LYMPHOMA HIGHLIGHTS
Checkpoint Inhibitors in Lymphoma: A New Universe
I
mmunotherapy is generating great ex citement in melanoma and non– small-cell lung cancer (NSCLC). The FDA approvals of checkpoint inhibitors in these tumor types, as well as encourag ing preliminary results in other solid tu mors, have paved the way for studying these therapies in hematologic cancers. At ASH 2015, Philippe Armand, MD, PhD, Senior Physician, Hemato logic Oncology, Dana-Farber Cancer Institute, Boston, discussed early studies of treating patients with lymphoma with checkpoint inhibitors. Thus far, the results with the anti– PD-1 inhibitor nivolumab (Opdivo) in lung cancer and in melanoma show case the durability of response with checkpoint inhibitors, Dr Armand ex plained. “This apparent durability of response is what is most exciting and has come to characterize checkpoint blockade,” he said.
Hodgkin Lymphoma
Studies of nivolumab suggested that the responses are confined to PD-1 li gand 1 (PD-L1)–positive tumors. This opened the hunt for other PD-L1–posi tive tumors, and led to studies in Hodg kin lymphoma, Dr Armand explained. “The pathophysiology of Hodgkin lymphoma is unique. Studies have shown that classic Hodgkin lymphoma fre quently harbors PD-1,” he said. “Hodg
© American Society of Hematology. All rights reserved.
By Phoebe Starr
“This apparent durability of response is what is most exciting and has come to characterize checkpoint blockade.” —Philippe Armand, MD, PhD
kin lymphoma may have a genetically driven, hardwired dependence on PD-L1 for survival. Based on this, Hodgkin lymphoma was included in the expan sion cohorts of phase 1 trials of nivolu mab and pembrolizumab [Keytruda].” In young, heavily pretreated patients with Hodgkin lymphoma, the objec tive response rates were approximately 87% with nivolumab and 65% with pembrolizumab. “Putting the data together, most Hodg kin lymphomas have some shrinkage of tumor as the best response, and respons
es tend to be durable—2 years with nivolumab and 1.5 years with pembroliz umab,” Dr Armand continued. Most of the patients with Hodgkin lymphoma who responded had PD-L1 expression. The results have been con firmed in large phase 2 studies. Ongo ing studies are being conducted in the first salvage, frontline, and posttrans plant settings. “No doubt, checkpoint inhibitors will be an important arrow in our quiv er,” Dr Armand said. Primary mediastinal B-cell lympho ma (PMBL) may also be a target for PD-1 blockade, he continued. The ge netics of this lymphoma are similar to those of Hodgkin lymphoma, with fre quent PD-L1 expression seen in 70% of patients. This tumor may be sensitive to PD-1 blockade. Pembrolizumab is being studied in PMBL in a phase 1 trial, and a phase 2 study is being launched. Nivolumab was studied in a small phase 1 trial of 11 patients with diffuse large B-cell lymphoma (DLBCL), but the responses and durable responses were seen less frequently than in Hodg kin lymphoma, Dr Armand said. “It may be possible to tease out subsets of DLBCL patients who will respond by using PD-L1 expression,” he suggested. What Lies Beyond PD-L1?
Testing for PD-L1 expression is con
troversial. “Our ability to predict PD-L1 positivity on the basis of a snapshot of archival tissue may not be valid,” Dr Armand told attendees. PD-L2 is being studied as a potential biomarker for PD-1 blockade. To complicate the issue, it has become clear with experience that patients with PD-L1–negative solid tumors respond to anti–PD-1 blockade. PD-L1 may not predict a survival benefit in patients with melanoma or with NSCLC. “We don’t really know yet what PD-L1 positivity and PD-L1 negativity mean,” Dr Armand stated. “PD-L1 is not the whole story. Studies suggest that the tumor microenvironment is playing an important role,” he continued. “For now, PD-L1–positive tumors are generally good targets for check point inhibitors. But PD-L1 positivity is not the only answer. We need to con tinue to discover how to broaden these treatments.” “We are really entering a new uni verse,” Dr Armand added. “We sense that checkpoint inhibitors will be broad ly useful in oncology. The possibility of combining these drugs with other drugs opens a whole avenue of study.” “This field is too big to fail,” he stat ed. “This will change the treatment paradigm for classic Hodgkin lympho ma as monotherapy or in combination therapy.”s
CAR T-Cell Therapy Highly Active in Various Lymphomas By Charles Bankhead
T
he use of therapy with chimeric antigen receptor (CAR)-modi fied T-cells consistently demon strated activity in advanced hematolog ic malignancies, including different types of lymphoma, in multiple trials reported at ASH 2015. In one trial, disease remission persist ed for as long as 36 months in 8 of 20 patients who were treated for hemato logic malignancies at the National Can cer Institute (NCI). The 40% overall response rate included 4 of 5 patients with treatment-refractory acute lym phoblastic leukemia (ALL). All the patients in the trial received a single infusion of donor T-cells modi fied by the addition of anti-CD19 CAR, and none of the patients received che motherapy. The treatment led to severe tumor lysis syndrome in some patients, which was manageable with conven tional interventions. “We have treated patients with very
advanced malignancies, including some patients who failed all standard thera pies and continued to progress after al logeneic stem-cell transplantation, a last-chance therapy for these types of patients,” said James Kochenderfer, MD, an investigator in the experimen tal transplantation and immunology branch of the NCI’s Center for Cancer Research. The remaining 15 patients consisted of 5 each with chronic lymphocytic leu kemia, mantle-cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). In each disease group, ≥1 patients responded to the therapy, said Dr Kochenderfer. Some patients, such as 1 patient with high-burden DLBCL, have had dramatic responses, including large tumors involv ing the cranium and an orbital cavity. All evidence of the disease disappeared with in 5 days of the CAR T-cell infusion. The University of Pennsylvania has
one of the most active CAR T-cell clin ical programs in the country, and inves tigators reported findings from ongoing trials of patients with non-Hodgkin lymphoma (NHL) and ALL.
“Our early results in this trial provide increasing evidence for the role of personalized cellular therapies in patients with NHL.” —Stephen J. Schuster, MD
CAR T-cells–based agents are an emerging treatment approach for NHL, and Penn researchers reported objective responses in 15 of 28 patients treated to date with the investigational anti-CD19 CAR T-cells agent known as CTL019.
All but 1 of the responses were com plete remissions. The overall responses consisted of those in 8 of 11 patients with follicular lymphoma, in 7 of 15 patients with DLBCL, and in 1 of 2 patients with MCL. All 28 patients were refractory to conventional therapies, including some who had progressive disease after stemcell transplantation. The median pro gression-free survival in the patients with follicular lymphoma and in those with DLBCL had yet to be reached after a median follow-up of >14 months. “Our early results in this trial provide increasing evidence for the role of per sonalized cellular therapies in patients with NHL,” said Stephen J. Schuster, MD, Robert and Margarita Louis-Drey fus Associate Professor in Chronic Lym phocytic Leukemia and Lymphoma Clinical Care and Research at Penn Medicine’s Abramson Cancer Center, Philadelphia. s
FEBRUARY 2016
19
Checkpoint Inhibitors in Lymphoma: A New Universe
I
mmunotherapy is generating great ex citement in melanoma and non– small-cell lung cancer (NSCLC). The FDA approvals of checkpoint inhibitors in these tumor types, as well as encourag ing preliminary results in other solid tu mors, have paved the way for studying these therapies in hematologic cancers. At ASH 2015, Philippe Armand, MD, PhD, Senior Physician, Hemato logic Oncology, Dana-Farber Cancer Institute, Boston, discussed early studies of treating patients with lymphoma with checkpoint inhibitors. Thus far, the results with the anti– PD-1 inhibitor nivolumab (Opdivo) in lung cancer and in melanoma show case the durability of response with checkpoint inhibitors, Dr Armand ex plained. “This apparent durability of response is what is most exciting and has come to characterize checkpoint blockade,” he said.
Hodgkin Lymphoma
Studies of nivolumab suggested that the responses are confined to PD-1 li gand 1 (PD-L1)–positive tumors. This opened the hunt for other PD-L1–posi tive tumors, and led to studies in Hodg kin lymphoma, Dr Armand explained. “The pathophysiology of Hodgkin lymphoma is unique. Studies have shown that classic Hodgkin lymphoma fre quently harbors PD-1,” he said. “Hodg
© American Society of Hematology. All rights reserved.
By Phoebe Starr
“This apparent durability of response is what is most exciting and has come to characterize checkpoint blockade.” —Philippe Armand, MD, PhD
kin lymphoma may have a genetically driven, hardwired dependence on PD-L1 for survival. Based on this, Hodgkin lymphoma was included in the expan sion cohorts of phase 1 trials of nivolu mab and pembrolizumab [Keytruda].” In young, heavily pretreated patients with Hodgkin lymphoma, the objec tive response rates were approximately 87% with nivolumab and 65% with pembrolizumab. “Putting the data together, most Hodg kin lymphomas have some shrinkage of tumor as the best response, and respons
es tend to be durable—2 years with nivolumab and 1.5 years with pembroliz umab,” Dr Armand continued. Most of the patients with Hodgkin lymphoma who responded had PD-L1 expression. The results have been con firmed in large phase 2 studies. Ongo ing studies are being conducted in the first salvage, frontline, and posttrans plant settings. “No doubt, checkpoint inhibitors will be an important arrow in our quiv er,” Dr Armand said. Primary mediastinal B-cell lympho ma (PMBL) may also be a target for PD-1 blockade, he continued. The ge netics of this lymphoma are similar to those of Hodgkin lymphoma, with fre quent PD-L1 expression seen in 70% of patients. This tumor may be sensitive to PD-1 blockade. Pembrolizumab is being studied in PMBL in a phase 1 trial, and a phase 2 study is being launched. Nivolumab was studied in a small phase 1 trial of 11 patients with diffuse large B-cell lymphoma (DLBCL), but the responses and durable responses were seen less frequently than in Hodg kin lymphoma, Dr Armand said. “It may be possible to tease out subsets of DLBCL patients who will respond by using PD-L1 expression,” he suggested. What Lies Beyond PD-L1?
Testing for PD-L1 expression is con
troversial. “Our ability to predict PD-L1 positivity on the basis of a snapshot of archival tissue may not be valid,” Dr Armand told attendees. PD-L2 is being studied as a potential biomarker for PD-1 blockade. To complicate the issue, it has become clear with experience that patients with PD-L1–negative solid tumors respond to anti–PD-1 blockade. PD-L1 may not predict a survival benefit in patients with melanoma or with NSCLC. “We don’t really know yet what PD-L1 positivity and PD-L1 negativity mean,” Dr Armand stated. “PD-L1 is not the whole story. Studies suggest that the tumor microenvironment is playing an important role,” he continued. “For now, PD-L1–positive tumors are generally good targets for check point inhibitors. But PD-L1 positivity is not the only answer. We need to con tinue to discover how to broaden these treatments.” “We are really entering a new uni verse,” Dr Armand added. “We sense that checkpoint inhibitors will be broad ly useful in oncology. The possibility of combining these drugs with other drugs opens a whole avenue of study.” “This field is too big to fail,” he stat ed. “This will change the treatment paradigm for classic Hodgkin lympho ma as monotherapy or in combination therapy.”s
CAR T-Cell Therapy Highly Active in Various Lymphomas By Charles Bankhead
T
he use of therapy with chimeric antigen receptor (CAR)-modi fied T-cells consistently demon strated activity in advanced hematolog ic malignancies, including different types of lymphoma, in multiple trials reported at ASH 2015. In one trial, disease remission persist ed for as long as 36 months in 8 of 20 patients who were treated for hemato logic malignancies at the National Can cer Institute (NCI). The 40% overall response rate included 4 of 5 patients with treatment-refractory acute lym phoblastic leukemia (ALL). All the patients in the trial received a single infusion of donor T-cells modi fied by the addition of anti-CD19 CAR, and none of the patients received che motherapy. The treatment led to severe tumor lysis syndrome in some patients, which was manageable with conven tional interventions. “We have treated patients with very
advanced malignancies, including some patients who failed all standard thera pies and continued to progress after al logeneic stem-cell transplantation, a last-chance therapy for these types of patients,” said James Kochenderfer, MD, an investigator in the experimen tal transplantation and immunology branch of the NCI’s Center for Cancer Research. The remaining 15 patients consisted of 5 each with chronic lymphocytic leu kemia, mantle-cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). In each disease group, ≥1 patients responded to the therapy, said Dr Kochenderfer. Some patients, such as 1 patient with high-burden DLBCL, have had dramatic responses, including large tumors involv ing the cranium and an orbital cavity. All evidence of the disease disappeared with in 5 days of the CAR T-cell infusion. The University of Pennsylvania has
one of the most active CAR T-cell clin ical programs in the country, and inves tigators reported findings from ongoing trials of patients with non-Hodgkin lymphoma (NHL) and ALL.
“Our early results in this trial provide increasing evidence for the role of personalized cellular therapies in patients with NHL.” —Stephen J. Schuster, MD
CAR T-cells–based agents are an emerging treatment approach for NHL, and Penn researchers reported objective responses in 15 of 28 patients treated to date with the investigational anti-CD19 CAR T-cells agent known as CTL019.
All but 1 of the responses were com plete remissions. The overall responses consisted of those in 8 of 11 patients with follicular lymphoma, in 7 of 15 patients with DLBCL, and in 1 of 2 patients with MCL. All 28 patients were refractory to conventional therapies, including some who had progressive disease after stemcell transplantation. The median pro gression-free survival in the patients with follicular lymphoma and in those with DLBCL had yet to be reached after a median follow-up of >14 months. “Our early results in this trial provide increasing evidence for the role of per sonalized cellular therapies in patients with NHL,” said Stephen J. Schuster, MD, Robert and Margarita Louis-Drey fus Associate Professor in Chronic Lym phocytic Leukemia and Lymphoma Clinical Care and Research at Penn Medicine’s Abramson Cancer Center, Philadelphia. s
FEBRUARY 2016
19
