T Cell Lymphomas

In patients with leukemic cutaneous T-cell lymphoma, diffuse cutaneous erythema without plaques or tumors predicted complete remission with low-dose alemtuzumab therapy, investigators reported online April 23 in a JAMA Dermatology research letter.

"Initial clinical presentation was more predictive of response than was complex cellular phenotyping of T cells from blood and skin," wrote Dr. Rei Watanabe at Brigham and Women’s Hospital in Boston and associates. "In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational research program in identifying complete responders to LDA [low-dose alemtuzumab] therapy."

The researchers treated 23 patients with leukemic cutaneous T-cell lymphoma with 10 mg subcutaneous LDA three times weekly. Seventeen patients presented with diffuse erythema without superimposed plaques or tumors, of whom 13 experienced complete remission after LDA treatment and 4 had residual or emergent disease that could be controlled with skin-directed therapy (JAMA Dermatol. 2014 [doi:10.1001/jamadermatol.2013.10099]).

However, none of the six patients who presented with discrete patches, plaques, or tumors experienced full remission with LDA, the researchers reported. One patient later remitted with electron beam therapy, while five had their disease recur or progress, including two who developed large cell transformation.

Patients also were more likely to respond to LDA if more than 80% of their malignant T cells had TCM markers (CCR7⁺/L-selectin⁺), but clinical presentation better predicted response, the investigators reported.

"On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA," noted Dr. Watanabe and her associates. "Fixed skin lesions are more likely to be caused by TRM [nonmigratory skin resident memory T cells], cells that escape LDA clearance by remaining long-term in skin."

Based on the findings, the investigators recommended using LDA with or without adjuvant skin-directed treatments in patients who present with diffuse cutaneous erythema. But "we caution against its use in patients with preexisting plaques and/or tumors," the researchers said.

The Leukemia & Lymphoma Society, the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and a private contribution from Edward P. Lawrence, Esq., funded the study. Coauthor Dr. Clark reported receiving honoraria from Novartis and Stiefel Laboratories. The authors disclosed no other conflicts of interest.

In patients with leukemic cutaneous T-cell lymphoma, diffuse cutaneous erythema without plaques or tumors predicted complete remission with low-dose alemtuzumab therapy, investigators reported online April 23 in a JAMA Dermatology research letter.

"Initial clinical presentation was more predictive of response than was complex cellular phenotyping of T cells from blood and skin," wrote Dr. Rei Watanabe at Brigham and Women’s Hospital in Boston and associates. "In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational research program in identifying complete responders to LDA [low-dose alemtuzumab] therapy."

The researchers treated 23 patients with leukemic cutaneous T-cell lymphoma with 10 mg subcutaneous LDA three times weekly. Seventeen patients presented with diffuse erythema without superimposed plaques or tumors, of whom 13 experienced complete remission after LDA treatment and 4 had residual or emergent disease that could be controlled with skin-directed therapy (JAMA Dermatol. 2014 [doi:10.1001/jamadermatol.2013.10099]).

However, none of the six patients who presented with discrete patches, plaques, or tumors experienced full remission with LDA, the researchers reported. One patient later remitted with electron beam therapy, while five had their disease recur or progress, including two who developed large cell transformation.

Patients also were more likely to respond to LDA if more than 80% of their malignant T cells had TCM markers (CCR7⁺/L-selectin⁺), but clinical presentation better predicted response, the investigators reported.

"On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA," noted Dr. Watanabe and her associates. "Fixed skin lesions are more likely to be caused by TRM [nonmigratory skin resident memory T cells], cells that escape LDA clearance by remaining long-term in skin."

Based on the findings, the investigators recommended using LDA with or without adjuvant skin-directed treatments in patients who present with diffuse cutaneous erythema. But "we caution against its use in patients with preexisting plaques and/or tumors," the researchers said.

The Leukemia & Lymphoma Society, the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and a private contribution from Edward P. Lawrence, Esq., funded the study. Coauthor Dr. Clark reported receiving honoraria from Novartis and Stiefel Laboratories. The authors disclosed no other conflicts of interest.

In patients with leukemic cutaneous T-cell lymphoma, diffuse cutaneous erythema without plaques or tumors predicted complete remission with low-dose alemtuzumab therapy, investigators reported online April 23 in a JAMA Dermatology research letter.

"Initial clinical presentation was more predictive of response than was complex cellular phenotyping of T cells from blood and skin," wrote Dr. Rei Watanabe at Brigham and Women’s Hospital in Boston and associates. "In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational research program in identifying complete responders to LDA [low-dose alemtuzumab] therapy."

The researchers treated 23 patients with leukemic cutaneous T-cell lymphoma with 10 mg subcutaneous LDA three times weekly. Seventeen patients presented with diffuse erythema without superimposed plaques or tumors, of whom 13 experienced complete remission after LDA treatment and 4 had residual or emergent disease that could be controlled with skin-directed therapy (JAMA Dermatol. 2014 [doi:10.1001/jamadermatol.2013.10099]).

However, none of the six patients who presented with discrete patches, plaques, or tumors experienced full remission with LDA, the researchers reported. One patient later remitted with electron beam therapy, while five had their disease recur or progress, including two who developed large cell transformation.

Patients also were more likely to respond to LDA if more than 80% of their malignant T cells had TCM markers (CCR7⁺/L-selectin⁺), but clinical presentation better predicted response, the investigators reported.

"On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA," noted Dr. Watanabe and her associates. "Fixed skin lesions are more likely to be caused by TRM [nonmigratory skin resident memory T cells], cells that escape LDA clearance by remaining long-term in skin."

Based on the findings, the investigators recommended using LDA with or without adjuvant skin-directed treatments in patients who present with diffuse cutaneous erythema. But "we caution against its use in patients with preexisting plaques and/or tumors," the researchers said.

The Leukemia & Lymphoma Society, the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and a private contribution from Edward P. Lawrence, Esq., funded the study. Coauthor Dr. Clark reported receiving honoraria from Novartis and Stiefel Laboratories. The authors disclosed no other conflicts of interest.

HOLLYWOOD, FLA. – The treatment of patients with lymphomatoid papulosis depends on the presentation, according to new National Comprehensive Cancer Network guidelines for managing primary cutaneous CD30+ T-cell lymphoproliferative disorders.

No treatment is needed in patients with lymphomatoid papulosis (LyP) who present without symptoms because spontaneous remission is extremely common in this disease, and these patients typically won’t have problems with progressive disease, Dr. Andrew D. Zelenetz said at the annual conference of the National Comprehensive Cancer Network.

For those who are symptomatic, topical or systemic treatments are useful in some cases.

Topical steroids "are effective, but not great," commented Dr. Zelenetz, vice chairman of medical informatics at Memorial Sloan Kettering Cancer Center, New York; professor of medicine at Cornell University, New York; and chair of the NCCN Non-Hodgkin's Lymphomas Guidelines panel.

Reported response rates are in the 50%-60% range, he said.

Bexarotene is another treatment option, although experience with this drug is quite limited. The largest series included only 11 patients. Unpublished data from that series at Memorial Sloan Kettering Cancer Center show a response rate of 45% at a maximum oral dose of 600 mg daily, Dr. Zelenetz said.

However, where this is a response, it is "dramatic and quite obvious," he noted, adding that treatment duration needs to be adequate before a patient is considered a nonresponder; the median duration of treatment in the 11-patient series was 35.5 weeks.

In a series of 57 patients from Memorial Sloan Kettering Cancer Center (including the 11 treated systemically with bexarotene), 16 received no therapy; 19 received topical treatment with steroids (13 patients), bexarotene (2 patients), UVB (2 patients), cryotherapy (1 patient), or nitrogen mustard (1 patient); and 5 received systemic treatment with methotrexate.

At follow-up, 14% of patients had no evidence of disease, and, with the exception of one who died of another cause, the remaining patients were alive with disease, Dr. Zelenetz said.

LyP is a rare CD30+ cutaneous lymphoproliferative disorder characterized by self-healing cropped or generalized eruptions of papules that come and go on the trunk or proximal extremities. In rare cases they present as solitary lesions.

"Even though many patients actually have intermittent recurrent disease ... the death rate from LyP is zero. So this is a very manageable disease; don’t overtreat these tumors," he said.

At the other end of the spectrum of CD30+ lymphoproliferative disorders addressed in the new NCCN guidelines is anaplastic large cell lymphoma (ALCL).

Primary cutaneous ALCL is characterized by skin-only presentation that is often localized but which can be disseminated in some cases. Lesions also tend to be larger and "more piled up" than those seen with LyP.

"You can get clustering in a specific area, but we don’t tend to have these big crops of lesions that we see with LyP," Dr. Zelenetz said.

The pathology is also different, with diffuse infiltration of the subcutaneous tissue. The cells are large and anaplastic, and there is intense expression of CD30.

The course of disease is usually indolent, with progression to extracutaneous sites in about 10%-15% of cases.

Nodules or tumors in cases of ALCL are less likely than LyP lesions to regress spontaneously, Dr. Zelenetz said.

This disease must be distinguished from a skin presentation of systemic ALCL, he noted.

"So what’s the big difference? In anaplastic large cell lymphoma that’s systemic, you will have multiple nodules all over and happen to have skin disease. With primary cutaneous ALCL, you have skin only or skin and some regional lymph nodes but nothing beyond that," he said, adding that these primary cutaneous tumors do extremely well nevertheless, with cumulative survival rates above 90%.

Those with systemic ALCL, however, have much lower cumulative survival, in the 25% range.

As with LyP, treatment for primary cutaneous ALCL is based on presentation.

For solitary or grouped lesions, the preferred treatment is surgical excision if needed for diagnosis or radiation if the diagnosis is already established.

Methotrexate is the preferred treatment for multifocal lesions.

The subtype that includes regional lymph nodes is typically treated with very mild chemotherapy including methotrexate or pralatrexate. Radiation can be used for locoregional disease, Dr. Zelenetz said.

An exception to the rule that patients with primary cutaneous ALCL do well is in cases of extensive limb disease. Patients with involvement of a single limb – usually lower extremity, but not always – have poor survival, and their disease is refractory to chemotherapy and radiation. It is unclear why there is a distinction in this presentation, but it is important to be aware of it, he said.

Dr. Zelenetz is a scientific adviser for Cancer Genetics Inc. and Gilead and has received consulting fees, honoraria, and/or grant or other research support from Celgene Corp., Cephalon Inc., Genentech Inc., GlaxoSmithKline, Roche Laboratories Inc., sanofi-aventis U.S., and Seattle Genetics Inc.

HOLLYWOOD, FLA. – The treatment of patients with lymphomatoid papulosis depends on the presentation, according to new National Comprehensive Cancer Network guidelines for managing primary cutaneous CD30+ T-cell lymphoproliferative disorders.

No treatment is needed in patients with lymphomatoid papulosis (LyP) who present without symptoms because spontaneous remission is extremely common in this disease, and these patients typically won’t have problems with progressive disease, Dr. Andrew D. Zelenetz said at the annual conference of the National Comprehensive Cancer Network.

For those who are symptomatic, topical or systemic treatments are useful in some cases.

Topical steroids "are effective, but not great," commented Dr. Zelenetz, vice chairman of medical informatics at Memorial Sloan Kettering Cancer Center, New York; professor of medicine at Cornell University, New York; and chair of the NCCN Non-Hodgkin's Lymphomas Guidelines panel.

Reported response rates are in the 50%-60% range, he said.

Bexarotene is another treatment option, although experience with this drug is quite limited. The largest series included only 11 patients. Unpublished data from that series at Memorial Sloan Kettering Cancer Center show a response rate of 45% at a maximum oral dose of 600 mg daily, Dr. Zelenetz said.

However, where this is a response, it is "dramatic and quite obvious," he noted, adding that treatment duration needs to be adequate before a patient is considered a nonresponder; the median duration of treatment in the 11-patient series was 35.5 weeks.

In a series of 57 patients from Memorial Sloan Kettering Cancer Center (including the 11 treated systemically with bexarotene), 16 received no therapy; 19 received topical treatment with steroids (13 patients), bexarotene (2 patients), UVB (2 patients), cryotherapy (1 patient), or nitrogen mustard (1 patient); and 5 received systemic treatment with methotrexate.

At follow-up, 14% of patients had no evidence of disease, and, with the exception of one who died of another cause, the remaining patients were alive with disease, Dr. Zelenetz said.

LyP is a rare CD30+ cutaneous lymphoproliferative disorder characterized by self-healing cropped or generalized eruptions of papules that come and go on the trunk or proximal extremities. In rare cases they present as solitary lesions.

"Even though many patients actually have intermittent recurrent disease ... the death rate from LyP is zero. So this is a very manageable disease; don’t overtreat these tumors," he said.

At the other end of the spectrum of CD30+ lymphoproliferative disorders addressed in the new NCCN guidelines is anaplastic large cell lymphoma (ALCL).

Primary cutaneous ALCL is characterized by skin-only presentation that is often localized but which can be disseminated in some cases. Lesions also tend to be larger and "more piled up" than those seen with LyP.

"You can get clustering in a specific area, but we don’t tend to have these big crops of lesions that we see with LyP," Dr. Zelenetz said.

The pathology is also different, with diffuse infiltration of the subcutaneous tissue. The cells are large and anaplastic, and there is intense expression of CD30.

The course of disease is usually indolent, with progression to extracutaneous sites in about 10%-15% of cases.

Nodules or tumors in cases of ALCL are less likely than LyP lesions to regress spontaneously, Dr. Zelenetz said.

This disease must be distinguished from a skin presentation of systemic ALCL, he noted.

"So what’s the big difference? In anaplastic large cell lymphoma that’s systemic, you will have multiple nodules all over and happen to have skin disease. With primary cutaneous ALCL, you have skin only or skin and some regional lymph nodes but nothing beyond that," he said, adding that these primary cutaneous tumors do extremely well nevertheless, with cumulative survival rates above 90%.

Those with systemic ALCL, however, have much lower cumulative survival, in the 25% range.

As with LyP, treatment for primary cutaneous ALCL is based on presentation.

For solitary or grouped lesions, the preferred treatment is surgical excision if needed for diagnosis or radiation if the diagnosis is already established.

Methotrexate is the preferred treatment for multifocal lesions.

The subtype that includes regional lymph nodes is typically treated with very mild chemotherapy including methotrexate or pralatrexate. Radiation can be used for locoregional disease, Dr. Zelenetz said.

An exception to the rule that patients with primary cutaneous ALCL do well is in cases of extensive limb disease. Patients with involvement of a single limb – usually lower extremity, but not always – have poor survival, and their disease is refractory to chemotherapy and radiation. It is unclear why there is a distinction in this presentation, but it is important to be aware of it, he said.

Dr. Zelenetz is a scientific adviser for Cancer Genetics Inc. and Gilead and has received consulting fees, honoraria, and/or grant or other research support from Celgene Corp., Cephalon Inc., Genentech Inc., GlaxoSmithKline, Roche Laboratories Inc., sanofi-aventis U.S., and Seattle Genetics Inc.

HOLLYWOOD, FLA. – The treatment of patients with lymphomatoid papulosis depends on the presentation, according to new National Comprehensive Cancer Network guidelines for managing primary cutaneous CD30+ T-cell lymphoproliferative disorders.

No treatment is needed in patients with lymphomatoid papulosis (LyP) who present without symptoms because spontaneous remission is extremely common in this disease, and these patients typically won’t have problems with progressive disease, Dr. Andrew D. Zelenetz said at the annual conference of the National Comprehensive Cancer Network.

For those who are symptomatic, topical or systemic treatments are useful in some cases.

Topical steroids "are effective, but not great," commented Dr. Zelenetz, vice chairman of medical informatics at Memorial Sloan Kettering Cancer Center, New York; professor of medicine at Cornell University, New York; and chair of the NCCN Non-Hodgkin's Lymphomas Guidelines panel.

Reported response rates are in the 50%-60% range, he said.

Bexarotene is another treatment option, although experience with this drug is quite limited. The largest series included only 11 patients. Unpublished data from that series at Memorial Sloan Kettering Cancer Center show a response rate of 45% at a maximum oral dose of 600 mg daily, Dr. Zelenetz said.

However, where this is a response, it is "dramatic and quite obvious," he noted, adding that treatment duration needs to be adequate before a patient is considered a nonresponder; the median duration of treatment in the 11-patient series was 35.5 weeks.

In a series of 57 patients from Memorial Sloan Kettering Cancer Center (including the 11 treated systemically with bexarotene), 16 received no therapy; 19 received topical treatment with steroids (13 patients), bexarotene (2 patients), UVB (2 patients), cryotherapy (1 patient), or nitrogen mustard (1 patient); and 5 received systemic treatment with methotrexate.

At follow-up, 14% of patients had no evidence of disease, and, with the exception of one who died of another cause, the remaining patients were alive with disease, Dr. Zelenetz said.

LyP is a rare CD30+ cutaneous lymphoproliferative disorder characterized by self-healing cropped or generalized eruptions of papules that come and go on the trunk or proximal extremities. In rare cases they present as solitary lesions.

"Even though many patients actually have intermittent recurrent disease ... the death rate from LyP is zero. So this is a very manageable disease; don’t overtreat these tumors," he said.

At the other end of the spectrum of CD30+ lymphoproliferative disorders addressed in the new NCCN guidelines is anaplastic large cell lymphoma (ALCL).

Primary cutaneous ALCL is characterized by skin-only presentation that is often localized but which can be disseminated in some cases. Lesions also tend to be larger and "more piled up" than those seen with LyP.

"You can get clustering in a specific area, but we don’t tend to have these big crops of lesions that we see with LyP," Dr. Zelenetz said.

The pathology is also different, with diffuse infiltration of the subcutaneous tissue. The cells are large and anaplastic, and there is intense expression of CD30.

The course of disease is usually indolent, with progression to extracutaneous sites in about 10%-15% of cases.

Nodules or tumors in cases of ALCL are less likely than LyP lesions to regress spontaneously, Dr. Zelenetz said.

This disease must be distinguished from a skin presentation of systemic ALCL, he noted.

"So what’s the big difference? In anaplastic large cell lymphoma that’s systemic, you will have multiple nodules all over and happen to have skin disease. With primary cutaneous ALCL, you have skin only or skin and some regional lymph nodes but nothing beyond that," he said, adding that these primary cutaneous tumors do extremely well nevertheless, with cumulative survival rates above 90%.

Those with systemic ALCL, however, have much lower cumulative survival, in the 25% range.

As with LyP, treatment for primary cutaneous ALCL is based on presentation.

For solitary or grouped lesions, the preferred treatment is surgical excision if needed for diagnosis or radiation if the diagnosis is already established.

Methotrexate is the preferred treatment for multifocal lesions.

The subtype that includes regional lymph nodes is typically treated with very mild chemotherapy including methotrexate or pralatrexate. Radiation can be used for locoregional disease, Dr. Zelenetz said.

An exception to the rule that patients with primary cutaneous ALCL do well is in cases of extensive limb disease. Patients with involvement of a single limb – usually lower extremity, but not always – have poor survival, and their disease is refractory to chemotherapy and radiation. It is unclear why there is a distinction in this presentation, but it is important to be aware of it, he said.

Dr. Zelenetz is a scientific adviser for Cancer Genetics Inc. and Gilead and has received consulting fees, honoraria, and/or grant or other research support from Celgene Corp., Cephalon Inc., Genentech Inc., GlaxoSmithKline, Roche Laboratories Inc., sanofi-aventis U.S., and Seattle Genetics Inc.

NEW ORLEANS – Tweaking experimental gene therapy for X-linked severe combined immunodeficiency may help to restore patient immune function while reducing the risk for subsequent leukemias.

In a small, multinational phase I/II trial, seven of nine children with SCID-X1 showed evidence of T-cell recovery and function, as well as a lower risk for promoting growth of leukemic cells, when a self-inactivating gamma-retroviral vector (SCID-2) was used to promote reconstitution of the child’s immune system without insertional oncogenesis, reported Dr. Sung-Yun Pai at the annual meeting of the American Society of Hematology.

"Outcomes for boys who do not have well-matched donors are suboptimal, and it’s particularly for these boys that we are targeting gene therapy," said Dr. Pai, of Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston.

In previous gene therapy trials, investigators used the Moloney leukemia virus (MLV)-based gamma-retroviral vector (SCID-1) with strong promoters and enhancers to express an IL-2 receptor that reconstituted the immune system successfully in 18 of 20 boys.

However, 5 of the 20 boys developed T-cell acute lymphoblastic leukemia; 1 of the children died, and the remaining 4 were successfully treated.

The investigators found that in the patients with leukemia, the SCID-1 vector had inserted into a chromosomal region close to proto-oncogenes such as LMO2, and the enhancers were driving expression of the neighboring oncogene, promoting expression of aberrant T cells. The vector was subsequently modified with the goal of improved safety but similar efficacy to the original, said Dr. Pai. The strong viral enhancers were removed to prevent accident enhancement should the inserted genes manage to find their way into oncogenes.

The phase I/II study is being conducted in London, Paris, Boston, Cincinnati, and Los Angeles, and to date has enrolled 9 male children of a planned 20.

Of the 9, one child died from a preexisting adenoviral infection before immune recovery was complete, and one child did not have engraftment of the gene-marked cells and went on to transplant.

"The other patients have 9 months to 36 months of follow-up, they have evidence of T-cell recovery, of T-cell function, have cleared SCID-related infections, and are all out of hospital, healthy at home, [and] leading essentially normal lives."

When the investigators looked at the comparative efficacy of the SCID-1 and SCID-2 vectors, they saw that 6 months after gene therapy, there was no significant difference in the median number of T cells generated.

"It’s far too early to comment on whether this vector will truly be safer in terms of leukemia," Dr. Pai said, noting that in the SCID-1 trial the leukemias developed 3-5 years after gene therapy, and the longest follow-up in the SCID-2 study is only 3 years.

The investigators are, however, conducting molecular surrogate safety analyses looking at gene insertion sites from the blood of patients treated with SCID-1 and are comparing those sites with the vector-insertion sites in cells from patients in SCID-2.

Looking at a global genomewide map of integrations, they found no significant differences between SCID-1 and SCID-2. However, when they focused on 38 genes that are to be proto-oncogenes in lymphoid cancer, they found that significantly more integration of the modified genes occurred in proximity to the oncogenes in SCID-1 than in SCID-2 (P = .003).

"We hope that these data suggest that the modified SCID vector will show less capacity to drive aberrant cell growth and lead to less leukemogenesis," said Dr. Pai.

SCID-X1 is caused by inherited mutations in the gamma subunit of the interleukin (IL)-2 receptor. As a result, males are born without T lymphocytes or natural killer cells. Without a bone marrow or stem cell transplantation, children with the disease die early from opportunistic or community-acquired infections.

"These are really paradigm-changing results for mortally wounded children," said Dr. Laurence James Neil Cooper of the University of Texas M.D. Anderson Cancer Center in Houston, who moderated the briefing but was not involved in the study.

The trial is being sponsored by Children’s Hospital Boston, Cincinnati Children’s Hospital Medical Center, and the University of California, Los Angeles. Dr. Pai and Dr. Cooper reported having no relevant conflicts of interest.

NEW ORLEANS – Tweaking experimental gene therapy for X-linked severe combined immunodeficiency may help to restore patient immune function while reducing the risk for subsequent leukemias.

In a small, multinational phase I/II trial, seven of nine children with SCID-X1 showed evidence of T-cell recovery and function, as well as a lower risk for promoting growth of leukemic cells, when a self-inactivating gamma-retroviral vector (SCID-2) was used to promote reconstitution of the child’s immune system without insertional oncogenesis, reported Dr. Sung-Yun Pai at the annual meeting of the American Society of Hematology.

"Outcomes for boys who do not have well-matched donors are suboptimal, and it’s particularly for these boys that we are targeting gene therapy," said Dr. Pai, of Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston.

In previous gene therapy trials, investigators used the Moloney leukemia virus (MLV)-based gamma-retroviral vector (SCID-1) with strong promoters and enhancers to express an IL-2 receptor that reconstituted the immune system successfully in 18 of 20 boys.

However, 5 of the 20 boys developed T-cell acute lymphoblastic leukemia; 1 of the children died, and the remaining 4 were successfully treated.

The investigators found that in the patients with leukemia, the SCID-1 vector had inserted into a chromosomal region close to proto-oncogenes such as LMO2, and the enhancers were driving expression of the neighboring oncogene, promoting expression of aberrant T cells. The vector was subsequently modified with the goal of improved safety but similar efficacy to the original, said Dr. Pai. The strong viral enhancers were removed to prevent accident enhancement should the inserted genes manage to find their way into oncogenes.

The phase I/II study is being conducted in London, Paris, Boston, Cincinnati, and Los Angeles, and to date has enrolled 9 male children of a planned 20.

Of the 9, one child died from a preexisting adenoviral infection before immune recovery was complete, and one child did not have engraftment of the gene-marked cells and went on to transplant.

"The other patients have 9 months to 36 months of follow-up, they have evidence of T-cell recovery, of T-cell function, have cleared SCID-related infections, and are all out of hospital, healthy at home, [and] leading essentially normal lives."

When the investigators looked at the comparative efficacy of the SCID-1 and SCID-2 vectors, they saw that 6 months after gene therapy, there was no significant difference in the median number of T cells generated.

"It’s far too early to comment on whether this vector will truly be safer in terms of leukemia," Dr. Pai said, noting that in the SCID-1 trial the leukemias developed 3-5 years after gene therapy, and the longest follow-up in the SCID-2 study is only 3 years.

The investigators are, however, conducting molecular surrogate safety analyses looking at gene insertion sites from the blood of patients treated with SCID-1 and are comparing those sites with the vector-insertion sites in cells from patients in SCID-2.

Looking at a global genomewide map of integrations, they found no significant differences between SCID-1 and SCID-2. However, when they focused on 38 genes that are to be proto-oncogenes in lymphoid cancer, they found that significantly more integration of the modified genes occurred in proximity to the oncogenes in SCID-1 than in SCID-2 (P = .003).

"We hope that these data suggest that the modified SCID vector will show less capacity to drive aberrant cell growth and lead to less leukemogenesis," said Dr. Pai.

SCID-X1 is caused by inherited mutations in the gamma subunit of the interleukin (IL)-2 receptor. As a result, males are born without T lymphocytes or natural killer cells. Without a bone marrow or stem cell transplantation, children with the disease die early from opportunistic or community-acquired infections.

"These are really paradigm-changing results for mortally wounded children," said Dr. Laurence James Neil Cooper of the University of Texas M.D. Anderson Cancer Center in Houston, who moderated the briefing but was not involved in the study.

The trial is being sponsored by Children’s Hospital Boston, Cincinnati Children’s Hospital Medical Center, and the University of California, Los Angeles. Dr. Pai and Dr. Cooper reported having no relevant conflicts of interest.

NEW ORLEANS – Tweaking experimental gene therapy for X-linked severe combined immunodeficiency may help to restore patient immune function while reducing the risk for subsequent leukemias.

In a small, multinational phase I/II trial, seven of nine children with SCID-X1 showed evidence of T-cell recovery and function, as well as a lower risk for promoting growth of leukemic cells, when a self-inactivating gamma-retroviral vector (SCID-2) was used to promote reconstitution of the child’s immune system without insertional oncogenesis, reported Dr. Sung-Yun Pai at the annual meeting of the American Society of Hematology.

"Outcomes for boys who do not have well-matched donors are suboptimal, and it’s particularly for these boys that we are targeting gene therapy," said Dr. Pai, of Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston.

In previous gene therapy trials, investigators used the Moloney leukemia virus (MLV)-based gamma-retroviral vector (SCID-1) with strong promoters and enhancers to express an IL-2 receptor that reconstituted the immune system successfully in 18 of 20 boys.

However, 5 of the 20 boys developed T-cell acute lymphoblastic leukemia; 1 of the children died, and the remaining 4 were successfully treated.

The investigators found that in the patients with leukemia, the SCID-1 vector had inserted into a chromosomal region close to proto-oncogenes such as LMO2, and the enhancers were driving expression of the neighboring oncogene, promoting expression of aberrant T cells. The vector was subsequently modified with the goal of improved safety but similar efficacy to the original, said Dr. Pai. The strong viral enhancers were removed to prevent accident enhancement should the inserted genes manage to find their way into oncogenes.

The phase I/II study is being conducted in London, Paris, Boston, Cincinnati, and Los Angeles, and to date has enrolled 9 male children of a planned 20.

Of the 9, one child died from a preexisting adenoviral infection before immune recovery was complete, and one child did not have engraftment of the gene-marked cells and went on to transplant.

"The other patients have 9 months to 36 months of follow-up, they have evidence of T-cell recovery, of T-cell function, have cleared SCID-related infections, and are all out of hospital, healthy at home, [and] leading essentially normal lives."

When the investigators looked at the comparative efficacy of the SCID-1 and SCID-2 vectors, they saw that 6 months after gene therapy, there was no significant difference in the median number of T cells generated.

"It’s far too early to comment on whether this vector will truly be safer in terms of leukemia," Dr. Pai said, noting that in the SCID-1 trial the leukemias developed 3-5 years after gene therapy, and the longest follow-up in the SCID-2 study is only 3 years.

The investigators are, however, conducting molecular surrogate safety analyses looking at gene insertion sites from the blood of patients treated with SCID-1 and are comparing those sites with the vector-insertion sites in cells from patients in SCID-2.

Looking at a global genomewide map of integrations, they found no significant differences between SCID-1 and SCID-2. However, when they focused on 38 genes that are to be proto-oncogenes in lymphoid cancer, they found that significantly more integration of the modified genes occurred in proximity to the oncogenes in SCID-1 than in SCID-2 (P = .003).

"We hope that these data suggest that the modified SCID vector will show less capacity to drive aberrant cell growth and lead to less leukemogenesis," said Dr. Pai.

SCID-X1 is caused by inherited mutations in the gamma subunit of the interleukin (IL)-2 receptor. As a result, males are born without T lymphocytes or natural killer cells. Without a bone marrow or stem cell transplantation, children with the disease die early from opportunistic or community-acquired infections.

"These are really paradigm-changing results for mortally wounded children," said Dr. Laurence James Neil Cooper of the University of Texas M.D. Anderson Cancer Center in Houston, who moderated the briefing but was not involved in the study.

The trial is being sponsored by Children’s Hospital Boston, Cincinnati Children’s Hospital Medical Center, and the University of California, Los Angeles. Dr. Pai and Dr. Cooper reported having no relevant conflicts of interest.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.