Evaluating Brentuximab Vedotin Plus AVD and Radiation Therapy for Early-Stage, Unfavorable-Risk Hodgkin Lymphoma

In a multicenter pilot study published in Blood, investigators reported that brentuximab vedotin plus adriamycin, vinblastine, and dacarbazine (BV + AVD) and involved-site radiation therapy (ISRT) could be a safe and effective approach for patients with early-stage, unfavorable-risk Hodgkin lymphoma (HL) – even those with bulky disease.

“The standard of care for [these] patients is adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in combination with radiation therapy … but the estimated five-year progression-free survival (PFS) for this approach is 80 to 85 percent,” the authors, led by Anita Kumar, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, explained. In addition, there is the real risk of long-term treatment-related toxicities – particularly bleomycin-related lung injury – in HL survivors who receive this combined chemotherapy and radiation therapy approach.

In the current study, Dr. Kumar and colleagues enrolled 30 patients with newly diagnosed, early-stage, CD30-positive, classic HL (median age = 31 years; age range = 18-59 years) from MSKCC and the Wilmot Cancer Institute at the University of Rochester between June 2013 and February 2015. Patients were included if they had:

  • untreated stage I/II disease with any of the unfavorable risk factors defined by German Hodgkin Study Group, including:
    • bulky mediastinal mass (≥1/3 maximum width of mass/maximum intrathoracic diameter on posterior-anterior-CXR or ≥10 cm by computed tomography [CT] imaging in transaxial plane)
    • erythrocyte sedimentation rate (ESR) ≥50 mm/h or ESR ≥30 mm/h in patients with B symptoms
    • extranodal involvement
    • >2 lymphoma node sites
  • infradiaphragmatic disease
  • stage IIB disease with bulk or extranodal involvement

Patients were scheduled to receive four cycles of BV (1.2 mg/kg) plus AVD chemotherapy (adriamycin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) administered on days one and 15 of each 28-day cycle. Prophylactic growth factor support was also administered with each cycle.

Positron emission tomography (PET) scans were performed after two and four cycles of BV + AVD. Patients who were PET-negative after four cycles of BV + AVD (defined as Deauville score 1-3) or those who were PET-positive after chemotherapy with a subsequent biopsy negative for HL then received 30 Gy ISRT (the recommended standard radiation therapy for HL patients per the International Lymphoma Radiation Oncology Group and the National Comprehensive Cancer Network). Those with a positive PET result and positive biopsy for lymphoma were subsequently treated off study.

Twenty-nine patients received BV + AVD; 25 of these patients received the additional treatment of 30.6 Gy ISRT in 17 daily fractions. Of the four patients who did not receive ISRT, two had biopsy-confirmed refractory classic HL, one elected to come off study to receive proton beam radiotherapy to the mantle field, and one elected to come off study to receive chemotherapy alone with two additional cycles of ABVD after four cycles of brentuximab vedotin plus AVD.

Adverse events (AEs) associated with BV + AVD, with or without ISRT, were generally grade 1-2 toxicities and “easily managed,” the authors noted. The most common grade ≥3 AE associated with BV + AVD was neutropenia (n=16; 53%), and peripheral neuropathy was observed in 40 percent of patients (n=12). Serious AEs occurred in six patients receiving BV + AVD, including grade 3 febrile neutropenia (n=3) and grade 1/2 fever without neutropenia (n=2). The most common acute toxicities associated with ISRT were fatigue (n=22; 88%), dermatitis (n=20), dysphagia (n=20), and esophagitis (n=13).

No clinically significant, drug-related pulmonary toxicity was observed. In most patients, PFTs showed an initial decline in diffusing capacity of the lung for carbon monoxide for hemoglobin (DLCO-Hb) after four cycles of BV + AVD; the addition of ISRT, though, did not worsen DLCO-Hb. At 12 months, PFTs also showed an improvement in mean DLCO-Hb and forced expiratory volume that was even higher than PFT measurements at baseline, which was “likely due to resolution of intrathoracic HL,” the authors wrote.

After four cycles of BV + AVD, 93 percent of patients (n=27) had a negative PET scan. One-year progression-free survival (PFS; secondary endpoint) in all patients was 93.3 percent (95% CI 84-102), and all 25 patients who received BV + AVD and ISRT achieved a complete response. After a median follow-up of 18.8 months, no relapses occurred among these 25 patients. (See TABLE for PET results during and after treatment.)

Ninety percent of patients (n=26) achieved a PET-negative response after two treatment cycles, including 11 of the 13 patients (85%) with bulky disease (defined as >7 cm in maximal transverse diameter or >7 cm in maximal coronal diameters). “Preliminarily, BV + AVD compares favorably to standard ABVD in terms of early conversion to PET-negativity after two cycles,” the authors wrote, “suggesting it is a highly active treatment program in this group of early-stage HL patients with substantial tumor bulk and extensive disease.”

The study is limited by its small sample size and limited follow-up time, the authors noted. In addition, this study “was not designed to definitively assess the efficacy of BV + AVD [after] four cycles followed by 30 Gy ISRT, and we cannot formally compare our results to previous trials due to differences in eligibility, type, and number of cycles of chemotherapy and radiotherapy field and dose,” the authors wrote.

Dr. Kumar and researchers have expanded this pilot study to include an additional 29 patients who will receive a decreased dose of ISRT (20 Gy) to further explore the efficacy of this combined modality. “Future studies to test whether radiation therapy can be eliminated or its volume further reduced in PET-negative, bulky, early-stage HL patients treated with BV + AVD chemotherapy are warranted,” they concluded.


Reference

Kumar A, Casulo C, Yahalom J, et al. Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2016;128:1458-64.

TABLE. PET Results During and Following Treatment
Deauville Score After 2 cycles

(n=29)

After 4 cycles

(n=29)

End of treatment/After ISRT

(n=25)

1* 3
(10%)
5

(20%)

2* 14

(48%)

21
(72%)
16

(64%)

3* 12

(41%)

3
(10%)
2

(8%)

4 3

(10%)

2

(7%)

2

(8%)

5
PET = positron emission tomography; ISRT = involved-site radiation therapy

*PET-negative response was defined as Deauville 1-3.

For one patient, repeat PET scan remained positive, but subsequent biopsy demonstrated granulomatous inflammation consistent with sarcoid. For the second patient, repeat PET after two months was negative (Deauville 3). Thus both patients achieved a complete response.

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