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Pruritus linked to wide variety of cancers
A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.
Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.
The results by race help address a gap in the literature, according to Shawn G. Kwatra, MD, of Johns Hopkins University, Baltimore, and his coinvestigators.
“Little is known about the association between pruritus and malignancy among different ethnic groups,” Dr. Kwatra and his coauthors wrote in the Journal of the American Academy of Dermatology.
The study shows a stronger association with more types of malignancies than has been reported previously, according to the investigators.
“The main difference is that prior studies focused on diagnosis of malignancy after the onset of pruritus, while our study includes malignancies diagnosed on or after pruritus onset,” they wrote.
Retrospective data for the study, which came from the Johns Hopkins Health System, included 16,925 patients aged 18 years or older who presented with itching or pruritus between April 4, 2013 and Dec. 31, 2017.
Of those 16,925 patients, 2,903 were also diagnosed with a concomitant malignancy during that time period. Compared with patients with no itching diagnosis during that time period, the pruritus patients more likely to have a concomitant malignancy, with an OR of 5.76 (95% confidence interval, 5.53-6.00), Dr. Kwatra and his colleagues found.
Malignancies most strongly associated with pruritus included those of the skin, liver, gallbladder and biliary tract, and hematopoietic system.
Among hematologic malignancies, pruritus was most strongly linked to myeloid leukemia and primary cutaneous lymphoma, while among skin cancers, squamous cell carcinoma was most strongly linked.
Whites had higher odds of any malignancy versus blacks, according to investigators, with ORs of 6.12 (95% CI, 5.81-6.46) and 5.61 (95% CI, 5.21-6.04), respectively.
Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.
The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.
The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.
Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.
Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.
The results by race help address a gap in the literature, according to Shawn G. Kwatra, MD, of Johns Hopkins University, Baltimore, and his coinvestigators.
“Little is known about the association between pruritus and malignancy among different ethnic groups,” Dr. Kwatra and his coauthors wrote in the Journal of the American Academy of Dermatology.
The study shows a stronger association with more types of malignancies than has been reported previously, according to the investigators.
“The main difference is that prior studies focused on diagnosis of malignancy after the onset of pruritus, while our study includes malignancies diagnosed on or after pruritus onset,” they wrote.
Retrospective data for the study, which came from the Johns Hopkins Health System, included 16,925 patients aged 18 years or older who presented with itching or pruritus between April 4, 2013 and Dec. 31, 2017.
Of those 16,925 patients, 2,903 were also diagnosed with a concomitant malignancy during that time period. Compared with patients with no itching diagnosis during that time period, the pruritus patients more likely to have a concomitant malignancy, with an OR of 5.76 (95% confidence interval, 5.53-6.00), Dr. Kwatra and his colleagues found.
Malignancies most strongly associated with pruritus included those of the skin, liver, gallbladder and biliary tract, and hematopoietic system.
Among hematologic malignancies, pruritus was most strongly linked to myeloid leukemia and primary cutaneous lymphoma, while among skin cancers, squamous cell carcinoma was most strongly linked.
Whites had higher odds of any malignancy versus blacks, according to investigators, with ORs of 6.12 (95% CI, 5.81-6.46) and 5.61 (95% CI, 5.21-6.04), respectively.
Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.
The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.
The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.
Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.
Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.
The results by race help address a gap in the literature, according to Shawn G. Kwatra, MD, of Johns Hopkins University, Baltimore, and his coinvestigators.
“Little is known about the association between pruritus and malignancy among different ethnic groups,” Dr. Kwatra and his coauthors wrote in the Journal of the American Academy of Dermatology.
The study shows a stronger association with more types of malignancies than has been reported previously, according to the investigators.
“The main difference is that prior studies focused on diagnosis of malignancy after the onset of pruritus, while our study includes malignancies diagnosed on or after pruritus onset,” they wrote.
Retrospective data for the study, which came from the Johns Hopkins Health System, included 16,925 patients aged 18 years or older who presented with itching or pruritus between April 4, 2013 and Dec. 31, 2017.
Of those 16,925 patients, 2,903 were also diagnosed with a concomitant malignancy during that time period. Compared with patients with no itching diagnosis during that time period, the pruritus patients more likely to have a concomitant malignancy, with an OR of 5.76 (95% confidence interval, 5.53-6.00), Dr. Kwatra and his colleagues found.
Malignancies most strongly associated with pruritus included those of the skin, liver, gallbladder and biliary tract, and hematopoietic system.
Among hematologic malignancies, pruritus was most strongly linked to myeloid leukemia and primary cutaneous lymphoma, while among skin cancers, squamous cell carcinoma was most strongly linked.
Whites had higher odds of any malignancy versus blacks, according to investigators, with ORs of 6.12 (95% CI, 5.81-6.46) and 5.61 (95% CI, 5.21-6.04), respectively.
Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.
The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.
The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.
Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Key clinical point:
Major finding: Blacks with pruritus had higher odds ratios for hematologic and soft tissue malignancies, while whites had higher ORs for skin and liver malignancies.
Study details: A retrospective study of 16,925 adults with itching or pruritus seen at a tertiary care center.
Disclosures: Dr. Kwatra reported serving as an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
Source: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
Evaluation of Acute Toxicity in Treating Pelvic Lymph Nodes With Prostate Boost With Hypofractionated Simultaneous Integrated Boost (SIB) Using Volumetric Arc Therapy (VMAT)
Purpose: It is conventional to treat pelvic lymph nodes, followed by prostate boost in a sequential manner, requiring 8-9 weeks to complete therapy. In the last several years there have been several randomized studies of implementing moderate hypofractionated radiotherapy in prostate cancer to shorten the treatment time, which has proven to be non-inferior to conventional treatment. The purpose of this retrospective study is to evaluate the acute toxicities of hypofractionated SIB radiotherapy in treating the lymph nodes with prostate boost.
Methods: Between 2015 and 2017, twenty five high risk prostate cancer patients received pelvic node radiotherapy with prostate boost in 25 fractions with SIB technique with neo-adjuvant and concurrent hormone therapy to 50 Gy/25 fractions at 2 Gy/fraction to pelvic nodes and prostate boost for a total of 67.5 - 75 Gy at 2.7 to 3.0 Gy/fraction. We followed QUNTAC dose-volume constraints for the rectum, bladder and bowel. All these patients received long-term hormone therapy.
Results: The median age was 66 years (range 57-81 years). There were 6 stage II C, 7 III A, 15 III C, and 1 stage IV A. All patients were restaged as per American Joint Committee on Cancer 8th edition. Gleason Score: 6 (1), 7 (4+3) (4), 8 (5), and 9-10 (15). The average PSA was 17.2 ng/mL with a range of 5.6 to 51.92 ng/mL, and average number of positive cores was 74%. These factors put the majority of patients into the very high risk group. The median follow up was 24 months. The majority of the patients tolerated treatment well. Grade 0 genitourinary (GU) toxicity occurred
in 8 (33%) patients, grade II 16 (67%) patients, one patient had a Foley catheter during treatment, a majority of patients were on alpha blockers either before, during or post radiotherapy. Grade 0 gastrointestinal (GI) toxicity occurred in 21 (84%) patients, grade 1 in one, and grade II in 3 (12%) patients. There were no grade 3 or 4 GU or GI toxicities.
Conclusions: Simultaneous integrated boost with VMAT is well tolerated in treating pelvic nodes and prostate boost, without any major acute toxicities. This technique is used in mostly for very high risk localized prostate cancer patients, reducing number of fractions from conventional sequential treatment.
Purpose: It is conventional to treat pelvic lymph nodes, followed by prostate boost in a sequential manner, requiring 8-9 weeks to complete therapy. In the last several years there have been several randomized studies of implementing moderate hypofractionated radiotherapy in prostate cancer to shorten the treatment time, which has proven to be non-inferior to conventional treatment. The purpose of this retrospective study is to evaluate the acute toxicities of hypofractionated SIB radiotherapy in treating the lymph nodes with prostate boost.
Methods: Between 2015 and 2017, twenty five high risk prostate cancer patients received pelvic node radiotherapy with prostate boost in 25 fractions with SIB technique with neo-adjuvant and concurrent hormone therapy to 50 Gy/25 fractions at 2 Gy/fraction to pelvic nodes and prostate boost for a total of 67.5 - 75 Gy at 2.7 to 3.0 Gy/fraction. We followed QUNTAC dose-volume constraints for the rectum, bladder and bowel. All these patients received long-term hormone therapy.
Results: The median age was 66 years (range 57-81 years). There were 6 stage II C, 7 III A, 15 III C, and 1 stage IV A. All patients were restaged as per American Joint Committee on Cancer 8th edition. Gleason Score: 6 (1), 7 (4+3) (4), 8 (5), and 9-10 (15). The average PSA was 17.2 ng/mL with a range of 5.6 to 51.92 ng/mL, and average number of positive cores was 74%. These factors put the majority of patients into the very high risk group. The median follow up was 24 months. The majority of the patients tolerated treatment well. Grade 0 genitourinary (GU) toxicity occurred
in 8 (33%) patients, grade II 16 (67%) patients, one patient had a Foley catheter during treatment, a majority of patients were on alpha blockers either before, during or post radiotherapy. Grade 0 gastrointestinal (GI) toxicity occurred in 21 (84%) patients, grade 1 in one, and grade II in 3 (12%) patients. There were no grade 3 or 4 GU or GI toxicities.
Conclusions: Simultaneous integrated boost with VMAT is well tolerated in treating pelvic nodes and prostate boost, without any major acute toxicities. This technique is used in mostly for very high risk localized prostate cancer patients, reducing number of fractions from conventional sequential treatment.
Purpose: It is conventional to treat pelvic lymph nodes, followed by prostate boost in a sequential manner, requiring 8-9 weeks to complete therapy. In the last several years there have been several randomized studies of implementing moderate hypofractionated radiotherapy in prostate cancer to shorten the treatment time, which has proven to be non-inferior to conventional treatment. The purpose of this retrospective study is to evaluate the acute toxicities of hypofractionated SIB radiotherapy in treating the lymph nodes with prostate boost.
Methods: Between 2015 and 2017, twenty five high risk prostate cancer patients received pelvic node radiotherapy with prostate boost in 25 fractions with SIB technique with neo-adjuvant and concurrent hormone therapy to 50 Gy/25 fractions at 2 Gy/fraction to pelvic nodes and prostate boost for a total of 67.5 - 75 Gy at 2.7 to 3.0 Gy/fraction. We followed QUNTAC dose-volume constraints for the rectum, bladder and bowel. All these patients received long-term hormone therapy.
Results: The median age was 66 years (range 57-81 years). There were 6 stage II C, 7 III A, 15 III C, and 1 stage IV A. All patients were restaged as per American Joint Committee on Cancer 8th edition. Gleason Score: 6 (1), 7 (4+3) (4), 8 (5), and 9-10 (15). The average PSA was 17.2 ng/mL with a range of 5.6 to 51.92 ng/mL, and average number of positive cores was 74%. These factors put the majority of patients into the very high risk group. The median follow up was 24 months. The majority of the patients tolerated treatment well. Grade 0 genitourinary (GU) toxicity occurred
in 8 (33%) patients, grade II 16 (67%) patients, one patient had a Foley catheter during treatment, a majority of patients were on alpha blockers either before, during or post radiotherapy. Grade 0 gastrointestinal (GI) toxicity occurred in 21 (84%) patients, grade 1 in one, and grade II in 3 (12%) patients. There were no grade 3 or 4 GU or GI toxicities.
Conclusions: Simultaneous integrated boost with VMAT is well tolerated in treating pelvic nodes and prostate boost, without any major acute toxicities. This technique is used in mostly for very high risk localized prostate cancer patients, reducing number of fractions from conventional sequential treatment.
A Case of Systemic Mastocytosis With Associated Clonal Hematological Non-Mast Cell Lineage Disease at VA Pittsburgh Healthcare System
Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm that is caused by accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. We present a case of systemic mastocytosis with associated clonal hematological non-mast cell disease (SM-AHNMD).
Background: A 71-year-old man presented with anemia, thrombocytopenia, absolute monocyte count of 2,000-4,000 and weight loss in August 2016. A CT showed splenomegaly and lymphadenopathy. Bone marrow biopsy revealed positive CD117 mast cells, CD34 myeloblasts and reticulin fibrosis consistent with SM. Immunohistochemistry confirmed the neoplastic cells were positive for CD25, but negative for CD2. PCR analysis revealed KIT D816V point mutation. Serum tryptase was 295 ug/L (normal 2.2-13.2). He was started on imatinib mesylate. However, his anemia, thrombocytopenia and splenomegaly worsened. He developed bilateral femoral neck fractures in April 2017. Imatinib was discontinued. He underwent bilateral hip hemiarthroplasty. Histology was consistent with SM (positive CD25 and CD117) with dysplastic megakaryocytes and increased monocytosis. By WHO classification he has SM-AHNMD with chronic myelomonocytic leukemia. He was started on cladribine for 4 cycles with good response in splenomegaly, anemia and thrombocytopenia, but he developed leukocytosis. Serum tryptase initially decreased to 141 but then rose to 243. Midostaurin 100 mg orally twice a day was initiated in December 2017. His cytopenia and splenomegaly improved. In March 2018 he was admitted for sigmoid colon obstruction due to inflammation or mass and underwent diverting loop ileostomy. Biopsy could not be performed. His serum tryptase decreased to 178 but increased to 275 in June 2018. He continues on midostaurin.
Discussion: SM-AHNMD constitutes approximately 40% of all SM with poor prognosis. SM is resistance to imatinib because of KIT D816V mutation. Cladribine has some activity. Midostaurin inhibits non-mutant and mutant KIT D816V with 58% response rate and median overall survival of 20 months. Our patient has a good response to both drugs.
Conclusions: Clinicians should be able to diagnose and treat SM. Cladribine and midostaurin are active drugs for SM.
Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm that is caused by accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. We present a case of systemic mastocytosis with associated clonal hematological non-mast cell disease (SM-AHNMD).
Background: A 71-year-old man presented with anemia, thrombocytopenia, absolute monocyte count of 2,000-4,000 and weight loss in August 2016. A CT showed splenomegaly and lymphadenopathy. Bone marrow biopsy revealed positive CD117 mast cells, CD34 myeloblasts and reticulin fibrosis consistent with SM. Immunohistochemistry confirmed the neoplastic cells were positive for CD25, but negative for CD2. PCR analysis revealed KIT D816V point mutation. Serum tryptase was 295 ug/L (normal 2.2-13.2). He was started on imatinib mesylate. However, his anemia, thrombocytopenia and splenomegaly worsened. He developed bilateral femoral neck fractures in April 2017. Imatinib was discontinued. He underwent bilateral hip hemiarthroplasty. Histology was consistent with SM (positive CD25 and CD117) with dysplastic megakaryocytes and increased monocytosis. By WHO classification he has SM-AHNMD with chronic myelomonocytic leukemia. He was started on cladribine for 4 cycles with good response in splenomegaly, anemia and thrombocytopenia, but he developed leukocytosis. Serum tryptase initially decreased to 141 but then rose to 243. Midostaurin 100 mg orally twice a day was initiated in December 2017. His cytopenia and splenomegaly improved. In March 2018 he was admitted for sigmoid colon obstruction due to inflammation or mass and underwent diverting loop ileostomy. Biopsy could not be performed. His serum tryptase decreased to 178 but increased to 275 in June 2018. He continues on midostaurin.
Discussion: SM-AHNMD constitutes approximately 40% of all SM with poor prognosis. SM is resistance to imatinib because of KIT D816V mutation. Cladribine has some activity. Midostaurin inhibits non-mutant and mutant KIT D816V with 58% response rate and median overall survival of 20 months. Our patient has a good response to both drugs.
Conclusions: Clinicians should be able to diagnose and treat SM. Cladribine and midostaurin are active drugs for SM.
Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm that is caused by accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. We present a case of systemic mastocytosis with associated clonal hematological non-mast cell disease (SM-AHNMD).
Background: A 71-year-old man presented with anemia, thrombocytopenia, absolute monocyte count of 2,000-4,000 and weight loss in August 2016. A CT showed splenomegaly and lymphadenopathy. Bone marrow biopsy revealed positive CD117 mast cells, CD34 myeloblasts and reticulin fibrosis consistent with SM. Immunohistochemistry confirmed the neoplastic cells were positive for CD25, but negative for CD2. PCR analysis revealed KIT D816V point mutation. Serum tryptase was 295 ug/L (normal 2.2-13.2). He was started on imatinib mesylate. However, his anemia, thrombocytopenia and splenomegaly worsened. He developed bilateral femoral neck fractures in April 2017. Imatinib was discontinued. He underwent bilateral hip hemiarthroplasty. Histology was consistent with SM (positive CD25 and CD117) with dysplastic megakaryocytes and increased monocytosis. By WHO classification he has SM-AHNMD with chronic myelomonocytic leukemia. He was started on cladribine for 4 cycles with good response in splenomegaly, anemia and thrombocytopenia, but he developed leukocytosis. Serum tryptase initially decreased to 141 but then rose to 243. Midostaurin 100 mg orally twice a day was initiated in December 2017. His cytopenia and splenomegaly improved. In March 2018 he was admitted for sigmoid colon obstruction due to inflammation or mass and underwent diverting loop ileostomy. Biopsy could not be performed. His serum tryptase decreased to 178 but increased to 275 in June 2018. He continues on midostaurin.
Discussion: SM-AHNMD constitutes approximately 40% of all SM with poor prognosis. SM is resistance to imatinib because of KIT D816V mutation. Cladribine has some activity. Midostaurin inhibits non-mutant and mutant KIT D816V with 58% response rate and median overall survival of 20 months. Our patient has a good response to both drugs.
Conclusions: Clinicians should be able to diagnose and treat SM. Cladribine and midostaurin are active drugs for SM.
Translocation T(11;14): Not Always Mantle Cell Lymphoma!
Background: The translocation t(11;14)(q13;q32) typically considered a hallmark of mantle cell lymphoma(MCL), has also been implicated in some cases of non-MCL lymphoproliferative disorders. Although uncommon, it has been reported in 2-5% of chronic lymphocytic leukemia (CLL) cases. Most of the cases identified have been observed mostly in relapsed CLL. This genetic aberration can be considered a significant prognostic indicator for CLL. t(11;14) positive CLL at the time of diagnosis has been rarely reported. We describe a case of a patient
diagnosed with CLL who was positive for this genetic abnormality.
Case Report: A 64-year-old white male presented with absolute lymphocytosis of 7 years. Lymphocyte immunophenotype detected a CD5(+) CD10(-) CD23(+) CD38(-) CD43(+) FMC7(partial dim) kappa-restricted B-cell population consistent with CLL. CT chest, abdomen, pelvis showed mildly prominent mediastinal and hilar lymph nodes only and was thus classified as Rai stage I. Peripheral FISH came back positive for t(11:14), cyclin D1-IgH translocation. His EPO, Jak2 and BCR-ABL mutation were all negative (done for mild erythrocytosis). Immunoglobulin and SPEP were negative. UPEP showed high Kappa/Lambda ratio. Although this tumor carries t(11;14) (q13;q32) translocation, immunostaining for BCL-1 was negative. It is possible that the gene is not expressed. Based on the staining and the clinical presentation, MCL was excluded. Per NCCN guidelines, patient is receiving clinical monitoring for stage I CLL.
Conclusions: Translocations involving the immunoglobulin genes are commonly identified. Uncommon genomic abnormalities in CLL should be recognized as significant independent predictors of disease progression and survival. It is important to recognize cases of CLL with t(11;14) translocation to achieve risk-adapted treatment strategies, which might be required to treat such patients.
Background: The translocation t(11;14)(q13;q32) typically considered a hallmark of mantle cell lymphoma(MCL), has also been implicated in some cases of non-MCL lymphoproliferative disorders. Although uncommon, it has been reported in 2-5% of chronic lymphocytic leukemia (CLL) cases. Most of the cases identified have been observed mostly in relapsed CLL. This genetic aberration can be considered a significant prognostic indicator for CLL. t(11;14) positive CLL at the time of diagnosis has been rarely reported. We describe a case of a patient
diagnosed with CLL who was positive for this genetic abnormality.
Case Report: A 64-year-old white male presented with absolute lymphocytosis of 7 years. Lymphocyte immunophenotype detected a CD5(+) CD10(-) CD23(+) CD38(-) CD43(+) FMC7(partial dim) kappa-restricted B-cell population consistent with CLL. CT chest, abdomen, pelvis showed mildly prominent mediastinal and hilar lymph nodes only and was thus classified as Rai stage I. Peripheral FISH came back positive for t(11:14), cyclin D1-IgH translocation. His EPO, Jak2 and BCR-ABL mutation were all negative (done for mild erythrocytosis). Immunoglobulin and SPEP were negative. UPEP showed high Kappa/Lambda ratio. Although this tumor carries t(11;14) (q13;q32) translocation, immunostaining for BCL-1 was negative. It is possible that the gene is not expressed. Based on the staining and the clinical presentation, MCL was excluded. Per NCCN guidelines, patient is receiving clinical monitoring for stage I CLL.
Conclusions: Translocations involving the immunoglobulin genes are commonly identified. Uncommon genomic abnormalities in CLL should be recognized as significant independent predictors of disease progression and survival. It is important to recognize cases of CLL with t(11;14) translocation to achieve risk-adapted treatment strategies, which might be required to treat such patients.
Background: The translocation t(11;14)(q13;q32) typically considered a hallmark of mantle cell lymphoma(MCL), has also been implicated in some cases of non-MCL lymphoproliferative disorders. Although uncommon, it has been reported in 2-5% of chronic lymphocytic leukemia (CLL) cases. Most of the cases identified have been observed mostly in relapsed CLL. This genetic aberration can be considered a significant prognostic indicator for CLL. t(11;14) positive CLL at the time of diagnosis has been rarely reported. We describe a case of a patient
diagnosed with CLL who was positive for this genetic abnormality.
Case Report: A 64-year-old white male presented with absolute lymphocytosis of 7 years. Lymphocyte immunophenotype detected a CD5(+) CD10(-) CD23(+) CD38(-) CD43(+) FMC7(partial dim) kappa-restricted B-cell population consistent with CLL. CT chest, abdomen, pelvis showed mildly prominent mediastinal and hilar lymph nodes only and was thus classified as Rai stage I. Peripheral FISH came back positive for t(11:14), cyclin D1-IgH translocation. His EPO, Jak2 and BCR-ABL mutation were all negative (done for mild erythrocytosis). Immunoglobulin and SPEP were negative. UPEP showed high Kappa/Lambda ratio. Although this tumor carries t(11;14) (q13;q32) translocation, immunostaining for BCL-1 was negative. It is possible that the gene is not expressed. Based on the staining and the clinical presentation, MCL was excluded. Per NCCN guidelines, patient is receiving clinical monitoring for stage I CLL.
Conclusions: Translocations involving the immunoglobulin genes are commonly identified. Uncommon genomic abnormalities in CLL should be recognized as significant independent predictors of disease progression and survival. It is important to recognize cases of CLL with t(11;14) translocation to achieve risk-adapted treatment strategies, which might be required to treat such patients.
FDA approves drug for hairy cell leukemia
The U.S. Food and Drug Administration (FDA) has approved moxetumomab pasudotox-tdfk (Lumoxiti), a CD22-directed cytotoxin, to treat hairy cell leukemia (HCL).
Moxetumomab pasudotox is approved to treat adults with relapsed or refractory HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
The prescribing information for moxetumomab pasudotox includes a Boxed Warning noting that the drug poses risks of capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS). Treatment with moxetumomab pasudotox should be delayed or discontinued in patients who develop CLS and discontinued in patients with HUS.
The FDA granted the application for moxetumomab pasudotox fast track and priority review designations, and the drug received orphan drug designation from the FDA.
The agency granted the approval of moxetumomab pasudotox to AstraZeneca Pharmaceuticals based on results from a phase 3 trial (NCT01829711).
Data from this study were presented at the 2018 ASCO Annual Meeting (abstract 7004).
The trial included 80 patients with relapsed or refractory HCL who had received at least two prior lines of therapy.
At a median of 16.7 months of follow-up, the objective response rate was 75% (60/80), the complete response (CR) rate was 41% (33/80), and the durable CR rate was 30% (24/80). Durable CR was defined as CR with hematologic remission for more than 180 days.
Most patients with a CR achieved minimal residual disease negativity (82%; 27/33).
The median duration of response was not reached, nor was the median progression-free survival.
The most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%). Other treatment-related AEs included infections (8%) and neutropenia (3%).
Treatment-related AEs that led to discontinuation included HUS (5%), CLS (3%), and increased blood creatinine (3%).
In all, seven patients (9%) had CLS, and seven (9%) had HUS. This includes four (5%) patients who had both. CLS and HUS proved manageable and reversible.
There were three deaths in this trial, but none of them were considered treatment-related.
The U.S. Food and Drug Administration (FDA) has approved moxetumomab pasudotox-tdfk (Lumoxiti), a CD22-directed cytotoxin, to treat hairy cell leukemia (HCL).
Moxetumomab pasudotox is approved to treat adults with relapsed or refractory HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
The prescribing information for moxetumomab pasudotox includes a Boxed Warning noting that the drug poses risks of capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS). Treatment with moxetumomab pasudotox should be delayed or discontinued in patients who develop CLS and discontinued in patients with HUS.
The FDA granted the application for moxetumomab pasudotox fast track and priority review designations, and the drug received orphan drug designation from the FDA.
The agency granted the approval of moxetumomab pasudotox to AstraZeneca Pharmaceuticals based on results from a phase 3 trial (NCT01829711).
Data from this study were presented at the 2018 ASCO Annual Meeting (abstract 7004).
The trial included 80 patients with relapsed or refractory HCL who had received at least two prior lines of therapy.
At a median of 16.7 months of follow-up, the objective response rate was 75% (60/80), the complete response (CR) rate was 41% (33/80), and the durable CR rate was 30% (24/80). Durable CR was defined as CR with hematologic remission for more than 180 days.
Most patients with a CR achieved minimal residual disease negativity (82%; 27/33).
The median duration of response was not reached, nor was the median progression-free survival.
The most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%). Other treatment-related AEs included infections (8%) and neutropenia (3%).
Treatment-related AEs that led to discontinuation included HUS (5%), CLS (3%), and increased blood creatinine (3%).
In all, seven patients (9%) had CLS, and seven (9%) had HUS. This includes four (5%) patients who had both. CLS and HUS proved manageable and reversible.
There were three deaths in this trial, but none of them were considered treatment-related.
The U.S. Food and Drug Administration (FDA) has approved moxetumomab pasudotox-tdfk (Lumoxiti), a CD22-directed cytotoxin, to treat hairy cell leukemia (HCL).
Moxetumomab pasudotox is approved to treat adults with relapsed or refractory HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
The prescribing information for moxetumomab pasudotox includes a Boxed Warning noting that the drug poses risks of capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS). Treatment with moxetumomab pasudotox should be delayed or discontinued in patients who develop CLS and discontinued in patients with HUS.
The FDA granted the application for moxetumomab pasudotox fast track and priority review designations, and the drug received orphan drug designation from the FDA.
The agency granted the approval of moxetumomab pasudotox to AstraZeneca Pharmaceuticals based on results from a phase 3 trial (NCT01829711).
Data from this study were presented at the 2018 ASCO Annual Meeting (abstract 7004).
The trial included 80 patients with relapsed or refractory HCL who had received at least two prior lines of therapy.
At a median of 16.7 months of follow-up, the objective response rate was 75% (60/80), the complete response (CR) rate was 41% (33/80), and the durable CR rate was 30% (24/80). Durable CR was defined as CR with hematologic remission for more than 180 days.
Most patients with a CR achieved minimal residual disease negativity (82%; 27/33).
The median duration of response was not reached, nor was the median progression-free survival.
The most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%). Other treatment-related AEs included infections (8%) and neutropenia (3%).
Treatment-related AEs that led to discontinuation included HUS (5%), CLS (3%), and increased blood creatinine (3%).
In all, seven patients (9%) had CLS, and seven (9%) had HUS. This includes four (5%) patients who had both. CLS and HUS proved manageable and reversible.
There were three deaths in this trial, but none of them were considered treatment-related.
FDA approves new hairy cell leukemia drug
The Food and Drug Administration (FDA) has approved moxetumomab pasudotox-tdfk (Lumoxiti), a CD22-directed cytotoxin, to treat hairy cell leukemia (HCL).
Moxetumomab pasudotox is approved to treat adults with relapsed or refractory HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
The prescribing information for moxetumomab pasudotox includes a boxed warning noting that the drug poses risks of capillary leak syndrome and hemolytic uremic syndrome. Other serious warnings include the risk of decreased renal function, infusion-related reactions, and electrolyte abnormalities.
The FDA granted the application for moxetumomab pasudotox fast track, priority review, and an orphan drug designation.
The agency approved AstraZeneca’s moxetumomab pasudotox based on results from a phase 3 trial (NCT01829711). Data from this study were presented at the 2018 annual meeting of the American Society of Clinical Oncology (abstract 7004).
The trial included 80 patients with relapsed or refractory HCL who had received at least two prior lines of therapy.
At a median of 16.7 months of follow-up, the objective response rate was 75%, the complete response (CR) rate was 41%, and the durable CR rate was 30%. Durable CR was defined as CR with hematologic remission for more than 180 days.
Most patients with a CR achieved minimal residual disease negativity (82%; 27/33).
The median duration of response was not reached, nor was the median progression-free survival.
The most common treatment-related adverse events (AEs) were nausea, peripheral edema, headache, and pyrexia. Other treatment-related AEs included infections and neutropenia.
Treatment-related AEs that led to discontinuation included capillary leak syndrome, hemolytic uremic syndrome, and increased blood creatinine.
There were three deaths in this trial, but none of them were considered treatment related.
The Food and Drug Administration (FDA) has approved moxetumomab pasudotox-tdfk (Lumoxiti), a CD22-directed cytotoxin, to treat hairy cell leukemia (HCL).
Moxetumomab pasudotox is approved to treat adults with relapsed or refractory HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
The prescribing information for moxetumomab pasudotox includes a boxed warning noting that the drug poses risks of capillary leak syndrome and hemolytic uremic syndrome. Other serious warnings include the risk of decreased renal function, infusion-related reactions, and electrolyte abnormalities.
The FDA granted the application for moxetumomab pasudotox fast track, priority review, and an orphan drug designation.
The agency approved AstraZeneca’s moxetumomab pasudotox based on results from a phase 3 trial (NCT01829711). Data from this study were presented at the 2018 annual meeting of the American Society of Clinical Oncology (abstract 7004).
The trial included 80 patients with relapsed or refractory HCL who had received at least two prior lines of therapy.
At a median of 16.7 months of follow-up, the objective response rate was 75%, the complete response (CR) rate was 41%, and the durable CR rate was 30%. Durable CR was defined as CR with hematologic remission for more than 180 days.
Most patients with a CR achieved minimal residual disease negativity (82%; 27/33).
The median duration of response was not reached, nor was the median progression-free survival.
The most common treatment-related adverse events (AEs) were nausea, peripheral edema, headache, and pyrexia. Other treatment-related AEs included infections and neutropenia.
Treatment-related AEs that led to discontinuation included capillary leak syndrome, hemolytic uremic syndrome, and increased blood creatinine.
There were three deaths in this trial, but none of them were considered treatment related.
The Food and Drug Administration (FDA) has approved moxetumomab pasudotox-tdfk (Lumoxiti), a CD22-directed cytotoxin, to treat hairy cell leukemia (HCL).
Moxetumomab pasudotox is approved to treat adults with relapsed or refractory HCL who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
The prescribing information for moxetumomab pasudotox includes a boxed warning noting that the drug poses risks of capillary leak syndrome and hemolytic uremic syndrome. Other serious warnings include the risk of decreased renal function, infusion-related reactions, and electrolyte abnormalities.
The FDA granted the application for moxetumomab pasudotox fast track, priority review, and an orphan drug designation.
The agency approved AstraZeneca’s moxetumomab pasudotox based on results from a phase 3 trial (NCT01829711). Data from this study were presented at the 2018 annual meeting of the American Society of Clinical Oncology (abstract 7004).
The trial included 80 patients with relapsed or refractory HCL who had received at least two prior lines of therapy.
At a median of 16.7 months of follow-up, the objective response rate was 75%, the complete response (CR) rate was 41%, and the durable CR rate was 30%. Durable CR was defined as CR with hematologic remission for more than 180 days.
Most patients with a CR achieved minimal residual disease negativity (82%; 27/33).
The median duration of response was not reached, nor was the median progression-free survival.
The most common treatment-related adverse events (AEs) were nausea, peripheral edema, headache, and pyrexia. Other treatment-related AEs included infections and neutropenia.
Treatment-related AEs that led to discontinuation included capillary leak syndrome, hemolytic uremic syndrome, and increased blood creatinine.
There were three deaths in this trial, but none of them were considered treatment related.
New U.S. cancer cases may exceed 2.3 million by 2035
The American Association for Cancer Research (AACR) has released its annual Cancer Progress Report, detailing recent advances in the fight against cancer and calling on elected officials to address the challenges that remain.
The AACR Cancer Progress Report 2018 lists the 22 new approvals for cancer treatments that have occurred during the last 12 months, including 12 therapies approved to treat hematologic malignancies.
However, the report also notes that cancer continues to pose immense public health challenges in the United States.
The estimated number of new cancer cases for 2018 is 1,735,350, and the estimated number of cancer deaths is 609,640.
The number of new cancer cases is predicted to increase to 2,387,304 in 2035. This is due, in large part, to the rising number of people age 65 and older, according to the report.
With this in mind, the AACR is calling on elected officials to:
Maintain “robust, sustained, and predictable growth” of the National Institutes of Health (NIH) budget, increasing it at least $2 billion in fiscal year (FY) 2019, for a total funding level of at least $39.1 billion.
Make sure the $711 million in funding provided through the 21st Century Cures Act for targeted initiatives—including the National Cancer Moonshot—“is fully appropriated in FY 2019 and is supplemental to the healthy increase for the NIH’s base budget.”
Raise the Food and Drug Administration’s base budget in FY 2019 to $3.1 billion—a $308 million increase above its FY 2018 level—to secure support for regulatory science and speed the development of medical products that are safe and effective.
Provide the Centers for Disease Control and Prevention’s Cancer Prevention and Control Programs with total funding of at least $517 million. This would include funding for “comprehensive cancer control, cancer registries, and screening and awareness programs for specific cancers.”
The American Association for Cancer Research (AACR) has released its annual Cancer Progress Report, detailing recent advances in the fight against cancer and calling on elected officials to address the challenges that remain.
The AACR Cancer Progress Report 2018 lists the 22 new approvals for cancer treatments that have occurred during the last 12 months, including 12 therapies approved to treat hematologic malignancies.
However, the report also notes that cancer continues to pose immense public health challenges in the United States.
The estimated number of new cancer cases for 2018 is 1,735,350, and the estimated number of cancer deaths is 609,640.
The number of new cancer cases is predicted to increase to 2,387,304 in 2035. This is due, in large part, to the rising number of people age 65 and older, according to the report.
With this in mind, the AACR is calling on elected officials to:
Maintain “robust, sustained, and predictable growth” of the National Institutes of Health (NIH) budget, increasing it at least $2 billion in fiscal year (FY) 2019, for a total funding level of at least $39.1 billion.
Make sure the $711 million in funding provided through the 21st Century Cures Act for targeted initiatives—including the National Cancer Moonshot—“is fully appropriated in FY 2019 and is supplemental to the healthy increase for the NIH’s base budget.”
Raise the Food and Drug Administration’s base budget in FY 2019 to $3.1 billion—a $308 million increase above its FY 2018 level—to secure support for regulatory science and speed the development of medical products that are safe and effective.
Provide the Centers for Disease Control and Prevention’s Cancer Prevention and Control Programs with total funding of at least $517 million. This would include funding for “comprehensive cancer control, cancer registries, and screening and awareness programs for specific cancers.”
The American Association for Cancer Research (AACR) has released its annual Cancer Progress Report, detailing recent advances in the fight against cancer and calling on elected officials to address the challenges that remain.
The AACR Cancer Progress Report 2018 lists the 22 new approvals for cancer treatments that have occurred during the last 12 months, including 12 therapies approved to treat hematologic malignancies.
However, the report also notes that cancer continues to pose immense public health challenges in the United States.
The estimated number of new cancer cases for 2018 is 1,735,350, and the estimated number of cancer deaths is 609,640.
The number of new cancer cases is predicted to increase to 2,387,304 in 2035. This is due, in large part, to the rising number of people age 65 and older, according to the report.
With this in mind, the AACR is calling on elected officials to:
Maintain “robust, sustained, and predictable growth” of the National Institutes of Health (NIH) budget, increasing it at least $2 billion in fiscal year (FY) 2019, for a total funding level of at least $39.1 billion.
Make sure the $711 million in funding provided through the 21st Century Cures Act for targeted initiatives—including the National Cancer Moonshot—“is fully appropriated in FY 2019 and is supplemental to the healthy increase for the NIH’s base budget.”
Raise the Food and Drug Administration’s base budget in FY 2019 to $3.1 billion—a $308 million increase above its FY 2018 level—to secure support for regulatory science and speed the development of medical products that are safe and effective.
Provide the Centers for Disease Control and Prevention’s Cancer Prevention and Control Programs with total funding of at least $517 million. This would include funding for “comprehensive cancer control, cancer registries, and screening and awareness programs for specific cancers.”
Novel AKT inhibitor active against MM cells
A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.
The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.
In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.
When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.
“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.
They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.
This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.
They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.
In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.
Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.
Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.
They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.
“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.
The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.
SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.
A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.
The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.
In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.
When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.
“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.
They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.
This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.
They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.
In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.
Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.
Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.
They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.
“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.
The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.
SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.
A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.
The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.
In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.
When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.
“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.
They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.
This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.
They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.
In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.
Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.
Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.
They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.
“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.
The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.
SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.
FROM CANCER LETTERS
Key clinical point:
Major finding: HS1793 showed significant multiple myeloma cytotoxicity in mouse models and in human cells isolated from patients with primary or relapsed/refractory myeloma.
Study details: Preclinical investigations in cell lines, murine models, and isolated human multiple myeloma cells.
Disclosures: The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.
Source: Song IS et al. Cancer Lett. 2018:432:205-15.
Intravascular Lymphoma Presenting as Acute Abdomen With Intestinal Perforation
Background: We present a case of a 69-year-old male with a past medical history of RA, Afib, COPD, and DVT with pulmonary embolism. He presented to the emergency department with encephalopathy and severe abdominal pain. On exam the patient was septic with a diffusely tender abdominal exam with peritoneal signs. The CT scan showed pneumoperitoneum. The patient underwent emergent laparotomy which revealed fecal peritonitis from a cecal perforation. After washout, patient had bowel resection of the involved intestine with a primary anastomosis. Biopsy of his resected small bowel and cecum showed submucosal blood vessels with numerous lymphoid cells. Immunohistochemical staining showed aberrant expression for CD43 and CD30 with an increased proliferation index (Ki67 80-90%). Molecular studies of both the lymphoid aggregates
and the atypical intravascular cells were negative for Ig heavy chain, t(11:18) & t(14,19). A diagnosis of intravascular lymphoma was still made. Patient underwent four further abdominal washouts with reconstruction of anterior abdominal wall with Permacol™ biological mesh. The patient condition continued to deteriorate, and he was transitioned to palliative care. He died a month after. An autopsy was not performed.
Discussion: Intravascular lymphoma is a rare and very aggressive malignancy characterized by proliferation of atypical B cell confined mostly to the vascular lumen. Its presentation is protean depending on the organs involved. It has been referred to as “the oncologists great imitator.” In a series of 38 patients by Ferreri et al, the most common symptoms were fever, cutaneous symptoms, neurological symptoms followed by abdominal pain. Most patients present in an advanced state, one series of 96 patients by Murase et al, 91% of the patient presenting with clinical stage III or stage IV disease.
There remain no standard diagnostic criteria for intravascular lymphoma. First step is demonstration of lymphoma cells in small- and medium-sized blood vessels with characteristic sparing of surrounding tissue. B cell clones are most common, but T and NK cells have also been reported. Molecular, immune histochemical and flow cytometry techniques may aid in establishing diagnosis. Prognosis remains poor even with aggressive treatment, the largest series by Murase et al, with mean survival of just 13 months with treatment.
Background: We present a case of a 69-year-old male with a past medical history of RA, Afib, COPD, and DVT with pulmonary embolism. He presented to the emergency department with encephalopathy and severe abdominal pain. On exam the patient was septic with a diffusely tender abdominal exam with peritoneal signs. The CT scan showed pneumoperitoneum. The patient underwent emergent laparotomy which revealed fecal peritonitis from a cecal perforation. After washout, patient had bowel resection of the involved intestine with a primary anastomosis. Biopsy of his resected small bowel and cecum showed submucosal blood vessels with numerous lymphoid cells. Immunohistochemical staining showed aberrant expression for CD43 and CD30 with an increased proliferation index (Ki67 80-90%). Molecular studies of both the lymphoid aggregates
and the atypical intravascular cells were negative for Ig heavy chain, t(11:18) & t(14,19). A diagnosis of intravascular lymphoma was still made. Patient underwent four further abdominal washouts with reconstruction of anterior abdominal wall with Permacol™ biological mesh. The patient condition continued to deteriorate, and he was transitioned to palliative care. He died a month after. An autopsy was not performed.
Discussion: Intravascular lymphoma is a rare and very aggressive malignancy characterized by proliferation of atypical B cell confined mostly to the vascular lumen. Its presentation is protean depending on the organs involved. It has been referred to as “the oncologists great imitator.” In a series of 38 patients by Ferreri et al, the most common symptoms were fever, cutaneous symptoms, neurological symptoms followed by abdominal pain. Most patients present in an advanced state, one series of 96 patients by Murase et al, 91% of the patient presenting with clinical stage III or stage IV disease.
There remain no standard diagnostic criteria for intravascular lymphoma. First step is demonstration of lymphoma cells in small- and medium-sized blood vessels with characteristic sparing of surrounding tissue. B cell clones are most common, but T and NK cells have also been reported. Molecular, immune histochemical and flow cytometry techniques may aid in establishing diagnosis. Prognosis remains poor even with aggressive treatment, the largest series by Murase et al, with mean survival of just 13 months with treatment.
Background: We present a case of a 69-year-old male with a past medical history of RA, Afib, COPD, and DVT with pulmonary embolism. He presented to the emergency department with encephalopathy and severe abdominal pain. On exam the patient was septic with a diffusely tender abdominal exam with peritoneal signs. The CT scan showed pneumoperitoneum. The patient underwent emergent laparotomy which revealed fecal peritonitis from a cecal perforation. After washout, patient had bowel resection of the involved intestine with a primary anastomosis. Biopsy of his resected small bowel and cecum showed submucosal blood vessels with numerous lymphoid cells. Immunohistochemical staining showed aberrant expression for CD43 and CD30 with an increased proliferation index (Ki67 80-90%). Molecular studies of both the lymphoid aggregates
and the atypical intravascular cells were negative for Ig heavy chain, t(11:18) & t(14,19). A diagnosis of intravascular lymphoma was still made. Patient underwent four further abdominal washouts with reconstruction of anterior abdominal wall with Permacol™ biological mesh. The patient condition continued to deteriorate, and he was transitioned to palliative care. He died a month after. An autopsy was not performed.
Discussion: Intravascular lymphoma is a rare and very aggressive malignancy characterized by proliferation of atypical B cell confined mostly to the vascular lumen. Its presentation is protean depending on the organs involved. It has been referred to as “the oncologists great imitator.” In a series of 38 patients by Ferreri et al, the most common symptoms were fever, cutaneous symptoms, neurological symptoms followed by abdominal pain. Most patients present in an advanced state, one series of 96 patients by Murase et al, 91% of the patient presenting with clinical stage III or stage IV disease.
There remain no standard diagnostic criteria for intravascular lymphoma. First step is demonstration of lymphoma cells in small- and medium-sized blood vessels with characteristic sparing of surrounding tissue. B cell clones are most common, but T and NK cells have also been reported. Molecular, immune histochemical and flow cytometry techniques may aid in establishing diagnosis. Prognosis remains poor even with aggressive treatment, the largest series by Murase et al, with mean survival of just 13 months with treatment.
MRD data added to venetoclax label
The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta®) to include data on minimal residual disease (MRD).
The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.
The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.
The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.
The patients were randomized to receive:
- Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m2 on day 1 for the first cycle and at 500 mg/m2 on day 1 for cycles 2 to 6 (n=194)
- Bendamustine at 70 mg/m2 on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).
Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.
The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.
The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.
Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.
“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.
The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta®) to include data on minimal residual disease (MRD).
The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.
The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.
The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.
The patients were randomized to receive:
- Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m2 on day 1 for the first cycle and at 500 mg/m2 on day 1 for cycles 2 to 6 (n=194)
- Bendamustine at 70 mg/m2 on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).
Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.
The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.
The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.
Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.
“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.
The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta®) to include data on minimal residual disease (MRD).
The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.
The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.
The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.
The patients were randomized to receive:
- Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m2 on day 1 for the first cycle and at 500 mg/m2 on day 1 for cycles 2 to 6 (n=194)
- Bendamustine at 70 mg/m2 on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).
Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.
The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.
The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.
Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.
“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.