NEJM: Brentuximab Vedotin treats high-risk Hodgkin lymphoma in children and adolescents with event-free 3-year survival rate of up to 92%

In an ECHELON-1 study involving patients with previously untreated stage III or IV Hodgkin lymphoma, treatment with antibody-drug conjugates targeting CD30, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) resulted in a mortality risk significantly lower than those observed with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)
regimens 。 At 6 years of follow-up, this result translated into an overall difference in mortality of 4.
5%, favouring brentuximab vedotin plus AVD
.
Dr.
Stephen M.
Ansell and ECHELON-1 researchers at Mayo Clinic in Rochester, Minnesota, USA, reported the findings in the New England Journal of Medicine on July 13, 2022, writing that the treatment of advanced Hodgkin lymphoma has been successful in the field of oncology, but has made only modest progress
over the past few decades 。 However, in ECHELON-1, brentuximab vedotin plus AVD treatment resulted in improvements
in progression-free survival (PFS) and overall survival (OS).

In the phase III ECHELON-1 study, first-line treatment with brentuximab vedotin, a CD30-directed monoclonal antibody conjugated to the microtubule destroyer monomethylauristatin E via a protease cleavable linker, plus AVD significantly improved modified PFS, defined as a time to progression, Death or incomplete remission and the use of subsequent treatment, a planned interim analysis suggests potential benefits
in terms of OS.
At 5 years, PFS with brentuximab vedotin plus AVD had long-term benefits (risk ratio [HR] 0.
68; 95% confidence interval [CI] 0.
53 to 0.
87) compared with ABVD.

These results suggest that CD30-targeted antibody-drug conjugate brentuximab vedotin in combination with multi-agent chemotherapy has been shown to be more effective than chemotherapy alone, but also more
toxic, in adults with advanced Hodgkin lymphoma.

J Clin Oncol.
In April 2021, the availability of first-line Brentuximab vedotin to reduce the prescribed dose of radiation therapy in children and adolescents with cHL was published, in an open-label, single-arm, multicenter trial enrolling patients (aged ≤ 18 years) with stage II.
B, III or IV cHL, Brentuximab vedotin replaced vincristine in OEPA/COPDac regimens according to GPOH-HD2002 treatment group 3 (TG3); 2 cycles of AEPA and 4 cycles of CAPDac
are administered.

After the end of all chemotherapy, residual lymph node radiotherapy (25.
5 Gy)
was applied only to the lymph node sites where the Early Response Assessment (ERA) after two courses did not achieve complete remission (CR).
The primary endpoints were safety and efficacy of the combination (complete response to ERA) and 3-year event-free survival (EFS) and overall survival (OS).

Results showed that of the 77 patients enrolled, 27 (35%) had a complete response at the time of ERA without radiotherapy
.
The radiation therapist receives irradiation
to a single residual lymph node tissue.
The median follow-up was 3.
4 years, with a 3-year EFS rate of 97.
4% and a 3-year OS rate of 98.
7%.

One patient with radiotherapy had disease progression at the end of treatment, and survived without disease after 6 years of salvage treatment
.
One accidental death
.
The incidence of grade 3 neurological disease is only 4%.

However, the results of this brentuximab vedotin treatment regimen in children and adolescents with Hodgkin lymphoma have not yet been studied
.

The results of AHOD1331 were published in the journal NEJM, just published today, demonstrating the efficacy and safety
of brentuximab vedotin in children and adolescents with high-risk Hodgkin lymphoma.
By combining targeted antibody-drug conjugate (ADC) brentuximab vedotin (BV) with standard chemotherapy regimens, children are 10%
less likely to relapse.

This is an open-label, multicenter, randomized, phase 3 trial in previously untreated stage IIB Hodgkin lymphoma with large tumors or patients
aged 2 to 21 years with stage IIIB, IVA, or IVB 。 Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen (standard-care group)
of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide.

Slow-responding lesions, defined as a score of 4 or 5 (on a 5-point scale, with 1 to 3 indicating a rapidly responsive-response lesion), is identified
after two cycles by centrally reviewed positron emission tomography - computed tomography.
After the fifth treatment cycle, radiation therapy
is administered to the affected area for slow-responding lesions and large mediastinal lymphadenopathy present at diagnosis.
The primary endpoint is event-free survival, defined as the time until disease progression, recurrence, the
development of a second malignancy, or patient death.
Safety and overall survival were assessed
.

Results showed that of 600 patients at 153 institutions, 587 were eligible
.
Compared with the brentuximab vedotin group, the median follow-up time in the brentuximab vedotin group was 42.
1 months (range, 0.
1 to 80.
9), and the 3-year event-free survival rate was 92.
1% (95% confidence interval [CI], 88.
4 to 94.
7).

。 82.
5% (95% CI, 77.
4 to 86.
5) was in the standard treatment group (risk ratio for event or death, 0.
41; 95% CI, 0.
25 to 0.
67; P<0.
001).

There was no significant difference in the percentage of patients receiving radiation therapy to the affected area between the brentuximab vedotin group and the standard care group (53.
4% and 56.
8%, respectively).

The toxic effects were similar
in both groups.
The 3-year overall survival rate was 99.
3% (95% CI, 97.
3 to 99.
8) in the brentuximab vedotin group and 98.
5% (95% CI, 96.
0 to 99.
4)
in the standard of care group.

Thus, the addition of brentuximab vedotin to standard chemotherapy yielded superior efficacy, a 59% reduction in the risk of event or death, and no increased
incidence of toxic effects at 3 years.

"We saw a 10 percent improvement in event-free survival — a real breakthrough," said study senior author Kara Kelly, MD, chair of the Oishei Childhood Cancer and Blood Disorders Program at Roswell Park, and chair of the Roswell Waldemar J.
Kaminski Pediatric Foundation, and chair of the Department of Pediatric Hematology/Oncology at the Jacobs School of
Medicine and Biomedical Sciences at the University at Buffalo.
"That's a pretty big gain, especially in this area
.
We anticipate that this regimen will soon become the standard of
care for pediatric patients with high-risk Hodgkin lymphoma.
”

"This trial reflects a paradigm shift in advanced childhood Hodgkin lymphoma and introduces the first targeted approach to the initial treatment of pediatric Hodgkin lymphoma and the first new regimen in two decades," said study lead author Sharon Castellino, M.
S.
, director of the Leukemia and Lymphoma Program at the Aflac Cancer and Blood Disorders Center in Children's Health Care Atlanta, professor of pediatrics at Emory University School of Medicine, and researcher at the Winship Cancer Institute at Emory University
。 Dr.
Castellino succeeded Dr.
Kelly as Chairman of the COG Hodgkin Committee this
year.
"We are optimistic that this trial will lay the groundwork
for FDA approval of this targeted antibody drug conjugate for children and adolescents.
"

Study Vice Chair and co-author Frank Keller, MD, pediatric hematologist/oncologist at the Aflac Center for Cancer and Blood Disorders in Atlanta, Child Care, Atlanta, and professor of pediatrics at Emory University School of Medicine, added: "Highly targeted therapy for malignant cell populations in pediatric and young adult patients newly diagnosed with high-risk Hodgkin lymphoma is an important step toward improving cure rates and may be done without adding significant long-term toxicity to the younger population for many years of life
。 ”

HL is the most common cancer
in patients aged 12 to 29 years.
Despite its high five-year survival rate – 97% of people under the age of 19 are alive five years after diagnosis – about a third of survivors are classified as high-risk; Of these, about 15-20% recur.

"Brentuximab vedotin is not expected to produce long-term toxicity," Dr.
Kelly said, noting that less than 10 percent of patients receiving it require dose
reduction during the therapeutic phase of clinical trials.
"Because the drug can be given more consistently, its efficacy is improved without an increase
in neuropathy or serious infections.
"

Dr.
Kelly, Dr.
Castellino and colleagues will build on these findings in a new clinical trial, which will begin
in early 2023, with support from the National Cancer Institute.
The Phase III randomized study will enroll approximately 1,900 intermediate- and low-risk HL children and adults
aged 5-60 years.
The objective was to determine whether a combination of CD30-targeting ADC brentuximab vedotin and the immunotherapy drug nivolumab could prolong progression-free survival and further reduce patient exposure
to standard chemotherapy and radiation.
Patients will be followed for 12 years to monitor their progress and evaluate results
.

Lucky Jain, MD, pediatrician in child care in Atlanta and chair of the Department of Pediatrics at Emory University School of Medicine, said, "A 10% reduction in recurrence rates in children with high-risk Hodgkin lymphoma is an important milestone
in the field of pediatric cancer.
Children's Health Center Atlanta and Emory University are proud
of this incredible leap forward led by our physicians, Sharon Castellino, PhDs, and Frank Keller, along with their collaborators and pediatric oncology teams.
”

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