Leukemia, Myelodysplasia, Transplantation

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

MONTREAL – Daratumumab may do for patients with T-cell acute lymphoblastic leukemia (T-ALL) what it has done for those with multiple myeloma. That, at least, is the hope of a team of investigators who are conducting preclinical studies and planning human trials of the CD38 inhibitor in leukemia.

“We believe daratumumab significantly inhibits disease progression as shown in our different [patient-derived xenograft] models,” said Karen L. Bride, MD, of Children’s Hospital of Philadelphia.

CD38 in T-ALL

Dr. Bride and her colleagues hope to bring daratumumab’s anti-CD38 action to bear on relapsed or refractory T-ALL.

“One of the reasons this is particularly challenging is that we find T-ALL is clinically and genetically heterogeneous,” she said. “With a number of different genetic mutations that have been identified, there are certainly some potentially targetable pathways. However, finding an appropriate target that can be broadly applicable is still needed.”

CD38 may be one such target. It is expressed at relatively high levels on both T-ALL and B-precursor ALL blasts but at only low levels on normal immune cells.

The investigators first used flow cytometry to measure CD38 levels in samples from 10 patients with early T-cell precursor (ETP) T-ALL and 11 with non-ETP disease, both at diagnosis and after 1 month of induction chemotherapy. CD38 expression was detectable in all of the samples and did not change significantly after chemotherapy, suggesting that CD38 was indeed a valid target in T-ALL.

They then grafted primary ALL blasts from patients with ETP-ALL and non-ETP-ALL into mice and randomly assigned them to be treated for 3 to 5 weeks with daratumumab or to serve as controls. The mice were initially treated after they developed more than 1% of peripheral blood blasts.

Daratumumab-treated models had significant reductions in disease burden as measured by blasts in both peripheral blood (P = .0112) and spleen (P = .0003).

There were six responses to daratumumab in the seven treated mice grafted with ETP-ALL and no cases of toxicity. Among the eight mice with non-ETP ALL, however, there was only one response, and five animals became moribund roughly 1 hour after injection.

The investigators could not find an explanation for these reactions either on necropsy or pathology studies.

“We hypothesized that there was potentially massive tumor lysis syndrome being experienced by the mice, and, as a consequence, they were becoming moribund,” Dr. Bride said.

In subsequent experiments, they have begun introducing the drug within 5 days of adoptive transfer, prior to full engraftment. This is akin to treating during a minimal residual disease phase, she said.

Despite the observed but unexplained toxicities in some animals, “our data are promising enough that we’re hopeful that we will open a phase I/II trial of daratumumab starting next year,” Dr. Bride said.
 

Not so fast

However, a pediatric hematologist/oncologist who was not involved in the study said in an interview that Dr. Bride and her colleagues would be wise not to proceed too quickly into human trials, at least until the potential toxicities of daratumumab in T-ALL have been more fully elucidated.

“I found it very striking that the mice responded the way they did, and that was just from receiving the drug. So, there is something else that’s going on, and I think it behooves them to investigate further. It’s not that I’m skeptical about the activity of the drug; I just don’t want studies to be shut down because the investigators didn’t have the best trial design,” said Valerie I. Brown, MD.

Dr. Brown, director of experimental therapeutics at Penn State Health Milton S. Hershey (Penn.) Medical Center, was a comoderator of the session where Dr. Bride presented the study findings.

Asked about her response to Dr. Brown’s comments in an interview, Dr. Bride said that “because of the success of daratumumab in humans already, I think I’m a bit less worried about this agent. You can’t necessarily translate exactly across diseases, but I do think it’s very promising, and I don’t think [the toxicity] is a reason to pull back.”

The study was supported by grants from the Leukemia and Lymphoma Society and the National Institutes of Health. Janssen donated the daratumumab. Dr. Bride and Dr. Brown reported no conflicts of interest to disclose.

[email protected]

MONTREAL – Daratumumab may do for patients with T-cell acute lymphoblastic leukemia (T-ALL) what it has done for those with multiple myeloma. That, at least, is the hope of a team of investigators who are conducting preclinical studies and planning human trials of the CD38 inhibitor in leukemia.

“We believe daratumumab significantly inhibits disease progression as shown in our different [patient-derived xenograft] models,” said Karen L. Bride, MD, of Children’s Hospital of Philadelphia.

CD38 in T-ALL

Dr. Bride and her colleagues hope to bring daratumumab’s anti-CD38 action to bear on relapsed or refractory T-ALL.

“One of the reasons this is particularly challenging is that we find T-ALL is clinically and genetically heterogeneous,” she said. “With a number of different genetic mutations that have been identified, there are certainly some potentially targetable pathways. However, finding an appropriate target that can be broadly applicable is still needed.”

CD38 may be one such target. It is expressed at relatively high levels on both T-ALL and B-precursor ALL blasts but at only low levels on normal immune cells.

The investigators first used flow cytometry to measure CD38 levels in samples from 10 patients with early T-cell precursor (ETP) T-ALL and 11 with non-ETP disease, both at diagnosis and after 1 month of induction chemotherapy. CD38 expression was detectable in all of the samples and did not change significantly after chemotherapy, suggesting that CD38 was indeed a valid target in T-ALL.

They then grafted primary ALL blasts from patients with ETP-ALL and non-ETP-ALL into mice and randomly assigned them to be treated for 3 to 5 weeks with daratumumab or to serve as controls. The mice were initially treated after they developed more than 1% of peripheral blood blasts.

Daratumumab-treated models had significant reductions in disease burden as measured by blasts in both peripheral blood (P = .0112) and spleen (P = .0003).

There were six responses to daratumumab in the seven treated mice grafted with ETP-ALL and no cases of toxicity. Among the eight mice with non-ETP ALL, however, there was only one response, and five animals became moribund roughly 1 hour after injection.

The investigators could not find an explanation for these reactions either on necropsy or pathology studies.

“We hypothesized that there was potentially massive tumor lysis syndrome being experienced by the mice, and, as a consequence, they were becoming moribund,” Dr. Bride said.

In subsequent experiments, they have begun introducing the drug within 5 days of adoptive transfer, prior to full engraftment. This is akin to treating during a minimal residual disease phase, she said.

Despite the observed but unexplained toxicities in some animals, “our data are promising enough that we’re hopeful that we will open a phase I/II trial of daratumumab starting next year,” Dr. Bride said.
 

Not so fast

However, a pediatric hematologist/oncologist who was not involved in the study said in an interview that Dr. Bride and her colleagues would be wise not to proceed too quickly into human trials, at least until the potential toxicities of daratumumab in T-ALL have been more fully elucidated.

“I found it very striking that the mice responded the way they did, and that was just from receiving the drug. So, there is something else that’s going on, and I think it behooves them to investigate further. It’s not that I’m skeptical about the activity of the drug; I just don’t want studies to be shut down because the investigators didn’t have the best trial design,” said Valerie I. Brown, MD.

Dr. Brown, director of experimental therapeutics at Penn State Health Milton S. Hershey (Penn.) Medical Center, was a comoderator of the session where Dr. Bride presented the study findings.

Asked about her response to Dr. Brown’s comments in an interview, Dr. Bride said that “because of the success of daratumumab in humans already, I think I’m a bit less worried about this agent. You can’t necessarily translate exactly across diseases, but I do think it’s very promising, and I don’t think [the toxicity] is a reason to pull back.”

The study was supported by grants from the Leukemia and Lymphoma Society and the National Institutes of Health. Janssen donated the daratumumab. Dr. Bride and Dr. Brown reported no conflicts of interest to disclose.

[email protected]

MONTREAL – Daratumumab may do for patients with T-cell acute lymphoblastic leukemia (T-ALL) what it has done for those with multiple myeloma. That, at least, is the hope of a team of investigators who are conducting preclinical studies and planning human trials of the CD38 inhibitor in leukemia.

“We believe daratumumab significantly inhibits disease progression as shown in our different [patient-derived xenograft] models,” said Karen L. Bride, MD, of Children’s Hospital of Philadelphia.

CD38 in T-ALL

Dr. Bride and her colleagues hope to bring daratumumab’s anti-CD38 action to bear on relapsed or refractory T-ALL.

“One of the reasons this is particularly challenging is that we find T-ALL is clinically and genetically heterogeneous,” she said. “With a number of different genetic mutations that have been identified, there are certainly some potentially targetable pathways. However, finding an appropriate target that can be broadly applicable is still needed.”

CD38 may be one such target. It is expressed at relatively high levels on both T-ALL and B-precursor ALL blasts but at only low levels on normal immune cells.

The investigators first used flow cytometry to measure CD38 levels in samples from 10 patients with early T-cell precursor (ETP) T-ALL and 11 with non-ETP disease, both at diagnosis and after 1 month of induction chemotherapy. CD38 expression was detectable in all of the samples and did not change significantly after chemotherapy, suggesting that CD38 was indeed a valid target in T-ALL.

They then grafted primary ALL blasts from patients with ETP-ALL and non-ETP-ALL into mice and randomly assigned them to be treated for 3 to 5 weeks with daratumumab or to serve as controls. The mice were initially treated after they developed more than 1% of peripheral blood blasts.

Daratumumab-treated models had significant reductions in disease burden as measured by blasts in both peripheral blood (P = .0112) and spleen (P = .0003).

There were six responses to daratumumab in the seven treated mice grafted with ETP-ALL and no cases of toxicity. Among the eight mice with non-ETP ALL, however, there was only one response, and five animals became moribund roughly 1 hour after injection.

The investigators could not find an explanation for these reactions either on necropsy or pathology studies.

“We hypothesized that there was potentially massive tumor lysis syndrome being experienced by the mice, and, as a consequence, they were becoming moribund,” Dr. Bride said.

In subsequent experiments, they have begun introducing the drug within 5 days of adoptive transfer, prior to full engraftment. This is akin to treating during a minimal residual disease phase, she said.

Despite the observed but unexplained toxicities in some animals, “our data are promising enough that we’re hopeful that we will open a phase I/II trial of daratumumab starting next year,” Dr. Bride said.
 

Not so fast

However, a pediatric hematologist/oncologist who was not involved in the study said in an interview that Dr. Bride and her colleagues would be wise not to proceed too quickly into human trials, at least until the potential toxicities of daratumumab in T-ALL have been more fully elucidated.

“I found it very striking that the mice responded the way they did, and that was just from receiving the drug. So, there is something else that’s going on, and I think it behooves them to investigate further. It’s not that I’m skeptical about the activity of the drug; I just don’t want studies to be shut down because the investigators didn’t have the best trial design,” said Valerie I. Brown, MD.

Dr. Brown, director of experimental therapeutics at Penn State Health Milton S. Hershey (Penn.) Medical Center, was a comoderator of the session where Dr. Bride presented the study findings.

Asked about her response to Dr. Brown’s comments in an interview, Dr. Bride said that “because of the success of daratumumab in humans already, I think I’m a bit less worried about this agent. You can’t necessarily translate exactly across diseases, but I do think it’s very promising, and I don’t think [the toxicity] is a reason to pull back.”

The study was supported by grants from the Leukemia and Lymphoma Society and the National Institutes of Health. Janssen donated the daratumumab. Dr. Bride and Dr. Brown reported no conflicts of interest to disclose.

[email protected]

Patients with chronic myeloid leukemia (CML) with high CD86⁺pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.

Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.

“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”

The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.

The frequency of CD86⁺pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.

The authors found that CML patients in molecular remission had a significantly higher frequency of CD86⁺pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86⁺pDC.

These results suggest that low CD86⁺pDC could be predictive of treatment-free remission.

To test the hypothesis that low CD86⁺pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86⁺pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.

Findings showed that the 122 EURO-SKI patients had a significantly higher CD86⁺pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).

When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86⁺pDC at baseline, compared with the 49 patients who did relapse (P = .014).

Patients who relapsed also demonstrated higher absolute CD86⁺pDC counts (CD86⁺pDC per 10⁵ lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).

Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”

The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.

Patients with chronic myeloid leukemia (CML) with high CD86⁺pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.

Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.

“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”

The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.

The frequency of CD86⁺pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.

The authors found that CML patients in molecular remission had a significantly higher frequency of CD86⁺pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86⁺pDC.

These results suggest that low CD86⁺pDC could be predictive of treatment-free remission.

To test the hypothesis that low CD86⁺pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86⁺pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.

Findings showed that the 122 EURO-SKI patients had a significantly higher CD86⁺pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).

When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86⁺pDC at baseline, compared with the 49 patients who did relapse (P = .014).

Patients who relapsed also demonstrated higher absolute CD86⁺pDC counts (CD86⁺pDC per 10⁵ lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).

Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”

The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.

Patients with chronic myeloid leukemia (CML) with high CD86⁺pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.

Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.

“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”

The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.

The frequency of CD86⁺pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.

The authors found that CML patients in molecular remission had a significantly higher frequency of CD86⁺pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86⁺pDC.

These results suggest that low CD86⁺pDC could be predictive of treatment-free remission.

To test the hypothesis that low CD86⁺pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86⁺pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.

Findings showed that the 122 EURO-SKI patients had a significantly higher CD86⁺pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).

When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86⁺pDC at baseline, compared with the 49 patients who did relapse (P = .014).

Patients who relapsed also demonstrated higher absolute CD86⁺pDC counts (CD86⁺pDC per 10⁵ lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).

Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”

The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

Photo by Trevor MacInnis

There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.

The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.

They also reviewed other recent studies investigating the health effects of formaldehyde.

“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.

Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.

The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).

The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.

In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.

The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.

The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.

Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”

Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.

The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.

Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”

Photo by Trevor MacInnis

There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.

The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.

They also reviewed other recent studies investigating the health effects of formaldehyde.

“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.

Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.

The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).

The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.

In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.

The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.

The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.

Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”

Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.

The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.

Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”

Photo by Trevor MacInnis

There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.

The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.

They also reviewed other recent studies investigating the health effects of formaldehyde.

“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.

Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.

The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).

The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.

In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.

The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.

The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.

Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”

Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.

The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.

Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”

AML cells

Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.

The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.

Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.

However, the company said it will continue developing the drug.

These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.

“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.

“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”

“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.” 

AML cells

Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.

The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.

Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.

However, the company said it will continue developing the drug.

These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.

“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.

“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”

“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.” 

AML cells

Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.

The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.

Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.

However, the company said it will continue developing the drug.

These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.

“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.

“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”

“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.” 

A diagnosis of chronic lymphocytic leukemia (CLL) usually occurs in people aged ≥ 72 years. But most clinical trials do not reflect that reality; thus, treatments and prognoses are based on younger patients’ experiences. Researchers from University of Pennsylvania, Emory University in Georgia, NorthShore University HealthSystem in Illinois, New York-Presbyterian Hospital/Columbia University Medical Center, Thomas Jefferson University in Pennsylvania, and Dana-Farber Cancer Institute in Massachusetts, conducted the largest comprehensive prospective evaluation of this patient population published to date to their knowledge to examine treatment patterns, outcomes, and disease-related mortality in CLL patients aged  ≥ 75 years in a real-world setting.

The researchers analyzed data from patients in the Connect® CLL registry, a prospective observational cohort study that took place between 2010 and 2014 at 199 U.S. sites. Of 1,494 patients enrolled in the registry, 259 patients aged  ≥ 75 years were enrolled within 2 months of starting first- line of therapy (LOT1), and 196 were enrolled in a subsequent line of therapy (LOT ≥ 2). The patients were almost entirely enrolled prior to the introduction of novel B-cell receptor-targeted therapies. The researchers say they aimed to establish a benchmark for outcomes in elderly patients with CLL who were treated before those therapies to help properly position newer agents in the treatment paradigm.

They found that elderly patients with CLL were more likely than were younger patients to receive rituximab monotherapy. In LOT ≥ 2 they were significantly less likely to receive bendamustine/rituximab. Only 6.9% of patients aged > 75 years received fludarabine/cyclophosphamide/rituximab, vs 33.7% of patients aged < 75 years. Interestingly, the researchers add, older patients were significantly more likely than were younger patients to receive chemotherapy alone without anti-CD20 antibody therapy.

Serious adverse events were more common in the elderly patients. Pneumonia was more common in elderly patients in LOT1; in LOT ≥ 2, rates of pneumonia were similar in both groups. In the follow-up with a median of 32.6 months, 433 of the 1,494 patients had died. Only 5% of patients aged < 75 years in LOT1 died of CLL, compared with 13% of elderly patients. Time to death from CLL or infection was also significantly shorter in patients aged > 75 years, compared with patients aged < 75 years. When stratified by risk, mortality due to CLL or infection was 10.3% in the lower risk group compared with 30.6% in the higher risk group.

The researchers identified 3 prognostic indicators: < 3 months from diagnosis to first treatment, enrollment therapy other than bendamustine/rituximab, and anemia. The researchers say the higher risk of CLL- or infection-related death has not, to their knowledge, been reported previously. This finding, they say, “highlights the urgent need for therapies tailored to this population.” Current therapies and strategies, they note, “appear suboptimal.”

Source:
Nabhan C, Mato A, Flowers CR, et al. BMC Cancer. 2017;17(1):198.
doi: 10.1186/s12885-017-3176-x.

A diagnosis of chronic lymphocytic leukemia (CLL) usually occurs in people aged ≥ 72 years. But most clinical trials do not reflect that reality; thus, treatments and prognoses are based on younger patients’ experiences. Researchers from University of Pennsylvania, Emory University in Georgia, NorthShore University HealthSystem in Illinois, New York-Presbyterian Hospital/Columbia University Medical Center, Thomas Jefferson University in Pennsylvania, and Dana-Farber Cancer Institute in Massachusetts, conducted the largest comprehensive prospective evaluation of this patient population published to date to their knowledge to examine treatment patterns, outcomes, and disease-related mortality in CLL patients aged  ≥ 75 years in a real-world setting.

The researchers analyzed data from patients in the Connect® CLL registry, a prospective observational cohort study that took place between 2010 and 2014 at 199 U.S. sites. Of 1,494 patients enrolled in the registry, 259 patients aged  ≥ 75 years were enrolled within 2 months of starting first- line of therapy (LOT1), and 196 were enrolled in a subsequent line of therapy (LOT ≥ 2). The patients were almost entirely enrolled prior to the introduction of novel B-cell receptor-targeted therapies. The researchers say they aimed to establish a benchmark for outcomes in elderly patients with CLL who were treated before those therapies to help properly position newer agents in the treatment paradigm.

They found that elderly patients with CLL were more likely than were younger patients to receive rituximab monotherapy. In LOT ≥ 2 they were significantly less likely to receive bendamustine/rituximab. Only 6.9% of patients aged > 75 years received fludarabine/cyclophosphamide/rituximab, vs 33.7% of patients aged < 75 years. Interestingly, the researchers add, older patients were significantly more likely than were younger patients to receive chemotherapy alone without anti-CD20 antibody therapy.

Serious adverse events were more common in the elderly patients. Pneumonia was more common in elderly patients in LOT1; in LOT ≥ 2, rates of pneumonia were similar in both groups. In the follow-up with a median of 32.6 months, 433 of the 1,494 patients had died. Only 5% of patients aged < 75 years in LOT1 died of CLL, compared with 13% of elderly patients. Time to death from CLL or infection was also significantly shorter in patients aged > 75 years, compared with patients aged < 75 years. When stratified by risk, mortality due to CLL or infection was 10.3% in the lower risk group compared with 30.6% in the higher risk group.

The researchers identified 3 prognostic indicators: < 3 months from diagnosis to first treatment, enrollment therapy other than bendamustine/rituximab, and anemia. The researchers say the higher risk of CLL- or infection-related death has not, to their knowledge, been reported previously. This finding, they say, “highlights the urgent need for therapies tailored to this population.” Current therapies and strategies, they note, “appear suboptimal.”

Source:
Nabhan C, Mato A, Flowers CR, et al. BMC Cancer. 2017;17(1):198.
doi: 10.1186/s12885-017-3176-x.

A diagnosis of chronic lymphocytic leukemia (CLL) usually occurs in people aged ≥ 72 years. But most clinical trials do not reflect that reality; thus, treatments and prognoses are based on younger patients’ experiences. Researchers from University of Pennsylvania, Emory University in Georgia, NorthShore University HealthSystem in Illinois, New York-Presbyterian Hospital/Columbia University Medical Center, Thomas Jefferson University in Pennsylvania, and Dana-Farber Cancer Institute in Massachusetts, conducted the largest comprehensive prospective evaluation of this patient population published to date to their knowledge to examine treatment patterns, outcomes, and disease-related mortality in CLL patients aged  ≥ 75 years in a real-world setting.

The researchers analyzed data from patients in the Connect® CLL registry, a prospective observational cohort study that took place between 2010 and 2014 at 199 U.S. sites. Of 1,494 patients enrolled in the registry, 259 patients aged  ≥ 75 years were enrolled within 2 months of starting first- line of therapy (LOT1), and 196 were enrolled in a subsequent line of therapy (LOT ≥ 2). The patients were almost entirely enrolled prior to the introduction of novel B-cell receptor-targeted therapies. The researchers say they aimed to establish a benchmark for outcomes in elderly patients with CLL who were treated before those therapies to help properly position newer agents in the treatment paradigm.

They found that elderly patients with CLL were more likely than were younger patients to receive rituximab monotherapy. In LOT ≥ 2 they were significantly less likely to receive bendamustine/rituximab. Only 6.9% of patients aged > 75 years received fludarabine/cyclophosphamide/rituximab, vs 33.7% of patients aged < 75 years. Interestingly, the researchers add, older patients were significantly more likely than were younger patients to receive chemotherapy alone without anti-CD20 antibody therapy.

Serious adverse events were more common in the elderly patients. Pneumonia was more common in elderly patients in LOT1; in LOT ≥ 2, rates of pneumonia were similar in both groups. In the follow-up with a median of 32.6 months, 433 of the 1,494 patients had died. Only 5% of patients aged < 75 years in LOT1 died of CLL, compared with 13% of elderly patients. Time to death from CLL or infection was also significantly shorter in patients aged > 75 years, compared with patients aged < 75 years. When stratified by risk, mortality due to CLL or infection was 10.3% in the lower risk group compared with 30.6% in the higher risk group.

The researchers identified 3 prognostic indicators: < 3 months from diagnosis to first treatment, enrollment therapy other than bendamustine/rituximab, and anemia. The researchers say the higher risk of CLL- or infection-related death has not, to their knowledge, been reported previously. This finding, they say, “highlights the urgent need for therapies tailored to this population.” Current therapies and strategies, they note, “appear suboptimal.”

Source:
Nabhan C, Mato A, Flowers CR, et al. BMC Cancer. 2017;17(1):198.
doi: 10.1186/s12885-017-3176-x.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved a ready-to-use oral solution of methotrexate (Xatmep) for use in certain pediatric patients.

The drug is approved as part of a multi-phase, combination chemotherapy maintenance regimen to treat pediatric patients with acute lymphoblastic leukemia.

Xatmep is also approved for use in pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient response to, or cannot tolerate, an adequate trial of first-line therapy, including full-dose non-steroidal anti-inflammatory agents.

Xatmep is the first ready-to-use oral solution of methotrexate to be approved by the FDA.

There was previously no such formulation of the drug approved for use in pediatric patients requiring body surface area dosing (mg/m²), patients who have difficulty swallowing or cannot consume tablets, or those with needle-phobia.

Xatmep (methotrexate) Oral Solution, 2.5 mg/mL, requires no preparation. It eliminates the need for needles, crushing or splitting tablets, or for compounding tablets into a liquid formulation.

Xatmep requires refrigeration but may be stored at room temperature for 60 days after dispensing.

For more on Xatmep, see the prescribing information, which includes a boxed warning detailing the risk of severe toxic reactions, including embryo-fetal toxicity.

Xatmep is available through pharmacies and a qualified mail-order service. For information on how to obtain the drug, call 1-855-379-0382.

Xatmep is a product of Silvergate Pharmaceuticals, Inc.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved a ready-to-use oral solution of methotrexate (Xatmep) for use in certain pediatric patients.

The drug is approved as part of a multi-phase, combination chemotherapy maintenance regimen to treat pediatric patients with acute lymphoblastic leukemia.

Xatmep is also approved for use in pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient response to, or cannot tolerate, an adequate trial of first-line therapy, including full-dose non-steroidal anti-inflammatory agents.

Xatmep is the first ready-to-use oral solution of methotrexate to be approved by the FDA.

There was previously no such formulation of the drug approved for use in pediatric patients requiring body surface area dosing (mg/m²), patients who have difficulty swallowing or cannot consume tablets, or those with needle-phobia.

Xatmep (methotrexate) Oral Solution, 2.5 mg/mL, requires no preparation. It eliminates the need for needles, crushing or splitting tablets, or for compounding tablets into a liquid formulation.

Xatmep requires refrigeration but may be stored at room temperature for 60 days after dispensing.

For more on Xatmep, see the prescribing information, which includes a boxed warning detailing the risk of severe toxic reactions, including embryo-fetal toxicity.

Xatmep is available through pharmacies and a qualified mail-order service. For information on how to obtain the drug, call 1-855-379-0382.

Xatmep is a product of Silvergate Pharmaceuticals, Inc.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved a ready-to-use oral solution of methotrexate (Xatmep) for use in certain pediatric patients.

The drug is approved as part of a multi-phase, combination chemotherapy maintenance regimen to treat pediatric patients with acute lymphoblastic leukemia.

Xatmep is also approved for use in pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient response to, or cannot tolerate, an adequate trial of first-line therapy, including full-dose non-steroidal anti-inflammatory agents.

Xatmep is the first ready-to-use oral solution of methotrexate to be approved by the FDA.

There was previously no such formulation of the drug approved for use in pediatric patients requiring body surface area dosing (mg/m²), patients who have difficulty swallowing or cannot consume tablets, or those with needle-phobia.

Xatmep (methotrexate) Oral Solution, 2.5 mg/mL, requires no preparation. It eliminates the need for needles, crushing or splitting tablets, or for compounding tablets into a liquid formulation.

Xatmep requires refrigeration but may be stored at room temperature for 60 days after dispensing.

For more on Xatmep, see the prescribing information, which includes a boxed warning detailing the risk of severe toxic reactions, including embryo-fetal toxicity.

Xatmep is available through pharmacies and a qualified mail-order service. For information on how to obtain the drug, call 1-855-379-0382.

Xatmep is a product of Silvergate Pharmaceuticals, Inc.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).

PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.

PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.

PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.

Results from this trial were published in Leukemia Research in November 2013.

The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.

Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.

The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.

The maximum-tolerated dose of PTX-200 was 55 mg/m². Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m² cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).

One dose-limiting toxicity (mucositis) occurred in the 35 mg/m² cohort. All DLTs resolved after patients stopped taking PTX-200.

Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).

Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.

Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).

PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.

PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.

PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.

Results from this trial were published in Leukemia Research in November 2013.

The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.

Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.

The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.

The maximum-tolerated dose of PTX-200 was 55 mg/m². Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m² cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).

One dose-limiting toxicity (mucositis) occurred in the 35 mg/m² cohort. All DLTs resolved after patients stopped taking PTX-200.

Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).

Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.

Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).

PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.

PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.

PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.

Results from this trial were published in Leukemia Research in November 2013.

The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.

Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.

The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.

The maximum-tolerated dose of PTX-200 was 55 mg/m². Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m² cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).

One dose-limiting toxicity (mucositis) occurred in the 35 mg/m² cohort. All DLTs resolved after patients stopped taking PTX-200.

Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).

Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.

Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.