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Follicular lymphoma (FL) is a type of non-Hodgkin lymphoma
that originates from the B cells in the center of the follicular center.
With the clinical application of drugs including anti-CD20 monoclonal antibodies, the survival and prognosis of FL patients have improved
.
However, FL is still an incurable disease, and about 20% of patients with first-line immunochemotherapy have early recurrence
of FL.
A number of studies have shown that the occurrence of disease progression (POD24) within 24 months after immunochemotherapy is associated with poor prognosis of FL patients, and early identification of such patients and formulation of individualized and precise treatment plans according to the patient's condition are the current hot spots and difficulties in FL treatment
.
With the emergence of immunomodulators such as lenalidomide, small molecule targeted drugs such as phosphatidylinositol 3-kinase (PI3K) inhibitors, and their encouraging clinical efficacy, the survival and quality of life
of patients with relapsed/refractory (R/R) FL have been further improved.
On this occasion, Yimaitong sincerely invited Professor Zhou Keshu of Henan Provincial Cancer Hospital to share the current status of early relapsed FL treatment and the progress of
new drugs based on clinical experience and relevant literature.
Forward-looking, POD24 helps FL to accurately layer
layers
1.
Early recurrence of FL
Early recurrence of FL in a broad sense refers to FL recurrence within 2 years after treatment with immunochemotherapy regimen or within 2 years after diagnosis; It is generally accepted that early recurrence of FL refers to the progression of the disease (POD24) within 24
months of initiating first-line immunochemotherapy regimen.
24 months was chosen as the node for early recurrence due to the fact that early recurrence of FL occurred within 24 months in multiple studies and was consistent and reproducible across studies1
.
2.
POD24-related predictors and their impact
on patient survival A large clinical study pooled 13 randomized clinical trials in patients with FL.
To verify whether POD24 can be used as a predictor of poor prognosis and shortened survival
.
A total of 5225 patients with FL were included in the pooled analysis, and the results showed that the baseline characteristics of patients without disease progression within 24 months were generally good physical performance status (PS), early disease (I/II), low FL international prognostic index (FLIPI) score, baseline hemoglobin and baseline β2 microglobulin (B2M) and other factors
。 In multivariate analysis, male men (OR=1.
30), PS≥2 (OR=1.
63), B2M≥3 mg/L (OR=1.
43), and high FLIPI scores (3-5, OR=3.
14) were associated
with an increased risk of disease progression at 24 months.
However, even after adjusting for these variables, POD24 remained the largest independent risk factor for poor survival (HR, 5.
67; P<0.
001)1,2
.
In addition, POD24 was associated with poorer subsequent overall survival (OS) in the time-dependent Cox model and 24-month landmark analysis (HR 4.
85 and 3.
06,
respectively).
The following (Figure 1) Kaplan-Meier curve shows the correlation between disease progression status and their OS at 24 months after randomization, with 5-year OS rates of 71.
2% vs.
93.
6% in POD24 versus 93.
6% in progression-free patients, respectively.
Fig.
1 Disease progression status and patient OS within 24 months
3.
Identify monitoring/diagnostic methods for patients with POD24
One study recommended standard risk stratification with FLIPI at the time of patient diagnosis and clinical monitoring
of all patients with FL after completion of first-line immunochemotherapy regimens.
Up to three-quarters of patients with POD24 FL transition to a tumor type with aggressive histological features upon disease progression and adversely affect patient outcomes, so routine biopsy should be considered at the time of relapse in FL patients3 to identify POD24 patients earlier and treat them with individual precision
.
A hundred flowers bloom, PI3K inhibitors are expected to become the preferred treatment of FL
The treatment of early relapsed FL has not yet developed a standard of care
.
The goal of re-treatment in such patients should be to overcome chemoresistance, target disease pathogenesis, and achieve long-lasting disease control, preferably with complete remission (CR).
Due to the limited prospective data to guide treatment decisions in this population, participation in clinical trials is one of
the treatment options for patients with POD24.
Immunochemotherapy regimens are also an option for
patients with POD24.
Bendamustine has good safety characteristics and disease control effects, so it has become a commonly used induction therapy drug
in patients with symptomatic advanced FL.
Patients treated with bendamustine or CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) had similar rates of early disease progression, but the proportion of disease progression was reduced when benmustine was combined with glycosylated humanized type II anti-CD20 monoclonal antibody obinutuzumab1
.
The advent of the era of new drugs and the emergence of targeted drugs have brought more treatment options
to patients with early relapsed FL.
The immunomodulator lenalidomide has significant antitumor activity
in the treatment of relapsed FL.
In a phase II clinical trial of 91 patients with relapsed FL who received lenalidomide monotherapy or lenalidomide plus rituximab for 12 cycles, the overall response rate (ORR) of lenalidomide monotherapy and combination group was 53% and 76%, and the CR rate was 20% and 39%, respectively1
.The GADOLIN study, a global multicenter phase III clinical trial of obinutuzumab, enrolled patients with indolent lymphoma (including FL) who relapsed and refractory to rituximab who received bendamustine monotherapy (group B) and obinutuzumab plus bendamustine (GB group), respectively, and the results of the FL subgroup showed that the progression-free survival (PFS) (25.
8 months and 14.
1 months, p<0.
001) and OS (p=0.
027) in the GB group were significantly longer than those in the B group <b10>4
。- PI3K inhibitors have become a research hotspot in the field of lymphoma, and the PI3K/AKT/mTOR signaling pathway is the classic signaling pathway of tumors, which participates in the regulation of the proliferation, survival, transcription, translation and metabolism of malignant tumor cells
.
PI3Kδ inhibitors can act on lymphoma cells, inhibit PI3Kδ expression, reduce AKT protein phosphorylation level, thereby inducing apoptosis of malignant B lymphocytes and inhibiting the proliferation of malignant B lymphocytes, which also shows good efficacy and safety
in patients with recurrent FL.
Andilise (HMPL-689) is a selective PI3K inhibitor that highly targets PI3Kδ to reduce adverse effects
due to inhibition of other subtypes.
HMPL-689 demonstrated good efficacy and safety in a Phase Ib clinical study in the treatment of R/R lymphoma patients in China, including 90 patients with R/R lymphoma who received HMPL-689 30mg daily
.
At a median follow-up of 5.
6 months, HMPL-689 had a rapid onset of action and a median-to-response (TTR) of 1.
9 months
, based on 76 patients with evaluable efficacy (22 patients with FL).
Encouraging efficacy was obtained in the FL subgroup (see Figure 2), with patient ORR of 81.
8%, CR rate of 36.
4%, 1-year duration of response (DOR) rate of 59.
7% (95% CI, 15.
8-86.
6), and 1-year PFS rate of 75.
8% (95% CI, 44.
8-90.
8).
。 In this clinical study, HMPL-689 also had good efficacy in POD24 patients, with an ORR of 87.
5%, a CR rate of 25%, and a clinical benefit rate (CBR) of 87.
5% in 8 POD24 patients in the FL subgroup.
In terms of safety, the most common adverse events (TEAEs) during ≥ level 3 treatment in all patients were pneumonia (13.
3%) and neutropenia (11.
1%); Liver and digestive tract AEs are mild, liver enzymes (AST/ALT) are mildly to moderately elevated (grade 1-2), the incidence of diarrhea is low, and the permanent withdrawal rate due to AEs is 5.
6%5
.
In summary, HMPL-689 has shown in clinical studies that it is a new drug
worth looking forward to in the treatment of patients with R/R FL, including patients with POD24, with clear efficacy, good tolerability and controllable safety.
Fig.
2 DOR and PFS in FL patients
Expert reviews
FL is a group of hematological tumors with high heterogeneity in terms of biological characteristics, clinical manifestations and prognosis, and many factors will affect the prognosis
of patients.
In recent years, a number of studies have found that disease progression, that is, POD24, within 24 months after first-line treatment, is one of the factors affecting the poor prognosis of patients, and how to identify such high-risk patients early and give personalized and efficient and safe treatment plans in time is a hot spot in FL treatment and an urgent problem
to be solved.
At present, researchers have combined molecular and clinical biomarkers to explore the identification of POD24 predictors, and after multivariate analysis, it is found that patients' physical performance status, B2M status and FLIPI score are all associated
with an increased risk of disease progression within 24 months.
The exploration of POD24 predictors is still ongoing, in order to realize the early identification of high-risk patients before disease progression, and provide a theoretical basis
for accurate prognosis stratification and subsequent individualized treatment of FL.
In the treatment of patients with early relapsed FL, there is no unified standard treatment plan, and the choice of regimen depends on the efficacy of previous regimens, the duration of remission, the age of the patient, the physical state, the type of pathology at the time of relapse, and the treatment goals
.
For such patients, non-cross-resistant regimens can be used, and clinical trials of new drugs can also be considered6
.
The advent of new drug eras, such as immunomodulator lenalidomide, anti-CD20 monoclonal antibody obinutuzumab and PI3K inhibitors, has brought new hope and treatment options
to patients with early relapsed FL.
HMPL-689, a highly selective small molecule inhibitor targeting PI3Kδ, demonstrated considerable efficacy and controlled safety
in patients with R/R FL in a multicenter, open-label Phase Ib clinical study.
The ORR of 22 FL patients was 81.
8%, the CR rate was 36.
4%, and the CBR was 90.
9%.
Among the 8 patients with POD24, the ORR was 87.
5% and the CR rate was 25%5
.
It is believed that with the deepening of research, HMPL-689 can bring more and better clinical benefits
to more FL patients.
The "Multicenter, Single-arm, Open-label Phase II Clinical Study of HMPL-689 to Evaluate the Efficacy and Safety of HMPL-689 in Patients with Relapsed/Refractory Marginal Zone Lymphoma and Follicular Lymphoma" is currently underway at various research centers in China (Registration Number: CTR20210264).
