CLL: No symptoms, no treatment still appropriate

CHICAGO – Despite exciting new advances in the understanding of chronic lymphocytic leukemia, particularly with respect to prognostic features that predict risk for relapse, a watch-and-wait approach remains appropriate for asymptomatic disease pending outcomes data for newer approaches, according to Dr. John G. Gribben.

“When the disease is diagnosed, if it is asymptomatic, the correct approach – of course – is to continue to watch and wait,” Dr. Gribben of Barts Cancer Institute, Queen Mary University of London, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Numerous clinical trials have demonstrated no advantage of early treatment vs. watch and wait, he said, adding that all of the trials published to date have used treatment of all-comers, and have used chlorambucil (CLB) as the treatment.

“There has been a whole variety of more modern trials that have used select prognostic features to identify subgroups of people who are at higher risk of relapse, who then go on to receive earlier treatment with either FCR [fludarabine, cyclophosphamide, rituximab], or more recently, ibrutinib,” he said.

These treatments are interesting, and the trials have demonstrated that prognostic features can identify patients who will progress more rapidly, but none have reported, he explained.

“In the absence of any published trial, I continue to ‘watch and wait’ patients, and there are no high-risk features which will make me alter that approach. Even the highest-risk features of complex karyotype and p53 abnormalities are not indications to treat patients until they become symptomatic,” he said.

It is striking how white counts vary widely in both asymptomatic and symptomatic patients, he noted.

“I don’t personally have any particular white count which is the number at which I’ll treat a patient. I don’t treat white counts, I treat patients,” he said.

When patients become symptomatic, the treatment of choice is now immunochemotherapies, irrespective of performance status, he said.

“Within the past year we have seen approval of obinutuzumab and ofatumumab for treatment of previously untreated CLL, as well as ibrutinib and idelalisib plus rituximab for treatment of both previously untreated CLL and those with 17p deletions for relapsed/refractory disease, as well as for up-front treatment,” he said, adding that these new agents greatly increase the available options for treating CLL.

Dr. Gribben said he considers these questions when it comes to treating CLL:

• Does the patient require treatment, or is watching and waiting appropriate?

• What is the goal of therapy? This is determined through conversation with the patient and the patient’s family regarding the side-effect profile they are willing to tolerate vs. the potential longer duration of response.

• What comorbidities are present to determine “fitness” for specific immunochemotherapy? Specifically, is the patient fit for an FCR-type approach, or is an alternative more appropriate?

• Is there a 17p deletion or P53 mutation that would make chemotherapy a less attractive option, and use of novel agents a more attractive option?

His approach, based on the answers to these questions, is as follows:

• In Rai stage 0-II patients with inactive disease, fitness and 17p deletion or p53 mutation status is irrelevant; no therapy is given.

• For active disease or Rai III-IV disease, a “go-go” patient, (or patient in good physical condition) is treated based on the presence or absence of 17p deletion or p53 mutation status. Those without 17p deletions or p53 mutations can be treated with FCR (his preference), or fludarabine-rituximab (FR). Bendamustine-rituximab (BR) is also an attractive option in certain cases, he said.

• For patients with active disease or Rai stage III-IV disease who do have a 17p deletion, his treatment of choice is either ibrutinib or idelalisib plus rituximab, depending on the patient.

• In “slow-go” patients (those with poorer physical condition) treatment is again based on mutational analysis. Those without mutation receive either FR, BR, or CLB plus obinutuzumab. These are very good options, and represent a spectrum to choose from based on the patient’s core abilities and ability to withstand particular types of treatments, he said.

“If they do have a 17p deletion, these patients are just as eligible for ibrutinib or idelalisib plus rituximab as the younger patients,” he noted.

His choices are based largely on the findings from the CLL8 trial (Lancet 2010 Oct;376[9747]:1164-74) which demonstrated an overall survival advantage with chemoimmunotherapy for front-line therapy vs. chemotherapy alone (hazard ratio, 0.68).

Over time, the advantage has become even more pronounced, according to follow-up data.

Starting with something “gentle” and saving the best treatment for later in the event of relapse was recently considered a reasonable approach, but in the wake of the CLL8 findings, this is no longer an acceptable plan, Dr. Gribben said.

“That’s why for my choice, FCR remains the treatment of choice for those patients who are fit enough to tolerate this type of approach,” he said.

In those with 17p deletions or P53 mutations, the CLL8 trial showed poor outcomes with FCR.

“This is a group of patients whom I believe chemoimmunotherapy would no longer be the treatment of choice,” he said, adding that newer findings suggest outcomes in these patients are better with novel agents.

He also noted that patients with 11q abnormalities, which were previously associated with a poor prognosis, were found in CLL8 to respond well to chemoimmunotherapy when used front line.

While there are special considerations in the elderly, and different strategies in relapsed and refractory disease, the future of CLL treatment is promising. The benefit of adding rituximab to combination chemotherapy is well established, the benefit of novel agents is also now established, and the future likely involves combining targeted therapies with each other and with immunochemotherapies, and combining targeted therapies across different pathways.

“And of course the hope is that we’re going to use the biology of the disease to decide what specific therapy is ideal for that patient. Better understanding of biology and genetics is facilitating rational development of new treatments,” he said, adding that whenever possible, patients should be treated within clinical trials.

Dr. Gribben has received research funding from the NIH, Cancer Research UK, MRC, and Wellcome Trust. He has received honoraria from Roche/Genentech, Celgene, Janssen, Pharmacyclics, Gilead, Mundipharma, Infinity, TG Therapeutics, and Ascerta, and he has a patent or receives royalties from Celgene. He also has been the principal investigator on a clinical trial for Roche, Takeda, Pharmacyclics, Gilead, and Infinity.

[email protected]

CHICAGO – Despite exciting new advances in the understanding of chronic lymphocytic leukemia, particularly with respect to prognostic features that predict risk for relapse, a watch-and-wait approach remains appropriate for asymptomatic disease pending outcomes data for newer approaches, according to Dr. John G. Gribben.

“When the disease is diagnosed, if it is asymptomatic, the correct approach – of course – is to continue to watch and wait,” Dr. Gribben of Barts Cancer Institute, Queen Mary University of London, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Numerous clinical trials have demonstrated no advantage of early treatment vs. watch and wait, he said, adding that all of the trials published to date have used treatment of all-comers, and have used chlorambucil (CLB) as the treatment.

“There has been a whole variety of more modern trials that have used select prognostic features to identify subgroups of people who are at higher risk of relapse, who then go on to receive earlier treatment with either FCR [fludarabine, cyclophosphamide, rituximab], or more recently, ibrutinib,” he said.

These treatments are interesting, and the trials have demonstrated that prognostic features can identify patients who will progress more rapidly, but none have reported, he explained.

“In the absence of any published trial, I continue to ‘watch and wait’ patients, and there are no high-risk features which will make me alter that approach. Even the highest-risk features of complex karyotype and p53 abnormalities are not indications to treat patients until they become symptomatic,” he said.

It is striking how white counts vary widely in both asymptomatic and symptomatic patients, he noted.

“I don’t personally have any particular white count which is the number at which I’ll treat a patient. I don’t treat white counts, I treat patients,” he said.

When patients become symptomatic, the treatment of choice is now immunochemotherapies, irrespective of performance status, he said.

“Within the past year we have seen approval of obinutuzumab and ofatumumab for treatment of previously untreated CLL, as well as ibrutinib and idelalisib plus rituximab for treatment of both previously untreated CLL and those with 17p deletions for relapsed/refractory disease, as well as for up-front treatment,” he said, adding that these new agents greatly increase the available options for treating CLL.

Dr. Gribben said he considers these questions when it comes to treating CLL:

• Does the patient require treatment, or is watching and waiting appropriate?

• What is the goal of therapy? This is determined through conversation with the patient and the patient’s family regarding the side-effect profile they are willing to tolerate vs. the potential longer duration of response.

• What comorbidities are present to determine “fitness” for specific immunochemotherapy? Specifically, is the patient fit for an FCR-type approach, or is an alternative more appropriate?

• Is there a 17p deletion or P53 mutation that would make chemotherapy a less attractive option, and use of novel agents a more attractive option?

His approach, based on the answers to these questions, is as follows:

• In Rai stage 0-II patients with inactive disease, fitness and 17p deletion or p53 mutation status is irrelevant; no therapy is given.

• For active disease or Rai III-IV disease, a “go-go” patient, (or patient in good physical condition) is treated based on the presence or absence of 17p deletion or p53 mutation status. Those without 17p deletions or p53 mutations can be treated with FCR (his preference), or fludarabine-rituximab (FR). Bendamustine-rituximab (BR) is also an attractive option in certain cases, he said.

• For patients with active disease or Rai stage III-IV disease who do have a 17p deletion, his treatment of choice is either ibrutinib or idelalisib plus rituximab, depending on the patient.

• In “slow-go” patients (those with poorer physical condition) treatment is again based on mutational analysis. Those without mutation receive either FR, BR, or CLB plus obinutuzumab. These are very good options, and represent a spectrum to choose from based on the patient’s core abilities and ability to withstand particular types of treatments, he said.

“If they do have a 17p deletion, these patients are just as eligible for ibrutinib or idelalisib plus rituximab as the younger patients,” he noted.

His choices are based largely on the findings from the CLL8 trial (Lancet 2010 Oct;376[9747]:1164-74) which demonstrated an overall survival advantage with chemoimmunotherapy for front-line therapy vs. chemotherapy alone (hazard ratio, 0.68).

Over time, the advantage has become even more pronounced, according to follow-up data.

Starting with something “gentle” and saving the best treatment for later in the event of relapse was recently considered a reasonable approach, but in the wake of the CLL8 findings, this is no longer an acceptable plan, Dr. Gribben said.

“That’s why for my choice, FCR remains the treatment of choice for those patients who are fit enough to tolerate this type of approach,” he said.

In those with 17p deletions or P53 mutations, the CLL8 trial showed poor outcomes with FCR.

“This is a group of patients whom I believe chemoimmunotherapy would no longer be the treatment of choice,” he said, adding that newer findings suggest outcomes in these patients are better with novel agents.

He also noted that patients with 11q abnormalities, which were previously associated with a poor prognosis, were found in CLL8 to respond well to chemoimmunotherapy when used front line.

While there are special considerations in the elderly, and different strategies in relapsed and refractory disease, the future of CLL treatment is promising. The benefit of adding rituximab to combination chemotherapy is well established, the benefit of novel agents is also now established, and the future likely involves combining targeted therapies with each other and with immunochemotherapies, and combining targeted therapies across different pathways.

“And of course the hope is that we’re going to use the biology of the disease to decide what specific therapy is ideal for that patient. Better understanding of biology and genetics is facilitating rational development of new treatments,” he said, adding that whenever possible, patients should be treated within clinical trials.

Dr. Gribben has received research funding from the NIH, Cancer Research UK, MRC, and Wellcome Trust. He has received honoraria from Roche/Genentech, Celgene, Janssen, Pharmacyclics, Gilead, Mundipharma, Infinity, TG Therapeutics, and Ascerta, and he has a patent or receives royalties from Celgene. He also has been the principal investigator on a clinical trial for Roche, Takeda, Pharmacyclics, Gilead, and Infinity.

[email protected]

CHICAGO – Despite exciting new advances in the understanding of chronic lymphocytic leukemia, particularly with respect to prognostic features that predict risk for relapse, a watch-and-wait approach remains appropriate for asymptomatic disease pending outcomes data for newer approaches, according to Dr. John G. Gribben.

“When the disease is diagnosed, if it is asymptomatic, the correct approach – of course – is to continue to watch and wait,” Dr. Gribben of Barts Cancer Institute, Queen Mary University of London, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Numerous clinical trials have demonstrated no advantage of early treatment vs. watch and wait, he said, adding that all of the trials published to date have used treatment of all-comers, and have used chlorambucil (CLB) as the treatment.

“There has been a whole variety of more modern trials that have used select prognostic features to identify subgroups of people who are at higher risk of relapse, who then go on to receive earlier treatment with either FCR [fludarabine, cyclophosphamide, rituximab], or more recently, ibrutinib,” he said.

These treatments are interesting, and the trials have demonstrated that prognostic features can identify patients who will progress more rapidly, but none have reported, he explained.

“In the absence of any published trial, I continue to ‘watch and wait’ patients, and there are no high-risk features which will make me alter that approach. Even the highest-risk features of complex karyotype and p53 abnormalities are not indications to treat patients until they become symptomatic,” he said.

It is striking how white counts vary widely in both asymptomatic and symptomatic patients, he noted.

“I don’t personally have any particular white count which is the number at which I’ll treat a patient. I don’t treat white counts, I treat patients,” he said.

When patients become symptomatic, the treatment of choice is now immunochemotherapies, irrespective of performance status, he said.

“Within the past year we have seen approval of obinutuzumab and ofatumumab for treatment of previously untreated CLL, as well as ibrutinib and idelalisib plus rituximab for treatment of both previously untreated CLL and those with 17p deletions for relapsed/refractory disease, as well as for up-front treatment,” he said, adding that these new agents greatly increase the available options for treating CLL.

Dr. Gribben said he considers these questions when it comes to treating CLL:

• Does the patient require treatment, or is watching and waiting appropriate?

• What is the goal of therapy? This is determined through conversation with the patient and the patient’s family regarding the side-effect profile they are willing to tolerate vs. the potential longer duration of response.

• What comorbidities are present to determine “fitness” for specific immunochemotherapy? Specifically, is the patient fit for an FCR-type approach, or is an alternative more appropriate?

• Is there a 17p deletion or P53 mutation that would make chemotherapy a less attractive option, and use of novel agents a more attractive option?

His approach, based on the answers to these questions, is as follows:

• In Rai stage 0-II patients with inactive disease, fitness and 17p deletion or p53 mutation status is irrelevant; no therapy is given.

• For active disease or Rai III-IV disease, a “go-go” patient, (or patient in good physical condition) is treated based on the presence or absence of 17p deletion or p53 mutation status. Those without 17p deletions or p53 mutations can be treated with FCR (his preference), or fludarabine-rituximab (FR). Bendamustine-rituximab (BR) is also an attractive option in certain cases, he said.

• For patients with active disease or Rai stage III-IV disease who do have a 17p deletion, his treatment of choice is either ibrutinib or idelalisib plus rituximab, depending on the patient.

• In “slow-go” patients (those with poorer physical condition) treatment is again based on mutational analysis. Those without mutation receive either FR, BR, or CLB plus obinutuzumab. These are very good options, and represent a spectrum to choose from based on the patient’s core abilities and ability to withstand particular types of treatments, he said.

“If they do have a 17p deletion, these patients are just as eligible for ibrutinib or idelalisib plus rituximab as the younger patients,” he noted.

His choices are based largely on the findings from the CLL8 trial (Lancet 2010 Oct;376[9747]:1164-74) which demonstrated an overall survival advantage with chemoimmunotherapy for front-line therapy vs. chemotherapy alone (hazard ratio, 0.68).

Over time, the advantage has become even more pronounced, according to follow-up data.

Starting with something “gentle” and saving the best treatment for later in the event of relapse was recently considered a reasonable approach, but in the wake of the CLL8 findings, this is no longer an acceptable plan, Dr. Gribben said.

“That’s why for my choice, FCR remains the treatment of choice for those patients who are fit enough to tolerate this type of approach,” he said.

In those with 17p deletions or P53 mutations, the CLL8 trial showed poor outcomes with FCR.

“This is a group of patients whom I believe chemoimmunotherapy would no longer be the treatment of choice,” he said, adding that newer findings suggest outcomes in these patients are better with novel agents.

He also noted that patients with 11q abnormalities, which were previously associated with a poor prognosis, were found in CLL8 to respond well to chemoimmunotherapy when used front line.

While there are special considerations in the elderly, and different strategies in relapsed and refractory disease, the future of CLL treatment is promising. The benefit of adding rituximab to combination chemotherapy is well established, the benefit of novel agents is also now established, and the future likely involves combining targeted therapies with each other and with immunochemotherapies, and combining targeted therapies across different pathways.

“And of course the hope is that we’re going to use the biology of the disease to decide what specific therapy is ideal for that patient. Better understanding of biology and genetics is facilitating rational development of new treatments,” he said, adding that whenever possible, patients should be treated within clinical trials.

Dr. Gribben has received research funding from the NIH, Cancer Research UK, MRC, and Wellcome Trust. He has received honoraria from Roche/Genentech, Celgene, Janssen, Pharmacyclics, Gilead, Mundipharma, Infinity, TG Therapeutics, and Ascerta, and he has a patent or receives royalties from Celgene. He also has been the principal investigator on a clinical trial for Roche, Takeda, Pharmacyclics, Gilead, and Infinity.

[email protected]