AML

Key clinical point: No significant differences were seen between urban and rural acute myeloid leukemia patients with regard to overall survival or progression to hematopoietic cell transplantation.

Major finding:  Overall survival at one year was 47.9% between the groups (45% for rural and 49% for urban). In addition, the proportions of patients with cytogenetic risk factors and who went on to hematopoietic cell transplantation (HCT) were not significantly different between the two groups.

Study details: The data come from a retrospective study of 163 acute myeloid leukemia patients diagnosed at a single center between September 2015 and December 2019, 42% of whom lived in a rural area at the time of diagnosis.

Disclosures: The study received no outside funding. Lead author Dr. Isaac had no financial conflicts to disclose. 

Source: Isaac KM et al. Cancer Rep 2021 Mar 9. doi: 10.1002/cnr2.1354.

Key clinical point: No significant differences were seen between urban and rural acute myeloid leukemia patients with regard to overall survival or progression to hematopoietic cell transplantation.

Major finding:  Overall survival at one year was 47.9% between the groups (45% for rural and 49% for urban). In addition, the proportions of patients with cytogenetic risk factors and who went on to hematopoietic cell transplantation (HCT) were not significantly different between the two groups.

Study details: The data come from a retrospective study of 163 acute myeloid leukemia patients diagnosed at a single center between September 2015 and December 2019, 42% of whom lived in a rural area at the time of diagnosis.

Disclosures: The study received no outside funding. Lead author Dr. Isaac had no financial conflicts to disclose. 

Source: Isaac KM et al. Cancer Rep 2021 Mar 9. doi: 10.1002/cnr2.1354.

Key clinical point: No significant differences were seen between urban and rural acute myeloid leukemia patients with regard to overall survival or progression to hematopoietic cell transplantation.

Major finding:  Overall survival at one year was 47.9% between the groups (45% for rural and 49% for urban). In addition, the proportions of patients with cytogenetic risk factors and who went on to hematopoietic cell transplantation (HCT) were not significantly different between the two groups.

Study details: The data come from a retrospective study of 163 acute myeloid leukemia patients diagnosed at a single center between September 2015 and December 2019, 42% of whom lived in a rural area at the time of diagnosis.

Disclosures: The study received no outside funding. Lead author Dr. Isaac had no financial conflicts to disclose. 

Source: Isaac KM et al. Cancer Rep 2021 Mar 9. doi: 10.1002/cnr2.1354.

Researchers developed a predictive score for the risk of graft failure in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation (aHSCT) with ex vivo T-cell depletion. T-cell depletion is performed in an effort to prevent subsequent graft-versus-host disease (GVHD) after transplant.

The risk score was based on patient age and the T-lymphocyte population pre-aHSCT with 1 point of risk possible in each category. Patients with 1 point had a graft failure risk of 5% and 13% if they had 2 points, according to the results of the study presented at the virtual meeting of the European Society for Blood and Marrow Transplantation.

Graft failure is a potentially severe complication in patients treated with aHSCT, but there are few studies analyzing risk factors when ex vivo T-cell depletion is used, Ivan López Torija of the Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues noted in their presentation, which won the Best Young Poster Abstract Award at the meeting.

The researchers assessed 148 pediatric patients (64% boys) with acute leukemia who underwent allogeneic HSCT from haploidentical donors using ex vivo T-cell depletion between 2005 and 2020. About 53% of the patients were diagnosed with acute lymphoblastic leukemia, the rest with acute myeloid leukemia. The donor mean age was 40 years, and all transplant patients received toxicity reduction conditioning based on fludarabine busulfan and thiotepa.
 

Predictive results

Multivariate analysis showed that T-cell count (CD3+/CD8+ ≥ 350/mL: hazard ratio, 2,6; P = .01) and patient age (less than 9 years: HR; 5.0; P = .04) were associated with graft failure. A risk score was established using these results and based on patient age and T lymphocyte pre-aHSCT with 1 point each for each increased risk category. Patients with 1 point had a graft failure risk of 5% and a risk of 13% if they had 2 points.

However, in this particular population, with a mean follow up of 4 years, the overall survival rate was 60%, with no significant differences seen between patients that presented graft failure and those without graft failure.

“Patient age and pretransplant number of CD3+/CD8+ are associated with [graft failure] in pediatric patients with acute leukemia undergoing ex vivo T-cell–depleted haploidentical transplantation. These findings highlight the importance of preexisting cellular immunity in the transplant recipient and support T-cell population analysis as part of a pretransplant working program,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

Researchers developed a predictive score for the risk of graft failure in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation (aHSCT) with ex vivo T-cell depletion. T-cell depletion is performed in an effort to prevent subsequent graft-versus-host disease (GVHD) after transplant.

The risk score was based on patient age and the T-lymphocyte population pre-aHSCT with 1 point of risk possible in each category. Patients with 1 point had a graft failure risk of 5% and 13% if they had 2 points, according to the results of the study presented at the virtual meeting of the European Society for Blood and Marrow Transplantation.

Graft failure is a potentially severe complication in patients treated with aHSCT, but there are few studies analyzing risk factors when ex vivo T-cell depletion is used, Ivan López Torija of the Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues noted in their presentation, which won the Best Young Poster Abstract Award at the meeting.

The researchers assessed 148 pediatric patients (64% boys) with acute leukemia who underwent allogeneic HSCT from haploidentical donors using ex vivo T-cell depletion between 2005 and 2020. About 53% of the patients were diagnosed with acute lymphoblastic leukemia, the rest with acute myeloid leukemia. The donor mean age was 40 years, and all transplant patients received toxicity reduction conditioning based on fludarabine busulfan and thiotepa.
 

Predictive results

Multivariate analysis showed that T-cell count (CD3+/CD8+ ≥ 350/mL: hazard ratio, 2,6; P = .01) and patient age (less than 9 years: HR; 5.0; P = .04) were associated with graft failure. A risk score was established using these results and based on patient age and T lymphocyte pre-aHSCT with 1 point each for each increased risk category. Patients with 1 point had a graft failure risk of 5% and a risk of 13% if they had 2 points.

However, in this particular population, with a mean follow up of 4 years, the overall survival rate was 60%, with no significant differences seen between patients that presented graft failure and those without graft failure.

“Patient age and pretransplant number of CD3+/CD8+ are associated with [graft failure] in pediatric patients with acute leukemia undergoing ex vivo T-cell–depleted haploidentical transplantation. These findings highlight the importance of preexisting cellular immunity in the transplant recipient and support T-cell population analysis as part of a pretransplant working program,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

Researchers developed a predictive score for the risk of graft failure in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation (aHSCT) with ex vivo T-cell depletion. T-cell depletion is performed in an effort to prevent subsequent graft-versus-host disease (GVHD) after transplant.

The risk score was based on patient age and the T-lymphocyte population pre-aHSCT with 1 point of risk possible in each category. Patients with 1 point had a graft failure risk of 5% and 13% if they had 2 points, according to the results of the study presented at the virtual meeting of the European Society for Blood and Marrow Transplantation.

Graft failure is a potentially severe complication in patients treated with aHSCT, but there are few studies analyzing risk factors when ex vivo T-cell depletion is used, Ivan López Torija of the Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues noted in their presentation, which won the Best Young Poster Abstract Award at the meeting.

The researchers assessed 148 pediatric patients (64% boys) with acute leukemia who underwent allogeneic HSCT from haploidentical donors using ex vivo T-cell depletion between 2005 and 2020. About 53% of the patients were diagnosed with acute lymphoblastic leukemia, the rest with acute myeloid leukemia. The donor mean age was 40 years, and all transplant patients received toxicity reduction conditioning based on fludarabine busulfan and thiotepa.
 

Predictive results

Multivariate analysis showed that T-cell count (CD3+/CD8+ ≥ 350/mL: hazard ratio, 2,6; P = .01) and patient age (less than 9 years: HR; 5.0; P = .04) were associated with graft failure. A risk score was established using these results and based on patient age and T lymphocyte pre-aHSCT with 1 point each for each increased risk category. Patients with 1 point had a graft failure risk of 5% and a risk of 13% if they had 2 points.

However, in this particular population, with a mean follow up of 4 years, the overall survival rate was 60%, with no significant differences seen between patients that presented graft failure and those without graft failure.

“Patient age and pretransplant number of CD3+/CD8+ are associated with [graft failure] in pediatric patients with acute leukemia undergoing ex vivo T-cell–depleted haploidentical transplantation. These findings highlight the importance of preexisting cellular immunity in the transplant recipient and support T-cell population analysis as part of a pretransplant working program,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.

The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.

“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.

“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.

Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”

Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.

Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
 

Expanding possibilities

Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.

Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.

“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.

In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
 

Details of phase 3 trial results

The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.

Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).

At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).

In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).

Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.

The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).

In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.

The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.

The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.

Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.

In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).

The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.

The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.

“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.

“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.

Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”

Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.

Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
 

Expanding possibilities

Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.

Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.

“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.

In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
 

Details of phase 3 trial results

The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.

Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).

At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).

In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).

Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.

The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).

In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.

The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.

The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.

Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.

In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).

The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.

The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.

“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.

“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.

Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”

Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.

Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
 

Expanding possibilities

Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.

Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.

“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.

In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
 

Details of phase 3 trial results

The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.

Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).

At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).

In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).

Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.

The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).

In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.

The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.

The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.

Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.

In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).

The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The first report on responses to COVID-19 vaccination among patients with cancer suggests that, for these patients, the immune response that occurs after the first dose of vaccine is reduced, in comparison with the response that occurs in healthy individuals.

The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.

Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.

The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).

This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.

The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).

The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.

Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.

“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.

“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.

The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.

These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.

“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”

Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.

Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.

“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”

Study details

Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.

There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”

To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.

The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.

The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.

All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.

The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.

The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).

T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.

Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.

Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The first report on responses to COVID-19 vaccination among patients with cancer suggests that, for these patients, the immune response that occurs after the first dose of vaccine is reduced, in comparison with the response that occurs in healthy individuals.

The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.

Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.

The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).

This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.

The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).

The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.

Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.

“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.

“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.

The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.

These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.

“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”

Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.

Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.

“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”

Study details

Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.

There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”

To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.

The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.

The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.

All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.

The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.

The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).

T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.

Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.

Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The first report on responses to COVID-19 vaccination among patients with cancer suggests that, for these patients, the immune response that occurs after the first dose of vaccine is reduced, in comparison with the response that occurs in healthy individuals.

The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.

Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.

The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).

This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.

The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).

The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.

Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.

“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.

“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.

The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.

These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.

“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”

Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.

Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.

“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”

Study details

Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.

There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”

To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.

The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.

The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.

All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.

The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.

The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).

T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.

Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.

Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Maribavir, an investigational antiviral agent with a novel mechanism of action, was superior to other antiviral strategies at clearing cytomegalovirus (CMV) viremia and controlling symptoms in hematopoietic cell or solid-organ transplant recipients, results of a phase 3 clinical trial showed.

CDC

CMV viremia clearance at study week 8 was seen in 55.7% of all patients randomized to receive maribavir, compared with 23.9% for patients assigned to receive investigator-assigned therapy (IAT), Francisco Marty, MD, from the Dana-Farber Cancer Institute in Boston reported at the Transplant & Cellular Therapies Meetings.

“Maribavir’s benefit was driven by lower incidence of treatment-limiting toxicities, compared with IAT,” he said a late-breaking abstract session during the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

“Available anti-CMV antivirals are limited by development of resistance and toxicities, particularly myelosuppression with the use of valganciclovir and nephrotoxicity with the use of foscarnet and cidofovir. Alternative treatment options are required to address this unmet medical need,” he said.

Maribavir inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
 

Details of trial

In the phase 3 SHP620-30e trial (NCT02931539), Dr. Marty and colleagues enrolled patients with relapsed or refractory CMV infections after hematopoietic cell transplant (HCT) or solid-organ transplant (SOT) and after stratification by transplant type and screening CMV DNA level randomly assigned them on a 2:1 basis to receive either maribavir 400 mg twice daily (235 patients) or IAT (117 patients), consisting of either ganciclovir/valganciclovir, foscarnet, cidofovir, or combined foscarnet and val/ganciclovir.

The primary endpoint of viremia clearance at 8 weeks was defined as plasma CMV DNA less than 137 IU/mL in two consecutive tests at a central laboratory at least 5 days apart beginning at the end of week 8.

The trial met its primary endpoint, with a viremia clearance rate of 55.7% with maribavir versus 23.9% with IAT.

The viremia clearance rates were similar in each of the transplant groups: 55.9% versus 20.8%, respectively, in patients who underwent HCT, and 55.6% versus 26.1% in patients who underwent SOT (P < .001).

Clearance rates among patients with CMV DNA below 9,100 IU/mL at baseline were 62.1% with maribavir versus 24.7% with IAT. Among patients with baseline CMV DNA of 9100 IU/mL or above, the respective rates were 43.9% versus 21.9%.

CMV viremia clearance continued from week 8 to week 16 in 18.7% of patients assigned to maribavir and to 10.3% of patients randomized to IAT (P < .013).

The median time to first CMV viremia clearance as 22 days with maribavir versus 27 days with IAT (P = .039).

All-cause mortality was similar between the groups, at 11.5% versus 11.1%, respectively.

The incidences of serious and severe treatment-emergent adverse events (TEAE) were 38.5% and 32.1%, respectively, in the maribavir group, and 37.1% and 37.9% in the IAT group.

Any TEAE leading to study drug discontinuation was less common with maribavir, occurring in 13.2% of patients, compared with 31.9% of patients on IAT. Serious TEAEs leading to drug discontinuation occurred in 8.5% versus 14.7%, respectively.

Serious TEAEs leading to death occurred in 6.8% of patients on maribavir versus 5.2% of those on IAT.
 

Role of letermovir

In the question-and-answer session following the presentation, comoderator Monalisa Ghosh, MD, from the University of Michigan, Ann Arbor, asked whether any patients in the study were currently on letermovir (Prevymis) prophylaxis, and whether any patients had previously been treated with letermovir but had CMV reactivation and were then treated on study.

Dr. Marty noted that the trial was designed before letermovir was approved for CMV prophylaxis in adults who have undergone an allogeneic HCT.

“Nobody was on letermovir at the beginning of the trial,” he replied, but noted that some patients who were enrolled and had infections that were refractory or resistant to valganciclovir, foscarnet, or a combination of the two received letermovir as secondary prophylaxis.

“I haven’t got the data to tell you how often [letermovir] was used; I think part of the lack of mortality benefit [with maribavir] may be due to the fact that people jumped into secondary prophylaxis with letermovir to minimize the toxicities that we saw,” he said.

Although maribavir has not as of this writing received Food and Drug Administration approval, the drug may be available to some patients through a compassionate-use program from Takeda, Dr. Marty noted.

The study was funded by Shire ViroPharma. Dr. Marty disclosed research funding from Shire and from others. Dr. Ghosh had no relevant disclosures.

Maribavir, an investigational antiviral agent with a novel mechanism of action, was superior to other antiviral strategies at clearing cytomegalovirus (CMV) viremia and controlling symptoms in hematopoietic cell or solid-organ transplant recipients, results of a phase 3 clinical trial showed.

CDC

CMV viremia clearance at study week 8 was seen in 55.7% of all patients randomized to receive maribavir, compared with 23.9% for patients assigned to receive investigator-assigned therapy (IAT), Francisco Marty, MD, from the Dana-Farber Cancer Institute in Boston reported at the Transplant & Cellular Therapies Meetings.

“Maribavir’s benefit was driven by lower incidence of treatment-limiting toxicities, compared with IAT,” he said a late-breaking abstract session during the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

“Available anti-CMV antivirals are limited by development of resistance and toxicities, particularly myelosuppression with the use of valganciclovir and nephrotoxicity with the use of foscarnet and cidofovir. Alternative treatment options are required to address this unmet medical need,” he said.

Maribavir inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
 

Details of trial

In the phase 3 SHP620-30e trial (NCT02931539), Dr. Marty and colleagues enrolled patients with relapsed or refractory CMV infections after hematopoietic cell transplant (HCT) or solid-organ transplant (SOT) and after stratification by transplant type and screening CMV DNA level randomly assigned them on a 2:1 basis to receive either maribavir 400 mg twice daily (235 patients) or IAT (117 patients), consisting of either ganciclovir/valganciclovir, foscarnet, cidofovir, or combined foscarnet and val/ganciclovir.

The primary endpoint of viremia clearance at 8 weeks was defined as plasma CMV DNA less than 137 IU/mL in two consecutive tests at a central laboratory at least 5 days apart beginning at the end of week 8.

The trial met its primary endpoint, with a viremia clearance rate of 55.7% with maribavir versus 23.9% with IAT.

The viremia clearance rates were similar in each of the transplant groups: 55.9% versus 20.8%, respectively, in patients who underwent HCT, and 55.6% versus 26.1% in patients who underwent SOT (P < .001).

Clearance rates among patients with CMV DNA below 9,100 IU/mL at baseline were 62.1% with maribavir versus 24.7% with IAT. Among patients with baseline CMV DNA of 9100 IU/mL or above, the respective rates were 43.9% versus 21.9%.

CMV viremia clearance continued from week 8 to week 16 in 18.7% of patients assigned to maribavir and to 10.3% of patients randomized to IAT (P < .013).

The median time to first CMV viremia clearance as 22 days with maribavir versus 27 days with IAT (P = .039).

All-cause mortality was similar between the groups, at 11.5% versus 11.1%, respectively.

The incidences of serious and severe treatment-emergent adverse events (TEAE) were 38.5% and 32.1%, respectively, in the maribavir group, and 37.1% and 37.9% in the IAT group.

Any TEAE leading to study drug discontinuation was less common with maribavir, occurring in 13.2% of patients, compared with 31.9% of patients on IAT. Serious TEAEs leading to drug discontinuation occurred in 8.5% versus 14.7%, respectively.

Serious TEAEs leading to death occurred in 6.8% of patients on maribavir versus 5.2% of those on IAT.
 

Role of letermovir

In the question-and-answer session following the presentation, comoderator Monalisa Ghosh, MD, from the University of Michigan, Ann Arbor, asked whether any patients in the study were currently on letermovir (Prevymis) prophylaxis, and whether any patients had previously been treated with letermovir but had CMV reactivation and were then treated on study.

Dr. Marty noted that the trial was designed before letermovir was approved for CMV prophylaxis in adults who have undergone an allogeneic HCT.

“Nobody was on letermovir at the beginning of the trial,” he replied, but noted that some patients who were enrolled and had infections that were refractory or resistant to valganciclovir, foscarnet, or a combination of the two received letermovir as secondary prophylaxis.

“I haven’t got the data to tell you how often [letermovir] was used; I think part of the lack of mortality benefit [with maribavir] may be due to the fact that people jumped into secondary prophylaxis with letermovir to minimize the toxicities that we saw,” he said.

Although maribavir has not as of this writing received Food and Drug Administration approval, the drug may be available to some patients through a compassionate-use program from Takeda, Dr. Marty noted.

The study was funded by Shire ViroPharma. Dr. Marty disclosed research funding from Shire and from others. Dr. Ghosh had no relevant disclosures.

Maribavir, an investigational antiviral agent with a novel mechanism of action, was superior to other antiviral strategies at clearing cytomegalovirus (CMV) viremia and controlling symptoms in hematopoietic cell or solid-organ transplant recipients, results of a phase 3 clinical trial showed.

CDC

CMV viremia clearance at study week 8 was seen in 55.7% of all patients randomized to receive maribavir, compared with 23.9% for patients assigned to receive investigator-assigned therapy (IAT), Francisco Marty, MD, from the Dana-Farber Cancer Institute in Boston reported at the Transplant & Cellular Therapies Meetings.

“Maribavir’s benefit was driven by lower incidence of treatment-limiting toxicities, compared with IAT,” he said a late-breaking abstract session during the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

“Available anti-CMV antivirals are limited by development of resistance and toxicities, particularly myelosuppression with the use of valganciclovir and nephrotoxicity with the use of foscarnet and cidofovir. Alternative treatment options are required to address this unmet medical need,” he said.

Maribavir inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
 

Details of trial

In the phase 3 SHP620-30e trial (NCT02931539), Dr. Marty and colleagues enrolled patients with relapsed or refractory CMV infections after hematopoietic cell transplant (HCT) or solid-organ transplant (SOT) and after stratification by transplant type and screening CMV DNA level randomly assigned them on a 2:1 basis to receive either maribavir 400 mg twice daily (235 patients) or IAT (117 patients), consisting of either ganciclovir/valganciclovir, foscarnet, cidofovir, or combined foscarnet and val/ganciclovir.

The primary endpoint of viremia clearance at 8 weeks was defined as plasma CMV DNA less than 137 IU/mL in two consecutive tests at a central laboratory at least 5 days apart beginning at the end of week 8.

The trial met its primary endpoint, with a viremia clearance rate of 55.7% with maribavir versus 23.9% with IAT.

The viremia clearance rates were similar in each of the transplant groups: 55.9% versus 20.8%, respectively, in patients who underwent HCT, and 55.6% versus 26.1% in patients who underwent SOT (P < .001).

Clearance rates among patients with CMV DNA below 9,100 IU/mL at baseline were 62.1% with maribavir versus 24.7% with IAT. Among patients with baseline CMV DNA of 9100 IU/mL or above, the respective rates were 43.9% versus 21.9%.

CMV viremia clearance continued from week 8 to week 16 in 18.7% of patients assigned to maribavir and to 10.3% of patients randomized to IAT (P < .013).

The median time to first CMV viremia clearance as 22 days with maribavir versus 27 days with IAT (P = .039).

All-cause mortality was similar between the groups, at 11.5% versus 11.1%, respectively.

The incidences of serious and severe treatment-emergent adverse events (TEAE) were 38.5% and 32.1%, respectively, in the maribavir group, and 37.1% and 37.9% in the IAT group.

Any TEAE leading to study drug discontinuation was less common with maribavir, occurring in 13.2% of patients, compared with 31.9% of patients on IAT. Serious TEAEs leading to drug discontinuation occurred in 8.5% versus 14.7%, respectively.

Serious TEAEs leading to death occurred in 6.8% of patients on maribavir versus 5.2% of those on IAT.
 

Role of letermovir

In the question-and-answer session following the presentation, comoderator Monalisa Ghosh, MD, from the University of Michigan, Ann Arbor, asked whether any patients in the study were currently on letermovir (Prevymis) prophylaxis, and whether any patients had previously been treated with letermovir but had CMV reactivation and were then treated on study.

Dr. Marty noted that the trial was designed before letermovir was approved for CMV prophylaxis in adults who have undergone an allogeneic HCT.

“Nobody was on letermovir at the beginning of the trial,” he replied, but noted that some patients who were enrolled and had infections that were refractory or resistant to valganciclovir, foscarnet, or a combination of the two received letermovir as secondary prophylaxis.

“I haven’t got the data to tell you how often [letermovir] was used; I think part of the lack of mortality benefit [with maribavir] may be due to the fact that people jumped into secondary prophylaxis with letermovir to minimize the toxicities that we saw,” he said.

Although maribavir has not as of this writing received Food and Drug Administration approval, the drug may be available to some patients through a compassionate-use program from Takeda, Dr. Marty noted.

The study was funded by Shire ViroPharma. Dr. Marty disclosed research funding from Shire and from others. Dr. Ghosh had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

In a clinical trial comparing three graft-versus-host disease (GVHD)–prevention regimens in patients undergoing hematopoietic stem cell transplants, a calcineurin inhibitor (CNI)–free strategy using CD34-selected peripheral blood stem cells (PBSCs) was associated with a nearly twofold increase in transplant-related mortality, compared with either a different CNI-free regimen or tacrolimus plus methotrexate, investigators reported.

In the phase 3 Progress II trial, patients who received CD34-selected PBSCs without post-transplant immune suppression had a hazard ratio for death of 1.74 compared with patients who received T-cell depletion with posttransplant cyclophosphamide, and a HR of 1.78, compared with patients who received tacrolimus and methotrexate after a bone marrow graft, Miguel-Angel Perales , MD, from Memorial Sloan Kettering Cancer Center, New York, reported at the Transplant & Cellular Therapies Meetings.

“CD34 selection was associated with worse overall survival, which offset any benefit from lower rates of moderate to severe chronic GVHD,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Neither of the two CNI-free interventions were superior to tacrolimus/methotrexate with bone marrow–derived stem cells for preventing chronic GVHD, and there were no differences in the primary endpoint of chronic GVHD/relapse-free survival, Dr. Perales said.
 

T-cell depletion vs. CNI

The Progress II trial was designed to see whether either of two CNI-free, T-cell depletion approaches could improve chronic GVHD rates post transplant over a CNI-based regimen.

The investigators enrolled patients aged 65 years or younger with acute leukemia or myelodysplasia with fewer than 5% blasts and a HLA-matched related or unrelated donor.

The patients were randomly assigned to either bone marrow grafts with tacrolimus/methotrexate (118 patients), bone marrow with in vivo posttransplant cyclophosphamide (114), or PBSCs with ex vivo CD34-selected cells (114).

The primary endpoint of chronic GVHD/relapse-free survival (CRFS) was a time-to-event outcome defined as moderate to severe chronic GVHD according to National Institutes of Health consensus criteria, disease relapse or progression, or death from any cause.

As noted before, there were no between-arm differences in the primary CRFS endpoint, and in multivariate analysis controlling for donor type, patient characteristics, disease category and disease risk index, the only factor significantly predictive for CRFS was being aged 50 years or older.

The 2-year posttransplant survival rates were 61.6% in the CD34-selected arm, 76.7% in the posttransplant cyclophosphamide arm, and 74.2% in the tacrolimus/methotrexate arm.

As noted before, the HR for CRFS with CD34 versus tacrolimus/methotrexate was 1.74, and for CD34 versus cyclophosphamide was 1.78 (P = .02 for both comparisons). In contrast, there was no differe­nce in CRFS between posttransplant cyclophosphamide and tacrolimus/methotrexate.

Both relapse-free survival and transplant-related mortality were worse with the CD34-selected group, compared with the other two groups, but there were no significant differences among the arms in disease relapse.

Hematologic recovery was faster in the CD34 arm, but there were no significant differences in graft failure.

In addition, the incidence of grade II-IV acute GVHD was increased in the posttransplant cyclophosphamide group, compared with the other two, while chronic GVHD and moderate to severe chronic GVHD were reduced in the CD34 group.

There were no differences in quality of life measures among the groups, Dr. Perales said.
 

Practice changing?

In the question-and answer-session following the presentation, comoderator Sarah Nikiforow , MD, PhD, from the Dana-Farber Cancer Institute in Boston, who was not involved in the study, asked whether the trial results could be considered as practice changing for any centers that historically have done CD34 selection, or whether CD34 selection is still a viable approach to GVHD prophylaxis.

“That’s obviously a key question from the study, and a question that we’re asking ourselves,” Dr. Perales said. “I think the lesson that we took from this study as it pertains to CD34 selection is obviously the increased mortality, likely related to regimen toxicity, and I think the use of high-dose radiation is something that we have to reexamine.”

He said that his center is also considering whether to reduce antithymocyte globulin dosing, move it earlier in the process, and to use pharmokinetic-directed ATG as a possible means of decreasing nonrelapse mortality.

“I think it remains a useful platform for adoptive cell therapy, potentially targeting relapsed disease,” he added.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Perales disclosed advisory board activities and consulting for multiple companies, and receiving research funding for clinical trials from several more. Dr. Nikiforow disclosed a consulting/advisory role for Kite Pharma, and travel accommodations and expense from Celyad Oncology.

In a clinical trial comparing three graft-versus-host disease (GVHD)–prevention regimens in patients undergoing hematopoietic stem cell transplants, a calcineurin inhibitor (CNI)–free strategy using CD34-selected peripheral blood stem cells (PBSCs) was associated with a nearly twofold increase in transplant-related mortality, compared with either a different CNI-free regimen or tacrolimus plus methotrexate, investigators reported.

In the phase 3 Progress II trial, patients who received CD34-selected PBSCs without post-transplant immune suppression had a hazard ratio for death of 1.74 compared with patients who received T-cell depletion with posttransplant cyclophosphamide, and a HR of 1.78, compared with patients who received tacrolimus and methotrexate after a bone marrow graft, Miguel-Angel Perales , MD, from Memorial Sloan Kettering Cancer Center, New York, reported at the Transplant & Cellular Therapies Meetings.

“CD34 selection was associated with worse overall survival, which offset any benefit from lower rates of moderate to severe chronic GVHD,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Neither of the two CNI-free interventions were superior to tacrolimus/methotrexate with bone marrow–derived stem cells for preventing chronic GVHD, and there were no differences in the primary endpoint of chronic GVHD/relapse-free survival, Dr. Perales said.
 

T-cell depletion vs. CNI

The Progress II trial was designed to see whether either of two CNI-free, T-cell depletion approaches could improve chronic GVHD rates post transplant over a CNI-based regimen.

The investigators enrolled patients aged 65 years or younger with acute leukemia or myelodysplasia with fewer than 5% blasts and a HLA-matched related or unrelated donor.

The patients were randomly assigned to either bone marrow grafts with tacrolimus/methotrexate (118 patients), bone marrow with in vivo posttransplant cyclophosphamide (114), or PBSCs with ex vivo CD34-selected cells (114).

The primary endpoint of chronic GVHD/relapse-free survival (CRFS) was a time-to-event outcome defined as moderate to severe chronic GVHD according to National Institutes of Health consensus criteria, disease relapse or progression, or death from any cause.

As noted before, there were no between-arm differences in the primary CRFS endpoint, and in multivariate analysis controlling for donor type, patient characteristics, disease category and disease risk index, the only factor significantly predictive for CRFS was being aged 50 years or older.

The 2-year posttransplant survival rates were 61.6% in the CD34-selected arm, 76.7% in the posttransplant cyclophosphamide arm, and 74.2% in the tacrolimus/methotrexate arm.

As noted before, the HR for CRFS with CD34 versus tacrolimus/methotrexate was 1.74, and for CD34 versus cyclophosphamide was 1.78 (P = .02 for both comparisons). In contrast, there was no differe­nce in CRFS between posttransplant cyclophosphamide and tacrolimus/methotrexate.

Both relapse-free survival and transplant-related mortality were worse with the CD34-selected group, compared with the other two groups, but there were no significant differences among the arms in disease relapse.

Hematologic recovery was faster in the CD34 arm, but there were no significant differences in graft failure.

In addition, the incidence of grade II-IV acute GVHD was increased in the posttransplant cyclophosphamide group, compared with the other two, while chronic GVHD and moderate to severe chronic GVHD were reduced in the CD34 group.

There were no differences in quality of life measures among the groups, Dr. Perales said.
 

Practice changing?

In the question-and answer-session following the presentation, comoderator Sarah Nikiforow , MD, PhD, from the Dana-Farber Cancer Institute in Boston, who was not involved in the study, asked whether the trial results could be considered as practice changing for any centers that historically have done CD34 selection, or whether CD34 selection is still a viable approach to GVHD prophylaxis.

“That’s obviously a key question from the study, and a question that we’re asking ourselves,” Dr. Perales said. “I think the lesson that we took from this study as it pertains to CD34 selection is obviously the increased mortality, likely related to regimen toxicity, and I think the use of high-dose radiation is something that we have to reexamine.”

He said that his center is also considering whether to reduce antithymocyte globulin dosing, move it earlier in the process, and to use pharmokinetic-directed ATG as a possible means of decreasing nonrelapse mortality.

“I think it remains a useful platform for adoptive cell therapy, potentially targeting relapsed disease,” he added.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Perales disclosed advisory board activities and consulting for multiple companies, and receiving research funding for clinical trials from several more. Dr. Nikiforow disclosed a consulting/advisory role for Kite Pharma, and travel accommodations and expense from Celyad Oncology.

In a clinical trial comparing three graft-versus-host disease (GVHD)–prevention regimens in patients undergoing hematopoietic stem cell transplants, a calcineurin inhibitor (CNI)–free strategy using CD34-selected peripheral blood stem cells (PBSCs) was associated with a nearly twofold increase in transplant-related mortality, compared with either a different CNI-free regimen or tacrolimus plus methotrexate, investigators reported.

In the phase 3 Progress II trial, patients who received CD34-selected PBSCs without post-transplant immune suppression had a hazard ratio for death of 1.74 compared with patients who received T-cell depletion with posttransplant cyclophosphamide, and a HR of 1.78, compared with patients who received tacrolimus and methotrexate after a bone marrow graft, Miguel-Angel Perales , MD, from Memorial Sloan Kettering Cancer Center, New York, reported at the Transplant & Cellular Therapies Meetings.

“CD34 selection was associated with worse overall survival, which offset any benefit from lower rates of moderate to severe chronic GVHD,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Neither of the two CNI-free interventions were superior to tacrolimus/methotrexate with bone marrow–derived stem cells for preventing chronic GVHD, and there were no differences in the primary endpoint of chronic GVHD/relapse-free survival, Dr. Perales said.
 

T-cell depletion vs. CNI

The Progress II trial was designed to see whether either of two CNI-free, T-cell depletion approaches could improve chronic GVHD rates post transplant over a CNI-based regimen.

The investigators enrolled patients aged 65 years or younger with acute leukemia or myelodysplasia with fewer than 5% blasts and a HLA-matched related or unrelated donor.

The patients were randomly assigned to either bone marrow grafts with tacrolimus/methotrexate (118 patients), bone marrow with in vivo posttransplant cyclophosphamide (114), or PBSCs with ex vivo CD34-selected cells (114).

The primary endpoint of chronic GVHD/relapse-free survival (CRFS) was a time-to-event outcome defined as moderate to severe chronic GVHD according to National Institutes of Health consensus criteria, disease relapse or progression, or death from any cause.

As noted before, there were no between-arm differences in the primary CRFS endpoint, and in multivariate analysis controlling for donor type, patient characteristics, disease category and disease risk index, the only factor significantly predictive for CRFS was being aged 50 years or older.

The 2-year posttransplant survival rates were 61.6% in the CD34-selected arm, 76.7% in the posttransplant cyclophosphamide arm, and 74.2% in the tacrolimus/methotrexate arm.

As noted before, the HR for CRFS with CD34 versus tacrolimus/methotrexate was 1.74, and for CD34 versus cyclophosphamide was 1.78 (P = .02 for both comparisons). In contrast, there was no differe­nce in CRFS between posttransplant cyclophosphamide and tacrolimus/methotrexate.

Both relapse-free survival and transplant-related mortality were worse with the CD34-selected group, compared with the other two groups, but there were no significant differences among the arms in disease relapse.

Hematologic recovery was faster in the CD34 arm, but there were no significant differences in graft failure.

In addition, the incidence of grade II-IV acute GVHD was increased in the posttransplant cyclophosphamide group, compared with the other two, while chronic GVHD and moderate to severe chronic GVHD were reduced in the CD34 group.

There were no differences in quality of life measures among the groups, Dr. Perales said.
 

Practice changing?

In the question-and answer-session following the presentation, comoderator Sarah Nikiforow , MD, PhD, from the Dana-Farber Cancer Institute in Boston, who was not involved in the study, asked whether the trial results could be considered as practice changing for any centers that historically have done CD34 selection, or whether CD34 selection is still a viable approach to GVHD prophylaxis.

“That’s obviously a key question from the study, and a question that we’re asking ourselves,” Dr. Perales said. “I think the lesson that we took from this study as it pertains to CD34 selection is obviously the increased mortality, likely related to regimen toxicity, and I think the use of high-dose radiation is something that we have to reexamine.”

He said that his center is also considering whether to reduce antithymocyte globulin dosing, move it earlier in the process, and to use pharmokinetic-directed ATG as a possible means of decreasing nonrelapse mortality.

“I think it remains a useful platform for adoptive cell therapy, potentially targeting relapsed disease,” he added.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Perales disclosed advisory board activities and consulting for multiple companies, and receiving research funding for clinical trials from several more. Dr. Nikiforow disclosed a consulting/advisory role for Kite Pharma, and travel accommodations and expense from Celyad Oncology.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.