Tag: Hodgkin Lymphoma

SUMMARY: The American Cancer Society estimates that in the United States for 2023, about 8830 new cases of Hodgkin Lymphoma will be diagnosed and about 900 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

Patients with Stage I/II classical Hodgkin Lymphoma (cHL) with bulky disease (mass more than 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray), are typically treated with chemotherapy followed by radiation. However radiotherapy to the chest can result in late complications which include risk of secondary malignancies, particularly breast cancer in women treated under the age of 30 years, cardiovascular disease, as well as the possibility of radiation-associated pneumonitis and fibrosis. Given the prognostic impact of interim PET scans after two cycles of chemotherapy (PET2) on Progression Free Survival, several trials evaluated response-adapted therapy, with de-escalation of treatment in patients with negative PET2, and intensifying therapy in patients with PET2-positive findings.

CALGB 50801 is a single-arm, Phase II trial with response-adapted therapy on the basis of centrally reviewed interim PET, and is the first study focusing exclusively on patients with bulky Stage I and II disease. The researchers hypothesized that a PET-adapted strategy would be effective and limit the use of mediastinal radiotherapy and prevent late complications in this high-risk group of patients. This study included 94 eligible and evaluable patients with bulky disease, for the safety and efficacy analyses. Patients were treated with two cycles of full-dose ABVD (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine) without delay, regardless of neutrophil count, followed by interim FDG PET (PET2). Patients with a negative PET2 defined as 1-3 on the Deauville 5 point scale received four additional cycles of ABVD. Patients with a positive interim PET2 defined as 4 and 5 on the Deauville 5 point scale were treated with escalated BEACOPP (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) for four cycles, followed by 30 Gy involved-field radiotherapy. Median age of patients was 30 years, 22% were PET2 positive and 78% were PET2 negative after two cycles of ABVD.

The Primary objectives of this study were to use a PET-adapted approach to maintain Progression Free Survival (PFS) in patients with negative PET2 without the use of radiotherapy, and to improve outcomes in PET2 positive patients by intensifying therapy. The researchers assessed whether PFS for PET2 positive patients receiving escalated BEACOPP was not inferior to that of PET2 negative patients receiving ABVD, compared with historical differences in PFS between PET2 positive patients and PET2 negative patients receiving ABVD.

This PET-adapted study met the primary objective of maintaining ongoing remissions in PET2 negative patients treated with chemotherapy only, without the addition of radiation therapy. The Primary end point of 3-year Progression Free Survival was 93.1% in PET2 negative patients and 89.7% in PET2 positive patients. The 3 year Overall Survival was 98.6% and 94.4%, respectively. Outcomes were similar with intensified chemotherapy followed by radiation for the 22% of PET2 positive patients. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia. The majority of PET2 positive patients remained disease free without the need for high-dose chemotherapy with Autologous Stem Cell Transplant. The researchers pointed out that this study was initiated before the publication of RATHL study, and consistent with current practice, recommended eliminating Bleomycin from cycles 3-6 in PET2 negative patients.

It was concluded from this study that PET-adapted therapy in bulky Stage I/II classical Hodgkin Lymphoma met its primary goal and was associated with an excellent 3-year Progression Free Survival in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Positron Emission Tomography–Adapted Therapy in Bulky Stage I/II Classic Hodgkin Lymphoma: CALGB 50801 (Alliance). LaCasce AS, Dockter T, Ruppert AS, et al. J Clin Oncol 2023; 41:1023-1034.

SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 8,540 new cases of Hodgkin lymphoma will be diagnosed and about 920 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Response-adapted therapy involves the administration of 2 cycles of chemotherapy with ABVD regimen, followed by an interim PET scan, which serves as the basis for either intensifying or de-escalating therapy. If PET negative after the second cycle, patients receive 4 additional cycles of AVD omitting Bleomycin from the ABVD regimen. Radiotherapy is not recommended for patients with negative findings on interim PET scans. This response-adapted therapy resulted in lower incidence of pulmonary toxicities, compared with continued treatment with ABVD, without compromising efficacy (NEJM 2016; 374:2419-2429).

ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In a previously published Phase I study, ADCETRIS® in combination with AVD (A+AVD) resulted in a Complete Response rate of 96% and a 5 year Overall Survival rate of 100%. Based on these finding, ECHELON-1 study was conducted, which is an international, open-label, randomized, multicenter, Phase III trial, comparing A+AVD with ABVD, as frontline therapy in patients with Stage III or IV Classical Hodgkin lymphoma. The goal of this study was to maintain the high probability of cure, while reducing the incidence of toxic effects.

ECHELON-1 study included 1334 previously untreated patients with Stage III or IV Classical Hodgkin lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously, on days 1 and 15 of each 28-day cycle, for up to 6 cycles. Both treatment groups were well balanced and approximately 14% of the patients in the trial were 60 years of age or older. The use of Granulocyte Colony Stimulating Factor (G-CSF), which was initially permitted according to institutional guidelines, was subsequently recommended after an increased incidence of febrile neutropenia with A+AVD therapy during an interim safety analysis. The Primary end point was “modified” Progression Free Survival (mPFS), which, in addition to disease progression or death, included less than Complete Response after the completion of frontline chemotherapy, based on independently assessed PET results. PET scan interpretation was based on Deauville score (The Deauville score is a 5-point scale on which higher scores indicate greater uptake of FDG glucose at involved sites on PET). Patients were stratified according to International Prognostic Score (IPS) risk group (Low risk versus Intermediate risk versus High risk). A PET scan was performed at the end of the second cycle of treatment (PET2) and patients were offered alternative frontline therapy at the discretion of the treating physician, for patients with a PET Deauville score of 5. Secondary end points included Overall Survival.

At a median follow up of 73.0 months, the analysis of Overall Survival significantly favored A+AVD over ABVD across various subgroups (HR for death=0.59; P=0.009). The 6-year Overall Survival estimates were 93.9% in the A+AVD group and 89.4% in the ABVD group. Progression Free Survival (PFS) outcomes also favored A+AVD over ABVD and the 6-year PFS estimates were 82.3% with A+AVD and 74.5% with ABVD (HR for disease progression or death=0.68). The PFS estimates again favored A+AVD over ABVD across various subgroups, including subgroups defined according to disease Stage (III or IV) and PET2-negative status. Further, fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation. Fewer second cancers were reported with A+AVD, but more patients had peripheral neuropathy with A+AVD than with ABVD. However, majority of patients in both treatment groups had resolution or amelioration of neuropathy by the last follow up.

It was concluded from the ECHELON-1 study that, after a median follow up of 6 years, treatment with ADCETRIS® in combination with Doxorubicin, Vinblastine and Dacarbazine (A+AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival.

Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma. Ansell SM, Radford J, Connors JM, et al. for the ECHELON-1 Study Group. N Engl J Med 2022; 387:310-320.

SUMMARY: The American Cancer Society estimates that in the United States for 2021, about 8,830 new cases of Hodgkin Lymphoma will be diagnosed and about 960 patients will die of the disease. Hodgkin lymphoma is most common in early adulthood and the average age of people when they are diagnosed is 39 years, although the risk of Hodgkin lymphoma rises again in late adulthood after age 55.

Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin Lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells.

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin Lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death.

Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL) are often treated with salvage chemotherapy and Autologous Stem Cell Transplant (ASCT). There are however no standard interventions for patients ineligible for ASCT due to chemo-refractory disease, comorbidity, or advanced stage. PD-1 inhibitor such as KEYTRUDA® as well as ADCETRIS® has shown antitumor activity in R/R cHL.

KEYNOTE-204 is a randomized, international, open-label, Phase III study in which KEYTRUDA® was compared with ADCETRIS® among patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL). In this study, 304 patients were randomized 1:1, and 300 patients were treated with either KEYTRUDA® 200 mg IV every 3 weeks (N=148) or ADCETRIS® 1.8 mg/kg IV every 3 weeks (N=152). Enrolled patients were post-Autologous Stem Cell Transplant (ASCT) or ineligible for ASCT, had measurable disease, and had an ECOG Performance Status of 0 or 1. Both ADCETRIS®-naive and ADCETRIS®-exposed patients were eligible. Patients were stratified by prior ASCT and status after first-line therapy (primary refractory versus relapsed less than 12 months versus relapsed 12 months or more after end of first-line therapy). The Primary endpoints were Progression Free Survival (PFS) per Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included PFS per investigator review, Objective Response Rate (ORR), and Safety. The authors presented results from the second interim analysis, after a median follow up was 25.7 months.

The median PFS was 13.2 months in the KEYTRUDA® group compared with 8.3 months in the ADCETRIS® group (HR=0.65, P=0.0027), suggesting an increase in PFS of 4.9 months with KEYTRUDA®. This benefit with KEYTRUDA® was observed in all subgroups tested, including those ineligible for ASCT (HR=0.61), those with primary refractory disease (HR=0.52), those who were ADCETRIS® naïve (HR=0.67), as well as those who received prior treatment with ADCETRIS® (HR=0.34). The ORR was 65.6% versus 54.2% and this was considered non significant (P=0.023). The median Duration of Response was 20.7 months versus 13.8 months, in the KEYTRUDA® and ADCETRIS® groups respectively, with 62% versus 50% of responses lasting for at least 12 months. Treatment Related Adverse Events were similar in both treatment groups and Grade 3-5 toxicities occurred in 19.6% of patients treated with KEYTRUDA® and 25% of patients treated with ADCETRIS®.

It was concluded that among patients with Relapsed/Refractory Classical Hodgkin Lymphoma, KEYTRUDA® was superior to ADCETRIS®, with a statistically significant and clinically meaningful improvement in PFS across all subgroups tested, and with safety consistent with previous reports. The authors added that KEYTRUDA® should be considered the preferred treatment option and the new standard of care in this patient population. Further, KEYTRUDA® can be tolerated for extended periods as it is not associated with neurotoxicity.

Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Kuruvilla J, Ramchandren R, Santoro A, et al. Lancet Oncol. 2021;22:512-524.

SUMMARY: The American Cancer Society estimates that in the United States for 2018, about 8,500 new cases of Hodgkin lymphoma will be diagnosed and about 1,050 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (stage III to stage IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

ADCETRIS® (Brentuximab vedotin) is an antibody-drug conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. ADCETRIS® is presently approved by the FDA for the treatment of Classical Hodgkin lymphoma, after failure of Autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates. It is also approved for Classical Hodgkin lymphoma at high risk of relapse or progression, as auto-HSCT consolidation.

In a previously published phase I study, ADCETRIS® in combination with AVD (A+AVD) resulted in a Complete Response rate of 96% and a 5 year Overall Survival rate of 100%. Based on these finding, ECHELON-1 study was conducted, which is an international, open-label, randomized, multicenter, phase III trial, comparing A+AVD with ABVD, as frontline therapy in patients with stage III or IV Classical Hodgkin lymphoma.

This study included 1334 previously untreated patients with stage III or IV Classical Hodgkin lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously, on days 1 and 15 of each 28-day cycle, for up to 6 cycles. The Primary end point was “modified” Progression Free Survival (mPFS), which, in addition to disease progression or death, included less than Complete Response after the completion of frontline chemotherapy, based on independently assessed PET results. PET scan interpretation was based on Deauville score (The Deauville score is a 5-point scale on which higher scores indicate greater uptake of FDG glucose at involved sites on PET). Patients were stratified according to International Prognostic Score (IPS) risk group (low risk vs. intermediate risk vs. high risk). A PET scan was performed at the end of the second cycle of treatment (PET2) and patients were offered alternative frontline therapy at the discretion of the treating physician, for patients with a PET Deauville score of 5. Secondary end points included Overall Survival.

At a median follow up of 24.6 months, the 2 year modified PFS in the A+AVD and ABVD groups were 82.1% and 77.2% respectively ( HR=0.77; P=0.04). All Secondary end points also trended in favor of A+AVD. Further, the benefit of A+AVD was noted across all prespecified subgroups, including those with involvement of more than one extranodal site, patients with a high IPS risk score and stage IV disease. Additionally, a higher proportion of the patients treated with A+AVD had negative PET2 results than those treated with ABVD (89% versus 86%). There was however a higher incidence of neutropenia in the A+AVD group, but this was alleviated with G-CSF prophylaxis. There was a higher incidence of peripheral neuropathy in the A+AVD group as well, and this improved or resolved over time. Pulmonary toxicity was lower in patients receiving A+AVD compared to those receiving ABVD.

The authors concluded that at 2 years, among patients with advanced stage Hodgkin lymphoma, A+AVD had superior efficacy when compared to ABVD, with a lower combined risk of progression, death or incomplete response and subsequent use of anticancer therapy. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. Connors JM, Jurczak W, Straus DJ, et al., for the ECHELON-1 Study Group. N Engl J Med 2018; 378:331-344