In ALL, early treatment decisions have “irrevocable” implications

SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.

Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.

Susan London/Frontline Medical News

Cytogenetics and genomics help risk-adapt therapy

“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.

Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.

“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.

Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).

Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.

A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.

“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”

Demographics can guide treatment choices as well

Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.

“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”

AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).

“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”

At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.

He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).

“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.

At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.

“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”

Immunotherapy shows promise in the salvage setting

“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.

“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).

This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.

The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.

Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”

Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.

Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.

“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”

SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.

Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.

Susan London/Frontline Medical News

Cytogenetics and genomics help risk-adapt therapy

“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.

Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.

“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.

Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).

Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.

A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.

“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”

Demographics can guide treatment choices as well

Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.

“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”

AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).

“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”

At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.

He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).

“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.

At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.

“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”

Immunotherapy shows promise in the salvage setting

“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.

“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).

This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.

The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.

Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”

Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.

Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.

“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”

SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.

Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.

Susan London/Frontline Medical News

Cytogenetics and genomics help risk-adapt therapy

“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.

Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.

“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.

Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).

Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.

A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.

“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”

Demographics can guide treatment choices as well

Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.

“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”

AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).

“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”

At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.

He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).

“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.

At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.

“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”

Immunotherapy shows promise in the salvage setting

“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.

“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).

This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.

The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.

Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”

Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.

Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.

“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”