Leukemia, Myelodysplasia, Transplantation

A contaminated hematopoietic stem cell (HSC) graft caused a clinically significant infection in a 15-year-old transplant recipient with B-cell acute lymphoblastic leukemia (B-ALL), according to a letter to the editor published in Infection Control & Hospital Epidemiology.

Strains of Staphylococcus aureus found in isolates from the HSC graft and the patient were confirmed to be identical using pulsed-field gel electrophoresis, the authors, led by Zachary I. Willis, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, said.

“While multiple reports have found that low-grade bacterial contamination of HSC products is rarely consequential, our patient’s experience demonstrated that clinically significant infections may occur,” Dr. Willis and his colleagues wrote in the case report.

When less virulent organisms are found in HSC grafts, close observation may be warranted, the investigators said; however, a more aggressive approach might be considered when more virulent organisms are found.

“In such a case, we suggest obtaining blood cultures and considering preemptive antibiotics as guided by the identity and susceptibility of the contaminating organism,” the investigators wrote.

Dr. Willis and his colleagues reported the case of a 15-year-old boy with hypodiploid B-ALL who achieved complete remission after treatment and then underwent a 10/10 HLA allele–matched unrelated donor hematopoietic cell transplant.

The patient developed a fever of 38.3º C with tachycardia but no other sepsis signs approximately 24 hours after the transplant. Soon afterward, the care team was informed that there was a single colony each of Micrococcus and S. aureus in the culture of the HSC product. Methicillin susceptibility was later confirmed. Antibiotic treatment was changed accordingly, and as of 117 days post transplant, the patient was “doing well with no evidence of further infectious complications,” the investigators said.

Bacterial contamination of HSC grafts is relatively common, with reported rates ranging from 1% to 45%. However, the clinical significance of the contamination has been unclear. Moreover, contamination is not an absolute contraindication to infusion, as options for the patient are limited after a myeloablative preparative regimen.

There are some previous case reports also identifying infections caused by contaminated grafts, but in those cases, the evidence linking the graft to the infection was based solely on finding identical species, while in the present report, the graft and patient isolates were confirmed to be identical using pulsed-field gel electrophoresis.

The investigators reported having no outside funding and no financial disclosures.

SOURCE: Willis Z et al, Infect Control Hosp Epidemiol. 2018 Jan 23. doi: 10.1017/ice.2017.285.

A contaminated hematopoietic stem cell (HSC) graft caused a clinically significant infection in a 15-year-old transplant recipient with B-cell acute lymphoblastic leukemia (B-ALL), according to a letter to the editor published in Infection Control & Hospital Epidemiology.

Strains of Staphylococcus aureus found in isolates from the HSC graft and the patient were confirmed to be identical using pulsed-field gel electrophoresis, the authors, led by Zachary I. Willis, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, said.

“While multiple reports have found that low-grade bacterial contamination of HSC products is rarely consequential, our patient’s experience demonstrated that clinically significant infections may occur,” Dr. Willis and his colleagues wrote in the case report.

When less virulent organisms are found in HSC grafts, close observation may be warranted, the investigators said; however, a more aggressive approach might be considered when more virulent organisms are found.

“In such a case, we suggest obtaining blood cultures and considering preemptive antibiotics as guided by the identity and susceptibility of the contaminating organism,” the investigators wrote.

Dr. Willis and his colleagues reported the case of a 15-year-old boy with hypodiploid B-ALL who achieved complete remission after treatment and then underwent a 10/10 HLA allele–matched unrelated donor hematopoietic cell transplant.

The patient developed a fever of 38.3º C with tachycardia but no other sepsis signs approximately 24 hours after the transplant. Soon afterward, the care team was informed that there was a single colony each of Micrococcus and S. aureus in the culture of the HSC product. Methicillin susceptibility was later confirmed. Antibiotic treatment was changed accordingly, and as of 117 days post transplant, the patient was “doing well with no evidence of further infectious complications,” the investigators said.

Bacterial contamination of HSC grafts is relatively common, with reported rates ranging from 1% to 45%. However, the clinical significance of the contamination has been unclear. Moreover, contamination is not an absolute contraindication to infusion, as options for the patient are limited after a myeloablative preparative regimen.

There are some previous case reports also identifying infections caused by contaminated grafts, but in those cases, the evidence linking the graft to the infection was based solely on finding identical species, while in the present report, the graft and patient isolates were confirmed to be identical using pulsed-field gel electrophoresis.

The investigators reported having no outside funding and no financial disclosures.

SOURCE: Willis Z et al, Infect Control Hosp Epidemiol. 2018 Jan 23. doi: 10.1017/ice.2017.285.

A contaminated hematopoietic stem cell (HSC) graft caused a clinically significant infection in a 15-year-old transplant recipient with B-cell acute lymphoblastic leukemia (B-ALL), according to a letter to the editor published in Infection Control & Hospital Epidemiology.

Strains of Staphylococcus aureus found in isolates from the HSC graft and the patient were confirmed to be identical using pulsed-field gel electrophoresis, the authors, led by Zachary I. Willis, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, said.

“While multiple reports have found that low-grade bacterial contamination of HSC products is rarely consequential, our patient’s experience demonstrated that clinically significant infections may occur,” Dr. Willis and his colleagues wrote in the case report.

When less virulent organisms are found in HSC grafts, close observation may be warranted, the investigators said; however, a more aggressive approach might be considered when more virulent organisms are found.

“In such a case, we suggest obtaining blood cultures and considering preemptive antibiotics as guided by the identity and susceptibility of the contaminating organism,” the investigators wrote.

Dr. Willis and his colleagues reported the case of a 15-year-old boy with hypodiploid B-ALL who achieved complete remission after treatment and then underwent a 10/10 HLA allele–matched unrelated donor hematopoietic cell transplant.

The patient developed a fever of 38.3º C with tachycardia but no other sepsis signs approximately 24 hours after the transplant. Soon afterward, the care team was informed that there was a single colony each of Micrococcus and S. aureus in the culture of the HSC product. Methicillin susceptibility was later confirmed. Antibiotic treatment was changed accordingly, and as of 117 days post transplant, the patient was “doing well with no evidence of further infectious complications,” the investigators said.

Bacterial contamination of HSC grafts is relatively common, with reported rates ranging from 1% to 45%. However, the clinical significance of the contamination has been unclear. Moreover, contamination is not an absolute contraindication to infusion, as options for the patient are limited after a myeloablative preparative regimen.

There are some previous case reports also identifying infections caused by contaminated grafts, but in those cases, the evidence linking the graft to the infection was based solely on finding identical species, while in the present report, the graft and patient isolates were confirmed to be identical using pulsed-field gel electrophoresis.

The investigators reported having no outside funding and no financial disclosures.

SOURCE: Willis Z et al, Infect Control Hosp Epidemiol. 2018 Jan 23. doi: 10.1017/ice.2017.285.

Micrograph showing ALL

A mutation that leads to relapse in patients with acute lymphoblastic leukemia (ALL) also causes a weakness that could be exploited to kill leukemia cells, according to research published in Nature.

Investigators found evidence to suggest that mutations in the NT5C2 gene make leukemic cells resistant to a common chemotherapy drug but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” said Adolfo Ferrando, MD, PhD, of Columbia University’s Herbert Irving Comprehensive Cancer Center in New York, New York.

Dr Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have mutations in NT5C2, which drives resistance to 6-mercaptopurine.

However, the investigators didn’t know how these mutations emerge as cancer recurs after remission.

In analyzing samples from ALL patients, the team found they could detect the NT5C2 mutation R367Q in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

These findings suggest that cells with the R367Q mutation only multiply in response to treatment, and the mutation may help predict relapse.

“This seems to be a late mutation involved in disease progression,” Dr Ferrando said. “Our data support that it may not be present at diagnosis in many cases, and that, in cases where it may be present, it represents a very minor population.”

The investigators also found the R367Q mutation impaired leukemia cell growth and leukemia-initiating cell activity. This was “associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool.”

These findings led the investigators to test mizoribine, an IMPDH inhibitor, in Nt5c2^+/R367Q mutant and Nt5c2^+/co-R367Q wild-type ALL lymphoblasts. The team found the mutant cells were significantly more sensitive to mizoribine.

In Nt5c2^+/R367Q leukemia-bearing mice, treatment with mizoribine produced a “marked” anti-leukemic response and significantly prolonged survival.

In immunodeficient mice transplanted with an NT5C2(R367Q) xenograft, mizoribine decreased tumor burden and tumor infiltration.

“IMPDH inhibitors could eventually emerge as relevant antileukemic drugs, but this would require additional preclinical work before clinical testing,” Dr Ferrando said.

Micrograph showing ALL

A mutation that leads to relapse in patients with acute lymphoblastic leukemia (ALL) also causes a weakness that could be exploited to kill leukemia cells, according to research published in Nature.

Investigators found evidence to suggest that mutations in the NT5C2 gene make leukemic cells resistant to a common chemotherapy drug but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” said Adolfo Ferrando, MD, PhD, of Columbia University’s Herbert Irving Comprehensive Cancer Center in New York, New York.

Dr Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have mutations in NT5C2, which drives resistance to 6-mercaptopurine.

However, the investigators didn’t know how these mutations emerge as cancer recurs after remission.

In analyzing samples from ALL patients, the team found they could detect the NT5C2 mutation R367Q in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

These findings suggest that cells with the R367Q mutation only multiply in response to treatment, and the mutation may help predict relapse.

“This seems to be a late mutation involved in disease progression,” Dr Ferrando said. “Our data support that it may not be present at diagnosis in many cases, and that, in cases where it may be present, it represents a very minor population.”

The investigators also found the R367Q mutation impaired leukemia cell growth and leukemia-initiating cell activity. This was “associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool.”

These findings led the investigators to test mizoribine, an IMPDH inhibitor, in Nt5c2^+/R367Q mutant and Nt5c2^+/co-R367Q wild-type ALL lymphoblasts. The team found the mutant cells were significantly more sensitive to mizoribine.

In Nt5c2^+/R367Q leukemia-bearing mice, treatment with mizoribine produced a “marked” anti-leukemic response and significantly prolonged survival.

In immunodeficient mice transplanted with an NT5C2(R367Q) xenograft, mizoribine decreased tumor burden and tumor infiltration.

“IMPDH inhibitors could eventually emerge as relevant antileukemic drugs, but this would require additional preclinical work before clinical testing,” Dr Ferrando said.

Micrograph showing ALL

A mutation that leads to relapse in patients with acute lymphoblastic leukemia (ALL) also causes a weakness that could be exploited to kill leukemia cells, according to research published in Nature.

Investigators found evidence to suggest that mutations in the NT5C2 gene make leukemic cells resistant to a common chemotherapy drug but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” said Adolfo Ferrando, MD, PhD, of Columbia University’s Herbert Irving Comprehensive Cancer Center in New York, New York.

Dr Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have mutations in NT5C2, which drives resistance to 6-mercaptopurine.

However, the investigators didn’t know how these mutations emerge as cancer recurs after remission.

In analyzing samples from ALL patients, the team found they could detect the NT5C2 mutation R367Q in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

These findings suggest that cells with the R367Q mutation only multiply in response to treatment, and the mutation may help predict relapse.

“This seems to be a late mutation involved in disease progression,” Dr Ferrando said. “Our data support that it may not be present at diagnosis in many cases, and that, in cases where it may be present, it represents a very minor population.”

The investigators also found the R367Q mutation impaired leukemia cell growth and leukemia-initiating cell activity. This was “associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool.”

These findings led the investigators to test mizoribine, an IMPDH inhibitor, in Nt5c2^+/R367Q mutant and Nt5c2^+/co-R367Q wild-type ALL lymphoblasts. The team found the mutant cells were significantly more sensitive to mizoribine.

In Nt5c2^+/R367Q leukemia-bearing mice, treatment with mizoribine produced a “marked” anti-leukemic response and significantly prolonged survival.

In immunodeficient mice transplanted with an NT5C2(R367Q) xenograft, mizoribine decreased tumor burden and tumor infiltration.

“IMPDH inhibitors could eventually emerge as relevant antileukemic drugs, but this would require additional preclinical work before clinical testing,” Dr Ferrando said.

Photo by Rhoda Baer

Treatment costs are the greatest threat to the growth of cancer programs, according to a survey of nearly 300 cancer program administrators and providers.

Sixty-eight percent of survey respondents said treatment costs were among the biggest threats to future cancer program growth at their organization.

Other top threats to growth included physician alignment around services and program goals—cited by 47% of respondents—and changes in healthcare coverage—cited by 46%.

This survey—the “2017 Trending Now in Cancer Care Survey”—was conducted by the Association of Community Cancer Centers (ACCC) and Advisory Board’s Oncology Roundtable. It was supported by Pfizer Oncology.

The survey was distributed via email on July 24, 2017. Respondents included 293 cancer program administrators and providers from 209 institutions. They submitted responses over 6 weeks.

Respondents identified the following “biggest threats” to cancer program growth:

• Cost of drugs and/or new treatment modalities—68%
• Physician alignment around services and program goals—47%
• Changes in healthcare coverage—46%
• Cuts to fee-for-service reimbursement—44%
• Shifting reimbursement to value-based care—43%
• Marketplace competition—35%
• Workforce planning (eg, managing staff shortages)—34%
• Network strategy and integration—33%
• Site of care policies issued by private payers—27%
• Access to capital—26%
• Quality reporting requirements—22%
• Health information technology—21%
• Other—6%.

When asked to identify their greatest opportunities for cost savings, respondents overwhelmingly pointed toward clinical standardization (63%) and drugs (62%).

Other opportunities included:

• Supplies—28%
• Capital expenses (eg, imaging technology)—24%
• Non-clinical staff (eg, billing and coding specialists)—22%
• Technology maintenance—20%
• Clinical staff—16%
• Retail pharmacy—14%
• Clinical research—10%
• Support services (eg, acupuncture)—9%
• Other—4%.

Respondents also said the investments most likely to yield a return for their cancer program were:

• Increasing the number of sub-specialists (eg, breast surgeons)—59%
• Marketing—41%
• Specialty pharmacy—36%
• Increasing the number of general oncology physicians—34%
• Screening services (eg, mobile screening unit)—29%
• Capital investments—24%
• Clinical research—16%
• Support services—15%
• Retail pharmacy—14%
• Building upgrades—14%.

More details on the “2017 Trending Now in Cancer Care Survey” can be found on the ACCC website.

Photo by Rhoda Baer

Treatment costs are the greatest threat to the growth of cancer programs, according to a survey of nearly 300 cancer program administrators and providers.

Sixty-eight percent of survey respondents said treatment costs were among the biggest threats to future cancer program growth at their organization.

Other top threats to growth included physician alignment around services and program goals—cited by 47% of respondents—and changes in healthcare coverage—cited by 46%.

This survey—the “2017 Trending Now in Cancer Care Survey”—was conducted by the Association of Community Cancer Centers (ACCC) and Advisory Board’s Oncology Roundtable. It was supported by Pfizer Oncology.

The survey was distributed via email on July 24, 2017. Respondents included 293 cancer program administrators and providers from 209 institutions. They submitted responses over 6 weeks.

Respondents identified the following “biggest threats” to cancer program growth:

• Cost of drugs and/or new treatment modalities—68%
• Physician alignment around services and program goals—47%
• Changes in healthcare coverage—46%
• Cuts to fee-for-service reimbursement—44%
• Shifting reimbursement to value-based care—43%
• Marketplace competition—35%
• Workforce planning (eg, managing staff shortages)—34%
• Network strategy and integration—33%
• Site of care policies issued by private payers—27%
• Access to capital—26%
• Quality reporting requirements—22%
• Health information technology—21%
• Other—6%.

When asked to identify their greatest opportunities for cost savings, respondents overwhelmingly pointed toward clinical standardization (63%) and drugs (62%).

Other opportunities included:

• Supplies—28%
• Capital expenses (eg, imaging technology)—24%
• Non-clinical staff (eg, billing and coding specialists)—22%
• Technology maintenance—20%
• Clinical staff—16%
• Retail pharmacy—14%
• Clinical research—10%
• Support services (eg, acupuncture)—9%
• Other—4%.

Respondents also said the investments most likely to yield a return for their cancer program were:

• Increasing the number of sub-specialists (eg, breast surgeons)—59%
• Marketing—41%
• Specialty pharmacy—36%
• Increasing the number of general oncology physicians—34%
• Screening services (eg, mobile screening unit)—29%
• Capital investments—24%
• Clinical research—16%
• Support services—15%
• Retail pharmacy—14%
• Building upgrades—14%.

More details on the “2017 Trending Now in Cancer Care Survey” can be found on the ACCC website.

Photo by Rhoda Baer

Treatment costs are the greatest threat to the growth of cancer programs, according to a survey of nearly 300 cancer program administrators and providers.

Sixty-eight percent of survey respondents said treatment costs were among the biggest threats to future cancer program growth at their organization.

Other top threats to growth included physician alignment around services and program goals—cited by 47% of respondents—and changes in healthcare coverage—cited by 46%.

This survey—the “2017 Trending Now in Cancer Care Survey”—was conducted by the Association of Community Cancer Centers (ACCC) and Advisory Board’s Oncology Roundtable. It was supported by Pfizer Oncology.

The survey was distributed via email on July 24, 2017. Respondents included 293 cancer program administrators and providers from 209 institutions. They submitted responses over 6 weeks.

Respondents identified the following “biggest threats” to cancer program growth:

• Cost of drugs and/or new treatment modalities—68%
• Physician alignment around services and program goals—47%
• Changes in healthcare coverage—46%
• Cuts to fee-for-service reimbursement—44%
• Shifting reimbursement to value-based care—43%
• Marketplace competition—35%
• Workforce planning (eg, managing staff shortages)—34%
• Network strategy and integration—33%
• Site of care policies issued by private payers—27%
• Access to capital—26%
• Quality reporting requirements—22%
• Health information technology—21%
• Other—6%.

When asked to identify their greatest opportunities for cost savings, respondents overwhelmingly pointed toward clinical standardization (63%) and drugs (62%).

Other opportunities included:

• Supplies—28%
• Capital expenses (eg, imaging technology)—24%
• Non-clinical staff (eg, billing and coding specialists)—22%
• Technology maintenance—20%
• Clinical staff—16%
• Retail pharmacy—14%
• Clinical research—10%
• Support services (eg, acupuncture)—9%
• Other—4%.

Respondents also said the investments most likely to yield a return for their cancer program were:

• Increasing the number of sub-specialists (eg, breast surgeons)—59%
• Marketing—41%
• Specialty pharmacy—36%
• Increasing the number of general oncology physicians—34%
• Screening services (eg, mobile screening unit)—29%
• Capital investments—24%
• Clinical research—16%
• Support services—15%
• Retail pharmacy—14%
• Building upgrades—14%.

More details on the “2017 Trending Now in Cancer Care Survey” can be found on the ACCC website.

ATLANTA – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.

Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD, reported at the annual meeting of the American Society of Hematology.

The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,

Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.

The median duration of any response was 12.2 months, he said.

Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.

Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.

The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.

“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”

In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.

The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.

These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial, and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.
 

Combination approach

Preliminary findings from the latter trial (AG-221-AML-005) were presented at the ASH meeting by Courtney D. DiNardo, MD, who is also a coauthor on the AG221-C-001 study.

Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.

In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.

The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.

The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.

In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.

Patients in this group had a median age of 76 years and the median number of treatment cycles was three.

The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.

One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.

The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.

Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.

Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.

The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”

These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.

Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.

[email protected]

SOURCE: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639

ATLANTA – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.

Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD, reported at the annual meeting of the American Society of Hematology.

The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,

Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.

The median duration of any response was 12.2 months, he said.

Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.

Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.

The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.

“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”

In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.

The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.

These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial, and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.
 

Combination approach

Preliminary findings from the latter trial (AG-221-AML-005) were presented at the ASH meeting by Courtney D. DiNardo, MD, who is also a coauthor on the AG221-C-001 study.

Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.

In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.

The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.

The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.

In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.

Patients in this group had a median age of 76 years and the median number of treatment cycles was three.

The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.

One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.

The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.

Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.

Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.

The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”

These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.

Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.

[email protected]

SOURCE: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639

ATLANTA – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.

Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD, reported at the annual meeting of the American Society of Hematology.

The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,

Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.

The median duration of any response was 12.2 months, he said.

Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.

Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.

The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.

“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”

In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.

The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.

These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial, and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.
 

Combination approach

Preliminary findings from the latter trial (AG-221-AML-005) were presented at the ASH meeting by Courtney D. DiNardo, MD, who is also a coauthor on the AG221-C-001 study.

Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.

In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.

The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.

The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.

In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.

Patients in this group had a median age of 76 years and the median number of treatment cycles was three.

The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.

One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.

The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.

Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.

Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.

The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”

These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.

Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.

[email protected]

SOURCE: Pollyea D et al. ASH 2017 Abstract 638; DiNardo C et al. ASH 2017 Abstract 639

of Western Australia

Researchers say they have developed a new technique for assessing chromosomal abnormalities in chronic lymphocytic leukemia (CLL).

The team believes their method, called immuno-flowFISH, could be used at the time of CLL diagnosis for disease stratification and after treatment to assess residual disease.

Kathryn A. Fuller, PhD, of The University of Western Australia in Crawley, Australia, and her colleagues described immuno-flowFISH in the journal Methods.

The name “immuno-flowFISH” acknowledges what has been incorporated into this technology.

“Immuno” recognizes that immunology testing is used to identify the CLL cells. “Flow” is used because the machine is an imaging flow cytometer. And “FISH” is the test that identifies the chromosomes inside the cells.

The researchers said they found that immuno-flowFISH could detect trisomic chromosomal abnormalities in cells with the phenotype of CLL.

And immuno-flowFISH provided greater specificity and sensitivity than standard FISH.

In particular, the researchers were able to analyze 10,000 to 20,000 cells in each sample, which is 100 to 200 times greater than traditional FISH methods.

“The imaging cytometer can analyze samples at a rate of up to 2000 cells per second, which means we can investigate a large number of cells in a relatively short amount of time, giving us greater sensitivity,” Dr Fuller said.

“This immuno-flowFISH method is an exciting development in personalizing pathology testing for leukemia,” added study author Wendy N. Erber, MD, DPhil, PhD, of The University of Western Australia.

Dr Erber and her colleagues are now expanding immuno-flowFISH so it can be applied to other malignancies as well.

of Western Australia

Researchers say they have developed a new technique for assessing chromosomal abnormalities in chronic lymphocytic leukemia (CLL).

The team believes their method, called immuno-flowFISH, could be used at the time of CLL diagnosis for disease stratification and after treatment to assess residual disease.

Kathryn A. Fuller, PhD, of The University of Western Australia in Crawley, Australia, and her colleagues described immuno-flowFISH in the journal Methods.

The name “immuno-flowFISH” acknowledges what has been incorporated into this technology.

“Immuno” recognizes that immunology testing is used to identify the CLL cells. “Flow” is used because the machine is an imaging flow cytometer. And “FISH” is the test that identifies the chromosomes inside the cells.

The researchers said they found that immuno-flowFISH could detect trisomic chromosomal abnormalities in cells with the phenotype of CLL.

And immuno-flowFISH provided greater specificity and sensitivity than standard FISH.

In particular, the researchers were able to analyze 10,000 to 20,000 cells in each sample, which is 100 to 200 times greater than traditional FISH methods.

“The imaging cytometer can analyze samples at a rate of up to 2000 cells per second, which means we can investigate a large number of cells in a relatively short amount of time, giving us greater sensitivity,” Dr Fuller said.

“This immuno-flowFISH method is an exciting development in personalizing pathology testing for leukemia,” added study author Wendy N. Erber, MD, DPhil, PhD, of The University of Western Australia.

Dr Erber and her colleagues are now expanding immuno-flowFISH so it can be applied to other malignancies as well.

of Western Australia

Researchers say they have developed a new technique for assessing chromosomal abnormalities in chronic lymphocytic leukemia (CLL).

The team believes their method, called immuno-flowFISH, could be used at the time of CLL diagnosis for disease stratification and after treatment to assess residual disease.

Kathryn A. Fuller, PhD, of The University of Western Australia in Crawley, Australia, and her colleagues described immuno-flowFISH in the journal Methods.

The name “immuno-flowFISH” acknowledges what has been incorporated into this technology.

“Immuno” recognizes that immunology testing is used to identify the CLL cells. “Flow” is used because the machine is an imaging flow cytometer. And “FISH” is the test that identifies the chromosomes inside the cells.

The researchers said they found that immuno-flowFISH could detect trisomic chromosomal abnormalities in cells with the phenotype of CLL.

And immuno-flowFISH provided greater specificity and sensitivity than standard FISH.

In particular, the researchers were able to analyze 10,000 to 20,000 cells in each sample, which is 100 to 200 times greater than traditional FISH methods.

“The imaging cytometer can analyze samples at a rate of up to 2000 cells per second, which means we can investigate a large number of cells in a relatively short amount of time, giving us greater sensitivity,” Dr Fuller said.

“This immuno-flowFISH method is an exciting development in personalizing pathology testing for leukemia,” added study author Wendy N. Erber, MD, DPhil, PhD, of The University of Western Australia.

Dr Erber and her colleagues are now expanding immuno-flowFISH so it can be applied to other malignancies as well.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

AML cells

The European Commission (EC) has granted orphan designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).

Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and the AXL receptor.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology last June.

The study enrolled 252 adults with relapsed/refractory AML. They received gilteritinib once daily in 1 of 7 dose-escalation (n=23) or dose-expansion (n=229) cohorts.

The maximum tolerated dose was 300 mg/day. There were 2 dose-limiting toxicities in the 450 mg dose-escalation cohort—grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.

Common treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and increased alanine aminotransferase (19%).

Serious adverse events related to treatment included febrile neutropenia (n=5), sepsis (n=2), acute renal failure (n=5), pyrexia (n=3), and bacteremia (n=1).

There were 7 deaths considered possibly or probably related to treatment—pulmonary embolism (200 mg/day), respiratory failure (120 mg/day), hemoptysis (80 mg/day), intracranial hemorrhage (20 mg/day), ventricular fibrillation (120 mg/day), septic shock (80 mg/day), and neutropenia (120 mg/day).

The overall response rate was 40% (100/249), and the complete response (CR) rate was 8% (n=19).

Four percent of patients (n=10) had a CR with incomplete platelet recovery, 18% (n=46) had a CR with incomplete hematological recovery, and 10% (n=25) had a partial response.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

AML cells

The European Commission (EC) has granted orphan designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).

Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and the AXL receptor.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology last June.

The study enrolled 252 adults with relapsed/refractory AML. They received gilteritinib once daily in 1 of 7 dose-escalation (n=23) or dose-expansion (n=229) cohorts.

The maximum tolerated dose was 300 mg/day. There were 2 dose-limiting toxicities in the 450 mg dose-escalation cohort—grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.

Common treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and increased alanine aminotransferase (19%).

Serious adverse events related to treatment included febrile neutropenia (n=5), sepsis (n=2), acute renal failure (n=5), pyrexia (n=3), and bacteremia (n=1).

There were 7 deaths considered possibly or probably related to treatment—pulmonary embolism (200 mg/day), respiratory failure (120 mg/day), hemoptysis (80 mg/day), intracranial hemorrhage (20 mg/day), ventricular fibrillation (120 mg/day), septic shock (80 mg/day), and neutropenia (120 mg/day).

The overall response rate was 40% (100/249), and the complete response (CR) rate was 8% (n=19).

Four percent of patients (n=10) had a CR with incomplete platelet recovery, 18% (n=46) had a CR with incomplete hematological recovery, and 10% (n=25) had a partial response.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

AML cells

The European Commission (EC) has granted orphan designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).

Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and the AXL receptor.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology last June.

The study enrolled 252 adults with relapsed/refractory AML. They received gilteritinib once daily in 1 of 7 dose-escalation (n=23) or dose-expansion (n=229) cohorts.

The maximum tolerated dose was 300 mg/day. There were 2 dose-limiting toxicities in the 450 mg dose-escalation cohort—grade 3 diarrhea and grade 3 elevated aspartate aminotransferase.

Common treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and increased alanine aminotransferase (19%).

Serious adverse events related to treatment included febrile neutropenia (n=5), sepsis (n=2), acute renal failure (n=5), pyrexia (n=3), and bacteremia (n=1).

There were 7 deaths considered possibly or probably related to treatment—pulmonary embolism (200 mg/day), respiratory failure (120 mg/day), hemoptysis (80 mg/day), intracranial hemorrhage (20 mg/day), ventricular fibrillation (120 mg/day), septic shock (80 mg/day), and neutropenia (120 mg/day).

The overall response rate was 40% (100/249), and the complete response (CR) rate was 8% (n=19).

Four percent of patients (n=10) had a CR with incomplete platelet recovery, 18% (n=46) had a CR with incomplete hematological recovery, and 10% (n=25) had a partial response.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Photo courtesy of GSK

Novartis is planning to stop marketing ofatumumab (Arzerra®) outside the US, but the drug will still be available for certain patients.

The company plans to work with regulatory authorities to establish compassionate use programs for chronic lymphocytic leukemia (CLL) patients outside the US who are currently receiving ofatumumab.

Patients accessing these programs will be offered continued treatment with ofatumumab for as long as they benefit from it, free of charge.

And Novartis will continue to market ofatumumab for CLL in the US.

“Novartis’s intention to transition Arzerra to compassionate use programs in the non-US markets reflects the fact that many more drugs have become available for CLL over the last 5 years and that there is a low number of patients using Arzerra outside of the US market,” said Jan van de Winkel, PhD, chief executive officer of Genmab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

Because Novartis has decided to pull ofatumumab from non-US markets, the company will pay Genmab a lump sum of $50 million (USD) for lost potential milestones and royalties. Royalties will continue to be earned on net sales of the drug.

Novartis intends to start the transition to compassionate use programs as soon as the company and regulatory authorities have agreed to a plan.

The two phase 3 studies of ofatumumab in relapsing multiple sclerosis and the study in indolent non-Hodgkin lymphoma will not be affected by this change. All 3 trials will continue.

About ofatumumab

Ofatumumab is a monoclonal antibody designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

In more than 60 countries worldwide, including the US and European Union member countries, ofatumumab is approved as monotherapy for CLL patients who are refractory to treatment with fludarabine and alemtuzumab.

Other approved indications for ofatumumab in the European Union include:

• In combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy
• In combination with fludarabine and cyclophosphamide to treat adults with relapsed CLL.

Other approved indications for ofatumumab in the US include:

• In combination with chlorambucil to treat previously untreated CLL patients for whom fludarabine-based therapy is considered inappropriate
• In combination with fludarabine and cyclophosphamide to treat patients with relapsed CLL
• For extended treatment of patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL.
  

Photo courtesy of GSK

Novartis is planning to stop marketing ofatumumab (Arzerra®) outside the US, but the drug will still be available for certain patients.

The company plans to work with regulatory authorities to establish compassionate use programs for chronic lymphocytic leukemia (CLL) patients outside the US who are currently receiving ofatumumab.

Patients accessing these programs will be offered continued treatment with ofatumumab for as long as they benefit from it, free of charge.

And Novartis will continue to market ofatumumab for CLL in the US.

“Novartis’s intention to transition Arzerra to compassionate use programs in the non-US markets reflects the fact that many more drugs have become available for CLL over the last 5 years and that there is a low number of patients using Arzerra outside of the US market,” said Jan van de Winkel, PhD, chief executive officer of Genmab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

Because Novartis has decided to pull ofatumumab from non-US markets, the company will pay Genmab a lump sum of $50 million (USD) for lost potential milestones and royalties. Royalties will continue to be earned on net sales of the drug.

Novartis intends to start the transition to compassionate use programs as soon as the company and regulatory authorities have agreed to a plan.

The two phase 3 studies of ofatumumab in relapsing multiple sclerosis and the study in indolent non-Hodgkin lymphoma will not be affected by this change. All 3 trials will continue.

About ofatumumab

Ofatumumab is a monoclonal antibody designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

In more than 60 countries worldwide, including the US and European Union member countries, ofatumumab is approved as monotherapy for CLL patients who are refractory to treatment with fludarabine and alemtuzumab.

Other approved indications for ofatumumab in the European Union include:

• In combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy
• In combination with fludarabine and cyclophosphamide to treat adults with relapsed CLL.

Other approved indications for ofatumumab in the US include:

• In combination with chlorambucil to treat previously untreated CLL patients for whom fludarabine-based therapy is considered inappropriate
• In combination with fludarabine and cyclophosphamide to treat patients with relapsed CLL
• For extended treatment of patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL.
  

Photo courtesy of GSK

Novartis is planning to stop marketing ofatumumab (Arzerra®) outside the US, but the drug will still be available for certain patients.

The company plans to work with regulatory authorities to establish compassionate use programs for chronic lymphocytic leukemia (CLL) patients outside the US who are currently receiving ofatumumab.

Patients accessing these programs will be offered continued treatment with ofatumumab for as long as they benefit from it, free of charge.

And Novartis will continue to market ofatumumab for CLL in the US.

“Novartis’s intention to transition Arzerra to compassionate use programs in the non-US markets reflects the fact that many more drugs have become available for CLL over the last 5 years and that there is a low number of patients using Arzerra outside of the US market,” said Jan van de Winkel, PhD, chief executive officer of Genmab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

Because Novartis has decided to pull ofatumumab from non-US markets, the company will pay Genmab a lump sum of $50 million (USD) for lost potential milestones and royalties. Royalties will continue to be earned on net sales of the drug.

Novartis intends to start the transition to compassionate use programs as soon as the company and regulatory authorities have agreed to a plan.

The two phase 3 studies of ofatumumab in relapsing multiple sclerosis and the study in indolent non-Hodgkin lymphoma will not be affected by this change. All 3 trials will continue.

About ofatumumab

Ofatumumab is a monoclonal antibody designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

In more than 60 countries worldwide, including the US and European Union member countries, ofatumumab is approved as monotherapy for CLL patients who are refractory to treatment with fludarabine and alemtuzumab.

Other approved indications for ofatumumab in the European Union include:

• In combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy
• In combination with fludarabine and cyclophosphamide to treat adults with relapsed CLL.

Other approved indications for ofatumumab in the US include:

• In combination with chlorambucil to treat previously untreated CLL patients for whom fludarabine-based therapy is considered inappropriate
• In combination with fludarabine and cyclophosphamide to treat patients with relapsed CLL
• For extended treatment of patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL.
  

Inotuzumab ozogamicin appeared active and safe when added to reduced-intensity chemotherapy for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia, according to the results of a single-arm phase 2 study.

After a median follow-up of 29 months, 2-year progression-free survival was 59% with a median of 25 months for 52 patients with newly diagnosed disease who were aged 60 years or older, Hagop Kantarjian, MD, and his associates reported online in the Lancet Oncology.

Nearly every patient experienced an overall response (98%). The treatment also appeared to be safe, Dr. Kantarjian and associates wrote.

They reported that no patient died within 4 weeks of treatment and that four patients experienced veno-occlusive disease. Common grade 3 or 4 side effects included thrombocytopenia (81%), consolidation chemotherapy (69%), hyperglycemia (54%), infections during induction (52%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%). Six patients died from treatment-related side effects, five of whom died from sepsis and one of whom died as a result of veno-occlusive disease.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that is bound to the toxin calicheamicin. It has shown “substantial improvements” for some patient subgroups when added to hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine); however, older patients have yet to experience a similar benefit, Dr. Kantarjian and his associates said.

Both CVAD and inotuzumab ozogamicin have shown to be quite toxic for older patients. So – in order limit increased toxicity – Dr. Kantarjian and his associates lowered the intensity of hyper-CVAD. They accomplished this by reducing some aspects of the regimen by up to 50% and eliminating anthracyclines altogether. The researchers referred to this regimen as “mini–hyper-CVD.” The mini–hyper-CVD did not appear to impact activity.

“In our study, activity did not appear to be compromised by the use of lower-intensity chemotherapy in combination with a novel monoclonal antibody,” they wrote.

Dr. Kantarjian and his associates noted that, while they observed fewer deaths compared with previously published data, the number of deaths they did observe in patients who achieved a complete response was high.

They suggested that modifications to the regimen could further improve safety and that such modifications required further research.

For the time being, however, the researchers noted that this low-intensity regimen, in combination in inotuzumab ozogamicin, is highly effective and that these data now require prospective confirmation in a randomized, phase 3 setting.

The study was funded by the MD Anderson Cancer Center. Researchers reported that Pfizer provided inotuzumab ozogamicin free of charge and that Dr. Kantarjian and two other researchers received grants from Pfizer.

SOURCE: Kantarjian H et al. Lancet Oncol. 2018 Jan 15. doi: 10.1016/S1470-2945(18)30011-1.

Inotuzumab ozogamicin appeared active and safe when added to reduced-intensity chemotherapy for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia, according to the results of a single-arm phase 2 study.

After a median follow-up of 29 months, 2-year progression-free survival was 59% with a median of 25 months for 52 patients with newly diagnosed disease who were aged 60 years or older, Hagop Kantarjian, MD, and his associates reported online in the Lancet Oncology.

Nearly every patient experienced an overall response (98%). The treatment also appeared to be safe, Dr. Kantarjian and associates wrote.

They reported that no patient died within 4 weeks of treatment and that four patients experienced veno-occlusive disease. Common grade 3 or 4 side effects included thrombocytopenia (81%), consolidation chemotherapy (69%), hyperglycemia (54%), infections during induction (52%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%). Six patients died from treatment-related side effects, five of whom died from sepsis and one of whom died as a result of veno-occlusive disease.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that is bound to the toxin calicheamicin. It has shown “substantial improvements” for some patient subgroups when added to hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine); however, older patients have yet to experience a similar benefit, Dr. Kantarjian and his associates said.

Both CVAD and inotuzumab ozogamicin have shown to be quite toxic for older patients. So – in order limit increased toxicity – Dr. Kantarjian and his associates lowered the intensity of hyper-CVAD. They accomplished this by reducing some aspects of the regimen by up to 50% and eliminating anthracyclines altogether. The researchers referred to this regimen as “mini–hyper-CVD.” The mini–hyper-CVD did not appear to impact activity.

“In our study, activity did not appear to be compromised by the use of lower-intensity chemotherapy in combination with a novel monoclonal antibody,” they wrote.

Dr. Kantarjian and his associates noted that, while they observed fewer deaths compared with previously published data, the number of deaths they did observe in patients who achieved a complete response was high.

They suggested that modifications to the regimen could further improve safety and that such modifications required further research.

For the time being, however, the researchers noted that this low-intensity regimen, in combination in inotuzumab ozogamicin, is highly effective and that these data now require prospective confirmation in a randomized, phase 3 setting.

The study was funded by the MD Anderson Cancer Center. Researchers reported that Pfizer provided inotuzumab ozogamicin free of charge and that Dr. Kantarjian and two other researchers received grants from Pfizer.

SOURCE: Kantarjian H et al. Lancet Oncol. 2018 Jan 15. doi: 10.1016/S1470-2945(18)30011-1.

Inotuzumab ozogamicin appeared active and safe when added to reduced-intensity chemotherapy for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia, according to the results of a single-arm phase 2 study.

After a median follow-up of 29 months, 2-year progression-free survival was 59% with a median of 25 months for 52 patients with newly diagnosed disease who were aged 60 years or older, Hagop Kantarjian, MD, and his associates reported online in the Lancet Oncology.

Nearly every patient experienced an overall response (98%). The treatment also appeared to be safe, Dr. Kantarjian and associates wrote.

They reported that no patient died within 4 weeks of treatment and that four patients experienced veno-occlusive disease. Common grade 3 or 4 side effects included thrombocytopenia (81%), consolidation chemotherapy (69%), hyperglycemia (54%), infections during induction (52%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%). Six patients died from treatment-related side effects, five of whom died from sepsis and one of whom died as a result of veno-occlusive disease.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that is bound to the toxin calicheamicin. It has shown “substantial improvements” for some patient subgroups when added to hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine); however, older patients have yet to experience a similar benefit, Dr. Kantarjian and his associates said.

Both CVAD and inotuzumab ozogamicin have shown to be quite toxic for older patients. So – in order limit increased toxicity – Dr. Kantarjian and his associates lowered the intensity of hyper-CVAD. They accomplished this by reducing some aspects of the regimen by up to 50% and eliminating anthracyclines altogether. The researchers referred to this regimen as “mini–hyper-CVD.” The mini–hyper-CVD did not appear to impact activity.

“In our study, activity did not appear to be compromised by the use of lower-intensity chemotherapy in combination with a novel monoclonal antibody,” they wrote.

Dr. Kantarjian and his associates noted that, while they observed fewer deaths compared with previously published data, the number of deaths they did observe in patients who achieved a complete response was high.

They suggested that modifications to the regimen could further improve safety and that such modifications required further research.

For the time being, however, the researchers noted that this low-intensity regimen, in combination in inotuzumab ozogamicin, is highly effective and that these data now require prospective confirmation in a randomized, phase 3 setting.

The study was funded by the MD Anderson Cancer Center. Researchers reported that Pfizer provided inotuzumab ozogamicin free of charge and that Dr. Kantarjian and two other researchers received grants from Pfizer.

SOURCE: Kantarjian H et al. Lancet Oncol. 2018 Jan 15. doi: 10.1016/S1470-2945(18)30011-1.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.

Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.

Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.

The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.

“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.

Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m² of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.

Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.

“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.

Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.

In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.

The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.

“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.

The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.

Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.

Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.

The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.

“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.

Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m² of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.

Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.

“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.

Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.

In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.

The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.

“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.

The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.

Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.

Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.

The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.

“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.

Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m² of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.

Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.

“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.

Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.

In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.

The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.

“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.

The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.