ASH Hematologic Malignancies

Maintenance is a important component of therapy for acute lymphoblastic leukemia, but it’s still a relatively new concept in the treat of patients with acute myeloid leukemia (AML).

The topic of AML maintenance “has become quite hot actually, recently, after languishing for years behind ALL, a disease where maintenance is absolutely critical to overall survival; we haven’t had that much to talk about it in AML until recently,” said Gail J. Roboz, MD, from Weill Cornell Medicine and The New York Presbyterian Hospital, both in New York.

Dr. Roboz discussed her approach to AML maintenance during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

The current AML treatment paradigm starts with remission induction via intensive or less-intensive therapies, followed by consolidation with chemotherapy or with autologous or allogeneic stem cell transplantation (SCT), with maintenance considered as a possibility for some patients.

“Strictly speaking, maintenance is the idea of keeping someone in remission, but we’ve gotten used to it that maintenance is postremission therapy that is different from what you had in your induction,” she noted. “That said, the exact nature of maintenance, while it most traditionally refers to an ongoing lower-intensity therapy, is a little bit complicated these days of what exactly constitutes maintenance.”

Current AML treatments generally fail to completely eliminate leukemic cells, so nearly all patients have remissions with minimal residual disease (MRD).

“You have a heterogeneous mix of leukemia stem cells, progenitors, blast cells, and you are in remission but there are still leftovers, and those leftovers result in disease relapse, and the goal of postremission therapy to basically target and hopefully eradicate the leftovers,” Dr. Roboz said.

Focusing on the postremission period is vital because most patients with AML will die within 1 year after disease relapse.
 

Many options, none great

National Comprehensive Cancer Network AML guidelines recommend a variety of approaches to postremission therapy for patients younger than 60 years with AML, including, depending on risk, either histone deacetylase inhibitors, gemtuzumab ozogamicin (Mylotarg), chemotherapy, and/or SCT, but none of these options, strictly speaking, is called maintenance, she noted.

For patients 60 years and older, “there’s also a likelihood of proceeding with hypomethylating [HMA]-based therapy in such a way that, if they’re responding to initial treatment, they get ongoing therapy with whatever HMA or hypomethylating-based regimen they’re responding to. So is that called maintenance? Is that called ongoing therapy? Continuing therapy? It’s a subject of some controversy,” she added.

For patients younger than 60, hematopoietic SCT has been the ultimate form of maintenance, and increasingly allogeneic SCT is being employed in the United States for patients older than 60 years, including those 70 years and older.

“That has been a good thing, because we’ve been able to offer more patients potentially curative therapy, but the problem is that allo transplant is not a free lunch either, and there are significant risks of nonrelapse mortality, especially for patients going into the transplant with other comorbidities,” Dr. Roboz said.

The majority of older patients may not be cured with transplant because of the use of reduced-intensity conditioning regimens with the result of extended disease-free survival but eventual relapse from residual disease.

“The question is, if you’re an older patient and you can’t get an ablative transplant and you do have residual disease, what’s the likelihood of actually being cured at 2 years, and do you really want to go through the headaches of having a transplant?” she said.
 

Nontransplant options

In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.

Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.

“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.

The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.

Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.

As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.

“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.

She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
 

Survival benefit

Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.

Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.

This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.

“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.

The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.

“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.

No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.

Maintenance is a important component of therapy for acute lymphoblastic leukemia, but it’s still a relatively new concept in the treat of patients with acute myeloid leukemia (AML).

The topic of AML maintenance “has become quite hot actually, recently, after languishing for years behind ALL, a disease where maintenance is absolutely critical to overall survival; we haven’t had that much to talk about it in AML until recently,” said Gail J. Roboz, MD, from Weill Cornell Medicine and The New York Presbyterian Hospital, both in New York.

Dr. Roboz discussed her approach to AML maintenance during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

The current AML treatment paradigm starts with remission induction via intensive or less-intensive therapies, followed by consolidation with chemotherapy or with autologous or allogeneic stem cell transplantation (SCT), with maintenance considered as a possibility for some patients.

“Strictly speaking, maintenance is the idea of keeping someone in remission, but we’ve gotten used to it that maintenance is postremission therapy that is different from what you had in your induction,” she noted. “That said, the exact nature of maintenance, while it most traditionally refers to an ongoing lower-intensity therapy, is a little bit complicated these days of what exactly constitutes maintenance.”

Current AML treatments generally fail to completely eliminate leukemic cells, so nearly all patients have remissions with minimal residual disease (MRD).

“You have a heterogeneous mix of leukemia stem cells, progenitors, blast cells, and you are in remission but there are still leftovers, and those leftovers result in disease relapse, and the goal of postremission therapy to basically target and hopefully eradicate the leftovers,” Dr. Roboz said.

Focusing on the postremission period is vital because most patients with AML will die within 1 year after disease relapse.
 

Many options, none great

National Comprehensive Cancer Network AML guidelines recommend a variety of approaches to postremission therapy for patients younger than 60 years with AML, including, depending on risk, either histone deacetylase inhibitors, gemtuzumab ozogamicin (Mylotarg), chemotherapy, and/or SCT, but none of these options, strictly speaking, is called maintenance, she noted.

For patients 60 years and older, “there’s also a likelihood of proceeding with hypomethylating [HMA]-based therapy in such a way that, if they’re responding to initial treatment, they get ongoing therapy with whatever HMA or hypomethylating-based regimen they’re responding to. So is that called maintenance? Is that called ongoing therapy? Continuing therapy? It’s a subject of some controversy,” she added.

For patients younger than 60, hematopoietic SCT has been the ultimate form of maintenance, and increasingly allogeneic SCT is being employed in the United States for patients older than 60 years, including those 70 years and older.

“That has been a good thing, because we’ve been able to offer more patients potentially curative therapy, but the problem is that allo transplant is not a free lunch either, and there are significant risks of nonrelapse mortality, especially for patients going into the transplant with other comorbidities,” Dr. Roboz said.

The majority of older patients may not be cured with transplant because of the use of reduced-intensity conditioning regimens with the result of extended disease-free survival but eventual relapse from residual disease.

“The question is, if you’re an older patient and you can’t get an ablative transplant and you do have residual disease, what’s the likelihood of actually being cured at 2 years, and do you really want to go through the headaches of having a transplant?” she said.
 

Nontransplant options

In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.

Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.

“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.

The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.

Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.

As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.

“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.

She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
 

Survival benefit

Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.

Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.

This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.

“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.

The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.

“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.

No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.

Maintenance is a important component of therapy for acute lymphoblastic leukemia, but it’s still a relatively new concept in the treat of patients with acute myeloid leukemia (AML).

The topic of AML maintenance “has become quite hot actually, recently, after languishing for years behind ALL, a disease where maintenance is absolutely critical to overall survival; we haven’t had that much to talk about it in AML until recently,” said Gail J. Roboz, MD, from Weill Cornell Medicine and The New York Presbyterian Hospital, both in New York.

Dr. Roboz discussed her approach to AML maintenance during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

The current AML treatment paradigm starts with remission induction via intensive or less-intensive therapies, followed by consolidation with chemotherapy or with autologous or allogeneic stem cell transplantation (SCT), with maintenance considered as a possibility for some patients.

“Strictly speaking, maintenance is the idea of keeping someone in remission, but we’ve gotten used to it that maintenance is postremission therapy that is different from what you had in your induction,” she noted. “That said, the exact nature of maintenance, while it most traditionally refers to an ongoing lower-intensity therapy, is a little bit complicated these days of what exactly constitutes maintenance.”

Current AML treatments generally fail to completely eliminate leukemic cells, so nearly all patients have remissions with minimal residual disease (MRD).

“You have a heterogeneous mix of leukemia stem cells, progenitors, blast cells, and you are in remission but there are still leftovers, and those leftovers result in disease relapse, and the goal of postremission therapy to basically target and hopefully eradicate the leftovers,” Dr. Roboz said.

Focusing on the postremission period is vital because most patients with AML will die within 1 year after disease relapse.
 

Many options, none great

National Comprehensive Cancer Network AML guidelines recommend a variety of approaches to postremission therapy for patients younger than 60 years with AML, including, depending on risk, either histone deacetylase inhibitors, gemtuzumab ozogamicin (Mylotarg), chemotherapy, and/or SCT, but none of these options, strictly speaking, is called maintenance, she noted.

For patients 60 years and older, “there’s also a likelihood of proceeding with hypomethylating [HMA]-based therapy in such a way that, if they’re responding to initial treatment, they get ongoing therapy with whatever HMA or hypomethylating-based regimen they’re responding to. So is that called maintenance? Is that called ongoing therapy? Continuing therapy? It’s a subject of some controversy,” she added.

For patients younger than 60, hematopoietic SCT has been the ultimate form of maintenance, and increasingly allogeneic SCT is being employed in the United States for patients older than 60 years, including those 70 years and older.

“That has been a good thing, because we’ve been able to offer more patients potentially curative therapy, but the problem is that allo transplant is not a free lunch either, and there are significant risks of nonrelapse mortality, especially for patients going into the transplant with other comorbidities,” Dr. Roboz said.

The majority of older patients may not be cured with transplant because of the use of reduced-intensity conditioning regimens with the result of extended disease-free survival but eventual relapse from residual disease.

“The question is, if you’re an older patient and you can’t get an ablative transplant and you do have residual disease, what’s the likelihood of actually being cured at 2 years, and do you really want to go through the headaches of having a transplant?” she said.
 

Nontransplant options

In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.

Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.

“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.

The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.

Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.

As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.

“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.

She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
 

Survival benefit

Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.

Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.

This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.

“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.

The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.

“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.

No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.

Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.

“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.

Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
 

Improving bioavailability

Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.

But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.

The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
 

New drugs, potential new targets

Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).

Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.

“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.

A randomized trial of the combination (NCT04401748) is currently recruiting.
 

Novel checkpoint inhibitor

Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).

Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.

The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.

Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.

Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.

The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
 

HMA-refractory disease

Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.

“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.

As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.

Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).

There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.

Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.

“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.

No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.

Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.

“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.

Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
 

Improving bioavailability

Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.

But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.

The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
 

New drugs, potential new targets

Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).

Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.

“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.

A randomized trial of the combination (NCT04401748) is currently recruiting.
 

Novel checkpoint inhibitor

Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).

Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.

The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.

Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.

Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.

The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
 

HMA-refractory disease

Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.

“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.

As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.

Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).

There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.

Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.

“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.

No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.

Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.

“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.

Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
 

Improving bioavailability

Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.

But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.

The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
 

New drugs, potential new targets

Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).

Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.

“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.

A randomized trial of the combination (NCT04401748) is currently recruiting.
 

Novel checkpoint inhibitor

Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).

Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.

The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.

Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.

Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.

The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
 

HMA-refractory disease

Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.

“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.

As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.

Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).

There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.

Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.

“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.

No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.

Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.

“I think it’s likely in future that we’re going to use less chemotherapy, and more combinations of TKI and antibody-based therapy,” said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.

Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.

“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”

With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.

Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).

Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).

A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).

As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
 

Transplants in the TKI era

Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).

“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.

In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.

The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”

In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.

Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.


 

Frail/unfit patients

Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).

In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.

A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.

The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.

There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).

“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
 

TKIs plus antibodies

The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.

A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.

No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.

Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.

“I think it’s likely in future that we’re going to use less chemotherapy, and more combinations of TKI and antibody-based therapy,” said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.

Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.

“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”

With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.

Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).

Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).

A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).

As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
 

Transplants in the TKI era

Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).

“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.

In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.

The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”

In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.

Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.


 

Frail/unfit patients

Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).

In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.

A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.

The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.

There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).

“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
 

TKIs plus antibodies

The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.

A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.

No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.

Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.

“I think it’s likely in future that we’re going to use less chemotherapy, and more combinations of TKI and antibody-based therapy,” said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.

Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.

“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”

With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.

Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).

Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).

A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).

As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
 

Transplants in the TKI era

Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).

“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.

In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.

The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”

In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.

Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.


 

Frail/unfit patients

Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).

In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.

A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.

The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.

There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).

“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
 

TKIs plus antibodies

The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.

A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.

No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

CHICAGO – Major molecular response rates at 12 months were better among chronic myeloid leukemia patients treated with dasatinib/nilotinib vs. imatinib for first-line therapy, and among patients enrolled vs. not enrolled in clinical trials, in a retrospective review of patients treated with first-line tyrosine kinase inhibitors between 2002 and 2014.

The overall rates of major molecular response (MMR) at 12 and 24 months in the 51 patients in the study were 23.5% (12 patients) and 44.9% (22 patients), which was comparable to historical data, Dr. Isabelle Phuong Le reported in a poster at the American Society of Hematology Meeting on Hematologic Malignancies.

The MMR rate among those treated with dasatinib/nilotinib first line was 53%, compared with 10% for those treated with imatinib, said Dr. Le of the University of Texas Health Science Center, San Antonio.

Further the MMR rates at 12 and 24 months among those enrolled vs. not enrolled in clinical trials were 83% vs 15% and 100% vs. 45%, respectively, she noted.

Patients in the analysis were adults with a mean age of 44.6 years who had chronic phase chronic myeloid leukemia (CML). Almost half (49%) were Hispanic, and 56.9% were women. Two-thirds (66.7%) received imatinib first line, and 33.3% received dasatinib/nilotinib first line. More than a third (37.2%) were younger than age 40 years, 15% had a language barrier, and 11.7% were enrolled in clinical trials.

No differences in the MMR rates at 12 and 24 months were seen between Hispanics and non-Hispanics, those with and without language barrier, or men and women, nor were any differences seen between those with more than three lines of therapy and those with three or fewer lines of therapy, or between patients older vs. younger than 40 years, although there was a trend toward improved response rates in older patients, she noted.

“Our patients have similar MMR rates at 12 months and 24 months compared to historical data,” Dr. Le wrote, noting that the findings regarding improved MMR rates with dasatinib/nilotinib were expected.

The findings regarding improved MMR rates among those enrolled in clinical trials could be due to “selective patients as clinical trial patients, more controlled and monitored treatment, frequent follow-ups, and better education regarding disease and treatment,” she said, concluding that “ we can improve treatment response rates in our patients with better disease education.”

Dr. Le reported having no disclosures.

[email protected]

CHICAGO – Major molecular response rates at 12 months were better among chronic myeloid leukemia patients treated with dasatinib/nilotinib vs. imatinib for first-line therapy, and among patients enrolled vs. not enrolled in clinical trials, in a retrospective review of patients treated with first-line tyrosine kinase inhibitors between 2002 and 2014.

The overall rates of major molecular response (MMR) at 12 and 24 months in the 51 patients in the study were 23.5% (12 patients) and 44.9% (22 patients), which was comparable to historical data, Dr. Isabelle Phuong Le reported in a poster at the American Society of Hematology Meeting on Hematologic Malignancies.

The MMR rate among those treated with dasatinib/nilotinib first line was 53%, compared with 10% for those treated with imatinib, said Dr. Le of the University of Texas Health Science Center, San Antonio.

Further the MMR rates at 12 and 24 months among those enrolled vs. not enrolled in clinical trials were 83% vs 15% and 100% vs. 45%, respectively, she noted.

Patients in the analysis were adults with a mean age of 44.6 years who had chronic phase chronic myeloid leukemia (CML). Almost half (49%) were Hispanic, and 56.9% were women. Two-thirds (66.7%) received imatinib first line, and 33.3% received dasatinib/nilotinib first line. More than a third (37.2%) were younger than age 40 years, 15% had a language barrier, and 11.7% were enrolled in clinical trials.

No differences in the MMR rates at 12 and 24 months were seen between Hispanics and non-Hispanics, those with and without language barrier, or men and women, nor were any differences seen between those with more than three lines of therapy and those with three or fewer lines of therapy, or between patients older vs. younger than 40 years, although there was a trend toward improved response rates in older patients, she noted.

“Our patients have similar MMR rates at 12 months and 24 months compared to historical data,” Dr. Le wrote, noting that the findings regarding improved MMR rates with dasatinib/nilotinib were expected.

The findings regarding improved MMR rates among those enrolled in clinical trials could be due to “selective patients as clinical trial patients, more controlled and monitored treatment, frequent follow-ups, and better education regarding disease and treatment,” she said, concluding that “ we can improve treatment response rates in our patients with better disease education.”

Dr. Le reported having no disclosures.

[email protected]

CHICAGO – Major molecular response rates at 12 months were better among chronic myeloid leukemia patients treated with dasatinib/nilotinib vs. imatinib for first-line therapy, and among patients enrolled vs. not enrolled in clinical trials, in a retrospective review of patients treated with first-line tyrosine kinase inhibitors between 2002 and 2014.

The overall rates of major molecular response (MMR) at 12 and 24 months in the 51 patients in the study were 23.5% (12 patients) and 44.9% (22 patients), which was comparable to historical data, Dr. Isabelle Phuong Le reported in a poster at the American Society of Hematology Meeting on Hematologic Malignancies.

The MMR rate among those treated with dasatinib/nilotinib first line was 53%, compared with 10% for those treated with imatinib, said Dr. Le of the University of Texas Health Science Center, San Antonio.

Further the MMR rates at 12 and 24 months among those enrolled vs. not enrolled in clinical trials were 83% vs 15% and 100% vs. 45%, respectively, she noted.

Patients in the analysis were adults with a mean age of 44.6 years who had chronic phase chronic myeloid leukemia (CML). Almost half (49%) were Hispanic, and 56.9% were women. Two-thirds (66.7%) received imatinib first line, and 33.3% received dasatinib/nilotinib first line. More than a third (37.2%) were younger than age 40 years, 15% had a language barrier, and 11.7% were enrolled in clinical trials.

No differences in the MMR rates at 12 and 24 months were seen between Hispanics and non-Hispanics, those with and without language barrier, or men and women, nor were any differences seen between those with more than three lines of therapy and those with three or fewer lines of therapy, or between patients older vs. younger than 40 years, although there was a trend toward improved response rates in older patients, she noted.

“Our patients have similar MMR rates at 12 months and 24 months compared to historical data,” Dr. Le wrote, noting that the findings regarding improved MMR rates with dasatinib/nilotinib were expected.

The findings regarding improved MMR rates among those enrolled in clinical trials could be due to “selective patients as clinical trial patients, more controlled and monitored treatment, frequent follow-ups, and better education regarding disease and treatment,” she said, concluding that “ we can improve treatment response rates in our patients with better disease education.”

Dr. Le reported having no disclosures.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Consider using novel agents in chronic lymphocytic leukemia (CLL) patients who are refractory to treatment or who relapse within 2 years of first-line therapy, Dr. John G. Gribben said.

Ibrutinib or idelalisib/rituximab, or other novel agent combinations within clinical trials are his choice in these patients, thus fitness for therapy becomes irrelevant, he said at the American Society of Hematology Meeting on Hematologic Malignancies.

“Of course, I’m particularly excited by the results in CLL of ABT-199. We saw at [the International Workshop on CLL] last week that there are increasing numbers of patients who are on this therapy in combination with anti-CD20 monoclonal antibodies who are achieving minimal residual disease (MRD) eradication and are able to stop that therapy, unlike what we’ve been seeing,” he said. “I have a patient at my own center now who was treated with ABT-199 plus obinutuzumab within a clinical trial – a 17p deletion patient refractory to seven previous lines of therapy. Had a donor, I was trying to get him to transplant, and now he’s MRD-negative and off therapy, having had 6 months of therapy with ABT-199 and obinutuzumab. [This is] a very exciting combination.”

Other novel-novel agent combinations are also being looked at, he noted.

In CLL patients without 17p deletions who progress later than 2 years after initial chemotherapy, novel agents can be considered, as could alternative approaches with chemotherapy.

“But of course, in the setting of p53 deletions or mutations, then ibrutinib or idelalisib/rituximab, or novel agents like ABT-199 within clinical trials become the treatment approach to be thinking about,” he said.

[email protected]

CHICAGO – Consider using novel agents in chronic lymphocytic leukemia (CLL) patients who are refractory to treatment or who relapse within 2 years of first-line therapy, Dr. John G. Gribben said.

Ibrutinib or idelalisib/rituximab, or other novel agent combinations within clinical trials are his choice in these patients, thus fitness for therapy becomes irrelevant, he said at the American Society of Hematology Meeting on Hematologic Malignancies.

“Of course, I’m particularly excited by the results in CLL of ABT-199. We saw at [the International Workshop on CLL] last week that there are increasing numbers of patients who are on this therapy in combination with anti-CD20 monoclonal antibodies who are achieving minimal residual disease (MRD) eradication and are able to stop that therapy, unlike what we’ve been seeing,” he said. “I have a patient at my own center now who was treated with ABT-199 plus obinutuzumab within a clinical trial – a 17p deletion patient refractory to seven previous lines of therapy. Had a donor, I was trying to get him to transplant, and now he’s MRD-negative and off therapy, having had 6 months of therapy with ABT-199 and obinutuzumab. [This is] a very exciting combination.”

Other novel-novel agent combinations are also being looked at, he noted.

In CLL patients without 17p deletions who progress later than 2 years after initial chemotherapy, novel agents can be considered, as could alternative approaches with chemotherapy.

“But of course, in the setting of p53 deletions or mutations, then ibrutinib or idelalisib/rituximab, or novel agents like ABT-199 within clinical trials become the treatment approach to be thinking about,” he said.

[email protected]

CHICAGO – Consider using novel agents in chronic lymphocytic leukemia (CLL) patients who are refractory to treatment or who relapse within 2 years of first-line therapy, Dr. John G. Gribben said.

Ibrutinib or idelalisib/rituximab, or other novel agent combinations within clinical trials are his choice in these patients, thus fitness for therapy becomes irrelevant, he said at the American Society of Hematology Meeting on Hematologic Malignancies.

“Of course, I’m particularly excited by the results in CLL of ABT-199. We saw at [the International Workshop on CLL] last week that there are increasing numbers of patients who are on this therapy in combination with anti-CD20 monoclonal antibodies who are achieving minimal residual disease (MRD) eradication and are able to stop that therapy, unlike what we’ve been seeing,” he said. “I have a patient at my own center now who was treated with ABT-199 plus obinutuzumab within a clinical trial – a 17p deletion patient refractory to seven previous lines of therapy. Had a donor, I was trying to get him to transplant, and now he’s MRD-negative and off therapy, having had 6 months of therapy with ABT-199 and obinutuzumab. [This is] a very exciting combination.”

Other novel-novel agent combinations are also being looked at, he noted.

In CLL patients without 17p deletions who progress later than 2 years after initial chemotherapy, novel agents can be considered, as could alternative approaches with chemotherapy.

“But of course, in the setting of p53 deletions or mutations, then ibrutinib or idelalisib/rituximab, or novel agents like ABT-199 within clinical trials become the treatment approach to be thinking about,” he said.

[email protected]

CHICAGO – Consider using novel agents in chronic lymphocytic leukemia (CLL) patients who are refractory to treatment or who relapse within 2 years of first-line therapy, Dr. John G. Gribben said.

Ibrutinib or idelalisib/rituximab, or other novel agent combinations within clinical trials are his choice in these patients, thus fitness for therapy becomes irrelevant, he said at the American Society of Hematology Meeting on Hematologic Malignancies.

“Of course, I’m particularly excited by the results in CLL of ABT-199. We saw at [the International Workshop on CLL] last week that there are increasing numbers of patients who are on this therapy in combination with anti-CD20 monoclonal antibodies who are achieving minimal residual disease (MRD) eradication and are able to stop that therapy, unlike what we’ve been seeing,” he said. “I have a patient at my own center now who was treated with ABT-199 plus obinutuzumab within a clinical trial – a 17p deletion patient refractory to seven previous lines of therapy. Had a donor, I was trying to get him to transplant, and now he’s MRD-negative and off therapy, having had 6 months of therapy with ABT-199 and obinutuzumab. [This is] a very exciting combination.”

Other novel-novel agent combinations are also being looked at, he noted.

In CLL patients without 17p deletions who progress later than 2 years after initial chemotherapy, novel agents can be considered, as could alternative approaches with chemotherapy.

“But of course, in the setting of p53 deletions or mutations, then ibrutinib or idelalisib/rituximab, or novel agents like ABT-199 within clinical trials become the treatment approach to be thinking about,” he said.

[email protected]

CHICAGO – Consider using novel agents in chronic lymphocytic leukemia (CLL) patients who are refractory to treatment or who relapse within 2 years of first-line therapy, Dr. John G. Gribben said.

Ibrutinib or idelalisib/rituximab, or other novel agent combinations within clinical trials are his choice in these patients, thus fitness for therapy becomes irrelevant, he said at the American Society of Hematology Meeting on Hematologic Malignancies.

“Of course, I’m particularly excited by the results in CLL of ABT-199. We saw at [the International Workshop on CLL] last week that there are increasing numbers of patients who are on this therapy in combination with anti-CD20 monoclonal antibodies who are achieving minimal residual disease (MRD) eradication and are able to stop that therapy, unlike what we’ve been seeing,” he said. “I have a patient at my own center now who was treated with ABT-199 plus obinutuzumab within a clinical trial – a 17p deletion patient refractory to seven previous lines of therapy. Had a donor, I was trying to get him to transplant, and now he’s MRD-negative and off therapy, having had 6 months of therapy with ABT-199 and obinutuzumab. [This is] a very exciting combination.”

Other novel-novel agent combinations are also being looked at, he noted.

In CLL patients without 17p deletions who progress later than 2 years after initial chemotherapy, novel agents can be considered, as could alternative approaches with chemotherapy.

“But of course, in the setting of p53 deletions or mutations, then ibrutinib or idelalisib/rituximab, or novel agents like ABT-199 within clinical trials become the treatment approach to be thinking about,” he said.

[email protected]

CHICAGO – Consider using novel agents in chronic lymphocytic leukemia (CLL) patients who are refractory to treatment or who relapse within 2 years of first-line therapy, Dr. John G. Gribben said.

Ibrutinib or idelalisib/rituximab, or other novel agent combinations within clinical trials are his choice in these patients, thus fitness for therapy becomes irrelevant, he said at the American Society of Hematology Meeting on Hematologic Malignancies.

“Of course, I’m particularly excited by the results in CLL of ABT-199. We saw at [the International Workshop on CLL] last week that there are increasing numbers of patients who are on this therapy in combination with anti-CD20 monoclonal antibodies who are achieving minimal residual disease (MRD) eradication and are able to stop that therapy, unlike what we’ve been seeing,” he said. “I have a patient at my own center now who was treated with ABT-199 plus obinutuzumab within a clinical trial – a 17p deletion patient refractory to seven previous lines of therapy. Had a donor, I was trying to get him to transplant, and now he’s MRD-negative and off therapy, having had 6 months of therapy with ABT-199 and obinutuzumab. [This is] a very exciting combination.”

Other novel-novel agent combinations are also being looked at, he noted.

In CLL patients without 17p deletions who progress later than 2 years after initial chemotherapy, novel agents can be considered, as could alternative approaches with chemotherapy.

“But of course, in the setting of p53 deletions or mutations, then ibrutinib or idelalisib/rituximab, or novel agents like ABT-199 within clinical trials become the treatment approach to be thinking about,” he said.

[email protected]

CHICAGO – The majority of patients with chronic lymphocytic leukemia (CLL) are elderly patients over age 65 years, which underscores the need for a careful assessment of fitness for therapy – not necessarily because of age, but because of comorbidity burden, according to Dr. John G. Gribben.

In fact, 68% of CLL patients are over age 65 years (median, 71 years), and 41% are over age 75 years. Perhaps more importantly, 89% of elderly CLL patients have one or more comorbidities, and 46% have at least one major comorbidity, said Dr. Gribben of Barts Cancer Institute, Queen Mary University of London.

Conventional wisdom has long suggested that CLL shortens the life span only in younger patients; older patients were thought to be more likely “to die with CLL rather than of CLL,” he said at the American Society of Hematology Meeting on Hematologic Malignancies.

However, recent findings suggest that CLL shortens the life span of elderly patients as well, he noted.

“I think we probably have been undertreating and underthinking about the impact that CLL can have on these more elderly patients, and I think it does represent an area of unmet need,” he said.

Treatment options in the elderly include FCR (fludarabine, cyclophosphamide, rituximab) in those deemed fit enough to tolerate the regimen, he said, adding, “if you are concerned about neutropenia associated with FCR, there are those who use rituximab-fludarabine [RF], and that’s certainly a good option.”

However, in those with an 11q abnormality, good data show that the addition of the alkylator does add benefit. “I do think that FCR is worthwhile pushing [in those cases],” he said.

Bendamustine-rituximab is also an attractive option, as demonstrated in the CLL10 trial, but it is important to remember that patients in that trial were “fit, healthy patients” based on Clinical Illness Rating Scale (CIRS) scores of less than 6; they were patients who were deemed fit to be randomized to receive FCR.

Chlorambucil-based therapies administered with anti-CD20 monoclonal antibodies are also an option, as are novel agents in those with 17p deletions or a P53 mutation, he said.

When it comes to assessing elderly patients’ fitness for therapy, comorbidities play a more important role than age, he said, explaining that many patients over age 65 are very fit and would do well with therapies such as FCR.

For this reason, comorbidities should be the determining factor in treatment selection, he said.

No standard criteria for assessing fitness exist, but there are a few tools that can help.

Eastern Cooperative Oncology Group performance status and organ function (for example, creatinine clearance) can be helpful and often are used in trial settings, as are criteria for excluding patients from participation, but CIRS, used by the German CLL study group, is a more formal tool for assessing comorbidity.

The German group is not the first to use the tool – CIRS is a widely validated test that provides an objective measurement of fitness for more aggressive chemotherapy regimens – but the group did demonstrate in CLL11 that it could be used to enroll more elderly patients with comorbidities into clinical trials, Dr. Gribben said.

A CIRS score of 6 or lower indicates fitness, whereas increasing scores indicate an increasing lack of fitness, he explained, noting that “like every scoring system there are some issues … somebody could easily have a score higher than 6 with comorbidities that really don’t impact on chemotherapy tolerability.

“But in general terms, this is a good way to be making these sorts of assessments,” he said.

Dr. Gribben has received research funding from the National Institutes of Health, 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 – The majority of patients with chronic lymphocytic leukemia (CLL) are elderly patients over age 65 years, which underscores the need for a careful assessment of fitness for therapy – not necessarily because of age, but because of comorbidity burden, according to Dr. John G. Gribben.

In fact, 68% of CLL patients are over age 65 years (median, 71 years), and 41% are over age 75 years. Perhaps more importantly, 89% of elderly CLL patients have one or more comorbidities, and 46% have at least one major comorbidity, said Dr. Gribben of Barts Cancer Institute, Queen Mary University of London.

Conventional wisdom has long suggested that CLL shortens the life span only in younger patients; older patients were thought to be more likely “to die with CLL rather than of CLL,” he said at the American Society of Hematology Meeting on Hematologic Malignancies.

However, recent findings suggest that CLL shortens the life span of elderly patients as well, he noted.

“I think we probably have been undertreating and underthinking about the impact that CLL can have on these more elderly patients, and I think it does represent an area of unmet need,” he said.

Treatment options in the elderly include FCR (fludarabine, cyclophosphamide, rituximab) in those deemed fit enough to tolerate the regimen, he said, adding, “if you are concerned about neutropenia associated with FCR, there are those who use rituximab-fludarabine [RF], and that’s certainly a good option.”

However, in those with an 11q abnormality, good data show that the addition of the alkylator does add benefit. “I do think that FCR is worthwhile pushing [in those cases],” he said.

Bendamustine-rituximab is also an attractive option, as demonstrated in the CLL10 trial, but it is important to remember that patients in that trial were “fit, healthy patients” based on Clinical Illness Rating Scale (CIRS) scores of less than 6; they were patients who were deemed fit to be randomized to receive FCR.

Chlorambucil-based therapies administered with anti-CD20 monoclonal antibodies are also an option, as are novel agents in those with 17p deletions or a P53 mutation, he said.

When it comes to assessing elderly patients’ fitness for therapy, comorbidities play a more important role than age, he said, explaining that many patients over age 65 are very fit and would do well with therapies such as FCR.

For this reason, comorbidities should be the determining factor in treatment selection, he said.

No standard criteria for assessing fitness exist, but there are a few tools that can help.

Eastern Cooperative Oncology Group performance status and organ function (for example, creatinine clearance) can be helpful and often are used in trial settings, as are criteria for excluding patients from participation, but CIRS, used by the German CLL study group, is a more formal tool for assessing comorbidity.

The German group is not the first to use the tool – CIRS is a widely validated test that provides an objective measurement of fitness for more aggressive chemotherapy regimens – but the group did demonstrate in CLL11 that it could be used to enroll more elderly patients with comorbidities into clinical trials, Dr. Gribben said.

A CIRS score of 6 or lower indicates fitness, whereas increasing scores indicate an increasing lack of fitness, he explained, noting that “like every scoring system there are some issues … somebody could easily have a score higher than 6 with comorbidities that really don’t impact on chemotherapy tolerability.

“But in general terms, this is a good way to be making these sorts of assessments,” he said.

Dr. Gribben has received research funding from the National Institutes of Health, 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 – The majority of patients with chronic lymphocytic leukemia (CLL) are elderly patients over age 65 years, which underscores the need for a careful assessment of fitness for therapy – not necessarily because of age, but because of comorbidity burden, according to Dr. John G. Gribben.

In fact, 68% of CLL patients are over age 65 years (median, 71 years), and 41% are over age 75 years. Perhaps more importantly, 89% of elderly CLL patients have one or more comorbidities, and 46% have at least one major comorbidity, said Dr. Gribben of Barts Cancer Institute, Queen Mary University of London.

Conventional wisdom has long suggested that CLL shortens the life span only in younger patients; older patients were thought to be more likely “to die with CLL rather than of CLL,” he said at the American Society of Hematology Meeting on Hematologic Malignancies.

However, recent findings suggest that CLL shortens the life span of elderly patients as well, he noted.

“I think we probably have been undertreating and underthinking about the impact that CLL can have on these more elderly patients, and I think it does represent an area of unmet need,” he said.

Treatment options in the elderly include FCR (fludarabine, cyclophosphamide, rituximab) in those deemed fit enough to tolerate the regimen, he said, adding, “if you are concerned about neutropenia associated with FCR, there are those who use rituximab-fludarabine [RF], and that’s certainly a good option.”

However, in those with an 11q abnormality, good data show that the addition of the alkylator does add benefit. “I do think that FCR is worthwhile pushing [in those cases],” he said.

Bendamustine-rituximab is also an attractive option, as demonstrated in the CLL10 trial, but it is important to remember that patients in that trial were “fit, healthy patients” based on Clinical Illness Rating Scale (CIRS) scores of less than 6; they were patients who were deemed fit to be randomized to receive FCR.

Chlorambucil-based therapies administered with anti-CD20 monoclonal antibodies are also an option, as are novel agents in those with 17p deletions or a P53 mutation, he said.

When it comes to assessing elderly patients’ fitness for therapy, comorbidities play a more important role than age, he said, explaining that many patients over age 65 are very fit and would do well with therapies such as FCR.

For this reason, comorbidities should be the determining factor in treatment selection, he said.

No standard criteria for assessing fitness exist, but there are a few tools that can help.

Eastern Cooperative Oncology Group performance status and organ function (for example, creatinine clearance) can be helpful and often are used in trial settings, as are criteria for excluding patients from participation, but CIRS, used by the German CLL study group, is a more formal tool for assessing comorbidity.

The German group is not the first to use the tool – CIRS is a widely validated test that provides an objective measurement of fitness for more aggressive chemotherapy regimens – but the group did demonstrate in CLL11 that it could be used to enroll more elderly patients with comorbidities into clinical trials, Dr. Gribben said.

A CIRS score of 6 or lower indicates fitness, whereas increasing scores indicate an increasing lack of fitness, he explained, noting that “like every scoring system there are some issues … somebody could easily have a score higher than 6 with comorbidities that really don’t impact on chemotherapy tolerability.

“But in general terms, this is a good way to be making these sorts of assessments,” he said.

Dr. Gribben has received research funding from the National Institutes of Health, 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]

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.

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