Aggressive Lymphomas

Photo by Bill Branson

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.

The new guidelines were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.

TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.

However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.

Photo by Bill Branson

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.

The new guidelines were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.

TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.

However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.

Photo by Bill Branson

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.

The new guidelines were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.

TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.

However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.

Photo courtesy of the CDC

Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.

The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.

“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”

Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

Photo courtesy of the CDC

Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.

The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.

“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”

Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

Photo courtesy of the CDC

Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.

The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.

“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”

Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

Patients undergoing autologous hematopoietic cell transplantation for lymphoma or plasma cell myeloma have 10-100 times the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) seen in the general population, according to a retrospective cohort study.

The elevated risk also exceeds that of similar patients largely untreated with autotransplant.

Exposure to DNA-damaging drugs and ionizing radiation – both used in autotransplant – is known to increase risk of these treatment-related myeloid neoplasms, according to Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation and his colleagues. Concern about this complication has been growing as long-term survivorship after transplant improves.

The investigators analyzed data reported to the Center for International Blood and Marrow Transplant Research. Analyses were based on 9,028 patients undergoing autotransplant during 1995-2010 for Hodgkin lymphoma (916 patients), non-Hodgkin lymphoma (3,546 patients), or plasma cell myeloma (4,566 patients). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant. More aggressive transplantation protocols increased the likelihood of this outcome: Risk was higher for patients with Hodgkin lymphoma who received conditioning with total body radiation versus chemotherapy alone (hazard ratio, 4.0); patients with non-Hodgkin lymphoma who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen; patients with non-Hodgkin lymphoma or plasma cell myeloma who received three or more lines of chemotherapy versus just one line (HR, 1.9 and 1.8, respectively); and patients with non-Hodgkin lymphoma who underwent transplantation in 2005-2010 versus 1995-1999 (HR, 2.1).

Patients reported to Surveillance, Epidemiology and End Results (SEER) database with the same lymphoma and plasma cell myeloma diagnoses, few of whom underwent autotransplant, had risks of AML and MDS that were 5-10 times higher than the background level in the population. But the study autotransplant cohort had a risk of AML that was 10-50 times higher, and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for the autotransplant, but this hypothesis can only be tested in a prospective study,” Dr. Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown. “One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased posttransplant surveillance resulted in a deficiency of AML,” they wrote. “A second is based on steeper MDS versus AML incidences versus age … and the possibility that transplantation recipient marrow ages (i.e., marrow biological ages) are perhaps decades older than calendar ages.”

The Center for International Blood and Marrow Transplant Research is supported by several U.S. government agencies and numerous pharmaceutical companies. The authors reported that they had no relevant conflicts of interest.

SOURCE: Radivoyevitch T et al. Leuk Res. 2018 Jul 19. pii: S0145-2126(18)30160-7.

Patients undergoing autologous hematopoietic cell transplantation for lymphoma or plasma cell myeloma have 10-100 times the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) seen in the general population, according to a retrospective cohort study.

The elevated risk also exceeds that of similar patients largely untreated with autotransplant.

Exposure to DNA-damaging drugs and ionizing radiation – both used in autotransplant – is known to increase risk of these treatment-related myeloid neoplasms, according to Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation and his colleagues. Concern about this complication has been growing as long-term survivorship after transplant improves.

The investigators analyzed data reported to the Center for International Blood and Marrow Transplant Research. Analyses were based on 9,028 patients undergoing autotransplant during 1995-2010 for Hodgkin lymphoma (916 patients), non-Hodgkin lymphoma (3,546 patients), or plasma cell myeloma (4,566 patients). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant. More aggressive transplantation protocols increased the likelihood of this outcome: Risk was higher for patients with Hodgkin lymphoma who received conditioning with total body radiation versus chemotherapy alone (hazard ratio, 4.0); patients with non-Hodgkin lymphoma who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen; patients with non-Hodgkin lymphoma or plasma cell myeloma who received three or more lines of chemotherapy versus just one line (HR, 1.9 and 1.8, respectively); and patients with non-Hodgkin lymphoma who underwent transplantation in 2005-2010 versus 1995-1999 (HR, 2.1).

Patients reported to Surveillance, Epidemiology and End Results (SEER) database with the same lymphoma and plasma cell myeloma diagnoses, few of whom underwent autotransplant, had risks of AML and MDS that were 5-10 times higher than the background level in the population. But the study autotransplant cohort had a risk of AML that was 10-50 times higher, and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for the autotransplant, but this hypothesis can only be tested in a prospective study,” Dr. Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown. “One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased posttransplant surveillance resulted in a deficiency of AML,” they wrote. “A second is based on steeper MDS versus AML incidences versus age … and the possibility that transplantation recipient marrow ages (i.e., marrow biological ages) are perhaps decades older than calendar ages.”

The Center for International Blood and Marrow Transplant Research is supported by several U.S. government agencies and numerous pharmaceutical companies. The authors reported that they had no relevant conflicts of interest.

SOURCE: Radivoyevitch T et al. Leuk Res. 2018 Jul 19. pii: S0145-2126(18)30160-7.

Patients undergoing autologous hematopoietic cell transplantation for lymphoma or plasma cell myeloma have 10-100 times the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) seen in the general population, according to a retrospective cohort study.

The elevated risk also exceeds that of similar patients largely untreated with autotransplant.

Exposure to DNA-damaging drugs and ionizing radiation – both used in autotransplant – is known to increase risk of these treatment-related myeloid neoplasms, according to Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation and his colleagues. Concern about this complication has been growing as long-term survivorship after transplant improves.

The investigators analyzed data reported to the Center for International Blood and Marrow Transplant Research. Analyses were based on 9,028 patients undergoing autotransplant during 1995-2010 for Hodgkin lymphoma (916 patients), non-Hodgkin lymphoma (3,546 patients), or plasma cell myeloma (4,566 patients). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant. More aggressive transplantation protocols increased the likelihood of this outcome: Risk was higher for patients with Hodgkin lymphoma who received conditioning with total body radiation versus chemotherapy alone (hazard ratio, 4.0); patients with non-Hodgkin lymphoma who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen; patients with non-Hodgkin lymphoma or plasma cell myeloma who received three or more lines of chemotherapy versus just one line (HR, 1.9 and 1.8, respectively); and patients with non-Hodgkin lymphoma who underwent transplantation in 2005-2010 versus 1995-1999 (HR, 2.1).

Patients reported to Surveillance, Epidemiology and End Results (SEER) database with the same lymphoma and plasma cell myeloma diagnoses, few of whom underwent autotransplant, had risks of AML and MDS that were 5-10 times higher than the background level in the population. But the study autotransplant cohort had a risk of AML that was 10-50 times higher, and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for the autotransplant, but this hypothesis can only be tested in a prospective study,” Dr. Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown. “One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased posttransplant surveillance resulted in a deficiency of AML,” they wrote. “A second is based on steeper MDS versus AML incidences versus age … and the possibility that transplantation recipient marrow ages (i.e., marrow biological ages) are perhaps decades older than calendar ages.”

The Center for International Blood and Marrow Transplant Research is supported by several U.S. government agencies and numerous pharmaceutical companies. The authors reported that they had no relevant conflicts of interest.

SOURCE: Radivoyevitch T et al. Leuk Res. 2018 Jul 19. pii: S0145-2126(18)30160-7.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

The Food and Drug Administration has approved mogamulizumab-kpkc (Poteligeo) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the United States.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations, as well as priority review.

The approval is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February 2018.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least one systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily. Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity. Baseline characteristics were similar between the treatment arms. The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio, 0.53; P less than .0001).

The global overall response rate was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P less than .0001). For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat; for patients with SS, the ORR was 37% and 2%, respectively. After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat; for SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), which occurred in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), included the following:

• Infusion-related reactions (33.2% vs. 0.5%).
• Drug eruptions (23.9% vs. 0.5%).
• Diarrhea (23.4% vs. 61.8%).
• Nausea (15.2% vs. 42.5%).
• Thrombocytopenia (11.4% vs. 30.6%).
• Dysgeusia (3.3% vs. 28.0%).
• Increased blood creatinine (3.3% vs. 28.0%).
• Decreased appetite (7.6% vs. 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n = 8), infusion-related reactions (n = 3), fatigue (n = 3), decreased appetite (n = 2), nausea (n = 1), pyrexia (n = 1), and diarrhea (n = 1).

The drug is marketed by Kyowa Kirin.

The Food and Drug Administration has approved mogamulizumab-kpkc (Poteligeo) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the United States.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations, as well as priority review.

The approval is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February 2018.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least one systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily. Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity. Baseline characteristics were similar between the treatment arms. The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio, 0.53; P less than .0001).

The global overall response rate was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P less than .0001). For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat; for patients with SS, the ORR was 37% and 2%, respectively. After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat; for SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), which occurred in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), included the following:

• Infusion-related reactions (33.2% vs. 0.5%).
• Drug eruptions (23.9% vs. 0.5%).
• Diarrhea (23.4% vs. 61.8%).
• Nausea (15.2% vs. 42.5%).
• Thrombocytopenia (11.4% vs. 30.6%).
• Dysgeusia (3.3% vs. 28.0%).
• Increased blood creatinine (3.3% vs. 28.0%).
• Decreased appetite (7.6% vs. 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n = 8), infusion-related reactions (n = 3), fatigue (n = 3), decreased appetite (n = 2), nausea (n = 1), pyrexia (n = 1), and diarrhea (n = 1).

The drug is marketed by Kyowa Kirin.

The Food and Drug Administration has approved mogamulizumab-kpkc (Poteligeo) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the United States.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations, as well as priority review.

The approval is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February 2018.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least one systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily. Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity. Baseline characteristics were similar between the treatment arms. The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio, 0.53; P less than .0001).

The global overall response rate was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P less than .0001). For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat; for patients with SS, the ORR was 37% and 2%, respectively. After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat; for SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), which occurred in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), included the following:

• Infusion-related reactions (33.2% vs. 0.5%).
• Drug eruptions (23.9% vs. 0.5%).
• Diarrhea (23.4% vs. 61.8%).
• Nausea (15.2% vs. 42.5%).
• Thrombocytopenia (11.4% vs. 30.6%).
• Dysgeusia (3.3% vs. 28.0%).
• Increased blood creatinine (3.3% vs. 28.0%).
• Decreased appetite (7.6% vs. 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n = 8), infusion-related reactions (n = 3), fatigue (n = 3), decreased appetite (n = 2), nausea (n = 1), pyrexia (n = 1), and diarrhea (n = 1).

The drug is marketed by Kyowa Kirin.

Patients with myeloproliferative neoplasms treated with Janus-kinase (JAK) 1/2 inhibitors may be at significantly increased risk of aggressive B cell non-Hodgkin lymphomas, according to a study published in Blood.

A retrospective cohort study of 626 Viennese patients with myeloproliferative neoplasms – 69 of whom were treated with JAK1/2 inhibitors – found that 4 of the 69 patients (5.8%) developed aggressive B-cell lymphoma, compared with just 2 patients (0.36%) in the rest of the group. This represented a significant, 16-fold higher risk of aggressive B cell lymphoma associated with JAK1/2 inhibitor therapy (P = .0017).

The lymphoma was diagnosed within 13-35 months of starting JAK1/2 inhibitors. In three patients, the disease was in the bone marrow and peripheral blood, one patient had it in mammary tissue, and another had it in mucosal tissue. All four lymphomas showed positive MYC and p53 staining.

All four patients had been treated with ruxolitinib, one was also treated with fedratinib, and three of the four had been pretreated with alkylating agents.

Meanwhile, a second retrospective cohort study in Paris of 929 patients with myeloproliferative neoplasms, reported in the same paper, found that 3.51% of those treated with ruxolitinib developed lymphoma, compared with 0.23% of conventionally-treated patients.

Using archived bone marrow samples from 54 of the 69 patients treated with JAK1/2 inhibitors, researchers discovered that 15.9% of them – including three of the B-cell lymphoma patients (the fourth was not tested) – had a preexisting B cell clone. This was present as early as 47-70 months before the lymphoma diagnosis.

“In patients, the clonal B-cell population was present as long as 6 years before overt lymphoma and preceded JAK1/2 inhibition which offers the opportunity to determine patients at risk,” wrote Edit Porpaczy, MD, of the Comprehensive Cancer Center at the Medical University of Vienna, and her coauthors. “Targeted inhibition of JAK-STAT signaling appears to be required to trigger the appearance of the B-cell clone as other treatments eliminating the myeloid cell load in men do not exert a comparable effect.”

In the Viennese cohort, three of the lymphomas were aggressive CD19⁺ B-cell type, and the fourth was a nonspecified high-grade B-cell lymphoma.

Researchers also looked at the effects of JAK1/2 inhibition in STAT1^-/- mice, and found that two-thirds developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B-cells.

“Upon STAT1-deficiency myeloid hyperplasia is paralleled by the occurrence of a malignant B-cell clone, which evolves into disease upon bone-marrow transplantation and gives rise to a leukemic lymphoma phenotype,” the authors wrote.

The study was supported by the Austrian Science Fund, the Anniversary Fund of the Austrian National Bank and the WWTF Precision Medicine Program. Several authors reported support, funding or advisory board positions with the pharmaceutical industry.

SOURCE: Porpaczy E et al. Blood. 2018 Jun 14. doi: 10.1182/blood-2017-10-810739.

Patients with myeloproliferative neoplasms treated with Janus-kinase (JAK) 1/2 inhibitors may be at significantly increased risk of aggressive B cell non-Hodgkin lymphomas, according to a study published in Blood.

A retrospective cohort study of 626 Viennese patients with myeloproliferative neoplasms – 69 of whom were treated with JAK1/2 inhibitors – found that 4 of the 69 patients (5.8%) developed aggressive B-cell lymphoma, compared with just 2 patients (0.36%) in the rest of the group. This represented a significant, 16-fold higher risk of aggressive B cell lymphoma associated with JAK1/2 inhibitor therapy (P = .0017).

The lymphoma was diagnosed within 13-35 months of starting JAK1/2 inhibitors. In three patients, the disease was in the bone marrow and peripheral blood, one patient had it in mammary tissue, and another had it in mucosal tissue. All four lymphomas showed positive MYC and p53 staining.

All four patients had been treated with ruxolitinib, one was also treated with fedratinib, and three of the four had been pretreated with alkylating agents.

Meanwhile, a second retrospective cohort study in Paris of 929 patients with myeloproliferative neoplasms, reported in the same paper, found that 3.51% of those treated with ruxolitinib developed lymphoma, compared with 0.23% of conventionally-treated patients.

Using archived bone marrow samples from 54 of the 69 patients treated with JAK1/2 inhibitors, researchers discovered that 15.9% of them – including three of the B-cell lymphoma patients (the fourth was not tested) – had a preexisting B cell clone. This was present as early as 47-70 months before the lymphoma diagnosis.

“In patients, the clonal B-cell population was present as long as 6 years before overt lymphoma and preceded JAK1/2 inhibition which offers the opportunity to determine patients at risk,” wrote Edit Porpaczy, MD, of the Comprehensive Cancer Center at the Medical University of Vienna, and her coauthors. “Targeted inhibition of JAK-STAT signaling appears to be required to trigger the appearance of the B-cell clone as other treatments eliminating the myeloid cell load in men do not exert a comparable effect.”

In the Viennese cohort, three of the lymphomas were aggressive CD19⁺ B-cell type, and the fourth was a nonspecified high-grade B-cell lymphoma.

Researchers also looked at the effects of JAK1/2 inhibition in STAT1^-/- mice, and found that two-thirds developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B-cells.

“Upon STAT1-deficiency myeloid hyperplasia is paralleled by the occurrence of a malignant B-cell clone, which evolves into disease upon bone-marrow transplantation and gives rise to a leukemic lymphoma phenotype,” the authors wrote.

The study was supported by the Austrian Science Fund, the Anniversary Fund of the Austrian National Bank and the WWTF Precision Medicine Program. Several authors reported support, funding or advisory board positions with the pharmaceutical industry.

SOURCE: Porpaczy E et al. Blood. 2018 Jun 14. doi: 10.1182/blood-2017-10-810739.

Patients with myeloproliferative neoplasms treated with Janus-kinase (JAK) 1/2 inhibitors may be at significantly increased risk of aggressive B cell non-Hodgkin lymphomas, according to a study published in Blood.

A retrospective cohort study of 626 Viennese patients with myeloproliferative neoplasms – 69 of whom were treated with JAK1/2 inhibitors – found that 4 of the 69 patients (5.8%) developed aggressive B-cell lymphoma, compared with just 2 patients (0.36%) in the rest of the group. This represented a significant, 16-fold higher risk of aggressive B cell lymphoma associated with JAK1/2 inhibitor therapy (P = .0017).

The lymphoma was diagnosed within 13-35 months of starting JAK1/2 inhibitors. In three patients, the disease was in the bone marrow and peripheral blood, one patient had it in mammary tissue, and another had it in mucosal tissue. All four lymphomas showed positive MYC and p53 staining.

All four patients had been treated with ruxolitinib, one was also treated with fedratinib, and three of the four had been pretreated with alkylating agents.

Meanwhile, a second retrospective cohort study in Paris of 929 patients with myeloproliferative neoplasms, reported in the same paper, found that 3.51% of those treated with ruxolitinib developed lymphoma, compared with 0.23% of conventionally-treated patients.

Using archived bone marrow samples from 54 of the 69 patients treated with JAK1/2 inhibitors, researchers discovered that 15.9% of them – including three of the B-cell lymphoma patients (the fourth was not tested) – had a preexisting B cell clone. This was present as early as 47-70 months before the lymphoma diagnosis.

“In patients, the clonal B-cell population was present as long as 6 years before overt lymphoma and preceded JAK1/2 inhibition which offers the opportunity to determine patients at risk,” wrote Edit Porpaczy, MD, of the Comprehensive Cancer Center at the Medical University of Vienna, and her coauthors. “Targeted inhibition of JAK-STAT signaling appears to be required to trigger the appearance of the B-cell clone as other treatments eliminating the myeloid cell load in men do not exert a comparable effect.”

In the Viennese cohort, three of the lymphomas were aggressive CD19⁺ B-cell type, and the fourth was a nonspecified high-grade B-cell lymphoma.

Researchers also looked at the effects of JAK1/2 inhibition in STAT1^-/- mice, and found that two-thirds developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B-cells.

“Upon STAT1-deficiency myeloid hyperplasia is paralleled by the occurrence of a malignant B-cell clone, which evolves into disease upon bone-marrow transplantation and gives rise to a leukemic lymphoma phenotype,” the authors wrote.

The study was supported by the Austrian Science Fund, the Anniversary Fund of the Austrian National Bank and the WWTF Precision Medicine Program. Several authors reported support, funding or advisory board positions with the pharmaceutical industry.

SOURCE: Porpaczy E et al. Blood. 2018 Jun 14. doi: 10.1182/blood-2017-10-810739.

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Micrograph showing DLBCL

Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).

However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.

Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).

The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.

Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”

Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.

The company is still conducting other studies of tazemetostat in patients with DLBCL.

In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.

In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.

Micrograph showing DLBCL

Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).

However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.

Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).

The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.

Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”

Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.

The company is still conducting other studies of tazemetostat in patients with DLBCL.

In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.

In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.

Micrograph showing DLBCL

Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).

However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.

Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).

The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.

Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”

Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.

The company is still conducting other studies of tazemetostat in patients with DLBCL.

In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.

In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.

Bone marrow involvement in mantle cell lymphoma could be assessed using just ¹⁸fluorodeoxyglucose (FDG)–PET/CT, according to findings from a small, retrospective study published in Clinical Lymphoma, Myeloma & Leukemia.

Brudersohn/CC BY-SA 3.0/Wikimedia Commons

Rustain Morgan, MD, of the University of Colorado, Aurora, and his colleagues found that, at a certain threshold of bone marrow voxels in standard uptake value (SUV), there was 100% sensitivity and 80% specificity in determining bone marrow involvement in mantle cell lymphoma (MCL).

Currently, National Comprehensive Cancer Network guidelines call for bone marrow biopsy and whole body FDG PET/CT scan to complete an initial diagnosis of MCL.

“One of the most important factors for correct staging is the identification of bone marrow involvement, occurring in approximately 55% of patients with MCL, which classifies patients as advanced stage. However, accurate analysis of bone marrow involvement can be challenging due to sampling error,” the researchers wrote. “While bone marrow biopsy remains the gold standard, it is not a perfect standard given unilateral variability.”

In previous studies, FDG PET/CT was not considered sensitive enough to detect gastrointestinal or bone marrow involvement. However, these earlier studies used SUV maximum or mean or a visual assessment of the bone marrow activity, compared with hepatic uptake. To address this issue, the researchers developed a new method of examining SUV distribution throughout the pelvic bones by analyzing thousands of bone marrow voxels within the bilateral iliacs.

During the developmental phase, an institutional dataset of 11 patients with MCL was used to define the voxel-based analysis. These patients had undergone both unilateral iliac bone marrow biopsy and FDG PET/CT at the initial diagnosis. Then, FDG PET/CT scans from another 12 patients with MCL from a different institution were used to validate the developmental phase findings. Finally, a control group of 5 people with no known malignancy were referred for FDG PET/CT pulmonary nodule evaluation.

“The hypothesis of the study was that, if the bone marrow was involved by lymphoma, then there would be a small increase in the SUV of each voxel, reflecting involvement by the lymphoma. In order to capture such changes, we analyzed the percent of total voxels in SUV ranging from 0.75 to 1.20, in increments of 0.05, as this is where the greatest divergence was visually identified,” the researchers wrote. “The goal was to identify if a percentage of voxels at a set SUV could detect lymphomatous involvement.”

The researchers identified 10 candidate thresholds in the developmental phase; 4 of these performed better than the others in the validation phase. Using those thresholds, 10 of the 12 patients in the validation cohort could be correctly staged using FDG PET/CT.

Further analysis identified a single threshold that performed best: If greater than 38% of the voxels (averaging 1,734 voxels) demonstrated an SUV of less than 0.95, the sensitivity was 100% and the specificity was 80%.

The researchers acknowledged that the findings are limited because of the study’s small sample size and said the results should be validated in a larger trial.

There was no external funding for the study and the researchers reported having no financial disclosures.

[email protected]

SOURCE: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.

Bone marrow involvement in mantle cell lymphoma could be assessed using just ¹⁸fluorodeoxyglucose (FDG)–PET/CT, according to findings from a small, retrospective study published in Clinical Lymphoma, Myeloma & Leukemia.

Brudersohn/CC BY-SA 3.0/Wikimedia Commons

Rustain Morgan, MD, of the University of Colorado, Aurora, and his colleagues found that, at a certain threshold of bone marrow voxels in standard uptake value (SUV), there was 100% sensitivity and 80% specificity in determining bone marrow involvement in mantle cell lymphoma (MCL).

Currently, National Comprehensive Cancer Network guidelines call for bone marrow biopsy and whole body FDG PET/CT scan to complete an initial diagnosis of MCL.

“One of the most important factors for correct staging is the identification of bone marrow involvement, occurring in approximately 55% of patients with MCL, which classifies patients as advanced stage. However, accurate analysis of bone marrow involvement can be challenging due to sampling error,” the researchers wrote. “While bone marrow biopsy remains the gold standard, it is not a perfect standard given unilateral variability.”

In previous studies, FDG PET/CT was not considered sensitive enough to detect gastrointestinal or bone marrow involvement. However, these earlier studies used SUV maximum or mean or a visual assessment of the bone marrow activity, compared with hepatic uptake. To address this issue, the researchers developed a new method of examining SUV distribution throughout the pelvic bones by analyzing thousands of bone marrow voxels within the bilateral iliacs.

During the developmental phase, an institutional dataset of 11 patients with MCL was used to define the voxel-based analysis. These patients had undergone both unilateral iliac bone marrow biopsy and FDG PET/CT at the initial diagnosis. Then, FDG PET/CT scans from another 12 patients with MCL from a different institution were used to validate the developmental phase findings. Finally, a control group of 5 people with no known malignancy were referred for FDG PET/CT pulmonary nodule evaluation.

“The hypothesis of the study was that, if the bone marrow was involved by lymphoma, then there would be a small increase in the SUV of each voxel, reflecting involvement by the lymphoma. In order to capture such changes, we analyzed the percent of total voxels in SUV ranging from 0.75 to 1.20, in increments of 0.05, as this is where the greatest divergence was visually identified,” the researchers wrote. “The goal was to identify if a percentage of voxels at a set SUV could detect lymphomatous involvement.”

The researchers identified 10 candidate thresholds in the developmental phase; 4 of these performed better than the others in the validation phase. Using those thresholds, 10 of the 12 patients in the validation cohort could be correctly staged using FDG PET/CT.

Further analysis identified a single threshold that performed best: If greater than 38% of the voxels (averaging 1,734 voxels) demonstrated an SUV of less than 0.95, the sensitivity was 100% and the specificity was 80%.

The researchers acknowledged that the findings are limited because of the study’s small sample size and said the results should be validated in a larger trial.

There was no external funding for the study and the researchers reported having no financial disclosures.

[email protected]

SOURCE: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.

Bone marrow involvement in mantle cell lymphoma could be assessed using just ¹⁸fluorodeoxyglucose (FDG)–PET/CT, according to findings from a small, retrospective study published in Clinical Lymphoma, Myeloma & Leukemia.

Brudersohn/CC BY-SA 3.0/Wikimedia Commons

Rustain Morgan, MD, of the University of Colorado, Aurora, and his colleagues found that, at a certain threshold of bone marrow voxels in standard uptake value (SUV), there was 100% sensitivity and 80% specificity in determining bone marrow involvement in mantle cell lymphoma (MCL).

Currently, National Comprehensive Cancer Network guidelines call for bone marrow biopsy and whole body FDG PET/CT scan to complete an initial diagnosis of MCL.

“One of the most important factors for correct staging is the identification of bone marrow involvement, occurring in approximately 55% of patients with MCL, which classifies patients as advanced stage. However, accurate analysis of bone marrow involvement can be challenging due to sampling error,” the researchers wrote. “While bone marrow biopsy remains the gold standard, it is not a perfect standard given unilateral variability.”

In previous studies, FDG PET/CT was not considered sensitive enough to detect gastrointestinal or bone marrow involvement. However, these earlier studies used SUV maximum or mean or a visual assessment of the bone marrow activity, compared with hepatic uptake. To address this issue, the researchers developed a new method of examining SUV distribution throughout the pelvic bones by analyzing thousands of bone marrow voxels within the bilateral iliacs.

During the developmental phase, an institutional dataset of 11 patients with MCL was used to define the voxel-based analysis. These patients had undergone both unilateral iliac bone marrow biopsy and FDG PET/CT at the initial diagnosis. Then, FDG PET/CT scans from another 12 patients with MCL from a different institution were used to validate the developmental phase findings. Finally, a control group of 5 people with no known malignancy were referred for FDG PET/CT pulmonary nodule evaluation.

“The hypothesis of the study was that, if the bone marrow was involved by lymphoma, then there would be a small increase in the SUV of each voxel, reflecting involvement by the lymphoma. In order to capture such changes, we analyzed the percent of total voxels in SUV ranging from 0.75 to 1.20, in increments of 0.05, as this is where the greatest divergence was visually identified,” the researchers wrote. “The goal was to identify if a percentage of voxels at a set SUV could detect lymphomatous involvement.”

The researchers identified 10 candidate thresholds in the developmental phase; 4 of these performed better than the others in the validation phase. Using those thresholds, 10 of the 12 patients in the validation cohort could be correctly staged using FDG PET/CT.

Further analysis identified a single threshold that performed best: If greater than 38% of the voxels (averaging 1,734 voxels) demonstrated an SUV of less than 0.95, the sensitivity was 100% and the specificity was 80%.

The researchers acknowledged that the findings are limited because of the study’s small sample size and said the results should be validated in a larger trial.

There was no external funding for the study and the researchers reported having no financial disclosures.

[email protected]

SOURCE: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.