Transplantation

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.

One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.

Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).

David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.

Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).

High response rate

The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.

All 16 patients analyzed had prior allogeneic

hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.

Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.

The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.

The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.

Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.

Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.

And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).

‘Promising’ donor immune modulation

Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.

Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.

Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.

The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.

Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.

And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.

Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.

*Information in the abstract differs from that presented at the meeting.

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.

One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.

Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).

David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.

Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).

High response rate

The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.

All 16 patients analyzed had prior allogeneic

hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.

Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.

The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.

The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.

Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.

Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.

And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).

‘Promising’ donor immune modulation

Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.

Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.

Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.

The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.

Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.

And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.

Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.

*Information in the abstract differs from that presented at the meeting.

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.

One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.

Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).

David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.

Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).

High response rate

The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.

All 16 patients analyzed had prior allogeneic

hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.

Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.

The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.

The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.

Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.

Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.

And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).

‘Promising’ donor immune modulation

Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.

Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.

Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.

The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.

Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.

And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.

Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Umbilical cord blood donation

Photo courtesy of NHS

SAN DIEGO—A product that promotes CD34 expansion has solved the problem of poor engraftment associated with umbilical cord blood transplant (UCBT), according to a speaker at the 2015 BMT Tandem Meetings.

John Wagner, MD, of the University of Minnesota in Minneapolis, supported this statement with early results from trials of HSC835, cord

blood units in which CD34 cells were expanded using the aryl hydrocarbon

receptor antagonist StemRegenin 1.

Dr Wagner and his colleagues conducted phase 1 and 2 trials of HSC835, which were supported by Novartis, the company developing the product.

Dr Wagner presented results of these trials at the BMT Tandem Meetings as abstract 29.*

The phase 1 trial included 18 patients who received double UCBT after myeloablative conditioning. They received an unmanipulated cord blood unit and an HSC835 unit.

In the phase 2 trial, 3 patients received a single HSC835 unit after myeloablative conditioning, and 3 received an HSC835 unit after non-myeloablative conditioning.

Manufacturing HSC835 took 15 days. Following expansion, the median CD34 cell dose increased 346-fold, and the median total nucleated cell (TNC) dose increased 848-fold.

Twenty-eight HSC835 products were produced, but 4 of them were not infused. Two products were contaminated, 1 was not infused due to patient relapse, and 1 product failed to expand. Dr Wagner noted that the failed unit started out at 50% viability, whereas the other units started at about 90% viability.

Phase 1

Eighteen patients were treated in the phase 1 trial. Eleven had acute lymphoblastic leukemia, 5 had acute myeloid leukemia, and 2 had myelodysplastic syndromes. The median age was 28 (range, 12 to 53).

The median TNC dose was 2.5 x 10⁷/kg for the unmanipulated cord blood unit and 5.1 x 10⁷/kg for the HSC835 unit. The median CD34 count was 0.4 x 10⁶/kg and 17.4 x 10⁶/kg, respectively. And the median CD3 count was 8.5 x 10⁶/kg and 2.5 x 10⁶/kg, respectively.

Most units were a 5/6 HLA match—50% for the unmanipulated unit and 67% for the HSC835 unit. Forty-four percent and 22% of the units, respectively, were 4/6 matches. And 6% and 11%, respectively, were 6/6 matches.

Neutrophil recovery was 100%, and the median time to recovery was 14.5 days.

Dr Wagner compared this to results in 121 matched historical controls who received UCBT with 2 unmanipulated units. Of those patients, 86% achieved neutrophil engraftment, and the median time to engraftment was 25 days (P<0.001).

In the current study, 6 patients had complete chimerism with HSC835, 6 had complete chimerism with the unmanipulated unit, and 6 had dual chimerism. In the dual-chimerism patients, both units were present, but all the T cells were derived from the unmanipulated unit.

“When we look at those patients who had engraftment of HSC835, whether it be this dual chimerism or complete chimerism, you see there is a very rapid recovery of 10.5 days, as compared to the historical control [recovery time] of 25 days,” Dr Wagner said. “And those that engrafted with the unmanipulated unit fall right where you’d expect them; that is, with the historical controls [23 days].”

Dr Wagner noted that the CD34 dose correlated with the pace of neutrophil recovery in patients who engrafted with the HSC835 unit, and patients with dual chimerism had the fastest neutrophil recovery.

Furthermore, the HSC835 unit predominated more than expected (P=0.05), winning out over the cord blood unit with a higher CD3 dose a disproportionate amount of time. The unit with a higher CD3 dose typically predominates two-thirds of the time in double UCBT.

“[These results] gave us enough information to say that [HSC835] could be a stand-alone product,” Dr Wagner said.

Phase 2

For phase 2, the researchers used a single HSC835 unit. They chose the lesser of 2 cord blood units (keeping the better unit as a backup), expanded it, and infused the resulting HSC835 unit into 3 patients who received myeloablative conditioning and 3 patients who did not.

In patients who received myeloablative conditioning, chimerism was complete at days 8, 12, and 14. Among the patients who received non-myeloablative conditioning, 1 had mixed chimerism at day 6. The other 2 had complete chimerism at days 5 and 7.

“So in conclusion, we believe that HSC835 is safe and effective in speeding neutrophil recovery after cord blood transplant,” Dr Wagner said. “These are very promising early results that compel us now to explore the single expanded product.”

Dr Wagner added that other considerations for HSC835 are that it may reduce the unit selection threshold, improve HLA match, enable re-cryopreservation (for transplant delays, backup, or multiple dosing), and perhaps allow for reduced-intensity conditioning with “mega-dose” grafts.

*Information in the abstract differs from that presented at the meeting.

Umbilical cord blood donation

Photo courtesy of NHS

SAN DIEGO—A product that promotes CD34 expansion has solved the problem of poor engraftment associated with umbilical cord blood transplant (UCBT), according to a speaker at the 2015 BMT Tandem Meetings.

John Wagner, MD, of the University of Minnesota in Minneapolis, supported this statement with early results from trials of HSC835, cord

blood units in which CD34 cells were expanded using the aryl hydrocarbon

receptor antagonist StemRegenin 1.

Dr Wagner and his colleagues conducted phase 1 and 2 trials of HSC835, which were supported by Novartis, the company developing the product.

Dr Wagner presented results of these trials at the BMT Tandem Meetings as abstract 29.*

The phase 1 trial included 18 patients who received double UCBT after myeloablative conditioning. They received an unmanipulated cord blood unit and an HSC835 unit.

In the phase 2 trial, 3 patients received a single HSC835 unit after myeloablative conditioning, and 3 received an HSC835 unit after non-myeloablative conditioning.

Manufacturing HSC835 took 15 days. Following expansion, the median CD34 cell dose increased 346-fold, and the median total nucleated cell (TNC) dose increased 848-fold.

Twenty-eight HSC835 products were produced, but 4 of them were not infused. Two products were contaminated, 1 was not infused due to patient relapse, and 1 product failed to expand. Dr Wagner noted that the failed unit started out at 50% viability, whereas the other units started at about 90% viability.

Phase 1

Eighteen patients were treated in the phase 1 trial. Eleven had acute lymphoblastic leukemia, 5 had acute myeloid leukemia, and 2 had myelodysplastic syndromes. The median age was 28 (range, 12 to 53).

The median TNC dose was 2.5 x 10⁷/kg for the unmanipulated cord blood unit and 5.1 x 10⁷/kg for the HSC835 unit. The median CD34 count was 0.4 x 10⁶/kg and 17.4 x 10⁶/kg, respectively. And the median CD3 count was 8.5 x 10⁶/kg and 2.5 x 10⁶/kg, respectively.

Most units were a 5/6 HLA match—50% for the unmanipulated unit and 67% for the HSC835 unit. Forty-four percent and 22% of the units, respectively, were 4/6 matches. And 6% and 11%, respectively, were 6/6 matches.

Neutrophil recovery was 100%, and the median time to recovery was 14.5 days.

Dr Wagner compared this to results in 121 matched historical controls who received UCBT with 2 unmanipulated units. Of those patients, 86% achieved neutrophil engraftment, and the median time to engraftment was 25 days (P<0.001).

In the current study, 6 patients had complete chimerism with HSC835, 6 had complete chimerism with the unmanipulated unit, and 6 had dual chimerism. In the dual-chimerism patients, both units were present, but all the T cells were derived from the unmanipulated unit.

“When we look at those patients who had engraftment of HSC835, whether it be this dual chimerism or complete chimerism, you see there is a very rapid recovery of 10.5 days, as compared to the historical control [recovery time] of 25 days,” Dr Wagner said. “And those that engrafted with the unmanipulated unit fall right where you’d expect them; that is, with the historical controls [23 days].”

Dr Wagner noted that the CD34 dose correlated with the pace of neutrophil recovery in patients who engrafted with the HSC835 unit, and patients with dual chimerism had the fastest neutrophil recovery.

Furthermore, the HSC835 unit predominated more than expected (P=0.05), winning out over the cord blood unit with a higher CD3 dose a disproportionate amount of time. The unit with a higher CD3 dose typically predominates two-thirds of the time in double UCBT.

“[These results] gave us enough information to say that [HSC835] could be a stand-alone product,” Dr Wagner said.

Phase 2

For phase 2, the researchers used a single HSC835 unit. They chose the lesser of 2 cord blood units (keeping the better unit as a backup), expanded it, and infused the resulting HSC835 unit into 3 patients who received myeloablative conditioning and 3 patients who did not.

In patients who received myeloablative conditioning, chimerism was complete at days 8, 12, and 14. Among the patients who received non-myeloablative conditioning, 1 had mixed chimerism at day 6. The other 2 had complete chimerism at days 5 and 7.

“So in conclusion, we believe that HSC835 is safe and effective in speeding neutrophil recovery after cord blood transplant,” Dr Wagner said. “These are very promising early results that compel us now to explore the single expanded product.”

Dr Wagner added that other considerations for HSC835 are that it may reduce the unit selection threshold, improve HLA match, enable re-cryopreservation (for transplant delays, backup, or multiple dosing), and perhaps allow for reduced-intensity conditioning with “mega-dose” grafts.

*Information in the abstract differs from that presented at the meeting.

Umbilical cord blood donation

Photo courtesy of NHS

SAN DIEGO—A product that promotes CD34 expansion has solved the problem of poor engraftment associated with umbilical cord blood transplant (UCBT), according to a speaker at the 2015 BMT Tandem Meetings.

John Wagner, MD, of the University of Minnesota in Minneapolis, supported this statement with early results from trials of HSC835, cord

blood units in which CD34 cells were expanded using the aryl hydrocarbon

receptor antagonist StemRegenin 1.

Dr Wagner and his colleagues conducted phase 1 and 2 trials of HSC835, which were supported by Novartis, the company developing the product.

Dr Wagner presented results of these trials at the BMT Tandem Meetings as abstract 29.*

The phase 1 trial included 18 patients who received double UCBT after myeloablative conditioning. They received an unmanipulated cord blood unit and an HSC835 unit.

In the phase 2 trial, 3 patients received a single HSC835 unit after myeloablative conditioning, and 3 received an HSC835 unit after non-myeloablative conditioning.

Manufacturing HSC835 took 15 days. Following expansion, the median CD34 cell dose increased 346-fold, and the median total nucleated cell (TNC) dose increased 848-fold.

Twenty-eight HSC835 products were produced, but 4 of them were not infused. Two products were contaminated, 1 was not infused due to patient relapse, and 1 product failed to expand. Dr Wagner noted that the failed unit started out at 50% viability, whereas the other units started at about 90% viability.

Phase 1

Eighteen patients were treated in the phase 1 trial. Eleven had acute lymphoblastic leukemia, 5 had acute myeloid leukemia, and 2 had myelodysplastic syndromes. The median age was 28 (range, 12 to 53).

The median TNC dose was 2.5 x 10⁷/kg for the unmanipulated cord blood unit and 5.1 x 10⁷/kg for the HSC835 unit. The median CD34 count was 0.4 x 10⁶/kg and 17.4 x 10⁶/kg, respectively. And the median CD3 count was 8.5 x 10⁶/kg and 2.5 x 10⁶/kg, respectively.

Most units were a 5/6 HLA match—50% for the unmanipulated unit and 67% for the HSC835 unit. Forty-four percent and 22% of the units, respectively, were 4/6 matches. And 6% and 11%, respectively, were 6/6 matches.

Neutrophil recovery was 100%, and the median time to recovery was 14.5 days.

Dr Wagner compared this to results in 121 matched historical controls who received UCBT with 2 unmanipulated units. Of those patients, 86% achieved neutrophil engraftment, and the median time to engraftment was 25 days (P<0.001).

In the current study, 6 patients had complete chimerism with HSC835, 6 had complete chimerism with the unmanipulated unit, and 6 had dual chimerism. In the dual-chimerism patients, both units were present, but all the T cells were derived from the unmanipulated unit.

“When we look at those patients who had engraftment of HSC835, whether it be this dual chimerism or complete chimerism, you see there is a very rapid recovery of 10.5 days, as compared to the historical control [recovery time] of 25 days,” Dr Wagner said. “And those that engrafted with the unmanipulated unit fall right where you’d expect them; that is, with the historical controls [23 days].”

Dr Wagner noted that the CD34 dose correlated with the pace of neutrophil recovery in patients who engrafted with the HSC835 unit, and patients with dual chimerism had the fastest neutrophil recovery.

Furthermore, the HSC835 unit predominated more than expected (P=0.05), winning out over the cord blood unit with a higher CD3 dose a disproportionate amount of time. The unit with a higher CD3 dose typically predominates two-thirds of the time in double UCBT.

“[These results] gave us enough information to say that [HSC835] could be a stand-alone product,” Dr Wagner said.

Phase 2

For phase 2, the researchers used a single HSC835 unit. They chose the lesser of 2 cord blood units (keeping the better unit as a backup), expanded it, and infused the resulting HSC835 unit into 3 patients who received myeloablative conditioning and 3 patients who did not.

In patients who received myeloablative conditioning, chimerism was complete at days 8, 12, and 14. Among the patients who received non-myeloablative conditioning, 1 had mixed chimerism at day 6. The other 2 had complete chimerism at days 5 and 7.

“So in conclusion, we believe that HSC835 is safe and effective in speeding neutrophil recovery after cord blood transplant,” Dr Wagner said. “These are very promising early results that compel us now to explore the single expanded product.”

Dr Wagner added that other considerations for HSC835 are that it may reduce the unit selection threshold, improve HLA match, enable re-cryopreservation (for transplant delays, backup, or multiple dosing), and perhaps allow for reduced-intensity conditioning with “mega-dose” grafts.

*Information in the abstract differs from that presented at the meeting.

Mesenchymal stem cells

SAN DIEGO—Infusions of expanded mesenchymal stem cells (MSCs) can treat severe, steroid-resistant, acute graft-vs-host disease (aGVHD) in pediatric patients, according to a study presented at the 2015 BMT Tandem Meetings.

The MSC product, known as remestemcel-L, induced responses in all grades of aGVHD and all organ systems.

Response at day 28 was associated with improved survival at day 100, and clinically significant toxicities were minimal, according to investigators.

“The enrolled patients represent a very challenging population with severe graft-vs-host disease that was non-responsive to treatments, including steroids and, for many of these children, multiple immunosuppressive agents, so we believe these results are very promising,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.

Dr Kurtzberg and her colleagues reported the results in a poster presentation (abstract 492*). Three investigators involved in this research are employed by Mesoblast, Inc., the company developing remestemcel-L.

The study included 160 patients who had a median age of 10 years (range, 0.3 to 17.5 years). Eighty-four percent of patients had received an unrelated donor transplant, and 46% received a mismatched transplant.

At baseline, 19% of patients had grade B aGVHD, 28% had grade C, and 53% had grade D. Eighty-nine percent of patients had gastrointestinal involvement, 50% had skin involvement, and 29% had liver involvement. Forty-one percent of patients had 2 organs involved, and 15% had 3.

The median duration of aGVHD before study enrollment was 28 days (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents.

Treatment and outcomes

Patients received 8 bi-weekly, intravenous infusions of 2 × 10⁶ MSCs/kg for 4 weeks. They could receive additional weekly infusions if deemed eligible at day 28.

The patients received a median of 11 infusions (range, 1-20) and were exposed to the treatment for a median of 43.5 days.

Fifty-three percent of patients had at least 1 serious adverse event. Eight patients (5%) had serious events that investigators thought might be treatment-related. These included neutropenia, infusion-related reaction, pulmonary hemorrhage, respiratory distress, tachycardia, respiratory failure, and hypertension.

Three events (6%) that were considered possibly treatment-related (pulmonary hemorrhage, respiratory distress, and respiratory failure) ultimately resulted in death. Fifty-four patients (34%) died in all.

At day 28, the overall response rate (ORR) was 64%. The ORR was 74% for grade B aGVHD, 66% for grade C, and 59% for grade D. The ORR was 62% for gastrointestinal, 77% for skin, and 53% for liver aGVHD.

Response correlated with a significant improvement in survival at day 100. Eighty-one percent of patients who responded at day 28 were still alive at day 100, compared to 21% of non-responders (P<0.0001).

The investigators said this study provides support for remestemcel-L to treat aGVHD in children. A single-arm, phase 3 trial of pediatric patients with aGVHD is underway.

*Information in the abstract differs from that presented at the meeting.

Mesenchymal stem cells

SAN DIEGO—Infusions of expanded mesenchymal stem cells (MSCs) can treat severe, steroid-resistant, acute graft-vs-host disease (aGVHD) in pediatric patients, according to a study presented at the 2015 BMT Tandem Meetings.

The MSC product, known as remestemcel-L, induced responses in all grades of aGVHD and all organ systems.

Response at day 28 was associated with improved survival at day 100, and clinically significant toxicities were minimal, according to investigators.

“The enrolled patients represent a very challenging population with severe graft-vs-host disease that was non-responsive to treatments, including steroids and, for many of these children, multiple immunosuppressive agents, so we believe these results are very promising,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.

Dr Kurtzberg and her colleagues reported the results in a poster presentation (abstract 492*). Three investigators involved in this research are employed by Mesoblast, Inc., the company developing remestemcel-L.

The study included 160 patients who had a median age of 10 years (range, 0.3 to 17.5 years). Eighty-four percent of patients had received an unrelated donor transplant, and 46% received a mismatched transplant.

At baseline, 19% of patients had grade B aGVHD, 28% had grade C, and 53% had grade D. Eighty-nine percent of patients had gastrointestinal involvement, 50% had skin involvement, and 29% had liver involvement. Forty-one percent of patients had 2 organs involved, and 15% had 3.

The median duration of aGVHD before study enrollment was 28 days (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents.

Treatment and outcomes

Patients received 8 bi-weekly, intravenous infusions of 2 × 10⁶ MSCs/kg for 4 weeks. They could receive additional weekly infusions if deemed eligible at day 28.

The patients received a median of 11 infusions (range, 1-20) and were exposed to the treatment for a median of 43.5 days.

Fifty-three percent of patients had at least 1 serious adverse event. Eight patients (5%) had serious events that investigators thought might be treatment-related. These included neutropenia, infusion-related reaction, pulmonary hemorrhage, respiratory distress, tachycardia, respiratory failure, and hypertension.

Three events (6%) that were considered possibly treatment-related (pulmonary hemorrhage, respiratory distress, and respiratory failure) ultimately resulted in death. Fifty-four patients (34%) died in all.

At day 28, the overall response rate (ORR) was 64%. The ORR was 74% for grade B aGVHD, 66% for grade C, and 59% for grade D. The ORR was 62% for gastrointestinal, 77% for skin, and 53% for liver aGVHD.

Response correlated with a significant improvement in survival at day 100. Eighty-one percent of patients who responded at day 28 were still alive at day 100, compared to 21% of non-responders (P<0.0001).

The investigators said this study provides support for remestemcel-L to treat aGVHD in children. A single-arm, phase 3 trial of pediatric patients with aGVHD is underway.

*Information in the abstract differs from that presented at the meeting.

Mesenchymal stem cells

SAN DIEGO—Infusions of expanded mesenchymal stem cells (MSCs) can treat severe, steroid-resistant, acute graft-vs-host disease (aGVHD) in pediatric patients, according to a study presented at the 2015 BMT Tandem Meetings.

The MSC product, known as remestemcel-L, induced responses in all grades of aGVHD and all organ systems.

Response at day 28 was associated with improved survival at day 100, and clinically significant toxicities were minimal, according to investigators.

“The enrolled patients represent a very challenging population with severe graft-vs-host disease that was non-responsive to treatments, including steroids and, for many of these children, multiple immunosuppressive agents, so we believe these results are very promising,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.

Dr Kurtzberg and her colleagues reported the results in a poster presentation (abstract 492*). Three investigators involved in this research are employed by Mesoblast, Inc., the company developing remestemcel-L.

The study included 160 patients who had a median age of 10 years (range, 0.3 to 17.5 years). Eighty-four percent of patients had received an unrelated donor transplant, and 46% received a mismatched transplant.

At baseline, 19% of patients had grade B aGVHD, 28% had grade C, and 53% had grade D. Eighty-nine percent of patients had gastrointestinal involvement, 50% had skin involvement, and 29% had liver involvement. Forty-one percent of patients had 2 organs involved, and 15% had 3.

The median duration of aGVHD before study enrollment was 28 days (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents.

Treatment and outcomes

Patients received 8 bi-weekly, intravenous infusions of 2 × 10⁶ MSCs/kg for 4 weeks. They could receive additional weekly infusions if deemed eligible at day 28.

The patients received a median of 11 infusions (range, 1-20) and were exposed to the treatment for a median of 43.5 days.

Fifty-three percent of patients had at least 1 serious adverse event. Eight patients (5%) had serious events that investigators thought might be treatment-related. These included neutropenia, infusion-related reaction, pulmonary hemorrhage, respiratory distress, tachycardia, respiratory failure, and hypertension.

Three events (6%) that were considered possibly treatment-related (pulmonary hemorrhage, respiratory distress, and respiratory failure) ultimately resulted in death. Fifty-four patients (34%) died in all.

At day 28, the overall response rate (ORR) was 64%. The ORR was 74% for grade B aGVHD, 66% for grade C, and 59% for grade D. The ORR was 62% for gastrointestinal, 77% for skin, and 53% for liver aGVHD.

Response correlated with a significant improvement in survival at day 100. Eighty-one percent of patients who responded at day 28 were still alive at day 100, compared to 21% of non-responders (P<0.0001).

The investigators said this study provides support for remestemcel-L to treat aGVHD in children. A single-arm, phase 3 trial of pediatric patients with aGVHD is underway.

*Information in the abstract differs from that presented at the meeting.

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

*Information in the abstract differs from that presented at the meeting.

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

*Information in the abstract differs from that presented at the meeting.

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

*Information in the abstract differs from that presented at the meeting.

HSCT preparation

Photo by Chad McNeeley

Leukocyte telomere length is associated with survival in patients who undergo hematopoietic stem cell transplant (HSCT) to treat severe aplastic anemia, according to research published in JAMA.

But it’s the donor’s telomere length—not the recipient’s—that makes the difference, the study showed.

Patients who received an HSCT from an unrelated donor had better overall survival at 5 years if that donor’s leukocytes had longer telomeres.

Shahinaz M. Gadalla, MD, PhD, of the National Cancer Institute in Rockville, Maryland, and colleagues conducted this research.

The group compared recipient and donor leukocyte telomere length prior to transplant with outcomes after unrelated HSCT for 330 patients with severe aplastic anemia.

The patients and their donors had pre-HSCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HSCT between 1989 and 2007 in 84 centers and were followed until March 2013.

The researchers categorized leukocyte telomere length for both recipients and donors based on the leukocyte telomere length tertiles in the donors: long (third tertile) and short (first and second tertiles combined).

The team found that longer donor leukocyte telomere length was associated with a higher overall survival. The 5-year overall survival was 56% in the longer telomere group and 40% in the shorter telomere group (P=0.009).

After adjusting for donor age and clinical factors associated with survival following HSCT in severe aplastic anemia, the risk of post-HSCT all-cause mortality remained approximately 40% lower in patients receiving HSCT from donors with long vs short leukocyte telomeres (hazard ratio [HR]=0.61).

There was no association between donor leukocyte telomere length and engraftment at 28 days (HR=0.94). Likewise, there was no association between telomere length and acute (HR=0.77) or chronic graft-vs-host disease (HR=0.81).

And recipient telomere length was not associated with overall survival (HR=0.91).

The researchers said these results suggest that donor leukocyte telomere length may have a role in long-term post-transplant survival. Authors of a related editorial explored what this discovery could mean for transplant centers.

HSCT preparation

Photo by Chad McNeeley

Leukocyte telomere length is associated with survival in patients who undergo hematopoietic stem cell transplant (HSCT) to treat severe aplastic anemia, according to research published in JAMA.

But it’s the donor’s telomere length—not the recipient’s—that makes the difference, the study showed.

Patients who received an HSCT from an unrelated donor had better overall survival at 5 years if that donor’s leukocytes had longer telomeres.

Shahinaz M. Gadalla, MD, PhD, of the National Cancer Institute in Rockville, Maryland, and colleagues conducted this research.

The group compared recipient and donor leukocyte telomere length prior to transplant with outcomes after unrelated HSCT for 330 patients with severe aplastic anemia.

The patients and their donors had pre-HSCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HSCT between 1989 and 2007 in 84 centers and were followed until March 2013.

The researchers categorized leukocyte telomere length for both recipients and donors based on the leukocyte telomere length tertiles in the donors: long (third tertile) and short (first and second tertiles combined).

The team found that longer donor leukocyte telomere length was associated with a higher overall survival. The 5-year overall survival was 56% in the longer telomere group and 40% in the shorter telomere group (P=0.009).

After adjusting for donor age and clinical factors associated with survival following HSCT in severe aplastic anemia, the risk of post-HSCT all-cause mortality remained approximately 40% lower in patients receiving HSCT from donors with long vs short leukocyte telomeres (hazard ratio [HR]=0.61).

There was no association between donor leukocyte telomere length and engraftment at 28 days (HR=0.94). Likewise, there was no association between telomere length and acute (HR=0.77) or chronic graft-vs-host disease (HR=0.81).

And recipient telomere length was not associated with overall survival (HR=0.91).

The researchers said these results suggest that donor leukocyte telomere length may have a role in long-term post-transplant survival. Authors of a related editorial explored what this discovery could mean for transplant centers.

HSCT preparation

Photo by Chad McNeeley

Leukocyte telomere length is associated with survival in patients who undergo hematopoietic stem cell transplant (HSCT) to treat severe aplastic anemia, according to research published in JAMA.

But it’s the donor’s telomere length—not the recipient’s—that makes the difference, the study showed.

Patients who received an HSCT from an unrelated donor had better overall survival at 5 years if that donor’s leukocytes had longer telomeres.

Shahinaz M. Gadalla, MD, PhD, of the National Cancer Institute in Rockville, Maryland, and colleagues conducted this research.

The group compared recipient and donor leukocyte telomere length prior to transplant with outcomes after unrelated HSCT for 330 patients with severe aplastic anemia.

The patients and their donors had pre-HSCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HSCT between 1989 and 2007 in 84 centers and were followed until March 2013.

The researchers categorized leukocyte telomere length for both recipients and donors based on the leukocyte telomere length tertiles in the donors: long (third tertile) and short (first and second tertiles combined).

The team found that longer donor leukocyte telomere length was associated with a higher overall survival. The 5-year overall survival was 56% in the longer telomere group and 40% in the shorter telomere group (P=0.009).

After adjusting for donor age and clinical factors associated with survival following HSCT in severe aplastic anemia, the risk of post-HSCT all-cause mortality remained approximately 40% lower in patients receiving HSCT from donors with long vs short leukocyte telomeres (hazard ratio [HR]=0.61).

There was no association between donor leukocyte telomere length and engraftment at 28 days (HR=0.94). Likewise, there was no association between telomere length and acute (HR=0.77) or chronic graft-vs-host disease (HR=0.81).

And recipient telomere length was not associated with overall survival (HR=0.91).

The researchers said these results suggest that donor leukocyte telomere length may have a role in long-term post-transplant survival. Authors of a related editorial explored what this discovery could mean for transplant centers.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Micrograph showing

CMV infection

Transplanting a small number of antiviral memory T cells along with donor hematopoietic stem cells can fight and may even prevent cytomegalovirus (CMV) disease in transplant recipients, according to preclinical research published in the Journal of Immunology.

To date, researchers have focused on developing anti-CMV immunotherapy with effector-phenotype CD8⁺ T cells (T_EFF cells), which attack and kill virally infected host cells.

But Christopher Snyder, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania, and his colleagues found that CMV-specific T_EFF cells divide poorly in response to CMV infection or reactivation in mouse models.

So they wondered if CMV-specific memory-phenotype CD8⁺ T cells (T_M cells)—which act more like stem cells—could help control the infection long-term.

The group showed that a small number of T_M cells were enough to produce and repeatedly replenish all of the T_EFF cells needed to fight CMV.

The infused T_M cells became major contributors to the recipient antiviral immune response, persisting for at least 3 months’ time and producing T_EFF cells at a steady stream.

To determine whether these cells have counterparts in humans, Dr Snyder and his colleagues compared the genomic fingerprints of mouse and human T_M cells that were specific for CMV. Results showed the two had similar profiles.

“This suggested that human and mouse CMV-specific memory T cells are very similar populations,” said study author Michael Quinn, an MD/PhD student at Thomas Jefferson University.

“Therefore, infusing similar cells into humans could improve on immunotherapeutic methods for controlling CMV infection. This may be a valuable approach to keep the disease from emerging in people.”

Dr Snyder added, “Our data argue for developing new clinical trials focused specifically on using these T memory cells, in order to determine if it would indeed be better than current therapeutic options.”

Micrograph showing

CMV infection

Transplanting a small number of antiviral memory T cells along with donor hematopoietic stem cells can fight and may even prevent cytomegalovirus (CMV) disease in transplant recipients, according to preclinical research published in the Journal of Immunology.

To date, researchers have focused on developing anti-CMV immunotherapy with effector-phenotype CD8⁺ T cells (T_EFF cells), which attack and kill virally infected host cells.

But Christopher Snyder, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania, and his colleagues found that CMV-specific T_EFF cells divide poorly in response to CMV infection or reactivation in mouse models.

So they wondered if CMV-specific memory-phenotype CD8⁺ T cells (T_M cells)—which act more like stem cells—could help control the infection long-term.

The group showed that a small number of T_M cells were enough to produce and repeatedly replenish all of the T_EFF cells needed to fight CMV.

The infused T_M cells became major contributors to the recipient antiviral immune response, persisting for at least 3 months’ time and producing T_EFF cells at a steady stream.

To determine whether these cells have counterparts in humans, Dr Snyder and his colleagues compared the genomic fingerprints of mouse and human T_M cells that were specific for CMV. Results showed the two had similar profiles.

“This suggested that human and mouse CMV-specific memory T cells are very similar populations,” said study author Michael Quinn, an MD/PhD student at Thomas Jefferson University.

“Therefore, infusing similar cells into humans could improve on immunotherapeutic methods for controlling CMV infection. This may be a valuable approach to keep the disease from emerging in people.”

Dr Snyder added, “Our data argue for developing new clinical trials focused specifically on using these T memory cells, in order to determine if it would indeed be better than current therapeutic options.”

Micrograph showing

CMV infection

Transplanting a small number of antiviral memory T cells along with donor hematopoietic stem cells can fight and may even prevent cytomegalovirus (CMV) disease in transplant recipients, according to preclinical research published in the Journal of Immunology.

To date, researchers have focused on developing anti-CMV immunotherapy with effector-phenotype CD8⁺ T cells (T_EFF cells), which attack and kill virally infected host cells.

But Christopher Snyder, PhD, of Thomas Jefferson University in Philadelphia, Pennsylvania, and his colleagues found that CMV-specific T_EFF cells divide poorly in response to CMV infection or reactivation in mouse models.

So they wondered if CMV-specific memory-phenotype CD8⁺ T cells (T_M cells)—which act more like stem cells—could help control the infection long-term.

The group showed that a small number of T_M cells were enough to produce and repeatedly replenish all of the T_EFF cells needed to fight CMV.

The infused T_M cells became major contributors to the recipient antiviral immune response, persisting for at least 3 months’ time and producing T_EFF cells at a steady stream.

To determine whether these cells have counterparts in humans, Dr Snyder and his colleagues compared the genomic fingerprints of mouse and human T_M cells that were specific for CMV. Results showed the two had similar profiles.

“This suggested that human and mouse CMV-specific memory T cells are very similar populations,” said study author Michael Quinn, an MD/PhD student at Thomas Jefferson University.

“Therefore, infusing similar cells into humans could improve on immunotherapeutic methods for controlling CMV infection. This may be a valuable approach to keep the disease from emerging in people.”

Dr Snyder added, “Our data argue for developing new clinical trials focused specifically on using these T memory cells, in order to determine if it would indeed be better than current therapeutic options.”

Skin biopsy showing GVHD

Credit: PLOS ONE

The European Medicines Agency (EMA) has granted orphan drug status to ApoCell for the prevention of graft-vs-host disease (GVHD).

ApoCell consists of matched-donor, mononuclear-enriched, early apoptotic cells. It has been shown to immunomodulate macrophages and dendritic cells, both of which are involved in GVHD pathogenesis.

ApoCell showed early promise in a phase 1/2a study, and a phase 2b/3 trial of the product is set to begin this year.

ApoCell, which is under development by Enlivex Therapeutics, received orphan drug designation in the US in 2013.

In the European Union (EU), orphan designation is granted to products intended for the treatment, prevention, or diagnosis of a life-threatening or chronically debilitating disease with a prevalence of no more than 5 in 10,000, with no satisfactory method of diagnosis, prevention, or treatment authorized by the EMA.

Orphan designation in the EU comes with a number of benefits, including protocol assistance and 10-year market exclusivity following regulatory approval.

Phase 1/2a trial of ApoCell

For this study, researchers tested an infusion of ApoCell, in addition to cyclosporine and methotrexate, as prophylaxis for acute GVHD.

The trial enrolled 13 leukemia patients who had a median age of 37 (range, 20-59). All of the patients received an HLA-matched, myeloablative, allogeneic hematopoietic stem cell transplant (HSCT) from a related donor.

All patients engrafted. The median time to neutrophil recovery was 13 days after HSCT (range, 11 to 19), and the median time to platelet recovery was 15 days (range, 11 to 59).

At 100 days post-HSCT, the cumulative incidence of acute grade 2-4 GVHD was 23.1%, and the incidence of acute grade 3-4 GVHD was 15.4%. None of the patients developed acute GVHD beyond day 100.

Among patients who received the 2 higher doses of ApoCell (n=6), the rate of acute grade 2-4 GVHD was 0%.

Ten patients experienced serious adverse events, but 7 were considered unrelated to ApoCell, and 3 were likely unrelated to the treatment.

The nonrelapse mortality rate was 7.7% at both 100 and 180 days after HSCT. The overall survival rate was 92% at 100 days and 85% at 180 days.

The researchers said these results suggest a single infusion of ApoCell is safe and may effectively prevent acute GVHD.

Skin biopsy showing GVHD

Credit: PLOS ONE

The European Medicines Agency (EMA) has granted orphan drug status to ApoCell for the prevention of graft-vs-host disease (GVHD).

ApoCell consists of matched-donor, mononuclear-enriched, early apoptotic cells. It has been shown to immunomodulate macrophages and dendritic cells, both of which are involved in GVHD pathogenesis.

ApoCell showed early promise in a phase 1/2a study, and a phase 2b/3 trial of the product is set to begin this year.

ApoCell, which is under development by Enlivex Therapeutics, received orphan drug designation in the US in 2013.

In the European Union (EU), orphan designation is granted to products intended for the treatment, prevention, or diagnosis of a life-threatening or chronically debilitating disease with a prevalence of no more than 5 in 10,000, with no satisfactory method of diagnosis, prevention, or treatment authorized by the EMA.

Orphan designation in the EU comes with a number of benefits, including protocol assistance and 10-year market exclusivity following regulatory approval.

Phase 1/2a trial of ApoCell

For this study, researchers tested an infusion of ApoCell, in addition to cyclosporine and methotrexate, as prophylaxis for acute GVHD.

The trial enrolled 13 leukemia patients who had a median age of 37 (range, 20-59). All of the patients received an HLA-matched, myeloablative, allogeneic hematopoietic stem cell transplant (HSCT) from a related donor.

All patients engrafted. The median time to neutrophil recovery was 13 days after HSCT (range, 11 to 19), and the median time to platelet recovery was 15 days (range, 11 to 59).

At 100 days post-HSCT, the cumulative incidence of acute grade 2-4 GVHD was 23.1%, and the incidence of acute grade 3-4 GVHD was 15.4%. None of the patients developed acute GVHD beyond day 100.

Among patients who received the 2 higher doses of ApoCell (n=6), the rate of acute grade 2-4 GVHD was 0%.

Ten patients experienced serious adverse events, but 7 were considered unrelated to ApoCell, and 3 were likely unrelated to the treatment.

The nonrelapse mortality rate was 7.7% at both 100 and 180 days after HSCT. The overall survival rate was 92% at 100 days and 85% at 180 days.

The researchers said these results suggest a single infusion of ApoCell is safe and may effectively prevent acute GVHD.

Skin biopsy showing GVHD

Credit: PLOS ONE

The European Medicines Agency (EMA) has granted orphan drug status to ApoCell for the prevention of graft-vs-host disease (GVHD).

ApoCell consists of matched-donor, mononuclear-enriched, early apoptotic cells. It has been shown to immunomodulate macrophages and dendritic cells, both of which are involved in GVHD pathogenesis.

ApoCell showed early promise in a phase 1/2a study, and a phase 2b/3 trial of the product is set to begin this year.

ApoCell, which is under development by Enlivex Therapeutics, received orphan drug designation in the US in 2013.

In the European Union (EU), orphan designation is granted to products intended for the treatment, prevention, or diagnosis of a life-threatening or chronically debilitating disease with a prevalence of no more than 5 in 10,000, with no satisfactory method of diagnosis, prevention, or treatment authorized by the EMA.

Orphan designation in the EU comes with a number of benefits, including protocol assistance and 10-year market exclusivity following regulatory approval.

Phase 1/2a trial of ApoCell

For this study, researchers tested an infusion of ApoCell, in addition to cyclosporine and methotrexate, as prophylaxis for acute GVHD.

The trial enrolled 13 leukemia patients who had a median age of 37 (range, 20-59). All of the patients received an HLA-matched, myeloablative, allogeneic hematopoietic stem cell transplant (HSCT) from a related donor.

All patients engrafted. The median time to neutrophil recovery was 13 days after HSCT (range, 11 to 19), and the median time to platelet recovery was 15 days (range, 11 to 59).

At 100 days post-HSCT, the cumulative incidence of acute grade 2-4 GVHD was 23.1%, and the incidence of acute grade 3-4 GVHD was 15.4%. None of the patients developed acute GVHD beyond day 100.

Among patients who received the 2 higher doses of ApoCell (n=6), the rate of acute grade 2-4 GVHD was 0%.

Ten patients experienced serious adverse events, but 7 were considered unrelated to ApoCell, and 3 were likely unrelated to the treatment.

The nonrelapse mortality rate was 7.7% at both 100 and 180 days after HSCT. The overall survival rate was 92% at 100 days and 85% at 180 days.

The researchers said these results suggest a single infusion of ApoCell is safe and may effectively prevent acute GVHD.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.