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No evidence for CLL transmission via blood transfusion
Analysis of data from blood transfusions that took place in Sweden and Denmark over a 30-year period showed no indication that chronic lymphocytic leukemia (CLL) risk is higher among recipients of blood from donors who subsequently developed CLL, according to researchers.
The study compared 7,413 recipients of blood from 796 donors who subsequently developed CLL (exposed group), with 80,431 recipients from 7,477 donors free of CLL (unexposed group). In total, 12 recipients in the exposed group and 107 in the unexposed group were later diagnosed with CLL, for an incidence rate ratio of 0.94 (95% confidence interval, 0.52-1.71). When defining “exposed” as receiving blood less than 10 years before donor CLL diagnosis, the incidence rate ratio was 0.46 (95% CI, 0.12-1.85).
“The analyses provided little evidence that donor MBL [monoclonal B-cell lymphocytosis]/CLL transmission in blood products influences recipient CLL risk,” wrote Dr. Henrik Hjalgrim of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his colleagues (Blood 2015 doi: 10.1182/blood-2015-03-632844).
MBL is fairly common in healthy individuals (estimated at 7.1% in a study of American blood donors aged 45-91 years) and may progress to CLL at various rates depending on the MBL cell count. Results from previous studies investigating the association between transfusion and risk of CLL or small lymphocytic lymphoma have been mixed, they noted.
Using a retrospective approach, Dr. Hjalgrim and his associates first identified donors subsequently diagnosed with CLL, then identified control donors free from CLL who were matched for age, sex, county, number of donations, and blood type.
In case MBL may have progressed in the recipient but not the donor, investigators also examined whether CLL clustered among recipients from an individual donor, regardless of donor CLL status, but found no such clusters.
Limiting the analysis was the lack of donor MBL status, for which postdonation CLL diagnosis substituted. Some recipients in the exposed group may have received blood drawn before the donor developed MBL.
Dr. Hjalgrim and his coauthors reported having no disclosures.
Analysis of data from blood transfusions that took place in Sweden and Denmark over a 30-year period showed no indication that chronic lymphocytic leukemia (CLL) risk is higher among recipients of blood from donors who subsequently developed CLL, according to researchers.
The study compared 7,413 recipients of blood from 796 donors who subsequently developed CLL (exposed group), with 80,431 recipients from 7,477 donors free of CLL (unexposed group). In total, 12 recipients in the exposed group and 107 in the unexposed group were later diagnosed with CLL, for an incidence rate ratio of 0.94 (95% confidence interval, 0.52-1.71). When defining “exposed” as receiving blood less than 10 years before donor CLL diagnosis, the incidence rate ratio was 0.46 (95% CI, 0.12-1.85).
“The analyses provided little evidence that donor MBL [monoclonal B-cell lymphocytosis]/CLL transmission in blood products influences recipient CLL risk,” wrote Dr. Henrik Hjalgrim of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his colleagues (Blood 2015 doi: 10.1182/blood-2015-03-632844).
MBL is fairly common in healthy individuals (estimated at 7.1% in a study of American blood donors aged 45-91 years) and may progress to CLL at various rates depending on the MBL cell count. Results from previous studies investigating the association between transfusion and risk of CLL or small lymphocytic lymphoma have been mixed, they noted.
Using a retrospective approach, Dr. Hjalgrim and his associates first identified donors subsequently diagnosed with CLL, then identified control donors free from CLL who were matched for age, sex, county, number of donations, and blood type.
In case MBL may have progressed in the recipient but not the donor, investigators also examined whether CLL clustered among recipients from an individual donor, regardless of donor CLL status, but found no such clusters.
Limiting the analysis was the lack of donor MBL status, for which postdonation CLL diagnosis substituted. Some recipients in the exposed group may have received blood drawn before the donor developed MBL.
Dr. Hjalgrim and his coauthors reported having no disclosures.
Analysis of data from blood transfusions that took place in Sweden and Denmark over a 30-year period showed no indication that chronic lymphocytic leukemia (CLL) risk is higher among recipients of blood from donors who subsequently developed CLL, according to researchers.
The study compared 7,413 recipients of blood from 796 donors who subsequently developed CLL (exposed group), with 80,431 recipients from 7,477 donors free of CLL (unexposed group). In total, 12 recipients in the exposed group and 107 in the unexposed group were later diagnosed with CLL, for an incidence rate ratio of 0.94 (95% confidence interval, 0.52-1.71). When defining “exposed” as receiving blood less than 10 years before donor CLL diagnosis, the incidence rate ratio was 0.46 (95% CI, 0.12-1.85).
“The analyses provided little evidence that donor MBL [monoclonal B-cell lymphocytosis]/CLL transmission in blood products influences recipient CLL risk,” wrote Dr. Henrik Hjalgrim of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his colleagues (Blood 2015 doi: 10.1182/blood-2015-03-632844).
MBL is fairly common in healthy individuals (estimated at 7.1% in a study of American blood donors aged 45-91 years) and may progress to CLL at various rates depending on the MBL cell count. Results from previous studies investigating the association between transfusion and risk of CLL or small lymphocytic lymphoma have been mixed, they noted.
Using a retrospective approach, Dr. Hjalgrim and his associates first identified donors subsequently diagnosed with CLL, then identified control donors free from CLL who were matched for age, sex, county, number of donations, and blood type.
In case MBL may have progressed in the recipient but not the donor, investigators also examined whether CLL clustered among recipients from an individual donor, regardless of donor CLL status, but found no such clusters.
Limiting the analysis was the lack of donor MBL status, for which postdonation CLL diagnosis substituted. Some recipients in the exposed group may have received blood drawn before the donor developed MBL.
Dr. Hjalgrim and his coauthors reported having no disclosures.
FROM BLOOD
Key clinical point: There is no evidence for higher risk of chronic lymphocytic leukemia (CLL) among recipients of blood products from donors who subsequently were diagnosed with CLL.
Major finding: Among exposed recipients (7,413 who received blood from 796 donors who subsequently developed CLL), 12 were diagnosed with CLL. Among unexposed recipients (80,431 who received blood from 7,477 donors free of CLL), 107 were diagnosed with CLL, for an incidence rate ratio of 0.94 (95% CI, 0.52-1.71).
Data source: The Scandinavian Donations and Transfusions (SCANDAT2) database comprises information, including donor and recipient health outcomes, for more than 20 million blood products handled by blood banks from 1968 to 2010.
Disclosures: Dr. Hjalgrim and his coauthors reported having no disclosures.
CLL exosomes promote stromal cell transition into cancer-associated fibroblasts
Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.
Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.
“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi:10.1182/blood-2014-12-618025).
Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.
Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.
The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.
Chronic lymphocytic leukemia results in clonal expansion and invasive migration of cells that infiltrate the lymph nodes and bone marrow. Understanding the tumor microenvironment and the communication that occurs between malignant cells and their surroundings is imperative to improving cancer therapies.
Alongside well-studied signaling mechanisms involving cytokines, growth factors, and receptors, exosome shedding has emerged recently as a key player in cancer signaling. Paggetti et al. comprehensively analyzed CLL-derived exosomes and provided functional data illustrating the impact of exosomes on the tumor microenvironment by reprogramming healthy stromal cells into cancer-associated fibroblasts.
The RNA and proteins delivered by exosomes to stromal cells induce an inflammatory phenotype characteristic of cancer-associated fibroblasts.
The work supports the theory that tumor cell induction of cancer-associated fibroblasts is a universal feature of progression in both solid and blood cancers. Continued research may identify novel therapies that reconfigure the tumor microenvironment for antitumorigenic effect.
Dr. Benedetta Apollonio is a researcher and Dr. Alan Ramsey is a senior lecturer in lymphoma biology at King’s College, London. Their remarks were part of an editorial accompanying the report (Blood 2015 Aug 27. doi:10.1182/blood-2015-07-655233). The authors had no disclosures to report.
Chronic lymphocytic leukemia results in clonal expansion and invasive migration of cells that infiltrate the lymph nodes and bone marrow. Understanding the tumor microenvironment and the communication that occurs between malignant cells and their surroundings is imperative to improving cancer therapies.
Alongside well-studied signaling mechanisms involving cytokines, growth factors, and receptors, exosome shedding has emerged recently as a key player in cancer signaling. Paggetti et al. comprehensively analyzed CLL-derived exosomes and provided functional data illustrating the impact of exosomes on the tumor microenvironment by reprogramming healthy stromal cells into cancer-associated fibroblasts.
The RNA and proteins delivered by exosomes to stromal cells induce an inflammatory phenotype characteristic of cancer-associated fibroblasts.
The work supports the theory that tumor cell induction of cancer-associated fibroblasts is a universal feature of progression in both solid and blood cancers. Continued research may identify novel therapies that reconfigure the tumor microenvironment for antitumorigenic effect.
Dr. Benedetta Apollonio is a researcher and Dr. Alan Ramsey is a senior lecturer in lymphoma biology at King’s College, London. Their remarks were part of an editorial accompanying the report (Blood 2015 Aug 27. doi:10.1182/blood-2015-07-655233). The authors had no disclosures to report.
Chronic lymphocytic leukemia results in clonal expansion and invasive migration of cells that infiltrate the lymph nodes and bone marrow. Understanding the tumor microenvironment and the communication that occurs between malignant cells and their surroundings is imperative to improving cancer therapies.
Alongside well-studied signaling mechanisms involving cytokines, growth factors, and receptors, exosome shedding has emerged recently as a key player in cancer signaling. Paggetti et al. comprehensively analyzed CLL-derived exosomes and provided functional data illustrating the impact of exosomes on the tumor microenvironment by reprogramming healthy stromal cells into cancer-associated fibroblasts.
The RNA and proteins delivered by exosomes to stromal cells induce an inflammatory phenotype characteristic of cancer-associated fibroblasts.
The work supports the theory that tumor cell induction of cancer-associated fibroblasts is a universal feature of progression in both solid and blood cancers. Continued research may identify novel therapies that reconfigure the tumor microenvironment for antitumorigenic effect.
Dr. Benedetta Apollonio is a researcher and Dr. Alan Ramsey is a senior lecturer in lymphoma biology at King’s College, London. Their remarks were part of an editorial accompanying the report (Blood 2015 Aug 27. doi:10.1182/blood-2015-07-655233). The authors had no disclosures to report.
Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.
Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.
“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi:10.1182/blood-2014-12-618025).
Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.
Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.
The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.
Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.
Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.
“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi:10.1182/blood-2014-12-618025).
Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.
Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.
The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.
FROM BLOOD
Key clinical point: Exosomes derived from chronic lymphocytic leukemia (CLL) cells induce stromal cell transition to cancer-associated fibroblasts.
Major finding: CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells.
Data source: In vitro and in vivo studies that used cells obtained from 21 CLL patients.
Disclosures: Jerome Paggetti, Ph.D., and coauthors reported having no disclosures.
Reovirus ready for clinical testing in CLL
Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.
Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.
“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.
Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.
Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.
Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.
The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.
Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.
Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.
“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.
Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.
Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.
Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.
The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.
Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.
Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.
“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.
Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.
Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.
Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.
The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.
FROM LEUKEMIA
Key clinical point: Reovirus, a naturally occurring oncolytic virus, in combination with anti-CD20 immunotherapy, may have benefit for the treatment of chronic lymphocytic leukemia.
Major finding: In cells from 24 CLL patients, about 75% responded to reovirus, with natural killer cell activation.
Data source: Preclinical trial that used human CLL lines and murine L929 cells.
Disclosures: The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.
CLL patients achieve remission with CAR-modified T-cells
Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved a response in 8 of 14 patients (57%) with advanced chronic lymphocytic leukemia (CLL), of whom 4 experienced a complete remission without relapse, based on the mature results of a small pilot study.
Of these four patients, two have remained free of their disease for up to 4 years after they received treatment. An analysis of blood samples also showed that these modified T cells can multiply and persist in the body for a period of years, the researchers report in a study published Sept. 2 in Science Translational Medicine
“Both patients remain alive and cancer free and just passed the 5-year anniversary of their treatment this summer,” said Dr. David L. Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of blood and marrow transplantation at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “A third patient in remission just passed the 3-year anniversary with no signs of leukemia” (Sci Transl Med. 2015;7:303ra139).
The current study indicates the mature results from this trial, which began in the summer of 2010. In 2011, preliminary findings from the first three patients to enroll in the study were published and showed that two of them had experienced a complete response. Their disease currently remains in remission more than 4 years after beginning treatment. The first patient to receive the therapy has been cancer free for 5 years.
In the current trial, 14 patients with relapsed or refractory CLL received at least one infusion of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector. All of the patients had active disease at the time they received the experimental treatment, and had received a median of 5 previous therapies (range, 1-11). One participant had undergone two previous autologous stem cell transplants and one had progressed on ibrutinib therapy.
In addition to those who achieved a complete remission, four other patients (29%) had partial responses to the therapy with responses that persisted for a median of 7 months. Two died of disease progression at 10 and 27 months after receiving CTL019, and one died from a pulmonary embolism; the remaining patient remains alive after CLL progressed at 13 months, and is receiving other therapies.
Overall, the CTL019 infusions were well tolerated, with grade less than 2 toxicities that included primarily low-grade fevers and chills. The most frequent related events were associated with complications of neutropenia and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. There were two cases of tumor lysis syndrome, and one patient died in remission 21 months after T cell infusion, after developing ecthyma gangrenosum after pseudomonas infection at a skin biopsy site.
Six subjects (43%) had no response and all six progressed within 1-9 months (median, 4 months) of CTL019 therapy. “We are working hard to determine why this therapy may be appropriate for some patients and not others, and trying to optimize either treatment conditions or patient-specific factors so that this might be more effective for more patients,” Dr. Porter wrote.
Minimal residual disease was not detectable in patients who achieved a complete response, suggesting that disease eradication may be possible in some patients with advanced CLL. The activity of CTLO19 seemed to be on par with results achieved with allogeneic stem cell transplantation, suggesting that this therapy could possibly cure CLL. But Dr. Porter pointed out that this study was conducted with a small number of patients and for CLL, a relatively short follow-up.
“However, these patients all had heavily pretreated resistant disease,” he said. “Though we do not know if patients are indeed cured, it is certainly our goal to find a cure for CLL and without the toxicities and limitations of allogeneic stem cell transplantation. Indeed, longer follow-up will be needed but we are quite excited about the results to date.”
Dr. Porter said he and his team have ongoing trials in CLL in progress, where they are working on trying to identify the optimal dose of T cells for this approach. Also, “this research has led to expansion of this approach to other B cell malignancies such as acute lymphocytic leukemia.”
Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.
Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved a response in 8 of 14 patients (57%) with advanced chronic lymphocytic leukemia (CLL), of whom 4 experienced a complete remission without relapse, based on the mature results of a small pilot study.
Of these four patients, two have remained free of their disease for up to 4 years after they received treatment. An analysis of blood samples also showed that these modified T cells can multiply and persist in the body for a period of years, the researchers report in a study published Sept. 2 in Science Translational Medicine
“Both patients remain alive and cancer free and just passed the 5-year anniversary of their treatment this summer,” said Dr. David L. Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of blood and marrow transplantation at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “A third patient in remission just passed the 3-year anniversary with no signs of leukemia” (Sci Transl Med. 2015;7:303ra139).
The current study indicates the mature results from this trial, which began in the summer of 2010. In 2011, preliminary findings from the first three patients to enroll in the study were published and showed that two of them had experienced a complete response. Their disease currently remains in remission more than 4 years after beginning treatment. The first patient to receive the therapy has been cancer free for 5 years.
In the current trial, 14 patients with relapsed or refractory CLL received at least one infusion of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector. All of the patients had active disease at the time they received the experimental treatment, and had received a median of 5 previous therapies (range, 1-11). One participant had undergone two previous autologous stem cell transplants and one had progressed on ibrutinib therapy.
In addition to those who achieved a complete remission, four other patients (29%) had partial responses to the therapy with responses that persisted for a median of 7 months. Two died of disease progression at 10 and 27 months after receiving CTL019, and one died from a pulmonary embolism; the remaining patient remains alive after CLL progressed at 13 months, and is receiving other therapies.
Overall, the CTL019 infusions were well tolerated, with grade less than 2 toxicities that included primarily low-grade fevers and chills. The most frequent related events were associated with complications of neutropenia and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. There were two cases of tumor lysis syndrome, and one patient died in remission 21 months after T cell infusion, after developing ecthyma gangrenosum after pseudomonas infection at a skin biopsy site.
Six subjects (43%) had no response and all six progressed within 1-9 months (median, 4 months) of CTL019 therapy. “We are working hard to determine why this therapy may be appropriate for some patients and not others, and trying to optimize either treatment conditions or patient-specific factors so that this might be more effective for more patients,” Dr. Porter wrote.
Minimal residual disease was not detectable in patients who achieved a complete response, suggesting that disease eradication may be possible in some patients with advanced CLL. The activity of CTLO19 seemed to be on par with results achieved with allogeneic stem cell transplantation, suggesting that this therapy could possibly cure CLL. But Dr. Porter pointed out that this study was conducted with a small number of patients and for CLL, a relatively short follow-up.
“However, these patients all had heavily pretreated resistant disease,” he said. “Though we do not know if patients are indeed cured, it is certainly our goal to find a cure for CLL and without the toxicities and limitations of allogeneic stem cell transplantation. Indeed, longer follow-up will be needed but we are quite excited about the results to date.”
Dr. Porter said he and his team have ongoing trials in CLL in progress, where they are working on trying to identify the optimal dose of T cells for this approach. Also, “this research has led to expansion of this approach to other B cell malignancies such as acute lymphocytic leukemia.”
Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.
Treatment with chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved a response in 8 of 14 patients (57%) with advanced chronic lymphocytic leukemia (CLL), of whom 4 experienced a complete remission without relapse, based on the mature results of a small pilot study.
Of these four patients, two have remained free of their disease for up to 4 years after they received treatment. An analysis of blood samples also showed that these modified T cells can multiply and persist in the body for a period of years, the researchers report in a study published Sept. 2 in Science Translational Medicine
“Both patients remain alive and cancer free and just passed the 5-year anniversary of their treatment this summer,” said Dr. David L. Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of blood and marrow transplantation at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “A third patient in remission just passed the 3-year anniversary with no signs of leukemia” (Sci Transl Med. 2015;7:303ra139).
The current study indicates the mature results from this trial, which began in the summer of 2010. In 2011, preliminary findings from the first three patients to enroll in the study were published and showed that two of them had experienced a complete response. Their disease currently remains in remission more than 4 years after beginning treatment. The first patient to receive the therapy has been cancer free for 5 years.
In the current trial, 14 patients with relapsed or refractory CLL received at least one infusion of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector. All of the patients had active disease at the time they received the experimental treatment, and had received a median of 5 previous therapies (range, 1-11). One participant had undergone two previous autologous stem cell transplants and one had progressed on ibrutinib therapy.
In addition to those who achieved a complete remission, four other patients (29%) had partial responses to the therapy with responses that persisted for a median of 7 months. Two died of disease progression at 10 and 27 months after receiving CTL019, and one died from a pulmonary embolism; the remaining patient remains alive after CLL progressed at 13 months, and is receiving other therapies.
Overall, the CTL019 infusions were well tolerated, with grade less than 2 toxicities that included primarily low-grade fevers and chills. The most frequent related events were associated with complications of neutropenia and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. There were two cases of tumor lysis syndrome, and one patient died in remission 21 months after T cell infusion, after developing ecthyma gangrenosum after pseudomonas infection at a skin biopsy site.
Six subjects (43%) had no response and all six progressed within 1-9 months (median, 4 months) of CTL019 therapy. “We are working hard to determine why this therapy may be appropriate for some patients and not others, and trying to optimize either treatment conditions or patient-specific factors so that this might be more effective for more patients,” Dr. Porter wrote.
Minimal residual disease was not detectable in patients who achieved a complete response, suggesting that disease eradication may be possible in some patients with advanced CLL. The activity of CTLO19 seemed to be on par with results achieved with allogeneic stem cell transplantation, suggesting that this therapy could possibly cure CLL. But Dr. Porter pointed out that this study was conducted with a small number of patients and for CLL, a relatively short follow-up.
“However, these patients all had heavily pretreated resistant disease,” he said. “Though we do not know if patients are indeed cured, it is certainly our goal to find a cure for CLL and without the toxicities and limitations of allogeneic stem cell transplantation. Indeed, longer follow-up will be needed but we are quite excited about the results to date.”
Dr. Porter said he and his team have ongoing trials in CLL in progress, where they are working on trying to identify the optimal dose of T cells for this approach. Also, “this research has led to expansion of this approach to other B cell malignancies such as acute lymphocytic leukemia.”
Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: CAR-modified T cell therapy lacks the toxicities and limitations of allogeneic stem cell transplantation and may be an effective treatment for chronic lymphocytic leukemia.
Major finding: CAR-modified T cell therapy elicited a response in 8 of 14 patients (57%) with relapsed and refractory chronic lymphocytic leukemia, and 4 patients (29%) achieved a complete remission.
Data source: Mature results from a pilot clinical trial.
Disclosures: Novartis, the Leukemia and Lymphoma Society (Specialized Center of Research Award), and the National Institutes of Health funded the study. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Some scientists involved in these trials, including Dr. Porter, are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially and/or may benefit financially in the future.
Melanoma twice as likely after CLL/SLL than other types of NHL
Survivors of chronic lymphocytic leukemia/small lymphocytic lymphoma are twice as likely to develop melanoma as are survivors of other types of non-Hodgkin lymphoma, according to a report published online Aug. 3 in Journal of Clinical Oncology.
Since patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have profound and prolonged immune dysfunction characterized by B-cell and T-cell defects, this finding suggests that immune perturbation may account for the excess of melanoma diagnoses observed in patients with non-Hodgkin lymphoma (NHL), said Dr. Clara J. K. Lam of the radiation epidemiology branch, National Cancer Institute, Bethesda Md., and her associates.
Although patients with NHL are known to be at increased risk for melanoma compared with the general population, the reasons remain unclear. Additional factors such as chemotherapy regimens and sunlight exposure likely complicate the picture, and no studies to date have been able to account for these confounders. To assess a large enough study sample to examine these issues, Dr. Lam and her associates analyzed data concerning 44,870 NHL survivors in the Surveillance, Epidemiology, and End Results (SEER) database. They focused on older patients aged 66-83 years at NHL diagnosis (mean age, 74 years) who were followed for at least 1 year (mean follow-up, 5.5 years), of whom 13,950 had CLL/SLL.
A total of 202 melanomas developed, and the median interval between NHL diagnosis and melanoma diagnosis was 3 years (range, 1-15 years). Nearly half of these melanomas occurred in patients with CLL/SLL rather than other types of NHL; 41% occurred on the face, head, or neck, and 43% were 1 mm or more in thickness. In contrast, among survivors of other NHL types, melanoma occurred most often on the trunk, and only 28% were 1 mm or more in thickness. This aligns with previous reports that melanomas arising after NHL tend to be more advanced and aggressive than those in the general population, the investigators said (J Clin Oncol. 2015 Aug 3. doi:10.1200/JCO.2014.60.2094).
Further analysis revealed that among patients with CLL/SLL, melanoma risk was significantly increased in those who received fludarabine rather than other treatments (HR, 1.90, 95% CI, 1.08 to 3.37)), with or without the addition of rituximab. In contrast, melanoma risks were unrelated to treatment among patients who had other types of NHL.
Similarly, patients with CLL/SLL who had T-cell-activating autoimmune disorders (such as Graves’ disease, localized scleroderma, psoriasis, chronic rheumatic heart disease, asthma, or skin-related conditions) either before or after diagnosis of their leukemia/lymphoma also had 2-4 times the risk of developing melanoma than that of patients without such autoimmune disorders. In contrast, melanoma risks were unrelated to autoimmune disorders in patients with other types of NHL. This finding underscores the importance of T-cell dysfunction as a contributor to melanoma risk after CLL/SLL, Dr. Lam and her associates said.
Taken together, their findings identify which survivors of NHL are at highest risk for developing melanoma and would benefit the most from undergoing regular full-skin examinations to facilitate early detection.
This study was limited in that it was confined to patients over age 65 with NHL. The results may not be generalizable to younger patients, Dr. Lam and her associates added.
Survivors of chronic lymphocytic leukemia/small lymphocytic lymphoma are twice as likely to develop melanoma as are survivors of other types of non-Hodgkin lymphoma, according to a report published online Aug. 3 in Journal of Clinical Oncology.
Since patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have profound and prolonged immune dysfunction characterized by B-cell and T-cell defects, this finding suggests that immune perturbation may account for the excess of melanoma diagnoses observed in patients with non-Hodgkin lymphoma (NHL), said Dr. Clara J. K. Lam of the radiation epidemiology branch, National Cancer Institute, Bethesda Md., and her associates.
Although patients with NHL are known to be at increased risk for melanoma compared with the general population, the reasons remain unclear. Additional factors such as chemotherapy regimens and sunlight exposure likely complicate the picture, and no studies to date have been able to account for these confounders. To assess a large enough study sample to examine these issues, Dr. Lam and her associates analyzed data concerning 44,870 NHL survivors in the Surveillance, Epidemiology, and End Results (SEER) database. They focused on older patients aged 66-83 years at NHL diagnosis (mean age, 74 years) who were followed for at least 1 year (mean follow-up, 5.5 years), of whom 13,950 had CLL/SLL.
A total of 202 melanomas developed, and the median interval between NHL diagnosis and melanoma diagnosis was 3 years (range, 1-15 years). Nearly half of these melanomas occurred in patients with CLL/SLL rather than other types of NHL; 41% occurred on the face, head, or neck, and 43% were 1 mm or more in thickness. In contrast, among survivors of other NHL types, melanoma occurred most often on the trunk, and only 28% were 1 mm or more in thickness. This aligns with previous reports that melanomas arising after NHL tend to be more advanced and aggressive than those in the general population, the investigators said (J Clin Oncol. 2015 Aug 3. doi:10.1200/JCO.2014.60.2094).
Further analysis revealed that among patients with CLL/SLL, melanoma risk was significantly increased in those who received fludarabine rather than other treatments (HR, 1.90, 95% CI, 1.08 to 3.37)), with or without the addition of rituximab. In contrast, melanoma risks were unrelated to treatment among patients who had other types of NHL.
Similarly, patients with CLL/SLL who had T-cell-activating autoimmune disorders (such as Graves’ disease, localized scleroderma, psoriasis, chronic rheumatic heart disease, asthma, or skin-related conditions) either before or after diagnosis of their leukemia/lymphoma also had 2-4 times the risk of developing melanoma than that of patients without such autoimmune disorders. In contrast, melanoma risks were unrelated to autoimmune disorders in patients with other types of NHL. This finding underscores the importance of T-cell dysfunction as a contributor to melanoma risk after CLL/SLL, Dr. Lam and her associates said.
Taken together, their findings identify which survivors of NHL are at highest risk for developing melanoma and would benefit the most from undergoing regular full-skin examinations to facilitate early detection.
This study was limited in that it was confined to patients over age 65 with NHL. The results may not be generalizable to younger patients, Dr. Lam and her associates added.
Survivors of chronic lymphocytic leukemia/small lymphocytic lymphoma are twice as likely to develop melanoma as are survivors of other types of non-Hodgkin lymphoma, according to a report published online Aug. 3 in Journal of Clinical Oncology.
Since patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have profound and prolonged immune dysfunction characterized by B-cell and T-cell defects, this finding suggests that immune perturbation may account for the excess of melanoma diagnoses observed in patients with non-Hodgkin lymphoma (NHL), said Dr. Clara J. K. Lam of the radiation epidemiology branch, National Cancer Institute, Bethesda Md., and her associates.
Although patients with NHL are known to be at increased risk for melanoma compared with the general population, the reasons remain unclear. Additional factors such as chemotherapy regimens and sunlight exposure likely complicate the picture, and no studies to date have been able to account for these confounders. To assess a large enough study sample to examine these issues, Dr. Lam and her associates analyzed data concerning 44,870 NHL survivors in the Surveillance, Epidemiology, and End Results (SEER) database. They focused on older patients aged 66-83 years at NHL diagnosis (mean age, 74 years) who were followed for at least 1 year (mean follow-up, 5.5 years), of whom 13,950 had CLL/SLL.
A total of 202 melanomas developed, and the median interval between NHL diagnosis and melanoma diagnosis was 3 years (range, 1-15 years). Nearly half of these melanomas occurred in patients with CLL/SLL rather than other types of NHL; 41% occurred on the face, head, or neck, and 43% were 1 mm or more in thickness. In contrast, among survivors of other NHL types, melanoma occurred most often on the trunk, and only 28% were 1 mm or more in thickness. This aligns with previous reports that melanomas arising after NHL tend to be more advanced and aggressive than those in the general population, the investigators said (J Clin Oncol. 2015 Aug 3. doi:10.1200/JCO.2014.60.2094).
Further analysis revealed that among patients with CLL/SLL, melanoma risk was significantly increased in those who received fludarabine rather than other treatments (HR, 1.90, 95% CI, 1.08 to 3.37)), with or without the addition of rituximab. In contrast, melanoma risks were unrelated to treatment among patients who had other types of NHL.
Similarly, patients with CLL/SLL who had T-cell-activating autoimmune disorders (such as Graves’ disease, localized scleroderma, psoriasis, chronic rheumatic heart disease, asthma, or skin-related conditions) either before or after diagnosis of their leukemia/lymphoma also had 2-4 times the risk of developing melanoma than that of patients without such autoimmune disorders. In contrast, melanoma risks were unrelated to autoimmune disorders in patients with other types of NHL. This finding underscores the importance of T-cell dysfunction as a contributor to melanoma risk after CLL/SLL, Dr. Lam and her associates said.
Taken together, their findings identify which survivors of NHL are at highest risk for developing melanoma and would benefit the most from undergoing regular full-skin examinations to facilitate early detection.
This study was limited in that it was confined to patients over age 65 with NHL. The results may not be generalizable to younger patients, Dr. Lam and her associates added.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Survivors of chronic lymphocytic leukemia/small lymphocytic lymphoma are twice as likely to develop melanoma as are survivors of other types of non-Hodgkin lymphoma.
Major finding: A total of 202 melanomas developed during 5.5 years of follow-up, and nearly half occurred in patients with CLL/SLL rather than other types of NHL.
Data source: A large population-based study using SEER data to assess melanoma risk in 44,870 older survivors of non-Hodgkin lymphoma.
Disclosures: The National Cancer Institute supported the study. Dr. Lam and her associates reported having no relevant financial disclosures.
Index discriminates prognostic groups in CLL
An international prognostic index for patients with chronic lymphocytic leukemia (CLL) may help to inform treatment decisions, based on a meta-analysis presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland.
The International Prognostic Index for patients with CLL (CLL-IPI) combines the most important genetic risk factors and traditional clinical stage, age, and serum beta-2-microglobulin measures. By discriminating between prognostic groups, the index may aid in informing treatment of CLL patients, Dr. Jasmin Bahlo of the University Hospital Cologne, Köln, Germany, said.
The CLL-IPI consists of five risk factors – age, clinical stage, IgHV (immunoglobulin heavy-chain variable-region) gene mutation status, serum beta-2-microglobulin measure, and the presence of del(17p) and/or TP53 mutation, Dr. Bahlo said.
To develop the index, Dr. Bahlo and colleagues performed an analysis of 26 possible prognostic factors by using data from eight phase III trials from France, Germany, the United Kingdom, the United States, and Poland. The data included a full analysis set of 3,742 previously untreated patients at early and advanced stages of disease. The median age of the patients was 61 years, the median observation time was 80 months, and the main endpoint was overall survival.
From the 26 variables, the researchers identified five independent predictors for overall survival: age (65 years or more), clinical stage (Binet A/Rai 0 vs. Binet B-C/Rai I-IV), del(17p) and/or TP53 mutation status, IgHV mutation status, and serum beta-2-microglobulin measure (3.5 mg/L or more).
The index was used to identify four risk groups – low risk (score 0-1), intermediate (score 2-3), high (score 4-6), and very high (score 7-10)) – with significantly different overall survival rates at 5 years of 93%, 79%, 64%, and 23%, respectively.
The value of the index was then confirmed in 575 patients, with a 5-year overall survival rate of 91%, 80%, 52%, and 19%, respectively.
Similar findings were seen in an external data set of patients from the Mayo Clinic data set, with 5-year overall survivals of 97%, 91%, 68%, and 21%, respectively. The CLL-IPI also provided accurate estimation regarding time to first treatment; 81%, 47%, 30%, and 19% of patients in the respective risk groups were free from treatment at 5 years.
In the era of more effective treatments for CLL, the established clinical staging systems (Rai and Binet) do not accurately discriminate between prognostic groups because they do not integrate the major clinical, biologic, and genetic variables into one widely accepted prognostic system, Dr. Bahlo noted. The CLL-IPI is, therefore, an important contribution to management of this condition.
The researchers had no relevant financial disclosures.
Until very recently, most treatment decisions in CLL have been based on age, overall fitness of the patient and presence of cytopenias. Biologic prognostic markers have been delineated, but not acted upon, with the recent exception of del17p given the advent of effective novel agents in this setting. This is an admirable attempt to establish a better prognostic index, building upon prior German CLL group data (Pflug et al Blood 2014), but it has limitations. It is a weighted score, heavily dependent on p53 mutation/del17p, which is uncommon at initial diagnosis, and today such patients should be receiving a targeted agent. It would be useful to have a CLL-IPI for patients without del17p. Further, while its ability to predict time to require therapy will remain useful, its survival predictions are likely already outdated given the array of new agents already, or soon to be, available.
Until very recently, most treatment decisions in CLL have been based on age, overall fitness of the patient and presence of cytopenias. Biologic prognostic markers have been delineated, but not acted upon, with the recent exception of del17p given the advent of effective novel agents in this setting. This is an admirable attempt to establish a better prognostic index, building upon prior German CLL group data (Pflug et al Blood 2014), but it has limitations. It is a weighted score, heavily dependent on p53 mutation/del17p, which is uncommon at initial diagnosis, and today such patients should be receiving a targeted agent. It would be useful to have a CLL-IPI for patients without del17p. Further, while its ability to predict time to require therapy will remain useful, its survival predictions are likely already outdated given the array of new agents already, or soon to be, available.
Until very recently, most treatment decisions in CLL have been based on age, overall fitness of the patient and presence of cytopenias. Biologic prognostic markers have been delineated, but not acted upon, with the recent exception of del17p given the advent of effective novel agents in this setting. This is an admirable attempt to establish a better prognostic index, building upon prior German CLL group data (Pflug et al Blood 2014), but it has limitations. It is a weighted score, heavily dependent on p53 mutation/del17p, which is uncommon at initial diagnosis, and today such patients should be receiving a targeted agent. It would be useful to have a CLL-IPI for patients without del17p. Further, while its ability to predict time to require therapy will remain useful, its survival predictions are likely already outdated given the array of new agents already, or soon to be, available.
An international prognostic index for patients with chronic lymphocytic leukemia (CLL) may help to inform treatment decisions, based on a meta-analysis presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland.
The International Prognostic Index for patients with CLL (CLL-IPI) combines the most important genetic risk factors and traditional clinical stage, age, and serum beta-2-microglobulin measures. By discriminating between prognostic groups, the index may aid in informing treatment of CLL patients, Dr. Jasmin Bahlo of the University Hospital Cologne, Köln, Germany, said.
The CLL-IPI consists of five risk factors – age, clinical stage, IgHV (immunoglobulin heavy-chain variable-region) gene mutation status, serum beta-2-microglobulin measure, and the presence of del(17p) and/or TP53 mutation, Dr. Bahlo said.
To develop the index, Dr. Bahlo and colleagues performed an analysis of 26 possible prognostic factors by using data from eight phase III trials from France, Germany, the United Kingdom, the United States, and Poland. The data included a full analysis set of 3,742 previously untreated patients at early and advanced stages of disease. The median age of the patients was 61 years, the median observation time was 80 months, and the main endpoint was overall survival.
From the 26 variables, the researchers identified five independent predictors for overall survival: age (65 years or more), clinical stage (Binet A/Rai 0 vs. Binet B-C/Rai I-IV), del(17p) and/or TP53 mutation status, IgHV mutation status, and serum beta-2-microglobulin measure (3.5 mg/L or more).
The index was used to identify four risk groups – low risk (score 0-1), intermediate (score 2-3), high (score 4-6), and very high (score 7-10)) – with significantly different overall survival rates at 5 years of 93%, 79%, 64%, and 23%, respectively.
The value of the index was then confirmed in 575 patients, with a 5-year overall survival rate of 91%, 80%, 52%, and 19%, respectively.
Similar findings were seen in an external data set of patients from the Mayo Clinic data set, with 5-year overall survivals of 97%, 91%, 68%, and 21%, respectively. The CLL-IPI also provided accurate estimation regarding time to first treatment; 81%, 47%, 30%, and 19% of patients in the respective risk groups were free from treatment at 5 years.
In the era of more effective treatments for CLL, the established clinical staging systems (Rai and Binet) do not accurately discriminate between prognostic groups because they do not integrate the major clinical, biologic, and genetic variables into one widely accepted prognostic system, Dr. Bahlo noted. The CLL-IPI is, therefore, an important contribution to management of this condition.
The researchers had no relevant financial disclosures.
An international prognostic index for patients with chronic lymphocytic leukemia (CLL) may help to inform treatment decisions, based on a meta-analysis presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland.
The International Prognostic Index for patients with CLL (CLL-IPI) combines the most important genetic risk factors and traditional clinical stage, age, and serum beta-2-microglobulin measures. By discriminating between prognostic groups, the index may aid in informing treatment of CLL patients, Dr. Jasmin Bahlo of the University Hospital Cologne, Köln, Germany, said.
The CLL-IPI consists of five risk factors – age, clinical stage, IgHV (immunoglobulin heavy-chain variable-region) gene mutation status, serum beta-2-microglobulin measure, and the presence of del(17p) and/or TP53 mutation, Dr. Bahlo said.
To develop the index, Dr. Bahlo and colleagues performed an analysis of 26 possible prognostic factors by using data from eight phase III trials from France, Germany, the United Kingdom, the United States, and Poland. The data included a full analysis set of 3,742 previously untreated patients at early and advanced stages of disease. The median age of the patients was 61 years, the median observation time was 80 months, and the main endpoint was overall survival.
From the 26 variables, the researchers identified five independent predictors for overall survival: age (65 years or more), clinical stage (Binet A/Rai 0 vs. Binet B-C/Rai I-IV), del(17p) and/or TP53 mutation status, IgHV mutation status, and serum beta-2-microglobulin measure (3.5 mg/L or more).
The index was used to identify four risk groups – low risk (score 0-1), intermediate (score 2-3), high (score 4-6), and very high (score 7-10)) – with significantly different overall survival rates at 5 years of 93%, 79%, 64%, and 23%, respectively.
The value of the index was then confirmed in 575 patients, with a 5-year overall survival rate of 91%, 80%, 52%, and 19%, respectively.
Similar findings were seen in an external data set of patients from the Mayo Clinic data set, with 5-year overall survivals of 97%, 91%, 68%, and 21%, respectively. The CLL-IPI also provided accurate estimation regarding time to first treatment; 81%, 47%, 30%, and 19% of patients in the respective risk groups were free from treatment at 5 years.
In the era of more effective treatments for CLL, the established clinical staging systems (Rai and Binet) do not accurately discriminate between prognostic groups because they do not integrate the major clinical, biologic, and genetic variables into one widely accepted prognostic system, Dr. Bahlo noted. The CLL-IPI is, therefore, an important contribution to management of this condition.
The researchers had no relevant financial disclosures.
FROM 13-ICML
Key clinical point: An international prognostic index for patients with chronic lymphocytic leukemia may help to inform treatment decisions.
Major finding: The index was used to identify four risk groups – low risk (score 0-1), intermediate (score 2-3), high (score 4-6), and very high (score 7-10)) – with significantly different overall survival rates at 5 years of 93%, 79%, 64%, and 23%, respectively.
Data source: A multivariate analysis of 3,742 previously untreated patients at early and advanced CLL stages.
Disclosures: The researchers had no relevant financial disclosures.
VIDEO: Ibrutinib should be therapy ‘backbone’ in relapsed CLL
CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.
In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.
“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.
In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.
In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.
“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.
In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.
In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.
“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.
In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE 2015 ASCO ANNUAL MEETING
EHA: Venetoclax-rituxumab combo highly active in relapsed/refractory CLL
VIENNA – A daily dose of the investigational BCL-2 inhibitor venetoclax plus rituximab induced responses in 84% of patients with relapsed or refractory chronic lymphocytic leukemia in a phase Ib study.
Of the 49 patients, 20 (41%) achieved a complete response by standard assessment and 13 (27%) achieved a complete response with no evidence of residual disease on flow cytometry.
Moreover, six patients elected to stop venetoclax after achieving a complete response and, to date, only one has had recurrence of disease after 24 months without therapy, lead investigator Dr. Andrew W. Roberts reported at the annual congress of the European Hematology Association.
Not only were patients able to come off treatment and continue to remain in complete response, but responses were seen at the same frequencies across all classes of cytogenetic and molecular abnormalities, he noted.
“The greatest advance that this drug brings is for those patients who currently have a terrible prognosis with all other drugs that we now have,” Dr. Roberts of Royal Melbourne Hospital said in a press briefing.
“This is an important step forward in finding chemotherapy-free regimens in these vulnerable, elderly patients,” said press briefing moderator Dr. Anton Hagenbeek of the University Medical Center, Utrecht, the Netherlands.
Patients in the open-label, dose-escalation study had received a median of two prior lines of therapy (range, one to five) for chronic lymphocytic leukemia (CLL); their median age was 68 years (50-88 years). They began treatment with 20 mg or 50 mg venetoclax daily, increasing weekly to final cohort doses of 200 mg to 600 mg. Six cycles of monthly standard rituximab were added after the weekly lead-in phase.
CLL depends on high levels of B-cell lymphoma-2 (BCL-2) to stay alive. Venetoclax binds to and switches off the BCL-2 protein function, triggering the death of the CLL cell.
Grade 3 or 4 adverse events occurring in more than 10% of patients were neutropenia (51%), thrombocytopenia (16%), and anemia (14%). There was one treatment-emergent case of tumor lysis syndrome leading to death early in the trial. This phenomenon can occur when the CLL breaks down very quickly and, as a consequence, the study was redesigned and a lower starting dose is now used, Dr. Roberts said.
“That problem has been eliminated, but we still see a very large improvement in patients in a few weeks,” he said. “Other than that, there is a little bit of neutropenia, but that is very manageable.”
“So do you think you are curing patients with this approach?” Dr. Hagenbeek asked, to which Dr. Roberts replied, “Too early to say.”
Venetoclax is currently being evaluated in less heavily pretreated patients and a phase III trial is comparing the combination of venetoclax and rituximab with standard bendamustine chemotherapy plus rituximab, he said.
In May, the Food and Drug Administration granted venetoclax breakthrough therapy designation for use in relapsed or refractory chronic lymphocytic leukemia with a 17p deletion mutation.
AbbVie, which is developing venetoclax in partnership with Roche and Genentech, plans to submit regulatory applications for venetoclax to the FDA and the European Medicines Agency before the end of 2015.
On Twitter @pwendl
VIENNA – A daily dose of the investigational BCL-2 inhibitor venetoclax plus rituximab induced responses in 84% of patients with relapsed or refractory chronic lymphocytic leukemia in a phase Ib study.
Of the 49 patients, 20 (41%) achieved a complete response by standard assessment and 13 (27%) achieved a complete response with no evidence of residual disease on flow cytometry.
Moreover, six patients elected to stop venetoclax after achieving a complete response and, to date, only one has had recurrence of disease after 24 months without therapy, lead investigator Dr. Andrew W. Roberts reported at the annual congress of the European Hematology Association.
Not only were patients able to come off treatment and continue to remain in complete response, but responses were seen at the same frequencies across all classes of cytogenetic and molecular abnormalities, he noted.
“The greatest advance that this drug brings is for those patients who currently have a terrible prognosis with all other drugs that we now have,” Dr. Roberts of Royal Melbourne Hospital said in a press briefing.
“This is an important step forward in finding chemotherapy-free regimens in these vulnerable, elderly patients,” said press briefing moderator Dr. Anton Hagenbeek of the University Medical Center, Utrecht, the Netherlands.
Patients in the open-label, dose-escalation study had received a median of two prior lines of therapy (range, one to five) for chronic lymphocytic leukemia (CLL); their median age was 68 years (50-88 years). They began treatment with 20 mg or 50 mg venetoclax daily, increasing weekly to final cohort doses of 200 mg to 600 mg. Six cycles of monthly standard rituximab were added after the weekly lead-in phase.
CLL depends on high levels of B-cell lymphoma-2 (BCL-2) to stay alive. Venetoclax binds to and switches off the BCL-2 protein function, triggering the death of the CLL cell.
Grade 3 or 4 adverse events occurring in more than 10% of patients were neutropenia (51%), thrombocytopenia (16%), and anemia (14%). There was one treatment-emergent case of tumor lysis syndrome leading to death early in the trial. This phenomenon can occur when the CLL breaks down very quickly and, as a consequence, the study was redesigned and a lower starting dose is now used, Dr. Roberts said.
“That problem has been eliminated, but we still see a very large improvement in patients in a few weeks,” he said. “Other than that, there is a little bit of neutropenia, but that is very manageable.”
“So do you think you are curing patients with this approach?” Dr. Hagenbeek asked, to which Dr. Roberts replied, “Too early to say.”
Venetoclax is currently being evaluated in less heavily pretreated patients and a phase III trial is comparing the combination of venetoclax and rituximab with standard bendamustine chemotherapy plus rituximab, he said.
In May, the Food and Drug Administration granted venetoclax breakthrough therapy designation for use in relapsed or refractory chronic lymphocytic leukemia with a 17p deletion mutation.
AbbVie, which is developing venetoclax in partnership with Roche and Genentech, plans to submit regulatory applications for venetoclax to the FDA and the European Medicines Agency before the end of 2015.
On Twitter @pwendl
VIENNA – A daily dose of the investigational BCL-2 inhibitor venetoclax plus rituximab induced responses in 84% of patients with relapsed or refractory chronic lymphocytic leukemia in a phase Ib study.
Of the 49 patients, 20 (41%) achieved a complete response by standard assessment and 13 (27%) achieved a complete response with no evidence of residual disease on flow cytometry.
Moreover, six patients elected to stop venetoclax after achieving a complete response and, to date, only one has had recurrence of disease after 24 months without therapy, lead investigator Dr. Andrew W. Roberts reported at the annual congress of the European Hematology Association.
Not only were patients able to come off treatment and continue to remain in complete response, but responses were seen at the same frequencies across all classes of cytogenetic and molecular abnormalities, he noted.
“The greatest advance that this drug brings is for those patients who currently have a terrible prognosis with all other drugs that we now have,” Dr. Roberts of Royal Melbourne Hospital said in a press briefing.
“This is an important step forward in finding chemotherapy-free regimens in these vulnerable, elderly patients,” said press briefing moderator Dr. Anton Hagenbeek of the University Medical Center, Utrecht, the Netherlands.
Patients in the open-label, dose-escalation study had received a median of two prior lines of therapy (range, one to five) for chronic lymphocytic leukemia (CLL); their median age was 68 years (50-88 years). They began treatment with 20 mg or 50 mg venetoclax daily, increasing weekly to final cohort doses of 200 mg to 600 mg. Six cycles of monthly standard rituximab were added after the weekly lead-in phase.
CLL depends on high levels of B-cell lymphoma-2 (BCL-2) to stay alive. Venetoclax binds to and switches off the BCL-2 protein function, triggering the death of the CLL cell.
Grade 3 or 4 adverse events occurring in more than 10% of patients were neutropenia (51%), thrombocytopenia (16%), and anemia (14%). There was one treatment-emergent case of tumor lysis syndrome leading to death early in the trial. This phenomenon can occur when the CLL breaks down very quickly and, as a consequence, the study was redesigned and a lower starting dose is now used, Dr. Roberts said.
“That problem has been eliminated, but we still see a very large improvement in patients in a few weeks,” he said. “Other than that, there is a little bit of neutropenia, but that is very manageable.”
“So do you think you are curing patients with this approach?” Dr. Hagenbeek asked, to which Dr. Roberts replied, “Too early to say.”
Venetoclax is currently being evaluated in less heavily pretreated patients and a phase III trial is comparing the combination of venetoclax and rituximab with standard bendamustine chemotherapy plus rituximab, he said.
In May, the Food and Drug Administration granted venetoclax breakthrough therapy designation for use in relapsed or refractory chronic lymphocytic leukemia with a 17p deletion mutation.
AbbVie, which is developing venetoclax in partnership with Roche and Genentech, plans to submit regulatory applications for venetoclax to the FDA and the European Medicines Agency before the end of 2015.
On Twitter @pwendl
AT THE EHA CONGRESS
Key clinical point: Venetoclax plus rituximab is a highly active nonchemotherapy combination for patients with relapsed or refractory chronic lymphocytic leukemia.
Major finding: Overall, 84% of patients responded to venetoclax plus rituximab.
Data source: Phase Ib trial in 49 patients with relapsed or refractory chronic lymphocytic leukemia.
Disclosures: AbbVie sponsored the study. Dr. Roberts’ financial disclosures were not available at press time.
Chronic lymphocytic leukemia prognosis relatively good after transplantation failure
Unlike for those with acute leukemia, patients with chronic lymphocytic leukemia who had disease progression after undergoing transplantation had a relatively good prognosis, with 2- and 5-year overall survival rates of 67% and 38%, investigators reported online April 6 in the Journal of Clinical Oncology.*
Patients with chronic lymphocytic leukemia (CLL) who experienced acute or chronic graft-versus-host disease (GVHD) had significantly longer overall survival (OS) than those who did not have GVHD (P = .04 and P = .05, respectively). “Nearly half our patients with active CLL after transplantation had chronic GVHD, and the association of chronic GVHD with achieving cure and its power to predict OS among patients for whom transplantation failed suggests that the GVL (graft-versus-leukemia) effect contributes to prolonged survival even in patients with a high burden of disease,” wrote Dr. Uri Rozovski and associates at the University of Texas MD Anderson Cancer Center, Houston (J. Clin. Oncol. 2015 Apr. 6 [doi:10.1200/JCO.2014.58.6750]).
A matched-pair analysis showed that patients who underwent allogeneic stem cell transplant (SCT) about the same time and did not relapse also had higher rates of acute and chronic GVHD (P = .004 and P = .011, respectively).
The retrospective review of the Bone Marrow Transplantation Program database identified 358 patients with CLL or RT who underwent SCT from 1998 to 2011. The study evaluated 72 patients who had disease progression at a median 74 months after SCT, most of whom received one to eight lines of treatment after relapse and had a median OS of almost 3 years from the time of progression. Multivariate analysis showed that low hemoglobin levels and the presence of Richter’s transformation (RT) were associated with shorter OS; chronic GVHD and response to the first post-SCT treatment predicted longer OS.
Patients with RT had a worse prognosis, with a median OS of 15 months (95% confidence interval, 2-28 months) and 2- and 5-year survival rates of 36% and 0%. Transplantation carried a significant risk for transformation: 16 (30%) patients with CLL developed RT after allogeneic SCT. Conversely, four patients with RT developed CLL after transplantation.
The authors note that even in patients who did not maintain a durable response, SCT was beneficial. The study cohort received a variety of salvage treatments, and patients who received ibrutinib responded well. “Because of the favorable outcomes with ibrutinib in relapsed/refractory CLL, we believe that ibrutinib might have a role in the treatment of disease progression following transplantation failure,” they wrote.
*Correction, 4/8/2015: A previous version of this article misstated the type of leukemia referenced in the study.
Unlike for those with acute leukemia, patients with chronic lymphocytic leukemia who had disease progression after undergoing transplantation had a relatively good prognosis, with 2- and 5-year overall survival rates of 67% and 38%, investigators reported online April 6 in the Journal of Clinical Oncology.*
Patients with chronic lymphocytic leukemia (CLL) who experienced acute or chronic graft-versus-host disease (GVHD) had significantly longer overall survival (OS) than those who did not have GVHD (P = .04 and P = .05, respectively). “Nearly half our patients with active CLL after transplantation had chronic GVHD, and the association of chronic GVHD with achieving cure and its power to predict OS among patients for whom transplantation failed suggests that the GVL (graft-versus-leukemia) effect contributes to prolonged survival even in patients with a high burden of disease,” wrote Dr. Uri Rozovski and associates at the University of Texas MD Anderson Cancer Center, Houston (J. Clin. Oncol. 2015 Apr. 6 [doi:10.1200/JCO.2014.58.6750]).
A matched-pair analysis showed that patients who underwent allogeneic stem cell transplant (SCT) about the same time and did not relapse also had higher rates of acute and chronic GVHD (P = .004 and P = .011, respectively).
The retrospective review of the Bone Marrow Transplantation Program database identified 358 patients with CLL or RT who underwent SCT from 1998 to 2011. The study evaluated 72 patients who had disease progression at a median 74 months after SCT, most of whom received one to eight lines of treatment after relapse and had a median OS of almost 3 years from the time of progression. Multivariate analysis showed that low hemoglobin levels and the presence of Richter’s transformation (RT) were associated with shorter OS; chronic GVHD and response to the first post-SCT treatment predicted longer OS.
Patients with RT had a worse prognosis, with a median OS of 15 months (95% confidence interval, 2-28 months) and 2- and 5-year survival rates of 36% and 0%. Transplantation carried a significant risk for transformation: 16 (30%) patients with CLL developed RT after allogeneic SCT. Conversely, four patients with RT developed CLL after transplantation.
The authors note that even in patients who did not maintain a durable response, SCT was beneficial. The study cohort received a variety of salvage treatments, and patients who received ibrutinib responded well. “Because of the favorable outcomes with ibrutinib in relapsed/refractory CLL, we believe that ibrutinib might have a role in the treatment of disease progression following transplantation failure,” they wrote.
*Correction, 4/8/2015: A previous version of this article misstated the type of leukemia referenced in the study.
Unlike for those with acute leukemia, patients with chronic lymphocytic leukemia who had disease progression after undergoing transplantation had a relatively good prognosis, with 2- and 5-year overall survival rates of 67% and 38%, investigators reported online April 6 in the Journal of Clinical Oncology.*
Patients with chronic lymphocytic leukemia (CLL) who experienced acute or chronic graft-versus-host disease (GVHD) had significantly longer overall survival (OS) than those who did not have GVHD (P = .04 and P = .05, respectively). “Nearly half our patients with active CLL after transplantation had chronic GVHD, and the association of chronic GVHD with achieving cure and its power to predict OS among patients for whom transplantation failed suggests that the GVL (graft-versus-leukemia) effect contributes to prolonged survival even in patients with a high burden of disease,” wrote Dr. Uri Rozovski and associates at the University of Texas MD Anderson Cancer Center, Houston (J. Clin. Oncol. 2015 Apr. 6 [doi:10.1200/JCO.2014.58.6750]).
A matched-pair analysis showed that patients who underwent allogeneic stem cell transplant (SCT) about the same time and did not relapse also had higher rates of acute and chronic GVHD (P = .004 and P = .011, respectively).
The retrospective review of the Bone Marrow Transplantation Program database identified 358 patients with CLL or RT who underwent SCT from 1998 to 2011. The study evaluated 72 patients who had disease progression at a median 74 months after SCT, most of whom received one to eight lines of treatment after relapse and had a median OS of almost 3 years from the time of progression. Multivariate analysis showed that low hemoglobin levels and the presence of Richter’s transformation (RT) were associated with shorter OS; chronic GVHD and response to the first post-SCT treatment predicted longer OS.
Patients with RT had a worse prognosis, with a median OS of 15 months (95% confidence interval, 2-28 months) and 2- and 5-year survival rates of 36% and 0%. Transplantation carried a significant risk for transformation: 16 (30%) patients with CLL developed RT after allogeneic SCT. Conversely, four patients with RT developed CLL after transplantation.
The authors note that even in patients who did not maintain a durable response, SCT was beneficial. The study cohort received a variety of salvage treatments, and patients who received ibrutinib responded well. “Because of the favorable outcomes with ibrutinib in relapsed/refractory CLL, we believe that ibrutinib might have a role in the treatment of disease progression following transplantation failure,” they wrote.
*Correction, 4/8/2015: A previous version of this article misstated the type of leukemia referenced in the study.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: The prognosis for patients with chronic lymphocytic* leukemia who have undergone failed stem cell transplantation (SCT) is relatively good.
Major finding: From the time of progression after SCT, median OS was 36 months (95% CI, 24-48) for patients with CLL, and 38% survived 5 or more years.
Data source: The retrospective database review identified 72 patients with CLL or Richter’s transformation who underwent allogenic SCT from 1998 to 2011 and progressed after transplantation.
Disclosures: Dr. Rozovski reported having no disclosures. Two of the coauthors reported ties to several industry sources.
Ofatumumab maintenance halves risk of progression in relapsed CLL
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
AT ASH 2014
Key clinical point: Maintenance ofatumumab cuts the risk of progression in half among patients with relapsed CLL.
Major finding: Progression-free survival was 15.2 months with observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Data source: Randomized phase III trial in 474 patients with relapsed CLL.
Disclosures: GlaxoSmithKline sponsored the study. Dr. van Oers reported having no financial disclosures.