For early massive Hodgkin's lymphoma, after verbutuximab combined with chemotherapy has achieved complete remission, can radiotherapy be reduced or omitted?

For a long time, people have believed that the standard of care for early massive Hodgkin's lymphoma (HL) is combination therapy, including consolidation radiotherapy.

However, combined radiotherapy has potential long-term toxicity, especially to the mediastinum, such as causing cardiopulmonary disease and secondary malignant tumors.

In order to minimize these toxicities, current radiotherapy for HL has reduced the radiation field and used more precise involved-site radiotherapy (ISRT).

In addition, the researchers tried to reduce the radiation dose.
In the HD15 study of the German Hodgkin Research Group (GHSG), the radiation dose of early HL patients was successfully reduced from 30Gy to 20Gy.

In addition to reducing the radiation field and dose of radiotherapy (RT), researchers are also trying to enable certain early-stage HL patients to omit RT.

The PET result-guided treatment strategy has been successfully applied to early non-large mass HL.

A number of studies have reported that patients with a short course of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) treatment and PET-negative patients who have not undergone consolidation radiotherapy can achieve minimal disease control, and Survival rates are similar.

However, patients with relatively large tumors with a baseline tumor size of ≥5 cm have a poor prognosis with only short-term ABVD treatment.

In addition, for patients with large lumps, and those with negative PET after 6 cycles of ABVD chemotherapy, chemotherapy alone can achieve similar results to the combined regimen.

Brentuximab Vedotin (BV), an antibody-drug conjugate targeting CD30, has been shown to be safe to use in combination with doxorubicin, vinblastine, and dacarbazine (AVD).

In the phase III ECHELON-1 study, newly treated patients with advanced HL received 6 cycles of BV+AVD treatment.
Compared with standard ABVD, the 3-year progression-free survival (PFS) rate of the BV+AVD group increased by 6%.

Based on the above results, the researchers designed a multi-center pilot study with 4 cycles of BV+AVD as the framework.

If the patient's PET test (PET-4) after the fourth cycle of treatment is negative, enter the following four cohorts to receive progressively reduced dose and field consolidation therapy: cohort 1 is 30 Gy ISRT, cohort 2 is 20 Gy ISRT, Cohort 3 was 30 Gy consolidation-volume radiotherapy (CVRT), cohort 4 had no radiotherapy.

Previous investigators have reported the results of cohort 1 (four cycles of BV + AVD, followed by 30-Gy ISRT), which are considered safe and well tolerated, with no obvious pulmonary toxicity.

This time the investigator reported the final analysis results of all patients.

Research methods Included population The study included patients with CD30+ classic HL who were 18-60 years old, newly treated, stage I/II, and confirmed by biopsy.

Patients enrolled in cohort 1 must meet any of the following unfavorable risk factors, including huge mediastinal masses (the ratio of mediastinal tumors in the posterior anterior X-ray examination of the chest is greater than 1/3, or the axial CT scan ≥10 cm), red blood cell sedimentation rate ≥50mm/h or erythrocyte sedimentation rate ≥30 mm/h with B symptoms, extranodal disease, more than 2 affected lymph node areas (defined by GHSG), or subdiaphragmatic disease.

Patients enrolled in cohort 2 used the same criteria for adverse risk factors, but updated the definition of a large mass, using the definition of Memorial Sloan Kettering (MSK): the maximum transverse diameter of the CT scan or the coronary diameter of the largest lymph node mass at any location> 7 cm.

Early HL patients included in cohort 3 and cohort 4 must have large masses that meet the MSK criteria.

The entire cohort included patients with stage IIB disease with large masses (X) and/or extranodal involvement (E).

Study design BV (1.
2 mg/m2), doxorubicin (25 mg/m2), vinblastine (6 mg/m2) and dacarbazine (375 mg/m2) on the 1st and 15th day of each cycle, respectively It is administered every 28 days, a cycle for a total of 4 cycles.

All patients are mandatory to receive preventive growth factor support treatment.

After 4 cycles of BV+AVD treatment, PET-negative patients and PET-positive patients with negative biopsy subsequently received 30 Gy ISRT in cohort 1, 20 Gy ISRT in cohort 2, 30 Gy CVRT in cohort 3, and no RT in cohort 4.

Compared with cohort 1, cohort 2 maintains the standard radiation field (ISRT) and reduces the dose to 20 Gy; while cohort 3 uses CVRT to reduce the radiation field while maintaining the standard dose (30 Gy).

The main research endpoint of statistical analysis cohort 1 is to evaluate the safety of BV+AVD sequential RT, paying special attention to the possible increased risk of pulmonary toxicity.

The primary endpoint of cohorts 2-4 was to assess the complete response rate (CR) of PET negative at the end of treatment (EOT).

With the simon two-stage design, when the preset CR rate is lower than 75%, the solution is hopeless, and when it is higher than 91%, the solution is promising.

The Kaplan-Meier method was used to estimate PFS.

Study Results 01 Patient characteristics and treatment management From June 3, 2013 to June 14, 2019, a total of 117 patients participated in the pilot study.
There were 30 patients in cohort 1 and 29 patients in cohorts 2-4.

It is worth noting that 86% of patients had a large mass defined by MSK (transverse or coronal diameter> 7 cm), 27% were a traditionally defined mass (transverse diameter> 10 cm), and 23% had progress that met the GHSG criteria Stage diseases: IIBX (n = 16), IIBE (n = 5) and IIBXE (n = 6).

Due to the difference in inclusion criteria, in cohorts 3 and 4, patients with large masses defined by MSK accounted for more, while the proportion of patients with traditionally defined masses in cohort 1 was higher than that in cohorts 2-4.

Throughout the study, 99% of the patients (116/117) received the planned 4 cycles of treatment, and in the cohort 1-3, 94% of the patients (82/87) received the planned radiotherapy.

One patient in cohort 1 withdrew from the study due to toxicity (grade 3 hypertension and peripheral neuropathy) after one BV+AVD treatment.

Four patients in cohort 1 did not receive 30-Gy ISRT.

In cohort 2, one patient refused to receive 20-Gy ISRT.

02 Safety and toxicity In the four cycles of BV+AVD treatment, the incidence of dose adjustment (such as delayed dosing, interruption of treatment, or dose reduction) is low.

The main reason for the dose adjustment is the development of peripheral neuropathy, which leads to a reduction in the BV dose, usually from 1.
2 to 0.
9 mg/kg.

In terms of safety, although neutropenia (all grades) is more common (44%), the incidence of febrile neutropenia is very low (8%).

According to the plan, all patients are mandatory to receive growth factor support therapy.

Peripheral sensory neuropathy related to BV+AVD has a higher incidence (n = 63, 54%), but most of them are of low grade (n = 60, 95%) or solvable (n = 48, 76%), or Remission to grade 1 at the last follow-up (n = 15, 24%).

No treatment-related pulmonary toxicity has been reported.

During the treatment period, 24 patients experienced 41 serious adverse events and required hospitalization.

The most common causes are fever and neutropenia, abdominal pain and infection.

There were no treatment-related deaths.

03 The overall PET negative rate of curative effect (5-PS score 1-3): 87% for PET-2 (PET examination after the second cycle of treatment), 88% for PET-4, and 85% for EOT.

In cohorts 1-4, the CR rates at EOT were 93%, 100%, 93%, and 97%, respectively.

Therefore, according to the protocol, cohort 2-4 groups reached the primary endpoint.

The PET negative rate at EOT is lower than the CR rate because many patients have positive EOT PET, but no residual lymphoma was found after repeated scans and/or biopsy.

04 The median follow-up time for survival results was 3.
8 years (cohorts 1-4 were 5.
9, 4.
5, 2.
5, and 2.
2 years, respectively), and the total 2-year PFS rate was 94% (95% CI, 89.
7-98.
3), and the total 2-year The survival rate was 99.
1% (95% CI, 97.
3-1.
0).

The two-year PFS rates for cohorts 1-4 were 93.
1% (95% CI, 83.
9-1.
0), 96.
6% (95% CI, 89.
9-1.
0), 89.
7% (95% CI, 78.
5-1.
0) and 96.
6% ( 95% CI, 89.
9-1.
0).

The 4-year PFS of Cohort 1 and Cohort 2 were both 93.
1%.

In cohort 1, 2 patients who were PET-4 positive after 4 cycles of BV + AVD treatment were confirmed by biopsy as primary refractory disease.

In cohort 2, one patient relapsed 34 months after starting chemotherapy.

In cohort 3, 2 patients were PET-positive after completing 30-Gy CVRT, biopsy confirmed primary refractory disease, and 1 patient relapsed 9 months after starting treatment.

In cohort 3, 3 patients experienced early treatment failure after CVRT, of which 2 relapses occurred outside the CVRT field but within the theoretical ISRT field.

In cohort 4, 1 patient was positive for PET-4 and/or EOT PET and was confirmed by biopsy as a primary refractory disease.

There are no clear baseline risk factors related to disease-related events, and the mid-term PET-2 results are not related to the risk of recurrence.

Research conclusions According to reports, this is the largest published study reporting first-line BV+AVD treatment-related results in patients with stage I/II classic HL.

Due to the limited number of patients in each cohort and the non-random design, the current pilot study is not intended to clearly compare these four treatment options.

However, the results of the study suggest that BV+AVD, whether combined with consolidation radiotherapy or not, shows excellent efficacy in high-risk early HL patients.

It is worth noting that queue 3 using CVRT has similar results compared to queues 1 and 2.

However, 2 of the 3 treatment failure cases in cohort 3 occurred in the theoretical ISRT field and outside the CVRT field, suggesting that the RT field may be more effective to cover the tumor before chemotherapy.

But overall, studies have shown that after receiving 4 cycles of BV+AVD treatment, the 30 Gy ISRT dose may not be needed.

In the future, research on other new drugs such as immune checkpoint inhibitors may achieve the goal of omitting RT and reducing the long-term toxicity of HL patients with early large masses.

In addition, the encouraging results obtained with only short-term BV+AVD treatment in this study provide support for the UK RADAR study.

The UK RADAR study is an ongoing randomized clinical trial designed to compare the efficacy of ABVD and BV+AVD in the treatment of early HL.

Reference: Kumar A, Casulo C, Advani RH, et.
al.
Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma.
J Clin Oncol[J].
2021 Apr 28:JCO2100108.
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