Leukemia, Myelodysplasia, Transplantation

HOUSTON – A novel anti-CD45 targeted conditioning regimen is feasible for use in older patients with relapsed or refractory acute myeloid leukemia undergoing transplant, according to preliminary results of a randomized, phase 3 trial.

Treatment with iodine-131 apamistamab (Iomab-B) has thus far has resulted in successful engraftment for all patients who have received it and gone on to transplant, despite active disease and high bone marrow blast burden prior to transplantation, according to Sergio A. Giralt, MD, of Memorial Sloan Kettering Cancer Center, New York.

There has been no nonrelapse mortality related to the novel regimen in the ongoing trial, which compares Iomab-B as targeted conditioning prior to allogeneic hematopoietic stem cell transplant (HCT) with standard of care regimens, Dr. Giralt said in an update on the trial, known as SIERRA.

SIERRA is the only ongoing, randomized, phase 3 clinical trial to offer a transplant option in patients aged 55 years or older with active relapsed or refractory acute myeloid leukemia (AML), Dr. Giralt said at the Transplantation & Cellular Therapy Meetings.

“This is an underserved population in which traditional transplant techniques have very poor results, and there are limited options for patients with active disease,” Dr. Giralt said. “Of note, many transplant centers today do not consider these patients eligible for transplant.”

A total of 150 patients are to be enrolled in SIERRA and randomized either to investigator’s choice of salvage induction chemotherapy including approved targeted agents or to the experimental arm, which consists of an individualized dose of Iomab-B 12 days prior to HCT with fludarabine and total body irradiation as transplant conditioning.

Dr. Giralt presented an update on the first 38 patients in SIERRA, representing 25% of the total enrollment target.

Of 18 patients randomized to Iomab-B and transplanted, the median number of days to absolute neutrophil count engraftment was 13, Dr. Giralt said.

In the control arm, 15 of 19 (79%) failed to achieve complete remission, and of those 10 crossed over to receive Iomab-B and transplant. Days to engraftment, full donor chimerism, and dose delivered to the bone marrow were all similar in the crossover group, compared with those initially randomized to the novel therapy.

Nonhematologic grade 3 or 4 toxicities were similar between the Iomab-B arm and the conventional care arm, and included febrile neutropenia, stomatitis, and other side effects typical for these patients.

There were no grade 3 or 4 Iomab-B infusion-related reactions, and four mild cases of chronic graft-versus-host disease occurred in Iomab-B treated patients.

Nonrelapse mortality was “extremely low” with no cases in the 100 days post transplant in those initially randomized to Iomab-B, and only one case in a crossover patient, Dr. Giralt said.

“These results are encouraging, and can broaden transplant eligibility and improve outcomes,” he added.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

The SIERRA study is supported by Actinium Pharmaceuticals. Dr. Giralt reported disclosures related to Actinium and several other companies.

SOURCE: Giralt SA et al. TCT 2019, Abstract LBA3.

HOUSTON – A novel anti-CD45 targeted conditioning regimen is feasible for use in older patients with relapsed or refractory acute myeloid leukemia undergoing transplant, according to preliminary results of a randomized, phase 3 trial.

Treatment with iodine-131 apamistamab (Iomab-B) has thus far has resulted in successful engraftment for all patients who have received it and gone on to transplant, despite active disease and high bone marrow blast burden prior to transplantation, according to Sergio A. Giralt, MD, of Memorial Sloan Kettering Cancer Center, New York.

There has been no nonrelapse mortality related to the novel regimen in the ongoing trial, which compares Iomab-B as targeted conditioning prior to allogeneic hematopoietic stem cell transplant (HCT) with standard of care regimens, Dr. Giralt said in an update on the trial, known as SIERRA.

SIERRA is the only ongoing, randomized, phase 3 clinical trial to offer a transplant option in patients aged 55 years or older with active relapsed or refractory acute myeloid leukemia (AML), Dr. Giralt said at the Transplantation & Cellular Therapy Meetings.

“This is an underserved population in which traditional transplant techniques have very poor results, and there are limited options for patients with active disease,” Dr. Giralt said. “Of note, many transplant centers today do not consider these patients eligible for transplant.”

A total of 150 patients are to be enrolled in SIERRA and randomized either to investigator’s choice of salvage induction chemotherapy including approved targeted agents or to the experimental arm, which consists of an individualized dose of Iomab-B 12 days prior to HCT with fludarabine and total body irradiation as transplant conditioning.

Dr. Giralt presented an update on the first 38 patients in SIERRA, representing 25% of the total enrollment target.

Of 18 patients randomized to Iomab-B and transplanted, the median number of days to absolute neutrophil count engraftment was 13, Dr. Giralt said.

In the control arm, 15 of 19 (79%) failed to achieve complete remission, and of those 10 crossed over to receive Iomab-B and transplant. Days to engraftment, full donor chimerism, and dose delivered to the bone marrow were all similar in the crossover group, compared with those initially randomized to the novel therapy.

Nonhematologic grade 3 or 4 toxicities were similar between the Iomab-B arm and the conventional care arm, and included febrile neutropenia, stomatitis, and other side effects typical for these patients.

There were no grade 3 or 4 Iomab-B infusion-related reactions, and four mild cases of chronic graft-versus-host disease occurred in Iomab-B treated patients.

Nonrelapse mortality was “extremely low” with no cases in the 100 days post transplant in those initially randomized to Iomab-B, and only one case in a crossover patient, Dr. Giralt said.

“These results are encouraging, and can broaden transplant eligibility and improve outcomes,” he added.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

The SIERRA study is supported by Actinium Pharmaceuticals. Dr. Giralt reported disclosures related to Actinium and several other companies.

SOURCE: Giralt SA et al. TCT 2019, Abstract LBA3.

HOUSTON – A novel anti-CD45 targeted conditioning regimen is feasible for use in older patients with relapsed or refractory acute myeloid leukemia undergoing transplant, according to preliminary results of a randomized, phase 3 trial.

Treatment with iodine-131 apamistamab (Iomab-B) has thus far has resulted in successful engraftment for all patients who have received it and gone on to transplant, despite active disease and high bone marrow blast burden prior to transplantation, according to Sergio A. Giralt, MD, of Memorial Sloan Kettering Cancer Center, New York.

There has been no nonrelapse mortality related to the novel regimen in the ongoing trial, which compares Iomab-B as targeted conditioning prior to allogeneic hematopoietic stem cell transplant (HCT) with standard of care regimens, Dr. Giralt said in an update on the trial, known as SIERRA.

SIERRA is the only ongoing, randomized, phase 3 clinical trial to offer a transplant option in patients aged 55 years or older with active relapsed or refractory acute myeloid leukemia (AML), Dr. Giralt said at the Transplantation & Cellular Therapy Meetings.

“This is an underserved population in which traditional transplant techniques have very poor results, and there are limited options for patients with active disease,” Dr. Giralt said. “Of note, many transplant centers today do not consider these patients eligible for transplant.”

A total of 150 patients are to be enrolled in SIERRA and randomized either to investigator’s choice of salvage induction chemotherapy including approved targeted agents or to the experimental arm, which consists of an individualized dose of Iomab-B 12 days prior to HCT with fludarabine and total body irradiation as transplant conditioning.

Dr. Giralt presented an update on the first 38 patients in SIERRA, representing 25% of the total enrollment target.

Of 18 patients randomized to Iomab-B and transplanted, the median number of days to absolute neutrophil count engraftment was 13, Dr. Giralt said.

In the control arm, 15 of 19 (79%) failed to achieve complete remission, and of those 10 crossed over to receive Iomab-B and transplant. Days to engraftment, full donor chimerism, and dose delivered to the bone marrow were all similar in the crossover group, compared with those initially randomized to the novel therapy.

Nonhematologic grade 3 or 4 toxicities were similar between the Iomab-B arm and the conventional care arm, and included febrile neutropenia, stomatitis, and other side effects typical for these patients.

There were no grade 3 or 4 Iomab-B infusion-related reactions, and four mild cases of chronic graft-versus-host disease occurred in Iomab-B treated patients.

Nonrelapse mortality was “extremely low” with no cases in the 100 days post transplant in those initially randomized to Iomab-B, and only one case in a crossover patient, Dr. Giralt said.

“These results are encouraging, and can broaden transplant eligibility and improve outcomes,” he added.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

The SIERRA study is supported by Actinium Pharmaceuticals. Dr. Giralt reported disclosures related to Actinium and several other companies.

SOURCE: Giralt SA et al. TCT 2019, Abstract LBA3.

For patients older than 65 years with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard induction therapy, adding the investigational pan-histone deacetylase (pan-HDAC) inhibitor pracinostat to azacitidine resulted in better complete remission and overall survival rates than azacitidine alone, results of a multicenter phase 2 trial showed.

Among 50 patients treated with the combination, 26 (52%) achieved the primary endpoint of either a complete remission (CR), CR with incomplete recovery of blood counts (CRi), or morphologic leukemia-free state (MLFS).

The median overall survival (OS) was 19.1 months, which compares favorably with historical data on similar patients treated with single-agent azacitidine, reported Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“[T]his study shows that pracinostat in combination with azacitidine has the potential to be a safe and effective regimen in the frontline treatment of older patients with AML unfit for [induction chemotherapy],” they wrote in Blood Advances.

Pracinostat is an oral pan-HDAC inhibitor that has been shown to have modest activity against AML as a single agent, but synergistic activity when combined with hypomethylating agent azacitidine, a standard of care for older patients with AML in the trial.

The investigators enrolled 50 patients with a median age of 75 years (range, 66-84 years). The cohort included 33 patients with de novo AML, 12 with AML secondary to myelodysplasia syndrome or myleoproliferative neoplasia, and five with therapy-related AML.

The patients were treated with pracinostat 60 mg daily for 3 days each week for 3 consecutive weeks in addition to azacitidine 75 mg/m² daily for 7 days in a 28-day cycle.

As noted, 26 patients reached the clinical endpoint, including 21 with a CR, 2 with a CRi, and 3 with MLFS. Additionally, two patients had a partial response (PR) and four had a PR with incomplete recovery of blood counts.

The median OS was 19.1 months, and the median progression-free survival (PFS) was 12.6 months. The 1-year OS rate was 62%. The 60-day mortality rate was 10%.

The authors noted that the survival data were superior to those seen in the phase 3 AZA-AML-001 study, which compared azacitidine therapy with conventional regimens in patients older than 65 years with newly diagnosed AML who were not eligible for stem cell transplants. In that trial, median OS was 10.4 months, the CR rate was 19.5% (vs. 49% in the present study), the 1-year OS rate was 46.5%, and the 60-day mortality rate was 16.2%.

They acknowledged, however, that the validity of the comparison is limited by their study’s small sample size, potential differences between the study populations, and lack of a control group in the present study. The investigators also found that clearance rates of baseline somatic mutations correlated with response to treatment.

Grade 3 or greater treatment-emergent adverse events occurred in 43 of the 50 patients, including infections, thrombocytopenias, and febrile neutropenias.

“On the basis of these encouraging results, a phase 3, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (NCT03151408) is currently ongoing to confirm superiority of the combination in this difficult-to-treat AML population,” the investigators wrote.

The study was supported by research funding from MEI Pharma, which helped develop pracinostat. Dr. Garcia-Manero reported having no disclosures. Multiple coauthors reported financial relationships with MEI and others. One coauthor is an MEI employee.

SOURCE: Garcia-Manero G et al. Blood Adv. 2019 Feb 26;3(4):508-18.

For patients older than 65 years with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard induction therapy, adding the investigational pan-histone deacetylase (pan-HDAC) inhibitor pracinostat to azacitidine resulted in better complete remission and overall survival rates than azacitidine alone, results of a multicenter phase 2 trial showed.

Among 50 patients treated with the combination, 26 (52%) achieved the primary endpoint of either a complete remission (CR), CR with incomplete recovery of blood counts (CRi), or morphologic leukemia-free state (MLFS).

The median overall survival (OS) was 19.1 months, which compares favorably with historical data on similar patients treated with single-agent azacitidine, reported Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“[T]his study shows that pracinostat in combination with azacitidine has the potential to be a safe and effective regimen in the frontline treatment of older patients with AML unfit for [induction chemotherapy],” they wrote in Blood Advances.

Pracinostat is an oral pan-HDAC inhibitor that has been shown to have modest activity against AML as a single agent, but synergistic activity when combined with hypomethylating agent azacitidine, a standard of care for older patients with AML in the trial.

The investigators enrolled 50 patients with a median age of 75 years (range, 66-84 years). The cohort included 33 patients with de novo AML, 12 with AML secondary to myelodysplasia syndrome or myleoproliferative neoplasia, and five with therapy-related AML.

The patients were treated with pracinostat 60 mg daily for 3 days each week for 3 consecutive weeks in addition to azacitidine 75 mg/m² daily for 7 days in a 28-day cycle.

As noted, 26 patients reached the clinical endpoint, including 21 with a CR, 2 with a CRi, and 3 with MLFS. Additionally, two patients had a partial response (PR) and four had a PR with incomplete recovery of blood counts.

The median OS was 19.1 months, and the median progression-free survival (PFS) was 12.6 months. The 1-year OS rate was 62%. The 60-day mortality rate was 10%.

The authors noted that the survival data were superior to those seen in the phase 3 AZA-AML-001 study, which compared azacitidine therapy with conventional regimens in patients older than 65 years with newly diagnosed AML who were not eligible for stem cell transplants. In that trial, median OS was 10.4 months, the CR rate was 19.5% (vs. 49% in the present study), the 1-year OS rate was 46.5%, and the 60-day mortality rate was 16.2%.

They acknowledged, however, that the validity of the comparison is limited by their study’s small sample size, potential differences between the study populations, and lack of a control group in the present study. The investigators also found that clearance rates of baseline somatic mutations correlated with response to treatment.

Grade 3 or greater treatment-emergent adverse events occurred in 43 of the 50 patients, including infections, thrombocytopenias, and febrile neutropenias.

“On the basis of these encouraging results, a phase 3, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (NCT03151408) is currently ongoing to confirm superiority of the combination in this difficult-to-treat AML population,” the investigators wrote.

The study was supported by research funding from MEI Pharma, which helped develop pracinostat. Dr. Garcia-Manero reported having no disclosures. Multiple coauthors reported financial relationships with MEI and others. One coauthor is an MEI employee.

SOURCE: Garcia-Manero G et al. Blood Adv. 2019 Feb 26;3(4):508-18.

For patients older than 65 years with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard induction therapy, adding the investigational pan-histone deacetylase (pan-HDAC) inhibitor pracinostat to azacitidine resulted in better complete remission and overall survival rates than azacitidine alone, results of a multicenter phase 2 trial showed.

Among 50 patients treated with the combination, 26 (52%) achieved the primary endpoint of either a complete remission (CR), CR with incomplete recovery of blood counts (CRi), or morphologic leukemia-free state (MLFS).

The median overall survival (OS) was 19.1 months, which compares favorably with historical data on similar patients treated with single-agent azacitidine, reported Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“[T]his study shows that pracinostat in combination with azacitidine has the potential to be a safe and effective regimen in the frontline treatment of older patients with AML unfit for [induction chemotherapy],” they wrote in Blood Advances.

Pracinostat is an oral pan-HDAC inhibitor that has been shown to have modest activity against AML as a single agent, but synergistic activity when combined with hypomethylating agent azacitidine, a standard of care for older patients with AML in the trial.

The investigators enrolled 50 patients with a median age of 75 years (range, 66-84 years). The cohort included 33 patients with de novo AML, 12 with AML secondary to myelodysplasia syndrome or myleoproliferative neoplasia, and five with therapy-related AML.

The patients were treated with pracinostat 60 mg daily for 3 days each week for 3 consecutive weeks in addition to azacitidine 75 mg/m² daily for 7 days in a 28-day cycle.

As noted, 26 patients reached the clinical endpoint, including 21 with a CR, 2 with a CRi, and 3 with MLFS. Additionally, two patients had a partial response (PR) and four had a PR with incomplete recovery of blood counts.

The median OS was 19.1 months, and the median progression-free survival (PFS) was 12.6 months. The 1-year OS rate was 62%. The 60-day mortality rate was 10%.

The authors noted that the survival data were superior to those seen in the phase 3 AZA-AML-001 study, which compared azacitidine therapy with conventional regimens in patients older than 65 years with newly diagnosed AML who were not eligible for stem cell transplants. In that trial, median OS was 10.4 months, the CR rate was 19.5% (vs. 49% in the present study), the 1-year OS rate was 46.5%, and the 60-day mortality rate was 16.2%.

They acknowledged, however, that the validity of the comparison is limited by their study’s small sample size, potential differences between the study populations, and lack of a control group in the present study. The investigators also found that clearance rates of baseline somatic mutations correlated with response to treatment.

Grade 3 or greater treatment-emergent adverse events occurred in 43 of the 50 patients, including infections, thrombocytopenias, and febrile neutropenias.

“On the basis of these encouraging results, a phase 3, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (NCT03151408) is currently ongoing to confirm superiority of the combination in this difficult-to-treat AML population,” the investigators wrote.

The study was supported by research funding from MEI Pharma, which helped develop pracinostat. Dr. Garcia-Manero reported having no disclosures. Multiple coauthors reported financial relationships with MEI and others. One coauthor is an MEI employee.

SOURCE: Garcia-Manero G et al. Blood Adv. 2019 Feb 26;3(4):508-18.

New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.

National Institutes of Health/Wikimedia Commons/Public Domain

In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) included 56 patients with the following disease types:

• Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
• RAEB type 1 (n = 11; 20%).
• Low-blast-count AML (n = 11; 20%).
• Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
• Chronic myelomonocytic leukemia (n = 1; 2%).

The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.

Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).

The patients received guadecitabine subcutaneously at 60 mg/m² on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.

Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.

The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.

The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.

In a multivariate analysis, the following factors were significantly associated with longer survival:
 

• Having low- to high-risk (vs. very-high-risk) disease (P = .03).
• Having experienced primary (vs. secondary) azacitidine failure (P = .01).
• Having a high rate of demethylation in blood during the first treatment cycle (P = .03).

There were 99 serious adverse events (AEs) reported in 44 patients. Most AEs were hematologic events, and the most common of these was myelosuppression (n = 88; 88%). The most common grade 3/4 nonhematologic AE was pulmonary toxicity (n = 7; 12.5%). Thirteen patients were hospitalized for febrile neutropenia for a median of 14 days.

The researchers said patients reported less pain and fewer secondary lesions with guadecitabine than they had with azacitidine.

This trial was sponsored by Groupe Francophone des Myelodysplasies in collaboration with Astex Pharmaceuticals. The researchers reported having no competing interests.

[email protected]

SOURCE: Sébert M et al. Haematologica. 2019 Feb 7. doi: 0.3324/haematol.2018.207118.

New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.

National Institutes of Health/Wikimedia Commons/Public Domain

In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) included 56 patients with the following disease types:

• Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
• RAEB type 1 (n = 11; 20%).
• Low-blast-count AML (n = 11; 20%).
• Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
• Chronic myelomonocytic leukemia (n = 1; 2%).

The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.

Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).

The patients received guadecitabine subcutaneously at 60 mg/m² on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.

Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.

The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.

The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.

In a multivariate analysis, the following factors were significantly associated with longer survival:
 

• Having low- to high-risk (vs. very-high-risk) disease (P = .03).
• Having experienced primary (vs. secondary) azacitidine failure (P = .01).
• Having a high rate of demethylation in blood during the first treatment cycle (P = .03).

There were 99 serious adverse events (AEs) reported in 44 patients. Most AEs were hematologic events, and the most common of these was myelosuppression (n = 88; 88%). The most common grade 3/4 nonhematologic AE was pulmonary toxicity (n = 7; 12.5%). Thirteen patients were hospitalized for febrile neutropenia for a median of 14 days.

The researchers said patients reported less pain and fewer secondary lesions with guadecitabine than they had with azacitidine.

This trial was sponsored by Groupe Francophone des Myelodysplasies in collaboration with Astex Pharmaceuticals. The researchers reported having no competing interests.

[email protected]

SOURCE: Sébert M et al. Haematologica. 2019 Feb 7. doi: 0.3324/haematol.2018.207118.

New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.

National Institutes of Health/Wikimedia Commons/Public Domain

In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) included 56 patients with the following disease types:

• Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
• RAEB type 1 (n = 11; 20%).
• Low-blast-count AML (n = 11; 20%).
• Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
• Chronic myelomonocytic leukemia (n = 1; 2%).

The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.

Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).

The patients received guadecitabine subcutaneously at 60 mg/m² on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.

Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.

The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.

The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.

In a multivariate analysis, the following factors were significantly associated with longer survival:
 

• Having low- to high-risk (vs. very-high-risk) disease (P = .03).
• Having experienced primary (vs. secondary) azacitidine failure (P = .01).
• Having a high rate of demethylation in blood during the first treatment cycle (P = .03).

There were 99 serious adverse events (AEs) reported in 44 patients. Most AEs were hematologic events, and the most common of these was myelosuppression (n = 88; 88%). The most common grade 3/4 nonhematologic AE was pulmonary toxicity (n = 7; 12.5%). Thirteen patients were hospitalized for febrile neutropenia for a median of 14 days.

The researchers said patients reported less pain and fewer secondary lesions with guadecitabine than they had with azacitidine.

This trial was sponsored by Groupe Francophone des Myelodysplasies in collaboration with Astex Pharmaceuticals. The researchers reported having no competing interests.

[email protected]

SOURCE: Sébert M et al. Haematologica. 2019 Feb 7. doi: 0.3324/haematol.2018.207118.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

HOUSTON — When given after transplant, azithromycin does not increase the risk of relapse in patients with moderate to severe chronic graft-versus-host disease (cGVHD) and bronchiolitis obliterans syndrome (BOS), according to a retrospective study.

A prior study, ALLOZITHRO (JAMA. 2017 Aug 8;318[6]:557-66), showed an increased risk of relapse and death in patients who received azithromycin as BOS prophylaxis prior to hematopoietic cell transplant (HCT).

That discovery prompted the Food and Drug Administration to release a safety communication warning prescribers about the risks associated with azithromycin as BOS prophylaxis. However, it wasn’t clear if the same risks exist when azithromycin is given for cGVHD management after HCT.

To gain some insight, Mark Shamoun, MD, of the University of Michigan, Ann Arbor, and his colleagues examined data on patients with moderate to severe cGVHD and BOS who received azithromycin after undergoing HCT to treat a hematologic malignancy.

Dr. Shamoun presented the group’s findings at the Transplantation & Cellular Therapy Meetings.

The researchers reviewed data on 239 patients enrolled in the University of Michigan’s HCT database from 2010 to 2017. The median age at baseline was 55 years (range, 4-72 years).

The patients received transplants to treat acute myeloid leukemia or myelodysplastic syndromes (n = 141), acute lymphoblastic leukemia (n = 40), lymphoma (n = 26), chronic leukemia (n = 24), multiple myeloma (n = 6), and myeloproliferative neoplasms (n = 2).

The patients had matched related donors (43%) or matched unrelated donors (57%). Most patients received peripheral blood transplants (84%), though some received bone marrow (14%) or cord blood (2%). All patients had moderate (38%) or severe (62%) cGVHD.

Patients were split into two cohorts. Patients in cohort A (n = 86) had BOS and received azithromycin for more than 14 days.

Patients in cohort B (n = 153) either did not receive azithromycin or received it for 14 days or less. Fewer than 5% of patients in cohort B had BOS.

Most other baseline characteristics were similar between the cohorts. However, severe cGVHD was more prevalent in cohort A than B — 78% and 51%, respectively.

In cohort A, the median time to the start of azithromycin was 15 months after HCT (range, 3-68 months). The median duration of azithromycin treatment was 26 months (range, 1-77 months).

Results

The 2-year relapse rate was significantly lower in patients who received azithromycin than in those who did not — 4% and 17%, respectively (P = .001).

There was a significant difference in relapse rate both from the time of HCT (P = .001) and from the start of azithromycin or cGVHD (P = .011).

There was no significant difference in overall survival between the cohorts, either from the time of HCT (P = .294) or from the start of azithromycin or cGVHD (P = .428).

Dr. Shamoun said these results suggest azithromycin does not increase the risk of relapse when it is used to manage cGVHD. However, this study is limited by its retrospective nature. In addition, most patients in cohort B did not have BOS, severe cGVHD was more common in cohort A, and the incidence of relapse was not calculated from the time of azithromycin initiation in both cohorts. Therefore, additional investigation is needed.

Dr. Shamoun presented these results at Transplantation & Cellular Therapy Meetings, which is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society, the American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Shamoun reported no conflicts of interest.

[email protected]

SOURCE: Shamoun M et al. TCT 2019, Abstract 33.

HOUSTON — When given after transplant, azithromycin does not increase the risk of relapse in patients with moderate to severe chronic graft-versus-host disease (cGVHD) and bronchiolitis obliterans syndrome (BOS), according to a retrospective study.

A prior study, ALLOZITHRO (JAMA. 2017 Aug 8;318[6]:557-66), showed an increased risk of relapse and death in patients who received azithromycin as BOS prophylaxis prior to hematopoietic cell transplant (HCT).

That discovery prompted the Food and Drug Administration to release a safety communication warning prescribers about the risks associated with azithromycin as BOS prophylaxis. However, it wasn’t clear if the same risks exist when azithromycin is given for cGVHD management after HCT.

To gain some insight, Mark Shamoun, MD, of the University of Michigan, Ann Arbor, and his colleagues examined data on patients with moderate to severe cGVHD and BOS who received azithromycin after undergoing HCT to treat a hematologic malignancy.

Dr. Shamoun presented the group’s findings at the Transplantation & Cellular Therapy Meetings.

The researchers reviewed data on 239 patients enrolled in the University of Michigan’s HCT database from 2010 to 2017. The median age at baseline was 55 years (range, 4-72 years).

The patients received transplants to treat acute myeloid leukemia or myelodysplastic syndromes (n = 141), acute lymphoblastic leukemia (n = 40), lymphoma (n = 26), chronic leukemia (n = 24), multiple myeloma (n = 6), and myeloproliferative neoplasms (n = 2).

The patients had matched related donors (43%) or matched unrelated donors (57%). Most patients received peripheral blood transplants (84%), though some received bone marrow (14%) or cord blood (2%). All patients had moderate (38%) or severe (62%) cGVHD.

Patients were split into two cohorts. Patients in cohort A (n = 86) had BOS and received azithromycin for more than 14 days.

Patients in cohort B (n = 153) either did not receive azithromycin or received it for 14 days or less. Fewer than 5% of patients in cohort B had BOS.

Most other baseline characteristics were similar between the cohorts. However, severe cGVHD was more prevalent in cohort A than B — 78% and 51%, respectively.

In cohort A, the median time to the start of azithromycin was 15 months after HCT (range, 3-68 months). The median duration of azithromycin treatment was 26 months (range, 1-77 months).

Results

The 2-year relapse rate was significantly lower in patients who received azithromycin than in those who did not — 4% and 17%, respectively (P = .001).

There was a significant difference in relapse rate both from the time of HCT (P = .001) and from the start of azithromycin or cGVHD (P = .011).

There was no significant difference in overall survival between the cohorts, either from the time of HCT (P = .294) or from the start of azithromycin or cGVHD (P = .428).

Dr. Shamoun said these results suggest azithromycin does not increase the risk of relapse when it is used to manage cGVHD. However, this study is limited by its retrospective nature. In addition, most patients in cohort B did not have BOS, severe cGVHD was more common in cohort A, and the incidence of relapse was not calculated from the time of azithromycin initiation in both cohorts. Therefore, additional investigation is needed.

Dr. Shamoun presented these results at Transplantation & Cellular Therapy Meetings, which is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society, the American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Shamoun reported no conflicts of interest.

[email protected]

SOURCE: Shamoun M et al. TCT 2019, Abstract 33.

HOUSTON — When given after transplant, azithromycin does not increase the risk of relapse in patients with moderate to severe chronic graft-versus-host disease (cGVHD) and bronchiolitis obliterans syndrome (BOS), according to a retrospective study.

A prior study, ALLOZITHRO (JAMA. 2017 Aug 8;318[6]:557-66), showed an increased risk of relapse and death in patients who received azithromycin as BOS prophylaxis prior to hematopoietic cell transplant (HCT).

That discovery prompted the Food and Drug Administration to release a safety communication warning prescribers about the risks associated with azithromycin as BOS prophylaxis. However, it wasn’t clear if the same risks exist when azithromycin is given for cGVHD management after HCT.

To gain some insight, Mark Shamoun, MD, of the University of Michigan, Ann Arbor, and his colleagues examined data on patients with moderate to severe cGVHD and BOS who received azithromycin after undergoing HCT to treat a hematologic malignancy.

Dr. Shamoun presented the group’s findings at the Transplantation & Cellular Therapy Meetings.

The researchers reviewed data on 239 patients enrolled in the University of Michigan’s HCT database from 2010 to 2017. The median age at baseline was 55 years (range, 4-72 years).

The patients received transplants to treat acute myeloid leukemia or myelodysplastic syndromes (n = 141), acute lymphoblastic leukemia (n = 40), lymphoma (n = 26), chronic leukemia (n = 24), multiple myeloma (n = 6), and myeloproliferative neoplasms (n = 2).

The patients had matched related donors (43%) or matched unrelated donors (57%). Most patients received peripheral blood transplants (84%), though some received bone marrow (14%) or cord blood (2%). All patients had moderate (38%) or severe (62%) cGVHD.

Patients were split into two cohorts. Patients in cohort A (n = 86) had BOS and received azithromycin for more than 14 days.

Patients in cohort B (n = 153) either did not receive azithromycin or received it for 14 days or less. Fewer than 5% of patients in cohort B had BOS.

Most other baseline characteristics were similar between the cohorts. However, severe cGVHD was more prevalent in cohort A than B — 78% and 51%, respectively.

In cohort A, the median time to the start of azithromycin was 15 months after HCT (range, 3-68 months). The median duration of azithromycin treatment was 26 months (range, 1-77 months).

Results

The 2-year relapse rate was significantly lower in patients who received azithromycin than in those who did not — 4% and 17%, respectively (P = .001).

There was a significant difference in relapse rate both from the time of HCT (P = .001) and from the start of azithromycin or cGVHD (P = .011).

There was no significant difference in overall survival between the cohorts, either from the time of HCT (P = .294) or from the start of azithromycin or cGVHD (P = .428).

Dr. Shamoun said these results suggest azithromycin does not increase the risk of relapse when it is used to manage cGVHD. However, this study is limited by its retrospective nature. In addition, most patients in cohort B did not have BOS, severe cGVHD was more common in cohort A, and the incidence of relapse was not calculated from the time of azithromycin initiation in both cohorts. Therefore, additional investigation is needed.

Dr. Shamoun presented these results at Transplantation & Cellular Therapy Meetings, which is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society, the American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Shamoun reported no conflicts of interest.

[email protected]

SOURCE: Shamoun M et al. TCT 2019, Abstract 33.

Previously unknown risk factors for secondary skin cancer linked with allogeneic hematopoietic cell transplantation (HCT) have been identified, researchers report after a retrospective analysis.

“We confirmed [graft-versus-host disease] as a risk factor, identified [chronic lymphocytic leukemia] as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer [basal cell carcinomas] than their counterparts,” Peggy A. Wu, MD, of the Beth Israel Deaconess Medical Center in Boston, and her colleagues wrote in the Journal of Investigative Dermatology.

The team analyzed 1,974 patients who underwent transplantation for various types of hematologic cancer and survived for a minimum of 100 days following transplant. Among this cohort, 119 patients developed various forms of skin cancer, including basal and squamous cell carcinoma.

Reports of skin malignancy were confirmed using physician records and pathology reports. Dr. Wu and her colleagues excluded patients whose indication for transplant was a primary immunodeficiency or Fanconi anemia.

“Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature,” the researchers wrote.

In univariable models, the researchers found that prior chronic lymphocytic leukemia (CLL) (hazard ratio, 2.2; 95% CI, 1.3-3.7), chronic graft-versus-host disease (GVHD) (HR, 3.1; 95% CI, 1.7-5.4), and age at transplant of more than 60 years (HR, 10.8; 95% CI, 3.3-35.6) were all linked to an increased risk for squamous cell carcinomas. A multivariable analysis found that these factors continued as significant risk factors.

For basal cell carcinomas, the risk factors identified were prior CLL (HR, 3.5; 95% CI, 2.0-6.4), acute GVHD (HR, 1.9; 95% CI, 1.1-3.3), and chronic GVHD (HR, 3.2; 95% CI, 1.6-6.5) using univariable models. These factors all continued to be significant in multivariable analysis.

Additionally, the researchers found that a myeloablative conditioning regimen and total body irradiation were protective against development of basal cell carcinomas in univariable models. However, the protective effect continued for myeloablative condition in the multivariable model only.

“To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma,” the researchers wrote.

The study was supported by the Skin Cancer Foundation, Women’s Dermatologic Society, Harvard Catalyst, and Harvard University. The authors reported having no conflicts of interest.
 

SOURCE: Wu PA et al. J Invest Dermatol. 2019 Mar;139(3):591-9.

Previously unknown risk factors for secondary skin cancer linked with allogeneic hematopoietic cell transplantation (HCT) have been identified, researchers report after a retrospective analysis.

“We confirmed [graft-versus-host disease] as a risk factor, identified [chronic lymphocytic leukemia] as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer [basal cell carcinomas] than their counterparts,” Peggy A. Wu, MD, of the Beth Israel Deaconess Medical Center in Boston, and her colleagues wrote in the Journal of Investigative Dermatology.

The team analyzed 1,974 patients who underwent transplantation for various types of hematologic cancer and survived for a minimum of 100 days following transplant. Among this cohort, 119 patients developed various forms of skin cancer, including basal and squamous cell carcinoma.

Reports of skin malignancy were confirmed using physician records and pathology reports. Dr. Wu and her colleagues excluded patients whose indication for transplant was a primary immunodeficiency or Fanconi anemia.

“Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature,” the researchers wrote.

In univariable models, the researchers found that prior chronic lymphocytic leukemia (CLL) (hazard ratio, 2.2; 95% CI, 1.3-3.7), chronic graft-versus-host disease (GVHD) (HR, 3.1; 95% CI, 1.7-5.4), and age at transplant of more than 60 years (HR, 10.8; 95% CI, 3.3-35.6) were all linked to an increased risk for squamous cell carcinomas. A multivariable analysis found that these factors continued as significant risk factors.

For basal cell carcinomas, the risk factors identified were prior CLL (HR, 3.5; 95% CI, 2.0-6.4), acute GVHD (HR, 1.9; 95% CI, 1.1-3.3), and chronic GVHD (HR, 3.2; 95% CI, 1.6-6.5) using univariable models. These factors all continued to be significant in multivariable analysis.

Additionally, the researchers found that a myeloablative conditioning regimen and total body irradiation were protective against development of basal cell carcinomas in univariable models. However, the protective effect continued for myeloablative condition in the multivariable model only.

“To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma,” the researchers wrote.

The study was supported by the Skin Cancer Foundation, Women’s Dermatologic Society, Harvard Catalyst, and Harvard University. The authors reported having no conflicts of interest.
 

SOURCE: Wu PA et al. J Invest Dermatol. 2019 Mar;139(3):591-9.

Previously unknown risk factors for secondary skin cancer linked with allogeneic hematopoietic cell transplantation (HCT) have been identified, researchers report after a retrospective analysis.

“We confirmed [graft-versus-host disease] as a risk factor, identified [chronic lymphocytic leukemia] as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer [basal cell carcinomas] than their counterparts,” Peggy A. Wu, MD, of the Beth Israel Deaconess Medical Center in Boston, and her colleagues wrote in the Journal of Investigative Dermatology.

The team analyzed 1,974 patients who underwent transplantation for various types of hematologic cancer and survived for a minimum of 100 days following transplant. Among this cohort, 119 patients developed various forms of skin cancer, including basal and squamous cell carcinoma.

Reports of skin malignancy were confirmed using physician records and pathology reports. Dr. Wu and her colleagues excluded patients whose indication for transplant was a primary immunodeficiency or Fanconi anemia.

“Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature,” the researchers wrote.

In univariable models, the researchers found that prior chronic lymphocytic leukemia (CLL) (hazard ratio, 2.2; 95% CI, 1.3-3.7), chronic graft-versus-host disease (GVHD) (HR, 3.1; 95% CI, 1.7-5.4), and age at transplant of more than 60 years (HR, 10.8; 95% CI, 3.3-35.6) were all linked to an increased risk for squamous cell carcinomas. A multivariable analysis found that these factors continued as significant risk factors.

For basal cell carcinomas, the risk factors identified were prior CLL (HR, 3.5; 95% CI, 2.0-6.4), acute GVHD (HR, 1.9; 95% CI, 1.1-3.3), and chronic GVHD (HR, 3.2; 95% CI, 1.6-6.5) using univariable models. These factors all continued to be significant in multivariable analysis.

Additionally, the researchers found that a myeloablative conditioning regimen and total body irradiation were protective against development of basal cell carcinomas in univariable models. However, the protective effect continued for myeloablative condition in the multivariable model only.

“To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma,” the researchers wrote.

The study was supported by the Skin Cancer Foundation, Women’s Dermatologic Society, Harvard Catalyst, and Harvard University. The authors reported having no conflicts of interest.
 

SOURCE: Wu PA et al. J Invest Dermatol. 2019 Mar;139(3):591-9.

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.

The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.

The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.

“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.

Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.

SOURCE: Beelen DW et al. TCT 2019, Abstract 4.

HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.

The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.

The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.

“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.

Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.

SOURCE: Beelen DW et al. TCT 2019, Abstract 4.

HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.

The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.

The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.

“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.

Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.

SOURCE: Beelen DW et al. TCT 2019, Abstract 4.

The Food and Drug Administration has cleared Bio-Rad’s digital polymerase chain reaction (PCR) testing solution to monitor patients’ molecular response to treatment for chronic myeloid leukemia.

The QXDx AutoDG ddPCR System combines Bio-Rad’s Droplet Digital PCR technology and the QXDx BCR-ABL %IS Kit, according to the company.

This so-called liquid biopsy test can “precisely and reproducibly” monitor the molecular response to tyrosine kinase inhibitor therapy. The current standard – reverse transcription quantitative PCR – can have variable results, especially at low levels of disease, according to Bio-Rad.

FDA clearance means that the product is “substantially equivalent” to an already-approved product and can be sold in the United States, according to the agency.

[email protected]

The Food and Drug Administration has cleared Bio-Rad’s digital polymerase chain reaction (PCR) testing solution to monitor patients’ molecular response to treatment for chronic myeloid leukemia.

The QXDx AutoDG ddPCR System combines Bio-Rad’s Droplet Digital PCR technology and the QXDx BCR-ABL %IS Kit, according to the company.

This so-called liquid biopsy test can “precisely and reproducibly” monitor the molecular response to tyrosine kinase inhibitor therapy. The current standard – reverse transcription quantitative PCR – can have variable results, especially at low levels of disease, according to Bio-Rad.

FDA clearance means that the product is “substantially equivalent” to an already-approved product and can be sold in the United States, according to the agency.

[email protected]

The Food and Drug Administration has cleared Bio-Rad’s digital polymerase chain reaction (PCR) testing solution to monitor patients’ molecular response to treatment for chronic myeloid leukemia.

The QXDx AutoDG ddPCR System combines Bio-Rad’s Droplet Digital PCR technology and the QXDx BCR-ABL %IS Kit, according to the company.

This so-called liquid biopsy test can “precisely and reproducibly” monitor the molecular response to tyrosine kinase inhibitor therapy. The current standard – reverse transcription quantitative PCR – can have variable results, especially at low levels of disease, according to Bio-Rad.

FDA clearance means that the product is “substantially equivalent” to an already-approved product and can be sold in the United States, according to the agency.

[email protected]

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.