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"Qunying Club - Lymphoma Diagnosis and Treatment Research Interpretation Series" is an exclusive academic exchange platform for young and middle-aged hematologists, through intensive reading of influential research literature in the field of lymphoma, discussion of hot topics in lymphoma diagnosis and treatment, and joint exploration and summary of optimal diagnosis and treatment strategies for lymphoma, so as to improve the survival rate
of lymphoma patients in China.
This issue is chaired by Professor Huang Ruibin of the First Affiliated Hospital of Nanchang University and Professor Gao Guangxun of the First Affiliated Hospital of Air Force Military Medical University, Professor Wei Wei of the First Affiliated Hospital of Anhui Medical University and Professor Li Jing of the First Affiliated Hospital of Xi'an Jiaotong University In order to interpret the cutting-edge literature of the exploration of obinutuzumab (G)-based "no chemotherapy" in the field of indolent lymphoma, Professor Guo Li from the Cancer Hospital Affiliated to Xinjiang Medical University, Professor Li Zijian from the First Hospital of Lanzhou University, and Professor Xiao Ruozhi from the Third Affiliated Hospital of Sun Yat-sen University were invited Professor Sheng Lixia of Ningbo First Hospital participated in the exchange and discussion, and the highlights of this session are summarized as follows
.
Literature Intensive Reading (1)
Use of GALEN-free chemotherapy regimens in the first-line treatment of FL
Professor Wei Wei shared a paper published by Blood titled "Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA.
" study (LYSA study: Use of obinalidomab in combination with lenalidomide [GALEN] in treatment-naïve follicular lymphoma [FL] requiring systemic therapy)" article [1].
To investigate the efficacy and safety
of GALEN regimens as first-line treatment for FL.
Ostuzumab is a novel anti-CD20 monoclonal antibody
.
In FL therapy, obinutuzumab in combination with chemotherapy significantly prolongs progression-free survival (PFS) and is less
toxic than first-line rituximab-based therapy.
This review assesses the efficacy and safety
of GALEN regimen as first-line treatment for FL.
The LYSA study is an international, multicenter Phase II clinical study to evaluate the efficacy and safety
of GALEN regimen in treatment-naïve patients with advanced FL.
The study included 100 patients with treatment-naïve FL, the median age of the enrolled patients was 60.
5 years, and nearly one-third of the patients showed large lesions (i.
e.
, the maximum diameter of 0.
7 cm).
The primary endpoint was complete response rate (CRR) at the end of induction (according to IWG 1999 criteria), and secondary endpoints were total response rate (ORR) at the end of induction, ORR and CRR at the end of treatment (induction + maintenance), optimal response during treatment, PFS, time to next antilymphoma treatment (TNALT), median duration of response (DOR), overall survival (OS), safety
.
Figure 1 Study design
According to the IWG 1999 criteria, the post-induction ORR of enrolled patients was 92%, of which CRR was 47% and PR rate was 45% (Table 1).
At the end of treatment, CRR and ORR (induction + maintenance) were 63% and 79%,
respectively.
Table 1 Response rates after induction therapy, induction + maintenance therapy according to IWG 1999 criteria
According to the 2014 Lugano criteria, the CRR was 80% and the ORR was 94% after the end of induction therapy in enrolled patients (Table 2).
Table 2 Remission rates after induction therapy according to the 2014 Lugano criteria
At a median follow-up of 3.
7 years, the 3-year PFS rate was 82% (95% CI, 73% to 88%), TNAL was 85% (95% CI, 76% to 91%), DOR was 83% (95% CI, 74% to 89%), and OS rate was 94% (95% CI, 87% to 97%) (Figure 2).
Fig.
2 Secondary endpoint results
The most common adverse event studied was neutropenia (48% of any grade; 47% ≥grade 3), only 2% of patients developed fever with neutropenia; Others are mainly ≤ level
2.
There was no other grade 3 toxicity ≥ 3% > 3% (Table 3).
Table 3 Adverse reactions during the study
Conclusion of the study
Overall, the results of the study showed that the chemotherapy-free GALEN regimen had good clinical efficacy and safety in treatment-naïve patients with high tumor burden FL.
After Professor Wei Wei's wonderful interpretation, many experts discussed
the study of LYSA and the application of obinutuzumab in FL treatment.
Professor Guo Li pointed out that the treatment of lymphoma is gradually shifting to a low-toxicity regimen or no chemotherapy regimen, and the overall clinical treatment effect of FL is good
regardless of whether it is initial treatment or recurrence.
According to previous clinical experience, the safety of obinutuzumab is high, and the adverse reactions of the GALEN regimen are mainly caused by
lenalidomide.
In addition, the LYSA study lacks studies on patients with POD24 and diffuse large B-cell lymphoma transformation, POD24 is an important prognostic factor in FL, how to further identify POD24 patients, and how to choose G-CHOP (obinutuzumab, cyclophosphamide, doxorubicin, vincristine, prednisone) and GB (obinutuzumab, bendamustine) regimens in the first-line treatment of FL are issues worth exploring
。 Professor Wei Wei added that POD24 patients can be identified according to the immunohistochemical classification of pathology, onset, and treatment remission time.
G-CHOP and GB regimens can be selected according to the patient's underlying physical condition and drug response, and the GB regimen
can be considered for older and poor physical condition.
A chemotherapy-free study of a three-drug combination treatment of MCL
Professor Li Jing shared a paper published by Blood entitled "Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial(OAsIs study: Ostuzumab, ibrutinib, and venetoclax in the treatment of relapsed or treatment-new mantle cell lymphoma [MCL]1/ Phase 2 trial)" article [2].
Most patients with MCL will relapse and TNAL will gradually shorten after the current treatment regimen, and a large number of studies have provided the theoretical basis for the combination of ibrutinib, obinutuzumab and venetoclax for the treatment of MCL, and this three-drug combination is expected to become an effective treatment for
MCL.
This OAsIs (NCT02558816) is a single-arm, multicenter, prospective Phase 1/2 clinical trial to evaluate the efficacy and safety of a three-drug combination in MCL and determine the maximum tolerability (MTD)
of venetoclax in combination with fixed-dose ibrutinib and obinutuzumab in patients with recurrent MCL.
From October 14, 2015 to May 29, 2018, a total of 48 patients were enrolled in the study, ≥ 18-year-old patients with R/R MCL (groups A and B) and patients with treatment-new MCL (group C).
Patients in group A received obinutuzumab plus ibrutinib, and patients in groups B and C received a three-drug combination regimen
.
Safety: No dose-limiting toxicity (DLT)
occurred in any of the three groups.
The rates of grade 3 and above adverse reactions (AEs) in the A, B and C groups were 89%, 75% and 53%,
respectively.
The most common grade 3 or 4 AEs in all patients are thrombocytopenia and neutropenia
.
Efficacy: According to Cheson or Lugano, a total of 9 patients with R/R MCL in Group A received fixed-dose obinutuzumab and ibrutinib, all achieving CR
by the end of week 6.
Six patients completed 24 cycles of treatment, and 3 patients stopped treatment (1 TP53 wild-type patient progression, 1 patient developed chronic graft-versus-host disease, and 1 patient received allogeneic hematopoietic stem cell transplantation).
One of the two patients with blast-like MCL achieved CR at the end of cycle 6 and one died of progression
.
The median follow-up was 45 months (Figure 3).
Median DOR
is not reached.
Fig.
3 PFS and OS results of group A
A total of 24 patients with R/R MCL were enrolled in Group B and received a combination of fixed-dose obinutuzumab and ibrutinib and different doses of venetoclax
.
At the end of the 6 cycles, 16 (67%) patients achieved CR/CRu, 4 progression, including 1 TP53 mutation
.
Of the 4 patients with blast-like MCL according to Lugano's criteria, 2 achieved CR at the end of 6 cycles, 1 received allogeneic transplantation (ASCT) after 4 cycles, and 1 progressed
.
One patient with MCL polymorphic progresses
in cycle 2.
At the time of the analysis, 18 patients survived and all were in remission
.
The mean follow-up was 17 months, and the 1-year PFS and OS rates were 74.
5% (95% CI, 58.
8% to 94.
5%) and 87.
5% (95% CI, 75.
2% to 100%) (Figure 4).
DOR
not reached.
Figure 4 PFS and OS results in group B
A total of 15 treatment-tactic-treated MCL patients were enrolled in group C and received a combination of fixed-dose obinutuzumab and ibrutinib and different doses of venetoclax
as patients in group B.
One patient progressed in cycle 4, and the remaining 14 patients continued to have objective remission
.
At a median follow-up of 14 months, the 1-year OS rate and PFS rate were 100% and 93.
3% (95% CI, 81.
5% to 100%), respectively (Figure 5).
Median DOR
is not reached.
Fig.
5 PFS and OS results of group C
The OAsIs trial demonstrated that a three-drug combination regimen of obinutuzumab, ibrutinib, and venetoclax was well tolerated and effective
against MCL.
A three-drug combination regimen in relapsed and treatment-naïve patients can achieve early, high proportion of CR and sustained clinical and molecular response
.
Deep remission is achieved even in patients at high risk of TP53 mutations or blast-like MCL.
After Professor Li Jing's wonderful interpretation, many experts discussed
the application of the combination of obinutuzumab, ibrutinib and venetoclax in the treatment of MCL.
Professor Xiao Ruozhi pointed out that the triple drug regimen has a good effect, but the risk of infection in the clinical application of BTK inhibitors and BCL-2 inhibitors is very large, how to reduce adverse reactions while ensuring similar efficacy, replacing venetoclax with other drugs with relatively small infection risk may be an important direction
of exploration.
Professor Sheng Lixia also pointed out that this triple program is difficult to popularize in China due to medical insurance, but it can provide some treatment ideas, such as BTK inhibitors and obinutuzumab combined with chemotherapy or other drugs
.
Regarding the efficacy of the triple regimen in the treatment of high-risk patients such as patients with TP53 mutations, Professor Li Jing added that the results of this study suggest that the triple regimen is not affected by TP53 mutations, which means that some TP53 patients can reach MRD negative, and the researchers have found that obinutuzumab can reverse venetoclax resistance, so such a triple drug regimen was designed, and the MRD negative effect of the program was obvious.
May be considered as a pre-transplant treatment option
.
The above is the wonderful content of this issue, so far, the "Qunying Club - Lymphoma Diagnosis and Treatment Research Interpretation Series" has come to a successful end! It is expected that the diagnosis and treatment level of lymphoma in China will continue to improve in the future, so that more patients will benefit!
1 | New Thinking
on the Diagnosis and Treatment of DLBCL at the Beginning of Literature Intensive Reading | Literature Intensive Reading: Treatment of Indolent Lymphoma QunYinghui No.
3 | New progress in the treatment of rituximab refractory iNHL in literature intensive reading
Qunying Club No.
4 | New progress in the treatment of relapsed and refractory DLBCL in literature intensive reading QunYinghui No.
5 | Literature intensive reading focuses on the treatment of CLL
Qun Ying Hui, No.
6 | Application of anti-CD20 in lymphoma
Qun Ying Hui, No.
7 | Application of bendamustine combined with anti-CD20 monoclonal antibody regimen in iNHL
Qun Ying Hui, No.
8 | Literature intensive reading of obinutuzumab combined with chemotherapy first-line treatment of FL and MCL
Qun Ying Hui, No.
9 | Literature intensive reading of the advanced path of DLBCL first-line treatment
Issue 10 | New directions for targeted therapy for B-cell lymphoma in the literature intensive reading
QunYinghui No.
11 | Literature intensive reading of treatment options after rituximab resistance in NHL patients
Vol.
12 | New Exploration of the Treatment of Aggressive Lymphoma in Literature Intensive Reading
References:
1.
Bachy E, Houot R, Feugier P, et al.
Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study.
Blood.
2022; 139(15):2338-2346.
2.
Le Gouill S, Morschhauser F, Chiron D, et al.
Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial.
Blood.
2021; 137(7):877-887.
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