KEYTRUDA® (Pembrolizumab)

The FDA on October 14, 2020 extended the approval of KEYTRUDA® (Pembrolizumab) for the following indications:

1) Adult patients with Relapsed or Refractory classical Hodgkin Lymphoma (cHL)

2) Pediatric patients with Refractory cHL, or cHL that has Relapsed after 2 or more lines of therapy.

KEYTRUDA® is a product of Merck Sharp & Dohme Corp.

KEYTRUDA® Superior to ADCETRIS® in Relapsed or Refractory Classical Hodgkin Lymphoma

SUMMARY: The American Cancer Society estimates that in the United States for 2020, about 8,480 new cases of Hodgkin Lymphoma will be diagnosed and about 970 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).The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells.WHO-Classification-of-Hodgkin-Lymphoma

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 and assigned to receive 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. Median follow up was 24.7 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=0.00271), 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 the median Duration of Response was 20.7 months versus 13.8 months, in the KEYTRUDA® and ADCETRIS® groups respectively. 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.

KEYNOTE-204: Randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodgkin lymphoma (R/R cHL). Kuruvilla J, Ramchandren R, Santoro A, et al. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. J Clin Oncol 38: 2020 (suppl; abstr 8005).

Survival Benefit Significantly More in North America with Frontline ADCETRIS® Chemotherapy Combination in Advanced Classical Hodgkin Lymphoma

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).WHO-Classification-of-Hodgkin-Lymphoma

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.

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 previously untreated Stage III or IV Classical Hodgkin Lymphoma (cHL), in combination with chemotherapy, for treatment of Classical Hodgkin lymphoma at high risk of relapse or progression, as post-autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) consolidation, and for treatment of Classical Hodgkin Lymphoma after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens, in patients who are not auto-HSCT candidates.

ECHELON-1 study, which is an international, open-label, randomized, multicenter, phase III trial, compared 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), defined as progression, death, or the receipt of additional treatment, for patients not achieving CR at the completion of frontline therapy. It was previously reported that 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), suggesting an approximately 5% benefit with A+AVD.

The North American subgroup analysis of the ECHELON-1 study was conducted because of potential regional differences in the outcomes in the primary study and mPFS benefit was not equally distributed globally. The authors in this prespecified analysis examined the efficacy and safety of A+AVD vs ABVD in North America, as these patients accounted for approximately 40% of the over 1300 patients included in the ECHELON-1 study. This population group included 497 North American patients with advanced Classical Hodgkin Lymphoma, randomized 1:1 to receive up to six cycles of A+AVD or ABVD.

This subgroup analysis revealed an absolute difference of 10.6% in the mPFS per IRF-Independent Review Facility (A+AVD and ABVD groups were 84.3% and 73.7% respectively, HR=0.60; P=0.012) and an 11.7% difference in PFS per investigator review (A+AVD and ABVD groups were 88.1% and 76.4% respectively, HR=0.50; P=0.002), at 2 years. This analysis suggested that a larger proportion of patients in North America benefitted with the A+AVD regimen (10%-12% in North America as opposed to 5% globally). It is postulated that there may be biologic differences in the disease, regional differences in drug metabolism and differences in practice patterns, between countries. Toxicity profile was similar globally. There was a higher incidence of neutropenia in the A+AVD group and G-CSF prophylaxis should be a part of the regimen when A+AVD is used, in contrast to ABVD. Use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS® dose delays and dose reductions compared to those without. There was a higher incidence of peripheral neuropathy in the A+AVD group as well, with majority of these events being grade 1 and 2, and this improved or resolved over time. Pulmonary toxicity was lower in patients receiving A+AVD compared to those receiving ABVD.

It was concluded that for patients treated in North America on the ECHELON-1 trial, the absolute difference between A+AVD and ABVD at 2 years for mPFS by IRF was 10.6% and for PFS per Investigator review was 11.7% (10%-12% benefit in North America as opposed to 5% globally). A prospective clinical trial is planned in advanced stage Hodgkin Lymphoma patients treated with A+AVD, to confirm these safety and efficacy findings, in the North American community setting. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. Ramchandren R, Advani RH, Ansell SM, et al. J Clin Oncol.2018;36(suppl; abstr 7541). doi: 10.1200/JCO.2018.36.15.

ADCETRIS® with Chemotherapy for the Frontline Treatment of Advanced Classical Hodgkin Lymphoma

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).WHO-Classification-of-Hodgkin-Lymphoma

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

FDA Approves KEYTRUDA® for Hodgkin Lymphoma

SUMMARY: The FDA on March 14, 2017 granted an accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of adult and pediatric patients with classical Hodgkin Lymphoma (cHL) who are Refractory, or have Relapsed, after 3 or more lines of therapy. This approved indication is based on tumor response rate and durability of response. The American Cancer Society estimates that in the United States for 2017, about 8,260 new cases of Hodgkin lymphoma will be diagnosed and about 1,070 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). 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’s 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. Under normal circumstances, Immune checkpoints or gate keepers inhibit intense immune responses by switching off the T cells of the immune system. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. 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.

The approval of KEYTRUDA® was based on data from the non-randomized, open-label KEYNOTE-087 trial, which included 210 adult patients with Relapsed/Refractory classical Hodgkin Lymphoma. Approximately 58% of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior treatment regimens. Patients received a median number of four prior therapies and prior therapies included Autologous Hematopoietic Stem Cell Transplantation (61%), ADCETRIS® -Brentuximab vedotin (83%), and radiation therapy (36%). The median age was 35 years and 9% of patients were older than 65 years. KEYTRUDA® was administered at 200 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years, in patients who did not have disease progression. Patients were assessed every 12 weeks to determine their disease status. The Primary end point was Overall Response Rate (ORR). Secondary end points included Complete Response Rate (CRR), Duration of Response, Progression Free Survival, and Overall Survival. The median follow-up was 9.4 months.

It was noted that the Overall Response Rate was 69% and this included Complete Responses in 22% of patients and Partial Responses in 47% of patients. The median Duration of Response was 11.1 months. The most common adverse events were fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, and skin rash. Serious adverse reactions occurred in 16% of patients and the most common grade 3/4 treatment-related adverse events were neutropenia, thrombocytopenia and diarrhea. Adverse reactions led to treatment discontinuation in 5% of the patients.

The authors concluded that PD-1 blockade with KEYTRUDA® has significant clinical activity in subsets of heavily pretreated patients with classical Hodgkin Lymphoma, with high Overall Response Rates and Duration of Response. This important study gives a fighting chance for these generally young patients with poor prognosis. Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma: Primary End Point Analysis of the Phase 2 Keynote-087 Study. Moskowitz CH, Zinzani PL, Fanale MA, et al. Presented at the ASH 58th Annual Meeting & Exposition, San Diego, CA. December 3-6, 2016. Abstract #1107

KEYTRUDA® (Pembrolizumab)

The FDA on March 15, 2017 granted accelerated approval to KEYTRUDA® injection for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or those who have relapsed after three or more prior lines of therapy. KEYTRUDA® is a product of Merck Sharp & Dohme Corp.

OPDIVO® (Nivolumab)

The FDA on May 17, 2016 granted accelerated approval to OPDIVO® for the treatment of patients with classical Hodgkin Lymphoma (cHL) that has relapsed or progressed after autologous Hematopoietic Stem Cell Transplantation (HSCT) and post-transplantation ADCETRIS® (Brentuximab vedotin). OPDIVO® is marketed by Bristol-Myers Squibb company

Interim PET Scan may Define Prognosis and Provide Treatment Guidance for Patients with Advanced Hodgkin Lymphoma

SUMMARY: The American Cancer Society estimates that in the United States for 2016, about 8500 new cases of Hodgkin lymphoma will be diagnosed and over 1100 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).

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 regimen). 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. The second most often used regimen in the first-line setting, e-BEACOPP (escalated doses of Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) has been associated with a higher Progression Free Survival as well as higher 5-year Overall Survival (approximately 90%). This regimen however is associated with short and long term toxicities such as prolonged fatigue, permanent fertility, Myelodysplasia and secondary malignancies.

A retrospective study by Gallamini and co-workers in 2007 had shown that a PET scan after two cycles of ABVD chemotherapy was an independent prognostic factor, with a 2-year Progression Free Survival rate of 95%, for those patients with negative interim PET scan, compared to only 12.8% for those with persistently positive PET scan. Based on these observations, the authors in this prospective trial evaluated the benefit of a “response-adapted” approach, by performing a PET scan following 2 cycles of ABVD treatment and modifying therapy based on the interim PET scan findings.

In this randomized controlled trial, 1203 eligible patients with newly diagnosed advanced Classical Hodgkin lymphoma were registered. The median age was 33 years. Following 2 cycles of chemotherapy with ABVD regimen, 1119 patients had an interim PET-CT scan and patients with negative PET findings (83.7%) were randomly assigned in a 1:1 ratio to continue ABVD regimen (ABVD group) or receive ABVD omitting Bleomycin (AVD group), for cycles 3 through 6. Radiotherapy was not recommended for patients with negative findings on interim PET scans. Patients with positive interim PET scan findings following two cycles of ABVD (16%), received 4-6 cycles of BEACOPP regimen. The primary outcome was the difference in the 3-year Progression Free Survival rate between randomized groups.

With a median follow up of 41 months, the 3-year Progression Free Survival was 85.7% with ABVD and 84.4% with AVD and 3 year Overall Survival was 97.2% and 97.6% in these two respective groups. Pulmonary toxicities were more severe in the ABVD group than in the AVD group and deleting Bleomycin following 2 cycles of ABVD, in patients with negative interim PET scan, did not compromise outcomes. Patients who received BEACOPP regimen based on a positive interim PET scan after the first 2 cycles of ABVD (N=172), had a 3-year Progression Free Survival of 67.5% and Overall Survival rate of 87.8%.

The authors concluded that following 2 cycles of ABVD regimen, omitting Bleomycin from the ABVD regimen, based on a negative interim PET scan (response-adapted therapy), resulted in lower incidence of pulmonary toxicities, compared with continued treatment with ABVD, without compromising efficacy. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. Johnson P, Federico M, Kirkwood A, et al. N Engl J Med 2016; 374:2419-2429

FDA Approves OPDIVO® for Relapsed Classical Hodgkin Lymphoma

SUMMARY: The FDA on May 17, 2016, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients with Classical Hodgkin Lymphoma (cHL) that has relapsed or progressed after autologous Hematopoietic Stem Cell Transplantation (HSCT) and post-transplantation ADCETRIS® (Brentuximab vedotin). The American Cancer Society estimates that in the United States for 2016, about 8500 new cases of Hodgkin lymphoma will be diagnosed and over 1100 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). 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's 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. Under normal circumstances, Immune checkpoints or gate keepers inhibit intense immune responses by switching off the T cells of the immune system. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that demonstrated significant responses in a phase 1b trial involving patients with relapsed/refractory cHL (Ansell SM et al. NEJM 2015;372:311–319).

This accelerated approval of OPDIVO® was based on two single-arm, open label, multicenter trials (CheckMate-205 and -039) of OPDIVO®, in adults with relapsed or refractory cHL. These trials enrolled patients regardless of PD-L1 expression status on Reed-Sternberg cells. The median age was 37 years and patients had a median of 5 prior therapies. The primary endpoint was Objective Response Rate (ORR) and additional outcome measures included Duration of Response (DOR). Patients received OPDIVO® (Nivolumab) at a dose of 3 mg/kg every 2 weeks and treatment was continued until patients had a complete response, tumor progression or severe toxicities.

The efficacy of OPDIVO® was evaluated in 95 patients with cHL from the two single-arm trials, previously treated with autologous Hematopoietic Stem Cell Transplantation (aHSCT) and post-transplantation ADCETRIS® (Brentuximab vedotin). Patients had received a median of 17 doses of OPDIVO®. The ORR with OPDIVO® was 65% with 58% Partial Remission and 7% Complete Remission. The median time to response was 2.1 months and the estimated median DOR was 8.7 months. The most common adverse reactions (20% or more) of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea.

The authors concluded that patients with Classical Hodgkin Lymphoma treated with OPDIVO® after autologous Hematopoietic Stem Cell Transplantation (aHSCT) and post-transplantation ADCETRIS®, have very high response rates and long Duration of Responses with acceptable toxicities. OPDIVO® is the first PD-1 inhibitor, approved for a hematologic malignancy. Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study. Younes A, Santoro A, Zinzani PL, et al. J Clin Oncol 34, 2016 (suppl; abstr 7535)