Professor Huang Haiwen: The position of allogeneic transplantation in the treatment of lymphoma in the era of new drugs and immunotherapy

Lymphocytic disease is currently one of the most vigorous fields in hematology at home and abroad.
In recent years, remarkable achievements have been made in the pathogenesis of the disease to targeted and immunotherapy.

In order to promote domestic and international peer exchanges, the First National Lymphocytic Disease Academic Conference of the Chinese Medical Association and the 2021 International Lymphoma Update Symposium will be held in Chengdu, Sichuan Province from April 16-18, 2021.

At this meeting, Professor Huang Haiwen from the First Affiliated Hospital of Soochow University, instead of Professor Wu Depei, gave a keynote report on "The Position of Allo-HCT in Lymphoma Treatment in the Era of New Drugs and Immunotherapy".
Yimaitong will present the main content Organized as follows.

At present, the survival outcome of newly diagnosed and treated lymphoma has been greatly improved, but the recurrence of the disease after standard treatment is still a problem that needs to be solved.

Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is an important means for patients with lymphoma to achieve long-term survival.

In the past 30 years, the overall survival (OS) of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) after Allo-HCT has improved significantly.

However, Allo-HCT also brings about infection complications, inhibitor versus host disease (GVHD), and high non-recurring mortality (NRM) after Allo-HCT.

 With the emergence of new drugs and new therapies in recent years, the position of Allo-HCT in lymphoma has been challenged.

Allo-HCT is usually used in patients with diffuse large B-cell lymphoma (DLBCL) that relapse after autologous hematopoietic stem cell transplantation (Auto-HCT), patients with diseases that do not respond to multiple treatments, and high-risk genomes, such as double-hit Patients with lymphoma or early recurrence (1 year from diagnosis).

However, data from the International Center for Blood and Bone Marrow Transplantation Research (CIBMTR) show that the use of Allo-HCT in DLBCL has declined since 2017.

Chimeric antigen receptor modified T cell therapy (CAR-T) is currently a promising treatment.
The decline in the use of Allo-HCT in DLBCL is related to the increase in the use of CAR-T in DLBCL.

Professor Huang Haiwen said that for the use of Allo-HCT in lymphoma at this stage, it is necessary to consider which lymphoma patients may benefit from it, the timing of treatment, and whether Allo-HCT is required after CAR-T.

The status of Allo-HCT in B-cell NHL (B-NHL) 1.
The standard treatment for diffuse large B-cell lymphoma with relapsed refractory DLBCL and primary refractory DLBCL is still the second-line salvage treatment, and complete remission is obtained after salvage treatment (CR) patients can receive Auto-HCT.

However, for DLBCL patients with disease progression during the first-line treatment, the effect of transplantation is not good, and CAR-T is an important treatment for these patients.

 For patients with relapsed and refractory DLBCL who have reached CR after CAR-T treatment, it is still controversial whether to perform Allo-HCT in the follow-up.

The results of the ZUMA-1 study showed that the 3-year OS rate of patients with relapsed and refractory DLBCL after CAR-T treatment reached 47%, and the median OS was 25.
8 months (95%CI: 12.
8 months-NE).

The two-year comparison of the efficacy of refractory DLBCL patients in the ZUMA-1 study and the SCHOLAR-1 study showed that more patients in the ZUMA-1 study received multiple treatments (≥3 lines) and the proportion of patients ≥2 lines was higher.
There were more primary refractory patients in the SCHOLAR-1 study, and the recurrence of patients within 1 year after transplantation was similar in the two studies.

 Professor Huang Haiwen then shared the statistics of the First Affiliated Hospital of Soochow University: After CAR-T treatment, the survival of patients with bridged transplantation is similar to that of patients without bridged transplantation (1 year OS rate: 83.
3% vs 82.
9%; 2-year OS rate : 72.
9% vs 64.
7%; 1-year progression-free survival [PFS] rate: 83.
3% vs 66.
7%; 2-year PFS rate: 62.
5% vs 54.
7%; there was no significant statistical difference; OS: P=0.
702; PFS: P =0.
489). 2.
Follicular lymphoma For patients with poor prognosis (POD24) follicular lymphoma (FL) within 24 months, transplantation can also bring survival benefits.

Data from the National LymphoCare/CIBMTR Collaborative Group and the German Low-Malignant Lymphoma Research Group show that: for patients with POD24 FL who have relapsed with chemotherapy sensitivity, early application of Auto-HCT has a survival advantage and should be regarded as a standard choice.

CIBMTR compared the efficacy of Allo-HCT and Auto-HCT in patients with POD24 FL, and also confirmed the efficacy of Auto-HCT as a consolidation treatment for patients with chemotherapy-sensitive POD24 FL.

Professor Huang Haiwen said that Allo-HCT is also a better treatment option for FL patients with multiple recurrences, recurrences after Auto-HCT, failure of autologous stem cell mobilization, and treatment-related myeloid tumors.

 Although Allo-HCT can bring 70%-80% of 5-year PFS and OS rates for patients with relapsed and refractory FL, and cure most FL patients.

But Allo-HCT can also cause frequent chronic GVHD and infectious complications, which impairs the quality of life of FL patients.

In recent years, CAR-T therapy has also challenged the status of Allo-HCT in relapsed and refractory FL.

The results of the ZUMA-5 study showed that: at a median follow-up of 17.
5 months, the objective remission rate (ORR) of CAR-T treatment for relapsed and refractory FL reached 94%, the CR rate reached 80%, and the median first treatment remission time was 1 month .

 3.
Professor Huang Haiwen of mantle cell lymphoma said that the emergence of new drugs represented by the BTK inhibitor ibrutinib and the BCL-2 inhibitor venecola has significantly improved the efficacy of MCL patients, brought deep relief, and achieved survival gains.
beneficial.

Although the combination of ibrutinib and venecla regimen (IV regimen) may overcome the poor prognosis of TP53 mutations, patients with MCL with double mutations of TP53 and SMARCA4 still need new treatment options.

 The ZUMA-2 study explored the efficacy of CAR-T in the treatment of patients with relapsed and refractory MCL.
The results of the study showed that at a median follow-up of 17.
5 months, the median PFS and OS of patients with relapsed and refractory MCL did not reach the 15% evaluated by the investigator.
The monthly PFS rate and OS rate were 59% and 76%, respectively.

And regardless of the cell morphology of MCL patients or the choice of front-line BTK inhibitors, they can benefit from CAR-T treatment.

 However, Professor Huang Haiwen said that Allo-HCT still has a place in the treatment of relapsed and refractory MCL, especially in the treatment of patients with ultra-high-risk MCL.

For patients with relapsed and refractory MCL, Allo-HCT has a long-term PFS rate of 35%-45%, which is a better curative option.

CIBMTR data showed that among high-risk MCL patients who did not achieve remission after chemotherapy treatment, Allo-HCT achieved lasting remission in approximately 25% of patients.

Therefore, Allo-HCT is still a viable treatment option for MCL patients with recurrence, ultra-high risk, and failure of new drug treatment.

 4.
Summarizing the era of new drugs and immunotherapy, the position of Allo-HCT in B-NHL has been challenged.

However, for patients who have failed CAR-T treatment, CAR-T treatment is not feasible, CAR-T treatment has only achieved partial remission (PR), and may relapse after CAR-T treatment, Allo-HCT still has a certain therapeutic status.

Especially for patients who may relapse after early CAR-T treatment, Professor Huang Haiwen recommends ctDNA detection of minimal residual disease (MRD) to identify the risk of recurrence in patients, and early Allo-HCT consolidation treatment for patients who may relapse to eradicate residual disease.

The status of Allo-HCT in T-cell lymphoma Although the current early trial data of CD30-CAR-T has confirmed its efficacy in anaplastic large cell lymphoma (ALCL), it still needs to be determined on a larger scale.
The long-term safety and effectiveness of CAR-T in T-cell lymphoma. Professor Huang Haiwen said that the current treatment controversy for patients with T-cell lymphoma is focused on the choice of Auto-HCT and Allo-HCT.

 The research data of the First Affiliated Hospital of Soochow University shows that for patients with T-cell lymphoma who do not reach CR after first-line and second-line treatment, Allo-HCT can bring better survival benefits than Auto-HCT, and it is half-matched to Allo.
There is no significant difference in the survival benefits of HCT and Allo-HCT for these patients.

In addition, for some of the more aggressive T-cell lymphoma subtypes (such as γδ T-cell lymphoma), it is difficult to improve the survival of patients with conventional treatment.

For these patients, Allo-HCT is also an important treatment.

 The role of Allo-HCT in Hodgkin’s lymphoma.
In recent years, the emergence of new drugs such as CD30 monoclonal antibody verbutuximab and immune checkpoint inhibitors (CPIs) has significantly improved the efficacy of HL patients, but most HL patients end up Will experience the failure of new drug treatments.

Allo-HCT can also bring survival benefits to HL patients, and is currently commonly used in HL patients who have failed previous Auto-HCT treatments.

Allo-HCT is also a better treatment option for HL patients who have previously failed treatment with Vebutuximab and CPIs, especially those with better physical status and better social support.

 Summary Professor Huang Haiwen concluded that the new immunotherapy challenges the role of Allo-HCT in lymphoma, especially B-NHL.

In areas where CAR-T treatment is available, Allo-HCT may be limited to B-NHL patients who have relapsed after CAR-T treatment or are not suitable for CAR-T treatment.

For patients with high-risk or recurrent T-cell lymphoma and HL, Allo-HCT is still a viable curative option.

Professor Huang Haiwen Doctor of Hematology, Chief Physician, Associate Professor, Master Supervisor, Member of Lymphoma Expert Group of Chinese Medical Association, Member of Chronic Lymphocytic Leukemia Working Group of Chinese Anti-Cancer Association, Hematology Branch of Jiangsu Medical Association, Lymphoma Myeloma Organizing Committee stamped "read the original text", we make progress together