefits with auto-HCT; PFS benefits persisted in long-term follow-up reports, and OS benefits
also occurred.
However, in subgroup analysis, PFS and OS benefits were found only in CHOP-induced patients and not in patients receiving R-CHOP-induction, suggesting that the benefit of auto-HCT may depend on the efficacy
of previous induction regimens for auto-HCT.
In addition to the variable differences in rituximab in induction therapy, the use of high-dose araC, the use of total body irradiation in auto-HCT pretreatment, and interferon maintenance in the control group are limited
in today's patients.

There are no published studies using modern MCL induction regimens and randomising auto-HCT versus non-transplanted regimens, and only two large ongoing prospective studies
.
ECOG-ACRIN 4151 (EA4151) allows for any induction and then randomization of patients with MRD-negative CR to receive auto-HCT followed by rituximab maintenance therapy (RM) for 3 years versus RM for 3 years only; The basic concept is that auto-HCT may not benefit
patients who are already in deep remission (MRD-negative).
The TRIANGLE study was completed with a study of 870 patients, divided into three arms: (1) RCHOP/RDHAP induction followed by autoHCT, followed by 3 years RM; (2) Similar to Group A, but with the addition of ibrutinib for the first 2 years of induction therapy and maintenance therapy; (3) Similar to group B, but excluding autoHCT
.
This review did not include MRD, but aimed to show whether the inclusion of ibrutinib in induction and maintenance therapy can compensate for the loss
of efficacy in the exclusion of auto-HCT.

Real-world data: In addition to the study data summarized above and the study in Table 1, real-world retrospective studies may also be valuable
in selecting first-line treatment for MCL.
The Nordic lymphoma group reported improvements in survival in 1389 lymphoma patients receiving auto-HCT as part of first-line therapy, and after adjusting for rituximab, age, and MIPI scores, multivariate analysis showed a persistent survival benefit
.
However, transplant versus no transplant enrollment studies had selection bias because patients who chose to transplant may be destined for longer
survival due to factors other than those included in the multivariate model.
Gerson et al.
attempted to minimize this bias
in a retrospective study of 1029 patients.
These patients were transplant-eligible and 64% of them actually received auto-HCT, resulting in improved PFS and OS in favor of auto-HCT
in unadjusted analyses.
In multivariate analysis and propensity score-weighted analysis, the PFS benefit persisted while the OS benefit lost statistical significance, suggesting that some degree of selection bias in unadjusted analyses may still contribute to OS benefit
.

Martin et al.
studied 3614 patients with MCL receiving first-line treatment using the Flatiron database in a real-world study and validated the results
using a separate dataset of 994 patients 。 The authors compared auto-HCT with those who did not receive auto-HCT but were suitable for transplantation, and the median time to next treatment (TTNT) was 5 years in those who received auto-HCT compared with 4 years (P = 0.
10) and similar OS (88 months vs.
84 months, P = 0.
40)
in those who did not receive auto-HCT 。 Although these results are instructive, they are inconsistent with the Swedish/Danish registry studies; In addition, patient outcomes appear to be inferior to those reported by Gerson et al.
(median PFS of 6.
2 years) and multiple prospective studies (median PFS of 8 to 11 years) in which auto-HCT is part of first-line treatment for MCL.

Maintenance therapy

Several randomized studies have evaluated rituximab maintenance therapy following first-line treatment with MCL (Table 2).

One study adding RM to the R-FCM regimen found that adding RM to patients with MCL improved PFS from 9% to 45%
at 2 years.
Although this confirms the possible benefit of RM after first-line treatment of MCL, subsequent studies have found better
results when RM is paired with other induction regimens.

A second randomization of interferon α maintenance therapy or RM until disease progression was conducted in the European MCL Network study comparing R-FC with R-CHOP, supporting indefinite RM
.
Many clinicians then extrapolated these data and began to give RM
after all rituximab-based induction regimens.
However, the situation became chaotic after the presentation of the 2016 MAINTAIN study, in which 120 patients were treated with BR and then randomly assigned to receive observation or 2-year RM, and the improvement of PFS and OS was not conducive to RM; The final results of this trial have not yet been published
.
The LyMa study evaluated the effect of RM 3 years after auto-HCT and found significant PFS and OS benefits
from RM compared to observations 。 The Alliance 50403 study tested two different post-transplant bortezomib strategies (skeleton added to CALGB 59909) with no observation group in the study, but PFS and OS improvements were observed compared to CALGB 59909 using the same induction and transplantation methods; This comparison suggests post-transplant benefit of bortezomib, but significant haematologic toxicity and neuropathy have been observed in post-transplant bortezomib, making bortezomib a less attractive maintenance therapy option
than rituximab.

Given the conflicting results of randomized clinical studies (RM has OS benefit after RCHOP or auto-HCT, but no benefit after BR), the new data from Martin et al.
are a very helpful addition to the literature, especially on the question
of whether there is RM after BR.
Their data confirm the results of previous trials, both BR is superior to RCHOP, and RM also has TTNT and OS benefits after RCHOP; But contrary to the MAINTAIN study, Martin et al.
found that RM was actually associated
with TTNT and OS improvements.
There are many possible explanations for these inconsistent results, including larger and more recent datasets by Martin et al.
, and differences
in patient characteristics between patients treated in practice and those treated in prospective clinical studies.

Recommended treatment strategies

Clinicians must make three main decisions: which induction regimen to use, whether auto-HCT, and whether to RM?

Efficacy is a major factor when considering various treatment options, but most patients with MCL are older than 65 years, and potential toxicity and impact
on quality of life must also be carefully considered as MCL is often not treated with curative intent.
For example, severe CD4 lymphopenia usually occurs after bendamustine administration and persists for 1 to 3 years, so patients with B-NHL may have significant opportunistic infections and even infectious death
during RM after BR.
In addition, MCL patients have a poor response to the new crown pneumonia vaccine, which is also a high-risk factor for death from
new crown pneumonia.

Choice of induction therapy

Figure 2 provides an overview of the author-recommended first-line treatment regimens
for MCL.

For young, fit-fit patients (age less than 65-70 years), the authors used the Nordic MCL2 induction regimen, preferred because it avoided cisplatin (grade 1 to 2 nephrotoxicity was observed in 43% of patients in the European MCL network RCHOP/RDHAP study10) and could be administered on an outpatient basis
.
BR/R-araC is another excellent option, but long-term follow-up is rare
.
Consideration of experimental induction therapy options is strongly recommended in patients with TP53 mutations, otherwise intensive and non-intensive therapy options are considered, and allogeneic HCT
is considered early.
BR or R2
is more likely to be used in older patients.
During the COVID pandemic, the authors used R2 more because of the comparable activity, durable response, and expected lower severe CD4 lymphopenia
compared to BR.

Whether to port

Although the question of whether auto-HCT increases benefit as a consolidation therapy after modern first-line treatment of MCL remains unanswered, it remains common practice
in many academic centers, including the authors, to provide auto-HCT after initial remission in young patients (age younger than 65 to 70 years) with no major comorbidities and good performance status.

Maintenance therapy

For maintenance therapy, the authors recommend 3 years of RM (based on LyMa studies) for patients receiving auto-HCT and at least 2 years of RM (based on the EuropeanMCL web study)
for patients who do not receive auto-HCT if they have received R-CHOP.
For patients treated with R2, the duration of treatment with either agent is unclear
.
RM
is generally not recommended for older patients receiving BR induction therapy due to the lack of benefit in the StiL MAINTAIN study and concerns about opportunistic infections during maintenance therapy.
But data from Martin et al.
will lead authors to begin to gravitate towards inclusion of RM after BR, when vigilance surveillance and infection prevention are essential
.

Cases

Returning to the previous case, given the patient's age (74 years) and PET-negative remission, the CD4 count was 60/mL, and the authors recommend omitting RM
.
Patients continued to remission 1 year after completion of BR, but their absolute CD4 count decreased to 114/mL
.
Low-level radiologic recurrence was detected 2 years after BR completion with an absolute CD4 count of 150/mL
.
It is then observed for several months, but eventually increases lymph node enlargement, fatigue, and mild anaemia
.
Patients were enrolled in a clinical trial of a novel BTK inhibitor and were well
tolerated in early response.
The patient is now 77 years old and has stopped taking the drug
.

References

Timothy S Fenske.
Frontline Therapy in Mantle Cell Lymphoma: When Clinical Trial and Real-World Data Collide.
J Clin Oncol .
2022 Sep 28; JCO2201661.
doi: 10.
1200/JCO.
22.
01661.

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