Until recently, there have been few treatment options for advanced prostate cancer that is resistant to androgen-directed therapies. Newer treatments that target residual androgen production offer some hope of prolonging the interval before chemotherapy, with fewer adverse effects (AEs) and better efficacy. One of those is abiraterone, which blocks extragonadal, testicular, and tumor androgen biosynthesis.

An ongoing multinational phase 3 study is evaluating the clinical benefits of abiraterone plus prednisone vs prednisone alone in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Follow-up for the study has now exceeded 27 months, giving a good opportunity to evaluate safety and efficacy. Thus, after having reviewed outcomes so far, the independent data-monitoring committee recommended that the study be unblinded and patients be allowed to cross over from prednisone to abiraterone. The researchers reported the results of the third interim analysis, with updated analysis.

Patients were stratified by Eastern Cooperative Oncology Group performance status (ECOG-PS) and randomly assigned to receive abiraterone 1,000 mg plus prednisone 5 mg twice daily or placebo plus prednisone.

Patients who received abiraterone had, compared with those on prednisone, statistically significant improvement in radiographic progression-free survival (PFS), with a median time to disease progression or death of 16.5 months, vs 8.2 months (95% CI, 0.45-0.61).

Overall survival also lengthened, from a median of 35.3 months vs 30.1 months (95% CI, 0.66-0.95).

All secondary endpoints also favored abiraterone over prednisone. For instance, abiraterone treatment delayed the time to the need for opiates for cancer-related pain and the time to initiation of chemotherapy. Abiraterone also delayed the time to deterioration in ECOG-PS and prostate-specific antigen (PSA) progression. Abiraterone more than doubled the PSA response rate: 68% vs 29% with prednisone.

Patients reported more pain relief. Those receiving abiraterone had statistically significant improvement in pain interference (P = .005), although the improvement in mean pain intensity was not significant.

Adverse effects leading to dose modifications or interruption of treatment were reported in 21% of patients on abiraterone, compared with 12% of the prednisone group. Six patients (1%) in each group died of drug-related treatment-emergent AEs. The AEs of “special interest,” the researchers say, included events related to mineralocorticoid excess, such as hypertension, hypokalemia, and fluid retention—all unsurprising, given the known mechanism of action of abiraterone. Grade 3 or 4 AEs with increased alanine aminotransferase and aspartate aminotransferase were more common in the abiraterone group.

The most common subsequent therapy for patients who terminated the study was docetaxel. However, another recent study, from Johns Hopkins researchers in Baltimore, Maryland, indicates the transition warrants caution: The findings suggest a potential cross-resistance between docetaxel and abiraterone.

Their study compared outcomes in 24 men who received abiraterone before docetaxel with 95 who were abiraterone-naïve. Men who were on abiraterone were less likely to achieve a PSA response, and their cancer was more likely to progress.

The researchers concede that their study groups were small; they also say it is possible that differences in disease severity may have influenced the time to progression. However, they say the fact that PSA-PFS was significantly different between the 2 groups (P = .002) supports their initial hypothesis—that is, that abiraterone pretreatment reduces responsiveness to docetaxel.

In spite of its limitations, the researchers say their study represents the only comparative analysis of PSA-PFS and PFS after docetaxel treatment for patients who have or have not received prior abiraterone. Their report, they add, offers the “strongest available evidence to date” of a clinically meaningful cross-resistance between abiraterone and docetaxel. They conclude that their findings provide “valuable information” about which patients are likely to derive the most benefit from docetaxel.

Sources
Rathkopf DE, Smith MR, de Bono JS, et al. Eur Urol. 2014;66(5):815-825.
doi: 10.1016/j.eururo.2014.02.056.

Schewizer MT, Zhou XC, Wang H, et al. Eur Urol. 2014;66(4):646-652.
doi: 10.1016/j.eururo.2014.01.018.

Until recently, there have been few treatment options for advanced prostate cancer that is resistant to androgen-directed therapies. Newer treatments that target residual androgen production offer some hope of prolonging the interval before chemotherapy, with fewer adverse effects (AEs) and better efficacy. One of those is abiraterone, which blocks extragonadal, testicular, and tumor androgen biosynthesis.

An ongoing multinational phase 3 study is evaluating the clinical benefits of abiraterone plus prednisone vs prednisone alone in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Follow-up for the study has now exceeded 27 months, giving a good opportunity to evaluate safety and efficacy. Thus, after having reviewed outcomes so far, the independent data-monitoring committee recommended that the study be unblinded and patients be allowed to cross over from prednisone to abiraterone. The researchers reported the results of the third interim analysis, with updated analysis.

Patients were stratified by Eastern Cooperative Oncology Group performance status (ECOG-PS) and randomly assigned to receive abiraterone 1,000 mg plus prednisone 5 mg twice daily or placebo plus prednisone.

Patients who received abiraterone had, compared with those on prednisone, statistically significant improvement in radiographic progression-free survival (PFS), with a median time to disease progression or death of 16.5 months, vs 8.2 months (95% CI, 0.45-0.61).

Overall survival also lengthened, from a median of 35.3 months vs 30.1 months (95% CI, 0.66-0.95).

All secondary endpoints also favored abiraterone over prednisone. For instance, abiraterone treatment delayed the time to the need for opiates for cancer-related pain and the time to initiation of chemotherapy. Abiraterone also delayed the time to deterioration in ECOG-PS and prostate-specific antigen (PSA) progression. Abiraterone more than doubled the PSA response rate: 68% vs 29% with prednisone.

Patients reported more pain relief. Those receiving abiraterone had statistically significant improvement in pain interference (P = .005), although the improvement in mean pain intensity was not significant.

Adverse effects leading to dose modifications or interruption of treatment were reported in 21% of patients on abiraterone, compared with 12% of the prednisone group. Six patients (1%) in each group died of drug-related treatment-emergent AEs. The AEs of “special interest,” the researchers say, included events related to mineralocorticoid excess, such as hypertension, hypokalemia, and fluid retention—all unsurprising, given the known mechanism of action of abiraterone. Grade 3 or 4 AEs with increased alanine aminotransferase and aspartate aminotransferase were more common in the abiraterone group.

The most common subsequent therapy for patients who terminated the study was docetaxel. However, another recent study, from Johns Hopkins researchers in Baltimore, Maryland, indicates the transition warrants caution: The findings suggest a potential cross-resistance between docetaxel and abiraterone.

Their study compared outcomes in 24 men who received abiraterone before docetaxel with 95 who were abiraterone-naïve. Men who were on abiraterone were less likely to achieve a PSA response, and their cancer was more likely to progress.

The researchers concede that their study groups were small; they also say it is possible that differences in disease severity may have influenced the time to progression. However, they say the fact that PSA-PFS was significantly different between the 2 groups (P = .002) supports their initial hypothesis—that is, that abiraterone pretreatment reduces responsiveness to docetaxel.

In spite of its limitations, the researchers say their study represents the only comparative analysis of PSA-PFS and PFS after docetaxel treatment for patients who have or have not received prior abiraterone. Their report, they add, offers the “strongest available evidence to date” of a clinically meaningful cross-resistance between abiraterone and docetaxel. They conclude that their findings provide “valuable information” about which patients are likely to derive the most benefit from docetaxel.

Sources
Rathkopf DE, Smith MR, de Bono JS, et al. Eur Urol. 2014;66(5):815-825.
doi: 10.1016/j.eururo.2014.02.056.

Schewizer MT, Zhou XC, Wang H, et al. Eur Urol. 2014;66(4):646-652.
doi: 10.1016/j.eururo.2014.01.018.

Until recently, there have been few treatment options for advanced prostate cancer that is resistant to androgen-directed therapies. Newer treatments that target residual androgen production offer some hope of prolonging the interval before chemotherapy, with fewer adverse effects (AEs) and better efficacy. One of those is abiraterone, which blocks extragonadal, testicular, and tumor androgen biosynthesis.

An ongoing multinational phase 3 study is evaluating the clinical benefits of abiraterone plus prednisone vs prednisone alone in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Follow-up for the study has now exceeded 27 months, giving a good opportunity to evaluate safety and efficacy. Thus, after having reviewed outcomes so far, the independent data-monitoring committee recommended that the study be unblinded and patients be allowed to cross over from prednisone to abiraterone. The researchers reported the results of the third interim analysis, with updated analysis.

Patients were stratified by Eastern Cooperative Oncology Group performance status (ECOG-PS) and randomly assigned to receive abiraterone 1,000 mg plus prednisone 5 mg twice daily or placebo plus prednisone.

Patients who received abiraterone had, compared with those on prednisone, statistically significant improvement in radiographic progression-free survival (PFS), with a median time to disease progression or death of 16.5 months, vs 8.2 months (95% CI, 0.45-0.61).

Overall survival also lengthened, from a median of 35.3 months vs 30.1 months (95% CI, 0.66-0.95).

All secondary endpoints also favored abiraterone over prednisone. For instance, abiraterone treatment delayed the time to the need for opiates for cancer-related pain and the time to initiation of chemotherapy. Abiraterone also delayed the time to deterioration in ECOG-PS and prostate-specific antigen (PSA) progression. Abiraterone more than doubled the PSA response rate: 68% vs 29% with prednisone.

Patients reported more pain relief. Those receiving abiraterone had statistically significant improvement in pain interference (P = .005), although the improvement in mean pain intensity was not significant.

Adverse effects leading to dose modifications or interruption of treatment were reported in 21% of patients on abiraterone, compared with 12% of the prednisone group. Six patients (1%) in each group died of drug-related treatment-emergent AEs. The AEs of “special interest,” the researchers say, included events related to mineralocorticoid excess, such as hypertension, hypokalemia, and fluid retention—all unsurprising, given the known mechanism of action of abiraterone. Grade 3 or 4 AEs with increased alanine aminotransferase and aspartate aminotransferase were more common in the abiraterone group.

The most common subsequent therapy for patients who terminated the study was docetaxel. However, another recent study, from Johns Hopkins researchers in Baltimore, Maryland, indicates the transition warrants caution: The findings suggest a potential cross-resistance between docetaxel and abiraterone.

Their study compared outcomes in 24 men who received abiraterone before docetaxel with 95 who were abiraterone-naïve. Men who were on abiraterone were less likely to achieve a PSA response, and their cancer was more likely to progress.

The researchers concede that their study groups were small; they also say it is possible that differences in disease severity may have influenced the time to progression. However, they say the fact that PSA-PFS was significantly different between the 2 groups (P = .002) supports their initial hypothesis—that is, that abiraterone pretreatment reduces responsiveness to docetaxel.

In spite of its limitations, the researchers say their study represents the only comparative analysis of PSA-PFS and PFS after docetaxel treatment for patients who have or have not received prior abiraterone. Their report, they add, offers the “strongest available evidence to date” of a clinically meaningful cross-resistance between abiraterone and docetaxel. They conclude that their findings provide “valuable information” about which patients are likely to derive the most benefit from docetaxel.

Sources
Rathkopf DE, Smith MR, de Bono JS, et al. Eur Urol. 2014;66(5):815-825.
doi: 10.1016/j.eururo.2014.02.056.

Schewizer MT, Zhou XC, Wang H, et al. Eur Urol. 2014;66(4):646-652.
doi: 10.1016/j.eururo.2014.01.018.

DNA methylation

Credit: Christoph Bock

New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.

The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.

In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.

The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.

“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.

“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”

To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.

They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.

“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”

To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.

“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”

The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.

The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.

“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.

“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”

“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”

DNA methylation

Credit: Christoph Bock

New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.

The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.

In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.

The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.

“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.

“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”

To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.

They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.

“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”

To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.

“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”

The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.

The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.

“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.

“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”

“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”

DNA methylation

Credit: Christoph Bock

New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.

The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.

In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.

The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.

“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.

“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”

To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.

They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.

“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”

To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.

“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”

The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.

The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.

“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.

“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”

“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Case Reports

Patient 1

A 16-year-old adolescent boy presented to the emergency department with painful, pruritic, erythematous nodules on the bilateral legs of 1 week’s duration. The lesions had developed 1 week after returning from a monthlong trip to Senegal with a volunteer youth group. He did not recall sustaining any painful insect bites or illnesses while traveling in Africa and only noticed the erythematous papules on the legs when he returned home to the United States. After consulting with his primary care physician and a local dermatologist, the patient began taking oral cephalexin for suspected bacterial furunculosis with no considerable improvement. Over the course of 1 week, the lesions became increasingly painful and pruritic, prompting a visit to the emergency department. Prior to his arrival, the patient reported squeezing a live worm from one of the lesions on the right ankle.

On presentation, the patient was afebrile (temperature, 36.7°C) and his vital signs revealed no abnormalities. Physical examination revealed tender erythematous nodules on the bilateral heels, ankles, and shins with pinpoint puncta noted at the center of many of the lesions (Figure 1). The nodules were warm and indurated and no pulsatile movement was appreciated. The legs appeared to be well perfused with intact sensation and motor function. The patient brought in the live mobile larva that he extruded from the lesion on the right ankle. Both the departments of infectious diseases and dermatology were consulted and a preliminary diagnosis of furuncular myiasis was made.

Figure 1. Tender erythematous nodules on the bilateral heels, ankles, and shins.

The lesions were occluded with petroleum jelly and the patient was instructed to follow-up with the dermatology department later that same day. On follow-up in the dermatology clinic, the tips of intact larvae were appreciated at the central puncta of some of the lesions (Figure 2). Lidocaine adrenaline tetracaine gel was applied to lesions on the legs for 40 minutes, then lidocaine gel 1% was injected into each lesion. On injection, immobile larvae were ejected from the central puncta of most of the lesions; the remaining lesions were treated via 3-mm punch biopsy as a means of extraction. Each nodule contained only a single larva, all of which were dead at the time of removal (Figure 3). The wounds were left open and the patient was instructed to continue treatment with cephalexin with leg elevation and rest. Pathologic examination of deep dermal skin sections revealed larval fragments encased by a thick chitinous cuticle with spines that were consistent with furuncular myiasis (Figures 4 and 5). Given the patient’s recent history of travel to Africa along with the morphology of the extracted specimens, the larvae were identified as Cordylobia anthropophaga, a common cause of furuncular myiasis in that region.

Patient 2

The next week, a 17-year-old adolescent girl who had been on the same trip to Senegal as patient 1 presented with 2 similar erythematous nodules with central crusts on the left inner thigh and buttock. On noticing the lesions approximately 3 days prior to presentation, the patient applied topical antibiotic ointment to each nodule, which incited the evacuation of white tube-shaped structures that were presented for examination. On presentation, the nodules were healing well. Given the patient’s travel history and physical examination, a presumptive diagnosis of furuncular myiasis from C anthropophaga also was made.

Figure 2. The tips of intact larvae were appreciated at the central puncta of some of the lesions following occlusion with petroleum jelly. Figure 3. Dead larva extracted by lidocaine injection and punch biopsy.

Comment

The term myiasis stems from the Greek term for fly and is used to describe the infestation of fly larvae in living vertebrates.¹ Myiasis has many classifications, the 3 most common being furuncular, migratory, and wound myiasis, which are differentiated by the different fly species found in distinct regions of the world. Furuncular myiasis is the most benign form, usually affecting only a localized region of the skin; migratory myiasis is characterized by larvae traveling substantial distances from one anatomic site to another within the lower layers of the epidermis; and wound myiasis involves rapid reproduction of larvae in necrotic tissue with subsequent tissue destruction.²

The clinical presentation of the lesions noted in our patients suggested a diagnosis of furuncular myiasis, which commonly is caused by Dermatobia hominis, C anthropophaga, Cuterebra species, Wohlfahrtia vigil, and Wohlfahrtia opaca larvae.³Dermatobia hominis is the most common cause of furuncular myiasis and usually is found in Central and South America. Our patients likely developed an infestation of C anthropophaga (also known as the tumbu fly), a yellow-brown, 7- to 12-mm blowfly commonly found throughout tropical Africa.³ Although C anthropophaga is historically limited to sub-Saharan Africa, there has been a report of a case acquired in Portugal.⁴

In a review of the literature, C anthropophaga myiasis was documented in Italian travelers returning from Senegal^5-7; our cases are unique because they represent North American travelers returning from Senegal with furuncular myiasis. Furuncular myiasis from C anthropophaga has been reported in travelers returning to North America from other African countries, including Angola,⁸ Tanzania,^9-11 Kenya,⁹ Sierra Leone,¹² and Ivory Coast.¹³ Several cases of ocular myiasis from D hominis and Oestrus ovis have been reported in European travelers returning from Tunisia.^14,15

Tumbu fly infestations typically affect dogs and rodents but can arise in human hosts.³ Children may be affected by C anthropophaga furuncular myiasis more often than adults because they have thinner skin and less immunity to the larvae.²

Figure 4. Deep dermal cavity containing larval fragments encased by a thick chitinous cuticle with spines surrounded by mixed dermal inflammation (H&E, original magnification ×40). Figure 5. Larval intestinal components were visualized as well as striated muscle (H&E, original magnification ×200).

There are 2 mechanisms by which infestation of human hosts by C anthropophaga can occur. Most commonly, female flies lay eggs in shady areas in soil that is contaminated by feces or urine. The hatched larvae can survive in the ground for up to 2 weeks and later attach to a host when prompted by heat or movement.³ Therefore, clothing set out to dry may be contaminated by this soil. Alternatively, female flies can lay eggs directly onto clothing that is contaminated by feces or urine and the larvae subsequently hatch outside the soil with easy access to human skin once the clothing is worn.²

Common penetration sites are the head, neck, and back, as well as areas covered by contaminated or infested clothing.^2,3 Penetration of the human skin occurs instantly and is a painless process that is rarely noticed by the human host.³ The larvae burrow into the skin for 8 to 12 days, resulting in a furuncle that occasionally secretes a serous fluid.² Within the first 2 days of infestation, the host may experience symptoms ranging from local pruritus to severe pain. Six days following initial onset, an intense inflammatory response may result in local lymphadenopathy along with fever and fatigue.² The larvae use their posterior spiracles to create openings in the skin to create air holes that allow them to breathe.³ On physical examination, the spiracles generally appear as 1- to 3-mm dark linear streaks within furuncles, which is important in the diagnosis of C anthropophaga furuncular myiasis.^1,3 If spiracles are not appreciated on initial examination, diagnosis can be made by submerging the affected areas in water or saliva to look for air bubbles arising from the central puncta of the lesions.¹

All causes of furuncular myiasis are characterized by a ratio of 1 larva to 1 furuncle.¹⁶ Although most of these types of larvae that can cause furuncular myiasis result in single lesions, C anthropophaga infestation often produces several furuncles that may coalesce into plaques.^1,2 The differential diagnosis for C anthropophaga furuncular myiasis includes pyoderma, impetigo, staphylococcal furunculosis, cutaneous leishmaniasis, infected cyst, retained foreign body, and facticial disease.^2,3 Dracunculiasis also may be considered, which occurs after ingestion of contaminated water.² Ultrasonography may be helpful for the diagnosis of furuncular myiasis, as it can facilitate identification of foreign bodies, abscesses, and even larvae in some cases.¹⁷ Definitive diagnosis of any type of myiasis involves extraction of the larva and identification of the family, genus, and species by a parasitologist.¹ Some experts suggest rearing preserved live larvae with raw meat after extraction because adult specimens are more reliable than larvae for species diagnosis.¹

Treatment of furuncular myiasis involves occlusion and extraction of the larvae from the skin. Suffocation of the larvae by occlusion of air holes with petroleum jelly, paraffin oil, bacon fat, glue, and other obstructing substances forces the larvae to emerge in search of oxygen, though immature larvae may be more reluctant than mature ones.^2,3 Definitive treatment involves the direct removal of the larvae by surgery or expulsion by pressure, though it is recommended that lesions are pretreated with occlusive techniques.^1,3 Other reported methods of extraction include injection of lidocaine and the use of a commercial venom extractor.¹ It should be noted that rupture and incomplete extraction of larvae can lead to secondary infections and allergic reactions. Lesions can be pretreated with lidocaine gel prior to extraction, and antibiotics should be used in cases of secondary bacterial infection. Ivermectin also has been reported as a treatment of furuncular myiasis and other types of myiasis.¹ Prevention of infestation by C anthropophaga includes avoidance of endemic areas, maintaining good hygiene, and ironing clothing or drying it in sunny locations.^1,2 Overall, furuncular myiasis has a good prognosis with rapid recovery and a low incidence of complications.¹

Conclusion

We present 2 cases of travelers returning to North America from Senegal with C anthropophaga furuncular myiasis. Careful review of travel history, physical examination, and identification of fly larvae are important for diagnosis. Individuals traveling to sub-Saharan Africa should avoid drying clothes in shady places and lying on the ground. They also are urged to iron their clothing before wearing it.

Case Reports

Patient 1

A 16-year-old adolescent boy presented to the emergency department with painful, pruritic, erythematous nodules on the bilateral legs of 1 week’s duration. The lesions had developed 1 week after returning from a monthlong trip to Senegal with a volunteer youth group. He did not recall sustaining any painful insect bites or illnesses while traveling in Africa and only noticed the erythematous papules on the legs when he returned home to the United States. After consulting with his primary care physician and a local dermatologist, the patient began taking oral cephalexin for suspected bacterial furunculosis with no considerable improvement. Over the course of 1 week, the lesions became increasingly painful and pruritic, prompting a visit to the emergency department. Prior to his arrival, the patient reported squeezing a live worm from one of the lesions on the right ankle.

On presentation, the patient was afebrile (temperature, 36.7°C) and his vital signs revealed no abnormalities. Physical examination revealed tender erythematous nodules on the bilateral heels, ankles, and shins with pinpoint puncta noted at the center of many of the lesions (Figure 1). The nodules were warm and indurated and no pulsatile movement was appreciated. The legs appeared to be well perfused with intact sensation and motor function. The patient brought in the live mobile larva that he extruded from the lesion on the right ankle. Both the departments of infectious diseases and dermatology were consulted and a preliminary diagnosis of furuncular myiasis was made.

Figure 1. Tender erythematous nodules on the bilateral heels, ankles, and shins.

The lesions were occluded with petroleum jelly and the patient was instructed to follow-up with the dermatology department later that same day. On follow-up in the dermatology clinic, the tips of intact larvae were appreciated at the central puncta of some of the lesions (Figure 2). Lidocaine adrenaline tetracaine gel was applied to lesions on the legs for 40 minutes, then lidocaine gel 1% was injected into each lesion. On injection, immobile larvae were ejected from the central puncta of most of the lesions; the remaining lesions were treated via 3-mm punch biopsy as a means of extraction. Each nodule contained only a single larva, all of which were dead at the time of removal (Figure 3). The wounds were left open and the patient was instructed to continue treatment with cephalexin with leg elevation and rest. Pathologic examination of deep dermal skin sections revealed larval fragments encased by a thick chitinous cuticle with spines that were consistent with furuncular myiasis (Figures 4 and 5). Given the patient’s recent history of travel to Africa along with the morphology of the extracted specimens, the larvae were identified as Cordylobia anthropophaga, a common cause of furuncular myiasis in that region.

Patient 2

The next week, a 17-year-old adolescent girl who had been on the same trip to Senegal as patient 1 presented with 2 similar erythematous nodules with central crusts on the left inner thigh and buttock. On noticing the lesions approximately 3 days prior to presentation, the patient applied topical antibiotic ointment to each nodule, which incited the evacuation of white tube-shaped structures that were presented for examination. On presentation, the nodules were healing well. Given the patient’s travel history and physical examination, a presumptive diagnosis of furuncular myiasis from C anthropophaga also was made.

Figure 2. The tips of intact larvae were appreciated at the central puncta of some of the lesions following occlusion with petroleum jelly. Figure 3. Dead larva extracted by lidocaine injection and punch biopsy.

Comment

The term myiasis stems from the Greek term for fly and is used to describe the infestation of fly larvae in living vertebrates.¹ Myiasis has many classifications, the 3 most common being furuncular, migratory, and wound myiasis, which are differentiated by the different fly species found in distinct regions of the world. Furuncular myiasis is the most benign form, usually affecting only a localized region of the skin; migratory myiasis is characterized by larvae traveling substantial distances from one anatomic site to another within the lower layers of the epidermis; and wound myiasis involves rapid reproduction of larvae in necrotic tissue with subsequent tissue destruction.²

The clinical presentation of the lesions noted in our patients suggested a diagnosis of furuncular myiasis, which commonly is caused by Dermatobia hominis, C anthropophaga, Cuterebra species, Wohlfahrtia vigil, and Wohlfahrtia opaca larvae.³Dermatobia hominis is the most common cause of furuncular myiasis and usually is found in Central and South America. Our patients likely developed an infestation of C anthropophaga (also known as the tumbu fly), a yellow-brown, 7- to 12-mm blowfly commonly found throughout tropical Africa.³ Although C anthropophaga is historically limited to sub-Saharan Africa, there has been a report of a case acquired in Portugal.⁴

In a review of the literature, C anthropophaga myiasis was documented in Italian travelers returning from Senegal^5-7; our cases are unique because they represent North American travelers returning from Senegal with furuncular myiasis. Furuncular myiasis from C anthropophaga has been reported in travelers returning to North America from other African countries, including Angola,⁸ Tanzania,^9-11 Kenya,⁹ Sierra Leone,¹² and Ivory Coast.¹³ Several cases of ocular myiasis from D hominis and Oestrus ovis have been reported in European travelers returning from Tunisia.^14,15

Tumbu fly infestations typically affect dogs and rodents but can arise in human hosts.³ Children may be affected by C anthropophaga furuncular myiasis more often than adults because they have thinner skin and less immunity to the larvae.²

Figure 4. Deep dermal cavity containing larval fragments encased by a thick chitinous cuticle with spines surrounded by mixed dermal inflammation (H&E, original magnification ×40). Figure 5. Larval intestinal components were visualized as well as striated muscle (H&E, original magnification ×200).

There are 2 mechanisms by which infestation of human hosts by C anthropophaga can occur. Most commonly, female flies lay eggs in shady areas in soil that is contaminated by feces or urine. The hatched larvae can survive in the ground for up to 2 weeks and later attach to a host when prompted by heat or movement.³ Therefore, clothing set out to dry may be contaminated by this soil. Alternatively, female flies can lay eggs directly onto clothing that is contaminated by feces or urine and the larvae subsequently hatch outside the soil with easy access to human skin once the clothing is worn.²

Common penetration sites are the head, neck, and back, as well as areas covered by contaminated or infested clothing.^2,3 Penetration of the human skin occurs instantly and is a painless process that is rarely noticed by the human host.³ The larvae burrow into the skin for 8 to 12 days, resulting in a furuncle that occasionally secretes a serous fluid.² Within the first 2 days of infestation, the host may experience symptoms ranging from local pruritus to severe pain. Six days following initial onset, an intense inflammatory response may result in local lymphadenopathy along with fever and fatigue.² The larvae use their posterior spiracles to create openings in the skin to create air holes that allow them to breathe.³ On physical examination, the spiracles generally appear as 1- to 3-mm dark linear streaks within furuncles, which is important in the diagnosis of C anthropophaga furuncular myiasis.^1,3 If spiracles are not appreciated on initial examination, diagnosis can be made by submerging the affected areas in water or saliva to look for air bubbles arising from the central puncta of the lesions.¹

All causes of furuncular myiasis are characterized by a ratio of 1 larva to 1 furuncle.¹⁶ Although most of these types of larvae that can cause furuncular myiasis result in single lesions, C anthropophaga infestation often produces several furuncles that may coalesce into plaques.^1,2 The differential diagnosis for C anthropophaga furuncular myiasis includes pyoderma, impetigo, staphylococcal furunculosis, cutaneous leishmaniasis, infected cyst, retained foreign body, and facticial disease.^2,3 Dracunculiasis also may be considered, which occurs after ingestion of contaminated water.² Ultrasonography may be helpful for the diagnosis of furuncular myiasis, as it can facilitate identification of foreign bodies, abscesses, and even larvae in some cases.¹⁷ Definitive diagnosis of any type of myiasis involves extraction of the larva and identification of the family, genus, and species by a parasitologist.¹ Some experts suggest rearing preserved live larvae with raw meat after extraction because adult specimens are more reliable than larvae for species diagnosis.¹

Treatment of furuncular myiasis involves occlusion and extraction of the larvae from the skin. Suffocation of the larvae by occlusion of air holes with petroleum jelly, paraffin oil, bacon fat, glue, and other obstructing substances forces the larvae to emerge in search of oxygen, though immature larvae may be more reluctant than mature ones.^2,3 Definitive treatment involves the direct removal of the larvae by surgery or expulsion by pressure, though it is recommended that lesions are pretreated with occlusive techniques.^1,3 Other reported methods of extraction include injection of lidocaine and the use of a commercial venom extractor.¹ It should be noted that rupture and incomplete extraction of larvae can lead to secondary infections and allergic reactions. Lesions can be pretreated with lidocaine gel prior to extraction, and antibiotics should be used in cases of secondary bacterial infection. Ivermectin also has been reported as a treatment of furuncular myiasis and other types of myiasis.¹ Prevention of infestation by C anthropophaga includes avoidance of endemic areas, maintaining good hygiene, and ironing clothing or drying it in sunny locations.^1,2 Overall, furuncular myiasis has a good prognosis with rapid recovery and a low incidence of complications.¹

Conclusion

We present 2 cases of travelers returning to North America from Senegal with C anthropophaga furuncular myiasis. Careful review of travel history, physical examination, and identification of fly larvae are important for diagnosis. Individuals traveling to sub-Saharan Africa should avoid drying clothes in shady places and lying on the ground. They also are urged to iron their clothing before wearing it.

Case Reports

Patient 1

A 16-year-old adolescent boy presented to the emergency department with painful, pruritic, erythematous nodules on the bilateral legs of 1 week’s duration. The lesions had developed 1 week after returning from a monthlong trip to Senegal with a volunteer youth group. He did not recall sustaining any painful insect bites or illnesses while traveling in Africa and only noticed the erythematous papules on the legs when he returned home to the United States. After consulting with his primary care physician and a local dermatologist, the patient began taking oral cephalexin for suspected bacterial furunculosis with no considerable improvement. Over the course of 1 week, the lesions became increasingly painful and pruritic, prompting a visit to the emergency department. Prior to his arrival, the patient reported squeezing a live worm from one of the lesions on the right ankle.

On presentation, the patient was afebrile (temperature, 36.7°C) and his vital signs revealed no abnormalities. Physical examination revealed tender erythematous nodules on the bilateral heels, ankles, and shins with pinpoint puncta noted at the center of many of the lesions (Figure 1). The nodules were warm and indurated and no pulsatile movement was appreciated. The legs appeared to be well perfused with intact sensation and motor function. The patient brought in the live mobile larva that he extruded from the lesion on the right ankle. Both the departments of infectious diseases and dermatology were consulted and a preliminary diagnosis of furuncular myiasis was made.

Figure 1. Tender erythematous nodules on the bilateral heels, ankles, and shins.

The lesions were occluded with petroleum jelly and the patient was instructed to follow-up with the dermatology department later that same day. On follow-up in the dermatology clinic, the tips of intact larvae were appreciated at the central puncta of some of the lesions (Figure 2). Lidocaine adrenaline tetracaine gel was applied to lesions on the legs for 40 minutes, then lidocaine gel 1% was injected into each lesion. On injection, immobile larvae were ejected from the central puncta of most of the lesions; the remaining lesions were treated via 3-mm punch biopsy as a means of extraction. Each nodule contained only a single larva, all of which were dead at the time of removal (Figure 3). The wounds were left open and the patient was instructed to continue treatment with cephalexin with leg elevation and rest. Pathologic examination of deep dermal skin sections revealed larval fragments encased by a thick chitinous cuticle with spines that were consistent with furuncular myiasis (Figures 4 and 5). Given the patient’s recent history of travel to Africa along with the morphology of the extracted specimens, the larvae were identified as Cordylobia anthropophaga, a common cause of furuncular myiasis in that region.

Patient 2

The next week, a 17-year-old adolescent girl who had been on the same trip to Senegal as patient 1 presented with 2 similar erythematous nodules with central crusts on the left inner thigh and buttock. On noticing the lesions approximately 3 days prior to presentation, the patient applied topical antibiotic ointment to each nodule, which incited the evacuation of white tube-shaped structures that were presented for examination. On presentation, the nodules were healing well. Given the patient’s travel history and physical examination, a presumptive diagnosis of furuncular myiasis from C anthropophaga also was made.

Figure 2. The tips of intact larvae were appreciated at the central puncta of some of the lesions following occlusion with petroleum jelly. Figure 3. Dead larva extracted by lidocaine injection and punch biopsy.

Comment

The term myiasis stems from the Greek term for fly and is used to describe the infestation of fly larvae in living vertebrates.¹ Myiasis has many classifications, the 3 most common being furuncular, migratory, and wound myiasis, which are differentiated by the different fly species found in distinct regions of the world. Furuncular myiasis is the most benign form, usually affecting only a localized region of the skin; migratory myiasis is characterized by larvae traveling substantial distances from one anatomic site to another within the lower layers of the epidermis; and wound myiasis involves rapid reproduction of larvae in necrotic tissue with subsequent tissue destruction.²

The clinical presentation of the lesions noted in our patients suggested a diagnosis of furuncular myiasis, which commonly is caused by Dermatobia hominis, C anthropophaga, Cuterebra species, Wohlfahrtia vigil, and Wohlfahrtia opaca larvae.³Dermatobia hominis is the most common cause of furuncular myiasis and usually is found in Central and South America. Our patients likely developed an infestation of C anthropophaga (also known as the tumbu fly), a yellow-brown, 7- to 12-mm blowfly commonly found throughout tropical Africa.³ Although C anthropophaga is historically limited to sub-Saharan Africa, there has been a report of a case acquired in Portugal.⁴

In a review of the literature, C anthropophaga myiasis was documented in Italian travelers returning from Senegal^5-7; our cases are unique because they represent North American travelers returning from Senegal with furuncular myiasis. Furuncular myiasis from C anthropophaga has been reported in travelers returning to North America from other African countries, including Angola,⁸ Tanzania,^9-11 Kenya,⁹ Sierra Leone,¹² and Ivory Coast.¹³ Several cases of ocular myiasis from D hominis and Oestrus ovis have been reported in European travelers returning from Tunisia.^14,15

Tumbu fly infestations typically affect dogs and rodents but can arise in human hosts.³ Children may be affected by C anthropophaga furuncular myiasis more often than adults because they have thinner skin and less immunity to the larvae.²

Figure 4. Deep dermal cavity containing larval fragments encased by a thick chitinous cuticle with spines surrounded by mixed dermal inflammation (H&E, original magnification ×40). Figure 5. Larval intestinal components were visualized as well as striated muscle (H&E, original magnification ×200).

There are 2 mechanisms by which infestation of human hosts by C anthropophaga can occur. Most commonly, female flies lay eggs in shady areas in soil that is contaminated by feces or urine. The hatched larvae can survive in the ground for up to 2 weeks and later attach to a host when prompted by heat or movement.³ Therefore, clothing set out to dry may be contaminated by this soil. Alternatively, female flies can lay eggs directly onto clothing that is contaminated by feces or urine and the larvae subsequently hatch outside the soil with easy access to human skin once the clothing is worn.²

Common penetration sites are the head, neck, and back, as well as areas covered by contaminated or infested clothing.^2,3 Penetration of the human skin occurs instantly and is a painless process that is rarely noticed by the human host.³ The larvae burrow into the skin for 8 to 12 days, resulting in a furuncle that occasionally secretes a serous fluid.² Within the first 2 days of infestation, the host may experience symptoms ranging from local pruritus to severe pain. Six days following initial onset, an intense inflammatory response may result in local lymphadenopathy along with fever and fatigue.² The larvae use their posterior spiracles to create openings in the skin to create air holes that allow them to breathe.³ On physical examination, the spiracles generally appear as 1- to 3-mm dark linear streaks within furuncles, which is important in the diagnosis of C anthropophaga furuncular myiasis.^1,3 If spiracles are not appreciated on initial examination, diagnosis can be made by submerging the affected areas in water or saliva to look for air bubbles arising from the central puncta of the lesions.¹

All causes of furuncular myiasis are characterized by a ratio of 1 larva to 1 furuncle.¹⁶ Although most of these types of larvae that can cause furuncular myiasis result in single lesions, C anthropophaga infestation often produces several furuncles that may coalesce into plaques.^1,2 The differential diagnosis for C anthropophaga furuncular myiasis includes pyoderma, impetigo, staphylococcal furunculosis, cutaneous leishmaniasis, infected cyst, retained foreign body, and facticial disease.^2,3 Dracunculiasis also may be considered, which occurs after ingestion of contaminated water.² Ultrasonography may be helpful for the diagnosis of furuncular myiasis, as it can facilitate identification of foreign bodies, abscesses, and even larvae in some cases.¹⁷ Definitive diagnosis of any type of myiasis involves extraction of the larva and identification of the family, genus, and species by a parasitologist.¹ Some experts suggest rearing preserved live larvae with raw meat after extraction because adult specimens are more reliable than larvae for species diagnosis.¹

Treatment of furuncular myiasis involves occlusion and extraction of the larvae from the skin. Suffocation of the larvae by occlusion of air holes with petroleum jelly, paraffin oil, bacon fat, glue, and other obstructing substances forces the larvae to emerge in search of oxygen, though immature larvae may be more reluctant than mature ones.^2,3 Definitive treatment involves the direct removal of the larvae by surgery or expulsion by pressure, though it is recommended that lesions are pretreated with occlusive techniques.^1,3 Other reported methods of extraction include injection of lidocaine and the use of a commercial venom extractor.¹ It should be noted that rupture and incomplete extraction of larvae can lead to secondary infections and allergic reactions. Lesions can be pretreated with lidocaine gel prior to extraction, and antibiotics should be used in cases of secondary bacterial infection. Ivermectin also has been reported as a treatment of furuncular myiasis and other types of myiasis.¹ Prevention of infestation by C anthropophaga includes avoidance of endemic areas, maintaining good hygiene, and ironing clothing or drying it in sunny locations.^1,2 Overall, furuncular myiasis has a good prognosis with rapid recovery and a low incidence of complications.¹

Conclusion

We present 2 cases of travelers returning to North America from Senegal with C anthropophaga furuncular myiasis. Careful review of travel history, physical examination, and identification of fly larvae are important for diagnosis. Individuals traveling to sub-Saharan Africa should avoid drying clothes in shady places and lying on the ground. They also are urged to iron their clothing before wearing it.

Patient mortality and morbidity outcomes have not changed since the most recent round of reforms to medical residents’ duty hours in 2011, according to two of the first nationwide studies to assess these “improvements,” which both were published online Dec. 9 in JAMA.

In addition, one of the studies found no difference between pre-reform and post-reform scores or on pass rates for oral or written national in-training and board certification examinations.

©Thinglass/thinkstockphotos.com

Thus, two separate studies involving millions of hospitalized patients across the country have both found that these reforms had no discernible effect on patient care. However, both groups of researchers cautioned that their studies were observational and therefore subject to potential biases and that they covered only the first 2 years that the duty-hours reforms have been in place.

The 2011 requirements expanded on those enacted in 2003 by further restricting residents’ duty hours, in the hope of reducing medical errors attributed to exhausted residents. The hours of continuous in-hospital duty were reduced from 30 to 16 for first-year residents and to 24 for upper-year residents, and the interval between shifts was increased to at least 8 hours off for first-year residents and at least 14 hours off for upper-year residents.

“Duty hour reform is arguably one of the largest efforts ever undertaken to improve the quality and safety of patient care in teaching hospitals,” said Dr. Mitesh S. Patel of the University of Pennsylvania and the Veterans Affairs Hospital Center for Health Equity Research and Promotion, both in Philadelphia, and his associates.

They assessed 30-day mortality and readmissions among 2,790,356 Medicare patients who were treated either for acute MI, stroke, gastrointestinal bleeding, or heart failure, or who underwent general, orthopedic, or vascular surgery, at 3,104 hospitals between 2009 and 2012. The investigators found no significant associations, either positive or negative, between the reforms to residents’ duty hours and any patient outcomes. Sensitivity analyses confirmed the results of the primary data analyses.

“Our findings suggest that ... the goals of improving the quality and safety of patient care ... were not being achieved. Conversely, concerns that outcomes might actually worsen because of decreased continuity of care have not been borne out,” Dr. Patel and his associates said (JAMA 2014 Dec. 9 [doi:10.1001/jama.2014.15273]).

The investigators noted that their study was limited in that it could not take into account hospitals’ adherence to the new requirements. Their study also did not assess other outcomes such as patient safety indicators or complication rates, which “may better elucidate the relative effects of decreased resident fatigue and increased patient hand offs.” And their study couldn’t address any possible confounding effects from other concurrent policy initiatives aimed at improving care for Medicare beneficiaries, such as the Hospital Readmissions Reduction Program.

In the other study, a separate group of researchers used data from the American College of Surgeons National Surgical Quality Improvement Program to assess outcomes for 535,499 patients who underwent general surgery at 131 hospitals during the 2 years before and the 2 years after the reforms to residents’ duty hours were implemented. This included 23 teaching hospitals in which residents were involved in at least 95% of general surgeries, said Dr. Ravi Rajaram of the division of research and optimal patient care, American College of Surgeons, and the Institute for Public Health and Medicine at Northwestern University, both in Chicago, and his associates.

The reforms were not associated with any change in rates of patient mortality or serious morbidity, either in the study population as a whole or in the subgroups of high-risk and low-risk patients. They also had no effect on secondary outcomes such as surgical-site infection or sepsis. These results remained consistent across several sensitivity analyses.

Neither mean scores for in-training, written board, and oral board examinations nor pass rates for those examinations showed any significant changes during the study period.

“Moreover, first-year trainees, who were most directly affected by the 2011 reforms, did not improve their ABSITE [American Board of Surgery In-Training Examination] scores, despite presumably more free time to prepare,” Dr. Rajaram and his associates said (JAMA 2014 Dec. 9 [doi:10.1001/JAMA.2014.15277]).

They cautioned that their study assessed only the first 2 years following duty-hour reform, and “there may be differences in patient care or resident examination performance that are evident only several years after implementation and adoption of new duty-hour requirements.” In addition, a retrospective observational study such as this one could not produce the high-level evidence needed to guide policy decisions. “To that end, a national multicenter cluster-randomized trial is being conducted (the Flexibility In duty hour Requirements for Surgical Trainees [FIRST] trial), comparing current duty-hour requirements with flexible duty hours to assess the effects of this intervention on patient outcomes and resident well-being. This trial may further inform the debate of how to optimally structure postgraduate training,” they said.

Patient mortality and morbidity outcomes have not changed since the most recent round of reforms to medical residents’ duty hours in 2011, according to two of the first nationwide studies to assess these “improvements,” which both were published online Dec. 9 in JAMA.

In addition, one of the studies found no difference between pre-reform and post-reform scores or on pass rates for oral or written national in-training and board certification examinations.

©Thinglass/thinkstockphotos.com

Thus, two separate studies involving millions of hospitalized patients across the country have both found that these reforms had no discernible effect on patient care. However, both groups of researchers cautioned that their studies were observational and therefore subject to potential biases and that they covered only the first 2 years that the duty-hours reforms have been in place.

The 2011 requirements expanded on those enacted in 2003 by further restricting residents’ duty hours, in the hope of reducing medical errors attributed to exhausted residents. The hours of continuous in-hospital duty were reduced from 30 to 16 for first-year residents and to 24 for upper-year residents, and the interval between shifts was increased to at least 8 hours off for first-year residents and at least 14 hours off for upper-year residents.

“Duty hour reform is arguably one of the largest efforts ever undertaken to improve the quality and safety of patient care in teaching hospitals,” said Dr. Mitesh S. Patel of the University of Pennsylvania and the Veterans Affairs Hospital Center for Health Equity Research and Promotion, both in Philadelphia, and his associates.

They assessed 30-day mortality and readmissions among 2,790,356 Medicare patients who were treated either for acute MI, stroke, gastrointestinal bleeding, or heart failure, or who underwent general, orthopedic, or vascular surgery, at 3,104 hospitals between 2009 and 2012. The investigators found no significant associations, either positive or negative, between the reforms to residents’ duty hours and any patient outcomes. Sensitivity analyses confirmed the results of the primary data analyses.

“Our findings suggest that ... the goals of improving the quality and safety of patient care ... were not being achieved. Conversely, concerns that outcomes might actually worsen because of decreased continuity of care have not been borne out,” Dr. Patel and his associates said (JAMA 2014 Dec. 9 [doi:10.1001/jama.2014.15273]).

The investigators noted that their study was limited in that it could not take into account hospitals’ adherence to the new requirements. Their study also did not assess other outcomes such as patient safety indicators or complication rates, which “may better elucidate the relative effects of decreased resident fatigue and increased patient hand offs.” And their study couldn’t address any possible confounding effects from other concurrent policy initiatives aimed at improving care for Medicare beneficiaries, such as the Hospital Readmissions Reduction Program.

In the other study, a separate group of researchers used data from the American College of Surgeons National Surgical Quality Improvement Program to assess outcomes for 535,499 patients who underwent general surgery at 131 hospitals during the 2 years before and the 2 years after the reforms to residents’ duty hours were implemented. This included 23 teaching hospitals in which residents were involved in at least 95% of general surgeries, said Dr. Ravi Rajaram of the division of research and optimal patient care, American College of Surgeons, and the Institute for Public Health and Medicine at Northwestern University, both in Chicago, and his associates.

The reforms were not associated with any change in rates of patient mortality or serious morbidity, either in the study population as a whole or in the subgroups of high-risk and low-risk patients. They also had no effect on secondary outcomes such as surgical-site infection or sepsis. These results remained consistent across several sensitivity analyses.

Neither mean scores for in-training, written board, and oral board examinations nor pass rates for those examinations showed any significant changes during the study period.

“Moreover, first-year trainees, who were most directly affected by the 2011 reforms, did not improve their ABSITE [American Board of Surgery In-Training Examination] scores, despite presumably more free time to prepare,” Dr. Rajaram and his associates said (JAMA 2014 Dec. 9 [doi:10.1001/JAMA.2014.15277]).

They cautioned that their study assessed only the first 2 years following duty-hour reform, and “there may be differences in patient care or resident examination performance that are evident only several years after implementation and adoption of new duty-hour requirements.” In addition, a retrospective observational study such as this one could not produce the high-level evidence needed to guide policy decisions. “To that end, a national multicenter cluster-randomized trial is being conducted (the Flexibility In duty hour Requirements for Surgical Trainees [FIRST] trial), comparing current duty-hour requirements with flexible duty hours to assess the effects of this intervention on patient outcomes and resident well-being. This trial may further inform the debate of how to optimally structure postgraduate training,” they said.

Patient mortality and morbidity outcomes have not changed since the most recent round of reforms to medical residents’ duty hours in 2011, according to two of the first nationwide studies to assess these “improvements,” which both were published online Dec. 9 in JAMA.

In addition, one of the studies found no difference between pre-reform and post-reform scores or on pass rates for oral or written national in-training and board certification examinations.

©Thinglass/thinkstockphotos.com

Thus, two separate studies involving millions of hospitalized patients across the country have both found that these reforms had no discernible effect on patient care. However, both groups of researchers cautioned that their studies were observational and therefore subject to potential biases and that they covered only the first 2 years that the duty-hours reforms have been in place.

The 2011 requirements expanded on those enacted in 2003 by further restricting residents’ duty hours, in the hope of reducing medical errors attributed to exhausted residents. The hours of continuous in-hospital duty were reduced from 30 to 16 for first-year residents and to 24 for upper-year residents, and the interval between shifts was increased to at least 8 hours off for first-year residents and at least 14 hours off for upper-year residents.

“Duty hour reform is arguably one of the largest efforts ever undertaken to improve the quality and safety of patient care in teaching hospitals,” said Dr. Mitesh S. Patel of the University of Pennsylvania and the Veterans Affairs Hospital Center for Health Equity Research and Promotion, both in Philadelphia, and his associates.

They assessed 30-day mortality and readmissions among 2,790,356 Medicare patients who were treated either for acute MI, stroke, gastrointestinal bleeding, or heart failure, or who underwent general, orthopedic, or vascular surgery, at 3,104 hospitals between 2009 and 2012. The investigators found no significant associations, either positive or negative, between the reforms to residents’ duty hours and any patient outcomes. Sensitivity analyses confirmed the results of the primary data analyses.

“Our findings suggest that ... the goals of improving the quality and safety of patient care ... were not being achieved. Conversely, concerns that outcomes might actually worsen because of decreased continuity of care have not been borne out,” Dr. Patel and his associates said (JAMA 2014 Dec. 9 [doi:10.1001/jama.2014.15273]).

The investigators noted that their study was limited in that it could not take into account hospitals’ adherence to the new requirements. Their study also did not assess other outcomes such as patient safety indicators or complication rates, which “may better elucidate the relative effects of decreased resident fatigue and increased patient hand offs.” And their study couldn’t address any possible confounding effects from other concurrent policy initiatives aimed at improving care for Medicare beneficiaries, such as the Hospital Readmissions Reduction Program.

In the other study, a separate group of researchers used data from the American College of Surgeons National Surgical Quality Improvement Program to assess outcomes for 535,499 patients who underwent general surgery at 131 hospitals during the 2 years before and the 2 years after the reforms to residents’ duty hours were implemented. This included 23 teaching hospitals in which residents were involved in at least 95% of general surgeries, said Dr. Ravi Rajaram of the division of research and optimal patient care, American College of Surgeons, and the Institute for Public Health and Medicine at Northwestern University, both in Chicago, and his associates.

The reforms were not associated with any change in rates of patient mortality or serious morbidity, either in the study population as a whole or in the subgroups of high-risk and low-risk patients. They also had no effect on secondary outcomes such as surgical-site infection or sepsis. These results remained consistent across several sensitivity analyses.

Neither mean scores for in-training, written board, and oral board examinations nor pass rates for those examinations showed any significant changes during the study period.

“Moreover, first-year trainees, who were most directly affected by the 2011 reforms, did not improve their ABSITE [American Board of Surgery In-Training Examination] scores, despite presumably more free time to prepare,” Dr. Rajaram and his associates said (JAMA 2014 Dec. 9 [doi:10.1001/JAMA.2014.15277]).

They cautioned that their study assessed only the first 2 years following duty-hour reform, and “there may be differences in patient care or resident examination performance that are evident only several years after implementation and adoption of new duty-hour requirements.” In addition, a retrospective observational study such as this one could not produce the high-level evidence needed to guide policy decisions. “To that end, a national multicenter cluster-randomized trial is being conducted (the Flexibility In duty hour Requirements for Surgical Trainees [FIRST] trial), comparing current duty-hour requirements with flexible duty hours to assess the effects of this intervention on patient outcomes and resident well-being. This trial may further inform the debate of how to optimally structure postgraduate training,” they said.

SAN FRANCISCO – A first-in-class investigational agent called sotatercept appears to be safe and to improve hematologic parameters in patients with lower-risk myelodysplastic syndrome or nonproliferative chronic myelomonocytic leukemia and anemia requiring transfusion, a study showed.

In the open-label phase II dose-finding study of sotatercept in patients with myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), hematologic improvement according to International Working Group (IWG) 2006 criteria was seen in 24 of 53 evaluable patients, said Dr. Rami Komrokji of the Moffitt Cancer Center,Tampa.

The patients were all refractory to, or were deemed to have a low chance of responding to, an erythropoiesis-stimulating agent (ESA), Dr. Komrokji said at the annual meeting of the American Society of Hematology.

Neil Osterweil/Frontline Medical News

“A medication like sotatercept would probably have a role in the management of anemia in lower-risk MDS patients. The treatment is administered every 3 weeks, which makes it also logistically easier for the patients to get the treatment. I don’t think we have seen any safety concern, at least at this point, about the chronic use of this medication,” he said in an interview.

Sotatercept (ACE-011) is an activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation. The mechanism of action is distinct from that of erythropoietins such as epoetin alfa (Procrit, Epogen) or darbapoietin alfa (Aranesp).

In clinical trials with healthy volunteers, sotatercept has been shown to increase hemoglobin levels, suggesting that it could help to reduce anemia and perhaps lessen dependence on transfusions among patients with lower-risk MDS, Dr. Komrokji said.

He and his colleagues at centers in the United States and France enrolled patients with low-risk or intermediate-1–risk MDS as defined by the International Prognostic Scoring System (IPSS), or nonproliferative CMML (fewer than 13,000 white blood cells per microliter). The patients had to have anemia requiring at least 2 red blood cell (RBC) transfusions in the 12 weeks before enrollment for hemoglobin levels below 9.0 g/dL, and no response, loss of response, or a low chance of response to an ESA. Those patients with serum erythropoietin levels greater than 500 mIU/mL were considered to have a low chance of responding to an ESA.

The patients received subcutaneous injections of sotatercept at doses of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks.

As noted, the rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation. Five of 44 patients with a high transfusion burden (4 or more RBC units required within 8 weeks) were able to be free of RBC transfusions for at least 8 weeks, as were 5 of 9 with a low transfusion burden (fewer than 4 RBC units over a period of 8 weeks).

Looking at the efficacy in patients with a high transfusion burden, the investigators found that 4 of 6 assigned to the 0.3-mg/kg dose group and 8 of 14 assigned to the 1-mg/kg dose group had a reduction in transfusion burden. The median duration of effect was 106 days, with the longest response lasting for 150 days.

There were no major adverse events in the study, and no apparent increase in risk for thrombosis, as had been seen in some studies of ESAs. Another theoretical risk with this type of agent is hypertension, but there was only one grade 3 case and no grade 4 cases of hypertension in the study, Dr. Komrokji said.

Sotatercept is currently in phase II trials for anemia related to hematologic malignancies and other diseases.

SAN FRANCISCO – A first-in-class investigational agent called sotatercept appears to be safe and to improve hematologic parameters in patients with lower-risk myelodysplastic syndrome or nonproliferative chronic myelomonocytic leukemia and anemia requiring transfusion, a study showed.

In the open-label phase II dose-finding study of sotatercept in patients with myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), hematologic improvement according to International Working Group (IWG) 2006 criteria was seen in 24 of 53 evaluable patients, said Dr. Rami Komrokji of the Moffitt Cancer Center,Tampa.

The patients were all refractory to, or were deemed to have a low chance of responding to, an erythropoiesis-stimulating agent (ESA), Dr. Komrokji said at the annual meeting of the American Society of Hematology.

Neil Osterweil/Frontline Medical News

“A medication like sotatercept would probably have a role in the management of anemia in lower-risk MDS patients. The treatment is administered every 3 weeks, which makes it also logistically easier for the patients to get the treatment. I don’t think we have seen any safety concern, at least at this point, about the chronic use of this medication,” he said in an interview.

Sotatercept (ACE-011) is an activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation. The mechanism of action is distinct from that of erythropoietins such as epoetin alfa (Procrit, Epogen) or darbapoietin alfa (Aranesp).

In clinical trials with healthy volunteers, sotatercept has been shown to increase hemoglobin levels, suggesting that it could help to reduce anemia and perhaps lessen dependence on transfusions among patients with lower-risk MDS, Dr. Komrokji said.

He and his colleagues at centers in the United States and France enrolled patients with low-risk or intermediate-1–risk MDS as defined by the International Prognostic Scoring System (IPSS), or nonproliferative CMML (fewer than 13,000 white blood cells per microliter). The patients had to have anemia requiring at least 2 red blood cell (RBC) transfusions in the 12 weeks before enrollment for hemoglobin levels below 9.0 g/dL, and no response, loss of response, or a low chance of response to an ESA. Those patients with serum erythropoietin levels greater than 500 mIU/mL were considered to have a low chance of responding to an ESA.

The patients received subcutaneous injections of sotatercept at doses of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks.

As noted, the rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation. Five of 44 patients with a high transfusion burden (4 or more RBC units required within 8 weeks) were able to be free of RBC transfusions for at least 8 weeks, as were 5 of 9 with a low transfusion burden (fewer than 4 RBC units over a period of 8 weeks).

Looking at the efficacy in patients with a high transfusion burden, the investigators found that 4 of 6 assigned to the 0.3-mg/kg dose group and 8 of 14 assigned to the 1-mg/kg dose group had a reduction in transfusion burden. The median duration of effect was 106 days, with the longest response lasting for 150 days.

There were no major adverse events in the study, and no apparent increase in risk for thrombosis, as had been seen in some studies of ESAs. Another theoretical risk with this type of agent is hypertension, but there was only one grade 3 case and no grade 4 cases of hypertension in the study, Dr. Komrokji said.

Sotatercept is currently in phase II trials for anemia related to hematologic malignancies and other diseases.

SAN FRANCISCO – A first-in-class investigational agent called sotatercept appears to be safe and to improve hematologic parameters in patients with lower-risk myelodysplastic syndrome or nonproliferative chronic myelomonocytic leukemia and anemia requiring transfusion, a study showed.

In the open-label phase II dose-finding study of sotatercept in patients with myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), hematologic improvement according to International Working Group (IWG) 2006 criteria was seen in 24 of 53 evaluable patients, said Dr. Rami Komrokji of the Moffitt Cancer Center,Tampa.

The patients were all refractory to, or were deemed to have a low chance of responding to, an erythropoiesis-stimulating agent (ESA), Dr. Komrokji said at the annual meeting of the American Society of Hematology.

Neil Osterweil/Frontline Medical News

“A medication like sotatercept would probably have a role in the management of anemia in lower-risk MDS patients. The treatment is administered every 3 weeks, which makes it also logistically easier for the patients to get the treatment. I don’t think we have seen any safety concern, at least at this point, about the chronic use of this medication,” he said in an interview.

Sotatercept (ACE-011) is an activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation. The mechanism of action is distinct from that of erythropoietins such as epoetin alfa (Procrit, Epogen) or darbapoietin alfa (Aranesp).

In clinical trials with healthy volunteers, sotatercept has been shown to increase hemoglobin levels, suggesting that it could help to reduce anemia and perhaps lessen dependence on transfusions among patients with lower-risk MDS, Dr. Komrokji said.

He and his colleagues at centers in the United States and France enrolled patients with low-risk or intermediate-1–risk MDS as defined by the International Prognostic Scoring System (IPSS), or nonproliferative CMML (fewer than 13,000 white blood cells per microliter). The patients had to have anemia requiring at least 2 red blood cell (RBC) transfusions in the 12 weeks before enrollment for hemoglobin levels below 9.0 g/dL, and no response, loss of response, or a low chance of response to an ESA. Those patients with serum erythropoietin levels greater than 500 mIU/mL were considered to have a low chance of responding to an ESA.

The patients received subcutaneous injections of sotatercept at doses of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks.

As noted, the rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation. Five of 44 patients with a high transfusion burden (4 or more RBC units required within 8 weeks) were able to be free of RBC transfusions for at least 8 weeks, as were 5 of 9 with a low transfusion burden (fewer than 4 RBC units over a period of 8 weeks).

Looking at the efficacy in patients with a high transfusion burden, the investigators found that 4 of 6 assigned to the 0.3-mg/kg dose group and 8 of 14 assigned to the 1-mg/kg dose group had a reduction in transfusion burden. The median duration of effect was 106 days, with the longest response lasting for 150 days.

There were no major adverse events in the study, and no apparent increase in risk for thrombosis, as had been seen in some studies of ESAs. Another theoretical risk with this type of agent is hypertension, but there was only one grade 3 case and no grade 4 cases of hypertension in the study, Dr. Komrokji said.

Sotatercept is currently in phase II trials for anemia related to hematologic malignancies and other diseases.

SAN FRANCISCO– The study was small but encouraging: Among 47 older patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome, 41 had a complete hematologic response to a combination of chemotherapy and the targeted agent nilotinib (Tasigna), report investigators from a European consortium.

“The data I have presented show that the combination of nilotinib with this age-adapted chemotherapy is highly effective. We do have quite a reasonable overall survival estimate at 2 years of just more than 70%,” said Dr. Oliver Ottmann of Goethe University in Frankfurt, on behalf of colleagues in the European Working Group for Adult ALL (EWALL).

The study also shows that although some centers are reluctant to offer allogeneic stem cell transplantation (SCT) to older patients, it is still a viable treatment option in this population, Dr. Ottmann said at a briefing at the annual meeting of the American Society of Hematology.

Although older patients with newly diagnosed Philadelphia-positive (Ph+) ALL have a high complete hematologic response rate (CHR) with imatinib (Gleevec), they generally have a poor prognosis because of a high rate of relapse.

Because nilotinib, a potent inhibitor of the ABL kinase, has good efficacy in the chronic and accelerated phase of Ph+ chronic myeloid leukemia, the EWALL investigators initiated a study to evaluate it in combination with chemotherapy in the front-line setting.

Adults aged 55 years and older with ALL positive for the Philadelphia chromosome and/or BCR-ABL1 fusion who were treatment naive or had not received therapy other than corticosteroids, single-dose vincristine, or three doses of cyclophosphamide were eligible.

Details of the combination regimen are available online.

Briefly, following a prephase with dexamethasone and optional cyclophosphamide, patients receive nilotinib 400 mg twice daily starting with induction and continuously thereafter. During induction, nilotinib is given with intravenous injections of vincristine and dexamethasone for 4 weeks, followed by consolidation with nilotinib, methotrexate, asparaginase and cytarabine. Maintenance consists of nilotinib, 6-mercaptopurine, and methotrexate once weekly for 1 month then every other month, and dexamethasone and vincristine in 2 month intervals up to 24 months.

The data Dr. Ottmann reported come from an interim analysis of the ongoing study. As of August 2014, data on 47 of 56 patients was available for an efficacy analysis, As noted before, the rate of CHR was 87%, occurring in 41 of 47 patients. The treatment evoked a partial response or no response in 2 patients, and there was one death during the induction phase. Additionally, three patients discontinued therapy early and were not included in the assessment, but at least one had a complete response later on, Dr. Ottmann noted.

The median time to a complete response (CR) was 41 days, but CRs occurred as early as 25 days and as late as 62 days after the start of therapy. The remissions at the time of data cutoff appeared to be durable, but follow-up is still early, he said.

Overall survival at a median follow-up for all patients of 8.6 months was 72.7% at 30 months for patients who did not undergo SCT (allowed under the protocol), and 67.1% at 30 months for patients who underwent SCT. This difference was not significant, but only nine patients at the time of data cutoff had undergone transplantation.

“It will be interesting to see how this will proceed if the transplant-free patients will do as well as the others,” Dr. Ottmann said.

An analysis of molecular response by minimal residual disease (MRD) time point showed a significant further increase with the consolidation chemotherapy and kinase inhibitor, emphasizing that “continuing the treatment in this form emphasizes the depth of response. If we then look at the rate of MRD negativity using high quality assays, then a quarter of the patients have undetectable polymerase chain reaction during the consolidation cycles, and approximately 80% achieves something that we call a major molecular response,” he said.

Dr. Ottmann did not provide updated safety data, but at the time of the data cutoff, there had been 34 serious adverse events reported, 11 of which occurred during induction, 16 during consolidation, 6 during maintenance, and 1 following discontinuation. The most-common adverse events were infections and neutropenic fevers. Single serious adverse events included metabolic, cardiovascular, neurologic, renal, and hepatic events.

The trial is expected to be completed in the next few months.

SAN FRANCISCO– The study was small but encouraging: Among 47 older patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome, 41 had a complete hematologic response to a combination of chemotherapy and the targeted agent nilotinib (Tasigna), report investigators from a European consortium.

“The data I have presented show that the combination of nilotinib with this age-adapted chemotherapy is highly effective. We do have quite a reasonable overall survival estimate at 2 years of just more than 70%,” said Dr. Oliver Ottmann of Goethe University in Frankfurt, on behalf of colleagues in the European Working Group for Adult ALL (EWALL).

The study also shows that although some centers are reluctant to offer allogeneic stem cell transplantation (SCT) to older patients, it is still a viable treatment option in this population, Dr. Ottmann said at a briefing at the annual meeting of the American Society of Hematology.

Although older patients with newly diagnosed Philadelphia-positive (Ph+) ALL have a high complete hematologic response rate (CHR) with imatinib (Gleevec), they generally have a poor prognosis because of a high rate of relapse.

Because nilotinib, a potent inhibitor of the ABL kinase, has good efficacy in the chronic and accelerated phase of Ph+ chronic myeloid leukemia, the EWALL investigators initiated a study to evaluate it in combination with chemotherapy in the front-line setting.

Adults aged 55 years and older with ALL positive for the Philadelphia chromosome and/or BCR-ABL1 fusion who were treatment naive or had not received therapy other than corticosteroids, single-dose vincristine, or three doses of cyclophosphamide were eligible.

Details of the combination regimen are available online.

Briefly, following a prephase with dexamethasone and optional cyclophosphamide, patients receive nilotinib 400 mg twice daily starting with induction and continuously thereafter. During induction, nilotinib is given with intravenous injections of vincristine and dexamethasone for 4 weeks, followed by consolidation with nilotinib, methotrexate, asparaginase and cytarabine. Maintenance consists of nilotinib, 6-mercaptopurine, and methotrexate once weekly for 1 month then every other month, and dexamethasone and vincristine in 2 month intervals up to 24 months.

The data Dr. Ottmann reported come from an interim analysis of the ongoing study. As of August 2014, data on 47 of 56 patients was available for an efficacy analysis, As noted before, the rate of CHR was 87%, occurring in 41 of 47 patients. The treatment evoked a partial response or no response in 2 patients, and there was one death during the induction phase. Additionally, three patients discontinued therapy early and were not included in the assessment, but at least one had a complete response later on, Dr. Ottmann noted.

The median time to a complete response (CR) was 41 days, but CRs occurred as early as 25 days and as late as 62 days after the start of therapy. The remissions at the time of data cutoff appeared to be durable, but follow-up is still early, he said.

Overall survival at a median follow-up for all patients of 8.6 months was 72.7% at 30 months for patients who did not undergo SCT (allowed under the protocol), and 67.1% at 30 months for patients who underwent SCT. This difference was not significant, but only nine patients at the time of data cutoff had undergone transplantation.

“It will be interesting to see how this will proceed if the transplant-free patients will do as well as the others,” Dr. Ottmann said.

An analysis of molecular response by minimal residual disease (MRD) time point showed a significant further increase with the consolidation chemotherapy and kinase inhibitor, emphasizing that “continuing the treatment in this form emphasizes the depth of response. If we then look at the rate of MRD negativity using high quality assays, then a quarter of the patients have undetectable polymerase chain reaction during the consolidation cycles, and approximately 80% achieves something that we call a major molecular response,” he said.

Dr. Ottmann did not provide updated safety data, but at the time of the data cutoff, there had been 34 serious adverse events reported, 11 of which occurred during induction, 16 during consolidation, 6 during maintenance, and 1 following discontinuation. The most-common adverse events were infections and neutropenic fevers. Single serious adverse events included metabolic, cardiovascular, neurologic, renal, and hepatic events.

The trial is expected to be completed in the next few months.

SAN FRANCISCO– The study was small but encouraging: Among 47 older patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome, 41 had a complete hematologic response to a combination of chemotherapy and the targeted agent nilotinib (Tasigna), report investigators from a European consortium.

“The data I have presented show that the combination of nilotinib with this age-adapted chemotherapy is highly effective. We do have quite a reasonable overall survival estimate at 2 years of just more than 70%,” said Dr. Oliver Ottmann of Goethe University in Frankfurt, on behalf of colleagues in the European Working Group for Adult ALL (EWALL).

The study also shows that although some centers are reluctant to offer allogeneic stem cell transplantation (SCT) to older patients, it is still a viable treatment option in this population, Dr. Ottmann said at a briefing at the annual meeting of the American Society of Hematology.

Although older patients with newly diagnosed Philadelphia-positive (Ph+) ALL have a high complete hematologic response rate (CHR) with imatinib (Gleevec), they generally have a poor prognosis because of a high rate of relapse.

Because nilotinib, a potent inhibitor of the ABL kinase, has good efficacy in the chronic and accelerated phase of Ph+ chronic myeloid leukemia, the EWALL investigators initiated a study to evaluate it in combination with chemotherapy in the front-line setting.

Adults aged 55 years and older with ALL positive for the Philadelphia chromosome and/or BCR-ABL1 fusion who were treatment naive or had not received therapy other than corticosteroids, single-dose vincristine, or three doses of cyclophosphamide were eligible.

Details of the combination regimen are available online.

Briefly, following a prephase with dexamethasone and optional cyclophosphamide, patients receive nilotinib 400 mg twice daily starting with induction and continuously thereafter. During induction, nilotinib is given with intravenous injections of vincristine and dexamethasone for 4 weeks, followed by consolidation with nilotinib, methotrexate, asparaginase and cytarabine. Maintenance consists of nilotinib, 6-mercaptopurine, and methotrexate once weekly for 1 month then every other month, and dexamethasone and vincristine in 2 month intervals up to 24 months.

The data Dr. Ottmann reported come from an interim analysis of the ongoing study. As of August 2014, data on 47 of 56 patients was available for an efficacy analysis, As noted before, the rate of CHR was 87%, occurring in 41 of 47 patients. The treatment evoked a partial response or no response in 2 patients, and there was one death during the induction phase. Additionally, three patients discontinued therapy early and were not included in the assessment, but at least one had a complete response later on, Dr. Ottmann noted.

The median time to a complete response (CR) was 41 days, but CRs occurred as early as 25 days and as late as 62 days after the start of therapy. The remissions at the time of data cutoff appeared to be durable, but follow-up is still early, he said.

Overall survival at a median follow-up for all patients of 8.6 months was 72.7% at 30 months for patients who did not undergo SCT (allowed under the protocol), and 67.1% at 30 months for patients who underwent SCT. This difference was not significant, but only nine patients at the time of data cutoff had undergone transplantation.

“It will be interesting to see how this will proceed if the transplant-free patients will do as well as the others,” Dr. Ottmann said.

An analysis of molecular response by minimal residual disease (MRD) time point showed a significant further increase with the consolidation chemotherapy and kinase inhibitor, emphasizing that “continuing the treatment in this form emphasizes the depth of response. If we then look at the rate of MRD negativity using high quality assays, then a quarter of the patients have undetectable polymerase chain reaction during the consolidation cycles, and approximately 80% achieves something that we call a major molecular response,” he said.

Dr. Ottmann did not provide updated safety data, but at the time of the data cutoff, there had been 34 serious adverse events reported, 11 of which occurred during induction, 16 during consolidation, 6 during maintenance, and 1 following discontinuation. The most-common adverse events were infections and neutropenic fevers. Single serious adverse events included metabolic, cardiovascular, neurologic, renal, and hepatic events.

The trial is expected to be completed in the next few months.

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

Scientist at a computer

Credit: Darren Baker

Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.

The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).

This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.

The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.

“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.

“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”

Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.

In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.

Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.

The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)

Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.

Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.

The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.

“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”

“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”

Scientist at a computer

Credit: Darren Baker

Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.

The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).

This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.

The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.

“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.

“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”

Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.

In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.

Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.

The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)

Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.

Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.

The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.

“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”

“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”

Scientist at a computer

Credit: Darren Baker

Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.

The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).

This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.

The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.

“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.

“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”

Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.

In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.

Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.

The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)

Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.

Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.

The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.

“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”

“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”