Lymphoma & Plasma Cell Disorders

Blood samples

Credit: Graham Colm

Hypercalcemia could be an early indication of cancer, according to a study published in the British Journal of Cancer.

The connection between hypercalcemia and cancer is well known, but this study shows the condition can predate cancer diagnosis in primary care.

The association between hypercalcemia and cancers was particularly strong in men. And myeloma and other hematologic malignancies were among the most common cancers associated with hypercalcemia.

“All previous studies on hypercalcemia and cancer had been carried out with patients who had already been diagnosed with cancer; hypercalcemia was seen as a late effect of the cancer,” said study author Fergus Hamilton, of the University of Bristol in the UK.

“We wanted to look at the issue from a different perspective and find out if high calcium levels in blood could be used as an early indicator of cancer and, therefore, in the diagnosis of cancer.”

So the researchers analyzed the electronic records of 54,267 patients with elevated calcium levels and found that hypercalcemia was strongly associated with cancer, especially in males.

The positive predictive values for cancer in men were 11.5% for calcium levels between 2.60 and 2.79 mmol l^-1, 27.9% for 2.8-2.99 mmol l^-1, and 50% for >3.0 mmol l^-1. In women, the corresponding values were 4.1%, 8.7%, and 16.7%, respectively.

In men, the most common cancers associated with hypercalcemia were lung (34%), prostate (21%), colorectal (8%), myeloma (8%), and other hematologic cancers (8%). There were 12 other cancer types recorded as well (19%).

In women, the most common cancers were myeloma (24%), breast (18%), other hematologic cancers (10%), lung (8%), and metastatic cancer with unknown primary (8%). There were 16 other cancers recorded among women (32%).

The researchers found no difference in calcium levels among the different cancers.

“We were surprised by the gender difference,” Dr Hamilton said. “There are a number of possible explanations for this, but we think it might be because women are much more likely to have hyperparathyroidism, another cause of hypercalcemia. Men rarely get this condition, so their hypercalcemia is more likely to be due to cancer.”

Blood samples

Credit: Graham Colm

Hypercalcemia could be an early indication of cancer, according to a study published in the British Journal of Cancer.

The connection between hypercalcemia and cancer is well known, but this study shows the condition can predate cancer diagnosis in primary care.

The association between hypercalcemia and cancers was particularly strong in men. And myeloma and other hematologic malignancies were among the most common cancers associated with hypercalcemia.

“All previous studies on hypercalcemia and cancer had been carried out with patients who had already been diagnosed with cancer; hypercalcemia was seen as a late effect of the cancer,” said study author Fergus Hamilton, of the University of Bristol in the UK.

“We wanted to look at the issue from a different perspective and find out if high calcium levels in blood could be used as an early indicator of cancer and, therefore, in the diagnosis of cancer.”

So the researchers analyzed the electronic records of 54,267 patients with elevated calcium levels and found that hypercalcemia was strongly associated with cancer, especially in males.

The positive predictive values for cancer in men were 11.5% for calcium levels between 2.60 and 2.79 mmol l^-1, 27.9% for 2.8-2.99 mmol l^-1, and 50% for >3.0 mmol l^-1. In women, the corresponding values were 4.1%, 8.7%, and 16.7%, respectively.

In men, the most common cancers associated with hypercalcemia were lung (34%), prostate (21%), colorectal (8%), myeloma (8%), and other hematologic cancers (8%). There were 12 other cancer types recorded as well (19%).

In women, the most common cancers were myeloma (24%), breast (18%), other hematologic cancers (10%), lung (8%), and metastatic cancer with unknown primary (8%). There were 16 other cancers recorded among women (32%).

The researchers found no difference in calcium levels among the different cancers.

“We were surprised by the gender difference,” Dr Hamilton said. “There are a number of possible explanations for this, but we think it might be because women are much more likely to have hyperparathyroidism, another cause of hypercalcemia. Men rarely get this condition, so their hypercalcemia is more likely to be due to cancer.”

Blood samples

Credit: Graham Colm

Hypercalcemia could be an early indication of cancer, according to a study published in the British Journal of Cancer.

The connection between hypercalcemia and cancer is well known, but this study shows the condition can predate cancer diagnosis in primary care.

The association between hypercalcemia and cancers was particularly strong in men. And myeloma and other hematologic malignancies were among the most common cancers associated with hypercalcemia.

“All previous studies on hypercalcemia and cancer had been carried out with patients who had already been diagnosed with cancer; hypercalcemia was seen as a late effect of the cancer,” said study author Fergus Hamilton, of the University of Bristol in the UK.

“We wanted to look at the issue from a different perspective and find out if high calcium levels in blood could be used as an early indicator of cancer and, therefore, in the diagnosis of cancer.”

So the researchers analyzed the electronic records of 54,267 patients with elevated calcium levels and found that hypercalcemia was strongly associated with cancer, especially in males.

The positive predictive values for cancer in men were 11.5% for calcium levels between 2.60 and 2.79 mmol l^-1, 27.9% for 2.8-2.99 mmol l^-1, and 50% for >3.0 mmol l^-1. In women, the corresponding values were 4.1%, 8.7%, and 16.7%, respectively.

In men, the most common cancers associated with hypercalcemia were lung (34%), prostate (21%), colorectal (8%), myeloma (8%), and other hematologic cancers (8%). There were 12 other cancer types recorded as well (19%).

In women, the most common cancers were myeloma (24%), breast (18%), other hematologic cancers (10%), lung (8%), and metastatic cancer with unknown primary (8%). There were 16 other cancers recorded among women (32%).

The researchers found no difference in calcium levels among the different cancers.

“We were surprised by the gender difference,” Dr Hamilton said. “There are a number of possible explanations for this, but we think it might be because women are much more likely to have hyperparathyroidism, another cause of hypercalcemia. Men rarely get this condition, so their hypercalcemia is more likely to be due to cancer.”

Hand washing

Credit: CDC/Kimberly Smith

and Christine Ford

NEW YORK—Hand washing is still the single most effective method to prevent the transmission of infection, but additional measures can reduce the risk of cancer-related infections, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.

In her presentation, Laura Zitella, RN, of the Stanford Cancer Institute in California, discussed current recommendations for pharmacologic and non-pharmacologic infection prophylaxis.

She noted that NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections state that the highest risk of infection is in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), acute leukemia patients undergoing induction or consolidation therapy, patients receiving alemtuzumab therapy, patients with graft-vs-host disease (GVHD) treated with high-dose steroids, and patients with neutropenia anticipated to last greater than 10 days.

Antibiotic prophylaxis

Prior to 2005, Zitella said, no survival benefit was observed for antibiotic prophylaxis. All of this changed with the results of a meta-analysis. The analysis included 95 randomized, controlled trials and 9283 patients, the majority having acute leukemia or undergoing HSCT.

For the first time, antibiotic prophylaxis was shown to confer a survival benefit. In neutropenic patients, prophylaxis reduced overall mortality by 33% and infection-related mortality by 42%, compared with placebo or no treatment.

Prophylaxis is not recommended for low-risk neutropenic patients, Zitella said, because it is not proven to decrease morality.

And the drugs of choice are levofloxacin (500-750 mg PO daily) or ciprofloxacin (500-750 mg PO twice daily).

Colony-stimulating factors

Consensus guidelines for the use of colony-stimulating factors (CSFs) are a compilation of ASCO, EORTC, ESMO, and NCCN guidelines.

CSFs may be used prophylactically to prevent chemotherapy-induced neutropenia, febrile neutropenia, and infection. They reduce the duration of hospitalization, the duration of parenteral antibiotics, and have shown a survival benefit.

CSFs are recommended if the risk of febrile neutropenia is 20% or greater. CSFs are not routinely recommended for patients undergoing radiation treatment, acute myeloid leukemia induction, or patients with Hodgkin lymphoma.

Antifungal prophylaxis

Zitella noted that fluconazole is the best-studied antifungal prophylaxis and is recommended as the primary prophylaxis for HSCT patients.

In double-blind, placebo-controlled trials, fluconazole reduced mucosal candidiasis and invasive Candida infections in patients undergoing HSCT. And it improved survival at day 110 after transplant.

Posaconazole prophylaxis has proven effective in patients with acute myeloid leukemia or myelodysplastic syndromes undergoing intensive chemotherapy. The drug reduced invasive fungal infections, including aspergillosis, and improved survival.

For patients with GVHD on immunosuppressive therapy, posaconazole and fluconazole prophylaxis were equivalent in preventing invasive fungal infections. However, posaconazole reduced the incidence of invasive aspergillosis and fungal-related mortality.

The NCCN guidelines, Zitella said, spell out which antifungal agents should be used for each disease or therapeutic intervention.

Antiviral prophylaxis

HSV and VZV

Patients requiring antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) should be seropositive and have acute leukemia, GVHD treated with steroids, prior HSV reactivation under treatment, or have undergone HSCT.

Zitella pointed out that patients treated with proteasome inhibitors, such as bortezomib, alemtuzumab, or purine analaogs, such as fludarabine, are more at risk and should also receive antiviral prophylaxis.

Recommended drugs include valacyclovir, acyclovir, or famciclovir.

CMV

Cytomegalovirus-positive (CMV+) patients at high risk include those who have received an allogeneic HSCT or treatment with alemtuzumab.

Zitella explained that for these patients, prophylaxis is uncommon, and a pre-emptive strategy should be used, including testing 3 to 6 months after transplant or in the setting of GVHD and 2 months after alemtuzumab therapy.

CMV viremia should be treated with valganciclovir, ganciclovir, foscarnet, or cidofovir.

HBV

Zitella noted that 30% of the world population has been infected with hepatitis B virus (HBV), and reactivation during cancer treatment can lead to fulminant hepatitis and death.

NCCN recommends that patients undergoing immunosuppressive therapy, allogeneic HSCT candidates, patients receiving anti-CD20 monoclonal antibodies, those treated with alemtuzumab, and patients receiving systemic therapy who have an obvious risk factor for HBV infection should be tested.

Entecavir, tenofovir, adefovir, telbivudine, or lamivudine may be used to prevent HBV reactivation.

Pneumocystis pneumonia prophylaxis

Patients undergoing allogeneic HSCT, patients with acute lymphoblastic leukemia, those treated with alemtuzumab, and those with a CD4 count below 200 cells/mcL should receive pneumocystis pneumonia prophylaxis.

Trimethorpim/sulfamethoxazole is the drug of choice. Atovaquone, dapsone, and inhaled or IV pentamidine are alternatives.

Vaccines

Zitella pointed out that recommended vaccines include influenza, pneumococcal, and tetanus, diphtheria, and acellular pertussis.

She cautioned that live attenuated vaccines should not be given to cancer patients. Other vaccines to avoid include smallpox; measles, mumps, and rubella; varicella zoster; rotavirus; yellow fever; oral typhoid; BCG; and oral polio vaccine.

Neutropenic precautions

Low microbial diets are a hot topic among patients undergoing cancer treatment, Zitella said. Fresh fruits and vegetables used to be restricted, but no studies show that dietary restrictions decrease the risk of infection.

Zitella stressed, however, that standard food safety recommendations of the USDA/FDA should be followed.

She also noted that HEPA filtration is protective against molds in high-risk patients, antiseptic bathing has contradictory evidence, the benefit of laminar airflow is unclear, and protective isolation has not been proven to reduce the risk of infection.

Hand washing

Credit: CDC/Kimberly Smith

and Christine Ford

NEW YORK—Hand washing is still the single most effective method to prevent the transmission of infection, but additional measures can reduce the risk of cancer-related infections, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.

In her presentation, Laura Zitella, RN, of the Stanford Cancer Institute in California, discussed current recommendations for pharmacologic and non-pharmacologic infection prophylaxis.

She noted that NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections state that the highest risk of infection is in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), acute leukemia patients undergoing induction or consolidation therapy, patients receiving alemtuzumab therapy, patients with graft-vs-host disease (GVHD) treated with high-dose steroids, and patients with neutropenia anticipated to last greater than 10 days.

Antibiotic prophylaxis

Prior to 2005, Zitella said, no survival benefit was observed for antibiotic prophylaxis. All of this changed with the results of a meta-analysis. The analysis included 95 randomized, controlled trials and 9283 patients, the majority having acute leukemia or undergoing HSCT.

For the first time, antibiotic prophylaxis was shown to confer a survival benefit. In neutropenic patients, prophylaxis reduced overall mortality by 33% and infection-related mortality by 42%, compared with placebo or no treatment.

Prophylaxis is not recommended for low-risk neutropenic patients, Zitella said, because it is not proven to decrease morality.

And the drugs of choice are levofloxacin (500-750 mg PO daily) or ciprofloxacin (500-750 mg PO twice daily).

Colony-stimulating factors

Consensus guidelines for the use of colony-stimulating factors (CSFs) are a compilation of ASCO, EORTC, ESMO, and NCCN guidelines.

CSFs may be used prophylactically to prevent chemotherapy-induced neutropenia, febrile neutropenia, and infection. They reduce the duration of hospitalization, the duration of parenteral antibiotics, and have shown a survival benefit.

CSFs are recommended if the risk of febrile neutropenia is 20% or greater. CSFs are not routinely recommended for patients undergoing radiation treatment, acute myeloid leukemia induction, or patients with Hodgkin lymphoma.

Antifungal prophylaxis

Zitella noted that fluconazole is the best-studied antifungal prophylaxis and is recommended as the primary prophylaxis for HSCT patients.

In double-blind, placebo-controlled trials, fluconazole reduced mucosal candidiasis and invasive Candida infections in patients undergoing HSCT. And it improved survival at day 110 after transplant.

Posaconazole prophylaxis has proven effective in patients with acute myeloid leukemia or myelodysplastic syndromes undergoing intensive chemotherapy. The drug reduced invasive fungal infections, including aspergillosis, and improved survival.

For patients with GVHD on immunosuppressive therapy, posaconazole and fluconazole prophylaxis were equivalent in preventing invasive fungal infections. However, posaconazole reduced the incidence of invasive aspergillosis and fungal-related mortality.

The NCCN guidelines, Zitella said, spell out which antifungal agents should be used for each disease or therapeutic intervention.

Antiviral prophylaxis

HSV and VZV

Patients requiring antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) should be seropositive and have acute leukemia, GVHD treated with steroids, prior HSV reactivation under treatment, or have undergone HSCT.

Zitella pointed out that patients treated with proteasome inhibitors, such as bortezomib, alemtuzumab, or purine analaogs, such as fludarabine, are more at risk and should also receive antiviral prophylaxis.

Recommended drugs include valacyclovir, acyclovir, or famciclovir.

CMV

Cytomegalovirus-positive (CMV+) patients at high risk include those who have received an allogeneic HSCT or treatment with alemtuzumab.

Zitella explained that for these patients, prophylaxis is uncommon, and a pre-emptive strategy should be used, including testing 3 to 6 months after transplant or in the setting of GVHD and 2 months after alemtuzumab therapy.

CMV viremia should be treated with valganciclovir, ganciclovir, foscarnet, or cidofovir.

HBV

Zitella noted that 30% of the world population has been infected with hepatitis B virus (HBV), and reactivation during cancer treatment can lead to fulminant hepatitis and death.

NCCN recommends that patients undergoing immunosuppressive therapy, allogeneic HSCT candidates, patients receiving anti-CD20 monoclonal antibodies, those treated with alemtuzumab, and patients receiving systemic therapy who have an obvious risk factor for HBV infection should be tested.

Entecavir, tenofovir, adefovir, telbivudine, or lamivudine may be used to prevent HBV reactivation.

Pneumocystis pneumonia prophylaxis

Patients undergoing allogeneic HSCT, patients with acute lymphoblastic leukemia, those treated with alemtuzumab, and those with a CD4 count below 200 cells/mcL should receive pneumocystis pneumonia prophylaxis.

Trimethorpim/sulfamethoxazole is the drug of choice. Atovaquone, dapsone, and inhaled or IV pentamidine are alternatives.

Vaccines

Zitella pointed out that recommended vaccines include influenza, pneumococcal, and tetanus, diphtheria, and acellular pertussis.

She cautioned that live attenuated vaccines should not be given to cancer patients. Other vaccines to avoid include smallpox; measles, mumps, and rubella; varicella zoster; rotavirus; yellow fever; oral typhoid; BCG; and oral polio vaccine.

Neutropenic precautions

Low microbial diets are a hot topic among patients undergoing cancer treatment, Zitella said. Fresh fruits and vegetables used to be restricted, but no studies show that dietary restrictions decrease the risk of infection.

Zitella stressed, however, that standard food safety recommendations of the USDA/FDA should be followed.

She also noted that HEPA filtration is protective against molds in high-risk patients, antiseptic bathing has contradictory evidence, the benefit of laminar airflow is unclear, and protective isolation has not been proven to reduce the risk of infection.

Hand washing

Credit: CDC/Kimberly Smith

and Christine Ford

NEW YORK—Hand washing is still the single most effective method to prevent the transmission of infection, but additional measures can reduce the risk of cancer-related infections, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.

In her presentation, Laura Zitella, RN, of the Stanford Cancer Institute in California, discussed current recommendations for pharmacologic and non-pharmacologic infection prophylaxis.

She noted that NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections state that the highest risk of infection is in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), acute leukemia patients undergoing induction or consolidation therapy, patients receiving alemtuzumab therapy, patients with graft-vs-host disease (GVHD) treated with high-dose steroids, and patients with neutropenia anticipated to last greater than 10 days.

Antibiotic prophylaxis

Prior to 2005, Zitella said, no survival benefit was observed for antibiotic prophylaxis. All of this changed with the results of a meta-analysis. The analysis included 95 randomized, controlled trials and 9283 patients, the majority having acute leukemia or undergoing HSCT.

For the first time, antibiotic prophylaxis was shown to confer a survival benefit. In neutropenic patients, prophylaxis reduced overall mortality by 33% and infection-related mortality by 42%, compared with placebo or no treatment.

Prophylaxis is not recommended for low-risk neutropenic patients, Zitella said, because it is not proven to decrease morality.

And the drugs of choice are levofloxacin (500-750 mg PO daily) or ciprofloxacin (500-750 mg PO twice daily).

Colony-stimulating factors

Consensus guidelines for the use of colony-stimulating factors (CSFs) are a compilation of ASCO, EORTC, ESMO, and NCCN guidelines.

CSFs may be used prophylactically to prevent chemotherapy-induced neutropenia, febrile neutropenia, and infection. They reduce the duration of hospitalization, the duration of parenteral antibiotics, and have shown a survival benefit.

CSFs are recommended if the risk of febrile neutropenia is 20% or greater. CSFs are not routinely recommended for patients undergoing radiation treatment, acute myeloid leukemia induction, or patients with Hodgkin lymphoma.

Antifungal prophylaxis

Zitella noted that fluconazole is the best-studied antifungal prophylaxis and is recommended as the primary prophylaxis for HSCT patients.

In double-blind, placebo-controlled trials, fluconazole reduced mucosal candidiasis and invasive Candida infections in patients undergoing HSCT. And it improved survival at day 110 after transplant.

Posaconazole prophylaxis has proven effective in patients with acute myeloid leukemia or myelodysplastic syndromes undergoing intensive chemotherapy. The drug reduced invasive fungal infections, including aspergillosis, and improved survival.

For patients with GVHD on immunosuppressive therapy, posaconazole and fluconazole prophylaxis were equivalent in preventing invasive fungal infections. However, posaconazole reduced the incidence of invasive aspergillosis and fungal-related mortality.

The NCCN guidelines, Zitella said, spell out which antifungal agents should be used for each disease or therapeutic intervention.

Antiviral prophylaxis

HSV and VZV

Patients requiring antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) should be seropositive and have acute leukemia, GVHD treated with steroids, prior HSV reactivation under treatment, or have undergone HSCT.

Zitella pointed out that patients treated with proteasome inhibitors, such as bortezomib, alemtuzumab, or purine analaogs, such as fludarabine, are more at risk and should also receive antiviral prophylaxis.

Recommended drugs include valacyclovir, acyclovir, or famciclovir.

CMV

Cytomegalovirus-positive (CMV+) patients at high risk include those who have received an allogeneic HSCT or treatment with alemtuzumab.

Zitella explained that for these patients, prophylaxis is uncommon, and a pre-emptive strategy should be used, including testing 3 to 6 months after transplant or in the setting of GVHD and 2 months after alemtuzumab therapy.

CMV viremia should be treated with valganciclovir, ganciclovir, foscarnet, or cidofovir.

HBV

Zitella noted that 30% of the world population has been infected with hepatitis B virus (HBV), and reactivation during cancer treatment can lead to fulminant hepatitis and death.

NCCN recommends that patients undergoing immunosuppressive therapy, allogeneic HSCT candidates, patients receiving anti-CD20 monoclonal antibodies, those treated with alemtuzumab, and patients receiving systemic therapy who have an obvious risk factor for HBV infection should be tested.

Entecavir, tenofovir, adefovir, telbivudine, or lamivudine may be used to prevent HBV reactivation.

Pneumocystis pneumonia prophylaxis

Patients undergoing allogeneic HSCT, patients with acute lymphoblastic leukemia, those treated with alemtuzumab, and those with a CD4 count below 200 cells/mcL should receive pneumocystis pneumonia prophylaxis.

Trimethorpim/sulfamethoxazole is the drug of choice. Atovaquone, dapsone, and inhaled or IV pentamidine are alternatives.

Vaccines

Zitella pointed out that recommended vaccines include influenza, pneumococcal, and tetanus, diphtheria, and acellular pertussis.

She cautioned that live attenuated vaccines should not be given to cancer patients. Other vaccines to avoid include smallpox; measles, mumps, and rubella; varicella zoster; rotavirus; yellow fever; oral typhoid; BCG; and oral polio vaccine.

Neutropenic precautions

Low microbial diets are a hot topic among patients undergoing cancer treatment, Zitella said. Fresh fruits and vegetables used to be restricted, but no studies show that dietary restrictions decrease the risk of infection.

Zitella stressed, however, that standard food safety recommendations of the USDA/FDA should be followed.

She also noted that HEPA filtration is protective against molds in high-risk patients, antiseptic bathing has contradictory evidence, the benefit of laminar airflow is unclear, and protective isolation has not been proven to reduce the risk of infection.

Multiple myeloma

PHILADELPHIA—A drug that targets the ribosome may be active in a broad range of hematologic malignancies, researchers say.

The drug, CX-5461, inhibits the protein RNA polymerase I (Pol I), which is consistently upregulated in hematologic and other cancers.

CX-5461 significantly prolonged survival in mouse models of refractory acute myeloid leukemia (AML) and multiple myeloma (MM). It also synergized with everolimus to extend survival in mice with B-cell lymphoma.

Furthermore, the drug did not elicit severe adverse effects.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said Ross D. Hannan, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia,

“Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called house-keeping protein that is essential to all cells for survival.”

Dr Hannan and his colleagues presented these findings in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

The researchers previously showed that cancer cells are much more dependent on ribosome biogenesis than normal cells. And blocking the accelerated reading of ribosomal genes in mice—using CX5461—can cause lymphoma and leukemia cells to die, while sparing normal cells.

With their latest research, the group expanded upon these findings by testing CX-5461 in MLL-driven AML, V*κ-Myc-driven MM, and Eμ-Myc lymphoma.

They found that CX-5461 improved overall survival in MLL/ENL Nras leukemic mice, compared to placebo and standard therapy. The median survival was 17 days for vehicle-treated mice, 21 days for mice treated with cytarabine and doxorubicin, and 36 days for mice that received CX-5461 (P<0.0001 for vehicle vs CX-5461).

CX-5461 treated MLL-driven AML by inducing apoptosis, delaying cell-cycle progression, and promoting differentiation.

The researchers also found the therapeutic benefit of CX-5461 is not p53-dependent, which contradicts their previous findings. Human AML cell lines and primary patient samples were sensitive to CX-5461 independent of p53 status.

And MLL/ENL Nras p53^-/- leukemic mice had significantly prolonged survival when treated with CX-5461, compared to vehicle-treated controls. The median survival was 11 days and 24 days, respectively (P<0.0001).

Likewise, CX-5461 significantly prolonged survival in mice bearing V*κ-Myc MM. The median survival was 103.5 days for controls and 175 days for mice that received CX-5461 (P<0.0001).

Finally, the researchers showed that CX-5461 synergizes with everolimus to treat Eμ-Myc lymphoma. The median survival was 15 days in control mice, 18 days in mice that received everolimus, 32 days in mice treated with CX-5461, and 54 days in mice that received both drugs (P<0.0001 for CX-5461 vs the combination).

“These results provide further rationale for the first-in-human phase 1 clinical trial that we initiated in July 2013 testing CX-5461 for patients with advanced hematological malignancies, including AML and multiple myeloma,” Dr Hannan said.

His group’s preclinical research was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences, the makers of CX-5461, provided the drug.

Multiple myeloma

PHILADELPHIA—A drug that targets the ribosome may be active in a broad range of hematologic malignancies, researchers say.

The drug, CX-5461, inhibits the protein RNA polymerase I (Pol I), which is consistently upregulated in hematologic and other cancers.

CX-5461 significantly prolonged survival in mouse models of refractory acute myeloid leukemia (AML) and multiple myeloma (MM). It also synergized with everolimus to extend survival in mice with B-cell lymphoma.

Furthermore, the drug did not elicit severe adverse effects.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said Ross D. Hannan, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia,

“Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called house-keeping protein that is essential to all cells for survival.”

Dr Hannan and his colleagues presented these findings in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

The researchers previously showed that cancer cells are much more dependent on ribosome biogenesis than normal cells. And blocking the accelerated reading of ribosomal genes in mice—using CX5461—can cause lymphoma and leukemia cells to die, while sparing normal cells.

With their latest research, the group expanded upon these findings by testing CX-5461 in MLL-driven AML, V*κ-Myc-driven MM, and Eμ-Myc lymphoma.

They found that CX-5461 improved overall survival in MLL/ENL Nras leukemic mice, compared to placebo and standard therapy. The median survival was 17 days for vehicle-treated mice, 21 days for mice treated with cytarabine and doxorubicin, and 36 days for mice that received CX-5461 (P<0.0001 for vehicle vs CX-5461).

CX-5461 treated MLL-driven AML by inducing apoptosis, delaying cell-cycle progression, and promoting differentiation.

The researchers also found the therapeutic benefit of CX-5461 is not p53-dependent, which contradicts their previous findings. Human AML cell lines and primary patient samples were sensitive to CX-5461 independent of p53 status.

And MLL/ENL Nras p53^-/- leukemic mice had significantly prolonged survival when treated with CX-5461, compared to vehicle-treated controls. The median survival was 11 days and 24 days, respectively (P<0.0001).

Likewise, CX-5461 significantly prolonged survival in mice bearing V*κ-Myc MM. The median survival was 103.5 days for controls and 175 days for mice that received CX-5461 (P<0.0001).

Finally, the researchers showed that CX-5461 synergizes with everolimus to treat Eμ-Myc lymphoma. The median survival was 15 days in control mice, 18 days in mice that received everolimus, 32 days in mice treated with CX-5461, and 54 days in mice that received both drugs (P<0.0001 for CX-5461 vs the combination).

“These results provide further rationale for the first-in-human phase 1 clinical trial that we initiated in July 2013 testing CX-5461 for patients with advanced hematological malignancies, including AML and multiple myeloma,” Dr Hannan said.

His group’s preclinical research was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences, the makers of CX-5461, provided the drug.

Multiple myeloma

PHILADELPHIA—A drug that targets the ribosome may be active in a broad range of hematologic malignancies, researchers say.

The drug, CX-5461, inhibits the protein RNA polymerase I (Pol I), which is consistently upregulated in hematologic and other cancers.

CX-5461 significantly prolonged survival in mouse models of refractory acute myeloid leukemia (AML) and multiple myeloma (MM). It also synergized with everolimus to extend survival in mice with B-cell lymphoma.

Furthermore, the drug did not elicit severe adverse effects.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said Ross D. Hannan, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia,

“Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called house-keeping protein that is essential to all cells for survival.”

Dr Hannan and his colleagues presented these findings in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

The researchers previously showed that cancer cells are much more dependent on ribosome biogenesis than normal cells. And blocking the accelerated reading of ribosomal genes in mice—using CX5461—can cause lymphoma and leukemia cells to die, while sparing normal cells.

With their latest research, the group expanded upon these findings by testing CX-5461 in MLL-driven AML, V*κ-Myc-driven MM, and Eμ-Myc lymphoma.

They found that CX-5461 improved overall survival in MLL/ENL Nras leukemic mice, compared to placebo and standard therapy. The median survival was 17 days for vehicle-treated mice, 21 days for mice treated with cytarabine and doxorubicin, and 36 days for mice that received CX-5461 (P<0.0001 for vehicle vs CX-5461).

CX-5461 treated MLL-driven AML by inducing apoptosis, delaying cell-cycle progression, and promoting differentiation.

The researchers also found the therapeutic benefit of CX-5461 is not p53-dependent, which contradicts their previous findings. Human AML cell lines and primary patient samples were sensitive to CX-5461 independent of p53 status.

And MLL/ENL Nras p53^-/- leukemic mice had significantly prolonged survival when treated with CX-5461, compared to vehicle-treated controls. The median survival was 11 days and 24 days, respectively (P<0.0001).

Likewise, CX-5461 significantly prolonged survival in mice bearing V*κ-Myc MM. The median survival was 103.5 days for controls and 175 days for mice that received CX-5461 (P<0.0001).

Finally, the researchers showed that CX-5461 synergizes with everolimus to treat Eμ-Myc lymphoma. The median survival was 15 days in control mice, 18 days in mice that received everolimus, 32 days in mice treated with CX-5461, and 54 days in mice that received both drugs (P<0.0001 for CX-5461 vs the combination).

“These results provide further rationale for the first-in-human phase 1 clinical trial that we initiated in July 2013 testing CX-5461 for patients with advanced hematological malignancies, including AML and multiple myeloma,” Dr Hannan said.

His group’s preclinical research was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences, the makers of CX-5461, provided the drug.

Lab mice

Credit: Aaron Logan

Exercising during doxorubicin treatment can amplify the drug’s cancer-fighting ability, according to preclinical research.

Previous studies showed that adopting an exercise regimen before receiving doxorubicin could protect against the cardiac side effects associated with the drug.

Now, researchers have reported that exercising during doxorubicin treatment does not protect the heart, but it does help shrink tumors in mice.

Joseph Libonati, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology.

The researchers conducted experiments with 4 groups of mice, all of which received an injection of melanoma cells.

During the next 2 weeks, 2 of the groups received doxorubicin in 2 doses, while the other 2 groups received placebo injections.

A treated group and a placebo group were put on exercise regimens, walking for 45 minutes 5 days a week on mouse-sized treadmills, while the rest of the mice remained sedentary.

After the 2-week trial, the researchers examined the animals’ hearts using echocardiogram and tissue analysis.

As expected, doxorubicin reduced the heart’s function and size and increased fibrosis. Mice that exercised were not protected from this damage.

“We looked, and the exercise didn’t do anything to the heart; it didn’t worsen it, it didn’t help it,” Dr Libonati said. “But the tumor data—I find them actually amazing.”

The mice that received doxorubicin and exercised had significantly smaller tumors after 2 weeks than mice that only received doxorubicin (P<0.05).

Further studies will investigate exactly how exercise enhances the effect of doxorubicin, but the researchers believe it could be, in part, because exercise increases blood flow to the tumor, bringing with it more of the drug in the bloodstream.

“If exercise helps in this way, you could potentially use a smaller dose of the drug and get fewer side effects,” Dr Libonati said.

Gaining a clearer understanding of the many ways that exercise affects various systems of the body could also pave the way for developing drugs that mimic the effects of exercise.

“People don’t take a drug and then sit down all day,” Dr Libonati said. “Something as simple as moving affects how drugs are metabolized. We’re only just beginning to understand the complexities.”

Lab mice

Credit: Aaron Logan

Exercising during doxorubicin treatment can amplify the drug’s cancer-fighting ability, according to preclinical research.

Previous studies showed that adopting an exercise regimen before receiving doxorubicin could protect against the cardiac side effects associated with the drug.

Now, researchers have reported that exercising during doxorubicin treatment does not protect the heart, but it does help shrink tumors in mice.

Joseph Libonati, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology.

The researchers conducted experiments with 4 groups of mice, all of which received an injection of melanoma cells.

During the next 2 weeks, 2 of the groups received doxorubicin in 2 doses, while the other 2 groups received placebo injections.

A treated group and a placebo group were put on exercise regimens, walking for 45 minutes 5 days a week on mouse-sized treadmills, while the rest of the mice remained sedentary.

After the 2-week trial, the researchers examined the animals’ hearts using echocardiogram and tissue analysis.

As expected, doxorubicin reduced the heart’s function and size and increased fibrosis. Mice that exercised were not protected from this damage.

“We looked, and the exercise didn’t do anything to the heart; it didn’t worsen it, it didn’t help it,” Dr Libonati said. “But the tumor data—I find them actually amazing.”

The mice that received doxorubicin and exercised had significantly smaller tumors after 2 weeks than mice that only received doxorubicin (P<0.05).

Further studies will investigate exactly how exercise enhances the effect of doxorubicin, but the researchers believe it could be, in part, because exercise increases blood flow to the tumor, bringing with it more of the drug in the bloodstream.

“If exercise helps in this way, you could potentially use a smaller dose of the drug and get fewer side effects,” Dr Libonati said.

Gaining a clearer understanding of the many ways that exercise affects various systems of the body could also pave the way for developing drugs that mimic the effects of exercise.

“People don’t take a drug and then sit down all day,” Dr Libonati said. “Something as simple as moving affects how drugs are metabolized. We’re only just beginning to understand the complexities.”

Lab mice

Credit: Aaron Logan

Exercising during doxorubicin treatment can amplify the drug’s cancer-fighting ability, according to preclinical research.

Previous studies showed that adopting an exercise regimen before receiving doxorubicin could protect against the cardiac side effects associated with the drug.

Now, researchers have reported that exercising during doxorubicin treatment does not protect the heart, but it does help shrink tumors in mice.

Joseph Libonati, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology.

The researchers conducted experiments with 4 groups of mice, all of which received an injection of melanoma cells.

During the next 2 weeks, 2 of the groups received doxorubicin in 2 doses, while the other 2 groups received placebo injections.

A treated group and a placebo group were put on exercise regimens, walking for 45 minutes 5 days a week on mouse-sized treadmills, while the rest of the mice remained sedentary.

After the 2-week trial, the researchers examined the animals’ hearts using echocardiogram and tissue analysis.

As expected, doxorubicin reduced the heart’s function and size and increased fibrosis. Mice that exercised were not protected from this damage.

“We looked, and the exercise didn’t do anything to the heart; it didn’t worsen it, it didn’t help it,” Dr Libonati said. “But the tumor data—I find them actually amazing.”

The mice that received doxorubicin and exercised had significantly smaller tumors after 2 weeks than mice that only received doxorubicin (P<0.05).

Further studies will investigate exactly how exercise enhances the effect of doxorubicin, but the researchers believe it could be, in part, because exercise increases blood flow to the tumor, bringing with it more of the drug in the bloodstream.

“If exercise helps in this way, you could potentially use a smaller dose of the drug and get fewer side effects,” Dr Libonati said.

Gaining a clearer understanding of the many ways that exercise affects various systems of the body could also pave the way for developing drugs that mimic the effects of exercise.

“People don’t take a drug and then sit down all day,” Dr Libonati said. “Something as simple as moving affects how drugs are metabolized. We’re only just beginning to understand the complexities.”

 

 

Micrograph showing FL

 

The European Commission has granted marketing authorization for the PI3K delta inhibitor idelalisib (Zydelig) to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in the European Union.

The drug is now approved for use in combination with rituximab for CLL patients who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and are not eligible for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for FL patients who were refractory to 2 prior lines of treatment.

These approvals are based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the rituximab-idelalisib arm had a much higher overall response rate than patients in the rituximab-placebo arm—81% and 13%, respectively (P<0.001). There were no complete responses.

At 24 weeks, the rate of progression-free survival was 93% in the rituximab-idelalisib arm and 46% in the rituximab-placebo arm (P<0.001). The median progression-free survival was 5.5 months in the rituximab-placebo arm and not reached in the rituximab-idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the rituximab-idelalisib arm and 80% in the rituximab-placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the rituximab-idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the rituximab-placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the rituximab-idelalisib arm than in the rituximab-placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

This phase 2 trial enrolled 125 patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent. Patients received idelalisib monotherapy.

Of the 72 subjects with FL, 54% achieved a response, and 8% had a complete response. The median duration of response was not reached (range, 0-14.8 months).

Improvements in survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

Idelalisib is under development by Gilead Sciences. The drug is already approved in the US for the aforementioned indications, as well as to treat small lymphocytic lymphoma.

 

 

Micrograph showing FL

 

The European Commission has granted marketing authorization for the PI3K delta inhibitor idelalisib (Zydelig) to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in the European Union.

The drug is now approved for use in combination with rituximab for CLL patients who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and are not eligible for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for FL patients who were refractory to 2 prior lines of treatment.

These approvals are based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the rituximab-idelalisib arm had a much higher overall response rate than patients in the rituximab-placebo arm—81% and 13%, respectively (P<0.001). There were no complete responses.

At 24 weeks, the rate of progression-free survival was 93% in the rituximab-idelalisib arm and 46% in the rituximab-placebo arm (P<0.001). The median progression-free survival was 5.5 months in the rituximab-placebo arm and not reached in the rituximab-idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the rituximab-idelalisib arm and 80% in the rituximab-placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the rituximab-idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the rituximab-placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the rituximab-idelalisib arm than in the rituximab-placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

This phase 2 trial enrolled 125 patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent. Patients received idelalisib monotherapy.

Of the 72 subjects with FL, 54% achieved a response, and 8% had a complete response. The median duration of response was not reached (range, 0-14.8 months).

Improvements in survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

Idelalisib is under development by Gilead Sciences. The drug is already approved in the US for the aforementioned indications, as well as to treat small lymphocytic lymphoma.

 

 

Micrograph showing FL

 

The European Commission has granted marketing authorization for the PI3K delta inhibitor idelalisib (Zydelig) to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in the European Union.

The drug is now approved for use in combination with rituximab for CLL patients who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and are not eligible for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for FL patients who were refractory to 2 prior lines of treatment.

These approvals are based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the rituximab-idelalisib arm had a much higher overall response rate than patients in the rituximab-placebo arm—81% and 13%, respectively (P<0.001). There were no complete responses.

At 24 weeks, the rate of progression-free survival was 93% in the rituximab-idelalisib arm and 46% in the rituximab-placebo arm (P<0.001). The median progression-free survival was 5.5 months in the rituximab-placebo arm and not reached in the rituximab-idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the rituximab-idelalisib arm and 80% in the rituximab-placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the rituximab-idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the rituximab-placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the rituximab-idelalisib arm than in the rituximab-placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

This phase 2 trial enrolled 125 patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent. Patients received idelalisib monotherapy.

Of the 72 subjects with FL, 54% achieved a response, and 8% had a complete response. The median duration of response was not reached (range, 0-14.8 months).

Improvements in survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

Idelalisib is under development by Gilead Sciences. The drug is already approved in the US for the aforementioned indications, as well as to treat small lymphocytic lymphoma.

Cancer patient receives therapy

Credit: Rhoda Baer

A mathematical formula may help physicians predict which cancer survivors are likely to have normal sperm production following chemotherapy with alkylating agents.

Researchers developed the formula to calculate survivors’ cumulative treatment exposure to alkylating agents as a cyclophosphamide-equivalent dose (CED).

The team used this formula to evaluate a cohort of cancer survivors and found that CEDs of 4 g/m² or less were associated with normal sperm concentrations.

An account of this research was published in The Lancet Oncology.

“Based on these results, we would recommend pretreatment fertility preservation be offered, whenever clinically possible, to any male whose projected treatment is expected to include a cyclophosphamide-equivalent dose greater than 4 g/m²,” said study author Daniel Green, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Green and his colleagues had studied 214 male survivors of childhood cancer who had a median age of 29. Subjects had received cyclophosphamide and other alkylating agents, but their treatment did not include radiation.

The researchers performed semen analysis in the survivors a median of 21 years from their diagnosis. The analysis showed that 47.6% of survivors had normal sperm concentrations (at least 15 million per milliliter), 27.6% had low sperm counts, and 24.8% produced no sperm.

To determine the impact of alkylating agents on the survivors’ sperm production, the researchers calculated each survivor’s cumulative treatment exposure as a CED.

They did this using the following formula: CED (mg/m²)= 1.0 (cumulative cyclophosphamide dose [mg/m²]) + 0.244 (cumulative ifosfamide dose [mg/m²]) + 0.857 (cumulative procarbazine dose [mg/m²]) + 14.286 (cumulative chlorambucil dose [mg/m²]) + 15.0 (cumulative carmustine dose [mg/m²]) + 16.0 (cumulative lomustine dose [mg/m²]) + 40 (cumulative melphalan dose [mg/m²]) + 50 (cumulative thiotepa dose [mg/m²]) + 100 cumulative chlormethine dose [mg/m²]) + 8.823 (cumulative busulfan dose [mg/m²]).

The researchers could not identify a uniformly safe or toxic dose of these drugs, but they found that survivor sperm concentrations generally decreased as cumulative exposure to alkylating agents increased.

And CEDs of 4 g/m² or less were associated with normal sperm concentrations. Almost 89% of survivors whose CED was 4 g/m² or less had a normal sperm count. Their sperm were also more likely than sperm from other survivors to look and behave normally.

Dr Green did note that, although a lower cumulative dose of alkylating agents was associated with normal sperm production, outcomes for individual patients were unpredictable and varied.

Cancer patient receives therapy

Credit: Rhoda Baer

A mathematical formula may help physicians predict which cancer survivors are likely to have normal sperm production following chemotherapy with alkylating agents.

Researchers developed the formula to calculate survivors’ cumulative treatment exposure to alkylating agents as a cyclophosphamide-equivalent dose (CED).

The team used this formula to evaluate a cohort of cancer survivors and found that CEDs of 4 g/m² or less were associated with normal sperm concentrations.

An account of this research was published in The Lancet Oncology.

“Based on these results, we would recommend pretreatment fertility preservation be offered, whenever clinically possible, to any male whose projected treatment is expected to include a cyclophosphamide-equivalent dose greater than 4 g/m²,” said study author Daniel Green, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Green and his colleagues had studied 214 male survivors of childhood cancer who had a median age of 29. Subjects had received cyclophosphamide and other alkylating agents, but their treatment did not include radiation.

The researchers performed semen analysis in the survivors a median of 21 years from their diagnosis. The analysis showed that 47.6% of survivors had normal sperm concentrations (at least 15 million per milliliter), 27.6% had low sperm counts, and 24.8% produced no sperm.

To determine the impact of alkylating agents on the survivors’ sperm production, the researchers calculated each survivor’s cumulative treatment exposure as a CED.

They did this using the following formula: CED (mg/m²)= 1.0 (cumulative cyclophosphamide dose [mg/m²]) + 0.244 (cumulative ifosfamide dose [mg/m²]) + 0.857 (cumulative procarbazine dose [mg/m²]) + 14.286 (cumulative chlorambucil dose [mg/m²]) + 15.0 (cumulative carmustine dose [mg/m²]) + 16.0 (cumulative lomustine dose [mg/m²]) + 40 (cumulative melphalan dose [mg/m²]) + 50 (cumulative thiotepa dose [mg/m²]) + 100 cumulative chlormethine dose [mg/m²]) + 8.823 (cumulative busulfan dose [mg/m²]).

The researchers could not identify a uniformly safe or toxic dose of these drugs, but they found that survivor sperm concentrations generally decreased as cumulative exposure to alkylating agents increased.

And CEDs of 4 g/m² or less were associated with normal sperm concentrations. Almost 89% of survivors whose CED was 4 g/m² or less had a normal sperm count. Their sperm were also more likely than sperm from other survivors to look and behave normally.

Dr Green did note that, although a lower cumulative dose of alkylating agents was associated with normal sperm production, outcomes for individual patients were unpredictable and varied.

Cancer patient receives therapy

Credit: Rhoda Baer

A mathematical formula may help physicians predict which cancer survivors are likely to have normal sperm production following chemotherapy with alkylating agents.

Researchers developed the formula to calculate survivors’ cumulative treatment exposure to alkylating agents as a cyclophosphamide-equivalent dose (CED).

The team used this formula to evaluate a cohort of cancer survivors and found that CEDs of 4 g/m² or less were associated with normal sperm concentrations.

An account of this research was published in The Lancet Oncology.

“Based on these results, we would recommend pretreatment fertility preservation be offered, whenever clinically possible, to any male whose projected treatment is expected to include a cyclophosphamide-equivalent dose greater than 4 g/m²,” said study author Daniel Green, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Green and his colleagues had studied 214 male survivors of childhood cancer who had a median age of 29. Subjects had received cyclophosphamide and other alkylating agents, but their treatment did not include radiation.

The researchers performed semen analysis in the survivors a median of 21 years from their diagnosis. The analysis showed that 47.6% of survivors had normal sperm concentrations (at least 15 million per milliliter), 27.6% had low sperm counts, and 24.8% produced no sperm.

To determine the impact of alkylating agents on the survivors’ sperm production, the researchers calculated each survivor’s cumulative treatment exposure as a CED.

They did this using the following formula: CED (mg/m²)= 1.0 (cumulative cyclophosphamide dose [mg/m²]) + 0.244 (cumulative ifosfamide dose [mg/m²]) + 0.857 (cumulative procarbazine dose [mg/m²]) + 14.286 (cumulative chlorambucil dose [mg/m²]) + 15.0 (cumulative carmustine dose [mg/m²]) + 16.0 (cumulative lomustine dose [mg/m²]) + 40 (cumulative melphalan dose [mg/m²]) + 50 (cumulative thiotepa dose [mg/m²]) + 100 cumulative chlormethine dose [mg/m²]) + 8.823 (cumulative busulfan dose [mg/m²]).

The researchers could not identify a uniformly safe or toxic dose of these drugs, but they found that survivor sperm concentrations generally decreased as cumulative exposure to alkylating agents increased.

And CEDs of 4 g/m² or less were associated with normal sperm concentrations. Almost 89% of survivors whose CED was 4 g/m² or less had a normal sperm count. Their sperm were also more likely than sperm from other survivors to look and behave normally.

Dr Green did note that, although a lower cumulative dose of alkylating agents was associated with normal sperm production, outcomes for individual patients were unpredictable and varied.

 

 

PET-CT scanner

 

PET-CT should be the new standard for response assessment in patients with follicular lymphoma (FL), according to researchers.

The group found evidence suggesting that PET-CT is more accurate than conventional CT in measuring treatment response and predicting survival in patients with FL.

“Our findings have important implications for patients with follicular lymphoma,” said study author Judith Trotman, MBChB, of the University of Sydney in Australia.

“Compared to conventional CT scanning, PET-CT is more accurate in mapping out the lymphoma and better identifies the majority of patients who have a prolonged remission after treatment.”

Dr Trotman and her colleagues reported these findings in The Lancet Haematology. The results will also be discussed at the International Workshop on PET in Lymphoma in Menton, France, which is taking place September 19-20.

By assessing imaging performed in 3 clinical trials, the researchers examined the link between PET-CT status and survival following first-line immunochemotherapy for advanced FL.

Independent, masked reviewers evaluated scans of 246 patients who underwent both PET-CT and traditional CT imaging within 3 months of their last dose of therapy. Patients were followed for a median of 54.8 months.

Seventeen percent of patients had a positive post-induction PET scan, according to a cutoff of 4 or higher on the 5PS.

When the researchers compared patients with a positive PET scan to those with a negative scan, the hazard ratio (HR) for progression-free survival (PFS) was 3.9 (P<0.0001). For overall survival, the HR was 6.7 (P=0.0002).

The 4-year PFS was 23.2% in patients with a positive PET scan and 63.4% in those who had a negative PET scan (P<0.0001). The 4-year overall survival was 87.2% and 97.1%, respectively (P<0.0001).

The researchers also discovered that conventional CT-based response—complete response or unconfirmed complete response compared to partial response—was weakly predictive of PFS. The HR was 1.7 (P=0.017).

“Our study shows that PET-CT is much better in evaluating treatment response and is an early predictor of survival,” Dr Trotman said. “This greater accuracy will assist physicians to more effectively monitor their patients.”

“We expect this research will result in PET-CT imaging replacing CT, becoming the new gold standard to evaluate patients with follicular lymphoma after treatment. Importantly, it will be a platform for future studies of response-adapted therapies aimed to improve the poor outcomes for those patients who remain PET-positive.”

This study may also pave the way for several new research opportunities, according to Bruce Cheson, MD, of Georgetown University in Washington DC, who wrote a comment article related to this study.

“One such possibility would be to assess if an early reaction to the PET scan result improves patient outcome,” he wrote. “Thus, patients with a positive PET scan after induction therapy could be randomly assigned to either deferred treatment until disease progression or immediate intervention.”

“A preferable alternative would be to introduce a unique agent at that time, such as the newly developed small molecules (eg, idelalisib, ibrutinib, or ABT-199) in a novel combination.”

 

 

PET-CT scanner

 

PET-CT should be the new standard for response assessment in patients with follicular lymphoma (FL), according to researchers.

The group found evidence suggesting that PET-CT is more accurate than conventional CT in measuring treatment response and predicting survival in patients with FL.

“Our findings have important implications for patients with follicular lymphoma,” said study author Judith Trotman, MBChB, of the University of Sydney in Australia.

“Compared to conventional CT scanning, PET-CT is more accurate in mapping out the lymphoma and better identifies the majority of patients who have a prolonged remission after treatment.”

Dr Trotman and her colleagues reported these findings in The Lancet Haematology. The results will also be discussed at the International Workshop on PET in Lymphoma in Menton, France, which is taking place September 19-20.

By assessing imaging performed in 3 clinical trials, the researchers examined the link between PET-CT status and survival following first-line immunochemotherapy for advanced FL.

Independent, masked reviewers evaluated scans of 246 patients who underwent both PET-CT and traditional CT imaging within 3 months of their last dose of therapy. Patients were followed for a median of 54.8 months.

Seventeen percent of patients had a positive post-induction PET scan, according to a cutoff of 4 or higher on the 5PS.

When the researchers compared patients with a positive PET scan to those with a negative scan, the hazard ratio (HR) for progression-free survival (PFS) was 3.9 (P<0.0001). For overall survival, the HR was 6.7 (P=0.0002).

The 4-year PFS was 23.2% in patients with a positive PET scan and 63.4% in those who had a negative PET scan (P<0.0001). The 4-year overall survival was 87.2% and 97.1%, respectively (P<0.0001).

The researchers also discovered that conventional CT-based response—complete response or unconfirmed complete response compared to partial response—was weakly predictive of PFS. The HR was 1.7 (P=0.017).

“Our study shows that PET-CT is much better in evaluating treatment response and is an early predictor of survival,” Dr Trotman said. “This greater accuracy will assist physicians to more effectively monitor their patients.”

“We expect this research will result in PET-CT imaging replacing CT, becoming the new gold standard to evaluate patients with follicular lymphoma after treatment. Importantly, it will be a platform for future studies of response-adapted therapies aimed to improve the poor outcomes for those patients who remain PET-positive.”

This study may also pave the way for several new research opportunities, according to Bruce Cheson, MD, of Georgetown University in Washington DC, who wrote a comment article related to this study.

“One such possibility would be to assess if an early reaction to the PET scan result improves patient outcome,” he wrote. “Thus, patients with a positive PET scan after induction therapy could be randomly assigned to either deferred treatment until disease progression or immediate intervention.”

“A preferable alternative would be to introduce a unique agent at that time, such as the newly developed small molecules (eg, idelalisib, ibrutinib, or ABT-199) in a novel combination.”

 

 

PET-CT scanner

 

PET-CT should be the new standard for response assessment in patients with follicular lymphoma (FL), according to researchers.

The group found evidence suggesting that PET-CT is more accurate than conventional CT in measuring treatment response and predicting survival in patients with FL.

“Our findings have important implications for patients with follicular lymphoma,” said study author Judith Trotman, MBChB, of the University of Sydney in Australia.

“Compared to conventional CT scanning, PET-CT is more accurate in mapping out the lymphoma and better identifies the majority of patients who have a prolonged remission after treatment.”

Dr Trotman and her colleagues reported these findings in The Lancet Haematology. The results will also be discussed at the International Workshop on PET in Lymphoma in Menton, France, which is taking place September 19-20.

By assessing imaging performed in 3 clinical trials, the researchers examined the link between PET-CT status and survival following first-line immunochemotherapy for advanced FL.

Independent, masked reviewers evaluated scans of 246 patients who underwent both PET-CT and traditional CT imaging within 3 months of their last dose of therapy. Patients were followed for a median of 54.8 months.

Seventeen percent of patients had a positive post-induction PET scan, according to a cutoff of 4 or higher on the 5PS.

When the researchers compared patients with a positive PET scan to those with a negative scan, the hazard ratio (HR) for progression-free survival (PFS) was 3.9 (P<0.0001). For overall survival, the HR was 6.7 (P=0.0002).

The 4-year PFS was 23.2% in patients with a positive PET scan and 63.4% in those who had a negative PET scan (P<0.0001). The 4-year overall survival was 87.2% and 97.1%, respectively (P<0.0001).

The researchers also discovered that conventional CT-based response—complete response or unconfirmed complete response compared to partial response—was weakly predictive of PFS. The HR was 1.7 (P=0.017).

“Our study shows that PET-CT is much better in evaluating treatment response and is an early predictor of survival,” Dr Trotman said. “This greater accuracy will assist physicians to more effectively monitor their patients.”

“We expect this research will result in PET-CT imaging replacing CT, becoming the new gold standard to evaluate patients with follicular lymphoma after treatment. Importantly, it will be a platform for future studies of response-adapted therapies aimed to improve the poor outcomes for those patients who remain PET-positive.”

This study may also pave the way for several new research opportunities, according to Bruce Cheson, MD, of Georgetown University in Washington DC, who wrote a comment article related to this study.

“One such possibility would be to assess if an early reaction to the PET scan result improves patient outcome,” he wrote. “Thus, patients with a positive PET scan after induction therapy could be randomly assigned to either deferred treatment until disease progression or immediate intervention.”

“A preferable alternative would be to introduce a unique agent at that time, such as the newly developed small molecules (eg, idelalisib, ibrutinib, or ABT-199) in a novel combination.”

Silicone breast implant

Credit: FDA

A newly published review provides insight into anaplastic large-cell lymphoma (ALCL) associated with breast implants.

Previous reports have demonstrated a link between breast implants and ALCL, but the reasons why implants may contribute to this type of lymphoma have remained unclear.

So Suzanne Turner, PhD, of the University of Cambridge in the UK, and her colleagues evaluated the 71 recorded cases of implant-associated ALCL (iALCL).

The researchers recounted their findings in Mutation Research/Reviews in Mutations Research.

The team calculated that the absolute risk of developing iALCL is low, ranging from 1:500,000 to 1:3,000,000 patients with breast implants per year.

Among the 71 cases of iALCL, the average patient was 50 years of age. The average time from breast augmentation/reconstruction to iALCL diagnosis was 10 years.

Most of the cases presented in the capsule surrounding the implant, as part of the periprosthetic fluid or the capsule itself.

The majority of cases were ALK-negative but had a good prognosis. Of the 49 cases where information on the patients’ progress was available, there were 5 deaths.

Some patients received chemotherapy and radiotherapy, but many achieved remission once the implant and surrounding tissue were removed. This suggests it is the body’s abnormal immune response to the implant that is causing iALCL, the researchers said.

There is some evidence to suggest that having any type of prosthetic implant can increase the risk of lymphoma. And some researchers have suggested that lifestyle differences between patients with and without breast implants may be at the root of iALCL.

But Dr Turner and her colleagues said the biological features of lymphomas in the presence of implants, such as the lack of ALK and the proximity to the implant, suggest a real link.

“It’s becoming clear that implant-related ALCL is a distinct clinical entity in itself,” Dr Turner said. “There are still unanswered questions, and only by getting to the bottom of this very rare disease will we be able to find alternative ways to treat it.”

Silicone breast implant

Credit: FDA

A newly published review provides insight into anaplastic large-cell lymphoma (ALCL) associated with breast implants.

Previous reports have demonstrated a link between breast implants and ALCL, but the reasons why implants may contribute to this type of lymphoma have remained unclear.

So Suzanne Turner, PhD, of the University of Cambridge in the UK, and her colleagues evaluated the 71 recorded cases of implant-associated ALCL (iALCL).

The researchers recounted their findings in Mutation Research/Reviews in Mutations Research.

The team calculated that the absolute risk of developing iALCL is low, ranging from 1:500,000 to 1:3,000,000 patients with breast implants per year.

Among the 71 cases of iALCL, the average patient was 50 years of age. The average time from breast augmentation/reconstruction to iALCL diagnosis was 10 years.

Most of the cases presented in the capsule surrounding the implant, as part of the periprosthetic fluid or the capsule itself.

The majority of cases were ALK-negative but had a good prognosis. Of the 49 cases where information on the patients’ progress was available, there were 5 deaths.

Some patients received chemotherapy and radiotherapy, but many achieved remission once the implant and surrounding tissue were removed. This suggests it is the body’s abnormal immune response to the implant that is causing iALCL, the researchers said.

There is some evidence to suggest that having any type of prosthetic implant can increase the risk of lymphoma. And some researchers have suggested that lifestyle differences between patients with and without breast implants may be at the root of iALCL.

But Dr Turner and her colleagues said the biological features of lymphomas in the presence of implants, such as the lack of ALK and the proximity to the implant, suggest a real link.

“It’s becoming clear that implant-related ALCL is a distinct clinical entity in itself,” Dr Turner said. “There are still unanswered questions, and only by getting to the bottom of this very rare disease will we be able to find alternative ways to treat it.”

Silicone breast implant

Credit: FDA

A newly published review provides insight into anaplastic large-cell lymphoma (ALCL) associated with breast implants.

Previous reports have demonstrated a link between breast implants and ALCL, but the reasons why implants may contribute to this type of lymphoma have remained unclear.

So Suzanne Turner, PhD, of the University of Cambridge in the UK, and her colleagues evaluated the 71 recorded cases of implant-associated ALCL (iALCL).

The researchers recounted their findings in Mutation Research/Reviews in Mutations Research.

The team calculated that the absolute risk of developing iALCL is low, ranging from 1:500,000 to 1:3,000,000 patients with breast implants per year.

Among the 71 cases of iALCL, the average patient was 50 years of age. The average time from breast augmentation/reconstruction to iALCL diagnosis was 10 years.

Most of the cases presented in the capsule surrounding the implant, as part of the periprosthetic fluid or the capsule itself.

The majority of cases were ALK-negative but had a good prognosis. Of the 49 cases where information on the patients’ progress was available, there were 5 deaths.

Some patients received chemotherapy and radiotherapy, but many achieved remission once the implant and surrounding tissue were removed. This suggests it is the body’s abnormal immune response to the implant that is causing iALCL, the researchers said.

There is some evidence to suggest that having any type of prosthetic implant can increase the risk of lymphoma. And some researchers have suggested that lifestyle differences between patients with and without breast implants may be at the root of iALCL.

But Dr Turner and her colleagues said the biological features of lymphomas in the presence of implants, such as the lack of ALK and the proximity to the implant, suggest a real link.

“It’s becoming clear that implant-related ALCL is a distinct clinical entity in itself,” Dr Turner said. “There are still unanswered questions, and only by getting to the bottom of this very rare disease will we be able to find alternative ways to treat it.”