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Brentuximab tops chemo in HL, doc says
NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.
She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.
“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”
She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.
After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.
“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”
She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.
The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.
“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”
On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.
“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”
Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.
Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.
Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.
In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”
For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.” 
NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.
She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.
“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”
She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.
After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.
“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”
She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.
The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.
“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”
On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.
“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”
Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.
Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.
Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.
In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”
For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”
NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.
She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.
“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”
She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.
After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.
“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”
She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.
The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.
“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”
On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.
“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”
Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.
Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.
Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.
In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”
For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”
Speaker advocates chemo-based salvage in HL
Credit: Rhoda Baer
NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent
Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.
First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.
“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.
She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.
“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”
Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.
Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.
In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.
Dr Wagner-Johnston expressed other concerns about brentuximab as well.
“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”
There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.
“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”
She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.
Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”
Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.
In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.
In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”
For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”
Credit: Rhoda Baer
NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent
Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.
First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.
“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.
She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.
“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”
Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.
Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.
In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.
Dr Wagner-Johnston expressed other concerns about brentuximab as well.
“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”
There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.
“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”
She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.
Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”
Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.
In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.
In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”
For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”
Credit: Rhoda Baer
NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent
Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.
First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.
“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.
She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.
“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”
Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.
Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.
In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.
Dr Wagner-Johnston expressed other concerns about brentuximab as well.
“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”
There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.
“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”
She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.
Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”
Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.
In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.
In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”
For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”
New agents challenge role of transplant in high-risk CLL
Credit: Chad McNeeley
NEW YORK—The role of allogeneic hematopoietic stem cell transplant (HSCT) for patients with high-risk chronic lymphocytic leukemia (CLL) is changing in the age of targeted therapy.
While allogeneic HSCT has been considered standard treatment for these patients, the question arises whether it will maintain its position in the era “of all these wonderful new drugs,” said David Maloney, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Maloney undertook to convince the audience at the Lymphoma & Myeloma 2014 congress that there is still a role for allogeneic transplant in CLL patients.
He noted that early allogeneic transplant trials used myeloablative conditioning regimens, which were “prohibitively toxic.” They have now given way to reduced-intensity regimens.
“But the breakthrough came about when it was realized that the reason that allogeneic transplant could cure patients with CLL had really nothing to do with their conditioning regimen . . . ,” he said. “[I]t was probably the donor T cells providing immunologic activity and graft-vs-host activity that was actually able to provide graft-vs-tumor activity and cure patients.”
Seattle regimen
Dr Maloney described the reduced-intensity regimen used in Seattle—fludarabine and 2 Gy total body irradiation. The single dose of radiation is typically 1/6 of what a myeloablative regimen would be.
“This is truly an outpatient regimen,” he said. “Most patients, 50%, get through this without ever being in the hospital.”
Follow-up at 5 years showed overall survival to be 43%, progression-free survival 36%, complete responses 52%, and relapse 34%.
“This may not look very good,” Dr Maloney said, but these are fludarabine-refractory CLL patients whose expected median survival is around 12 months.
Dr Maloney noted that approximately the same outcomes were achieved whether the graft was from a matched related or unrelated donor, and cytogenetics really didn’t play a huge role in outcome.
The biggest factor affecting outcome was lymph node size. Patients with nodes 5 cm or larger did very poorly. And patients with lymph nodes smaller than 5 cm, irrespective of white cell count or bone marrow infiltration, actually did quite well in comparison to the group with large lymph nodes.
“So the graft-vs-tumor activity seems to be limited in its ability to get rid of bulky lymphadenopathy in this population,” Dr Maloney said.
Prior alemtuzumab therapy was also associated with the worst outcome in terms of relapse and disease progression.
Patients without comorbidities and without bulky lymphadenopathy have a very good outcome, Dr Maloney noted, saying, “You can cure 60% to 70% with an allogeneic transplant.”
He also pointed out that many groups are now doing this type of transplant with related and unrelated donors.
Transplant vs new agents
In addition to offering a potential cure, allogeneic transplant may provide better-functioning hematopoietic and immune systems after transplant than before, especially in those patients who received FCR (fludarabine, mitoxantrone, and rituximab) or other treatments.
Transplant, while potentially curative with a high complete response rate, has early non-relapse mortality around 15% to 20%.
“So this makes it hard to position in this era of pills that you can take,” Dr Maloney said.
He pointed out that while ibrutinib and idelalisib have excellent outcomes and overall survival, “these studies are very, very early . . . but obviously extremely promising.”
A group of European physicians recently published a position paper proposing a treatment algorithm that includes transplant for high-risk CLL patients. The algorithm indicates that relapsed/refractory patients should try the novel agents first.
Then, if patients respond, they can continue with the novel agent or proceed to transplant. Patients with lower-risk disease or those who are a higher transplant risk should probably continue on the novel agent.
Those who are younger with higher-risk disease, such as a 17p deletion, or who are a low transplant risk may be willing to choose transplant earlier.
Patients who do not respond to the novel agents can consider transplant or an alternative salvage regimen.
“[O]bviously, this is extremely controversial,” Dr Maloney said, “and what everyone is going to do is use these new agents to push transplant further down the road. And I think that’s appropriate.”
At the very least, Dr Maloney believes patients deserve a discussion of options early on.
He added that chimeric antigen receptor (CAR) T cells “will likely bump transplant even down another notch” because patients are likely to be willing to take the risk of CAR T cells before they’ll take the risk of chronic graft-vs-host disease with an unrelated donor.”
Credit: Chad McNeeley
NEW YORK—The role of allogeneic hematopoietic stem cell transplant (HSCT) for patients with high-risk chronic lymphocytic leukemia (CLL) is changing in the age of targeted therapy.
While allogeneic HSCT has been considered standard treatment for these patients, the question arises whether it will maintain its position in the era “of all these wonderful new drugs,” said David Maloney, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Maloney undertook to convince the audience at the Lymphoma & Myeloma 2014 congress that there is still a role for allogeneic transplant in CLL patients.
He noted that early allogeneic transplant trials used myeloablative conditioning regimens, which were “prohibitively toxic.” They have now given way to reduced-intensity regimens.
“But the breakthrough came about when it was realized that the reason that allogeneic transplant could cure patients with CLL had really nothing to do with their conditioning regimen . . . ,” he said. “[I]t was probably the donor T cells providing immunologic activity and graft-vs-host activity that was actually able to provide graft-vs-tumor activity and cure patients.”
Seattle regimen
Dr Maloney described the reduced-intensity regimen used in Seattle—fludarabine and 2 Gy total body irradiation. The single dose of radiation is typically 1/6 of what a myeloablative regimen would be.
“This is truly an outpatient regimen,” he said. “Most patients, 50%, get through this without ever being in the hospital.”
Follow-up at 5 years showed overall survival to be 43%, progression-free survival 36%, complete responses 52%, and relapse 34%.
“This may not look very good,” Dr Maloney said, but these are fludarabine-refractory CLL patients whose expected median survival is around 12 months.
Dr Maloney noted that approximately the same outcomes were achieved whether the graft was from a matched related or unrelated donor, and cytogenetics really didn’t play a huge role in outcome.
The biggest factor affecting outcome was lymph node size. Patients with nodes 5 cm or larger did very poorly. And patients with lymph nodes smaller than 5 cm, irrespective of white cell count or bone marrow infiltration, actually did quite well in comparison to the group with large lymph nodes.
“So the graft-vs-tumor activity seems to be limited in its ability to get rid of bulky lymphadenopathy in this population,” Dr Maloney said.
Prior alemtuzumab therapy was also associated with the worst outcome in terms of relapse and disease progression.
Patients without comorbidities and without bulky lymphadenopathy have a very good outcome, Dr Maloney noted, saying, “You can cure 60% to 70% with an allogeneic transplant.”
He also pointed out that many groups are now doing this type of transplant with related and unrelated donors.
Transplant vs new agents
In addition to offering a potential cure, allogeneic transplant may provide better-functioning hematopoietic and immune systems after transplant than before, especially in those patients who received FCR (fludarabine, mitoxantrone, and rituximab) or other treatments.
Transplant, while potentially curative with a high complete response rate, has early non-relapse mortality around 15% to 20%.
“So this makes it hard to position in this era of pills that you can take,” Dr Maloney said.
He pointed out that while ibrutinib and idelalisib have excellent outcomes and overall survival, “these studies are very, very early . . . but obviously extremely promising.”
A group of European physicians recently published a position paper proposing a treatment algorithm that includes transplant for high-risk CLL patients. The algorithm indicates that relapsed/refractory patients should try the novel agents first.
Then, if patients respond, they can continue with the novel agent or proceed to transplant. Patients with lower-risk disease or those who are a higher transplant risk should probably continue on the novel agent.
Those who are younger with higher-risk disease, such as a 17p deletion, or who are a low transplant risk may be willing to choose transplant earlier.
Patients who do not respond to the novel agents can consider transplant or an alternative salvage regimen.
“[O]bviously, this is extremely controversial,” Dr Maloney said, “and what everyone is going to do is use these new agents to push transplant further down the road. And I think that’s appropriate.”
At the very least, Dr Maloney believes patients deserve a discussion of options early on.
He added that chimeric antigen receptor (CAR) T cells “will likely bump transplant even down another notch” because patients are likely to be willing to take the risk of CAR T cells before they’ll take the risk of chronic graft-vs-host disease with an unrelated donor.”
Credit: Chad McNeeley
NEW YORK—The role of allogeneic hematopoietic stem cell transplant (HSCT) for patients with high-risk chronic lymphocytic leukemia (CLL) is changing in the age of targeted therapy.
While allogeneic HSCT has been considered standard treatment for these patients, the question arises whether it will maintain its position in the era “of all these wonderful new drugs,” said David Maloney, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Maloney undertook to convince the audience at the Lymphoma & Myeloma 2014 congress that there is still a role for allogeneic transplant in CLL patients.
He noted that early allogeneic transplant trials used myeloablative conditioning regimens, which were “prohibitively toxic.” They have now given way to reduced-intensity regimens.
“But the breakthrough came about when it was realized that the reason that allogeneic transplant could cure patients with CLL had really nothing to do with their conditioning regimen . . . ,” he said. “[I]t was probably the donor T cells providing immunologic activity and graft-vs-host activity that was actually able to provide graft-vs-tumor activity and cure patients.”
Seattle regimen
Dr Maloney described the reduced-intensity regimen used in Seattle—fludarabine and 2 Gy total body irradiation. The single dose of radiation is typically 1/6 of what a myeloablative regimen would be.
“This is truly an outpatient regimen,” he said. “Most patients, 50%, get through this without ever being in the hospital.”
Follow-up at 5 years showed overall survival to be 43%, progression-free survival 36%, complete responses 52%, and relapse 34%.
“This may not look very good,” Dr Maloney said, but these are fludarabine-refractory CLL patients whose expected median survival is around 12 months.
Dr Maloney noted that approximately the same outcomes were achieved whether the graft was from a matched related or unrelated donor, and cytogenetics really didn’t play a huge role in outcome.
The biggest factor affecting outcome was lymph node size. Patients with nodes 5 cm or larger did very poorly. And patients with lymph nodes smaller than 5 cm, irrespective of white cell count or bone marrow infiltration, actually did quite well in comparison to the group with large lymph nodes.
“So the graft-vs-tumor activity seems to be limited in its ability to get rid of bulky lymphadenopathy in this population,” Dr Maloney said.
Prior alemtuzumab therapy was also associated with the worst outcome in terms of relapse and disease progression.
Patients without comorbidities and without bulky lymphadenopathy have a very good outcome, Dr Maloney noted, saying, “You can cure 60% to 70% with an allogeneic transplant.”
He also pointed out that many groups are now doing this type of transplant with related and unrelated donors.
Transplant vs new agents
In addition to offering a potential cure, allogeneic transplant may provide better-functioning hematopoietic and immune systems after transplant than before, especially in those patients who received FCR (fludarabine, mitoxantrone, and rituximab) or other treatments.
Transplant, while potentially curative with a high complete response rate, has early non-relapse mortality around 15% to 20%.
“So this makes it hard to position in this era of pills that you can take,” Dr Maloney said.
He pointed out that while ibrutinib and idelalisib have excellent outcomes and overall survival, “these studies are very, very early . . . but obviously extremely promising.”
A group of European physicians recently published a position paper proposing a treatment algorithm that includes transplant for high-risk CLL patients. The algorithm indicates that relapsed/refractory patients should try the novel agents first.
Then, if patients respond, they can continue with the novel agent or proceed to transplant. Patients with lower-risk disease or those who are a higher transplant risk should probably continue on the novel agent.
Those who are younger with higher-risk disease, such as a 17p deletion, or who are a low transplant risk may be willing to choose transplant earlier.
Patients who do not respond to the novel agents can consider transplant or an alternative salvage regimen.
“[O]bviously, this is extremely controversial,” Dr Maloney said, “and what everyone is going to do is use these new agents to push transplant further down the road. And I think that’s appropriate.”
At the very least, Dr Maloney believes patients deserve a discussion of options early on.
He added that chimeric antigen receptor (CAR) T cells “will likely bump transplant even down another notch” because patients are likely to be willing to take the risk of CAR T cells before they’ll take the risk of chronic graft-vs-host disease with an unrelated donor.”
Panobinostat demonstrates ‘profound’ synergy with bortezomib
NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
Chlorambucil’s role in untreated CLL debated
NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.
NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.
NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.