Neil Osterweil

European respiratory disease and infectious disease specialists have banded together to issue new clinical guidelines on the diagnosis and management of an uncommon but serious problem: chronic pulmonary aspergillosis (CPA).

Pulmonary infections with Aspergillus species, although uncommon, are a complicating factor in several lung diseases, especially tuberculosis, and aspergillosis is a serious, often fatal opportunistic infection in transplant recipients who are on chronic immunosuppression or patients who are immunocompromised from disease or cytotoxic chemotherapy.

Approximately 240,000 people in Europe and 3 million people worldwide have chronic pulmonary aspergillosis (CPA). The Centers for Disease Control and Prevention notes that because aspergillosis is not classified as a reportable disease, data on the actual incidence of infections in the United States are hard to come by.

“You don’t see this every day, whether you’re an infectious disease specialist or pulmonologist, so you really can’t rely on your experience to guide you in managing these cases, which is why guidelines such as this can be very helpful,” commented Dr. Norman Edelman, a pulmonologist and senior consultant for scientific affairs for the American Lung Association.

The guidelines, issued by the European Society for Clinical Microbiology and Infectious Diseases in cooperation with the European Confederation of Medical Mycology and the European Respiratory Society, are an attempt to provide clinicians with the best possible evidence-based guidance on managing patients with aspergillosis, primarily those with CPA (Eur Respir J. 2015. doi: 10.1183/13993003.00583-2015).

Dr. Edelman noted that the most frequent presentation he sees – and that very infrequently – is allergic bronchopulmonary aspergillosis in patients with asthma.

The most recent U.S. guidelines, issued under the aegis of the Infectious Diseases Society of America (IDSA) in 2000 and revised in 2008 (CID 2008;46:327-360), differ from the European recommendations in their level of detail, explained Prof. David W. Denning, professor of infectious diseases in global health at the University of Manchester (England) and lead author of the European guidelines.

“The IDSA guidelines assume that you know how to make the diagnosis, but actually for chronic pulmonary aspergillosis that’s not so easy with some patients,” he said in an interview.

“The European ones go into in great detail the diagnosis, the radiology, whether this test is better than that test, how they all add up, and all that sort of stuff,” he said,

The European guidelines also make recommendations for duration of therapy and comment on the use of steroids and immunotherapy with interferon-gamma, Dr. Denning noted.

Diagnostic criteria

The European guidelines categorize Aspergillus infections according to differences in clinical management:

• Simple aspergilloma. A single pulmonary cavity containing a fungal ball, supported by serologic or microbiologic evidence of infections with Aspergillus species in patients who are not immunocompromised and are asymptomatic or have only minor symptoms and no radiographic evidence of progression for at least 3 months.

• Chronic cavitary pulmonary aspergillosis (CCPA). The presence of one or more pulmonary cavities that may contain one or more aspergillomas or irregular intraluminal material, evidence of Aspergillus species, significant pulmonary/systemic symptoms, and overt progression on radiography over 3 or more months of observations.

• Chronic fibrosing pulmonary aspergillosis (CFPA). Severe, fibrotic destruction of at least two lung lobes as a complication of CCPA, causing a major loss of lung function. The guidelines note that destruction of a single lobe is designated as CCPA of that lobe.

• Aspergillus nodules. This unusual presentation is marked by the presence of one or more nodules that may or may not cavitate. The nodules may resemble tuberculoma, carcinoma of the lung, or coccidioidomycosis; histology is required to make an accurate diagnosis.

• Subacute invasive aspergillosis (SAIA). This can occur over the course of 1-3 months in patients who are mildly immunocompromised. Radiologic features can vary, and may include cavitation, the presence of nodules, and progressive consolidation with the appearance of abscess formation. Fungal hyphae (filaments) can be seen in biopsied lung tissues, and there may be evidence of Aspergillus galactomannan antigen in respiratory fluids or blood.

Treatment

The guidelines note that most of the evidence for managing CPA are based on cohort studies and case reports rather than randomized clinical trials, and that there have been no head-to-head trials comparing oral triazole agents.

For treatment of CPA, the European guidelines recommend:

• Itraconazole 200 mg twice daily, with therapeutic drug monitoring and dose adjustment as necessary (Grade A [strong] recommendation).

• Voriconazole 150-200 mg twice daily, with monitoring and dose adjustment. The guidelines recommend lower doses for patients older than 70 years, those with low body weight, significant liver disease, and/or those of Northeast Asian descent, who may be genetically inclined to slow drug metabolism (Grade A).

• Posaconazole liquid 400 mg twice daily, or tablets 300 mg once daily (Grade B [moderate] recommendation].

In general, the recommended duration of therapy for control of infection in patients with CPA or curative intent for patients with SAIA or chronic necrotizing pulmonary aspergillosis is 6 months or more, depending on patient status and drug tolerance.

For patients with CPA with progressive disease, those whom therapy has failed, or those who are intolerant of or have disease resistant to triazoles, intravenous therapy with micafungin, 150 mg day (Grade B); amphotericin B deoxycholate, 0.7-1.0 mg/kg per day (Grade C [marginal] recommendation); liposomal amphotericin B, 3 mg/kg per day (Grade B); or caspofungin, 50-70 mg/day (Grade C) are recommended.

The guidelines also recommend surgical excision of simple aspergilloma, preferably by a video-assisted thoracic surgery technique, if technically feasible.

“In my own experience, we resort to surgery very infrequently,” Dr. Edelman said.

He noted that it would be helpful if the guidelines had also allergic bronchopulmonary aspergillosis as a separate entity.

Ideal not always achievable

Prof. Denning points out that the optimum therapies and practices described in the guidelines can’t always be implemented. Worldwide, he said, antifungal therapy is not widely available, with the exception of fluconazole, which has no activity against Aspergillus, and is inferior to itraconazole and other extended azoles for other fungal diseases such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.

The price of antifungal therapies can also be a barrier to effective treatment in many parts of the world.

“If you’re having to pay for your medicines and you’re living on $5 or $10 a day in Kenya, say, you can’t afford to buy them. So even if the drugs are physically there, it may not be really affordable for a course of therapy for these patients, and there’s some advocacy to be done around that for the whole world,” he said.

The guidelines were funded primarily by grants from ESCMID and ERS with additional support from ECMM. Authors’ travel expenses were funded jointly by ESCMID and ERS. Dr. Denning has received grant support and founder shares in F2G, and has received grants from the Fungal Research Trust, Wellcome Trust, Moulton Trust, Medical Research Council, Chronic Granulomatous Disease Research Trust, National Institute of Allergy and Infectious Diseases, National Institute of Health Research and the European Union, and AstraZeneca. Dr. Edelman reported no relevant disclosures.

imnews@frontlinemedcom.com

European respiratory disease and infectious disease specialists have banded together to issue new clinical guidelines on the diagnosis and management of an uncommon but serious problem: chronic pulmonary aspergillosis (CPA).

Pulmonary infections with Aspergillus species, although uncommon, are a complicating factor in several lung diseases, especially tuberculosis, and aspergillosis is a serious, often fatal opportunistic infection in transplant recipients who are on chronic immunosuppression or patients who are immunocompromised from disease or cytotoxic chemotherapy.

Approximately 240,000 people in Europe and 3 million people worldwide have chronic pulmonary aspergillosis (CPA). The Centers for Disease Control and Prevention notes that because aspergillosis is not classified as a reportable disease, data on the actual incidence of infections in the United States are hard to come by.

“You don’t see this every day, whether you’re an infectious disease specialist or pulmonologist, so you really can’t rely on your experience to guide you in managing these cases, which is why guidelines such as this can be very helpful,” commented Dr. Norman Edelman, a pulmonologist and senior consultant for scientific affairs for the American Lung Association.

The guidelines, issued by the European Society for Clinical Microbiology and Infectious Diseases in cooperation with the European Confederation of Medical Mycology and the European Respiratory Society, are an attempt to provide clinicians with the best possible evidence-based guidance on managing patients with aspergillosis, primarily those with CPA (Eur Respir J. 2015. doi: 10.1183/13993003.00583-2015).

Dr. Edelman noted that the most frequent presentation he sees – and that very infrequently – is allergic bronchopulmonary aspergillosis in patients with asthma.

The most recent U.S. guidelines, issued under the aegis of the Infectious Diseases Society of America (IDSA) in 2000 and revised in 2008 (CID 2008;46:327-360), differ from the European recommendations in their level of detail, explained Prof. David W. Denning, professor of infectious diseases in global health at the University of Manchester (England) and lead author of the European guidelines.

“The IDSA guidelines assume that you know how to make the diagnosis, but actually for chronic pulmonary aspergillosis that’s not so easy with some patients,” he said in an interview.

“The European ones go into in great detail the diagnosis, the radiology, whether this test is better than that test, how they all add up, and all that sort of stuff,” he said,

The European guidelines also make recommendations for duration of therapy and comment on the use of steroids and immunotherapy with interferon-gamma, Dr. Denning noted.

Diagnostic criteria

The European guidelines categorize Aspergillus infections according to differences in clinical management:

• Simple aspergilloma. A single pulmonary cavity containing a fungal ball, supported by serologic or microbiologic evidence of infections with Aspergillus species in patients who are not immunocompromised and are asymptomatic or have only minor symptoms and no radiographic evidence of progression for at least 3 months.

• Chronic cavitary pulmonary aspergillosis (CCPA). The presence of one or more pulmonary cavities that may contain one or more aspergillomas or irregular intraluminal material, evidence of Aspergillus species, significant pulmonary/systemic symptoms, and overt progression on radiography over 3 or more months of observations.

• Chronic fibrosing pulmonary aspergillosis (CFPA). Severe, fibrotic destruction of at least two lung lobes as a complication of CCPA, causing a major loss of lung function. The guidelines note that destruction of a single lobe is designated as CCPA of that lobe.

• Aspergillus nodules. This unusual presentation is marked by the presence of one or more nodules that may or may not cavitate. The nodules may resemble tuberculoma, carcinoma of the lung, or coccidioidomycosis; histology is required to make an accurate diagnosis.

• Subacute invasive aspergillosis (SAIA). This can occur over the course of 1-3 months in patients who are mildly immunocompromised. Radiologic features can vary, and may include cavitation, the presence of nodules, and progressive consolidation with the appearance of abscess formation. Fungal hyphae (filaments) can be seen in biopsied lung tissues, and there may be evidence of Aspergillus galactomannan antigen in respiratory fluids or blood.

Treatment

The guidelines note that most of the evidence for managing CPA are based on cohort studies and case reports rather than randomized clinical trials, and that there have been no head-to-head trials comparing oral triazole agents.

For treatment of CPA, the European guidelines recommend:

• Itraconazole 200 mg twice daily, with therapeutic drug monitoring and dose adjustment as necessary (Grade A [strong] recommendation).

• Voriconazole 150-200 mg twice daily, with monitoring and dose adjustment. The guidelines recommend lower doses for patients older than 70 years, those with low body weight, significant liver disease, and/or those of Northeast Asian descent, who may be genetically inclined to slow drug metabolism (Grade A).

• Posaconazole liquid 400 mg twice daily, or tablets 300 mg once daily (Grade B [moderate] recommendation].

In general, the recommended duration of therapy for control of infection in patients with CPA or curative intent for patients with SAIA or chronic necrotizing pulmonary aspergillosis is 6 months or more, depending on patient status and drug tolerance.

For patients with CPA with progressive disease, those whom therapy has failed, or those who are intolerant of or have disease resistant to triazoles, intravenous therapy with micafungin, 150 mg day (Grade B); amphotericin B deoxycholate, 0.7-1.0 mg/kg per day (Grade C [marginal] recommendation); liposomal amphotericin B, 3 mg/kg per day (Grade B); or caspofungin, 50-70 mg/day (Grade C) are recommended.

The guidelines also recommend surgical excision of simple aspergilloma, preferably by a video-assisted thoracic surgery technique, if technically feasible.

“In my own experience, we resort to surgery very infrequently,” Dr. Edelman said.

He noted that it would be helpful if the guidelines had also allergic bronchopulmonary aspergillosis as a separate entity.

Ideal not always achievable

Prof. Denning points out that the optimum therapies and practices described in the guidelines can’t always be implemented. Worldwide, he said, antifungal therapy is not widely available, with the exception of fluconazole, which has no activity against Aspergillus, and is inferior to itraconazole and other extended azoles for other fungal diseases such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.

The price of antifungal therapies can also be a barrier to effective treatment in many parts of the world.

“If you’re having to pay for your medicines and you’re living on $5 or $10 a day in Kenya, say, you can’t afford to buy them. So even if the drugs are physically there, it may not be really affordable for a course of therapy for these patients, and there’s some advocacy to be done around that for the whole world,” he said.

The guidelines were funded primarily by grants from ESCMID and ERS with additional support from ECMM. Authors’ travel expenses were funded jointly by ESCMID and ERS. Dr. Denning has received grant support and founder shares in F2G, and has received grants from the Fungal Research Trust, Wellcome Trust, Moulton Trust, Medical Research Council, Chronic Granulomatous Disease Research Trust, National Institute of Allergy and Infectious Diseases, National Institute of Health Research and the European Union, and AstraZeneca. Dr. Edelman reported no relevant disclosures.

imnews@frontlinemedcom.com

European respiratory disease and infectious disease specialists have banded together to issue new clinical guidelines on the diagnosis and management of an uncommon but serious problem: chronic pulmonary aspergillosis (CPA).

Pulmonary infections with Aspergillus species, although uncommon, are a complicating factor in several lung diseases, especially tuberculosis, and aspergillosis is a serious, often fatal opportunistic infection in transplant recipients who are on chronic immunosuppression or patients who are immunocompromised from disease or cytotoxic chemotherapy.

Approximately 240,000 people in Europe and 3 million people worldwide have chronic pulmonary aspergillosis (CPA). The Centers for Disease Control and Prevention notes that because aspergillosis is not classified as a reportable disease, data on the actual incidence of infections in the United States are hard to come by.

“You don’t see this every day, whether you’re an infectious disease specialist or pulmonologist, so you really can’t rely on your experience to guide you in managing these cases, which is why guidelines such as this can be very helpful,” commented Dr. Norman Edelman, a pulmonologist and senior consultant for scientific affairs for the American Lung Association.

The guidelines, issued by the European Society for Clinical Microbiology and Infectious Diseases in cooperation with the European Confederation of Medical Mycology and the European Respiratory Society, are an attempt to provide clinicians with the best possible evidence-based guidance on managing patients with aspergillosis, primarily those with CPA (Eur Respir J. 2015. doi: 10.1183/13993003.00583-2015).

Dr. Edelman noted that the most frequent presentation he sees – and that very infrequently – is allergic bronchopulmonary aspergillosis in patients with asthma.

The most recent U.S. guidelines, issued under the aegis of the Infectious Diseases Society of America (IDSA) in 2000 and revised in 2008 (CID 2008;46:327-360), differ from the European recommendations in their level of detail, explained Prof. David W. Denning, professor of infectious diseases in global health at the University of Manchester (England) and lead author of the European guidelines.

“The IDSA guidelines assume that you know how to make the diagnosis, but actually for chronic pulmonary aspergillosis that’s not so easy with some patients,” he said in an interview.

“The European ones go into in great detail the diagnosis, the radiology, whether this test is better than that test, how they all add up, and all that sort of stuff,” he said,

The European guidelines also make recommendations for duration of therapy and comment on the use of steroids and immunotherapy with interferon-gamma, Dr. Denning noted.

Diagnostic criteria

The European guidelines categorize Aspergillus infections according to differences in clinical management:

• Simple aspergilloma. A single pulmonary cavity containing a fungal ball, supported by serologic or microbiologic evidence of infections with Aspergillus species in patients who are not immunocompromised and are asymptomatic or have only minor symptoms and no radiographic evidence of progression for at least 3 months.

• Chronic cavitary pulmonary aspergillosis (CCPA). The presence of one or more pulmonary cavities that may contain one or more aspergillomas or irregular intraluminal material, evidence of Aspergillus species, significant pulmonary/systemic symptoms, and overt progression on radiography over 3 or more months of observations.

• Chronic fibrosing pulmonary aspergillosis (CFPA). Severe, fibrotic destruction of at least two lung lobes as a complication of CCPA, causing a major loss of lung function. The guidelines note that destruction of a single lobe is designated as CCPA of that lobe.

• Aspergillus nodules. This unusual presentation is marked by the presence of one or more nodules that may or may not cavitate. The nodules may resemble tuberculoma, carcinoma of the lung, or coccidioidomycosis; histology is required to make an accurate diagnosis.

• Subacute invasive aspergillosis (SAIA). This can occur over the course of 1-3 months in patients who are mildly immunocompromised. Radiologic features can vary, and may include cavitation, the presence of nodules, and progressive consolidation with the appearance of abscess formation. Fungal hyphae (filaments) can be seen in biopsied lung tissues, and there may be evidence of Aspergillus galactomannan antigen in respiratory fluids or blood.

Treatment

The guidelines note that most of the evidence for managing CPA are based on cohort studies and case reports rather than randomized clinical trials, and that there have been no head-to-head trials comparing oral triazole agents.

For treatment of CPA, the European guidelines recommend:

• Itraconazole 200 mg twice daily, with therapeutic drug monitoring and dose adjustment as necessary (Grade A [strong] recommendation).

• Voriconazole 150-200 mg twice daily, with monitoring and dose adjustment. The guidelines recommend lower doses for patients older than 70 years, those with low body weight, significant liver disease, and/or those of Northeast Asian descent, who may be genetically inclined to slow drug metabolism (Grade A).

• Posaconazole liquid 400 mg twice daily, or tablets 300 mg once daily (Grade B [moderate] recommendation].

In general, the recommended duration of therapy for control of infection in patients with CPA or curative intent for patients with SAIA or chronic necrotizing pulmonary aspergillosis is 6 months or more, depending on patient status and drug tolerance.

For patients with CPA with progressive disease, those whom therapy has failed, or those who are intolerant of or have disease resistant to triazoles, intravenous therapy with micafungin, 150 mg day (Grade B); amphotericin B deoxycholate, 0.7-1.0 mg/kg per day (Grade C [marginal] recommendation); liposomal amphotericin B, 3 mg/kg per day (Grade B); or caspofungin, 50-70 mg/day (Grade C) are recommended.

The guidelines also recommend surgical excision of simple aspergilloma, preferably by a video-assisted thoracic surgery technique, if technically feasible.

“In my own experience, we resort to surgery very infrequently,” Dr. Edelman said.

He noted that it would be helpful if the guidelines had also allergic bronchopulmonary aspergillosis as a separate entity.

Ideal not always achievable

Prof. Denning points out that the optimum therapies and practices described in the guidelines can’t always be implemented. Worldwide, he said, antifungal therapy is not widely available, with the exception of fluconazole, which has no activity against Aspergillus, and is inferior to itraconazole and other extended azoles for other fungal diseases such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.

The price of antifungal therapies can also be a barrier to effective treatment in many parts of the world.

“If you’re having to pay for your medicines and you’re living on $5 or $10 a day in Kenya, say, you can’t afford to buy them. So even if the drugs are physically there, it may not be really affordable for a course of therapy for these patients, and there’s some advocacy to be done around that for the whole world,” he said.

The guidelines were funded primarily by grants from ESCMID and ERS with additional support from ECMM. Authors’ travel expenses were funded jointly by ESCMID and ERS. Dr. Denning has received grant support and founder shares in F2G, and has received grants from the Fungal Research Trust, Wellcome Trust, Moulton Trust, Medical Research Council, Chronic Granulomatous Disease Research Trust, National Institute of Allergy and Infectious Diseases, National Institute of Health Research and the European Union, and AstraZeneca. Dr. Edelman reported no relevant disclosures.

imnews@frontlinemedcom.com

ORLANDO – Patients who undergo cytotoxic chemotherapy, even in the modern era, are at increased risk for developing myeloid neoplasms, based on data from a cohort of nearly 750,000 adults who were initially treated with chemotherapy and survived at least 1 year after diagnosis.

In the cohort, the standardized incidence ratio (SIR) for treatment-related acute myeloid leukemia (tAML) or myelodysplastic syndrome (MDS) was four times greater than would be expected in the general population, reported Lindsay M. Morton, Ph.D., of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

RTEmagicC_6cd30bb_Morton_Lindsay_S_MD.jpg.jpg

“We now demonstrate that there are elevated risks for treatment-related leukemia after treatment for a broad spectrum of first primary malignancies that are generally consistent with what we know about changing treatment practices,” she said at the American Society of Hematology annual meeting.

“The number of cancer survivors in the United States has increased dramatically, to reach nearly 14 million individuals today, and in just the next few years the number is expected to reach more than 18 million people, which means that the long-term health of this population is of great clinical importance as well as public health importance,” Dr. Morton emphasized.

The link between cytotoxic chemotherapy and leukemia risk has been known since the 1960s, with certain classes of agents carrying higher risks than others, including platinum-containing compounds, alkylating agents (for example, cyclophosphamide, melphalan, chlorambucil), topoisomerase II inhibitors (doxorubicin, daunorubicin, epirubicin, etc.), and antimetabolites (5-fluorauracil, capecitabine, gemcitabine, et al.).

Treatment-related leukemias are associated with higher doses of these agents, and the trend in contemporary medicine is to use more of these agents upfront for the treatment of primary malignancies. Yet estimates of the risk of tAML, MDS, or other malignancies have been hard to come by because of the relative rarity of cases and the sporadic reports in the literature, Dr. Morton said.

The investigators previously reported that risk for tAML and other myeloid neoplasms changed over time, and showed that since the 1990s there was an uptick in risk for patients treated with chemotherapy for cancers of bone, joints, and endometrium, and since 2000 for patients treated with chemotherapy for cancers of the esophagus, cervix and prostate.

For example, risks for tAML were higher in the 1970s for patients with ovarian cancer treated with melphalan, a highly leukemogenic agent, but dropped somewhat with the switch to platinum-based agents. Similarly, women with breast cancer had a comparatively high risk with the use of melphalan, a decline in risk with the introduction of cyclophosphamide, and then an increase with the addition of anthracyclines and dose-dense regimens.

Risk update

To get a better idea of the magnitude of risk in the modern era, Dr. Morton and colleagues sifted through Surveillance, Epidemiology, and End Results (SEER) data to identify a cohort of 746,007 adults who were initially treated with chemotherapy and survived for at least 1 year following a diagnosis with a first primary malignancy from 2000 through 2012. They calculated SIRs based on variables that included age, race, sex, malignancy type and treatment period.

They looked at four categories of myeloid neoplasms as defined by World Health Organization criteria: AML/MDS, chronic myeloid leukemia, myeloproliferative neoplasms (MPN) negative for BCR-ABL (Philadelphia-negative), and chronic myelomonocytic leukemia (CMML).

They found that 2,071 patients developed treatment-related AML/MDS, translating into a fourfold incidence compared with the general population (SIR 4.1, 95% confidence interval [CI] 3.9-4.2), 106 were diagnosed with CMML

They also identified novel risk for tAML/MDS after chemotherapy by malignancy (see table).

RTEmagicC_6cd30bb_115029_graphic.png.png

The investigators found that breast cancer, non-Hodgkin lymphoma, and lung cancer were most commonly associated with tAML/MDS (SIRs 4.1, 7.3, and 4.1, respectively, all significant).

In addition, although the overall numbers of cases were small, the investigators noted “strikingly elevated” risks for cancers of bone (SIR 35.1, CI. 16.9-64.6). testes (15.6, CI, 9.2-24.6), and soft tissue (12.6, CI=7.7-19.4),

Risk for tAML/MD was more modestly elevated for cancers of the brain, ovaries, endometrium, cervix, and prostate, and for Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

Adding radiotherapy to chemotherapy for cancers of the breast, lung, and stomach cancers showed a trend toward heightened tAML/MDS risk, but this was not significant.

An elevated risk for CMML was also seen after chemotherapy for lung cancer (SIR 2.5, CI, 1.3-4.4), breast cancer (1.8, CI, 1.3-2.5), and non-Hodgkin lymphoma (2.1, CI, 1.2-3.4). There was elevated risk for CMML following chemotherapy for breast cancer (3.0, CI. 1.7-5.0) and non-Hodgkin lymphoma (4.2, CI, 2.4-6.9).

There were no increased risks for other myeloproliferative neoplasms after chemotherapy for any first primary cancer, however.

“This reminds us that with new uses of standard agents and introduction of new agents, it’s critical to carefully weigh the risks and benefits of systemic therapy,” Dr. Morton said.

The investigators plan to quantify risks associated with specific drugs and doses, she added.

The study was supported by the National Cancer Institute. Dr. Morton reported no relevant conflicts of interest to disclose.

ORLANDO – Patients who undergo cytotoxic chemotherapy, even in the modern era, are at increased risk for developing myeloid neoplasms, based on data from a cohort of nearly 750,000 adults who were initially treated with chemotherapy and survived at least 1 year after diagnosis.

In the cohort, the standardized incidence ratio (SIR) for treatment-related acute myeloid leukemia (tAML) or myelodysplastic syndrome (MDS) was four times greater than would be expected in the general population, reported Lindsay M. Morton, Ph.D., of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

RTEmagicC_6cd30bb_Morton_Lindsay_S_MD.jpg.jpg

“We now demonstrate that there are elevated risks for treatment-related leukemia after treatment for a broad spectrum of first primary malignancies that are generally consistent with what we know about changing treatment practices,” she said at the American Society of Hematology annual meeting.

“The number of cancer survivors in the United States has increased dramatically, to reach nearly 14 million individuals today, and in just the next few years the number is expected to reach more than 18 million people, which means that the long-term health of this population is of great clinical importance as well as public health importance,” Dr. Morton emphasized.

The link between cytotoxic chemotherapy and leukemia risk has been known since the 1960s, with certain classes of agents carrying higher risks than others, including platinum-containing compounds, alkylating agents (for example, cyclophosphamide, melphalan, chlorambucil), topoisomerase II inhibitors (doxorubicin, daunorubicin, epirubicin, etc.), and antimetabolites (5-fluorauracil, capecitabine, gemcitabine, et al.).

Treatment-related leukemias are associated with higher doses of these agents, and the trend in contemporary medicine is to use more of these agents upfront for the treatment of primary malignancies. Yet estimates of the risk of tAML, MDS, or other malignancies have been hard to come by because of the relative rarity of cases and the sporadic reports in the literature, Dr. Morton said.

The investigators previously reported that risk for tAML and other myeloid neoplasms changed over time, and showed that since the 1990s there was an uptick in risk for patients treated with chemotherapy for cancers of bone, joints, and endometrium, and since 2000 for patients treated with chemotherapy for cancers of the esophagus, cervix and prostate.

For example, risks for tAML were higher in the 1970s for patients with ovarian cancer treated with melphalan, a highly leukemogenic agent, but dropped somewhat with the switch to platinum-based agents. Similarly, women with breast cancer had a comparatively high risk with the use of melphalan, a decline in risk with the introduction of cyclophosphamide, and then an increase with the addition of anthracyclines and dose-dense regimens.

Risk update

To get a better idea of the magnitude of risk in the modern era, Dr. Morton and colleagues sifted through Surveillance, Epidemiology, and End Results (SEER) data to identify a cohort of 746,007 adults who were initially treated with chemotherapy and survived for at least 1 year following a diagnosis with a first primary malignancy from 2000 through 2012. They calculated SIRs based on variables that included age, race, sex, malignancy type and treatment period.

They looked at four categories of myeloid neoplasms as defined by World Health Organization criteria: AML/MDS, chronic myeloid leukemia, myeloproliferative neoplasms (MPN) negative for BCR-ABL (Philadelphia-negative), and chronic myelomonocytic leukemia (CMML).

They found that 2,071 patients developed treatment-related AML/MDS, translating into a fourfold incidence compared with the general population (SIR 4.1, 95% confidence interval [CI] 3.9-4.2), 106 were diagnosed with CMML

They also identified novel risk for tAML/MDS after chemotherapy by malignancy (see table).

RTEmagicC_6cd30bb_115029_graphic.png.png

The investigators found that breast cancer, non-Hodgkin lymphoma, and lung cancer were most commonly associated with tAML/MDS (SIRs 4.1, 7.3, and 4.1, respectively, all significant).

In addition, although the overall numbers of cases were small, the investigators noted “strikingly elevated” risks for cancers of bone (SIR 35.1, CI. 16.9-64.6). testes (15.6, CI, 9.2-24.6), and soft tissue (12.6, CI=7.7-19.4),

Risk for tAML/MD was more modestly elevated for cancers of the brain, ovaries, endometrium, cervix, and prostate, and for Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

Adding radiotherapy to chemotherapy for cancers of the breast, lung, and stomach cancers showed a trend toward heightened tAML/MDS risk, but this was not significant.

An elevated risk for CMML was also seen after chemotherapy for lung cancer (SIR 2.5, CI, 1.3-4.4), breast cancer (1.8, CI, 1.3-2.5), and non-Hodgkin lymphoma (2.1, CI, 1.2-3.4). There was elevated risk for CMML following chemotherapy for breast cancer (3.0, CI. 1.7-5.0) and non-Hodgkin lymphoma (4.2, CI, 2.4-6.9).

There were no increased risks for other myeloproliferative neoplasms after chemotherapy for any first primary cancer, however.

“This reminds us that with new uses of standard agents and introduction of new agents, it’s critical to carefully weigh the risks and benefits of systemic therapy,” Dr. Morton said.

The investigators plan to quantify risks associated with specific drugs and doses, she added.

The study was supported by the National Cancer Institute. Dr. Morton reported no relevant conflicts of interest to disclose.

ORLANDO – Patients who undergo cytotoxic chemotherapy, even in the modern era, are at increased risk for developing myeloid neoplasms, based on data from a cohort of nearly 750,000 adults who were initially treated with chemotherapy and survived at least 1 year after diagnosis.

In the cohort, the standardized incidence ratio (SIR) for treatment-related acute myeloid leukemia (tAML) or myelodysplastic syndrome (MDS) was four times greater than would be expected in the general population, reported Lindsay M. Morton, Ph.D., of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

RTEmagicC_6cd30bb_Morton_Lindsay_S_MD.jpg.jpg

“We now demonstrate that there are elevated risks for treatment-related leukemia after treatment for a broad spectrum of first primary malignancies that are generally consistent with what we know about changing treatment practices,” she said at the American Society of Hematology annual meeting.

“The number of cancer survivors in the United States has increased dramatically, to reach nearly 14 million individuals today, and in just the next few years the number is expected to reach more than 18 million people, which means that the long-term health of this population is of great clinical importance as well as public health importance,” Dr. Morton emphasized.

The link between cytotoxic chemotherapy and leukemia risk has been known since the 1960s, with certain classes of agents carrying higher risks than others, including platinum-containing compounds, alkylating agents (for example, cyclophosphamide, melphalan, chlorambucil), topoisomerase II inhibitors (doxorubicin, daunorubicin, epirubicin, etc.), and antimetabolites (5-fluorauracil, capecitabine, gemcitabine, et al.).

Treatment-related leukemias are associated with higher doses of these agents, and the trend in contemporary medicine is to use more of these agents upfront for the treatment of primary malignancies. Yet estimates of the risk of tAML, MDS, or other malignancies have been hard to come by because of the relative rarity of cases and the sporadic reports in the literature, Dr. Morton said.

The investigators previously reported that risk for tAML and other myeloid neoplasms changed over time, and showed that since the 1990s there was an uptick in risk for patients treated with chemotherapy for cancers of bone, joints, and endometrium, and since 2000 for patients treated with chemotherapy for cancers of the esophagus, cervix and prostate.

For example, risks for tAML were higher in the 1970s for patients with ovarian cancer treated with melphalan, a highly leukemogenic agent, but dropped somewhat with the switch to platinum-based agents. Similarly, women with breast cancer had a comparatively high risk with the use of melphalan, a decline in risk with the introduction of cyclophosphamide, and then an increase with the addition of anthracyclines and dose-dense regimens.

Risk update

To get a better idea of the magnitude of risk in the modern era, Dr. Morton and colleagues sifted through Surveillance, Epidemiology, and End Results (SEER) data to identify a cohort of 746,007 adults who were initially treated with chemotherapy and survived for at least 1 year following a diagnosis with a first primary malignancy from 2000 through 2012. They calculated SIRs based on variables that included age, race, sex, malignancy type and treatment period.

They looked at four categories of myeloid neoplasms as defined by World Health Organization criteria: AML/MDS, chronic myeloid leukemia, myeloproliferative neoplasms (MPN) negative for BCR-ABL (Philadelphia-negative), and chronic myelomonocytic leukemia (CMML).

They found that 2,071 patients developed treatment-related AML/MDS, translating into a fourfold incidence compared with the general population (SIR 4.1, 95% confidence interval [CI] 3.9-4.2), 106 were diagnosed with CMML

They also identified novel risk for tAML/MDS after chemotherapy by malignancy (see table).

RTEmagicC_6cd30bb_115029_graphic.png.png

The investigators found that breast cancer, non-Hodgkin lymphoma, and lung cancer were most commonly associated with tAML/MDS (SIRs 4.1, 7.3, and 4.1, respectively, all significant).

In addition, although the overall numbers of cases were small, the investigators noted “strikingly elevated” risks for cancers of bone (SIR 35.1, CI. 16.9-64.6). testes (15.6, CI, 9.2-24.6), and soft tissue (12.6, CI=7.7-19.4),

Risk for tAML/MD was more modestly elevated for cancers of the brain, ovaries, endometrium, cervix, and prostate, and for Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

Adding radiotherapy to chemotherapy for cancers of the breast, lung, and stomach cancers showed a trend toward heightened tAML/MDS risk, but this was not significant.

An elevated risk for CMML was also seen after chemotherapy for lung cancer (SIR 2.5, CI, 1.3-4.4), breast cancer (1.8, CI, 1.3-2.5), and non-Hodgkin lymphoma (2.1, CI, 1.2-3.4). There was elevated risk for CMML following chemotherapy for breast cancer (3.0, CI. 1.7-5.0) and non-Hodgkin lymphoma (4.2, CI, 2.4-6.9).

There were no increased risks for other myeloproliferative neoplasms after chemotherapy for any first primary cancer, however.

“This reminds us that with new uses of standard agents and introduction of new agents, it’s critical to carefully weigh the risks and benefits of systemic therapy,” Dr. Morton said.

The investigators plan to quantify risks associated with specific drugs and doses, she added.

The study was supported by the National Cancer Institute. Dr. Morton reported no relevant conflicts of interest to disclose.

ORLANDO – An experimental combination of obinutuzumab and venetoclax appears safe as frontline therapy for patients with active, untreated chronic lymphocytic leukemia and comorbidities.

In the safety run-in portion of a phase 3, open-label trial comparing the combination of obinutuzumab (Gazyva) and the investigational Bcl-2 inhibitor venetoclax with obinutuzumab and its usual partner chlorambucil in 12 patients, only two of seven patients classified as being at high risk for the tumor lysis syndrome (TLS) developed laboratory-defined TLS, and no patients had clinical TLS.

The combination did not meet any of the pre-specified stopping criteria, and early data hinted at efficacy for the combination, said Dr. Kirsten Fischer, from the Center for Integrated Oncology at University Hospital Cologne in Germany.

RTEmagicC_12a53ac_Fischer_Kirsten_GERMANY.jpg.jpg

“As with previous reports, our data confirm rapid and profound reduction in lymphocyte counts after the first dose obinutuzumab in all 12 [evaluable] patients,” she said at the American Society of Hematology annual meeting.

In the CLL 11 trial, investigators in the German CLL group previously showed that the combination of the anti-CD20 antibody obinutuzumab and chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. The combination is approved in the United States for adults with treatment-naïve CLL.

Venetoclax has been shown to have good efficacy against relapsed/refractory CLL both as monotherapy and in combination with rituximab, prompting the investigators to explore it in combination with the rituximab follow-on drug obinutuzumab.

In the safety run-in phase of the CLL 14 trial, the investigators enrolled 13 adults (median age 75, range 59-88 years) with newly diagnosed, active confirmed CLL and coexisting medical conditions as determined either by a score greater 6 on the cumulative illness rating scale (CIRS) or by estimated creatinine clearance less than 70 mL/min.

The patients were treated with 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously 100 mg on day 1 and 900 mg on day 2, with the option to deliver 1,000 mg on day 1 instead, then 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 for cycles 2-6.

The dose of venetoclax was titrated upward gradually, with doses of 20 mg, 50 mg, 100 mg, 200 mg, and up to 400 mg administered starting on day 22 of cycle 1.

Planned stopping criteria were one treatment-related death or a grade 4 adverse event related to clinical TLS despite prophylaxis as specified by the protocol.

At the time of data cutoff (October 2015), 12 patients had been on treatment for at least 4 weeks and had reached the maximum venetoclax dose. Two patients had reached 11 cycles, three had reached 10 cycles, and seven had reached 8 cycles.

Grade 1 or 2 adverse events in all 13 enrolled patients included infusion-related reactions in 8; infections in 6; diarrhea, hyperkalemia, and constipation in 5; nausea, dizziness and cough in 4; and fatigue, headache and pruritus in 3.

Grade 3 or 4 adverse events were neutropenia in five patients; infusion related reactions; syncope, thrombocytopenia and laboratory-defined TLS in two patients; and bradycardia, hyperglycemia, influenza, leucopenia, pyrexia, respiratory tract infection, and elevated transaminases in one patient each.

As noted, all 12 evaluable patients had rapid drops in absolute lymphocyte counts, and all but one had complete resolution of lymphadenopathy after three cycles, with the improvement maintained after six cycles. The remaining patient had a decrease to near normal after both three and six cycles.

Of the 12 patients, 11 had a partial response after three cycles, and the remaining patient had stable disease, for an overall response rate of 92%. The overall response rate after six cycles was 100%, with all patients having a partial response.

The data were sufficiently good to justify continuing with the randomized phase, which began in August 2015, Dr. Fischer noted.

The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.

ORLANDO – An experimental combination of obinutuzumab and venetoclax appears safe as frontline therapy for patients with active, untreated chronic lymphocytic leukemia and comorbidities.

In the safety run-in portion of a phase 3, open-label trial comparing the combination of obinutuzumab (Gazyva) and the investigational Bcl-2 inhibitor venetoclax with obinutuzumab and its usual partner chlorambucil in 12 patients, only two of seven patients classified as being at high risk for the tumor lysis syndrome (TLS) developed laboratory-defined TLS, and no patients had clinical TLS.

The combination did not meet any of the pre-specified stopping criteria, and early data hinted at efficacy for the combination, said Dr. Kirsten Fischer, from the Center for Integrated Oncology at University Hospital Cologne in Germany.

RTEmagicC_12a53ac_Fischer_Kirsten_GERMANY.jpg.jpg

“As with previous reports, our data confirm rapid and profound reduction in lymphocyte counts after the first dose obinutuzumab in all 12 [evaluable] patients,” she said at the American Society of Hematology annual meeting.

In the CLL 11 trial, investigators in the German CLL group previously showed that the combination of the anti-CD20 antibody obinutuzumab and chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. The combination is approved in the United States for adults with treatment-naïve CLL.

Venetoclax has been shown to have good efficacy against relapsed/refractory CLL both as monotherapy and in combination with rituximab, prompting the investigators to explore it in combination with the rituximab follow-on drug obinutuzumab.

In the safety run-in phase of the CLL 14 trial, the investigators enrolled 13 adults (median age 75, range 59-88 years) with newly diagnosed, active confirmed CLL and coexisting medical conditions as determined either by a score greater 6 on the cumulative illness rating scale (CIRS) or by estimated creatinine clearance less than 70 mL/min.

The patients were treated with 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously 100 mg on day 1 and 900 mg on day 2, with the option to deliver 1,000 mg on day 1 instead, then 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 for cycles 2-6.

The dose of venetoclax was titrated upward gradually, with doses of 20 mg, 50 mg, 100 mg, 200 mg, and up to 400 mg administered starting on day 22 of cycle 1.

Planned stopping criteria were one treatment-related death or a grade 4 adverse event related to clinical TLS despite prophylaxis as specified by the protocol.

At the time of data cutoff (October 2015), 12 patients had been on treatment for at least 4 weeks and had reached the maximum venetoclax dose. Two patients had reached 11 cycles, three had reached 10 cycles, and seven had reached 8 cycles.

Grade 1 or 2 adverse events in all 13 enrolled patients included infusion-related reactions in 8; infections in 6; diarrhea, hyperkalemia, and constipation in 5; nausea, dizziness and cough in 4; and fatigue, headache and pruritus in 3.

Grade 3 or 4 adverse events were neutropenia in five patients; infusion related reactions; syncope, thrombocytopenia and laboratory-defined TLS in two patients; and bradycardia, hyperglycemia, influenza, leucopenia, pyrexia, respiratory tract infection, and elevated transaminases in one patient each.

As noted, all 12 evaluable patients had rapid drops in absolute lymphocyte counts, and all but one had complete resolution of lymphadenopathy after three cycles, with the improvement maintained after six cycles. The remaining patient had a decrease to near normal after both three and six cycles.

Of the 12 patients, 11 had a partial response after three cycles, and the remaining patient had stable disease, for an overall response rate of 92%. The overall response rate after six cycles was 100%, with all patients having a partial response.

The data were sufficiently good to justify continuing with the randomized phase, which began in August 2015, Dr. Fischer noted.

The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.

ORLANDO – An experimental combination of obinutuzumab and venetoclax appears safe as frontline therapy for patients with active, untreated chronic lymphocytic leukemia and comorbidities.

In the safety run-in portion of a phase 3, open-label trial comparing the combination of obinutuzumab (Gazyva) and the investigational Bcl-2 inhibitor venetoclax with obinutuzumab and its usual partner chlorambucil in 12 patients, only two of seven patients classified as being at high risk for the tumor lysis syndrome (TLS) developed laboratory-defined TLS, and no patients had clinical TLS.

The combination did not meet any of the pre-specified stopping criteria, and early data hinted at efficacy for the combination, said Dr. Kirsten Fischer, from the Center for Integrated Oncology at University Hospital Cologne in Germany.

RTEmagicC_12a53ac_Fischer_Kirsten_GERMANY.jpg.jpg

“As with previous reports, our data confirm rapid and profound reduction in lymphocyte counts after the first dose obinutuzumab in all 12 [evaluable] patients,” she said at the American Society of Hematology annual meeting.

In the CLL 11 trial, investigators in the German CLL group previously showed that the combination of the anti-CD20 antibody obinutuzumab and chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. The combination is approved in the United States for adults with treatment-naïve CLL.

Venetoclax has been shown to have good efficacy against relapsed/refractory CLL both as monotherapy and in combination with rituximab, prompting the investigators to explore it in combination with the rituximab follow-on drug obinutuzumab.

In the safety run-in phase of the CLL 14 trial, the investigators enrolled 13 adults (median age 75, range 59-88 years) with newly diagnosed, active confirmed CLL and coexisting medical conditions as determined either by a score greater 6 on the cumulative illness rating scale (CIRS) or by estimated creatinine clearance less than 70 mL/min.

The patients were treated with 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously 100 mg on day 1 and 900 mg on day 2, with the option to deliver 1,000 mg on day 1 instead, then 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 for cycles 2-6.

The dose of venetoclax was titrated upward gradually, with doses of 20 mg, 50 mg, 100 mg, 200 mg, and up to 400 mg administered starting on day 22 of cycle 1.

Planned stopping criteria were one treatment-related death or a grade 4 adverse event related to clinical TLS despite prophylaxis as specified by the protocol.

At the time of data cutoff (October 2015), 12 patients had been on treatment for at least 4 weeks and had reached the maximum venetoclax dose. Two patients had reached 11 cycles, three had reached 10 cycles, and seven had reached 8 cycles.

Grade 1 or 2 adverse events in all 13 enrolled patients included infusion-related reactions in 8; infections in 6; diarrhea, hyperkalemia, and constipation in 5; nausea, dizziness and cough in 4; and fatigue, headache and pruritus in 3.

Grade 3 or 4 adverse events were neutropenia in five patients; infusion related reactions; syncope, thrombocytopenia and laboratory-defined TLS in two patients; and bradycardia, hyperglycemia, influenza, leucopenia, pyrexia, respiratory tract infection, and elevated transaminases in one patient each.

As noted, all 12 evaluable patients had rapid drops in absolute lymphocyte counts, and all but one had complete resolution of lymphadenopathy after three cycles, with the improvement maintained after six cycles. The remaining patient had a decrease to near normal after both three and six cycles.

Of the 12 patients, 11 had a partial response after three cycles, and the remaining patient had stable disease, for an overall response rate of 92%. The overall response rate after six cycles was 100%, with all patients having a partial response.

The data were sufficiently good to justify continuing with the randomized phase, which began in August 2015, Dr. Fischer noted.

The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.

ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_cd7690c_Zelenetz_Andrew_NYC.jpg.jpg

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_cd7690c_Zelenetz_Andrew_NYC.jpg.jpg

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_cd7690c_Zelenetz_Andrew_NYC.jpg.jpg

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

RTEmagicC_e6e846b_Lampson_Benjamin_BOSTON.jpg.jpg

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

RTEmagicC_e6e846b_Lampson_Benjamin_BOSTON.jpg.jpg

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

RTEmagicC_e6e846b_Lampson_Benjamin_BOSTON.jpg.jpg

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr. Lampson said.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“In general, our experience has been if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.