Qunyinghui No. 10 Intensive Literature Reading: A New Direction of Targeted Therapy for B-Cell Lymphoma

"Qunyinghui - Lymphoma Diagnosis and Treatment Research Interpretation Series" is an exclusive academic exchange platform created for young and middle-aged hematologists, through the intensive reading of influential research literature in the field of lymphoma, discussing hot topics in lymphoma diagnosis and treatment, jointly exploring and summarizing the optimal diagnosis and treatment strategy of lymphoma, in order to improve the survival rate

Professor Yang Haiyan of the Affiliated Cancer Hospital of the University of Chinese Academy of Sciences and Professor Zhang Huilai of the Cancer Hospital of Tianjin Medical University served as the chairman of the conference, Professor Xu Yongjin and Professor Chen Xi of the Affiliated Cancer Hospital of the University of Chinese Academy of Sciences interpreted the cutting-edge literature in the field of B-cell lymphoma for everyone, and invited Professor Li Wuping of Jiangxi Provincial Cancer Hospital, Professor Tan Xiaohong of the Affiliated Cancer Hospital of Guangxi Medical University, Professor Wang Li of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and Professor Jin Zhengming of the First Affiliated Hospital of Soochow University to participate in the exchange and discussion.

Intensive Literature Reading (1)

DHL targeted therapy research shines

Professor Yongjin Xu shared an article

Chemotherapy immunotherapy has failed to meet the needs of DHL patients

Standard therapy for DHL is currently not established, and chemotherapy is the first choice for

Note: R-CHOP protocol: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone

R-DA-EPOCH regimen: rituximab + dose-adjusted etoposide + prednisone + vincristine + cyclophosphamide + epidrustoxin

R⁃Hyper CVAD protocol: rituximab + cyclophosphamide + vincristine + doxorubicin + dexamethasone with rituximab + high-dose methotrexate + cytarabine alternately

R-CODOX-M/R-IVAC scheme: rituximab + cyclophosphamide + vincristine + doxorubicin combined methotrexate; Ifosfamide + etoposide + cytarabine are used alternately

Initial efficacy of targeted monotherapy for DHL based on signaling pathway changes

The discovery of genetic variants in the two subtypes of DHL (DHL-BCL2 and DHL-BCL6) helps to infer the therapeutic sensitivity and resistance of the two subtypes, thereby facilitating the exploration

The key to the treatment of DHL-BCL2 is to intervene in its most susceptible proteins, such as MYC, BCL2, and epigenetic regulators

DHL-BCL6 is characterized by the dual translocation

Novel targeted drugs combined with immunotherapy may be expected in the future

Targeted drugs show good efficacy and potential in monotherapy DHL, and the researchers further evaluated DHL patients with a combination regimen such as NCT04479267 (Table 1).


The study evaluated the effects
of Polatuzumab Vedotin (Pola) in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP) in patients with initial treatment of double or triple-hit lymphoma.

As the world's first antibody drug conjugate (ADC) targeting CD79b, Pola binds to tumor cells and releases the cytotoxic drug monomethyl oristadine E (MMAE) into cells, resulting in tumor cell death
.

Therefore, Pola in combination with R-CHP is better able to treat patients with DHL/triple-blow lymphoma than chemotherapy^[2
].

Table 1 Research related to targeted drugs combined with immunotherapy

After Professor Xu Yongjin's wonderful interpretation, many experts discussed
DHL targeted therapy.

Professor Zhang Huilai pointed out that DHL treatment is a bottleneck in the treatment of lymphoma, although the 5th edition of the WHO Hematopoietic and Lymphoid Tissue Tumor Classification this year isolated DHL-BCL6 from DHL, it is undeniable that DHL-BCL6 patients are still a group of people
with poor prognosis.

Professor Li Wuping said that in addition to the infinite proliferation of cells caused by MYC and the high expression of BCL-2, THE DHL mechanism is also related to many other factors, such as the stability of the mitochondrial membrane and iron death
.

Professor Tan Xiaohong said that at present, DHL seems to have a lot of targeted drugs available, but the actual clinical effect is not good, which may be related to the high heterogeneity of DHL, although the molecular pathway abnormality was found, but it is not clear which molecular pathway has the greatest
abnormal effect.

In addition, protac technology has been shown to improve BTK inhibitor resistance in patients, but it may take years
to really apply it to the clinic.

At present, the results of the POLARIX Phase III study have been published, and overall, for patients with new treatment of DLBCL, Pola-R-CHP has shown a clinical benefit that is worth looking forward to, and is expected to become a new standard for
first-line treatment of DLBCL.

Finally, Professor Yang Haiyan concluded that how to optimize the treatment strategy of DHL is an urgent problem to be solved, and more research is needed for in-depth exploration
of the pathogenesis of DHL.

Intensive Literature Reading (2)

Pola will be promising in further research at the NHL

Prof.
Xi Chen shared an article published by Lancet Haematol as "Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised.
" study (ROMULUS) (ROMULUS study: rituximab combined with Pola or Pinatuzumab vedotin for the treatment of relapsed refractory NHL final results)"^[3] article
.

The study confirmed that the median duration of remission (DOR) of R-Pola was superior to R-Pina in R/R DLBCL and follicular lymphoma (FL), and further studies
of NHL have been conducted using Pola.

Research background

Pola and Pina demonstrated good drug activity and tolerance in Phase 1 clinical studies
.

ROMULUS was a randomized, multicenter, open-label Phase 2 study to compare the role
of rituximab plus Pola (R-Pola) or Pina (R-Pina) in patients with R/R DLBCL and R/R FL.

Research methodology

Criteria for admission: R/R DLBCL or R/R 1-3a FL, age ≥ 18 years, at least one two-dimensional measurable lesion (CT or MRI maximum diameter > 1.
5 cm), ECOG score 0-2 points, life expectancy of at least 12 weeks, normal
liver and hematologic function.

Patients were randomly assigned on a 1:1 basis and received R-Pola and R-Pina (R: 375 mg/^m2 + ADC: 2.
4 mg/kg) every 21 days until disease progression or intolerable toxicity persisted for more than 1 year
.

The primary endpoint of the study was to compare the safety, tolerability, and antitumor activity
of the drug.

Research results

A total of 81 patients with DBBCL and 42 patients with FL were included in the study (41 were actually included
in the analysis).

Rituximab resistance, other treatment resistance, or non-resistance to rituximab, other treatments, and previous treatments are presented in the individual antitumor response as shown in
Figure 1.

Figure 1 Individual antitumor response

R/R DLBCL queue r-Pina group (A), R-Pola (B); R/R FL queue r-Pina group (C), R-Pola (D)

In the R/R DLBCL cohort, the R-Pola group had a superior DOR over the R-Pina group (13.
4 months vs 6.
2 months, Figure 2), the R-Pina group had an objective response rate (ORR) of 60% (95% CI 43–74), a complete response (CR) rate of 26% (95% CI 14–42), an R-Pola group orr of 54% (95% CI 37–70), and a CR rate of 21% (95% CI 9–36
。
The incidence of grade 3-5 adverse events in the R-Pola group and R-Pina group was 77% and 79%,
respectively.

Figure 2 R/R DLBCL queues in the median DOR

In the R/R FL cohort, the R-Pola group still had superior DORs to the R-Pina group (9.
4 months vs 6.
5 months, Figure 3), the R-Pola group had an ORR of 62% (95% CI 38–82) with a CR rate of 45% (95% CI 23–68), while the R-Pina group had an ORR of 70% (95% CI 46–88) and a CR rate of only 5% (95% CI 01–24).


The incidence of grade 3-5 adverse events in the R-Pola group and R-Pina group was 50% and 62%,
respectively.

Figure 3 R/R FL queues in the median DOR

Conclusions of the study

For patients with R/R DLBCL and R/R FL, both R-Pola and R-Pina are potential treatment options, but R-Pola has a longer median DOR compared with R-Pina and the overall benefit-risk ratio is more advantageous, so the investigators chose Pola for further studies
on NHL.

Expert hot topic discussions

After Professor Chen Xi's wonderful interpretation, many experts discussed
the differences and application prospects of ADC drugs and other small molecule targeted drugs.

Professor Wang Li pointed out that compared with traditional chemotherapy, ADC drugs can bring more accurate targeted therapy, and previous studies carried out by the department have shown that Pola+BR still has a good efficacy for patients who have previously received CAR-T treatment failure or are resistant to chemotherapy, and the prospect is promising
.

Subsequently, Professor Jin Zhengming expressed his views on combination therapy, the degree of remission of small molecule targeted drugs monotherapy and chemotherapy combination is insufficient, and the addition of BCL-2 inhibitors may improve the efficacy
.

For high-risk patients, autologous transplantation combined with cell immunotherapy has great therapeutic potential, even for patients who are not sensitive to conventional intensity chemotherapy, after large-dose chemotherapy sequential autologous transplantation treatment, there is also a good effect, combined with CAR-T therapy, is expected to bring deeper relief
.

Finally, Professor Yang Haiyan concluded that for patients who have failed CAR-T treatment, Pola may be a very good treatment choice, and for DHL, high-risk patients with TP53 mutations, ADC drug combination transplantation or bridged CAR-T therapy may be the future development direction
.

This issue of "Heroes of the Crowd - Lymphoma Diagnosis and Treatment Research and Interpretation Series" has been successfully concluded, see you in the next issue!

Past Issues Review: Heroes of the Crowd No.
1 | Literature Intensive Reading of the Initial Diagnosis and Treatment of DLBCL New Thinking
Group Yinghui· No.
2 | Intensive literature reading focuses on the treatment
of indolent lymphoma, Issue 3, | New Advances
in the Treatment of Rituximab Refractory iNHL in Intensive Literature Reading Group Yinghui No.
4 | New Advances
in the Treatment of Relapsed Refractory DLBCL, No.
5 | Intensive reading of the literature focuses on the treatment of CLL

Qunyinghui No.
6 | Application of anti-CD20 in lymphoma in intensive literature

Qunyinghui No.
7 | Application of bendamustine combined with anti-CD20 monoclonal antibody regimen in iNHL

QunyingHui No.
8 | Intensive reading of the literature on otolizumab plus chemotherapy in the first line treatment of FL and MCL

Qunyinghui No.
9 | Intensive reading of the literature: The Advanced Path to DLBCL First-Line Therapy

References

[1] Zhuang Y, Che J, Wu M, Guo Y, Xu Y, et al.
Altered pathways and targeted therapy in double hit lymphoma.
J Hematol Oncol.
2022 Mar 18; 15(1):26.
doi: 10.
1186/s13045-022-01249-9.

[2]https://clinicaltrials.
gov/ct2/show/study/NCT04479267?term=NCT04479267&draw=2&rank=1

[3] Morschhauser F, Flinn IW, Advani R, et al.
Polatuzumab vedotin or Pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS).
Lancet Haematol.
2019 May; 6(5):e254-e265.
doi: 10.
1016/S2352-3026(19)30026-2.

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