Lymphoma & Plasma Cell Disorders

SAN FRANCISCO – A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco.

Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress here. Others come from classes not previously used in this disease.

"There is a rush to develop new drugs in myeloma," Dr. Wolf told attendees. "We [understand] some mechanisms that the disease seems to favor, so we can interfere with those."

The prospects, in turn, are excellent: "We have made such tremendous headway in myeloma, except for those exceptional cases with 17p deletions and some other adverse prognostic features," he said. "As a disease, it seems to be on the ropes."

A Less-Toxic Proteasome Inhibitor

The first-generation proteasome inhibitor bortezomib (Velcade) improves myeloma outcomes, but maximizing its benefit will require addressing the peripheral neuropathy that limits its use. Three strategies may lessen this toxicity without compromising efficacy, Dr. Wolf suggested: modestly reducing the standard dose, adjusting the schedule from twice to once weekly, and altering the route of administration from intravenous to subcutaneous.

For example, in patients with pretreated myeloma, giving bortezomib subcutaneously instead of intravenously results in an identical overall response rate of 52% (Lancet Oncol. 2011;12:431-40). But there are significant reductions in rates of peripheral neuropathy of any grade (38% vs. 53%) and grade 3 or higher (6% vs. 16%).

"Practically everybody that we see now at UCSF gets subcutaneous [bortezomib]," Dr. Wolf said. It’s a great way to go back and treat patients who maybe otherwise have stopped their therapy because of their neuropathy."

Carfilzomib, an investigational next-generation proteasome inhibitor in phase III trials, is showing good antimyeloma activity and a low rate of peripheral neuropathy. Among patients with pretreated, relapsed, or refractory disease, carfilzomib monotherapy achieved overall response rates of 42% to 53% in a bortezomib-naive group (ASCO 2011 annual meeting. Abstract 8026) and 21% in a bortezomib-exposed group (Haematologica 2010;95:452 Abstract 1099). Median time to progression was at least 8 months for both.

Dr. Wolf said that unpublished data suggest that the response rate was still 17% specifically among patients who had had progression on bortezomib, "so there appears to be some activity in patients who are already refractory to a prior proteasome inhibitor."

Meanwhile, the rates of grade 1/2 and grade 3 peripheral neuropathy were 6% and 1%, respectively. And only a single patient of the 155 had to stop treatment because of this adverse effect.

When carfilzomib is combined with lenalidomide-dexamethasone (the so-called CRd regimen), the overall response rate in patients with pretreated, relapsed, and refractory disease is 78%, and the rate of complete or near complete response is 24% (ASCO 2011 meeting. Abstract 8025).

And, in newly diagnosed myeloma, among 18 patients receiving eight cycles of CRd, the overall response rate was 100%, and the rate of stringent-complete, complete, or near-complete response was 61% (2011 International Myeloma Workshop. Poster P-253). "This is very, very exciting—I don’t think we’ve seen this in any other combination," Dr. Wolf commented. "But these are small numbers of patients; we still need to increase the numbers of patients studied with this combination."

Bortezomib and carfilzomib may soon have company from several investigational proteasome inhibitors available in oral formulations that have shown promise in preclinical testing or have advanced to clinical trials: CEP-18770 (Cephalon), ONX-0912 (Onyx), and MLN-9708 (Millenium).

A Third-Generation IMiD in Trials

Pomalidomide, a third-generation immunomodulatory drug (IMiD), coming after thalidomide (Thalomid), and lenalidomide (Revlimid), is also showing good antimyeloma activity in clinical trials, according to Dr. Wolf.

Among patients with pretreated myeloma, the rate of partial or better response when pomalidomide is combined with dexamethasone has ranged from 25% to 42%, depending on the trial and patient population. Adverse events are primarily hematologic.

And in patients who have previously received lenalidomide, the response rate is similar, at 35% (ASCO 2011 annual meeting. Abstract 8067). "So, as with carfilzomib, where there appear to be responses in patients who have prior resistance to bortezomib, it appears that pomalidomide can give us responses in patients who have already had resistance to lenalidomide," he said.

HDAC Inhibitors Show Activity

The histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) is approved for treatment of lymphoma. But it is being tested in clinical trials for myeloma, in combination therapy, with promising results, according to Dr. Wolf. Overall response rates have ranged from 40% to 94%, depending on the patient population and combination.

Similarly, the HDAC inhibitor romidepsin (Istodax) is approved for lymphoma treatment but is also being studied for antimyeloma activity. And panobinostat, an investigational member of this drug class, is being evaluated as a component of combination therapy in phase II and III myeloma trials.

Monoclonal Antibodies Tested

Elotuzumab is an investigational monoclonal antibody directed against CS1, a glycoprotein that is highly expressed on the surface of plasma cells and implicated in myeloma pathogenesis.

In a phase I trial among patients with relapsed or refractory myeloma, the combination of elotuzumab with lenalidomide and low-dose dexamethasone yielded an overall response rate of 82% (ASCO 2011 meeting. Abstract 8076). The rate was 83% among the subset of patients whose disease was refractory to the most recent therapy and 95% among the subset of lenalidomide-naive patients.

The combination of elotuzumab with bortezomib has also been tested in patients with relapsed or refractory myeloma. But the overall response rate with this combination was less impressive, at 48% (ASH 2010 meeting. Abstract 3023).

Other Agents and Pathways

Several other agents are being eyed for roles in myeloma therapy as well. They include bendamustine (Treanda), an old drug initially revived for lymphoma treatment; aurora kinase inhibitors (for example, MLN-8237); and inhibitors of the mammalian target of rapamycin, or mTOR (for example, INK-128).

Additionally, there is considerable interest in agents that target fibroblast growth factor receptor 3 (FGFR3) for one subgroup. "In patients with the 4;14 translocation, FGFR3 is overexpressed," Dr. Wolf explained. "Finding an inhibitor for that or a direct antibody ... may be quite effective in those patients."

Investigators are also assessing the impact of targeting certain signaling pathways, such as the Jak/Stat pathway and the AKT pathway. For instance, a phase III trial is testing perifosine, an investigational AKT inhibitor, in combination therapy among patients with relapsed or refractory myeloma (NCT01002248).

The Oncology Congress is presented by Reed Medical Education. Reed Medical Education and this news organization are owned by Reed Elsevier Inc.

Dr. Wolf disclosed that he is on the speakers bureaus of Millenium, Celgene, and Ortho-Biotech, and is a consultant to and speaker for Onyx.

SAN FRANCISCO – A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco.

Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress here. Others come from classes not previously used in this disease.

"There is a rush to develop new drugs in myeloma," Dr. Wolf told attendees. "We [understand] some mechanisms that the disease seems to favor, so we can interfere with those."

The prospects, in turn, are excellent: "We have made such tremendous headway in myeloma, except for those exceptional cases with 17p deletions and some other adverse prognostic features," he said. "As a disease, it seems to be on the ropes."

A Less-Toxic Proteasome Inhibitor

The first-generation proteasome inhibitor bortezomib (Velcade) improves myeloma outcomes, but maximizing its benefit will require addressing the peripheral neuropathy that limits its use. Three strategies may lessen this toxicity without compromising efficacy, Dr. Wolf suggested: modestly reducing the standard dose, adjusting the schedule from twice to once weekly, and altering the route of administration from intravenous to subcutaneous.

For example, in patients with pretreated myeloma, giving bortezomib subcutaneously instead of intravenously results in an identical overall response rate of 52% (Lancet Oncol. 2011;12:431-40). But there are significant reductions in rates of peripheral neuropathy of any grade (38% vs. 53%) and grade 3 or higher (6% vs. 16%).

"Practically everybody that we see now at UCSF gets subcutaneous [bortezomib]," Dr. Wolf said. It’s a great way to go back and treat patients who maybe otherwise have stopped their therapy because of their neuropathy."

Carfilzomib, an investigational next-generation proteasome inhibitor in phase III trials, is showing good antimyeloma activity and a low rate of peripheral neuropathy. Among patients with pretreated, relapsed, or refractory disease, carfilzomib monotherapy achieved overall response rates of 42% to 53% in a bortezomib-naive group (ASCO 2011 annual meeting. Abstract 8026) and 21% in a bortezomib-exposed group (Haematologica 2010;95:452 Abstract 1099). Median time to progression was at least 8 months for both.

Dr. Wolf said that unpublished data suggest that the response rate was still 17% specifically among patients who had had progression on bortezomib, "so there appears to be some activity in patients who are already refractory to a prior proteasome inhibitor."

Meanwhile, the rates of grade 1/2 and grade 3 peripheral neuropathy were 6% and 1%, respectively. And only a single patient of the 155 had to stop treatment because of this adverse effect.

When carfilzomib is combined with lenalidomide-dexamethasone (the so-called CRd regimen), the overall response rate in patients with pretreated, relapsed, and refractory disease is 78%, and the rate of complete or near complete response is 24% (ASCO 2011 meeting. Abstract 8025).

And, in newly diagnosed myeloma, among 18 patients receiving eight cycles of CRd, the overall response rate was 100%, and the rate of stringent-complete, complete, or near-complete response was 61% (2011 International Myeloma Workshop. Poster P-253). "This is very, very exciting—I don’t think we’ve seen this in any other combination," Dr. Wolf commented. "But these are small numbers of patients; we still need to increase the numbers of patients studied with this combination."

Bortezomib and carfilzomib may soon have company from several investigational proteasome inhibitors available in oral formulations that have shown promise in preclinical testing or have advanced to clinical trials: CEP-18770 (Cephalon), ONX-0912 (Onyx), and MLN-9708 (Millenium).

A Third-Generation IMiD in Trials

Pomalidomide, a third-generation immunomodulatory drug (IMiD), coming after thalidomide (Thalomid), and lenalidomide (Revlimid), is also showing good antimyeloma activity in clinical trials, according to Dr. Wolf.

Among patients with pretreated myeloma, the rate of partial or better response when pomalidomide is combined with dexamethasone has ranged from 25% to 42%, depending on the trial and patient population. Adverse events are primarily hematologic.

And in patients who have previously received lenalidomide, the response rate is similar, at 35% (ASCO 2011 annual meeting. Abstract 8067). "So, as with carfilzomib, where there appear to be responses in patients who have prior resistance to bortezomib, it appears that pomalidomide can give us responses in patients who have already had resistance to lenalidomide," he said.

HDAC Inhibitors Show Activity

The histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) is approved for treatment of lymphoma. But it is being tested in clinical trials for myeloma, in combination therapy, with promising results, according to Dr. Wolf. Overall response rates have ranged from 40% to 94%, depending on the patient population and combination.

Similarly, the HDAC inhibitor romidepsin (Istodax) is approved for lymphoma treatment but is also being studied for antimyeloma activity. And panobinostat, an investigational member of this drug class, is being evaluated as a component of combination therapy in phase II and III myeloma trials.

Monoclonal Antibodies Tested

Elotuzumab is an investigational monoclonal antibody directed against CS1, a glycoprotein that is highly expressed on the surface of plasma cells and implicated in myeloma pathogenesis.

In a phase I trial among patients with relapsed or refractory myeloma, the combination of elotuzumab with lenalidomide and low-dose dexamethasone yielded an overall response rate of 82% (ASCO 2011 meeting. Abstract 8076). The rate was 83% among the subset of patients whose disease was refractory to the most recent therapy and 95% among the subset of lenalidomide-naive patients.

The combination of elotuzumab with bortezomib has also been tested in patients with relapsed or refractory myeloma. But the overall response rate with this combination was less impressive, at 48% (ASH 2010 meeting. Abstract 3023).

Other Agents and Pathways

Several other agents are being eyed for roles in myeloma therapy as well. They include bendamustine (Treanda), an old drug initially revived for lymphoma treatment; aurora kinase inhibitors (for example, MLN-8237); and inhibitors of the mammalian target of rapamycin, or mTOR (for example, INK-128).

Additionally, there is considerable interest in agents that target fibroblast growth factor receptor 3 (FGFR3) for one subgroup. "In patients with the 4;14 translocation, FGFR3 is overexpressed," Dr. Wolf explained. "Finding an inhibitor for that or a direct antibody ... may be quite effective in those patients."

Investigators are also assessing the impact of targeting certain signaling pathways, such as the Jak/Stat pathway and the AKT pathway. For instance, a phase III trial is testing perifosine, an investigational AKT inhibitor, in combination therapy among patients with relapsed or refractory myeloma (NCT01002248).

The Oncology Congress is presented by Reed Medical Education. Reed Medical Education and this news organization are owned by Reed Elsevier Inc.

Dr. Wolf disclosed that he is on the speakers bureaus of Millenium, Celgene, and Ortho-Biotech, and is a consultant to and speaker for Onyx.

SAN FRANCISCO – A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco.

Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress here. Others come from classes not previously used in this disease.

"There is a rush to develop new drugs in myeloma," Dr. Wolf told attendees. "We [understand] some mechanisms that the disease seems to favor, so we can interfere with those."

The prospects, in turn, are excellent: "We have made such tremendous headway in myeloma, except for those exceptional cases with 17p deletions and some other adverse prognostic features," he said. "As a disease, it seems to be on the ropes."

A Less-Toxic Proteasome Inhibitor

The first-generation proteasome inhibitor bortezomib (Velcade) improves myeloma outcomes, but maximizing its benefit will require addressing the peripheral neuropathy that limits its use. Three strategies may lessen this toxicity without compromising efficacy, Dr. Wolf suggested: modestly reducing the standard dose, adjusting the schedule from twice to once weekly, and altering the route of administration from intravenous to subcutaneous.

For example, in patients with pretreated myeloma, giving bortezomib subcutaneously instead of intravenously results in an identical overall response rate of 52% (Lancet Oncol. 2011;12:431-40). But there are significant reductions in rates of peripheral neuropathy of any grade (38% vs. 53%) and grade 3 or higher (6% vs. 16%).

"Practically everybody that we see now at UCSF gets subcutaneous [bortezomib]," Dr. Wolf said. It’s a great way to go back and treat patients who maybe otherwise have stopped their therapy because of their neuropathy."

Carfilzomib, an investigational next-generation proteasome inhibitor in phase III trials, is showing good antimyeloma activity and a low rate of peripheral neuropathy. Among patients with pretreated, relapsed, or refractory disease, carfilzomib monotherapy achieved overall response rates of 42% to 53% in a bortezomib-naive group (ASCO 2011 annual meeting. Abstract 8026) and 21% in a bortezomib-exposed group (Haematologica 2010;95:452 Abstract 1099). Median time to progression was at least 8 months for both.

Dr. Wolf said that unpublished data suggest that the response rate was still 17% specifically among patients who had had progression on bortezomib, "so there appears to be some activity in patients who are already refractory to a prior proteasome inhibitor."

Meanwhile, the rates of grade 1/2 and grade 3 peripheral neuropathy were 6% and 1%, respectively. And only a single patient of the 155 had to stop treatment because of this adverse effect.

When carfilzomib is combined with lenalidomide-dexamethasone (the so-called CRd regimen), the overall response rate in patients with pretreated, relapsed, and refractory disease is 78%, and the rate of complete or near complete response is 24% (ASCO 2011 meeting. Abstract 8025).

And, in newly diagnosed myeloma, among 18 patients receiving eight cycles of CRd, the overall response rate was 100%, and the rate of stringent-complete, complete, or near-complete response was 61% (2011 International Myeloma Workshop. Poster P-253). "This is very, very exciting—I don’t think we’ve seen this in any other combination," Dr. Wolf commented. "But these are small numbers of patients; we still need to increase the numbers of patients studied with this combination."

Bortezomib and carfilzomib may soon have company from several investigational proteasome inhibitors available in oral formulations that have shown promise in preclinical testing or have advanced to clinical trials: CEP-18770 (Cephalon), ONX-0912 (Onyx), and MLN-9708 (Millenium).

A Third-Generation IMiD in Trials

Pomalidomide, a third-generation immunomodulatory drug (IMiD), coming after thalidomide (Thalomid), and lenalidomide (Revlimid), is also showing good antimyeloma activity in clinical trials, according to Dr. Wolf.

Among patients with pretreated myeloma, the rate of partial or better response when pomalidomide is combined with dexamethasone has ranged from 25% to 42%, depending on the trial and patient population. Adverse events are primarily hematologic.

And in patients who have previously received lenalidomide, the response rate is similar, at 35% (ASCO 2011 annual meeting. Abstract 8067). "So, as with carfilzomib, where there appear to be responses in patients who have prior resistance to bortezomib, it appears that pomalidomide can give us responses in patients who have already had resistance to lenalidomide," he said.

HDAC Inhibitors Show Activity

The histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) is approved for treatment of lymphoma. But it is being tested in clinical trials for myeloma, in combination therapy, with promising results, according to Dr. Wolf. Overall response rates have ranged from 40% to 94%, depending on the patient population and combination.

Similarly, the HDAC inhibitor romidepsin (Istodax) is approved for lymphoma treatment but is also being studied for antimyeloma activity. And panobinostat, an investigational member of this drug class, is being evaluated as a component of combination therapy in phase II and III myeloma trials.

Monoclonal Antibodies Tested

Elotuzumab is an investigational monoclonal antibody directed against CS1, a glycoprotein that is highly expressed on the surface of plasma cells and implicated in myeloma pathogenesis.

In a phase I trial among patients with relapsed or refractory myeloma, the combination of elotuzumab with lenalidomide and low-dose dexamethasone yielded an overall response rate of 82% (ASCO 2011 meeting. Abstract 8076). The rate was 83% among the subset of patients whose disease was refractory to the most recent therapy and 95% among the subset of lenalidomide-naive patients.

The combination of elotuzumab with bortezomib has also been tested in patients with relapsed or refractory myeloma. But the overall response rate with this combination was less impressive, at 48% (ASH 2010 meeting. Abstract 3023).

Other Agents and Pathways

Several other agents are being eyed for roles in myeloma therapy as well. They include bendamustine (Treanda), an old drug initially revived for lymphoma treatment; aurora kinase inhibitors (for example, MLN-8237); and inhibitors of the mammalian target of rapamycin, or mTOR (for example, INK-128).

Additionally, there is considerable interest in agents that target fibroblast growth factor receptor 3 (FGFR3) for one subgroup. "In patients with the 4;14 translocation, FGFR3 is overexpressed," Dr. Wolf explained. "Finding an inhibitor for that or a direct antibody ... may be quite effective in those patients."

Investigators are also assessing the impact of targeting certain signaling pathways, such as the Jak/Stat pathway and the AKT pathway. For instance, a phase III trial is testing perifosine, an investigational AKT inhibitor, in combination therapy among patients with relapsed or refractory myeloma (NCT01002248).

The Oncology Congress is presented by Reed Medical Education. Reed Medical Education and this news organization are owned by Reed Elsevier Inc.

Dr. Wolf disclosed that he is on the speakers bureaus of Millenium, Celgene, and Ortho-Biotech, and is a consultant to and speaker for Onyx.

An analysis of long-term outcomes for elderly patients with advanced hematologic malignancies suggests they do as well as younger patients when treated with allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning.

In patients aged 60-75 years, the protocol yielded a 5-year overall survival rate of 35% and a progression-free survival rate of 32%, according to a report in the Nov. 2 issue of JAMA. The overall 5-year survival rate was as high as 69% among the patients who had the lowest comorbidity scores and lowest disease risk.

Half of these older patients never required hospitalization either during or after treatment, and two-thirds of the survivors returned to normal or near-normal physical functioning, said Dr. Mohamed L. Sorror of the transplantation biology program at the Fred Hutchinson Cancer Research Center, Seattle, and his associates.

"These results are encouraging given the poor outcomes with nontransplantation treatments, especially for patients with high-risk acute myeloid leukemia, fludarabine-refractory chronic lymphocytic leukemia, or progressive lymphoma," the investigators noted. They assessed outcomes in 372 patients aged 60-75 years who were enrolled in prospective clinical trials of the therapy at 18 medical centers in 1998-2008. The study subjects were being treated for hematologic malignancies including leukemia, myelodysplastic syndromes, myeloproliferative diseases, multiple myeloma, and lymphoma.

Since older patients are not eligible for the intense cytotoxic conditioning regimens that precede high-dose allogeneic hematopoietic cell transplantation, these patients instead underwent nonmyeloablative conditioning that relies on graft-versus-tumor effects to cure the cancer. This included fludarabine and a low dose of total-body irradiation before transplantation and a course of immunosuppression with mycophenolate mofetil and a calcineurin inhibitor (cyclosporine or tacrolimus) afterward.

"These findings should help allay reluctance in entering older patients with hematologic cancers in non- myeloablative [transplant] protocols."

After a median follow-up of 55 months (range, 12-133 months), 133 patients were still alive. Overall 5-year survival was 35%, and 5-year progression-free survival was 32%.

When the data were analyzed by patient age, 5-year overall survival was 38% for those aged 60-64 years, 33% for those aged 65-69, and 25% for those aged 70 and older. "Regardless of age, 5-year survivals ranged from 23% in patients with high comorbidity scores and high disease risk to 69% in patients with low comorbidity scores and low disease risk," Dr. Sorror and his colleagues said (JAMA 2011;306:1874-83).

Approximately two-thirds of the survivors at 5 years had complete resolution of their graft-versus-host disease (GVHD) symptoms and were able to discontinue immunosuppressive medications after a median of 2.5 years. Both the incidence and the resolution of GVHD in these older study subjects were comparable to those reported in the literature for younger patients treated with high-dose hematopoietic cell transplantation.

"These findings, together with the normal to near-normal performance status of surviving patients, should help allay reluctance in entering older patients with hematologic cancers in nonmyeloablative [transplant] protocols," the researchers noted.

Disease progression and relapse accounted for most (135) of the 239 deaths. Relapse rates were 33% at 1 year and 41% at 5 years. Most nonrelapse deaths were attributed to multiple organ failure, GVHD, and infections.

Dr. Sorror and his associates noted that hematologic malignancies are predominantly diseases of the elderly, and the incidence is expected to increase up to 77% during the next 20 years, due in part to the aging of the general population. Yet the latest figures show that only 12% of patients treated with hematopoietic cell transplantation in recent years were older than 60 years.

"This clearly highlights the reluctance of physicians to offer allogeneic hematopoietic cell transplantation to elderly patients," they said.

The investigators are now starting a multicenter longitudinal study to follow such patients from diagnosis onward, in the hope of elucidating "the reasons behind the low rate of referral of older patients to transplantation, [as well as] how nonmyeloablative [transplantation] outcomes compare with those after conventional therapies."

This study was supported by the National Institutes of Health and the Leukemia & Lymphoma Society. Dr. Sorror’s associates reported numerous ties to industry sources.

An analysis of long-term outcomes for elderly patients with advanced hematologic malignancies suggests they do as well as younger patients when treated with allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning.

In patients aged 60-75 years, the protocol yielded a 5-year overall survival rate of 35% and a progression-free survival rate of 32%, according to a report in the Nov. 2 issue of JAMA. The overall 5-year survival rate was as high as 69% among the patients who had the lowest comorbidity scores and lowest disease risk.

Half of these older patients never required hospitalization either during or after treatment, and two-thirds of the survivors returned to normal or near-normal physical functioning, said Dr. Mohamed L. Sorror of the transplantation biology program at the Fred Hutchinson Cancer Research Center, Seattle, and his associates.

"These results are encouraging given the poor outcomes with nontransplantation treatments, especially for patients with high-risk acute myeloid leukemia, fludarabine-refractory chronic lymphocytic leukemia, or progressive lymphoma," the investigators noted. They assessed outcomes in 372 patients aged 60-75 years who were enrolled in prospective clinical trials of the therapy at 18 medical centers in 1998-2008. The study subjects were being treated for hematologic malignancies including leukemia, myelodysplastic syndromes, myeloproliferative diseases, multiple myeloma, and lymphoma.

Since older patients are not eligible for the intense cytotoxic conditioning regimens that precede high-dose allogeneic hematopoietic cell transplantation, these patients instead underwent nonmyeloablative conditioning that relies on graft-versus-tumor effects to cure the cancer. This included fludarabine and a low dose of total-body irradiation before transplantation and a course of immunosuppression with mycophenolate mofetil and a calcineurin inhibitor (cyclosporine or tacrolimus) afterward.

"These findings should help allay reluctance in entering older patients with hematologic cancers in non- myeloablative [transplant] protocols."

After a median follow-up of 55 months (range, 12-133 months), 133 patients were still alive. Overall 5-year survival was 35%, and 5-year progression-free survival was 32%.

When the data were analyzed by patient age, 5-year overall survival was 38% for those aged 60-64 years, 33% for those aged 65-69, and 25% for those aged 70 and older. "Regardless of age, 5-year survivals ranged from 23% in patients with high comorbidity scores and high disease risk to 69% in patients with low comorbidity scores and low disease risk," Dr. Sorror and his colleagues said (JAMA 2011;306:1874-83).

Approximately two-thirds of the survivors at 5 years had complete resolution of their graft-versus-host disease (GVHD) symptoms and were able to discontinue immunosuppressive medications after a median of 2.5 years. Both the incidence and the resolution of GVHD in these older study subjects were comparable to those reported in the literature for younger patients treated with high-dose hematopoietic cell transplantation.

"These findings, together with the normal to near-normal performance status of surviving patients, should help allay reluctance in entering older patients with hematologic cancers in nonmyeloablative [transplant] protocols," the researchers noted.

Disease progression and relapse accounted for most (135) of the 239 deaths. Relapse rates were 33% at 1 year and 41% at 5 years. Most nonrelapse deaths were attributed to multiple organ failure, GVHD, and infections.

Dr. Sorror and his associates noted that hematologic malignancies are predominantly diseases of the elderly, and the incidence is expected to increase up to 77% during the next 20 years, due in part to the aging of the general population. Yet the latest figures show that only 12% of patients treated with hematopoietic cell transplantation in recent years were older than 60 years.

"This clearly highlights the reluctance of physicians to offer allogeneic hematopoietic cell transplantation to elderly patients," they said.

The investigators are now starting a multicenter longitudinal study to follow such patients from diagnosis onward, in the hope of elucidating "the reasons behind the low rate of referral of older patients to transplantation, [as well as] how nonmyeloablative [transplantation] outcomes compare with those after conventional therapies."

This study was supported by the National Institutes of Health and the Leukemia & Lymphoma Society. Dr. Sorror’s associates reported numerous ties to industry sources.

An analysis of long-term outcomes for elderly patients with advanced hematologic malignancies suggests they do as well as younger patients when treated with allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning.

In patients aged 60-75 years, the protocol yielded a 5-year overall survival rate of 35% and a progression-free survival rate of 32%, according to a report in the Nov. 2 issue of JAMA. The overall 5-year survival rate was as high as 69% among the patients who had the lowest comorbidity scores and lowest disease risk.

Half of these older patients never required hospitalization either during or after treatment, and two-thirds of the survivors returned to normal or near-normal physical functioning, said Dr. Mohamed L. Sorror of the transplantation biology program at the Fred Hutchinson Cancer Research Center, Seattle, and his associates.

"These results are encouraging given the poor outcomes with nontransplantation treatments, especially for patients with high-risk acute myeloid leukemia, fludarabine-refractory chronic lymphocytic leukemia, or progressive lymphoma," the investigators noted. They assessed outcomes in 372 patients aged 60-75 years who were enrolled in prospective clinical trials of the therapy at 18 medical centers in 1998-2008. The study subjects were being treated for hematologic malignancies including leukemia, myelodysplastic syndromes, myeloproliferative diseases, multiple myeloma, and lymphoma.

Since older patients are not eligible for the intense cytotoxic conditioning regimens that precede high-dose allogeneic hematopoietic cell transplantation, these patients instead underwent nonmyeloablative conditioning that relies on graft-versus-tumor effects to cure the cancer. This included fludarabine and a low dose of total-body irradiation before transplantation and a course of immunosuppression with mycophenolate mofetil and a calcineurin inhibitor (cyclosporine or tacrolimus) afterward.

"These findings should help allay reluctance in entering older patients with hematologic cancers in non- myeloablative [transplant] protocols."

After a median follow-up of 55 months (range, 12-133 months), 133 patients were still alive. Overall 5-year survival was 35%, and 5-year progression-free survival was 32%.

When the data were analyzed by patient age, 5-year overall survival was 38% for those aged 60-64 years, 33% for those aged 65-69, and 25% for those aged 70 and older. "Regardless of age, 5-year survivals ranged from 23% in patients with high comorbidity scores and high disease risk to 69% in patients with low comorbidity scores and low disease risk," Dr. Sorror and his colleagues said (JAMA 2011;306:1874-83).

Approximately two-thirds of the survivors at 5 years had complete resolution of their graft-versus-host disease (GVHD) symptoms and were able to discontinue immunosuppressive medications after a median of 2.5 years. Both the incidence and the resolution of GVHD in these older study subjects were comparable to those reported in the literature for younger patients treated with high-dose hematopoietic cell transplantation.

"These findings, together with the normal to near-normal performance status of surviving patients, should help allay reluctance in entering older patients with hematologic cancers in nonmyeloablative [transplant] protocols," the researchers noted.

Disease progression and relapse accounted for most (135) of the 239 deaths. Relapse rates were 33% at 1 year and 41% at 5 years. Most nonrelapse deaths were attributed to multiple organ failure, GVHD, and infections.

Dr. Sorror and his associates noted that hematologic malignancies are predominantly diseases of the elderly, and the incidence is expected to increase up to 77% during the next 20 years, due in part to the aging of the general population. Yet the latest figures show that only 12% of patients treated with hematopoietic cell transplantation in recent years were older than 60 years.

"This clearly highlights the reluctance of physicians to offer allogeneic hematopoietic cell transplantation to elderly patients," they said.

The investigators are now starting a multicenter longitudinal study to follow such patients from diagnosis onward, in the hope of elucidating "the reasons behind the low rate of referral of older patients to transplantation, [as well as] how nonmyeloablative [transplantation] outcomes compare with those after conventional therapies."

This study was supported by the National Institutes of Health and the Leukemia & Lymphoma Society. Dr. Sorror’s associates reported numerous ties to industry sources.

MIAMI BEACH – Patients with Hodgkin’s lymphoma may be spared additional radiotherapy following chemotherapy if they have a negative positron-emission tomography result, investigators from the German Hodgkin Study Group reported.

The negative predictive value for FDG (¹⁸fluorodeoxyglucose)–PET at 1 year was 94%, said Dr. Rolf P. Mueller of the University of Cologne (Germany). Among patients who had residual tumors measuring 2.5 cm or greater in diameter following chemotherapy, only 4% of those who were negative for residual disease on FDG-PET scans relapsed or required additional radiotherapy, compared with 11% of FDG-PET–positive patients.

"Thus, only those advanced-stage Hodgkin lymphoma patients with residual disease who are PET-positive patients might need additional radiotherapy," Dr. Mueller said at the annual meeting of the American Society of Radiation Oncology (ASTRO).

The investigators also found a significant difference in time-to-progression favoring PET-negative patients (P =.008) with Hodgkin’s lymphoma, also known as Hodgkin’s disease.

The percentage of patients who received radiation in this clinical trial, designated GHSG (German Hodgkin Study Group) HD-15, was 11%, compared with 70% of patients in the group’s GHSG-9 trial, Mueller noted. GHSG-15 studied the role of FDG-PET for evaluating residual disease and relapse risk among patients with advanced-stage Hodgkin’s lymphoma who had undergone six to eight cycles of chemotherapy with the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (J. Clin. Oncol. 2003;21:1734-9).

Early results were published in 2008 (Blood 2008;112: 3989-94). In the current report, Mueller presented data on a larger cohort.

All patients with a partial response or better and a residual mass measuring 2.5 cm or greater received FDG-PET scans. Of the 728 patients with residual disease following BEACOPP, 540 (74.2%) were PET negative, and 188 were PET positive. Mueller presented data on 701 patients who had at least 1 year of follow-up.

At 1 year, 96% (522) of PET-negative patients had neither progression nor relapse, compared with 11% of those who were PET positive. Of the PET-negative patients, 23 experienced disease progression (eight in the residual mass, six with new disease outside of the mass, and nine with progression/relapse in both areas). An additional eight PET-negative patients required additional radiotherapy.

The study was funded by the member centers of the GSHG. Dr. Mueller had no conflict of interest disclosures.

MIAMI BEACH – Patients with Hodgkin’s lymphoma may be spared additional radiotherapy following chemotherapy if they have a negative positron-emission tomography result, investigators from the German Hodgkin Study Group reported.

The negative predictive value for FDG (¹⁸fluorodeoxyglucose)–PET at 1 year was 94%, said Dr. Rolf P. Mueller of the University of Cologne (Germany). Among patients who had residual tumors measuring 2.5 cm or greater in diameter following chemotherapy, only 4% of those who were negative for residual disease on FDG-PET scans relapsed or required additional radiotherapy, compared with 11% of FDG-PET–positive patients.

"Thus, only those advanced-stage Hodgkin lymphoma patients with residual disease who are PET-positive patients might need additional radiotherapy," Dr. Mueller said at the annual meeting of the American Society of Radiation Oncology (ASTRO).

The investigators also found a significant difference in time-to-progression favoring PET-negative patients (P =.008) with Hodgkin’s lymphoma, also known as Hodgkin’s disease.

The percentage of patients who received radiation in this clinical trial, designated GHSG (German Hodgkin Study Group) HD-15, was 11%, compared with 70% of patients in the group’s GHSG-9 trial, Mueller noted. GHSG-15 studied the role of FDG-PET for evaluating residual disease and relapse risk among patients with advanced-stage Hodgkin’s lymphoma who had undergone six to eight cycles of chemotherapy with the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (J. Clin. Oncol. 2003;21:1734-9).

Early results were published in 2008 (Blood 2008;112: 3989-94). In the current report, Mueller presented data on a larger cohort.

All patients with a partial response or better and a residual mass measuring 2.5 cm or greater received FDG-PET scans. Of the 728 patients with residual disease following BEACOPP, 540 (74.2%) were PET negative, and 188 were PET positive. Mueller presented data on 701 patients who had at least 1 year of follow-up.

At 1 year, 96% (522) of PET-negative patients had neither progression nor relapse, compared with 11% of those who were PET positive. Of the PET-negative patients, 23 experienced disease progression (eight in the residual mass, six with new disease outside of the mass, and nine with progression/relapse in both areas). An additional eight PET-negative patients required additional radiotherapy.

The study was funded by the member centers of the GSHG. Dr. Mueller had no conflict of interest disclosures.

MIAMI BEACH – Patients with Hodgkin’s lymphoma may be spared additional radiotherapy following chemotherapy if they have a negative positron-emission tomography result, investigators from the German Hodgkin Study Group reported.

The negative predictive value for FDG (¹⁸fluorodeoxyglucose)–PET at 1 year was 94%, said Dr. Rolf P. Mueller of the University of Cologne (Germany). Among patients who had residual tumors measuring 2.5 cm or greater in diameter following chemotherapy, only 4% of those who were negative for residual disease on FDG-PET scans relapsed or required additional radiotherapy, compared with 11% of FDG-PET–positive patients.

"Thus, only those advanced-stage Hodgkin lymphoma patients with residual disease who are PET-positive patients might need additional radiotherapy," Dr. Mueller said at the annual meeting of the American Society of Radiation Oncology (ASTRO).

The investigators also found a significant difference in time-to-progression favoring PET-negative patients (P =.008) with Hodgkin’s lymphoma, also known as Hodgkin’s disease.

The percentage of patients who received radiation in this clinical trial, designated GHSG (German Hodgkin Study Group) HD-15, was 11%, compared with 70% of patients in the group’s GHSG-9 trial, Mueller noted. GHSG-15 studied the role of FDG-PET for evaluating residual disease and relapse risk among patients with advanced-stage Hodgkin’s lymphoma who had undergone six to eight cycles of chemotherapy with the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (J. Clin. Oncol. 2003;21:1734-9).

Early results were published in 2008 (Blood 2008;112: 3989-94). In the current report, Mueller presented data on a larger cohort.

All patients with a partial response or better and a residual mass measuring 2.5 cm or greater received FDG-PET scans. Of the 728 patients with residual disease following BEACOPP, 540 (74.2%) were PET negative, and 188 were PET positive. Mueller presented data on 701 patients who had at least 1 year of follow-up.

At 1 year, 96% (522) of PET-negative patients had neither progression nor relapse, compared with 11% of those who were PET positive. Of the PET-negative patients, 23 experienced disease progression (eight in the residual mass, six with new disease outside of the mass, and nine with progression/relapse in both areas). An additional eight PET-negative patients required additional radiotherapy.

The study was funded by the member centers of the GSHG. Dr. Mueller had no conflict of interest disclosures.

Micrograph showing HL

The US Food and Drug Administration (FDA) has granted accelerated approval for brentuximab vedotin (Adcetris) to treat patients with Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL).

The drug can now be used to treat HL patients after the failure of autologous stem cell transplant (ASCT) or, in patients who are not ASCT candidates, after they fail at least 2 prior multiagent chemotherapy regimens.

Brentuximab vedotin can also be used to treat patients with sALCL after the failure of at least 1 prior multiagent chemotherapy regimen.

About accelerated approval

The FDA instituted its accelerated approval program to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need. The approval is based on a surrogate endpoint that is not a measure of clinical benefit.

Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If these confirmatory trials suggest the drug actually provides a clinical benefit, the FDA grants traditional approval for the drug. If the confirmatory trial does not show a clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

Brentuximab vedotin in HL

Accelerated approval for the HL indication was based on a single-arm, multicenter trial to evaluate the objective response rate of brentuximab vedotin as a single agent. The 102 patients enrolled in the trial had CD30-positive HL that relapsed following ASCT.

Brentuximab vedotin prompted an overall response rate in these patients of 73%, with a median response duration of 6.7 months.

Thirty-two percent of patients achieved a complete remission, with a median duration of 20.5 months. Forty percent of patients achieved a partial remission, with a median duration of 3.5 months.

Brentuximab vedotin in sALCL

Accelerated approval for the treatment of sALCL was based on a single-arm, multicenter trial as well. The study included 58 patients with CD30-positive sALCL who had previously received frontline, multiagent chemotherapy treatment.

The primary efficacy endpoint of overall response rate was achieved in 86% of sALCL patients, with a median duration of 12.6 months.

Fifty-seven percent of patients achieved a complete remission, with a median duration of 13.2 months. Twenty-nine percent of patients achieved a partial response, with a median duration of 2.1 months.

The recommended dose and schedule for both indications is 1.8 mg/kg given intravenously over 30 minutes every 3 weeks. Treatment may last a total of 16 cycles, or until disease progresses or toxicity becomes unacceptable.

The agent, manufactured by Seattle Genetics under the trade name Adcetris, is the first new treatment for HL to be approved by the FDA since 1977 and the first to be indicated for sALCL.

Micrograph showing HL

The US Food and Drug Administration (FDA) has granted accelerated approval for brentuximab vedotin (Adcetris) to treat patients with Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL).

The drug can now be used to treat HL patients after the failure of autologous stem cell transplant (ASCT) or, in patients who are not ASCT candidates, after they fail at least 2 prior multiagent chemotherapy regimens.

Brentuximab vedotin can also be used to treat patients with sALCL after the failure of at least 1 prior multiagent chemotherapy regimen.

About accelerated approval

The FDA instituted its accelerated approval program to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need. The approval is based on a surrogate endpoint that is not a measure of clinical benefit.

Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If these confirmatory trials suggest the drug actually provides a clinical benefit, the FDA grants traditional approval for the drug. If the confirmatory trial does not show a clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

Brentuximab vedotin in HL

Accelerated approval for the HL indication was based on a single-arm, multicenter trial to evaluate the objective response rate of brentuximab vedotin as a single agent. The 102 patients enrolled in the trial had CD30-positive HL that relapsed following ASCT.

Brentuximab vedotin prompted an overall response rate in these patients of 73%, with a median response duration of 6.7 months.

Thirty-two percent of patients achieved a complete remission, with a median duration of 20.5 months. Forty percent of patients achieved a partial remission, with a median duration of 3.5 months.

Brentuximab vedotin in sALCL

Accelerated approval for the treatment of sALCL was based on a single-arm, multicenter trial as well. The study included 58 patients with CD30-positive sALCL who had previously received frontline, multiagent chemotherapy treatment.

The primary efficacy endpoint of overall response rate was achieved in 86% of sALCL patients, with a median duration of 12.6 months.

Fifty-seven percent of patients achieved a complete remission, with a median duration of 13.2 months. Twenty-nine percent of patients achieved a partial response, with a median duration of 2.1 months.

The recommended dose and schedule for both indications is 1.8 mg/kg given intravenously over 30 minutes every 3 weeks. Treatment may last a total of 16 cycles, or until disease progresses or toxicity becomes unacceptable.

The agent, manufactured by Seattle Genetics under the trade name Adcetris, is the first new treatment for HL to be approved by the FDA since 1977 and the first to be indicated for sALCL.

Micrograph showing HL

The US Food and Drug Administration (FDA) has granted accelerated approval for brentuximab vedotin (Adcetris) to treat patients with Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL).

The drug can now be used to treat HL patients after the failure of autologous stem cell transplant (ASCT) or, in patients who are not ASCT candidates, after they fail at least 2 prior multiagent chemotherapy regimens.

Brentuximab vedotin can also be used to treat patients with sALCL after the failure of at least 1 prior multiagent chemotherapy regimen.

About accelerated approval

The FDA instituted its accelerated approval program to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need. The approval is based on a surrogate endpoint that is not a measure of clinical benefit.

Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If these confirmatory trials suggest the drug actually provides a clinical benefit, the FDA grants traditional approval for the drug. If the confirmatory trial does not show a clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

Brentuximab vedotin in HL

Accelerated approval for the HL indication was based on a single-arm, multicenter trial to evaluate the objective response rate of brentuximab vedotin as a single agent. The 102 patients enrolled in the trial had CD30-positive HL that relapsed following ASCT.

Brentuximab vedotin prompted an overall response rate in these patients of 73%, with a median response duration of 6.7 months.

Thirty-two percent of patients achieved a complete remission, with a median duration of 20.5 months. Forty percent of patients achieved a partial remission, with a median duration of 3.5 months.

Brentuximab vedotin in sALCL

Accelerated approval for the treatment of sALCL was based on a single-arm, multicenter trial as well. The study included 58 patients with CD30-positive sALCL who had previously received frontline, multiagent chemotherapy treatment.

The primary efficacy endpoint of overall response rate was achieved in 86% of sALCL patients, with a median duration of 12.6 months.

Fifty-seven percent of patients achieved a complete remission, with a median duration of 13.2 months. Twenty-nine percent of patients achieved a partial response, with a median duration of 2.1 months.

The recommended dose and schedule for both indications is 1.8 mg/kg given intravenously over 30 minutes every 3 weeks. Treatment may last a total of 16 cycles, or until disease progresses or toxicity becomes unacceptable.

The agent, manufactured by Seattle Genetics under the trade name Adcetris, is the first new treatment for HL to be approved by the FDA since 1977 and the first to be indicated for sALCL.

The Food and Drug Administration on Aug. 19 approved brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

Specifically, brentuximab was approved for the treatment of patients with Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates. It is the first new treatment approved for HL by the FDA since 1977, according to the FDA statement. The indications are based on response rates, and there are no available data that show "improvement in patient reported outcomes or survival" with treatment, according to the prescribing information.

The FDA also approved brentuximab for patients with systemic anaplastic large-cell lymphoma (ALCL), a rare form of lymphoma, after failure of at least one prior multiagent chemotherapy regimen. It is the first treatment approved for this rare lymphoma; approximately 2,000 new cases are diagnosed yearly in the United States.

Both types of lymphomas express the CD30 antigen. Brentuximab is a combination of an anti-CD30 antibody and a drug, monomethyl auristatin E (MMAE), a microtubule disrupting agent. The antibody directs the drug to C30-expressing tumor cells, where it is released.

Brentuximab is administered intravenously every 3 weeks; it will be marketed in the United States as Adcetris by Seattle Genetics. It will be available the week of Aug. 22, according to a company spokesperson.

The product was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug for a serious disease based on data showing the drug is effective on a surrogate end point that is "reasonably likely" to predict clinical benefit. Accelerated approvals provide patients with access to promising treatments, but companies are required to provide confirmatory clinical data in order for the drug to be converted to a full approval and remain on the market.

"Early clinical data suggest that patients who received Adcetris for Hodgkin’s lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

In a study of 102 patients with HL treated with brentuximab, 73% of the patients had either a complete or partial response to treatment. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response to treatment. Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper-respiratory infection, diarrhea, fever, cough, vomiting, and thrombocytopenia were among the most common adverse effects associated with treatment, according to the FDA.

At a meeting in July, an FDA advisory panel recommended the accelerated approval of both indications.

Brentuximab is under review for the same indications in Europe; a decision on approval is expected in the first half of 2012, according to a spokesperson for Millennium: the Takeda Oncology Co., which has rights to commercialize brentuximab outside the United States and Canada.

The Food and Drug Administration on Aug. 19 approved brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

Specifically, brentuximab was approved for the treatment of patients with Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates. It is the first new treatment approved for HL by the FDA since 1977, according to the FDA statement. The indications are based on response rates, and there are no available data that show "improvement in patient reported outcomes or survival" with treatment, according to the prescribing information.

The FDA also approved brentuximab for patients with systemic anaplastic large-cell lymphoma (ALCL), a rare form of lymphoma, after failure of at least one prior multiagent chemotherapy regimen. It is the first treatment approved for this rare lymphoma; approximately 2,000 new cases are diagnosed yearly in the United States.

Both types of lymphomas express the CD30 antigen. Brentuximab is a combination of an anti-CD30 antibody and a drug, monomethyl auristatin E (MMAE), a microtubule disrupting agent. The antibody directs the drug to C30-expressing tumor cells, where it is released.

Brentuximab is administered intravenously every 3 weeks; it will be marketed in the United States as Adcetris by Seattle Genetics. It will be available the week of Aug. 22, according to a company spokesperson.

The product was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug for a serious disease based on data showing the drug is effective on a surrogate end point that is "reasonably likely" to predict clinical benefit. Accelerated approvals provide patients with access to promising treatments, but companies are required to provide confirmatory clinical data in order for the drug to be converted to a full approval and remain on the market.

"Early clinical data suggest that patients who received Adcetris for Hodgkin’s lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

In a study of 102 patients with HL treated with brentuximab, 73% of the patients had either a complete or partial response to treatment. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response to treatment. Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper-respiratory infection, diarrhea, fever, cough, vomiting, and thrombocytopenia were among the most common adverse effects associated with treatment, according to the FDA.

At a meeting in July, an FDA advisory panel recommended the accelerated approval of both indications.

Brentuximab is under review for the same indications in Europe; a decision on approval is expected in the first half of 2012, according to a spokesperson for Millennium: the Takeda Oncology Co., which has rights to commercialize brentuximab outside the United States and Canada.

The Food and Drug Administration on Aug. 19 approved brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

Specifically, brentuximab was approved for the treatment of patients with Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates. It is the first new treatment approved for HL by the FDA since 1977, according to the FDA statement. The indications are based on response rates, and there are no available data that show "improvement in patient reported outcomes or survival" with treatment, according to the prescribing information.

The FDA also approved brentuximab for patients with systemic anaplastic large-cell lymphoma (ALCL), a rare form of lymphoma, after failure of at least one prior multiagent chemotherapy regimen. It is the first treatment approved for this rare lymphoma; approximately 2,000 new cases are diagnosed yearly in the United States.

Both types of lymphomas express the CD30 antigen. Brentuximab is a combination of an anti-CD30 antibody and a drug, monomethyl auristatin E (MMAE), a microtubule disrupting agent. The antibody directs the drug to C30-expressing tumor cells, where it is released.

Brentuximab is administered intravenously every 3 weeks; it will be marketed in the United States as Adcetris by Seattle Genetics. It will be available the week of Aug. 22, according to a company spokesperson.

The product was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug for a serious disease based on data showing the drug is effective on a surrogate end point that is "reasonably likely" to predict clinical benefit. Accelerated approvals provide patients with access to promising treatments, but companies are required to provide confirmatory clinical data in order for the drug to be converted to a full approval and remain on the market.

"Early clinical data suggest that patients who received Adcetris for Hodgkin’s lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

In a study of 102 patients with HL treated with brentuximab, 73% of the patients had either a complete or partial response to treatment. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response to treatment. Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper-respiratory infection, diarrhea, fever, cough, vomiting, and thrombocytopenia were among the most common adverse effects associated with treatment, according to the FDA.

At a meeting in July, an FDA advisory panel recommended the accelerated approval of both indications.

Brentuximab is under review for the same indications in Europe; a decision on approval is expected in the first half of 2012, according to a spokesperson for Millennium: the Takeda Oncology Co., which has rights to commercialize brentuximab outside the United States and Canada.

Gene therapy with a lentiviral vector expressing a chimeric antigen receptor with specificity for CD19 (CART19) has induced complete remission in 3 patients with chronic lymphocytic leukemia (CLL), according to research published simultaneously in the August 10 issues of The New England Journal of Medicine and Science Translational Medicine.

The research team, from the University of Pennsylvania, reported that the reinfused, modified T cells expanded to more than 1000 times the initial engraftment level. The patients’ remission was ongoing at 10 months after treatment.

The investigators believe the big difference between this genetically modified T cell and previous ones that had disappointing clinical activity is the addition of the CD137 (4-1BB) costimulatory signaling domain that significantly increases antitumor activity.

The team, led by Carl June, MD, described in the NEJM article the T-cell treatment of one of the patients with advanced, p53-deficient CLL.

A half year prior to enrolling in the trial, the 64-year-old patient’s T cells were collected and frozen. Before reinfusing the T cells into the patient, the investigators thawed the cells and transduced them with lentivirus expressing CD19-specific chimeric antigen receptor.

Four days prior to reinfusion, the patient received chemotherapy with pentostatin and cyclophosphamide to deplete his lymphocytes. After 3 days of chemotherapy, his bone marrow was hypercellular with approximately 40% involvement by CLL.

After 4 days of chemotherapy, the patient received an infusion of T cells, of which 5% were transduced, totaling 1.42 x 10⁷ transduced cells, split into 3 consecutive daily infusions.

Two weeks after the infusion, the patient experienced chills, fever, and fatigue, which intensified over the subsequent days. He was diagnosed with tumor lysis syndrome on day 22 after infusion. On day 23 after the CART19-cell infusion, the patient had no evidence of CLL in the bone marrow, and by day 28, his adenopathy was not palpable.

In addition to tumor lysis syndrome, the only other grade 3/4 toxicity observed was lymphopenia.

The investigators did not expect that such a low dose of chimeric antigen receptor T cells would result in a clinically evident antitumor response. The dose was several orders of magnitude lower than that used in previous studies of modified T cells.

They speculated that the course of chemotherapy administered to the patient prior to the CART19-cell infusion may have been responsible for the increased engraftment and for “potentiating the ability of chimeric antigen receptor T cells to kill stressed tumor cells that would otherwise survive the chemotherapy.”

The researchers conclude that continued study of CD19-redirected T cells is warranted and plan to test the approach in other CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia.

Gene therapy with a lentiviral vector expressing a chimeric antigen receptor with specificity for CD19 (CART19) has induced complete remission in 3 patients with chronic lymphocytic leukemia (CLL), according to research published simultaneously in the August 10 issues of The New England Journal of Medicine and Science Translational Medicine.

The research team, from the University of Pennsylvania, reported that the reinfused, modified T cells expanded to more than 1000 times the initial engraftment level. The patients’ remission was ongoing at 10 months after treatment.

The investigators believe the big difference between this genetically modified T cell and previous ones that had disappointing clinical activity is the addition of the CD137 (4-1BB) costimulatory signaling domain that significantly increases antitumor activity.

The team, led by Carl June, MD, described in the NEJM article the T-cell treatment of one of the patients with advanced, p53-deficient CLL.

A half year prior to enrolling in the trial, the 64-year-old patient’s T cells were collected and frozen. Before reinfusing the T cells into the patient, the investigators thawed the cells and transduced them with lentivirus expressing CD19-specific chimeric antigen receptor.

Four days prior to reinfusion, the patient received chemotherapy with pentostatin and cyclophosphamide to deplete his lymphocytes. After 3 days of chemotherapy, his bone marrow was hypercellular with approximately 40% involvement by CLL.

After 4 days of chemotherapy, the patient received an infusion of T cells, of which 5% were transduced, totaling 1.42 x 10⁷ transduced cells, split into 3 consecutive daily infusions.

Two weeks after the infusion, the patient experienced chills, fever, and fatigue, which intensified over the subsequent days. He was diagnosed with tumor lysis syndrome on day 22 after infusion. On day 23 after the CART19-cell infusion, the patient had no evidence of CLL in the bone marrow, and by day 28, his adenopathy was not palpable.

In addition to tumor lysis syndrome, the only other grade 3/4 toxicity observed was lymphopenia.

The investigators did not expect that such a low dose of chimeric antigen receptor T cells would result in a clinically evident antitumor response. The dose was several orders of magnitude lower than that used in previous studies of modified T cells.

They speculated that the course of chemotherapy administered to the patient prior to the CART19-cell infusion may have been responsible for the increased engraftment and for “potentiating the ability of chimeric antigen receptor T cells to kill stressed tumor cells that would otherwise survive the chemotherapy.”

The researchers conclude that continued study of CD19-redirected T cells is warranted and plan to test the approach in other CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia.

Gene therapy with a lentiviral vector expressing a chimeric antigen receptor with specificity for CD19 (CART19) has induced complete remission in 3 patients with chronic lymphocytic leukemia (CLL), according to research published simultaneously in the August 10 issues of The New England Journal of Medicine and Science Translational Medicine.

The research team, from the University of Pennsylvania, reported that the reinfused, modified T cells expanded to more than 1000 times the initial engraftment level. The patients’ remission was ongoing at 10 months after treatment.

The investigators believe the big difference between this genetically modified T cell and previous ones that had disappointing clinical activity is the addition of the CD137 (4-1BB) costimulatory signaling domain that significantly increases antitumor activity.

The team, led by Carl June, MD, described in the NEJM article the T-cell treatment of one of the patients with advanced, p53-deficient CLL.

A half year prior to enrolling in the trial, the 64-year-old patient’s T cells were collected and frozen. Before reinfusing the T cells into the patient, the investigators thawed the cells and transduced them with lentivirus expressing CD19-specific chimeric antigen receptor.

Four days prior to reinfusion, the patient received chemotherapy with pentostatin and cyclophosphamide to deplete his lymphocytes. After 3 days of chemotherapy, his bone marrow was hypercellular with approximately 40% involvement by CLL.

After 4 days of chemotherapy, the patient received an infusion of T cells, of which 5% were transduced, totaling 1.42 x 10⁷ transduced cells, split into 3 consecutive daily infusions.

Two weeks after the infusion, the patient experienced chills, fever, and fatigue, which intensified over the subsequent days. He was diagnosed with tumor lysis syndrome on day 22 after infusion. On day 23 after the CART19-cell infusion, the patient had no evidence of CLL in the bone marrow, and by day 28, his adenopathy was not palpable.

In addition to tumor lysis syndrome, the only other grade 3/4 toxicity observed was lymphopenia.

The investigators did not expect that such a low dose of chimeric antigen receptor T cells would result in a clinically evident antitumor response. The dose was several orders of magnitude lower than that used in previous studies of modified T cells.

They speculated that the course of chemotherapy administered to the patient prior to the CART19-cell infusion may have been responsible for the increased engraftment and for “potentiating the ability of chimeric antigen receptor T cells to kill stressed tumor cells that would otherwise survive the chemotherapy.”

The researchers conclude that continued study of CD19-redirected T cells is warranted and plan to test the approach in other CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia.

The skin may hold the key to differentiating classic pemphigus from the heterogenous autoimmune syndrome known as paraneoplastic autoimmune multiorgan syndrome.

It is a distinction of critical prognostic importance, because paraneoplastic autoimmune multiorgan syndrome (PAMS) typically is rapidly fatal, according to Dr. Sergei A. Grando, professor of dermatology and biologic chemistry at the University of California, Irvine. "The vast majority of patients die within several months of diagnosis, usually due to infections or respiratory failure, often taking the form of multiorgan system failure."

Two-thirds of patients with PAMS have a known internal malignancy at the time of their first mucocutaneous eruption. The most common of these neoplasms are non-Hodgkin’s lymphoma, which is present in more than 40% of PAMS patients; chronic lymphocytic leukemia, present in 30%; Castleman disease, present in 10%; and thymoma, present in 6%.

When a patient meets the diagnostic criteria for PAMS without having a known cancer, it is appropriate to launch a search for hidden malignancy, said Dr. Grando.

A key distinction between the skin lesions of PAMS and classic pemphigus is that PAMS involves inflammatory macules, papules, plaques, and blisters occurring on an inflammatory background over the trunk and extremities, including the palms and soles, but sparing the scalp.

In contrast, the generally more vesicular blisters and crusted erosions of pemphigus vulgaris display little erythema and usually occur on a noninflammatory background on the scalp, trunk, and extremities (but sparing the palms and soles). The most common location for skin lesions in PAMS is the palms; in pemphigus vulgaris, it is the scalp.

Also, Nikolsky's sign is positive in pemphigus vulgaris, but negative in PAMS, added Dr. Grando, who was among the investigators who first described PAMS a decade ago (Arch. Dermatol. 2001;137:193-206).

PAMS is characterized by severe and diffuse oral mucous membrane involvement, with persistent painful stomatitis because of blisters and erosions, and frequent involvement of other mucous membranes, including the eyes and genitalia. Cicatrizing conjunctivitis is particularly common in PAMS. In contrast, oral mucous membrane involvement in pemphigus is more discrete, with the eyes or other nonoral mucosa rarely involved.

Photo courtesy Dr. Rania Abdel Hay

Another key in the differential diagnosis: PAMS is associated with the HLA-DRB1*03 allele, whereas pemphigus vulgaris and foliaceous are strongly associated with the -04 and -14 alleles, respectively.

A hallmark of PAMS is respiratory involvement, with the sloughing of bronchial epithelial cells contributing to small airway occlusion and bronchiolitis obliterans. Classic pemphigus is free of respiratory involvement.

Both the esophagus and colon may be involved in PAMS, whereas only the esophagus is affected in pemphigus vulgaris.

In a published series of 28 PAMS patients, painful and generalized oral stomatitis was present in all 28, respiratory involvement was in 26, death from respiratory failure occurred in 22, and lichenoid skin involvement was present in 19. Only seven patients had no skin lesions (Br. J. Dermatol. 2003;149:1143-51).

At least five different subtypes of PAMS can be distinguished on the basis of the skin disease manifestations they most resemble. These subtypes of pemphiguslike PAMS include paraneoplastic pemphigus, bullous pemphigoid–like, erythema multiforme–like, lichen planus–like, and graft-vs.-host-disease–like versions of PAMS.

Dr. Grando eschews the term "paraneoplastic pemphigus" as too restrictive. After all, true pemphigus doesn’t usually affect the lungs, he noted.

Photo (c) Elsevier Inc.

Whereas most patients with classic pemphigus respond well to high-dose corticosteroids and recalcitrant disease can be effectively treated with cytotoxic agents, cyclosporine, intravenous gamma globulin, and other second-line agents, PAMS is resistant to all conventional forms of therapy.

"What can we offer? Really not much," Dr. Grando said during his presentation at the World Congress of Dermatology in Seoul, South Korea.

The preferred treatment regimen is a combination of prednisone and cyclosporine, with or without cyclophosphamide. Monthly courses of IVIG can buy patients a few extra months, he added.

Dr. Grando declared having no relevant financial interests.

The skin may hold the key to differentiating classic pemphigus from the heterogenous autoimmune syndrome known as paraneoplastic autoimmune multiorgan syndrome.

It is a distinction of critical prognostic importance, because paraneoplastic autoimmune multiorgan syndrome (PAMS) typically is rapidly fatal, according to Dr. Sergei A. Grando, professor of dermatology and biologic chemistry at the University of California, Irvine. "The vast majority of patients die within several months of diagnosis, usually due to infections or respiratory failure, often taking the form of multiorgan system failure."

Two-thirds of patients with PAMS have a known internal malignancy at the time of their first mucocutaneous eruption. The most common of these neoplasms are non-Hodgkin’s lymphoma, which is present in more than 40% of PAMS patients; chronic lymphocytic leukemia, present in 30%; Castleman disease, present in 10%; and thymoma, present in 6%.

When a patient meets the diagnostic criteria for PAMS without having a known cancer, it is appropriate to launch a search for hidden malignancy, said Dr. Grando.

A key distinction between the skin lesions of PAMS and classic pemphigus is that PAMS involves inflammatory macules, papules, plaques, and blisters occurring on an inflammatory background over the trunk and extremities, including the palms and soles, but sparing the scalp.

In contrast, the generally more vesicular blisters and crusted erosions of pemphigus vulgaris display little erythema and usually occur on a noninflammatory background on the scalp, trunk, and extremities (but sparing the palms and soles). The most common location for skin lesions in PAMS is the palms; in pemphigus vulgaris, it is the scalp.

Also, Nikolsky's sign is positive in pemphigus vulgaris, but negative in PAMS, added Dr. Grando, who was among the investigators who first described PAMS a decade ago (Arch. Dermatol. 2001;137:193-206).

PAMS is characterized by severe and diffuse oral mucous membrane involvement, with persistent painful stomatitis because of blisters and erosions, and frequent involvement of other mucous membranes, including the eyes and genitalia. Cicatrizing conjunctivitis is particularly common in PAMS. In contrast, oral mucous membrane involvement in pemphigus is more discrete, with the eyes or other nonoral mucosa rarely involved.

Photo courtesy Dr. Rania Abdel Hay

Another key in the differential diagnosis: PAMS is associated with the HLA-DRB1*03 allele, whereas pemphigus vulgaris and foliaceous are strongly associated with the -04 and -14 alleles, respectively.

A hallmark of PAMS is respiratory involvement, with the sloughing of bronchial epithelial cells contributing to small airway occlusion and bronchiolitis obliterans. Classic pemphigus is free of respiratory involvement.

Both the esophagus and colon may be involved in PAMS, whereas only the esophagus is affected in pemphigus vulgaris.

In a published series of 28 PAMS patients, painful and generalized oral stomatitis was present in all 28, respiratory involvement was in 26, death from respiratory failure occurred in 22, and lichenoid skin involvement was present in 19. Only seven patients had no skin lesions (Br. J. Dermatol. 2003;149:1143-51).

At least five different subtypes of PAMS can be distinguished on the basis of the skin disease manifestations they most resemble. These subtypes of pemphiguslike PAMS include paraneoplastic pemphigus, bullous pemphigoid–like, erythema multiforme–like, lichen planus–like, and graft-vs.-host-disease–like versions of PAMS.

Dr. Grando eschews the term "paraneoplastic pemphigus" as too restrictive. After all, true pemphigus doesn’t usually affect the lungs, he noted.

Photo (c) Elsevier Inc.

Whereas most patients with classic pemphigus respond well to high-dose corticosteroids and recalcitrant disease can be effectively treated with cytotoxic agents, cyclosporine, intravenous gamma globulin, and other second-line agents, PAMS is resistant to all conventional forms of therapy.

"What can we offer? Really not much," Dr. Grando said during his presentation at the World Congress of Dermatology in Seoul, South Korea.

The preferred treatment regimen is a combination of prednisone and cyclosporine, with or without cyclophosphamide. Monthly courses of IVIG can buy patients a few extra months, he added.

Dr. Grando declared having no relevant financial interests.

The skin may hold the key to differentiating classic pemphigus from the heterogenous autoimmune syndrome known as paraneoplastic autoimmune multiorgan syndrome.

It is a distinction of critical prognostic importance, because paraneoplastic autoimmune multiorgan syndrome (PAMS) typically is rapidly fatal, according to Dr. Sergei A. Grando, professor of dermatology and biologic chemistry at the University of California, Irvine. "The vast majority of patients die within several months of diagnosis, usually due to infections or respiratory failure, often taking the form of multiorgan system failure."

Two-thirds of patients with PAMS have a known internal malignancy at the time of their first mucocutaneous eruption. The most common of these neoplasms are non-Hodgkin’s lymphoma, which is present in more than 40% of PAMS patients; chronic lymphocytic leukemia, present in 30%; Castleman disease, present in 10%; and thymoma, present in 6%.

When a patient meets the diagnostic criteria for PAMS without having a known cancer, it is appropriate to launch a search for hidden malignancy, said Dr. Grando.

A key distinction between the skin lesions of PAMS and classic pemphigus is that PAMS involves inflammatory macules, papules, plaques, and blisters occurring on an inflammatory background over the trunk and extremities, including the palms and soles, but sparing the scalp.

In contrast, the generally more vesicular blisters and crusted erosions of pemphigus vulgaris display little erythema and usually occur on a noninflammatory background on the scalp, trunk, and extremities (but sparing the palms and soles). The most common location for skin lesions in PAMS is the palms; in pemphigus vulgaris, it is the scalp.

Also, Nikolsky's sign is positive in pemphigus vulgaris, but negative in PAMS, added Dr. Grando, who was among the investigators who first described PAMS a decade ago (Arch. Dermatol. 2001;137:193-206).

PAMS is characterized by severe and diffuse oral mucous membrane involvement, with persistent painful stomatitis because of blisters and erosions, and frequent involvement of other mucous membranes, including the eyes and genitalia. Cicatrizing conjunctivitis is particularly common in PAMS. In contrast, oral mucous membrane involvement in pemphigus is more discrete, with the eyes or other nonoral mucosa rarely involved.

Photo courtesy Dr. Rania Abdel Hay

Another key in the differential diagnosis: PAMS is associated with the HLA-DRB1*03 allele, whereas pemphigus vulgaris and foliaceous are strongly associated with the -04 and -14 alleles, respectively.

A hallmark of PAMS is respiratory involvement, with the sloughing of bronchial epithelial cells contributing to small airway occlusion and bronchiolitis obliterans. Classic pemphigus is free of respiratory involvement.

Both the esophagus and colon may be involved in PAMS, whereas only the esophagus is affected in pemphigus vulgaris.

In a published series of 28 PAMS patients, painful and generalized oral stomatitis was present in all 28, respiratory involvement was in 26, death from respiratory failure occurred in 22, and lichenoid skin involvement was present in 19. Only seven patients had no skin lesions (Br. J. Dermatol. 2003;149:1143-51).

At least five different subtypes of PAMS can be distinguished on the basis of the skin disease manifestations they most resemble. These subtypes of pemphiguslike PAMS include paraneoplastic pemphigus, bullous pemphigoid–like, erythema multiforme–like, lichen planus–like, and graft-vs.-host-disease–like versions of PAMS.

Dr. Grando eschews the term "paraneoplastic pemphigus" as too restrictive. After all, true pemphigus doesn’t usually affect the lungs, he noted.

Photo (c) Elsevier Inc.

Whereas most patients with classic pemphigus respond well to high-dose corticosteroids and recalcitrant disease can be effectively treated with cytotoxic agents, cyclosporine, intravenous gamma globulin, and other second-line agents, PAMS is resistant to all conventional forms of therapy.

"What can we offer? Really not much," Dr. Grando said during his presentation at the World Congress of Dermatology in Seoul, South Korea.

The preferred treatment regimen is a combination of prednisone and cyclosporine, with or without cyclophosphamide. Monthly courses of IVIG can buy patients a few extra months, he added.

Dr. Grando declared having no relevant financial interests.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.