EXPERT INSIGHT

Brentuximab vedotin serves as a viable option to combine with chemotherapy for advanced stage Hodgkin lymphoma

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Dr. Law, Man-Fai

Division of Haematology,
Department of Medicine & Therapeutics,
Prince of Wales Hospital,
Hong Kong

The combination treatment approach of chemotherapy and radiotherapy has significantly improved the survival outcomes of patients with Hodgkin lymphoma (HL) over the past several decades.1 Whereas the conventional frontline therapies, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), can induce complete remission (CR) in approximately 80-90% of patients, up to 50% of advanced-stage cases have relapses and up to 20% are refractory to first-line treatments.1 Although various salvage chemotherapies are available, their efficacy are limited and are accompanied with potential serious adverse effects such as pulmonary toxicities.2 In a recent interview with Omnihealth Practice, Dr. Law, Man-Fai, Division of Haematology, Department of Medicine & Therapeutics, Prince of Wales Hospital, Hong Kong, shared his insights on the addition of brentuximab vedotin (BV), a targeted therapy to chemotherapy for the management of advanced stage HL, can be a potentially more efficacious option than the chemotherapies.3,4

Treatment barriers for CD30+ lymphomas

CD30 is a type of tumor necrosis factor receptor involved in promoting cell proliferation and survival via various signal transduction pathways.2 The common lymphomas characterized by CD30 expression include HL and anaplastic large-cell lymphoma (ALCL).5 Approximately 8.6% of all malignant lymphomas belong to HL in the Chinese population.6 ALCL, which includes both systemic ALCL (sALCL) and cutaneous T-cell lymphoma (CTCL), accounts for about 3% of non-Hodgkin lymphoma (NHL) in adults.1,7,8,9

Currently, the conventional therapies such as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), can pose significant risk of refractory or relapsed disease, in addition to the risk of treatment-related toxicities, to advanced stage HL patients.1,2 For instance, up to 40% of patients with HL will have relapsed or become refractory after initial ABVD therapy.2 The 5-year overall survival (OS) rate of stage III or IV HL was only 74.7% after receiving ABVD, as compared to more than 90% in the early stages of HL; the 5-year OS rate of relapsed or refractory sALCL was at most 56% after receiving high dose chemotherapy and autologous stem cell transplant (ASCT).6,10 To address the unmet medical needs for patients with advanced, relapsed or refractory diseases, alternative therapies with more favorable survival outcomes can be incorporated into the treatment regimen.

Brentuximab vedotin: A novel treatment option

Being expressed in the activated eosinophils and lymphocytes specifically and having no involvement and cross-reactivity with other normal peripheral blood cells, CD30 is an ideal target for the development of new therapies.7 BV is one such antibody-drug conjugate (ADC) that targets the CD30 antigen and has demonstrated promising efficacy in various types of CD30+ lymphomas.1,3,4,10-13

In a 5-year study conducted in the United States, patients with relapsed/refractory HL (RRHL) who failed the ASCT demonstrated an OS and progression-free survival (PFS) of 40.5 and 9.3 months respectively, with an estimated 5-year OS rate of 41% and PFS rate of 22%, after receiving BV monotherapy.11 In another study investigating patients with HL at risk of relapse or progression, BV as consolidation therapy after ASCT had improved median PFS of 42.9 months versus 24.1 months in the placebo group (HR=0.57, 95% CI: 0.40-0.81; p=0.0013).12 The estimated 2-year PFS rate was also improved to 65% in the BV group versus 45% in the placebo group (HR=0.55, 95% CI: 0.39-0.77).12Being expressed in the activated eosinophils and lymphocytes specifically and having no involvement and cross-reactivity with other normal peripheral blood cells, CD30 is an ideal target for the development of new therapies.7 BV is one such antibody-drug conjugate (ADC) that targets the CD30 antigen and has demonstrated promising efficacy in various types of CD30+ lymphomas.1,3,4,10-13 In a 5-year study conducted in the United States, patients with relapsed/refractory HL (RRHL) who failed the ASCT demonstrated an OS and progression-free survival (PFS) of 40.5 and 9.3 months respectively, with an estimated 5-year OS rate of 41% and PFS rate of 22%, after receiving BV monotherapy.11 In another study investigating patients with HL at risk of relapse or progression, BV as consolidation therapy after ASCT had improved median PFS of 42.9 months versus 24.1 months in the placebo group (HR=0.57, 95% CI: 0.40-0.81; p=0.0013).12 The estimated 2-year PFS rate was also improved to 65% in the BV group versus 45% in the placebo group (HR=0.55, 95% CI: 0.39-0.77).12

For patients with RR sALCL, those treated with BV achieved a 5-year survival rate of 60% and median OS was not reached (95% CI: 21.3-not estimable).10 The estimated 5-year PFS rate was 39% and the median PFS was also not reached in patients who achieved CR (95% CI: 21.3%-not estimable).10 Similarly, in the ALCANZA study that recruited patients with CD30+ CTCL, 56.3% of patients on BV achieved a global response lasting for at least 4 months versus 12.5% on physician’s choice of therapy (difference=43.8%, 95% CI: 29.1-58.4; p<0.0001).13

In the ECHELON-1 study, BV+AVD (doxorubicin, vinblastine and dacarbazine) demonstrated a better 2-year modified PFS rate of 82.1% among patients with previously untreated stage III and IV classic HL versus 77.2% in patients treated with ABVD.3 The hazard ratio for progression, death or modified progression was 0.77 (95% CI: 0.60-0.98; p=0.03), indicating a 23% risk reduction when patients received BV+AVD over ABVD treatment.3 In the 3-year follow-up study of ECHELON-1, the 3-year PFS with BV+AVD continued to demonstrate superiority at 83.1% versus 76.0% on ABVD treated patients who were independent of positron emission tomography (PET) scan results after cycle 2 (PET2) (HR=0.704, 95% CI, 0.550-0.901; p=0.005) (Figure 1).4 This benefit of BV+AVD appears to be independent of disease stage and prognostic risk factors.4

Based on the promising survival benefit and durability results of BV+AVD, Dr. Law shared his clinical experience of using this regimen in an advanced stage classic HL patient.

The clinical use of brentuximab vedotin in stage IV CD30+ HL: A case sharing

A 51-year-old man with good health history presented with high fever and upper respiratory symptoms. Chest was clear. There was no palpable lymph node or hepatosplenomegaly.

Initial investigation on 9th April 2020 indicated that the patient had pancytopenia with hemoglobin count of 8.7g/dL, white blood cells of 3.5x109/L (neutrophils 61%, lymphocytes 16%, monocytes 23%), and platelets of 16x109/L. Red cells were hypochromic and microcytic with increased target cells present. Monocytes were increased with some reactive lymphocytes observed. Liver and renal function tests were unremarkable. The lactate dehydrogenase (LDH) level was elevated at 400U/L. Chest X-ray showed clear lung fields and there was no mediastinal mass.

Bone marrow examination was performed in view of pancytopenia. An adequate core of trephine biopsy was obtained and showed hypercellular marrow. Multiple abnormal lymphoid infiltrates consisting of predominantly small lymphocytes with some large cells admixed were spotted. Clusters of large cells with moderate amount of cytoplasm, having round or irregular nuclei and multiple nucleoli, were present in the focal areas (Figure 2). Immunostaining indicated that the large cells were CD30+, CD20 negative (-), CD56-, and EBER+ (Figure 3).

Trilineage hematopoietic precursors were adequate in less-affected areas and showed normal maturation. Reticulin fibers were coarsened in the areas with lymphoid infiltrates. Further immunostaining revealed that the large cells were PAX5+ and ALK- (Figure 3).

Cytogenetic study was carried out to analyze 6 out of 27 metaphases; complex changes near triploid clone and rearrangement of chromosome 21 and marker chromosome were found that were compatible with the presence of bone marrow clonal condition.

The patient was concluded to have bone marrow involvement by CD30+ large cell lymphoma with reactive hemophagocytosis (Figure 4). Based on these results of immunostaining, the patient was then diagnosed to have stage IV HL.

After the diagnosis of the stage IV HL and a consensual discussion with the patient, BV+AVD was adopted as frontline treatment strategy. Prior to the start of first treatment cycle on 20th April, a positron emission tomography-computed tomography (PETCT) scan was performed that showed multiple mildly enlarged and hypermetabolic lymph nodes throughout the body along the neck, thorax, axilla, abdomen, and the pelvis region. Mild splenomegaly, with few hypermetabolic foci within, were also discovered. There were two non-specific changes noted, including a hypermetabolic and mildly radiolucent area (SUVmax: 4.9) at the left 1st rib posterior aspect, and a hypermetabolic right thyroid lobe nodule (size=0.8cm, SUVmax: 3.6).

After 2 cycles of BV+AVD therapy, interim PET-CT scan analysis on 19th June showed that there was metabolic improvement of lymphadenopathies that were detected previously. There were multiple metabolically resolved or residual active nodes with none to mild fluorodeoxyglucose (FDG) avidity (Deauville scores: 1-2) in the body torso. Metabolic resolution of previous focal hypermetabolic lesions was seen in the spleen and right thyroid lobe. No new hypermetabolic lymphomatous lesion could be detected. Overall, the patient responded positively towards BV+AVD treatment.

Although the patient experienced pneumonia once after the fourth treatment cycle, the symptoms were quickly resolved with antibiotics. As the pneumonia was an isolated event and that the patient had recovered well, dose reduction of BV was not necessary and full dose was continued throughout the whole treatment. Granulocyte colony-stimulating factor (G-CSF) was also given to help raise the number of white blood cells on day 5-11 and day 19-25 of each cycle as per the protocol of ECHELON-1 study.

For the past 6 months since the first treatment cycle, the patient was stable without B symptoms of lymphoma. The treatment was well-tolerated, and a final PET-CT scan had been scheduled to further evaluate his response.

Discussion

In addition to having risk of relapsed disease or become refractory after initial ABVD treatment, bleomycin, a key component of the ABVD regimen, is also a known cause of oxidative stress in the lungs that can lead to pulmonary fibrosis.2,14 Bleomycin should be avoided in the elderly patients who may be at risk of serious pulmonary-related adverse events.15

The use of BV in the frontline setting has demonstrated favorable survival benefits despite the advanced stage of the disease. After 2 cycles of BV+AVD, interim PET-CT scan already showed that the patient had multiple metabolic improvement as well as resolution of lesions. By replacing bleomycin in the current chemotherapy combination therapy, BV can minimize the risk of serious pulmonary toxicity and reduce the mortality, and thus can be a treatment option for patients who may be at risk of pulmonary involvement.15,16 Consistent with the ECHELON-1 study results, the durable and robust efficacy benefit of BV indicates that it can be prescribed in the frontline setting for previously untreated HL patients of advanced stages, regardless of the PET2 status, without the need for treatment intensification or bleomycin exposure.4 In view of the poorer prognosis of advanced-stage disease, patients with stage IV HL who are previously untreated may receive better survival benefit from a BV vedotin based treatment regimen.17

Conclusion

CD30 antigen expression is common in HL and some types of T-cell lymphomas, and now becomes a feasible target for therapeutic intervention. BV is one of the latest therapies that targets the CD30 antigen. Traditional chemotherapy regimens may provide satisfactory survival benefits to HL patients of early stages. Yet, for those with advanced diseases, the survival outcomes and prognosis are still not satisfactory that has left an unmet treatment need for alternative therapies to prolong survival. The goal of frontline therapy for HL is to cure patients without the need for additional therapy. BV can be a tolerable and efficacious option to combine with the conventional chemotherapy as frontline treatment for the advanced stage HL.

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