TBD Meeting (5407-20)

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.