Myelodysplastic Syndrome

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

 

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

 

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

 

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

 

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

 

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

 

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

 

Vemurafenib (Zelboraf) has been granted a supplemental new drug application and priority review by the Food and Drug Administration for the treatment of Erdheim-Chester disease with BRAF V600 mutation, according to a press release issued by Genentech.

The FDA is expected to make a decision on the indication by Dec. 7, 2017. Vemurafenib is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. “This first potential treatment submitted to the FDA for this rare disease was identified by an innovative trial studying Zelboraf across different diseases with the same genetic mutation,” Sandra Horning, MD, chief medical officer and head of global product development, said in the press release.

The supportive data for the application came from VE-BASKET, a phase 2, nonrandomized study investigating the use of vemurafenib for people with various BRAF V600 mutation–positive cancers and other diseases. Final results for the 22 people with Erdheim-Chester disease showed a best overall response rate of 54.5% by RECIST v1.1 criteria.

The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up time of 26.6 months. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain. Initial study results were published in the New England Journal of Medicine in August 2015.

Based on available published data, there are fewer than 500 cases of Erdheim-Chester disease in the United States. More than half of affected people have BRAF V600 mutation–positive disease, and there are no approved treatments, according to the release.

[email protected]

 

Vemurafenib (Zelboraf) has been granted a supplemental new drug application and priority review by the Food and Drug Administration for the treatment of Erdheim-Chester disease with BRAF V600 mutation, according to a press release issued by Genentech.

The FDA is expected to make a decision on the indication by Dec. 7, 2017. Vemurafenib is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. “This first potential treatment submitted to the FDA for this rare disease was identified by an innovative trial studying Zelboraf across different diseases with the same genetic mutation,” Sandra Horning, MD, chief medical officer and head of global product development, said in the press release.

The supportive data for the application came from VE-BASKET, a phase 2, nonrandomized study investigating the use of vemurafenib for people with various BRAF V600 mutation–positive cancers and other diseases. Final results for the 22 people with Erdheim-Chester disease showed a best overall response rate of 54.5% by RECIST v1.1 criteria.

The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up time of 26.6 months. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain. Initial study results were published in the New England Journal of Medicine in August 2015.

Based on available published data, there are fewer than 500 cases of Erdheim-Chester disease in the United States. More than half of affected people have BRAF V600 mutation–positive disease, and there are no approved treatments, according to the release.

[email protected]

 

Vemurafenib (Zelboraf) has been granted a supplemental new drug application and priority review by the Food and Drug Administration for the treatment of Erdheim-Chester disease with BRAF V600 mutation, according to a press release issued by Genentech.

The FDA is expected to make a decision on the indication by Dec. 7, 2017. Vemurafenib is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. “This first potential treatment submitted to the FDA for this rare disease was identified by an innovative trial studying Zelboraf across different diseases with the same genetic mutation,” Sandra Horning, MD, chief medical officer and head of global product development, said in the press release.

The supportive data for the application came from VE-BASKET, a phase 2, nonrandomized study investigating the use of vemurafenib for people with various BRAF V600 mutation–positive cancers and other diseases. Final results for the 22 people with Erdheim-Chester disease showed a best overall response rate of 54.5% by RECIST v1.1 criteria.

The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up time of 26.6 months. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain. Initial study results were published in the New England Journal of Medicine in August 2015.

Based on available published data, there are fewer than 500 cases of Erdheim-Chester disease in the United States. More than half of affected people have BRAF V600 mutation–positive disease, and there are no approved treatments, according to the release.

[email protected]

AML cells

Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.

The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.

The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.

And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.

In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.

The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.

Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.

The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.

DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.

In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

AML cells

Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.

The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.

The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.

And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.

In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.

The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.

Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.

The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.

DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.

In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

AML cells

Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.

The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.

The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.

And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.

In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.

The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.

Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.

The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.

DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.

In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

Micrograph showing MDS

Research published in Cell Reports helps explain why some patients with myelodysplastic syndrome (MDS) do not respond to treatment with azacitidine.

The study showed that patients who were resistant to the drug had relatively quiescent hematopoietic progenitor cells (HPCs).

A smaller proportion of their HPCs were undergoing active cell-cycle progression when compared to the HPCs of patients who responded to azacitidine.

This discovery could provide the first method to identify non-responders to azacitidine early, according to study author Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

“These are early days, but this could avoid what has really been a ‘wait and see’ approach with patients that sometimes results in them receiving futile treatment for 6 months,” Dr Unnikrishnan said.

“By that stage, the patient’s disease has progressed, and there’s no alternative for them.”

Dr Unnikrishnan and his colleagues also found the HPC quiescence in non-responders was mediated by integrin α5 (ITGA5) signaling, and the cells’ hematopoietic potential improved when the team combined azacitidine treatment with an ITGA5 inhibitor.

This suggests a potential avenue for future combination therapies that would improve azacitidine responsiveness.

Lastly, the researchers made discoveries that could explain why some patients who initially respond to azacitidine eventually relapse.

“All of the pernicious mutations that we associate with MDS never disappear in these patients, even after years of treatment,” Dr Unnikrishnan said. “From a clinical perspective, blood cell production is restored in patients, but they are a ticking time bomb, waiting to relapse.”

“[Azacitidine] is not a cure, and we are starting to understand why it does what it does. We need to find better treatments than azacitidine if we want a more durable therapy for MDS, and that’s the basis for our future work.”

Micrograph showing MDS

Research published in Cell Reports helps explain why some patients with myelodysplastic syndrome (MDS) do not respond to treatment with azacitidine.

The study showed that patients who were resistant to the drug had relatively quiescent hematopoietic progenitor cells (HPCs).

A smaller proportion of their HPCs were undergoing active cell-cycle progression when compared to the HPCs of patients who responded to azacitidine.

This discovery could provide the first method to identify non-responders to azacitidine early, according to study author Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

“These are early days, but this could avoid what has really been a ‘wait and see’ approach with patients that sometimes results in them receiving futile treatment for 6 months,” Dr Unnikrishnan said.

“By that stage, the patient’s disease has progressed, and there’s no alternative for them.”

Dr Unnikrishnan and his colleagues also found the HPC quiescence in non-responders was mediated by integrin α5 (ITGA5) signaling, and the cells’ hematopoietic potential improved when the team combined azacitidine treatment with an ITGA5 inhibitor.

This suggests a potential avenue for future combination therapies that would improve azacitidine responsiveness.

Lastly, the researchers made discoveries that could explain why some patients who initially respond to azacitidine eventually relapse.

“All of the pernicious mutations that we associate with MDS never disappear in these patients, even after years of treatment,” Dr Unnikrishnan said. “From a clinical perspective, blood cell production is restored in patients, but they are a ticking time bomb, waiting to relapse.”

“[Azacitidine] is not a cure, and we are starting to understand why it does what it does. We need to find better treatments than azacitidine if we want a more durable therapy for MDS, and that’s the basis for our future work.”

Micrograph showing MDS

Research published in Cell Reports helps explain why some patients with myelodysplastic syndrome (MDS) do not respond to treatment with azacitidine.

The study showed that patients who were resistant to the drug had relatively quiescent hematopoietic progenitor cells (HPCs).

A smaller proportion of their HPCs were undergoing active cell-cycle progression when compared to the HPCs of patients who responded to azacitidine.

This discovery could provide the first method to identify non-responders to azacitidine early, according to study author Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

“These are early days, but this could avoid what has really been a ‘wait and see’ approach with patients that sometimes results in them receiving futile treatment for 6 months,” Dr Unnikrishnan said.

“By that stage, the patient’s disease has progressed, and there’s no alternative for them.”

Dr Unnikrishnan and his colleagues also found the HPC quiescence in non-responders was mediated by integrin α5 (ITGA5) signaling, and the cells’ hematopoietic potential improved when the team combined azacitidine treatment with an ITGA5 inhibitor.

This suggests a potential avenue for future combination therapies that would improve azacitidine responsiveness.

Lastly, the researchers made discoveries that could explain why some patients who initially respond to azacitidine eventually relapse.

“All of the pernicious mutations that we associate with MDS never disappear in these patients, even after years of treatment,” Dr Unnikrishnan said. “From a clinical perspective, blood cell production is restored in patients, but they are a ticking time bomb, waiting to relapse.”

“[Azacitidine] is not a cure, and we are starting to understand why it does what it does. We need to find better treatments than azacitidine if we want a more durable therapy for MDS, and that’s the basis for our future work.”

 

Beckman Coulter has been authorized to market its ClearLLab Reagents (T1, T2, B1, B2, M) tests for use with flow cytometry to detect leukemias, lymphomas, and myeloproliferative disorders in blood, bone marrow, and lymph nodes, according to the U.S. Food and Drug Administration.

As the tests were not substantially equivalent to an already existing test and are low to moderate risk, the FDA reviewed them through its de novo premarket review pathway.

A study evaluating the efficacy of the test compared the test results (n = 279) with clinical evaluations at four independent clinical sites. The results matched the diagnoses 93.4% of the time and correctly detected cancer 84.2% of the time.

“This represents a major step forward for the hematology-oncology community,” Alberto Gutierrez, PhD, of the FDA’s Center for Devices and Radiological Health said in the FDA’s release. “Laboratories and health care professionals now have access to an FDA-validated test that provides consistent results to aid in the diagnoses of these serious cancers.”

The approval coincides with criteria for ongoing evaluation of the ClearLLab tests and approval of future tests. The release notes that the ClearLLab test results must be reviewed by a trained professional.

[email protected]

 

Beckman Coulter has been authorized to market its ClearLLab Reagents (T1, T2, B1, B2, M) tests for use with flow cytometry to detect leukemias, lymphomas, and myeloproliferative disorders in blood, bone marrow, and lymph nodes, according to the U.S. Food and Drug Administration.

As the tests were not substantially equivalent to an already existing test and are low to moderate risk, the FDA reviewed them through its de novo premarket review pathway.

A study evaluating the efficacy of the test compared the test results (n = 279) with clinical evaluations at four independent clinical sites. The results matched the diagnoses 93.4% of the time and correctly detected cancer 84.2% of the time.

“This represents a major step forward for the hematology-oncology community,” Alberto Gutierrez, PhD, of the FDA’s Center for Devices and Radiological Health said in the FDA’s release. “Laboratories and health care professionals now have access to an FDA-validated test that provides consistent results to aid in the diagnoses of these serious cancers.”

The approval coincides with criteria for ongoing evaluation of the ClearLLab tests and approval of future tests. The release notes that the ClearLLab test results must be reviewed by a trained professional.

[email protected]

 

Beckman Coulter has been authorized to market its ClearLLab Reagents (T1, T2, B1, B2, M) tests for use with flow cytometry to detect leukemias, lymphomas, and myeloproliferative disorders in blood, bone marrow, and lymph nodes, according to the U.S. Food and Drug Administration.

As the tests were not substantially equivalent to an already existing test and are low to moderate risk, the FDA reviewed them through its de novo premarket review pathway.

A study evaluating the efficacy of the test compared the test results (n = 279) with clinical evaluations at four independent clinical sites. The results matched the diagnoses 93.4% of the time and correctly detected cancer 84.2% of the time.

“This represents a major step forward for the hematology-oncology community,” Alberto Gutierrez, PhD, of the FDA’s Center for Devices and Radiological Health said in the FDA’s release. “Laboratories and health care professionals now have access to an FDA-validated test that provides consistent results to aid in the diagnoses of these serious cancers.”

The approval coincides with criteria for ongoing evaluation of the ClearLLab tests and approval of future tests. The release notes that the ClearLLab test results must be reviewed by a trained professional.

[email protected]

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to DSP-7888, an investigational cancer peptide vaccine, for the treatment of myelodysplastic syndromes (MDS).

DSP-7888 contains peptides to induce Wilms’ tumor gene 1 (WT1)-specific cytotoxic T lymphocytes and helper T cells, which attack WT1-expressing cancerous cells found in various hematologic and solid tumor malignancies.

DSP-7888 is being developed by Boston Biomedical, Inc.

The first clinical data for DSP-7888, from a phase 1/2 study in patients with MDS who progressed on or after first-line azacitidine treatment, were presented at the 2016 ASH Annual Meeting.

Results were reported in 12 patients—7 with higher-risk MDS and 5 with lower-risk disease.

DSP-7888 was given at doses of 3.5 mg/body (n=6) or 10.5 mg/body (n=6) by intradermal injections every 2 to 4 weeks.

There were no dose-limiting toxicities. The most common adverse event was injection site reactions. Six patients had grade 3 injection site reactions.

There were 5 serious adverse events—3 injection site reactions, 1 case of pyrexia, and 1 case of myocarditis.

Eight patients had stable disease, 2 with hematological improvements.

Cytotoxic T lymphocyte induction was observed in 6 patients, and delayed type hypersensitivity response was observed in 10 patients.

About orphan designation

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

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved. 

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to DSP-7888, an investigational cancer peptide vaccine, for the treatment of myelodysplastic syndromes (MDS).

DSP-7888 contains peptides to induce Wilms’ tumor gene 1 (WT1)-specific cytotoxic T lymphocytes and helper T cells, which attack WT1-expressing cancerous cells found in various hematologic and solid tumor malignancies.

DSP-7888 is being developed by Boston Biomedical, Inc.

The first clinical data for DSP-7888, from a phase 1/2 study in patients with MDS who progressed on or after first-line azacitidine treatment, were presented at the 2016 ASH Annual Meeting.

Results were reported in 12 patients—7 with higher-risk MDS and 5 with lower-risk disease.

DSP-7888 was given at doses of 3.5 mg/body (n=6) or 10.5 mg/body (n=6) by intradermal injections every 2 to 4 weeks.

There were no dose-limiting toxicities. The most common adverse event was injection site reactions. Six patients had grade 3 injection site reactions.

There were 5 serious adverse events—3 injection site reactions, 1 case of pyrexia, and 1 case of myocarditis.

Eight patients had stable disease, 2 with hematological improvements.

Cytotoxic T lymphocyte induction was observed in 6 patients, and delayed type hypersensitivity response was observed in 10 patients.

About orphan designation

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

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved. 

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to DSP-7888, an investigational cancer peptide vaccine, for the treatment of myelodysplastic syndromes (MDS).

DSP-7888 contains peptides to induce Wilms’ tumor gene 1 (WT1)-specific cytotoxic T lymphocytes and helper T cells, which attack WT1-expressing cancerous cells found in various hematologic and solid tumor malignancies.

DSP-7888 is being developed by Boston Biomedical, Inc.

The first clinical data for DSP-7888, from a phase 1/2 study in patients with MDS who progressed on or after first-line azacitidine treatment, were presented at the 2016 ASH Annual Meeting.

Results were reported in 12 patients—7 with higher-risk MDS and 5 with lower-risk disease.

DSP-7888 was given at doses of 3.5 mg/body (n=6) or 10.5 mg/body (n=6) by intradermal injections every 2 to 4 weeks.

There were no dose-limiting toxicities. The most common adverse event was injection site reactions. Six patients had grade 3 injection site reactions.

There were 5 serious adverse events—3 injection site reactions, 1 case of pyrexia, and 1 case of myocarditis.

Eight patients had stable disease, 2 with hematological improvements.

Cytotoxic T lymphocyte induction was observed in 6 patients, and delayed type hypersensitivity response was observed in 10 patients.

About orphan designation

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

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved. 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

---

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

---

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

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On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

Micrograph showing MDS

A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.

However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.

And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.

Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.

Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m²/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.

Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.

Patient characteristics

Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.

The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).

 Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.

Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.

Adverse events

 For the most part, therapy-related adverse events were similar across the arms.

Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.

However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.

And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.

Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.

Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.

Responses

The ORR for the entire study population was 38%.

Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.

Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.

The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.

Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.

 

The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.

CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.

Subgroup responses

Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).

Median duration of response for CMML patients was 19 months, with no differences between the arms.

The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.

However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).

One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).

Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).

Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23).  Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).

Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.

Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).

The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted. 

Micrograph showing MDS

A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.

However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.

And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.

Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.

Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m²/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.

Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.

Patient characteristics

Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.

The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).

 Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.

Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.

Adverse events

 For the most part, therapy-related adverse events were similar across the arms.

Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.

However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.

And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.

Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.

Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.

Responses

The ORR for the entire study population was 38%.

Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.

Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.

The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.

Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.

 

The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.

CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.

Subgroup responses

Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).

Median duration of response for CMML patients was 19 months, with no differences between the arms.

The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.

However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).

One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).

Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).

Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23).  Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).

Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.

Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).

The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted. 

Micrograph showing MDS

A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.

However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.

And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.

Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.

Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m²/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.

Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.

Patient characteristics

Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.

The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).

 Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.

Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.

Adverse events

 For the most part, therapy-related adverse events were similar across the arms.

Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.

However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.

And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.

Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.

Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.

Responses

The ORR for the entire study population was 38%.

Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.

Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.

The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.

Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.

 

The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.

CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.

Subgroup responses

Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).

Median duration of response for CMML patients was 19 months, with no differences between the arms.

The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.

However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).

One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).

Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).

Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23).  Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).

Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.

Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).

The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted.