ALL

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

The high price of chimeric antigen receptor (CAR) T-cell therapy for pediatric leukemia may prove cost effective if long-term survival benefits are realized, researchers reported.

utah778/Thinkstock

A cost-effectiveness analysis of the CAR T-cell therapy tisagenlecleucel suggests that the $475,000 price tag is in alignment with the lifetime benefits of the treatment. The findings were published in JAMA Pediatrics.

Tisagenlecleucel – marketed as Kymriah – is a one-dose treatment for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL) and the first CAR T-cell therapy approved by the Food and Drug Administration.

In this cost-effectiveness analysis, researchers used a decision analytic model that extrapolated the evidence from clinical trials over a patient’s lifetime to assess life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. The comparator was the chemoimmunotherapeutic agent clofarabine.

While tisagenlecleucel has a list price of $475,000, researchers discounted the price by 3% and added several additional costs, such as hospital administration, pretreatment, and potential adverse events, to get to a total discounted cost of about $667,000. They estimated that 42.6% of patients were considered to be long-term survivors with tisagenlecleucel, 10.34 life-years would be gained, and 9.28 QALYs would be gained.

In comparison, clofarabine had a total discounted cost of approximately $337,000 (including an initial discounted price of $164,000 plus additional treatment and administrative costs), 10.8% of patients were long-term survivors, 2.43 life-years were gained, and 2.10 QALYs were gained in the model.

Overall, the mean incremental cost-effectiveness ratio was about $46,000 per QALY gained in this base-case model.

In analyses of different scenarios, such as a deeper discount, a different treatment start, or a different calculation of future treatment costs, the cost-effectiveness ratio varied from $37,000 to $78,000 per QALY gained.

“We acknowledge that considerable uncertainty remains around the long-term benefit of tisagenlecleucel owing to limited available evidence; however, with current evidence and assumptions, tisagenlecleucel meets commonly cited value thresholds over a patient lifetime horizon, assuming payment for treatment acquisition for responders at 1 month,” wrote Melanie D. Whittington, PhD, from the University of Colorado at Denver, Aurora, and her colleagues.

The authors noted that the clinical trial evidence for tisagenlecleucel came from single-arm trials, which made selection of a comparator challenging. Clofarabine was chosen because it had the most similar baseline population characteristics, but they acknowledged that blinatumomab was also frequently used as a treatment for these patients.

“We suspect that tisagenlecleucel would remain cost effective, compared with blinatumomab,” they wrote. “A study conducted by other researchers found the incremental cost-effectiveness ratio of tisagenlecleucel versus blinatumomab was similar to the incremental cost-effectiveness ratio of tisagenlecleucel versus clofarabine [i.e., $3,000 more per QALY].”

The authors suggested that uncertainties in the evidence should be considered as payers are negotiating coverage and payment for tisagenlecleucel.

“Novel payment models consistent with the present evidence may reduce the risk and uncertainty in long-term value and be more closely aligned with ensuring high-value care,” they wrote. “Financing cures in the United States is challenging, owing to the high up-front price, rapid uptake, and uncertainty in long-term outcomes; however, innovative payment models are an opportunity to address some of these challenges and to promote patient access to novel and promising therapies.”

The study was funded by the Institute for Clinical and Economic Review, which receives some funding from the pharmaceutical industry. Four authors are employees of the Institute for Clinical and Economic Review.

SOURCE: Whittington MD et al. JAMA Pediatr. 2018 Oct 8. doi: 10.1001/jamapediatrics.2018.2530.

The high price of chimeric antigen receptor (CAR) T-cell therapy for pediatric leukemia may prove cost effective if long-term survival benefits are realized, researchers reported.

utah778/Thinkstock

A cost-effectiveness analysis of the CAR T-cell therapy tisagenlecleucel suggests that the $475,000 price tag is in alignment with the lifetime benefits of the treatment. The findings were published in JAMA Pediatrics.

Tisagenlecleucel – marketed as Kymriah – is a one-dose treatment for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL) and the first CAR T-cell therapy approved by the Food and Drug Administration.

In this cost-effectiveness analysis, researchers used a decision analytic model that extrapolated the evidence from clinical trials over a patient’s lifetime to assess life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. The comparator was the chemoimmunotherapeutic agent clofarabine.

While tisagenlecleucel has a list price of $475,000, researchers discounted the price by 3% and added several additional costs, such as hospital administration, pretreatment, and potential adverse events, to get to a total discounted cost of about $667,000. They estimated that 42.6% of patients were considered to be long-term survivors with tisagenlecleucel, 10.34 life-years would be gained, and 9.28 QALYs would be gained.

In comparison, clofarabine had a total discounted cost of approximately $337,000 (including an initial discounted price of $164,000 plus additional treatment and administrative costs), 10.8% of patients were long-term survivors, 2.43 life-years were gained, and 2.10 QALYs were gained in the model.

Overall, the mean incremental cost-effectiveness ratio was about $46,000 per QALY gained in this base-case model.

In analyses of different scenarios, such as a deeper discount, a different treatment start, or a different calculation of future treatment costs, the cost-effectiveness ratio varied from $37,000 to $78,000 per QALY gained.

“We acknowledge that considerable uncertainty remains around the long-term benefit of tisagenlecleucel owing to limited available evidence; however, with current evidence and assumptions, tisagenlecleucel meets commonly cited value thresholds over a patient lifetime horizon, assuming payment for treatment acquisition for responders at 1 month,” wrote Melanie D. Whittington, PhD, from the University of Colorado at Denver, Aurora, and her colleagues.

The authors noted that the clinical trial evidence for tisagenlecleucel came from single-arm trials, which made selection of a comparator challenging. Clofarabine was chosen because it had the most similar baseline population characteristics, but they acknowledged that blinatumomab was also frequently used as a treatment for these patients.

“We suspect that tisagenlecleucel would remain cost effective, compared with blinatumomab,” they wrote. “A study conducted by other researchers found the incremental cost-effectiveness ratio of tisagenlecleucel versus blinatumomab was similar to the incremental cost-effectiveness ratio of tisagenlecleucel versus clofarabine [i.e., $3,000 more per QALY].”

The authors suggested that uncertainties in the evidence should be considered as payers are negotiating coverage and payment for tisagenlecleucel.

“Novel payment models consistent with the present evidence may reduce the risk and uncertainty in long-term value and be more closely aligned with ensuring high-value care,” they wrote. “Financing cures in the United States is challenging, owing to the high up-front price, rapid uptake, and uncertainty in long-term outcomes; however, innovative payment models are an opportunity to address some of these challenges and to promote patient access to novel and promising therapies.”

The study was funded by the Institute for Clinical and Economic Review, which receives some funding from the pharmaceutical industry. Four authors are employees of the Institute for Clinical and Economic Review.

SOURCE: Whittington MD et al. JAMA Pediatr. 2018 Oct 8. doi: 10.1001/jamapediatrics.2018.2530.

The high price of chimeric antigen receptor (CAR) T-cell therapy for pediatric leukemia may prove cost effective if long-term survival benefits are realized, researchers reported.

utah778/Thinkstock

A cost-effectiveness analysis of the CAR T-cell therapy tisagenlecleucel suggests that the $475,000 price tag is in alignment with the lifetime benefits of the treatment. The findings were published in JAMA Pediatrics.

Tisagenlecleucel – marketed as Kymriah – is a one-dose treatment for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL) and the first CAR T-cell therapy approved by the Food and Drug Administration.

In this cost-effectiveness analysis, researchers used a decision analytic model that extrapolated the evidence from clinical trials over a patient’s lifetime to assess life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. The comparator was the chemoimmunotherapeutic agent clofarabine.

While tisagenlecleucel has a list price of $475,000, researchers discounted the price by 3% and added several additional costs, such as hospital administration, pretreatment, and potential adverse events, to get to a total discounted cost of about $667,000. They estimated that 42.6% of patients were considered to be long-term survivors with tisagenlecleucel, 10.34 life-years would be gained, and 9.28 QALYs would be gained.

In comparison, clofarabine had a total discounted cost of approximately $337,000 (including an initial discounted price of $164,000 plus additional treatment and administrative costs), 10.8% of patients were long-term survivors, 2.43 life-years were gained, and 2.10 QALYs were gained in the model.

Overall, the mean incremental cost-effectiveness ratio was about $46,000 per QALY gained in this base-case model.

In analyses of different scenarios, such as a deeper discount, a different treatment start, or a different calculation of future treatment costs, the cost-effectiveness ratio varied from $37,000 to $78,000 per QALY gained.

“We acknowledge that considerable uncertainty remains around the long-term benefit of tisagenlecleucel owing to limited available evidence; however, with current evidence and assumptions, tisagenlecleucel meets commonly cited value thresholds over a patient lifetime horizon, assuming payment for treatment acquisition for responders at 1 month,” wrote Melanie D. Whittington, PhD, from the University of Colorado at Denver, Aurora, and her colleagues.

The authors noted that the clinical trial evidence for tisagenlecleucel came from single-arm trials, which made selection of a comparator challenging. Clofarabine was chosen because it had the most similar baseline population characteristics, but they acknowledged that blinatumomab was also frequently used as a treatment for these patients.

“We suspect that tisagenlecleucel would remain cost effective, compared with blinatumomab,” they wrote. “A study conducted by other researchers found the incremental cost-effectiveness ratio of tisagenlecleucel versus blinatumomab was similar to the incremental cost-effectiveness ratio of tisagenlecleucel versus clofarabine [i.e., $3,000 more per QALY].”

The authors suggested that uncertainties in the evidence should be considered as payers are negotiating coverage and payment for tisagenlecleucel.

“Novel payment models consistent with the present evidence may reduce the risk and uncertainty in long-term value and be more closely aligned with ensuring high-value care,” they wrote. “Financing cures in the United States is challenging, owing to the high up-front price, rapid uptake, and uncertainty in long-term outcomes; however, innovative payment models are an opportunity to address some of these challenges and to promote patient access to novel and promising therapies.”

The study was funded by the Institute for Clinical and Economic Review, which receives some funding from the pharmaceutical industry. Four authors are employees of the Institute for Clinical and Economic Review.

SOURCE: Whittington MD et al. JAMA Pediatr. 2018 Oct 8. doi: 10.1001/jamapediatrics.2018.2530.

CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.

“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.

At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
 

Blinatumomab

“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.

“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”

The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).

Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.

“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.

The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.

Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.

Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).

“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”

One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.

“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.

Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.

“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.

Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.

“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
 

Inotuzumab

Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.

Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.

“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.

The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).

The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.

Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.

“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.

The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.

It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
 

CAR T-cell therapy

As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.

Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.

“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
 

Overall outcomes

“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”

Two trials seek to address this, she said.

The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.

The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.

The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.

“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

[email protected]

CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.

“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.

At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
 

Blinatumomab

“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.

“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”

The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).

Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.

“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.

The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.

Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.

Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).

“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”

One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.

“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.

Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.

“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.

Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.

“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
 

Inotuzumab

Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.

Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.

“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.

The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).

The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.

Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.

“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.

The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.

It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
 

CAR T-cell therapy

As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.

Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.

“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
 

Overall outcomes

“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”

Two trials seek to address this, she said.

The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.

The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.

The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.

“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

[email protected]

CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.

“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.

At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
 

Blinatumomab

“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.

“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”

The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).

Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.

“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.

The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.

Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.

Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).

“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”

One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.

“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.

Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.

“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.

Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.

“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
 

Inotuzumab

Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.

Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.

“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.

The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).

The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.

Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.

“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.

The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.

It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
 

CAR T-cell therapy

As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.

Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.

“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
 

Overall outcomes

“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”

Two trials seek to address this, she said.

The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.

The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.

The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.

“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

[email protected]

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Bill Branson

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all patients participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other patients, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% CI, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear.

“In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” the investigators said in their report.

Further study is needed to look at potential brain injury mechanisms and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

Photo by Bill Branson

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all patients participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other patients, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% CI, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear.

“In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” the investigators said in their report.

Further study is needed to look at potential brain injury mechanisms and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

Photo by Bill Branson

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all patients participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other patients, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% CI, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear.

“In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” the investigators said in their report.

Further study is needed to look at potential brain injury mechanisms and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

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. 

Credit: Penn Medicine

Investigators report that a single leukemic cell unintentionally engineered into the chimeric antigen receptor (CAR) T-cell product can mask it from recognition and confer resistance to CAR T-cell therapy.

They described the case of a 20-year-old male who received the anti-CD19 CAR tisagenlecleucel (Kymriah) and relapsed at day 252 after the infusion.

The transduction of a leukemic cell during manufacture of the CAR T-cell product “is a rare event,” they wrote, and indicated that “this is the only case out of 369 patients reported worldwide at the time of publication.”

Lead author Marco Ruella, MD, of the University of Pennsylvania, and colleagues described the case in a Brief Communication published in Nature Medicine.

"In this case,” Dr. Ruella said, “we found that 100 percent of relapsed leukemic cells carried the CAR that we use to genetically modify T cells."

The patient had B-cell acute lymphoblastic leukemia (B-ALL) and relapsed three times after chemotherapy and a cord blood transplant before enrolling in the phase 1 trial of CTL019 (NCT 01626495).

The investigators reported that the infused CAR cells “displayed the typical pattern of in vivo engraftment and expansion.” At day 28 after the infusion, the patient was in complete remission.

But by day 252, he experienced a second expansion of CAR cells that did not correspond to the re-expansion of CAR+ T cells.

At day 261, the patient relapsed with more than 90% CD10+CD19- leukemic cells in the bone marrow and circulating blasts. The cells were CAR-transduced B-cell leukemia (CARB) cells.

The CARB cells continued to expand, and the patient died of progressive leukemia.

The investigators tracked the origin of the CARB cells by analyzing the relapsed CAR19+ cells using next-generation sequencing.

They hypothesized that the CAR19+ leukemia relapse occurred through lentiviral transduction during the manufacturing process, since they detected no replication-competent lentivirus when testing the patient’s peripheral blood at numerous time points after CTL019 infusion.

Further analysis confirmed the CARB cells were a byproduct made during CTL019 cell manufacturing.

To confirm that the leukemia relapse originated from a single clone, the investigators expanded in mice blast cells detected in the patient at month 9. Nine of 71 cells analyzed were positive for vector-host junctions. This confirmed that the relapsed cells originated from a single blast clone.

The investigators also excluded other possible reasons for the loss of CD19, including mutations, splicing variants, and structural alteration of the B-cell receptor complex.

They found that expression of the CAR in cis on B-ALL blasts masked the CAR target epitope.

The investigators concluded that their results “provide a direct confirmation of the cancer stem cell hypothesis in humans, given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo.”

They called for improved manufacturing technologies that can eliminate contamination by residual tumor cells from engineered T cells.

Interestingly, this case developed not long after a case that showed essentially the opposite situation—a patient with chronic lymphocytic leukemia went into remission because of a single CAR T cell that reproduced and fought off the disease. 

Credit: Penn Medicine

Investigators report that a single leukemic cell unintentionally engineered into the chimeric antigen receptor (CAR) T-cell product can mask it from recognition and confer resistance to CAR T-cell therapy.

They described the case of a 20-year-old male who received the anti-CD19 CAR tisagenlecleucel (Kymriah) and relapsed at day 252 after the infusion.

The transduction of a leukemic cell during manufacture of the CAR T-cell product “is a rare event,” they wrote, and indicated that “this is the only case out of 369 patients reported worldwide at the time of publication.”

Lead author Marco Ruella, MD, of the University of Pennsylvania, and colleagues described the case in a Brief Communication published in Nature Medicine.

"In this case,” Dr. Ruella said, “we found that 100 percent of relapsed leukemic cells carried the CAR that we use to genetically modify T cells."

The patient had B-cell acute lymphoblastic leukemia (B-ALL) and relapsed three times after chemotherapy and a cord blood transplant before enrolling in the phase 1 trial of CTL019 (NCT 01626495).

The investigators reported that the infused CAR cells “displayed the typical pattern of in vivo engraftment and expansion.” At day 28 after the infusion, the patient was in complete remission.

But by day 252, he experienced a second expansion of CAR cells that did not correspond to the re-expansion of CAR+ T cells.

At day 261, the patient relapsed with more than 90% CD10+CD19- leukemic cells in the bone marrow and circulating blasts. The cells were CAR-transduced B-cell leukemia (CARB) cells.

The CARB cells continued to expand, and the patient died of progressive leukemia.

The investigators tracked the origin of the CARB cells by analyzing the relapsed CAR19+ cells using next-generation sequencing.

They hypothesized that the CAR19+ leukemia relapse occurred through lentiviral transduction during the manufacturing process, since they detected no replication-competent lentivirus when testing the patient’s peripheral blood at numerous time points after CTL019 infusion.

Further analysis confirmed the CARB cells were a byproduct made during CTL019 cell manufacturing.

To confirm that the leukemia relapse originated from a single clone, the investigators expanded in mice blast cells detected in the patient at month 9. Nine of 71 cells analyzed were positive for vector-host junctions. This confirmed that the relapsed cells originated from a single blast clone.

The investigators also excluded other possible reasons for the loss of CD19, including mutations, splicing variants, and structural alteration of the B-cell receptor complex.

They found that expression of the CAR in cis on B-ALL blasts masked the CAR target epitope.

The investigators concluded that their results “provide a direct confirmation of the cancer stem cell hypothesis in humans, given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo.”

They called for improved manufacturing technologies that can eliminate contamination by residual tumor cells from engineered T cells.

Interestingly, this case developed not long after a case that showed essentially the opposite situation—a patient with chronic lymphocytic leukemia went into remission because of a single CAR T cell that reproduced and fought off the disease. 

Credit: Penn Medicine

Investigators report that a single leukemic cell unintentionally engineered into the chimeric antigen receptor (CAR) T-cell product can mask it from recognition and confer resistance to CAR T-cell therapy.

They described the case of a 20-year-old male who received the anti-CD19 CAR tisagenlecleucel (Kymriah) and relapsed at day 252 after the infusion.

The transduction of a leukemic cell during manufacture of the CAR T-cell product “is a rare event,” they wrote, and indicated that “this is the only case out of 369 patients reported worldwide at the time of publication.”

Lead author Marco Ruella, MD, of the University of Pennsylvania, and colleagues described the case in a Brief Communication published in Nature Medicine.

"In this case,” Dr. Ruella said, “we found that 100 percent of relapsed leukemic cells carried the CAR that we use to genetically modify T cells."

The patient had B-cell acute lymphoblastic leukemia (B-ALL) and relapsed three times after chemotherapy and a cord blood transplant before enrolling in the phase 1 trial of CTL019 (NCT 01626495).

The investigators reported that the infused CAR cells “displayed the typical pattern of in vivo engraftment and expansion.” At day 28 after the infusion, the patient was in complete remission.

But by day 252, he experienced a second expansion of CAR cells that did not correspond to the re-expansion of CAR+ T cells.

At day 261, the patient relapsed with more than 90% CD10+CD19- leukemic cells in the bone marrow and circulating blasts. The cells were CAR-transduced B-cell leukemia (CARB) cells.

The CARB cells continued to expand, and the patient died of progressive leukemia.

The investigators tracked the origin of the CARB cells by analyzing the relapsed CAR19+ cells using next-generation sequencing.

They hypothesized that the CAR19+ leukemia relapse occurred through lentiviral transduction during the manufacturing process, since they detected no replication-competent lentivirus when testing the patient’s peripheral blood at numerous time points after CTL019 infusion.

Further analysis confirmed the CARB cells were a byproduct made during CTL019 cell manufacturing.

To confirm that the leukemia relapse originated from a single clone, the investigators expanded in mice blast cells detected in the patient at month 9. Nine of 71 cells analyzed were positive for vector-host junctions. This confirmed that the relapsed cells originated from a single blast clone.

The investigators also excluded other possible reasons for the loss of CD19, including mutations, splicing variants, and structural alteration of the B-cell receptor complex.

They found that expression of the CAR in cis on B-ALL blasts masked the CAR target epitope.

The investigators concluded that their results “provide a direct confirmation of the cancer stem cell hypothesis in humans, given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo.”

They called for improved manufacturing technologies that can eliminate contamination by residual tumor cells from engineered T cells.

Interestingly, this case developed not long after a case that showed essentially the opposite situation—a patient with chronic lymphocytic leukemia went into remission because of a single CAR T cell that reproduced and fought off the disease. 

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

The ClonoSEQ assay is the first next generation sequencing–based test to be granted marketing approval for detecting minimal residual disease in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.

The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.

The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.

Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.

“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.

For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.

[email protected]

The ClonoSEQ assay is the first next generation sequencing–based test to be granted marketing approval for detecting minimal residual disease in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.

The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.

The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.

Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.

“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.

For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.

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The ClonoSEQ assay is the first next generation sequencing–based test to be granted marketing approval for detecting minimal residual disease in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.

The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.

The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.

Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.

“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.

For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.

[email protected]