B-Cell Lymphoma ICYMI

Photo from Novartis

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of Stanford University, and his colleagues.

Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the U.S. Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL).

In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects.

However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology.

“Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant.

Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award.

One of the study coauthors reported consulting and research funding from Novartis. 

Photo from Novartis

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of Stanford University, and his colleagues.

Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the U.S. Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL).

In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects.

However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology.

“Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant.

Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award.

One of the study coauthors reported consulting and research funding from Novartis. 

Photo from Novartis

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of Stanford University, and his colleagues.

Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the U.S. Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL).

In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects.

However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology.

“Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant.

Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award.

One of the study coauthors reported consulting and research funding from Novartis. 

Photo courtesy of NCCN

New York—Although the data set is small and not yet mature, chimeric antigen receptor (CAR) T-cell therapy appears to be a promising approach for Hodgkin lymphoma, according to Philippe Armand, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and the Massachusetts General Hospital Cancer Center.

While based on a handful of patients, the data do suggest this approach may play a role either by targeting CD30 or Epstein Barr virus (EBV), Dr. Armand said in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

“Most importantly perhaps, like it's experience outside of Hodgkin lymphoma, it may really have curative potential, based on the long CR rates that have been already exhibited,” he told attendees at the NCCN conference.

Much of the published clinical experience to date is with CD30-directed CAR Ts, Dr. Armand said, noting that in Hodgkin lymphoma, results so far show promise for this particular approach.

In a recent phase 1 dose escalation study, 9 patients with relapsed/refractory Hodgkin lymphoma or anaplastic large-cell lymphoma (ALCL) received infusions of autologous T cells modified to express CD30-specific CAR T cells encoding the CD28 costimulatory domain, with no conditioning regimen.

Out of 7 relapsed Hodgkin patients, one had a complete response (CR) lasting beyond 2.5 years following a second infusion. Another had a CR persisting almost 2 years and 3 had transient stable disease.

One of the 2 ALCL patients had a CR lasting 9 months after a fourth infusion. No toxicities attributable to the therapy were seen, according to investigators.

The CD30 CAR T cells are being evaluated with a conditioning regimen in the phase 1 RELY-30 trial. According to Dr. Armand, preliminary results presented at the EBMT 2018 meeting showed better expansion of CAR T cells and responses in 3 out of 5 patients, including 2 CRs.

A CD30-directed CAR T-cell therapy with a 4-1bb costimulatory domain has also been tested in a small group of Hodgkin patients with a response rate of 35%, including some CRs. Response rates were lower in patients with extranodal involvement, although that needs to be validated with further study, according to Dr. Armand.

A considerable amount of active research is ongoing in China, Dr. Armand said, while a phase 1 study of T cells expressing a fully human anti-CD30 CAR is being evaluated in the United States in CD30-expressing lymphomas, he added.

Among non-CD30-targeted products, a CD19 CAR-T approach has been tried in Hodgkin lymphoma, though preliminary results suggest only transient activity.

An interesting approach has been the targeting of EBV, Dr. Armand noted. Recently reported results showed that two doses of T cells with specificity for EBV-derived tumor antigens induced clinical responses in patients with EBV-positive Hodgkin lymphoma.

The cells were engineered to express dominant-negative TGF-β receptor type 2 (DNRII).

“We know that TGF-β provides a strong immunosuppressant signal in the tumor microenvironment,” Dr. Armand said, noting that some of the responses in the 7 evaluable patients lasted 4 years or more. 

Photo courtesy of NCCN

New York—Although the data set is small and not yet mature, chimeric antigen receptor (CAR) T-cell therapy appears to be a promising approach for Hodgkin lymphoma, according to Philippe Armand, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and the Massachusetts General Hospital Cancer Center.

While based on a handful of patients, the data do suggest this approach may play a role either by targeting CD30 or Epstein Barr virus (EBV), Dr. Armand said in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

“Most importantly perhaps, like it's experience outside of Hodgkin lymphoma, it may really have curative potential, based on the long CR rates that have been already exhibited,” he told attendees at the NCCN conference.

Much of the published clinical experience to date is with CD30-directed CAR Ts, Dr. Armand said, noting that in Hodgkin lymphoma, results so far show promise for this particular approach.

In a recent phase 1 dose escalation study, 9 patients with relapsed/refractory Hodgkin lymphoma or anaplastic large-cell lymphoma (ALCL) received infusions of autologous T cells modified to express CD30-specific CAR T cells encoding the CD28 costimulatory domain, with no conditioning regimen.

Out of 7 relapsed Hodgkin patients, one had a complete response (CR) lasting beyond 2.5 years following a second infusion. Another had a CR persisting almost 2 years and 3 had transient stable disease.

One of the 2 ALCL patients had a CR lasting 9 months after a fourth infusion. No toxicities attributable to the therapy were seen, according to investigators.

The CD30 CAR T cells are being evaluated with a conditioning regimen in the phase 1 RELY-30 trial. According to Dr. Armand, preliminary results presented at the EBMT 2018 meeting showed better expansion of CAR T cells and responses in 3 out of 5 patients, including 2 CRs.

A CD30-directed CAR T-cell therapy with a 4-1bb costimulatory domain has also been tested in a small group of Hodgkin patients with a response rate of 35%, including some CRs. Response rates were lower in patients with extranodal involvement, although that needs to be validated with further study, according to Dr. Armand.

A considerable amount of active research is ongoing in China, Dr. Armand said, while a phase 1 study of T cells expressing a fully human anti-CD30 CAR is being evaluated in the United States in CD30-expressing lymphomas, he added.

Among non-CD30-targeted products, a CD19 CAR-T approach has been tried in Hodgkin lymphoma, though preliminary results suggest only transient activity.

An interesting approach has been the targeting of EBV, Dr. Armand noted. Recently reported results showed that two doses of T cells with specificity for EBV-derived tumor antigens induced clinical responses in patients with EBV-positive Hodgkin lymphoma.

The cells were engineered to express dominant-negative TGF-β receptor type 2 (DNRII).

“We know that TGF-β provides a strong immunosuppressant signal in the tumor microenvironment,” Dr. Armand said, noting that some of the responses in the 7 evaluable patients lasted 4 years or more. 

Photo courtesy of NCCN

New York—Although the data set is small and not yet mature, chimeric antigen receptor (CAR) T-cell therapy appears to be a promising approach for Hodgkin lymphoma, according to Philippe Armand, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and the Massachusetts General Hospital Cancer Center.

While based on a handful of patients, the data do suggest this approach may play a role either by targeting CD30 or Epstein Barr virus (EBV), Dr. Armand said in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

“Most importantly perhaps, like it's experience outside of Hodgkin lymphoma, it may really have curative potential, based on the long CR rates that have been already exhibited,” he told attendees at the NCCN conference.

Much of the published clinical experience to date is with CD30-directed CAR Ts, Dr. Armand said, noting that in Hodgkin lymphoma, results so far show promise for this particular approach.

In a recent phase 1 dose escalation study, 9 patients with relapsed/refractory Hodgkin lymphoma or anaplastic large-cell lymphoma (ALCL) received infusions of autologous T cells modified to express CD30-specific CAR T cells encoding the CD28 costimulatory domain, with no conditioning regimen.

Out of 7 relapsed Hodgkin patients, one had a complete response (CR) lasting beyond 2.5 years following a second infusion. Another had a CR persisting almost 2 years and 3 had transient stable disease.

One of the 2 ALCL patients had a CR lasting 9 months after a fourth infusion. No toxicities attributable to the therapy were seen, according to investigators.

The CD30 CAR T cells are being evaluated with a conditioning regimen in the phase 1 RELY-30 trial. According to Dr. Armand, preliminary results presented at the EBMT 2018 meeting showed better expansion of CAR T cells and responses in 3 out of 5 patients, including 2 CRs.

A CD30-directed CAR T-cell therapy with a 4-1bb costimulatory domain has also been tested in a small group of Hodgkin patients with a response rate of 35%, including some CRs. Response rates were lower in patients with extranodal involvement, although that needs to be validated with further study, according to Dr. Armand.

A considerable amount of active research is ongoing in China, Dr. Armand said, while a phase 1 study of T cells expressing a fully human anti-CD30 CAR is being evaluated in the United States in CD30-expressing lymphomas, he added.

Among non-CD30-targeted products, a CD19 CAR-T approach has been tried in Hodgkin lymphoma, though preliminary results suggest only transient activity.

An interesting approach has been the targeting of EBV, Dr. Armand noted. Recently reported results showed that two doses of T cells with specificity for EBV-derived tumor antigens induced clinical responses in patients with EBV-positive Hodgkin lymphoma.

The cells were engineered to express dominant-negative TGF-β receptor type 2 (DNRII).

“We know that TGF-β provides a strong immunosuppressant signal in the tumor microenvironment,” Dr. Armand said, noting that some of the responses in the 7 evaluable patients lasted 4 years or more. 

CHICAGO – A number of mutation tests – including immunoglobulin heavy chain gene (IgVH), fluorescence in situ hybridization (FISH), and TP53 – provide useful prognostic information at the time of chronic lymphocytic leukemia (CLL) diagnosis, according to Paul M. Barr, MD.

©Ed Uthman/Flickr

“It’s understood that IgVH mutation status is certainly prognostic,” Dr. Barr, associate professor of hematology/oncology at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

The B-cell receptor of the CLL cells uses IgVH genes that may or may not have undergone somatic mutations, with unmutated being defined as 98% or more sequence homology to germline.

“This is indicative of stronger signaling through the B-cell receptor and, as we all know, predicts for an inferior prognosis,” he explained, citing a study that demonstrated superior survival rates with mutated IgVH genes (Blood. 1999;94[6]:1840-7).

“It’s also well understood and accepted that we should perform a FISH panel; we should look for interphase cytogenetics based on FISH in our patients,” Dr. Barr said. “Having said that, we, as medical oncologists, do not do a very good job of using this testing appropriately. Patterns of care studies have suggested that a significant number of patients don’t get FISH testing at diagnosis or before first-line therapy.”

In fact, a typical interphase FISH panel identifies cytogenetic lesions, including del(17p), del(11q), del(13q), and trisomy 12 in more than 80% of CLL cases, with del(13q) being the most common.

Another marker that can be assessed in CLL patients and has maintained prognostic value across multiple analyses is serum beta-2 microglobulin, Dr. Barr noted.

TP53 sequencing is valuable as well and has been associated with outcomes similar to those seen in patients with del(17p), he said, citing data from a study that found similarly poor outcomes with TP53 mutations or deletions and del(17p), even when minor subclones are identified using next-generation sequencing (Blood. 2014;123:2139-47).

“One of the primary reasons for this is that the two aberrations go together. Most often, if you have del(17p) you’re also going to find a TP53 mutation, but in about 30% of patients or so, only one allele is affected, so this is why it’s still important to test for TP53 mutations when you’re looking for a 17p deletion,” he said.

Numerous other recurrent mutations in CLL have been associated with poor overall survival and/or progression-free survival, including SF3B1, ATM, NOTCH1, POT1, BIRC3, and NFKBIE.

“The gut instinct is that maybe we should start testing for all of these mutations now, but I would caution everybody that we still need further validation before we can apply these to the majority of patients,” Dr. Barr said. “We still don’t know exactly what to do with all of these mutations – when and how often we should test for them, if the novel agents are truly better – so while, again, they can predict for inferior outcomes, I would say these are not yet standard of care to be tested in all patients.”

It is likely, though, that new prognostic systems will evolve as more is learned about how to use these molecular aberrations. Attempts are already being made to incorporate novel mutations into a prognostic system. Dr. Barr pointed to a report that looked at the integration of mutations and cytogenetic lesions to improve the accuracy of survival prediction in CLL (Blood. 2013;121:1403-12).

“But this still requires prospective testing, especially in patients getting the novel agents,” he said.

Conventional karyotyping also has potential, though a limited role in this setting, he said, noting that it can be reliably performed with stimulation of CLL cells.

“We also know additional aberrations are prognostic and that a complex karyotype predicts for a very poor outcome,” he said. The International Workshop on CLL (iwCLL) guidelines, which were recently updated for the first time in a decade, state that further validation is needed.

“I think it’s potentially useful in a very young patient you are considering taking to transplant, but again, I agree with the stance that this is not something that should be performed in every patient across the board,” he said.

The tests currently recommended by iwCLL before CLL treatment include IgVH mutation status; FISH for del(13q), del(11q), del(17p), and trisomy 12 in peripheral blood lymphocytes; and TP53.

“Some folks... don’t check a lot of these markers at diagnosis, but wait for patients to require therapy, and that’s a reasonable way to practice,” Dr. Barr said, noting, however, that he prefers knowing patients’ risk up front – especially for those patients he will see just once before they are “managed closer to home for the majority of their course.

“But if you [wait], then knowing what to repeat later is important,” he added. Namely, the FISH and TP53 tests are worth repeating as patients can acquire additional molecular aberrations over time.

Dr. Barr reported serving as a consultant for Pharmacyclics, AbbVie, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Novartis, and Seattle Genetics. He also reported receiving research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A number of mutation tests – including immunoglobulin heavy chain gene (IgVH), fluorescence in situ hybridization (FISH), and TP53 – provide useful prognostic information at the time of chronic lymphocytic leukemia (CLL) diagnosis, according to Paul M. Barr, MD.

©Ed Uthman/Flickr

“It’s understood that IgVH mutation status is certainly prognostic,” Dr. Barr, associate professor of hematology/oncology at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

The B-cell receptor of the CLL cells uses IgVH genes that may or may not have undergone somatic mutations, with unmutated being defined as 98% or more sequence homology to germline.

“This is indicative of stronger signaling through the B-cell receptor and, as we all know, predicts for an inferior prognosis,” he explained, citing a study that demonstrated superior survival rates with mutated IgVH genes (Blood. 1999;94[6]:1840-7).

“It’s also well understood and accepted that we should perform a FISH panel; we should look for interphase cytogenetics based on FISH in our patients,” Dr. Barr said. “Having said that, we, as medical oncologists, do not do a very good job of using this testing appropriately. Patterns of care studies have suggested that a significant number of patients don’t get FISH testing at diagnosis or before first-line therapy.”

In fact, a typical interphase FISH panel identifies cytogenetic lesions, including del(17p), del(11q), del(13q), and trisomy 12 in more than 80% of CLL cases, with del(13q) being the most common.

Another marker that can be assessed in CLL patients and has maintained prognostic value across multiple analyses is serum beta-2 microglobulin, Dr. Barr noted.

TP53 sequencing is valuable as well and has been associated with outcomes similar to those seen in patients with del(17p), he said, citing data from a study that found similarly poor outcomes with TP53 mutations or deletions and del(17p), even when minor subclones are identified using next-generation sequencing (Blood. 2014;123:2139-47).

“One of the primary reasons for this is that the two aberrations go together. Most often, if you have del(17p) you’re also going to find a TP53 mutation, but in about 30% of patients or so, only one allele is affected, so this is why it’s still important to test for TP53 mutations when you’re looking for a 17p deletion,” he said.

Numerous other recurrent mutations in CLL have been associated with poor overall survival and/or progression-free survival, including SF3B1, ATM, NOTCH1, POT1, BIRC3, and NFKBIE.

“The gut instinct is that maybe we should start testing for all of these mutations now, but I would caution everybody that we still need further validation before we can apply these to the majority of patients,” Dr. Barr said. “We still don’t know exactly what to do with all of these mutations – when and how often we should test for them, if the novel agents are truly better – so while, again, they can predict for inferior outcomes, I would say these are not yet standard of care to be tested in all patients.”

It is likely, though, that new prognostic systems will evolve as more is learned about how to use these molecular aberrations. Attempts are already being made to incorporate novel mutations into a prognostic system. Dr. Barr pointed to a report that looked at the integration of mutations and cytogenetic lesions to improve the accuracy of survival prediction in CLL (Blood. 2013;121:1403-12).

“But this still requires prospective testing, especially in patients getting the novel agents,” he said.

Conventional karyotyping also has potential, though a limited role in this setting, he said, noting that it can be reliably performed with stimulation of CLL cells.

“We also know additional aberrations are prognostic and that a complex karyotype predicts for a very poor outcome,” he said. The International Workshop on CLL (iwCLL) guidelines, which were recently updated for the first time in a decade, state that further validation is needed.

“I think it’s potentially useful in a very young patient you are considering taking to transplant, but again, I agree with the stance that this is not something that should be performed in every patient across the board,” he said.

The tests currently recommended by iwCLL before CLL treatment include IgVH mutation status; FISH for del(13q), del(11q), del(17p), and trisomy 12 in peripheral blood lymphocytes; and TP53.

“Some folks... don’t check a lot of these markers at diagnosis, but wait for patients to require therapy, and that’s a reasonable way to practice,” Dr. Barr said, noting, however, that he prefers knowing patients’ risk up front – especially for those patients he will see just once before they are “managed closer to home for the majority of their course.

“But if you [wait], then knowing what to repeat later is important,” he added. Namely, the FISH and TP53 tests are worth repeating as patients can acquire additional molecular aberrations over time.

Dr. Barr reported serving as a consultant for Pharmacyclics, AbbVie, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Novartis, and Seattle Genetics. He also reported receiving research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A number of mutation tests – including immunoglobulin heavy chain gene (IgVH), fluorescence in situ hybridization (FISH), and TP53 – provide useful prognostic information at the time of chronic lymphocytic leukemia (CLL) diagnosis, according to Paul M. Barr, MD.

©Ed Uthman/Flickr

“It’s understood that IgVH mutation status is certainly prognostic,” Dr. Barr, associate professor of hematology/oncology at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

The B-cell receptor of the CLL cells uses IgVH genes that may or may not have undergone somatic mutations, with unmutated being defined as 98% or more sequence homology to germline.

“This is indicative of stronger signaling through the B-cell receptor and, as we all know, predicts for an inferior prognosis,” he explained, citing a study that demonstrated superior survival rates with mutated IgVH genes (Blood. 1999;94[6]:1840-7).

“It’s also well understood and accepted that we should perform a FISH panel; we should look for interphase cytogenetics based on FISH in our patients,” Dr. Barr said. “Having said that, we, as medical oncologists, do not do a very good job of using this testing appropriately. Patterns of care studies have suggested that a significant number of patients don’t get FISH testing at diagnosis or before first-line therapy.”

In fact, a typical interphase FISH panel identifies cytogenetic lesions, including del(17p), del(11q), del(13q), and trisomy 12 in more than 80% of CLL cases, with del(13q) being the most common.

Another marker that can be assessed in CLL patients and has maintained prognostic value across multiple analyses is serum beta-2 microglobulin, Dr. Barr noted.

TP53 sequencing is valuable as well and has been associated with outcomes similar to those seen in patients with del(17p), he said, citing data from a study that found similarly poor outcomes with TP53 mutations or deletions and del(17p), even when minor subclones are identified using next-generation sequencing (Blood. 2014;123:2139-47).

“One of the primary reasons for this is that the two aberrations go together. Most often, if you have del(17p) you’re also going to find a TP53 mutation, but in about 30% of patients or so, only one allele is affected, so this is why it’s still important to test for TP53 mutations when you’re looking for a 17p deletion,” he said.

Numerous other recurrent mutations in CLL have been associated with poor overall survival and/or progression-free survival, including SF3B1, ATM, NOTCH1, POT1, BIRC3, and NFKBIE.

“The gut instinct is that maybe we should start testing for all of these mutations now, but I would caution everybody that we still need further validation before we can apply these to the majority of patients,” Dr. Barr said. “We still don’t know exactly what to do with all of these mutations – when and how often we should test for them, if the novel agents are truly better – so while, again, they can predict for inferior outcomes, I would say these are not yet standard of care to be tested in all patients.”

It is likely, though, that new prognostic systems will evolve as more is learned about how to use these molecular aberrations. Attempts are already being made to incorporate novel mutations into a prognostic system. Dr. Barr pointed to a report that looked at the integration of mutations and cytogenetic lesions to improve the accuracy of survival prediction in CLL (Blood. 2013;121:1403-12).

“But this still requires prospective testing, especially in patients getting the novel agents,” he said.

Conventional karyotyping also has potential, though a limited role in this setting, he said, noting that it can be reliably performed with stimulation of CLL cells.

“We also know additional aberrations are prognostic and that a complex karyotype predicts for a very poor outcome,” he said. The International Workshop on CLL (iwCLL) guidelines, which were recently updated for the first time in a decade, state that further validation is needed.

“I think it’s potentially useful in a very young patient you are considering taking to transplant, but again, I agree with the stance that this is not something that should be performed in every patient across the board,” he said.

The tests currently recommended by iwCLL before CLL treatment include IgVH mutation status; FISH for del(13q), del(11q), del(17p), and trisomy 12 in peripheral blood lymphocytes; and TP53.

“Some folks... don’t check a lot of these markers at diagnosis, but wait for patients to require therapy, and that’s a reasonable way to practice,” Dr. Barr said, noting, however, that he prefers knowing patients’ risk up front – especially for those patients he will see just once before they are “managed closer to home for the majority of their course.

“But if you [wait], then knowing what to repeat later is important,” he added. Namely, the FISH and TP53 tests are worth repeating as patients can acquire additional molecular aberrations over time.

Dr. Barr reported serving as a consultant for Pharmacyclics, AbbVie, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Novartis, and Seattle Genetics. He also reported receiving research funding from Pharmacyclics and AbbVie.

[email protected]

Advanced indolent lymphoma patients can be treated with a rituximab-containing regimen as first-line therapy and, in some cases, skip chemotherapy altogether, a study with 10 years of follow-up data suggests.

Patho/Wikimedia Commons/CC BY-SA 3.0

After a median of 10.6 years’ follow-up, almost three-quarters of patients (73%) in the study were alive, and 36% never required chemotherapy.

“This [overall survival] is at least as good as that observed in modern immunochemotherapy trials,” Sandra Lockmer, MD, of Karolinska University Hospital in Stockholm and her colleagues reported in the Journal of Clinical Oncology.

The study included 321 patients who were previously untreated and had been enrolled in two randomized clinical trials performed by the Nordic Lymphoma Group. The trials randomized patients to receive either rituximab monotherapy or rituximab combined with interferon alfa-2a. Neither trial used up-front chemotherapy.

Patients included in the follow-up analysis had follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or indolent lymphoma not otherwise specified.

The overall survival rate at 10 years after trial assignment was 75% and 66% after 15 years. Similarly, the lymphoma-specific survival rate was 81% at 10 years after trial assignment and 77% at 15 years, the researchers reported.

Overall, 117 patients did not require treatment with chemotherapy, but 24 patients were further treated with antibodies and/or radiation. Of the 93 patients who received no additional therapies after frontline treatment, 9 patients died from causes unrelated to their lymphoma.

Among the 237 patients who failed initial treatment, the median time to treatment failure was 1.5 years.

In terms of transformation to aggressive lymphoma, the rate was 2.4%/person-year overall. The cumulative risk of transformation was 20% at 10 years after trial assignment and 24% at 15 years.

The study was funded in part by the Stockholm County Council and by the Nordic Lymphoma Group. The trials analyzed in the study were supported by Roche. Dr. Lockmer reported having no financial disclosures. Her coauthors reported relationships with Novartis, Gilead, Roche, and Takeda, among others.

[email protected]

SOURCE: Lockmer S et al. J Clin Oncol. 2018 Oct 4:JCO1800262. doi: 10.1200/JCO.18.00262.

Advanced indolent lymphoma patients can be treated with a rituximab-containing regimen as first-line therapy and, in some cases, skip chemotherapy altogether, a study with 10 years of follow-up data suggests.

Patho/Wikimedia Commons/CC BY-SA 3.0

After a median of 10.6 years’ follow-up, almost three-quarters of patients (73%) in the study were alive, and 36% never required chemotherapy.

“This [overall survival] is at least as good as that observed in modern immunochemotherapy trials,” Sandra Lockmer, MD, of Karolinska University Hospital in Stockholm and her colleagues reported in the Journal of Clinical Oncology.

The study included 321 patients who were previously untreated and had been enrolled in two randomized clinical trials performed by the Nordic Lymphoma Group. The trials randomized patients to receive either rituximab monotherapy or rituximab combined with interferon alfa-2a. Neither trial used up-front chemotherapy.

Patients included in the follow-up analysis had follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or indolent lymphoma not otherwise specified.

The overall survival rate at 10 years after trial assignment was 75% and 66% after 15 years. Similarly, the lymphoma-specific survival rate was 81% at 10 years after trial assignment and 77% at 15 years, the researchers reported.

Overall, 117 patients did not require treatment with chemotherapy, but 24 patients were further treated with antibodies and/or radiation. Of the 93 patients who received no additional therapies after frontline treatment, 9 patients died from causes unrelated to their lymphoma.

Among the 237 patients who failed initial treatment, the median time to treatment failure was 1.5 years.

In terms of transformation to aggressive lymphoma, the rate was 2.4%/person-year overall. The cumulative risk of transformation was 20% at 10 years after trial assignment and 24% at 15 years.

The study was funded in part by the Stockholm County Council and by the Nordic Lymphoma Group. The trials analyzed in the study were supported by Roche. Dr. Lockmer reported having no financial disclosures. Her coauthors reported relationships with Novartis, Gilead, Roche, and Takeda, among others.

[email protected]

SOURCE: Lockmer S et al. J Clin Oncol. 2018 Oct 4:JCO1800262. doi: 10.1200/JCO.18.00262.

Advanced indolent lymphoma patients can be treated with a rituximab-containing regimen as first-line therapy and, in some cases, skip chemotherapy altogether, a study with 10 years of follow-up data suggests.

Patho/Wikimedia Commons/CC BY-SA 3.0

After a median of 10.6 years’ follow-up, almost three-quarters of patients (73%) in the study were alive, and 36% never required chemotherapy.

“This [overall survival] is at least as good as that observed in modern immunochemotherapy trials,” Sandra Lockmer, MD, of Karolinska University Hospital in Stockholm and her colleagues reported in the Journal of Clinical Oncology.

The study included 321 patients who were previously untreated and had been enrolled in two randomized clinical trials performed by the Nordic Lymphoma Group. The trials randomized patients to receive either rituximab monotherapy or rituximab combined with interferon alfa-2a. Neither trial used up-front chemotherapy.

Patients included in the follow-up analysis had follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or indolent lymphoma not otherwise specified.

The overall survival rate at 10 years after trial assignment was 75% and 66% after 15 years. Similarly, the lymphoma-specific survival rate was 81% at 10 years after trial assignment and 77% at 15 years, the researchers reported.

Overall, 117 patients did not require treatment with chemotherapy, but 24 patients were further treated with antibodies and/or radiation. Of the 93 patients who received no additional therapies after frontline treatment, 9 patients died from causes unrelated to their lymphoma.

Among the 237 patients who failed initial treatment, the median time to treatment failure was 1.5 years.

In terms of transformation to aggressive lymphoma, the rate was 2.4%/person-year overall. The cumulative risk of transformation was 20% at 10 years after trial assignment and 24% at 15 years.

The study was funded in part by the Stockholm County Council and by the Nordic Lymphoma Group. The trials analyzed in the study were supported by Roche. Dr. Lockmer reported having no financial disclosures. Her coauthors reported relationships with Novartis, Gilead, Roche, and Takeda, among others.

[email protected]

SOURCE: Lockmer S et al. J Clin Oncol. 2018 Oct 4:JCO1800262. doi: 10.1200/JCO.18.00262.

New evidence provides estimates of the pregnancy rates for American women with multiple sclerosis (MS), their complication rates, and the rates of relapse and disease-modifying drug treatment during different phases before and after pregnancy.

The two new studies, conducted by Maria K. Houtchens, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues involved retrospective mining of U.S. commercial health plan data in the IQVIA Real-World Data Adjudicated Claims–U.S. database between Jan. 1, 2006, and June 30, 2015.

The mean age of pregnant women in the nine annual cohorts during that period was just over 32 years for those with MS and just over 29 years for those without. The percentage of women without MS who had a pregnancy-related claim in the database declined from 8.83% in 2006 to 7.75% in 2014 after adjusting for age, region, payer, and Charlson Comorbidity Index score, whereas the percentage increased in women with MS during the same period, from 7.91% to 9.47%. The investigators matched 2,115 women with MS and 2,115 without MS who had live births for a variety of variables and found that women with MS had higher rates of premature labor (31.4% vs. 27.4%; P = .005), infection in pregnancy (13.3% vs. 10.9%; P = .016), maternal cardiovascular disease (3.0% vs. 1.9%; P = .028), anemia or acquired coagulation disorder (2.5% vs. 1.3%; P = .007), neurologic complications in pregnancy (1.6% vs. 0.6%; P = .005), and sexually transmitted diseases in pregnancy (0.4% vs. 0%; P = .045). During labor and delivery, women with MS who had a live birth more often had a claim for acquired damage to the fetus (27.8% vs. 23.5%; P = .002) and congenital fetal malformations (13.2% vs. 10.3%; P = .004) than did women without MS.

In the second study, Dr. Houtchens and two coauthors from the first study of the database reported on a set of 2,158 women who had a live birth during the study period and had 1 year of continuous insurance eligibility before and after pregnancy. The odds for having an MS relapse declined during pregnancy (odds ratio, 0.623; 95% confidence interval, 0.521-0.744), rose during the 6-week postpartum puerperium (OR, 1.710; 95% CI, 1.358-2.152), and leveled off during the last three postpartum quarters to remain at a higher level than before pregnancy (OR, 1.216; 95% CI, 1.052-1.406). Disease-modifying drug treatment followed the same pattern with 20% using it before pregnancy, dropping to about 2% in the second trimester, and peaking in about a quarter of all patients 9-12 months post partum.

[email protected]

SOURCES: Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006382; Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006384.

New evidence provides estimates of the pregnancy rates for American women with multiple sclerosis (MS), their complication rates, and the rates of relapse and disease-modifying drug treatment during different phases before and after pregnancy.

The two new studies, conducted by Maria K. Houtchens, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues involved retrospective mining of U.S. commercial health plan data in the IQVIA Real-World Data Adjudicated Claims–U.S. database between Jan. 1, 2006, and June 30, 2015.

The mean age of pregnant women in the nine annual cohorts during that period was just over 32 years for those with MS and just over 29 years for those without. The percentage of women without MS who had a pregnancy-related claim in the database declined from 8.83% in 2006 to 7.75% in 2014 after adjusting for age, region, payer, and Charlson Comorbidity Index score, whereas the percentage increased in women with MS during the same period, from 7.91% to 9.47%. The investigators matched 2,115 women with MS and 2,115 without MS who had live births for a variety of variables and found that women with MS had higher rates of premature labor (31.4% vs. 27.4%; P = .005), infection in pregnancy (13.3% vs. 10.9%; P = .016), maternal cardiovascular disease (3.0% vs. 1.9%; P = .028), anemia or acquired coagulation disorder (2.5% vs. 1.3%; P = .007), neurologic complications in pregnancy (1.6% vs. 0.6%; P = .005), and sexually transmitted diseases in pregnancy (0.4% vs. 0%; P = .045). During labor and delivery, women with MS who had a live birth more often had a claim for acquired damage to the fetus (27.8% vs. 23.5%; P = .002) and congenital fetal malformations (13.2% vs. 10.3%; P = .004) than did women without MS.

In the second study, Dr. Houtchens and two coauthors from the first study of the database reported on a set of 2,158 women who had a live birth during the study period and had 1 year of continuous insurance eligibility before and after pregnancy. The odds for having an MS relapse declined during pregnancy (odds ratio, 0.623; 95% confidence interval, 0.521-0.744), rose during the 6-week postpartum puerperium (OR, 1.710; 95% CI, 1.358-2.152), and leveled off during the last three postpartum quarters to remain at a higher level than before pregnancy (OR, 1.216; 95% CI, 1.052-1.406). Disease-modifying drug treatment followed the same pattern with 20% using it before pregnancy, dropping to about 2% in the second trimester, and peaking in about a quarter of all patients 9-12 months post partum.

[email protected]

SOURCES: Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006382; Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006384.

New evidence provides estimates of the pregnancy rates for American women with multiple sclerosis (MS), their complication rates, and the rates of relapse and disease-modifying drug treatment during different phases before and after pregnancy.

The two new studies, conducted by Maria K. Houtchens, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues involved retrospective mining of U.S. commercial health plan data in the IQVIA Real-World Data Adjudicated Claims–U.S. database between Jan. 1, 2006, and June 30, 2015.

The mean age of pregnant women in the nine annual cohorts during that period was just over 32 years for those with MS and just over 29 years for those without. The percentage of women without MS who had a pregnancy-related claim in the database declined from 8.83% in 2006 to 7.75% in 2014 after adjusting for age, region, payer, and Charlson Comorbidity Index score, whereas the percentage increased in women with MS during the same period, from 7.91% to 9.47%. The investigators matched 2,115 women with MS and 2,115 without MS who had live births for a variety of variables and found that women with MS had higher rates of premature labor (31.4% vs. 27.4%; P = .005), infection in pregnancy (13.3% vs. 10.9%; P = .016), maternal cardiovascular disease (3.0% vs. 1.9%; P = .028), anemia or acquired coagulation disorder (2.5% vs. 1.3%; P = .007), neurologic complications in pregnancy (1.6% vs. 0.6%; P = .005), and sexually transmitted diseases in pregnancy (0.4% vs. 0%; P = .045). During labor and delivery, women with MS who had a live birth more often had a claim for acquired damage to the fetus (27.8% vs. 23.5%; P = .002) and congenital fetal malformations (13.2% vs. 10.3%; P = .004) than did women without MS.

In the second study, Dr. Houtchens and two coauthors from the first study of the database reported on a set of 2,158 women who had a live birth during the study period and had 1 year of continuous insurance eligibility before and after pregnancy. The odds for having an MS relapse declined during pregnancy (odds ratio, 0.623; 95% confidence interval, 0.521-0.744), rose during the 6-week postpartum puerperium (OR, 1.710; 95% CI, 1.358-2.152), and leveled off during the last three postpartum quarters to remain at a higher level than before pregnancy (OR, 1.216; 95% CI, 1.052-1.406). Disease-modifying drug treatment followed the same pattern with 20% using it before pregnancy, dropping to about 2% in the second trimester, and peaking in about a quarter of all patients 9-12 months post partum.

[email protected]

SOURCES: Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006382; Houtchens MK et al. Neurology. 2018 Sep 28. doi: 10.1212/WNL.0000000000006384.

Photo from Sarah Cannon

Final analysis of the phase 3 DUO trial has shown monotherapy with oral duvelisib results in a statistically significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to monotherapy with ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia/small lympchocytic lymphoma (CLL/SLL).

PFS for all patients as assessed by Independent Review Committee (IRC) was a median 13.3 months with duvelisib compared to 9.9 months with ofatumumab (P<0.0001).

ORR was significantly higher with duvelisib, 74% compared to 45%, P<0.0001, regardless of deletion 17p status.

Duvelisib (Copiktra™) was recently approved by the U.S. Food and Drug Administration for CLL/SLL based in part on this head-to-head trial.

The investigators reported the results in Blood.

"The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies," said principal investigator Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute in Nashville.

"Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options."

Duvelisib is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and -γ, which means it blocks the survival and proliferation of malignant B cells and also disrupts the recruitment and differentiation of T cells and macrophages within the tumor microenvironment.

Ofatumumab is a humanized anti-CD20 antibody with single-agent efficacy in refractory CLL. It is approved by the FDA as a treatment option in CLL.

Study design

Investigators randomized 319 relapsed or refractory CLL/SLL patients, 160 to the duvelisib arm and 159 to the ofatumumab arm.

Patients in the duvelisib arm self-administered 25 mg capsules twice daily continuously in 28-day cycles. They could take duvelisib for up to 18 cycles, until disease progression or unacceptable toxicity.

Ofatumumab-treated patients received infusions as approved in the product labeling for monotherapy in relapsed CLL. Dosing of ofatumumab could not exceed 12 doses in 7 cycles.

Prophylaxis for Pneumocystis jirovecci was required for all patients on both treatment arms.

Patients were allowed to crossover to a separate extension study to receive the opposite therapy if they had progressive disease.

They were followed for a median of 22.4 months.

Patient characteristics

According to the investigators, patient characteristics were well balanced between the arms.

The majority (60%) were male and the median age in both arms was 69. Most had an ECOG performance status of 0 or 1; 7% in the duvelisib arm and 10% in the ofatumumab arm had a performance status of 2.

Other patient characteristics in the duvelisib and ofatumumab arms, respectively, were:

• Time from initial diagnosis: 7.5 years, 6.7 years
• CLL/SLL, %: 97/5, 99/2
• Bulky disease: 46%, 45%
• Baseline lymphocyte counts: 38x109/L, 35x109/L
• Deletion 17p and/or TP53 mutation: 31%, 33%
• Median number of prior therapies: 2 in each arm
• Previous alkylating agent: 93%, 95%
• Previous monoclonal antibody: 78%, 83%
• Prior purine analog: 60%, 71%

Of the total patients enrolled, 158 patients in the duvelisib arm and 155 in the ofatumumab arm received treatment, for a median exposure of 50 weeks and 23 weeks, respectively.

Efficacy

In addition to the significantly improved overall PFS and ORR with duvelisib, further analysis revealed that PFS also improved for all predefined subgroups.

High-risk patients with deletion 17p/TP53 mutations also experienced a significant improvement in PFS with duvelisib of 12.7 months compared to 9.0 months with ofatumumab by IRC (P=0.0002).

The estimated probability of being progression-free for these patients at 6 and 12 moths was 73% and 55% with duvelisib and 63% and 30% with ofatumumab.

The investigators pointed out that duvelisib treatment was particularly effective in eliciting a lymph node response—85.0% compared to 15.7% with ofatumumab as assessed by IRC (P<0.0001).

Median overall survival was not reached in either arm. The 12-month probability of survival was 86% for both treatments.

Safety

Median treatment exposure was almost twice as long in the duvelisib arm because ofatumumab treatment was not allowed to exceed 12 doses as specified in the prescribing information.

The investigators explained this resulted in a longer adverse event (AE) reporting period for duvelisib.

One hundred twenty-four duvelisib-treated patients discontinued treatment, most commonly due to AEs (35%), disease progression (22%), subject withdrawal (8%), and death (8%).

All ofatumumab-treated patients discontinued treatment by the time of data cutoff, and 67% had completed treatment as per protocol. Others discontinued due to disease progression (20%), subject withdrawal (5%), and AEs (4%).

Eight (5%) duvelisib patients crossed over to ofatumumab therapy at the time of disease progression, and 89 (57%) ofatumumab-treated patients crossed over to duvelisib.

Nearly all patients in both arms experienced an AE.

The most common hematologic malignancies with duvelisib and ofatumumab, respectively, occurring in 10% or more patients were neutropenia (33%, 21%), anemia (23%, 10%), and thrombocytopenia (15%, 6%).

The most common nonhematologic AES with duvelisib were diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%).

With ofatumumab, the most common nonhematologic AES were infusion-related reaction (19%), cough (14%), and diarrhea, rash, and fatigue (12% each).

Grade 3 or greater AEs occurred in 87% of duvelisib-treated patients and 48% in the ofatumumab arm.

The most common grade 3 or greater events with duvelisib were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%).

With ofatumumab, only neutropenia (17%) of grade 3 or higher occurred in 10% or more patients.

Severe immune-related toxicities with duvelisib included colitis (12%) and pneumonitis, alanine transaminase (ALT) or aspartate transaminase (AST) increase (3% each). The events were managed with dose interruptions and steroid therapy for pneumonitis or colitis. All reported events resolved, and none was fatal.

Infectious AEs occurred more frequently with duvelisib, 69% compared to 43% in the ofatumumab arm. Pneumonia (18%) and upper respiratory tract infection (16%) were the most common events.

Three patients in the duvelisib arm and 1 in the ofatumumab arm contracted Pneumocystis jirovecii.

The most frequently reported serious AE was pneumonia (duvelisib 15%; ofatumumab 3%).

Nineteen fatal AEs occurred in patients on the duvelisib arm, 4 of which were related to the study drug: staphylococcal pneumonia (n = 2), sepsis (n=1), and general health deterioration (n = 1).

Seven fatal AEs occurred in patients on the ofatumumab arm, although none was attributed to ofatumumab.

The DUO trial was sponsored by Verastem Oncology and Infinity Pharmaceuticals , Inc. 

Photo from Sarah Cannon

Final analysis of the phase 3 DUO trial has shown monotherapy with oral duvelisib results in a statistically significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to monotherapy with ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia/small lympchocytic lymphoma (CLL/SLL).

PFS for all patients as assessed by Independent Review Committee (IRC) was a median 13.3 months with duvelisib compared to 9.9 months with ofatumumab (P<0.0001).

ORR was significantly higher with duvelisib, 74% compared to 45%, P<0.0001, regardless of deletion 17p status.

Duvelisib (Copiktra™) was recently approved by the U.S. Food and Drug Administration for CLL/SLL based in part on this head-to-head trial.

The investigators reported the results in Blood.

"The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies," said principal investigator Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute in Nashville.

"Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options."

Duvelisib is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and -γ, which means it blocks the survival and proliferation of malignant B cells and also disrupts the recruitment and differentiation of T cells and macrophages within the tumor microenvironment.

Ofatumumab is a humanized anti-CD20 antibody with single-agent efficacy in refractory CLL. It is approved by the FDA as a treatment option in CLL.

Study design

Investigators randomized 319 relapsed or refractory CLL/SLL patients, 160 to the duvelisib arm and 159 to the ofatumumab arm.

Patients in the duvelisib arm self-administered 25 mg capsules twice daily continuously in 28-day cycles. They could take duvelisib for up to 18 cycles, until disease progression or unacceptable toxicity.

Ofatumumab-treated patients received infusions as approved in the product labeling for monotherapy in relapsed CLL. Dosing of ofatumumab could not exceed 12 doses in 7 cycles.

Prophylaxis for Pneumocystis jirovecci was required for all patients on both treatment arms.

Patients were allowed to crossover to a separate extension study to receive the opposite therapy if they had progressive disease.

They were followed for a median of 22.4 months.

Patient characteristics

According to the investigators, patient characteristics were well balanced between the arms.

The majority (60%) were male and the median age in both arms was 69. Most had an ECOG performance status of 0 or 1; 7% in the duvelisib arm and 10% in the ofatumumab arm had a performance status of 2.

Other patient characteristics in the duvelisib and ofatumumab arms, respectively, were:

• Time from initial diagnosis: 7.5 years, 6.7 years
• CLL/SLL, %: 97/5, 99/2
• Bulky disease: 46%, 45%
• Baseline lymphocyte counts: 38x109/L, 35x109/L
• Deletion 17p and/or TP53 mutation: 31%, 33%
• Median number of prior therapies: 2 in each arm
• Previous alkylating agent: 93%, 95%
• Previous monoclonal antibody: 78%, 83%
• Prior purine analog: 60%, 71%

Of the total patients enrolled, 158 patients in the duvelisib arm and 155 in the ofatumumab arm received treatment, for a median exposure of 50 weeks and 23 weeks, respectively.

Efficacy

In addition to the significantly improved overall PFS and ORR with duvelisib, further analysis revealed that PFS also improved for all predefined subgroups.

High-risk patients with deletion 17p/TP53 mutations also experienced a significant improvement in PFS with duvelisib of 12.7 months compared to 9.0 months with ofatumumab by IRC (P=0.0002).

The estimated probability of being progression-free for these patients at 6 and 12 moths was 73% and 55% with duvelisib and 63% and 30% with ofatumumab.

The investigators pointed out that duvelisib treatment was particularly effective in eliciting a lymph node response—85.0% compared to 15.7% with ofatumumab as assessed by IRC (P<0.0001).

Median overall survival was not reached in either arm. The 12-month probability of survival was 86% for both treatments.

Safety

Median treatment exposure was almost twice as long in the duvelisib arm because ofatumumab treatment was not allowed to exceed 12 doses as specified in the prescribing information.

The investigators explained this resulted in a longer adverse event (AE) reporting period for duvelisib.

One hundred twenty-four duvelisib-treated patients discontinued treatment, most commonly due to AEs (35%), disease progression (22%), subject withdrawal (8%), and death (8%).

All ofatumumab-treated patients discontinued treatment by the time of data cutoff, and 67% had completed treatment as per protocol. Others discontinued due to disease progression (20%), subject withdrawal (5%), and AEs (4%).

Eight (5%) duvelisib patients crossed over to ofatumumab therapy at the time of disease progression, and 89 (57%) ofatumumab-treated patients crossed over to duvelisib.

Nearly all patients in both arms experienced an AE.

The most common hematologic malignancies with duvelisib and ofatumumab, respectively, occurring in 10% or more patients were neutropenia (33%, 21%), anemia (23%, 10%), and thrombocytopenia (15%, 6%).

The most common nonhematologic AES with duvelisib were diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%).

With ofatumumab, the most common nonhematologic AES were infusion-related reaction (19%), cough (14%), and diarrhea, rash, and fatigue (12% each).

Grade 3 or greater AEs occurred in 87% of duvelisib-treated patients and 48% in the ofatumumab arm.

The most common grade 3 or greater events with duvelisib were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%).

With ofatumumab, only neutropenia (17%) of grade 3 or higher occurred in 10% or more patients.

Severe immune-related toxicities with duvelisib included colitis (12%) and pneumonitis, alanine transaminase (ALT) or aspartate transaminase (AST) increase (3% each). The events were managed with dose interruptions and steroid therapy for pneumonitis or colitis. All reported events resolved, and none was fatal.

Infectious AEs occurred more frequently with duvelisib, 69% compared to 43% in the ofatumumab arm. Pneumonia (18%) and upper respiratory tract infection (16%) were the most common events.

Three patients in the duvelisib arm and 1 in the ofatumumab arm contracted Pneumocystis jirovecii.

The most frequently reported serious AE was pneumonia (duvelisib 15%; ofatumumab 3%).

Nineteen fatal AEs occurred in patients on the duvelisib arm, 4 of which were related to the study drug: staphylococcal pneumonia (n = 2), sepsis (n=1), and general health deterioration (n = 1).

Seven fatal AEs occurred in patients on the ofatumumab arm, although none was attributed to ofatumumab.

The DUO trial was sponsored by Verastem Oncology and Infinity Pharmaceuticals , Inc. 

Photo from Sarah Cannon

Final analysis of the phase 3 DUO trial has shown monotherapy with oral duvelisib results in a statistically significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to monotherapy with ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia/small lympchocytic lymphoma (CLL/SLL).

PFS for all patients as assessed by Independent Review Committee (IRC) was a median 13.3 months with duvelisib compared to 9.9 months with ofatumumab (P<0.0001).

ORR was significantly higher with duvelisib, 74% compared to 45%, P<0.0001, regardless of deletion 17p status.

Duvelisib (Copiktra™) was recently approved by the U.S. Food and Drug Administration for CLL/SLL based in part on this head-to-head trial.

The investigators reported the results in Blood.

"The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies," said principal investigator Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute in Nashville.

"Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options."

Duvelisib is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and -γ, which means it blocks the survival and proliferation of malignant B cells and also disrupts the recruitment and differentiation of T cells and macrophages within the tumor microenvironment.

Ofatumumab is a humanized anti-CD20 antibody with single-agent efficacy in refractory CLL. It is approved by the FDA as a treatment option in CLL.

Study design

Investigators randomized 319 relapsed or refractory CLL/SLL patients, 160 to the duvelisib arm and 159 to the ofatumumab arm.

Patients in the duvelisib arm self-administered 25 mg capsules twice daily continuously in 28-day cycles. They could take duvelisib for up to 18 cycles, until disease progression or unacceptable toxicity.

Ofatumumab-treated patients received infusions as approved in the product labeling for monotherapy in relapsed CLL. Dosing of ofatumumab could not exceed 12 doses in 7 cycles.

Prophylaxis for Pneumocystis jirovecci was required for all patients on both treatment arms.

Patients were allowed to crossover to a separate extension study to receive the opposite therapy if they had progressive disease.

They were followed for a median of 22.4 months.

Patient characteristics

According to the investigators, patient characteristics were well balanced between the arms.

The majority (60%) were male and the median age in both arms was 69. Most had an ECOG performance status of 0 or 1; 7% in the duvelisib arm and 10% in the ofatumumab arm had a performance status of 2.

Other patient characteristics in the duvelisib and ofatumumab arms, respectively, were:

• Time from initial diagnosis: 7.5 years, 6.7 years
• CLL/SLL, %: 97/5, 99/2
• Bulky disease: 46%, 45%
• Baseline lymphocyte counts: 38x109/L, 35x109/L
• Deletion 17p and/or TP53 mutation: 31%, 33%
• Median number of prior therapies: 2 in each arm
• Previous alkylating agent: 93%, 95%
• Previous monoclonal antibody: 78%, 83%
• Prior purine analog: 60%, 71%

Of the total patients enrolled, 158 patients in the duvelisib arm and 155 in the ofatumumab arm received treatment, for a median exposure of 50 weeks and 23 weeks, respectively.

Efficacy

In addition to the significantly improved overall PFS and ORR with duvelisib, further analysis revealed that PFS also improved for all predefined subgroups.

High-risk patients with deletion 17p/TP53 mutations also experienced a significant improvement in PFS with duvelisib of 12.7 months compared to 9.0 months with ofatumumab by IRC (P=0.0002).

The estimated probability of being progression-free for these patients at 6 and 12 moths was 73% and 55% with duvelisib and 63% and 30% with ofatumumab.

The investigators pointed out that duvelisib treatment was particularly effective in eliciting a lymph node response—85.0% compared to 15.7% with ofatumumab as assessed by IRC (P<0.0001).

Median overall survival was not reached in either arm. The 12-month probability of survival was 86% for both treatments.

Safety

Median treatment exposure was almost twice as long in the duvelisib arm because ofatumumab treatment was not allowed to exceed 12 doses as specified in the prescribing information.

The investigators explained this resulted in a longer adverse event (AE) reporting period for duvelisib.

One hundred twenty-four duvelisib-treated patients discontinued treatment, most commonly due to AEs (35%), disease progression (22%), subject withdrawal (8%), and death (8%).

All ofatumumab-treated patients discontinued treatment by the time of data cutoff, and 67% had completed treatment as per protocol. Others discontinued due to disease progression (20%), subject withdrawal (5%), and AEs (4%).

Eight (5%) duvelisib patients crossed over to ofatumumab therapy at the time of disease progression, and 89 (57%) ofatumumab-treated patients crossed over to duvelisib.

Nearly all patients in both arms experienced an AE.

The most common hematologic malignancies with duvelisib and ofatumumab, respectively, occurring in 10% or more patients were neutropenia (33%, 21%), anemia (23%, 10%), and thrombocytopenia (15%, 6%).

The most common nonhematologic AES with duvelisib were diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%).

With ofatumumab, the most common nonhematologic AES were infusion-related reaction (19%), cough (14%), and diarrhea, rash, and fatigue (12% each).

Grade 3 or greater AEs occurred in 87% of duvelisib-treated patients and 48% in the ofatumumab arm.

The most common grade 3 or greater events with duvelisib were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%).

With ofatumumab, only neutropenia (17%) of grade 3 or higher occurred in 10% or more patients.

Severe immune-related toxicities with duvelisib included colitis (12%) and pneumonitis, alanine transaminase (ALT) or aspartate transaminase (AST) increase (3% each). The events were managed with dose interruptions and steroid therapy for pneumonitis or colitis. All reported events resolved, and none was fatal.

Infectious AEs occurred more frequently with duvelisib, 69% compared to 43% in the ofatumumab arm. Pneumonia (18%) and upper respiratory tract infection (16%) were the most common events.

Three patients in the duvelisib arm and 1 in the ofatumumab arm contracted Pneumocystis jirovecii.

The most frequently reported serious AE was pneumonia (duvelisib 15%; ofatumumab 3%).

Nineteen fatal AEs occurred in patients on the duvelisib arm, 4 of which were related to the study drug: staphylococcal pneumonia (n = 2), sepsis (n=1), and general health deterioration (n = 1).

Seven fatal AEs occurred in patients on the ofatumumab arm, although none was attributed to ofatumumab.

The DUO trial was sponsored by Verastem Oncology and Infinity Pharmaceuticals , Inc. 

Mantle cell lymphoma

Long-term results of a phase 2 clinical trial of the lenalidomide and rituximab combination as first-line therapy for mantle cell lymphoma (MCL) show continued durable responses with manageable toxicities after 5 years.

With a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University in New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote.

Their report was published in Blood.

In the multicenter, phase 2 single-arm study (NCT01472562), 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase.

Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Results

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P=0.04).

Safety

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption.

Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting,” the investigators wrote, “lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach.”

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. 

Mantle cell lymphoma

Long-term results of a phase 2 clinical trial of the lenalidomide and rituximab combination as first-line therapy for mantle cell lymphoma (MCL) show continued durable responses with manageable toxicities after 5 years.

With a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University in New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote.

Their report was published in Blood.

In the multicenter, phase 2 single-arm study (NCT01472562), 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase.

Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Results

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P=0.04).

Safety

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption.

Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting,” the investigators wrote, “lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach.”

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. 

Mantle cell lymphoma

Long-term results of a phase 2 clinical trial of the lenalidomide and rituximab combination as first-line therapy for mantle cell lymphoma (MCL) show continued durable responses with manageable toxicities after 5 years.

With a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University in New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote.

Their report was published in Blood.

In the multicenter, phase 2 single-arm study (NCT01472562), 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase.

Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Results

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P=0.04).

Safety

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption.

Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting,” the investigators wrote, “lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach.”

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. 

NEW YORK – Ibrutinib, and now moxetumomab pasudotox, are two novel therapies that can be tried in patients with previously treated hairy cell leukemia, although data and experience with them are so far limited in this rare disease, experts said during a panel discussion at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Since there are so few patients, data on the BTK inhibitor ibrutinib in hairy cell leukemia is largely “anecdotal,” said Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

The anti-CD22 monoclonal antibody moxetumomab pasudotox – approved for hairy cell leukemia in September – isn’t yet on the formulary at Memorial Sloan Kettering, Dr. Zelenetz added in a panel discussion of treatment options for a patient previously treated with purine analogueues and vemurafenib.

Between the two agents, moxetumomab pasudotox has more robust data in this disease, said John N. Allan, MD, of Weill Cornell Medicine, New York.

“I think if you can get access to the drug, that’s probably the best answer,” Dr. Allan said in the case discussion.

Hairy cell leukemia is an indolent B-cell lymphoma that makes up just 2% of all lymphoid leukemias, according to NCCN guidelines.

It is a chronic disease that requires long-term management, according to Dr. Allan.

First-line treatment is usually a purine analogue, either cladribine or pentostatin, and multiple treatments are possible as long as responses of greater than 2 years are achieved, he told attendees at the NCCN conference.

For relapses more than 2 years after first-line treatment, patients can be retreated with the same purine analogue, with or without rituximab, or can be switched to the alternative purine analogue, he said.

Vemurafenib, the BRAF inhibitor, is “surprisingly” effective in 90% of classic hairy cell leukemia patients with the BRAF V600E mutation, Dr. Allan added, though only about 40% of patients achieve complete response.

In discussing therapy options for a hairy cell leukemia patient previously treated with purine analogues and vemurafenib, Dr. Allan noted that the data behind ibrutinib includes case reports and early clinical investigations.

Several phase 1 studies with small numbers of patients show response rates “in the 50% range,” he said.

“This is an option,” he said. “It’s in the guidelines, and it’s something to consider.”

Moxetumomab pasudotox was recently approved for intravenous use in adults with relapsed or refractory hairy cell leukemia who have had at least two previous systemic treatments, including a purine nucleoside analogue. The CD22-directed cytotoxin is the first of its kind for treating patients with hairy cell leukemia, according to the Food and Drug Administration.

In a single-arm, open-label clinical trial including 80 patients with hairy cell leukemia who had previous treatment in line with that indication, 75% had a partial or complete response, of whom 30% had a durable complete response (CR), defined as maintaining hematologic remission for at least 180 days following CR.

Following the FDA’s approval of moxetumomab pasudotox, the NCCN updated its hairy cell leukemia clinical practice guidelines to include the drug as a category 2A recommendation for relapsed/refractory treatment. Other category 2A options in that setting include ibrutinib, vemurafenib with or without rituximab, or a clinical trial.

Along with that, NCCN guideline authors added a full page on special considerations for use of moxetumomab pasudotox. That includes advice on monitoring for capillary leak syndrome and hemolytic uremic syndrome, along with guidance on capillary leak syndrome grading and management by grade.

Dr. Zelenetz reported financial disclosures related to Adaptive Biotechnology, Amgen, AstraZeneca, Celgene, Genentech, Gilead, Hoffman La Roche, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Roche, and Verastem Oncology. Dr. Allan reported disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis, and Verastem Oncology.

NEW YORK – Ibrutinib, and now moxetumomab pasudotox, are two novel therapies that can be tried in patients with previously treated hairy cell leukemia, although data and experience with them are so far limited in this rare disease, experts said during a panel discussion at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Since there are so few patients, data on the BTK inhibitor ibrutinib in hairy cell leukemia is largely “anecdotal,” said Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

The anti-CD22 monoclonal antibody moxetumomab pasudotox – approved for hairy cell leukemia in September – isn’t yet on the formulary at Memorial Sloan Kettering, Dr. Zelenetz added in a panel discussion of treatment options for a patient previously treated with purine analogueues and vemurafenib.

Between the two agents, moxetumomab pasudotox has more robust data in this disease, said John N. Allan, MD, of Weill Cornell Medicine, New York.

“I think if you can get access to the drug, that’s probably the best answer,” Dr. Allan said in the case discussion.

Hairy cell leukemia is an indolent B-cell lymphoma that makes up just 2% of all lymphoid leukemias, according to NCCN guidelines.

It is a chronic disease that requires long-term management, according to Dr. Allan.

First-line treatment is usually a purine analogue, either cladribine or pentostatin, and multiple treatments are possible as long as responses of greater than 2 years are achieved, he told attendees at the NCCN conference.

For relapses more than 2 years after first-line treatment, patients can be retreated with the same purine analogue, with or without rituximab, or can be switched to the alternative purine analogue, he said.

Vemurafenib, the BRAF inhibitor, is “surprisingly” effective in 90% of classic hairy cell leukemia patients with the BRAF V600E mutation, Dr. Allan added, though only about 40% of patients achieve complete response.

In discussing therapy options for a hairy cell leukemia patient previously treated with purine analogues and vemurafenib, Dr. Allan noted that the data behind ibrutinib includes case reports and early clinical investigations.

Several phase 1 studies with small numbers of patients show response rates “in the 50% range,” he said.

“This is an option,” he said. “It’s in the guidelines, and it’s something to consider.”

Moxetumomab pasudotox was recently approved for intravenous use in adults with relapsed or refractory hairy cell leukemia who have had at least two previous systemic treatments, including a purine nucleoside analogue. The CD22-directed cytotoxin is the first of its kind for treating patients with hairy cell leukemia, according to the Food and Drug Administration.

In a single-arm, open-label clinical trial including 80 patients with hairy cell leukemia who had previous treatment in line with that indication, 75% had a partial or complete response, of whom 30% had a durable complete response (CR), defined as maintaining hematologic remission for at least 180 days following CR.

Following the FDA’s approval of moxetumomab pasudotox, the NCCN updated its hairy cell leukemia clinical practice guidelines to include the drug as a category 2A recommendation for relapsed/refractory treatment. Other category 2A options in that setting include ibrutinib, vemurafenib with or without rituximab, or a clinical trial.

Along with that, NCCN guideline authors added a full page on special considerations for use of moxetumomab pasudotox. That includes advice on monitoring for capillary leak syndrome and hemolytic uremic syndrome, along with guidance on capillary leak syndrome grading and management by grade.

Dr. Zelenetz reported financial disclosures related to Adaptive Biotechnology, Amgen, AstraZeneca, Celgene, Genentech, Gilead, Hoffman La Roche, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Roche, and Verastem Oncology. Dr. Allan reported disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis, and Verastem Oncology.

NEW YORK – Ibrutinib, and now moxetumomab pasudotox, are two novel therapies that can be tried in patients with previously treated hairy cell leukemia, although data and experience with them are so far limited in this rare disease, experts said during a panel discussion at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Since there are so few patients, data on the BTK inhibitor ibrutinib in hairy cell leukemia is largely “anecdotal,” said Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

The anti-CD22 monoclonal antibody moxetumomab pasudotox – approved for hairy cell leukemia in September – isn’t yet on the formulary at Memorial Sloan Kettering, Dr. Zelenetz added in a panel discussion of treatment options for a patient previously treated with purine analogueues and vemurafenib.

Between the two agents, moxetumomab pasudotox has more robust data in this disease, said John N. Allan, MD, of Weill Cornell Medicine, New York.

“I think if you can get access to the drug, that’s probably the best answer,” Dr. Allan said in the case discussion.

Hairy cell leukemia is an indolent B-cell lymphoma that makes up just 2% of all lymphoid leukemias, according to NCCN guidelines.

It is a chronic disease that requires long-term management, according to Dr. Allan.

First-line treatment is usually a purine analogue, either cladribine or pentostatin, and multiple treatments are possible as long as responses of greater than 2 years are achieved, he told attendees at the NCCN conference.

For relapses more than 2 years after first-line treatment, patients can be retreated with the same purine analogue, with or without rituximab, or can be switched to the alternative purine analogue, he said.

Vemurafenib, the BRAF inhibitor, is “surprisingly” effective in 90% of classic hairy cell leukemia patients with the BRAF V600E mutation, Dr. Allan added, though only about 40% of patients achieve complete response.

In discussing therapy options for a hairy cell leukemia patient previously treated with purine analogues and vemurafenib, Dr. Allan noted that the data behind ibrutinib includes case reports and early clinical investigations.

Several phase 1 studies with small numbers of patients show response rates “in the 50% range,” he said.

“This is an option,” he said. “It’s in the guidelines, and it’s something to consider.”

Moxetumomab pasudotox was recently approved for intravenous use in adults with relapsed or refractory hairy cell leukemia who have had at least two previous systemic treatments, including a purine nucleoside analogue. The CD22-directed cytotoxin is the first of its kind for treating patients with hairy cell leukemia, according to the Food and Drug Administration.

In a single-arm, open-label clinical trial including 80 patients with hairy cell leukemia who had previous treatment in line with that indication, 75% had a partial or complete response, of whom 30% had a durable complete response (CR), defined as maintaining hematologic remission for at least 180 days following CR.

Following the FDA’s approval of moxetumomab pasudotox, the NCCN updated its hairy cell leukemia clinical practice guidelines to include the drug as a category 2A recommendation for relapsed/refractory treatment. Other category 2A options in that setting include ibrutinib, vemurafenib with or without rituximab, or a clinical trial.

Along with that, NCCN guideline authors added a full page on special considerations for use of moxetumomab pasudotox. That includes advice on monitoring for capillary leak syndrome and hemolytic uremic syndrome, along with guidance on capillary leak syndrome grading and management by grade.

Dr. Zelenetz reported financial disclosures related to Adaptive Biotechnology, Amgen, AstraZeneca, Celgene, Genentech, Gilead, Hoffman La Roche, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Roche, and Verastem Oncology. Dr. Allan reported disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis, and Verastem Oncology.

As technology continues to advance, so too does its accessibility to the general population. In 2013, 56% of Americans owned a smartphone versus 77% in 2017.¹With the increase in mobile applications (apps) available, it is no surprise that the market has extended into the medical field, with dermatology being no exception.² The majority of dermatology apps can be classified as teledermatology apps, followed by self-surveillance, disease guide, and reference apps. Additional types of dermatology apps include dermoscopy, conference, education, photograph storage and sharing, and journal apps, and others.² In this study, we examined Apple App Store rankings to determine the types of dermatology apps that are most popular among patients and physicians.

METHODS

A popular app rankings analyzer (App Annie) was used to search for dermatology apps along with their App Store rankings.³ Although iOS is not the most popular mobile device operating system, we chose to evaluate app rankings via the App Store because iPhones are the top-selling individual phones of any kind in the United States.⁴

We performed our analysis on a single day (July 14, 2018) given that app rankings can change daily. We incorporated the following keywords, which were commonly used in other dermatology app studies: dermatology, psoriasis, rosacea, acne, skin cancer, melanoma, eczema, and teledermatology. The category ranking was defined as the rank of a free or paid app in the App Store’s top charts for the selected country (United States), market (Apple), and device (iPhone) within their app category (Medical). Inclusion criteria required a ranking in the top 1500 Medical apps and being categorized in the App Store as a Medical app. Exclusion criteria included apps that focused on cosmetics, private practice, direct advertisements, photograph editing, or claims to cure skin disease, as well as non–English-language apps. The App Store descriptions were assessed to determine the type of each app (eg, teledermatology, disease guide) and target audience (patient, physician, or both).

Another search was performed using the same keywords but within the Health and Fitness category to capture potentially more highly ranked apps among patients. We also conducted separate searches within the Medical category using the keywords billing, coding, and ICD (International Classification of Diseases) to evaluate rankings for billing/coding apps, as well as EMR and electronic medical records for electronic medical record (EMR) apps.

RESULTS

The initial search yielded 851 results, which was narrowed down to 29 apps after applying the exclusion criteria. Of note, prior to application of the exclusion criteria, one dermatology app that was considered to be a direct advertisement app claiming to cure acne was ranked fourth of 1500 apps in the Medical category. However, the majority of the search results were excluded because they were not popular enough to be ranked among the top 1500 apps. There were more ranked dermatology apps in the Medical category targeting patients than physicians; 18 of 29 (62%) qualifying apps targeted patients and 11 (38%) targeted physicians (Tables 1 and 2). No apps targeted both groups. The most common type of ranked app targeting patients was self-surveillance (11/18), and the most common type targeting physicians was reference (8/11). The highest ranked app targeting patients was a teledermatology app with a ranking of 184, and the highest ranked app targeting physicians was educational, ranked 353. The least common type of ranked apps targeting patients were “other” (2/18 [11%]; 1 prescription and 1 UV monitor app) and conference (1/18 [6%]). The least common type of ranked apps targeting physicians were education (2/11 [18%]) and dermoscopy (1/11 [9%]).

Our search of the Health and Fitness category yielded 6 apps, all targeting patients; 3 (50%) were self-surveillance apps, and 3 (50%) were classified as other (2 UV monitors and a conferencing app for cancer emotional support)(Table 3).

Our search of the Medical category for billing/coding and EMR apps yielded 232 and 164 apps, respectively; of them, 49 (21%) and 54 (33%) apps were ranked. These apps did not overlap with the dermatology-related search criteria; thus, we were not able to ascertain how many of these apps were used specifically by health care providers in dermatology.

COMMENT

Patient Apps

The most common apps used by patients are fitness and nutrition tracker apps categorized as Health and Fitness^5,6; however, the majority of ranked dermatology apps are categorized as Medical per our findings. In a study of 557 dermatology patients, it was found that among the health-related apps they used, the most common apps after fitness/nutrition were references, followed by patient portals, self-surveillance, and emotional assistance apps.⁶ Our search was consistent with these findings, suggesting that the most desired dermatology apps by patients are those that allow them to be proactive with their health. It is no surprise that the top-ranked app targeting patients was a teledermatology app, followed by multiple self-surveillance apps. The highest ranked self-surveillance app in the Health and Fitness category focused on monitoring the effects of nutrition on symptoms of diseases including skin disorders, while the highest ranked (as well as the majority of) self-surveillance apps in the Medical category encompassed mole monitoring and cancer risk calculators.

Benefits of the ranked dermatology apps in the Medical and Health and Fitness categories targeting patients include more immediate access to health care and education. Despite this popularity among patients, Masud et al⁷ demonstrated that only 20.5% (9/44) of dermatology apps targeting patients may be reliable resources based on a rubric created by the investigators. Overall, there remains a research gap for a standardized scientific approach to evaluating app validity and reliability.

Teledermatology
Teledermatology apps are the most common dermatology apps,² allowing for remote evaluation of patients through either live consultations or transmittance of medical information for later review by board-certified physicians.⁸ Features common to many teledermatology apps include accessibility on Android (Google Inc) and iOS as well as a web version. Security and Health Insurance Portability and Accountability Act compliance is especially important and is enforced through user authentications, data encryption, and automatic logout features. Data is not stored locally and is secured on a private server with backup. Referring providers and consultants often can communicate within the app. Insurance providers also may cover teledermatology services, and if not, the out-of-pocket costs often are affordable.

The highest-ranked patient app (ranked 184 in the Medical category) was a teledermatology app that did not meet the American Telemedicine Association standards for teledermatology apps.⁹ The popularity of this app among patients may have been attributable to multiple ease-of-use and turnaround time features. The user interface was simplistic, and the design was appealing to the eye. The entry field options were minimal to avoid confusion. The turnaround time to receive a diagnosis depended on 1 of 3 options, including a more rapid response for an increased cost. Ease of use was the highlight of this app at the cost of accuracy, as the limited amount of information that users were required to provide physicians compromised diagnostic accuracy in this app.

For comparison, we chose a nonranked (and thus less frequently used) teledermatology app that had previously undergone scientific evaluation using 13 evaluation criteria specific to teledermatology.¹⁰ The app also met the American Telemedicine Association standard for teledermatology apps.⁹ The app was originally a broader telemedicine app but featured a section specific to teledermatology. The user interface was simple but professional, almost resembling an EMR. The input fields included a comprehensive history that permitted a better evaluation of a lesion but might be tedious for users. This app boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.

Striking a balance between ensuring proper care versus appealing to patients is a difficult but important task. Based on this study, it appears that popular patient apps may in fact have less scientific rationale and therefore potentially less accuracy.

Self-surveillance
Although self-surveillance apps did not account for the highest-ranked app, they were the most frequently ranked app type in our study. Most of the ranked self-surveillance apps in the Medical category were for monitoring lesions over time to assess for changes. These apps help users take photographs that are well organized in a single, easy-to-find location. Some apps were risk calculators that assessed the risk for malignancies using a questionnaire. The majority of these self-surveillance apps were specific to skin cancer detection. Of note, one of the ranked self-surveillance apps assessed drug effectiveness by monitoring clinical appearance and symptoms. The lowest ranked self-surveillance app in the top 1500 ranked Medical apps in our search monitored cancer symptoms not specific to dermatology. Although this app had a low ranking (1380/1500), it received a high number of reviews and was well rated at 4.8 out of 5 stars; therefore, it seemed more helpful than the other higher-ranked apps targeting patients, which had higher rankings but minimal to no reviews or ratings. A comparison of the ease-of-use features of all the ranked patient-targeted self-surveillance apps in the Medical category is provided in Table 4.

Physician Apps

After examining the results of apps targeting physicians, we realized that the data may be accurate but may not be as representative of all currently practicing dermatology providers. Given the increased usage of apps among younger age groups,¹¹ our data may be skewed toward medical students and residents, supported by the fact that the top-ranked physician app in our study was an education app and the majority were reference apps. Future studies are needed to reexamine app ranking as this age group transitions from entry-level health care providers in the next 5 to 10 years. These findings also suggest less frequent app use among more veteran health care providers within our specific search parameters. Therefore, we decided to do subsequent searches for available billing/coding and EMR apps, which were many, but as mentioned above, none were specific to dermatology.

General Dermatology References
Most of the dermatology reference apps were formatted as e-books; however, other apps such as the Amazon Kindle app (categorized under Books) providing access to multiple e-books within one app were not included. Some apps included study aid features (eg, flash cards, quizzes), and topics spanned both dermatology and dermatopathology. Apps provide a unique way for on-the-go studying for dermatologists in training, and if the usage continues to grow, there may be a need for increased formal integration in dermatology education in the future.

Journals
Journal apps were not among those listed in the top-ranked apps we evaluated, which we suspect may be because journals were categorized differently from one journal to the next; for example, the Journal of the American Academy of Dermatology was ranked 1168 in the Magazines and Newspapers category. On the other hand, Dermatology World was ranked 1363 in the Reference category. An article’s citation affects the publishing journal’s impact factor, which is one of the most important variables in measuring a journal’s influence. In the future, there may be other variables that could aid in understanding journal impact as it relates to the journal’s accessibility.

Limitations

Our study did not look at Android apps. The top chart apps in the Android and Apple App Stores use undisclosed algorithms likely involving different characteristics such as number of downloads, frequency of updates, number of reviews, ratings, and more. Thus, the rankings across these different markets would not be comparable. Although our choice of keywords stemmed from the majority of prior studies looking at dermatology apps, our search was limited due to the use of these specific keywords. To avoid skewing data by cross-comparison of noncomparable categories, we could not compare apps in the Medical category versus those in other categories.

CONCLUSION

There seems to be a disconnect between the apps that are popular among patients and the scientific validity of the apps. As app usage increases among dermatology providers, whose demographic is shifting younger and younger, apps may become more incorporated in our education, and as such, it will become more critical to develop formal scientific standards. Given these future trends, we may need to increase our current literature and understanding of apps in dermatology with regard to their impact on both patients and health care providers.

As technology continues to advance, so too does its accessibility to the general population. In 2013, 56% of Americans owned a smartphone versus 77% in 2017.¹With the increase in mobile applications (apps) available, it is no surprise that the market has extended into the medical field, with dermatology being no exception.² The majority of dermatology apps can be classified as teledermatology apps, followed by self-surveillance, disease guide, and reference apps. Additional types of dermatology apps include dermoscopy, conference, education, photograph storage and sharing, and journal apps, and others.² In this study, we examined Apple App Store rankings to determine the types of dermatology apps that are most popular among patients and physicians.

METHODS

A popular app rankings analyzer (App Annie) was used to search for dermatology apps along with their App Store rankings.³ Although iOS is not the most popular mobile device operating system, we chose to evaluate app rankings via the App Store because iPhones are the top-selling individual phones of any kind in the United States.⁴

We performed our analysis on a single day (July 14, 2018) given that app rankings can change daily. We incorporated the following keywords, which were commonly used in other dermatology app studies: dermatology, psoriasis, rosacea, acne, skin cancer, melanoma, eczema, and teledermatology. The category ranking was defined as the rank of a free or paid app in the App Store’s top charts for the selected country (United States), market (Apple), and device (iPhone) within their app category (Medical). Inclusion criteria required a ranking in the top 1500 Medical apps and being categorized in the App Store as a Medical app. Exclusion criteria included apps that focused on cosmetics, private practice, direct advertisements, photograph editing, or claims to cure skin disease, as well as non–English-language apps. The App Store descriptions were assessed to determine the type of each app (eg, teledermatology, disease guide) and target audience (patient, physician, or both).

Another search was performed using the same keywords but within the Health and Fitness category to capture potentially more highly ranked apps among patients. We also conducted separate searches within the Medical category using the keywords billing, coding, and ICD (International Classification of Diseases) to evaluate rankings for billing/coding apps, as well as EMR and electronic medical records for electronic medical record (EMR) apps.

RESULTS

The initial search yielded 851 results, which was narrowed down to 29 apps after applying the exclusion criteria. Of note, prior to application of the exclusion criteria, one dermatology app that was considered to be a direct advertisement app claiming to cure acne was ranked fourth of 1500 apps in the Medical category. However, the majority of the search results were excluded because they were not popular enough to be ranked among the top 1500 apps. There were more ranked dermatology apps in the Medical category targeting patients than physicians; 18 of 29 (62%) qualifying apps targeted patients and 11 (38%) targeted physicians (Tables 1 and 2). No apps targeted both groups. The most common type of ranked app targeting patients was self-surveillance (11/18), and the most common type targeting physicians was reference (8/11). The highest ranked app targeting patients was a teledermatology app with a ranking of 184, and the highest ranked app targeting physicians was educational, ranked 353. The least common type of ranked apps targeting patients were “other” (2/18 [11%]; 1 prescription and 1 UV monitor app) and conference (1/18 [6%]). The least common type of ranked apps targeting physicians were education (2/11 [18%]) and dermoscopy (1/11 [9%]).

Our search of the Health and Fitness category yielded 6 apps, all targeting patients; 3 (50%) were self-surveillance apps, and 3 (50%) were classified as other (2 UV monitors and a conferencing app for cancer emotional support)(Table 3).

Our search of the Medical category for billing/coding and EMR apps yielded 232 and 164 apps, respectively; of them, 49 (21%) and 54 (33%) apps were ranked. These apps did not overlap with the dermatology-related search criteria; thus, we were not able to ascertain how many of these apps were used specifically by health care providers in dermatology.

COMMENT

Patient Apps

The most common apps used by patients are fitness and nutrition tracker apps categorized as Health and Fitness^5,6; however, the majority of ranked dermatology apps are categorized as Medical per our findings. In a study of 557 dermatology patients, it was found that among the health-related apps they used, the most common apps after fitness/nutrition were references, followed by patient portals, self-surveillance, and emotional assistance apps.⁶ Our search was consistent with these findings, suggesting that the most desired dermatology apps by patients are those that allow them to be proactive with their health. It is no surprise that the top-ranked app targeting patients was a teledermatology app, followed by multiple self-surveillance apps. The highest ranked self-surveillance app in the Health and Fitness category focused on monitoring the effects of nutrition on symptoms of diseases including skin disorders, while the highest ranked (as well as the majority of) self-surveillance apps in the Medical category encompassed mole monitoring and cancer risk calculators.

Benefits of the ranked dermatology apps in the Medical and Health and Fitness categories targeting patients include more immediate access to health care and education. Despite this popularity among patients, Masud et al⁷ demonstrated that only 20.5% (9/44) of dermatology apps targeting patients may be reliable resources based on a rubric created by the investigators. Overall, there remains a research gap for a standardized scientific approach to evaluating app validity and reliability.

Teledermatology
Teledermatology apps are the most common dermatology apps,² allowing for remote evaluation of patients through either live consultations or transmittance of medical information for later review by board-certified physicians.⁸ Features common to many teledermatology apps include accessibility on Android (Google Inc) and iOS as well as a web version. Security and Health Insurance Portability and Accountability Act compliance is especially important and is enforced through user authentications, data encryption, and automatic logout features. Data is not stored locally and is secured on a private server with backup. Referring providers and consultants often can communicate within the app. Insurance providers also may cover teledermatology services, and if not, the out-of-pocket costs often are affordable.

The highest-ranked patient app (ranked 184 in the Medical category) was a teledermatology app that did not meet the American Telemedicine Association standards for teledermatology apps.⁹ The popularity of this app among patients may have been attributable to multiple ease-of-use and turnaround time features. The user interface was simplistic, and the design was appealing to the eye. The entry field options were minimal to avoid confusion. The turnaround time to receive a diagnosis depended on 1 of 3 options, including a more rapid response for an increased cost. Ease of use was the highlight of this app at the cost of accuracy, as the limited amount of information that users were required to provide physicians compromised diagnostic accuracy in this app.

For comparison, we chose a nonranked (and thus less frequently used) teledermatology app that had previously undergone scientific evaluation using 13 evaluation criteria specific to teledermatology.¹⁰ The app also met the American Telemedicine Association standard for teledermatology apps.⁹ The app was originally a broader telemedicine app but featured a section specific to teledermatology. The user interface was simple but professional, almost resembling an EMR. The input fields included a comprehensive history that permitted a better evaluation of a lesion but might be tedious for users. This app boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.

Striking a balance between ensuring proper care versus appealing to patients is a difficult but important task. Based on this study, it appears that popular patient apps may in fact have less scientific rationale and therefore potentially less accuracy.

Self-surveillance
Although self-surveillance apps did not account for the highest-ranked app, they were the most frequently ranked app type in our study. Most of the ranked self-surveillance apps in the Medical category were for monitoring lesions over time to assess for changes. These apps help users take photographs that are well organized in a single, easy-to-find location. Some apps were risk calculators that assessed the risk for malignancies using a questionnaire. The majority of these self-surveillance apps were specific to skin cancer detection. Of note, one of the ranked self-surveillance apps assessed drug effectiveness by monitoring clinical appearance and symptoms. The lowest ranked self-surveillance app in the top 1500 ranked Medical apps in our search monitored cancer symptoms not specific to dermatology. Although this app had a low ranking (1380/1500), it received a high number of reviews and was well rated at 4.8 out of 5 stars; therefore, it seemed more helpful than the other higher-ranked apps targeting patients, which had higher rankings but minimal to no reviews or ratings. A comparison of the ease-of-use features of all the ranked patient-targeted self-surveillance apps in the Medical category is provided in Table 4.

Physician Apps

After examining the results of apps targeting physicians, we realized that the data may be accurate but may not be as representative of all currently practicing dermatology providers. Given the increased usage of apps among younger age groups,¹¹ our data may be skewed toward medical students and residents, supported by the fact that the top-ranked physician app in our study was an education app and the majority were reference apps. Future studies are needed to reexamine app ranking as this age group transitions from entry-level health care providers in the next 5 to 10 years. These findings also suggest less frequent app use among more veteran health care providers within our specific search parameters. Therefore, we decided to do subsequent searches for available billing/coding and EMR apps, which were many, but as mentioned above, none were specific to dermatology.

General Dermatology References
Most of the dermatology reference apps were formatted as e-books; however, other apps such as the Amazon Kindle app (categorized under Books) providing access to multiple e-books within one app were not included. Some apps included study aid features (eg, flash cards, quizzes), and topics spanned both dermatology and dermatopathology. Apps provide a unique way for on-the-go studying for dermatologists in training, and if the usage continues to grow, there may be a need for increased formal integration in dermatology education in the future.

Journals
Journal apps were not among those listed in the top-ranked apps we evaluated, which we suspect may be because journals were categorized differently from one journal to the next; for example, the Journal of the American Academy of Dermatology was ranked 1168 in the Magazines and Newspapers category. On the other hand, Dermatology World was ranked 1363 in the Reference category. An article’s citation affects the publishing journal’s impact factor, which is one of the most important variables in measuring a journal’s influence. In the future, there may be other variables that could aid in understanding journal impact as it relates to the journal’s accessibility.

Limitations

Our study did not look at Android apps. The top chart apps in the Android and Apple App Stores use undisclosed algorithms likely involving different characteristics such as number of downloads, frequency of updates, number of reviews, ratings, and more. Thus, the rankings across these different markets would not be comparable. Although our choice of keywords stemmed from the majority of prior studies looking at dermatology apps, our search was limited due to the use of these specific keywords. To avoid skewing data by cross-comparison of noncomparable categories, we could not compare apps in the Medical category versus those in other categories.

CONCLUSION

There seems to be a disconnect between the apps that are popular among patients and the scientific validity of the apps. As app usage increases among dermatology providers, whose demographic is shifting younger and younger, apps may become more incorporated in our education, and as such, it will become more critical to develop formal scientific standards. Given these future trends, we may need to increase our current literature and understanding of apps in dermatology with regard to their impact on both patients and health care providers.

As technology continues to advance, so too does its accessibility to the general population. In 2013, 56% of Americans owned a smartphone versus 77% in 2017.¹With the increase in mobile applications (apps) available, it is no surprise that the market has extended into the medical field, with dermatology being no exception.² The majority of dermatology apps can be classified as teledermatology apps, followed by self-surveillance, disease guide, and reference apps. Additional types of dermatology apps include dermoscopy, conference, education, photograph storage and sharing, and journal apps, and others.² In this study, we examined Apple App Store rankings to determine the types of dermatology apps that are most popular among patients and physicians.

METHODS

A popular app rankings analyzer (App Annie) was used to search for dermatology apps along with their App Store rankings.³ Although iOS is not the most popular mobile device operating system, we chose to evaluate app rankings via the App Store because iPhones are the top-selling individual phones of any kind in the United States.⁴

We performed our analysis on a single day (July 14, 2018) given that app rankings can change daily. We incorporated the following keywords, which were commonly used in other dermatology app studies: dermatology, psoriasis, rosacea, acne, skin cancer, melanoma, eczema, and teledermatology. The category ranking was defined as the rank of a free or paid app in the App Store’s top charts for the selected country (United States), market (Apple), and device (iPhone) within their app category (Medical). Inclusion criteria required a ranking in the top 1500 Medical apps and being categorized in the App Store as a Medical app. Exclusion criteria included apps that focused on cosmetics, private practice, direct advertisements, photograph editing, or claims to cure skin disease, as well as non–English-language apps. The App Store descriptions were assessed to determine the type of each app (eg, teledermatology, disease guide) and target audience (patient, physician, or both).

Another search was performed using the same keywords but within the Health and Fitness category to capture potentially more highly ranked apps among patients. We also conducted separate searches within the Medical category using the keywords billing, coding, and ICD (International Classification of Diseases) to evaluate rankings for billing/coding apps, as well as EMR and electronic medical records for electronic medical record (EMR) apps.

RESULTS

The initial search yielded 851 results, which was narrowed down to 29 apps after applying the exclusion criteria. Of note, prior to application of the exclusion criteria, one dermatology app that was considered to be a direct advertisement app claiming to cure acne was ranked fourth of 1500 apps in the Medical category. However, the majority of the search results were excluded because they were not popular enough to be ranked among the top 1500 apps. There were more ranked dermatology apps in the Medical category targeting patients than physicians; 18 of 29 (62%) qualifying apps targeted patients and 11 (38%) targeted physicians (Tables 1 and 2). No apps targeted both groups. The most common type of ranked app targeting patients was self-surveillance (11/18), and the most common type targeting physicians was reference (8/11). The highest ranked app targeting patients was a teledermatology app with a ranking of 184, and the highest ranked app targeting physicians was educational, ranked 353. The least common type of ranked apps targeting patients were “other” (2/18 [11%]; 1 prescription and 1 UV monitor app) and conference (1/18 [6%]). The least common type of ranked apps targeting physicians were education (2/11 [18%]) and dermoscopy (1/11 [9%]).

Our search of the Health and Fitness category yielded 6 apps, all targeting patients; 3 (50%) were self-surveillance apps, and 3 (50%) were classified as other (2 UV monitors and a conferencing app for cancer emotional support)(Table 3).

Our search of the Medical category for billing/coding and EMR apps yielded 232 and 164 apps, respectively; of them, 49 (21%) and 54 (33%) apps were ranked. These apps did not overlap with the dermatology-related search criteria; thus, we were not able to ascertain how many of these apps were used specifically by health care providers in dermatology.

COMMENT

Patient Apps

The most common apps used by patients are fitness and nutrition tracker apps categorized as Health and Fitness^5,6; however, the majority of ranked dermatology apps are categorized as Medical per our findings. In a study of 557 dermatology patients, it was found that among the health-related apps they used, the most common apps after fitness/nutrition were references, followed by patient portals, self-surveillance, and emotional assistance apps.⁶ Our search was consistent with these findings, suggesting that the most desired dermatology apps by patients are those that allow them to be proactive with their health. It is no surprise that the top-ranked app targeting patients was a teledermatology app, followed by multiple self-surveillance apps. The highest ranked self-surveillance app in the Health and Fitness category focused on monitoring the effects of nutrition on symptoms of diseases including skin disorders, while the highest ranked (as well as the majority of) self-surveillance apps in the Medical category encompassed mole monitoring and cancer risk calculators.

Benefits of the ranked dermatology apps in the Medical and Health and Fitness categories targeting patients include more immediate access to health care and education. Despite this popularity among patients, Masud et al⁷ demonstrated that only 20.5% (9/44) of dermatology apps targeting patients may be reliable resources based on a rubric created by the investigators. Overall, there remains a research gap for a standardized scientific approach to evaluating app validity and reliability.

Teledermatology
Teledermatology apps are the most common dermatology apps,² allowing for remote evaluation of patients through either live consultations or transmittance of medical information for later review by board-certified physicians.⁸ Features common to many teledermatology apps include accessibility on Android (Google Inc) and iOS as well as a web version. Security and Health Insurance Portability and Accountability Act compliance is especially important and is enforced through user authentications, data encryption, and automatic logout features. Data is not stored locally and is secured on a private server with backup. Referring providers and consultants often can communicate within the app. Insurance providers also may cover teledermatology services, and if not, the out-of-pocket costs often are affordable.

The highest-ranked patient app (ranked 184 in the Medical category) was a teledermatology app that did not meet the American Telemedicine Association standards for teledermatology apps.⁹ The popularity of this app among patients may have been attributable to multiple ease-of-use and turnaround time features. The user interface was simplistic, and the design was appealing to the eye. The entry field options were minimal to avoid confusion. The turnaround time to receive a diagnosis depended on 1 of 3 options, including a more rapid response for an increased cost. Ease of use was the highlight of this app at the cost of accuracy, as the limited amount of information that users were required to provide physicians compromised diagnostic accuracy in this app.

For comparison, we chose a nonranked (and thus less frequently used) teledermatology app that had previously undergone scientific evaluation using 13 evaluation criteria specific to teledermatology.¹⁰ The app also met the American Telemedicine Association standard for teledermatology apps.⁹ The app was originally a broader telemedicine app but featured a section specific to teledermatology. The user interface was simple but professional, almost resembling an EMR. The input fields included a comprehensive history that permitted a better evaluation of a lesion but might be tedious for users. This app boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.

Striking a balance between ensuring proper care versus appealing to patients is a difficult but important task. Based on this study, it appears that popular patient apps may in fact have less scientific rationale and therefore potentially less accuracy.

Self-surveillance
Although self-surveillance apps did not account for the highest-ranked app, they were the most frequently ranked app type in our study. Most of the ranked self-surveillance apps in the Medical category were for monitoring lesions over time to assess for changes. These apps help users take photographs that are well organized in a single, easy-to-find location. Some apps were risk calculators that assessed the risk for malignancies using a questionnaire. The majority of these self-surveillance apps were specific to skin cancer detection. Of note, one of the ranked self-surveillance apps assessed drug effectiveness by monitoring clinical appearance and symptoms. The lowest ranked self-surveillance app in the top 1500 ranked Medical apps in our search monitored cancer symptoms not specific to dermatology. Although this app had a low ranking (1380/1500), it received a high number of reviews and was well rated at 4.8 out of 5 stars; therefore, it seemed more helpful than the other higher-ranked apps targeting patients, which had higher rankings but minimal to no reviews or ratings. A comparison of the ease-of-use features of all the ranked patient-targeted self-surveillance apps in the Medical category is provided in Table 4.

Physician Apps

After examining the results of apps targeting physicians, we realized that the data may be accurate but may not be as representative of all currently practicing dermatology providers. Given the increased usage of apps among younger age groups,¹¹ our data may be skewed toward medical students and residents, supported by the fact that the top-ranked physician app in our study was an education app and the majority were reference apps. Future studies are needed to reexamine app ranking as this age group transitions from entry-level health care providers in the next 5 to 10 years. These findings also suggest less frequent app use among more veteran health care providers within our specific search parameters. Therefore, we decided to do subsequent searches for available billing/coding and EMR apps, which were many, but as mentioned above, none were specific to dermatology.

General Dermatology References
Most of the dermatology reference apps were formatted as e-books; however, other apps such as the Amazon Kindle app (categorized under Books) providing access to multiple e-books within one app were not included. Some apps included study aid features (eg, flash cards, quizzes), and topics spanned both dermatology and dermatopathology. Apps provide a unique way for on-the-go studying for dermatologists in training, and if the usage continues to grow, there may be a need for increased formal integration in dermatology education in the future.

Journals
Journal apps were not among those listed in the top-ranked apps we evaluated, which we suspect may be because journals were categorized differently from one journal to the next; for example, the Journal of the American Academy of Dermatology was ranked 1168 in the Magazines and Newspapers category. On the other hand, Dermatology World was ranked 1363 in the Reference category. An article’s citation affects the publishing journal’s impact factor, which is one of the most important variables in measuring a journal’s influence. In the future, there may be other variables that could aid in understanding journal impact as it relates to the journal’s accessibility.

Limitations

Our study did not look at Android apps. The top chart apps in the Android and Apple App Stores use undisclosed algorithms likely involving different characteristics such as number of downloads, frequency of updates, number of reviews, ratings, and more. Thus, the rankings across these different markets would not be comparable. Although our choice of keywords stemmed from the majority of prior studies looking at dermatology apps, our search was limited due to the use of these specific keywords. To avoid skewing data by cross-comparison of noncomparable categories, we could not compare apps in the Medical category versus those in other categories.

CONCLUSION

There seems to be a disconnect between the apps that are popular among patients and the scientific validity of the apps. As app usage increases among dermatology providers, whose demographic is shifting younger and younger, apps may become more incorporated in our education, and as such, it will become more critical to develop formal scientific standards. Given these future trends, we may need to increase our current literature and understanding of apps in dermatology with regard to their impact on both patients and health care providers.

Photo courtesy of NCCN

NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.

A third, lisocabtagene maraleucel, will most likely be approved before too long.

Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.

Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.

“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”

“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”

Dr. Karmali outlined those challenges in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

Patient selection

One of the biggest challenges, according to Dr. Karmali, is patient selection.

First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.

Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.

Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.

Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”

Toxicities

The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).

Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.

The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.

The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.

“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”

Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.

“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”

“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.

The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.

Future directions

Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.

“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said.  “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”

“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.

The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.

“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.

“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.” 

Photo courtesy of NCCN

NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.

A third, lisocabtagene maraleucel, will most likely be approved before too long.

Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.

Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.

“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”

“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”

Dr. Karmali outlined those challenges in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

Patient selection

One of the biggest challenges, according to Dr. Karmali, is patient selection.

First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.

Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.

Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.

Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”

Toxicities

The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).

Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.

The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.

The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.

“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”

Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.

“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”

“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.

The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.

Future directions

Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.

“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said.  “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”

“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.

The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.

“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.

“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.” 

Photo courtesy of NCCN

NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.

A third, lisocabtagene maraleucel, will most likely be approved before too long.

Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.

Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.

“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”

“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”

Dr. Karmali outlined those challenges in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

Patient selection

One of the biggest challenges, according to Dr. Karmali, is patient selection.

First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.

Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.

Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.

Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”

Toxicities

The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).

Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.

The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.

The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.

“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”

Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.

“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”

“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.

The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.

Future directions

Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.

“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said.  “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”

“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.

The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.

“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.

“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.”