Lymphoma & Plasma Cell Disorders

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Cell culture in a petri dish

Researchers say they’ve identified 20 proteins specific to primary effusion lymphoma (PEL).

The proteins, which were found by growing PEL cells in culture and analyzing the secretome, may explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.

The investigators also uncovered related oncogenic pathways, which could pave the way for more individualized treatment of PEL.

These findings appear in The American Journal of Pathology.

The researchers analyzed secretomes from 4 established PEL cell lines—CRO-AP2, CRO-AP3, CRO-AP5, and CRO-AP6—as well as from 4 PEL clinical samples and 3 primary solid lymphomas. PEL cells are characterized by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, and the primary solid lymphomas were KSHV-positive as well.

The investigators measured protein content using 2 complementary mass spectrometry platforms. The experiments allowed cells to grow for 16 to 18 hours and were performed under serum-free conditions to increase the ability to detect secreted proteins.

Of the 266 proteins identified, 139 (52%) were secreted, and 127 were considered to have an intracellular origin or were secreted in an unconventional fashion.

“Most of the proteins we recognized in the secretome of PEL are new with respect to previous studies utilizing conventional proteomic analysis and gene expression profiling,” said study author Annunziata Gloghini, PhD, of Istituto Nazionale dei Tumori in Milan, Italy.

“Importantly, 27 proteins were shared by secretomes from all PEL cell lines.”

The PEL secretomes were enriched with proteins specifically involved in inflammation and the immune response—such as HMGB1, GRAA, and PCBP2—as well as cell growth—such as LEG1, STMN1, and S10A6.

Other proteins are known to play roles in mRNA processing—such as ANM1 and PCBP2—or cell structure, adhesion, migration, and organization—such as EZRI and MOES. Some of the proteins have enzymatic activity—such as CATA and GSTK1.

A comparison of secretomes from PEL with those from other tumor cell lines revealed 20 proteins specific to the PEL cell lines. This suggests secretome profiling provides a source of tumor biomarkers and may ultimately improve patient management, the researchers said.

The group also conducted pathway/network enrichment analyses and found that the pathways most activated in PEL cell lines were involved with the regulation of autophagy through LRRK2-mediated signaling pathways and with apoptosis and survival through granzyme A signaling.

“The extracellular functions of granzyme A might be involved in the particular tropism of PEL and its cell growth,” said study author Italia Bongarzone, PhD, also of the Istituto Nazionale dei Tumori.

“Further studies are needed to confirm and validate the importance of these pathways/processes and their roles in lymphoma tumorigenesis and progression.”

Cell culture in a petri dish

Researchers say they’ve identified 20 proteins specific to primary effusion lymphoma (PEL).

The proteins, which were found by growing PEL cells in culture and analyzing the secretome, may explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.

The investigators also uncovered related oncogenic pathways, which could pave the way for more individualized treatment of PEL.

These findings appear in The American Journal of Pathology.

The researchers analyzed secretomes from 4 established PEL cell lines—CRO-AP2, CRO-AP3, CRO-AP5, and CRO-AP6—as well as from 4 PEL clinical samples and 3 primary solid lymphomas. PEL cells are characterized by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, and the primary solid lymphomas were KSHV-positive as well.

The investigators measured protein content using 2 complementary mass spectrometry platforms. The experiments allowed cells to grow for 16 to 18 hours and were performed under serum-free conditions to increase the ability to detect secreted proteins.

Of the 266 proteins identified, 139 (52%) were secreted, and 127 were considered to have an intracellular origin or were secreted in an unconventional fashion.

“Most of the proteins we recognized in the secretome of PEL are new with respect to previous studies utilizing conventional proteomic analysis and gene expression profiling,” said study author Annunziata Gloghini, PhD, of Istituto Nazionale dei Tumori in Milan, Italy.

“Importantly, 27 proteins were shared by secretomes from all PEL cell lines.”

The PEL secretomes were enriched with proteins specifically involved in inflammation and the immune response—such as HMGB1, GRAA, and PCBP2—as well as cell growth—such as LEG1, STMN1, and S10A6.

Other proteins are known to play roles in mRNA processing—such as ANM1 and PCBP2—or cell structure, adhesion, migration, and organization—such as EZRI and MOES. Some of the proteins have enzymatic activity—such as CATA and GSTK1.

A comparison of secretomes from PEL with those from other tumor cell lines revealed 20 proteins specific to the PEL cell lines. This suggests secretome profiling provides a source of tumor biomarkers and may ultimately improve patient management, the researchers said.

The group also conducted pathway/network enrichment analyses and found that the pathways most activated in PEL cell lines were involved with the regulation of autophagy through LRRK2-mediated signaling pathways and with apoptosis and survival through granzyme A signaling.

“The extracellular functions of granzyme A might be involved in the particular tropism of PEL and its cell growth,” said study author Italia Bongarzone, PhD, also of the Istituto Nazionale dei Tumori.

“Further studies are needed to confirm and validate the importance of these pathways/processes and their roles in lymphoma tumorigenesis and progression.”

Cell culture in a petri dish

Researchers say they’ve identified 20 proteins specific to primary effusion lymphoma (PEL).

The proteins, which were found by growing PEL cells in culture and analyzing the secretome, may explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.

The investigators also uncovered related oncogenic pathways, which could pave the way for more individualized treatment of PEL.

These findings appear in The American Journal of Pathology.

The researchers analyzed secretomes from 4 established PEL cell lines—CRO-AP2, CRO-AP3, CRO-AP5, and CRO-AP6—as well as from 4 PEL clinical samples and 3 primary solid lymphomas. PEL cells are characterized by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, and the primary solid lymphomas were KSHV-positive as well.

The investigators measured protein content using 2 complementary mass spectrometry platforms. The experiments allowed cells to grow for 16 to 18 hours and were performed under serum-free conditions to increase the ability to detect secreted proteins.

Of the 266 proteins identified, 139 (52%) were secreted, and 127 were considered to have an intracellular origin or were secreted in an unconventional fashion.

“Most of the proteins we recognized in the secretome of PEL are new with respect to previous studies utilizing conventional proteomic analysis and gene expression profiling,” said study author Annunziata Gloghini, PhD, of Istituto Nazionale dei Tumori in Milan, Italy.

“Importantly, 27 proteins were shared by secretomes from all PEL cell lines.”

The PEL secretomes were enriched with proteins specifically involved in inflammation and the immune response—such as HMGB1, GRAA, and PCBP2—as well as cell growth—such as LEG1, STMN1, and S10A6.

Other proteins are known to play roles in mRNA processing—such as ANM1 and PCBP2—or cell structure, adhesion, migration, and organization—such as EZRI and MOES. Some of the proteins have enzymatic activity—such as CATA and GSTK1.

A comparison of secretomes from PEL with those from other tumor cell lines revealed 20 proteins specific to the PEL cell lines. This suggests secretome profiling provides a source of tumor biomarkers and may ultimately improve patient management, the researchers said.

The group also conducted pathway/network enrichment analyses and found that the pathways most activated in PEL cell lines were involved with the regulation of autophagy through LRRK2-mediated signaling pathways and with apoptosis and survival through granzyme A signaling.

“The extracellular functions of granzyme A might be involved in the particular tropism of PEL and its cell growth,” said study author Italia Bongarzone, PhD, also of the Istituto Nazionale dei Tumori.

“Further studies are needed to confirm and validate the importance of these pathways/processes and their roles in lymphoma tumorigenesis and progression.”

Tumor cells with DNA damage

after treatment with etoposide

Credit: CNIO

A compound that interferes with the cell cycle can increase the antineoplastic effects of etoposide, according to research published in Cell Reports.

Etoposide works by inhibiting topoisomerase II (TOP2), a protein needed for DNA repair during cell division.

Researchers discovered a relationship between TOP2 and Cdh1, a protein that (along with Cdc20) controls cell division by activating the anaphase-promoting complex/cyclosome (APC/C).

So the team hypothesized that combining etoposide with a compound that inhibits Cdh1 might improve etoposide’s antineoplastic effects. Experiments in cancer cell lines confirmed this theory.

Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO) in Madrid, and his colleagues began this research by investigating Cdh1 in vitro and in mouse models.

The team found that a decrease in Cdh1 activity increases cells’ TOP2 levels. So they decided to combine etoposide with a Cdh1 inhibitor and evaluate the effect on cancer cells, which divide more than normal cells and therefore have a greater dependency on TOP2 to maintain DNA integrity.

The researchers tested proTAME, a small molecule that targets APC/C-Cdh1 and APC/C-Cdc20, in combination with etoposide. And they found the drugs had a synergistic effect against cancer cells.

In experiments with a lung cancer cell line (A549) and 2 breast cancer cell lines (HeLa and MCF7), administering proTAME and etoposide together proved more effective than administering either compound alone.

The researchers believe these findings could apply to other malignancies as well. Etoposide has demonstrated activity against a number of cancers, including leukemias, lymphomas, and multiple myeloma.

The team said their next step is to study the etoposide-proTAME combination in patients and investigate the malignancies in which this therapeutic strategy would be most effective.

The researchers also noted that previous studies have shown Cdh1 is inactive in some patients due to various oncogenic mutations. So stratifying patients according to their tumor’s Cdh1 status could optimize treatment with etoposide.

Tumor cells with DNA damage

after treatment with etoposide

Credit: CNIO

A compound that interferes with the cell cycle can increase the antineoplastic effects of etoposide, according to research published in Cell Reports.

Etoposide works by inhibiting topoisomerase II (TOP2), a protein needed for DNA repair during cell division.

Researchers discovered a relationship between TOP2 and Cdh1, a protein that (along with Cdc20) controls cell division by activating the anaphase-promoting complex/cyclosome (APC/C).

So the team hypothesized that combining etoposide with a compound that inhibits Cdh1 might improve etoposide’s antineoplastic effects. Experiments in cancer cell lines confirmed this theory.

Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO) in Madrid, and his colleagues began this research by investigating Cdh1 in vitro and in mouse models.

The team found that a decrease in Cdh1 activity increases cells’ TOP2 levels. So they decided to combine etoposide with a Cdh1 inhibitor and evaluate the effect on cancer cells, which divide more than normal cells and therefore have a greater dependency on TOP2 to maintain DNA integrity.

The researchers tested proTAME, a small molecule that targets APC/C-Cdh1 and APC/C-Cdc20, in combination with etoposide. And they found the drugs had a synergistic effect against cancer cells.

In experiments with a lung cancer cell line (A549) and 2 breast cancer cell lines (HeLa and MCF7), administering proTAME and etoposide together proved more effective than administering either compound alone.

The researchers believe these findings could apply to other malignancies as well. Etoposide has demonstrated activity against a number of cancers, including leukemias, lymphomas, and multiple myeloma.

The team said their next step is to study the etoposide-proTAME combination in patients and investigate the malignancies in which this therapeutic strategy would be most effective.

The researchers also noted that previous studies have shown Cdh1 is inactive in some patients due to various oncogenic mutations. So stratifying patients according to their tumor’s Cdh1 status could optimize treatment with etoposide.

Tumor cells with DNA damage

after treatment with etoposide

Credit: CNIO

A compound that interferes with the cell cycle can increase the antineoplastic effects of etoposide, according to research published in Cell Reports.

Etoposide works by inhibiting topoisomerase II (TOP2), a protein needed for DNA repair during cell division.

Researchers discovered a relationship between TOP2 and Cdh1, a protein that (along with Cdc20) controls cell division by activating the anaphase-promoting complex/cyclosome (APC/C).

So the team hypothesized that combining etoposide with a compound that inhibits Cdh1 might improve etoposide’s antineoplastic effects. Experiments in cancer cell lines confirmed this theory.

Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO) in Madrid, and his colleagues began this research by investigating Cdh1 in vitro and in mouse models.

The team found that a decrease in Cdh1 activity increases cells’ TOP2 levels. So they decided to combine etoposide with a Cdh1 inhibitor and evaluate the effect on cancer cells, which divide more than normal cells and therefore have a greater dependency on TOP2 to maintain DNA integrity.

The researchers tested proTAME, a small molecule that targets APC/C-Cdh1 and APC/C-Cdc20, in combination with etoposide. And they found the drugs had a synergistic effect against cancer cells.

In experiments with a lung cancer cell line (A549) and 2 breast cancer cell lines (HeLa and MCF7), administering proTAME and etoposide together proved more effective than administering either compound alone.

The researchers believe these findings could apply to other malignancies as well. Etoposide has demonstrated activity against a number of cancers, including leukemias, lymphomas, and multiple myeloma.

The team said their next step is to study the etoposide-proTAME combination in patients and investigate the malignancies in which this therapeutic strategy would be most effective.

The researchers also noted that previous studies have shown Cdh1 is inactive in some patients due to various oncogenic mutations. So stratifying patients according to their tumor’s Cdh1 status could optimize treatment with etoposide.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

Monoclonal antibodies

Credit: Linda Bartlett

Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.

mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.

Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.

Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.

Finding hidden ALL cells

Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.

The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.

The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.

Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.

The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.

“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.

Tricking the immune system

Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they discovered that cyclophosphamide can “rewire” the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there.

“After you treat with cyclophosphamide, you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Dr Hemann said.

“Essentially, we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”

Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.

However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.

The team also obtained good results by combining cyclophosphamide with rituximab.

They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients.

Monoclonal antibodies

Credit: Linda Bartlett

Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.

mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.

Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.

Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.

Finding hidden ALL cells

Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.

The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.

The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.

Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.

The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.

“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.

Tricking the immune system

Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they discovered that cyclophosphamide can “rewire” the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there.

“After you treat with cyclophosphamide, you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Dr Hemann said.

“Essentially, we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”

Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.

However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.

The team also obtained good results by combining cyclophosphamide with rituximab.

They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients.

Monoclonal antibodies

Credit: Linda Bartlett

Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.

mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.

Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.

Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.

Finding hidden ALL cells

Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.

The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.

The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.

Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.

The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.

“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.

Tricking the immune system

Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they discovered that cyclophosphamide can “rewire” the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there.

“After you treat with cyclophosphamide, you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Dr Hemann said.

“Essentially, we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”

Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.

However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.

The team also obtained good results by combining cyclophosphamide with rituximab.

They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients.

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.