Lung cancer is a major cause of cancer deaths with approximately 80% of cases accounting to nonsmall cell lung cancer (NSCLC) . In NSCLC target therapy, epidermal growth factor receptor (EGFR) is a promising candidate.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, making up 30-40% of cases. DLBCL is an aggressive or intermediate-grade lymphoma characterized by large malignant B cells. Risk factors include family history of lymphoma, autoimmune disease, HIV/HCV infection, and high body mass index. Treatment involves chemotherapy such as R-CHOP along with radiation or stem cell transplant depending on risk factors and age. Prognosis depends on factors like stage and the international prognostic index, with 5-year survival rates around 46% on average.
PD-L1 is a protein that is expressed on tumor cells and suppresses the immune system's ability to attack tumors. Blocking the PD-1/PD-L1 pathway through antibodies or other inhibitors can help the immune system recognize and destroy cancer cells. Several PD-L1 antibody drugs have been approved to treat cancers like lung cancer and urothelial carcinoma. Clinical trials are also testing combinations of PD-L1 inhibitors with other cancer therapies to improve treatment outcomes. Researchers continue to develop new approaches for targeting the PD-1/PD-L1 pathway, including gene silencing techniques and pathway inhibitors.
The document discusses immunotherapy and the role of pathologists in assessing tumor samples. It describes how certain tumors express PD-L1 antigens that can be recognized by the immune system, but the tumors also engage immune checkpoint pathways like PD-1 and CTLA-4 to evade the immune response. Immunotherapy drugs target these checkpoint pathways to enhance the immune response. The document outlines the FDA-approved PD-L1 immunohistochemistry assays and biomarkers used to identify cancer patients most likely to respond to immune checkpoint inhibitors for various cancer types including NSCLC, melanoma, bladder cancer, and colorectal cancer.
This document provides an overview of chronic myeloid leukemia (CML) and its treatment. It discusses prognostic factors in CML, the phases of the disease, and historical treatments including interferon and chemotherapy. It then focuses on current first-line treatments for chronic phase CML, including the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. It reviews clinical trials that have demonstrated the superiority of these targeted therapies compared to historical options. The document concludes with recommendations for monitoring patient response to CML treatments.
This document provides background information on microsatellite instability (MSI). It discusses how microsatellites are short repetitive sequences prone to mutations during DNA replication due to slipped strand mispairing or unequal crossing over. MSI occurs when mutations inactivate DNA mismatch repair genes, leading to length alterations in microsatellite regions. This causes microsatellite instability, which is seen in certain cancers like colorectal cancer and can be assessed through testing tumor DNA for instability in microsatellite markers. Immunohistochemistry for mismatch repair proteins or direct testing for MSI can help identify tumors associated with defective mismatch repair and microsatellite instability.
EGFR mutations are present in 10-20% of Caucasian and 40-60% of Asian patients with NSCLC. First-generation EGFR TKIs such as gefitinib and erlotinib are the standard of care for patients with EGFR mutations. The FLAURA trial found that the third-generation EGFR TKI osimertinib significantly improved progression-free survival compared to gefitinib or erlotinib as a first-line treatment for EGFR mutant NSCLC. Osimertinib also showed benefits for patients with CNS metastases. However, combination of first-generation EGFR TKIs with chemotherapy may provide further benefits like improved overall response rate, progression-free
Lung cancer is a major cause of cancer deaths with approximately 80% of cases accounting to nonsmall cell lung cancer (NSCLC) . In NSCLC target therapy, epidermal growth factor receptor (EGFR) is a promising candidate.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, making up 30-40% of cases. DLBCL is an aggressive or intermediate-grade lymphoma characterized by large malignant B cells. Risk factors include family history of lymphoma, autoimmune disease, HIV/HCV infection, and high body mass index. Treatment involves chemotherapy such as R-CHOP along with radiation or stem cell transplant depending on risk factors and age. Prognosis depends on factors like stage and the international prognostic index, with 5-year survival rates around 46% on average.
PD-L1 is a protein that is expressed on tumor cells and suppresses the immune system's ability to attack tumors. Blocking the PD-1/PD-L1 pathway through antibodies or other inhibitors can help the immune system recognize and destroy cancer cells. Several PD-L1 antibody drugs have been approved to treat cancers like lung cancer and urothelial carcinoma. Clinical trials are also testing combinations of PD-L1 inhibitors with other cancer therapies to improve treatment outcomes. Researchers continue to develop new approaches for targeting the PD-1/PD-L1 pathway, including gene silencing techniques and pathway inhibitors.
The document discusses immunotherapy and the role of pathologists in assessing tumor samples. It describes how certain tumors express PD-L1 antigens that can be recognized by the immune system, but the tumors also engage immune checkpoint pathways like PD-1 and CTLA-4 to evade the immune response. Immunotherapy drugs target these checkpoint pathways to enhance the immune response. The document outlines the FDA-approved PD-L1 immunohistochemistry assays and biomarkers used to identify cancer patients most likely to respond to immune checkpoint inhibitors for various cancer types including NSCLC, melanoma, bladder cancer, and colorectal cancer.
This document provides an overview of chronic myeloid leukemia (CML) and its treatment. It discusses prognostic factors in CML, the phases of the disease, and historical treatments including interferon and chemotherapy. It then focuses on current first-line treatments for chronic phase CML, including the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. It reviews clinical trials that have demonstrated the superiority of these targeted therapies compared to historical options. The document concludes with recommendations for monitoring patient response to CML treatments.
This document provides background information on microsatellite instability (MSI). It discusses how microsatellites are short repetitive sequences prone to mutations during DNA replication due to slipped strand mispairing or unequal crossing over. MSI occurs when mutations inactivate DNA mismatch repair genes, leading to length alterations in microsatellite regions. This causes microsatellite instability, which is seen in certain cancers like colorectal cancer and can be assessed through testing tumor DNA for instability in microsatellite markers. Immunohistochemistry for mismatch repair proteins or direct testing for MSI can help identify tumors associated with defective mismatch repair and microsatellite instability.
EGFR mutations are present in 10-20% of Caucasian and 40-60% of Asian patients with NSCLC. First-generation EGFR TKIs such as gefitinib and erlotinib are the standard of care for patients with EGFR mutations. The FLAURA trial found that the third-generation EGFR TKI osimertinib significantly improved progression-free survival compared to gefitinib or erlotinib as a first-line treatment for EGFR mutant NSCLC. Osimertinib also showed benefits for patients with CNS metastases. However, combination of first-generation EGFR TKIs with chemotherapy may provide further benefits like improved overall response rate, progression-free
Co-Chairs Srdan Verstovsek, MD, PhD, and Ruben A. Mesa, MD, FACP, prepared useful Practice Aids pertaining to myelofibrosis for this CME activity titled “Understanding the Clinical Spectrum of Myelofibrosis: Expert Perspectives on Molecular Biology, JAK Inhibitors, and Emerging Therapeutics.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3wzK6zG. CME credit will be available until October 9, 2022.
PD1PDL1 Pathway and its inhibitors for slideshare.pptxdrshrikantraut
PD-1 and its ligand PD-L1 act as an immune checkpoint that inhibits T cell activation and allows tumors to evade immune detection. Blocking this pathway with monoclonal antibodies such as nivolumab and pembrolizumab has shown clinical efficacy in cancer treatment. A meta-analysis of over 28,000 cancer patients found that PD-1/PD-L1 inhibitors achieved an overall response rate of 20.21% and higher response rates in PD-L1 positive versus negative tumors. PD-1/PD-L1 blockade also improved progression-free and overall survival more in PD-L1 positive patients compared to conventional therapies. However, predictive biomarkers beyond PD-L1 expression are still needed to
Update on Management of Triple Negative Breast Cancerspa718
This document provides an update on the management of triple negative breast cancer from Dr. Banu Arun at MD Anderson Cancer Center. It discusses that triple negative breast cancer is a heterogeneous disease comprised of several molecular subtypes with different characteristics and potential treatment targets. Clinical trials exploring chemotherapy regimens, platinum agents, PARP inhibitors, anti-angiogenic drugs, and immunotherapies are summarized. Ongoing research aims to better define the subtypes in order to personalize treatment for triple negative breast cancer patients.
This document discusses liquid biopsy, a non-invasive technique to detect tumor biomarkers shed into body fluids like blood. It can identify circulating tumor cells, circulating tumor DNA, exosomes, and newly, tumor educated platelets. Liquid biopsy offers advantages over tissue biopsy like being less invasive, allowing repeated sampling over time. While sensitivity remains a limitation, liquid biopsy shows promise for early cancer detection, monitoring treatment response and tumor evolution, and assessing tumor heterogeneity. The document reviews technologies to analyze various biomarkers and potential clinical applications of liquid biopsy.
This document discusses common malignancies in children and embryonal tumors specifically. It outlines four main embryonal tumors - Wilms tumor, retinoblastoma, neuroblastoma, and medulloblastoma. For each tumor, it describes the clinical presentation, cellular origins based on embryonic development, molecular pathology including key genetic drivers, and current treatment approaches. It concludes by noting certain genetic predisposition syndromes can increase the risk of developing cancer in childhood.
Role of Chemotherapy, Targeted therapy and Immunotherapy in NSCLC (Part II)Mohammed Fathy
1) The document discusses targeted therapies for non-small cell lung cancer (NSCLC) with ALK translocations, including crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib.
2) Alectinib is now considered the preferred first-line treatment for ALK-positive NSCLC based on Phase III trials showing it is more effective than crizotinib.
3) For patients who progress on a first-generation ALK inhibitor like crizotinib, later-generation ALK inhibitors such as ceritinib, brigatinib, and lorlatinib have demonstrated efficacy in clinical trials as subsequent therapies.
This document summarizes research on mantle cell lymphoma (MCL), a rare type of non-Hodgkin's lymphoma. Key points include:
1) MCL was established as a distinct subtype of lymphoma in 1992 and is characterized by the t(11;14) chromosomal translocation and overexpression of cyclin D1.
2) Current treatments can achieve high response rates but MCL often relapses and no treatment is considered curative for advanced disease.
3) A study found that the combination of lenalidomide and rituximab showed promising efficacy against MCL with an overall response rate of 57% and 33% complete response rate in relapsed/refractory patients.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It is characterized by the overproduction of immature white blood cells called lymphoblasts. The disease is classified based on immunophenotyping and cytogenetics. Prognostic factors include age, white blood cell count, cytogenetics, and immunophenotype. Diagnosis involves examination of peripheral blood, bone marrow aspirate, immunophenotyping, cytogenetics, and molecular testing. Treatment and monitoring of minimal residual disease is important. Genetic conditions and environmental exposures can predispose children to developing ALL.
This document provides information on Chronic Myeloid Leukemia (CML), including its pathogenesis, diagnosis, staging, and management. It notes that CML is associated with the Philadelphia chromosome containing the BCR-ABL oncogene. Diagnosis involves cytogenetic testing showing the translocation and RT-PCR detecting BCR-ABL copies. CML progresses through chronic, accelerated, and blast crisis phases. First-line treatment is typically imatinib, nilotinib, or dasatinib, with switching to another tyrosine kinase inhibitor or allogeneic stem cell transplant for advanced or resistant disease.
This document provides an overview of the principles of immunotherapy. It begins by describing the cancer-immunity cycle and how the adaptive anticancer immune response is initiated. It then discusses how tumors can evade the immune system, such as by overexpressing inhibitory receptors like PD-L1. The document reviews different approaches to immunotherapy, including passive approaches using checkpoint inhibitors and active approaches like cancer vaccines. It also covers topics like evaluating the efficacy of immunotherapy, biomarkers, combination immunotherapy, and immune-related adverse events.
This document provides an overview of diffuse large B-cell lymphoma (DLBCL), including epidemiology, risk factors, presentation, histology, genetics, therapy, and treatment options. DLBCL is the most common subtype of non-Hodgkin lymphoma. The standard first-line treatment is rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). For early stage disease, options include full chemotherapy or abbreviated chemotherapy with radiation. Advanced disease is treated with full chemotherapy. Refractory cases may be treated with newer agents or CAR T-cell therapy.
Immunological Checkpoints and Cancer Immunotherapyimgcommcall
Immunological checkpoints and cancer immunotherapy were reviewed. Immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies can activate the immune system against cancer by blocking inhibitory signals to T cells. Clinical trials show these drugs produce durable responses in various cancers like melanoma, lung cancer, and Merkel cell carcinoma. Combining different immunotherapies or with other treatments may help more patients by overcoming resistance. Ongoing research aims to better understand combination approaches and biomarkers of response.
Primary germ cell tumors arise from malignant transformation of primordial germ cells. They most commonly occur in testes in males aged 15-35 years. The document discusses the classification, epidemiology, risk factors, diagnostic markers, staging, and management of testicular germ cell tumors. It outlines that seminomas and non-seminomatous germ cell tumors are the main types and describes their characteristic histopathological features and tumor markers.
HEREDITARY BREAST and OVARY CANCER [HBOC] SYNDROME, Dr BUI DAC CHI.hungnguyenthien
The BRCA genes normally help repair DNA damage but mutations increase cancer risk. Hereditary Breast and Ovarian Cancer (HBOC) Syndrome is caused by mutations in the BRCA1 and BRCA2 genes, increasing risks for early-onset breast, ovarian, pancreatic, and other cancers. Genetic testing can identify BRCA mutations to diagnose HBOC and determine risks for family members. Referral for genetic testing should be considered for those with personal or family histories of certain cancers.
Multiple myeloma is a cancer of plasma cells that produce abnormal antibodies. It causes bone destruction and can damage the kidneys and suppress the bone marrow. While the cause is unknown, risk factors include age, family history, and exposure to radiation. Symptoms include bone pain, fatigue, recurrent infection, and kidney problems. Diagnosis involves blood and urine tests and a bone marrow biopsy. Staging uses tests such as MRI, blood tests, and bone surveys. Treatment may include chemotherapy, steroids, radiation, stem cell transplants, and newer drugs that target specific pathways in myeloma cells. While not yet curable, novel agents have improved survival rates and quality of life compared to conventional chemotherapy alone.
This document discusses the molecular biology of colorectal cancers. It notes that colorectal cancer results from the accumulation of genetic and epigenetic alterations in colonic epithelium that lead to adenocarcinoma. There are two main molecular pathways - the chromosomal instability pathway characterized by abnormalities like aneuploidy, and the microsatellite instability pathway where genes involved in DNA mismatch repair are mutated. The key genes and mutations involved in progression along these pathways are described, as well as biomarkers that have prognostic or predictive value for colorectal cancer.
This document summarizes the molecular biology of esophageal and gastric cancers. It discusses common genetic alterations in these cancers, including oncogenes and tumor suppressor genes. For esophageal cancer, it describes alterations in EGFR, cyclin D1, p53, E-cadherin and other genes. For gastric cancer, it discusses differences between intestinal and diffuse subtypes and common mutations in genes like p53, CDH1 and mismatch repair genes. The document also summarizes proposed molecular classifications of gastric cancer from TCGA and ACRG and their prognostic implications, along with targeted therapies in development or approved for treatment.
Cytomegalovirus (CMV) is an important infection after allogeneic hematopoietic stem cell transplantation that can cause multiorgan disease. It interacts with the immune system and is a risk factor for acute and chronic graft-versus-host disease. Prevention strategies include using CMV-seronegative blood products for seronegative patients and a seronegative donor when possible. For seropositive patients and recipients, pre-emptive antiviral therapy based on CMV antigenemia or PCR testing is superior to prophylaxis and has reduced CMV-associated mortality. Ganciclovir is the standard treatment but foscarnet is used if resistance or toxicity develops.
Dasatinib is an effective first-line treatment for chronic myeloid leukemia (CML) based on results from the DASISION trial. The trial showed that dasatinib induced higher and faster rates of complete cytogenetic response and major molecular response compared to imatinib. At 5 years of follow-up, dasatinib maintained superior rates of molecular responses including deeper responses below 0.1% BCR-ABL1. Dasatinib therefore provides improved long-term outcomes for patients with newly diagnosed CML compared to standard imatinib treatment.
Co-Chairs Srdan Verstovsek, MD, PhD, and Ruben A. Mesa, MD, FACP, prepared useful Practice Aids pertaining to myelofibrosis for this CME activity titled “Understanding the Clinical Spectrum of Myelofibrosis: Expert Perspectives on Molecular Biology, JAK Inhibitors, and Emerging Therapeutics.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3wzK6zG. CME credit will be available until October 9, 2022.
PD1PDL1 Pathway and its inhibitors for slideshare.pptxdrshrikantraut
PD-1 and its ligand PD-L1 act as an immune checkpoint that inhibits T cell activation and allows tumors to evade immune detection. Blocking this pathway with monoclonal antibodies such as nivolumab and pembrolizumab has shown clinical efficacy in cancer treatment. A meta-analysis of over 28,000 cancer patients found that PD-1/PD-L1 inhibitors achieved an overall response rate of 20.21% and higher response rates in PD-L1 positive versus negative tumors. PD-1/PD-L1 blockade also improved progression-free and overall survival more in PD-L1 positive patients compared to conventional therapies. However, predictive biomarkers beyond PD-L1 expression are still needed to
Update on Management of Triple Negative Breast Cancerspa718
This document provides an update on the management of triple negative breast cancer from Dr. Banu Arun at MD Anderson Cancer Center. It discusses that triple negative breast cancer is a heterogeneous disease comprised of several molecular subtypes with different characteristics and potential treatment targets. Clinical trials exploring chemotherapy regimens, platinum agents, PARP inhibitors, anti-angiogenic drugs, and immunotherapies are summarized. Ongoing research aims to better define the subtypes in order to personalize treatment for triple negative breast cancer patients.
This document discusses liquid biopsy, a non-invasive technique to detect tumor biomarkers shed into body fluids like blood. It can identify circulating tumor cells, circulating tumor DNA, exosomes, and newly, tumor educated platelets. Liquid biopsy offers advantages over tissue biopsy like being less invasive, allowing repeated sampling over time. While sensitivity remains a limitation, liquid biopsy shows promise for early cancer detection, monitoring treatment response and tumor evolution, and assessing tumor heterogeneity. The document reviews technologies to analyze various biomarkers and potential clinical applications of liquid biopsy.
This document discusses common malignancies in children and embryonal tumors specifically. It outlines four main embryonal tumors - Wilms tumor, retinoblastoma, neuroblastoma, and medulloblastoma. For each tumor, it describes the clinical presentation, cellular origins based on embryonic development, molecular pathology including key genetic drivers, and current treatment approaches. It concludes by noting certain genetic predisposition syndromes can increase the risk of developing cancer in childhood.
Role of Chemotherapy, Targeted therapy and Immunotherapy in NSCLC (Part II)Mohammed Fathy
1) The document discusses targeted therapies for non-small cell lung cancer (NSCLC) with ALK translocations, including crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib.
2) Alectinib is now considered the preferred first-line treatment for ALK-positive NSCLC based on Phase III trials showing it is more effective than crizotinib.
3) For patients who progress on a first-generation ALK inhibitor like crizotinib, later-generation ALK inhibitors such as ceritinib, brigatinib, and lorlatinib have demonstrated efficacy in clinical trials as subsequent therapies.
This document summarizes research on mantle cell lymphoma (MCL), a rare type of non-Hodgkin's lymphoma. Key points include:
1) MCL was established as a distinct subtype of lymphoma in 1992 and is characterized by the t(11;14) chromosomal translocation and overexpression of cyclin D1.
2) Current treatments can achieve high response rates but MCL often relapses and no treatment is considered curative for advanced disease.
3) A study found that the combination of lenalidomide and rituximab showed promising efficacy against MCL with an overall response rate of 57% and 33% complete response rate in relapsed/refractory patients.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It is characterized by the overproduction of immature white blood cells called lymphoblasts. The disease is classified based on immunophenotyping and cytogenetics. Prognostic factors include age, white blood cell count, cytogenetics, and immunophenotype. Diagnosis involves examination of peripheral blood, bone marrow aspirate, immunophenotyping, cytogenetics, and molecular testing. Treatment and monitoring of minimal residual disease is important. Genetic conditions and environmental exposures can predispose children to developing ALL.
This document provides information on Chronic Myeloid Leukemia (CML), including its pathogenesis, diagnosis, staging, and management. It notes that CML is associated with the Philadelphia chromosome containing the BCR-ABL oncogene. Diagnosis involves cytogenetic testing showing the translocation and RT-PCR detecting BCR-ABL copies. CML progresses through chronic, accelerated, and blast crisis phases. First-line treatment is typically imatinib, nilotinib, or dasatinib, with switching to another tyrosine kinase inhibitor or allogeneic stem cell transplant for advanced or resistant disease.
This document provides an overview of the principles of immunotherapy. It begins by describing the cancer-immunity cycle and how the adaptive anticancer immune response is initiated. It then discusses how tumors can evade the immune system, such as by overexpressing inhibitory receptors like PD-L1. The document reviews different approaches to immunotherapy, including passive approaches using checkpoint inhibitors and active approaches like cancer vaccines. It also covers topics like evaluating the efficacy of immunotherapy, biomarkers, combination immunotherapy, and immune-related adverse events.
This document provides an overview of diffuse large B-cell lymphoma (DLBCL), including epidemiology, risk factors, presentation, histology, genetics, therapy, and treatment options. DLBCL is the most common subtype of non-Hodgkin lymphoma. The standard first-line treatment is rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). For early stage disease, options include full chemotherapy or abbreviated chemotherapy with radiation. Advanced disease is treated with full chemotherapy. Refractory cases may be treated with newer agents or CAR T-cell therapy.
Immunological Checkpoints and Cancer Immunotherapyimgcommcall
Immunological checkpoints and cancer immunotherapy were reviewed. Immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies can activate the immune system against cancer by blocking inhibitory signals to T cells. Clinical trials show these drugs produce durable responses in various cancers like melanoma, lung cancer, and Merkel cell carcinoma. Combining different immunotherapies or with other treatments may help more patients by overcoming resistance. Ongoing research aims to better understand combination approaches and biomarkers of response.
Primary germ cell tumors arise from malignant transformation of primordial germ cells. They most commonly occur in testes in males aged 15-35 years. The document discusses the classification, epidemiology, risk factors, diagnostic markers, staging, and management of testicular germ cell tumors. It outlines that seminomas and non-seminomatous germ cell tumors are the main types and describes their characteristic histopathological features and tumor markers.
HEREDITARY BREAST and OVARY CANCER [HBOC] SYNDROME, Dr BUI DAC CHI.hungnguyenthien
The BRCA genes normally help repair DNA damage but mutations increase cancer risk. Hereditary Breast and Ovarian Cancer (HBOC) Syndrome is caused by mutations in the BRCA1 and BRCA2 genes, increasing risks for early-onset breast, ovarian, pancreatic, and other cancers. Genetic testing can identify BRCA mutations to diagnose HBOC and determine risks for family members. Referral for genetic testing should be considered for those with personal or family histories of certain cancers.
Multiple myeloma is a cancer of plasma cells that produce abnormal antibodies. It causes bone destruction and can damage the kidneys and suppress the bone marrow. While the cause is unknown, risk factors include age, family history, and exposure to radiation. Symptoms include bone pain, fatigue, recurrent infection, and kidney problems. Diagnosis involves blood and urine tests and a bone marrow biopsy. Staging uses tests such as MRI, blood tests, and bone surveys. Treatment may include chemotherapy, steroids, radiation, stem cell transplants, and newer drugs that target specific pathways in myeloma cells. While not yet curable, novel agents have improved survival rates and quality of life compared to conventional chemotherapy alone.
This document discusses the molecular biology of colorectal cancers. It notes that colorectal cancer results from the accumulation of genetic and epigenetic alterations in colonic epithelium that lead to adenocarcinoma. There are two main molecular pathways - the chromosomal instability pathway characterized by abnormalities like aneuploidy, and the microsatellite instability pathway where genes involved in DNA mismatch repair are mutated. The key genes and mutations involved in progression along these pathways are described, as well as biomarkers that have prognostic or predictive value for colorectal cancer.
This document summarizes the molecular biology of esophageal and gastric cancers. It discusses common genetic alterations in these cancers, including oncogenes and tumor suppressor genes. For esophageal cancer, it describes alterations in EGFR, cyclin D1, p53, E-cadherin and other genes. For gastric cancer, it discusses differences between intestinal and diffuse subtypes and common mutations in genes like p53, CDH1 and mismatch repair genes. The document also summarizes proposed molecular classifications of gastric cancer from TCGA and ACRG and their prognostic implications, along with targeted therapies in development or approved for treatment.
Cytomegalovirus (CMV) is an important infection after allogeneic hematopoietic stem cell transplantation that can cause multiorgan disease. It interacts with the immune system and is a risk factor for acute and chronic graft-versus-host disease. Prevention strategies include using CMV-seronegative blood products for seronegative patients and a seronegative donor when possible. For seropositive patients and recipients, pre-emptive antiviral therapy based on CMV antigenemia or PCR testing is superior to prophylaxis and has reduced CMV-associated mortality. Ganciclovir is the standard treatment but foscarnet is used if resistance or toxicity develops.
Dasatinib is an effective first-line treatment for chronic myeloid leukemia (CML) based on results from the DASISION trial. The trial showed that dasatinib induced higher and faster rates of complete cytogenetic response and major molecular response compared to imatinib. At 5 years of follow-up, dasatinib maintained superior rates of molecular responses including deeper responses below 0.1% BCR-ABL1. Dasatinib therefore provides improved long-term outcomes for patients with newly diagnosed CML compared to standard imatinib treatment.
Pathogenesis and treatment of Chronic Myeloid LeukemiaAlok Gupta
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the Philadelphia chromosome and BCR-ABL fusion gene. The natural history involves chronic, accelerated, and blast crisis phases if untreated. Tyrosine kinase inhibitors (TKIs) like imatinib revolutionized CML treatment by targeting BCR-ABL. TKIs induce high rates of response but resistance and intolerance occur in some patients. For these cases, second-generation TKIs or allogeneic stem cell transplant are recommended. Advanced phase CML has a poorer prognosis but TKIs can induce responses before transplant, which offers the best chance of cure.
Transplant in pediatrics in Acute lymphoblastic Luekemia in CR1Dr. Liza Bulsara
to transplant or not to transplant pediatric luekemia in CR1 Has also been a controversial topic . here we give clear recommendation to transplant in difeerent biology group
Predictors of imatinib failure in cml by prof. abinyaKesho Conference
This study examined predictors of treatment failure in chronic myeloid leukemia (CML) patients receiving imatinib therapy at a hospital in Nairobi, Kenya. The study found that 20.9% of 206 CML patients treated with imatinib experienced hematologic treatment failure, with most having secondary rather than primary failure. Missed imatinib doses, higher BCR-ABL levels at diagnosis, and a longer duration between CML diagnosis and starting imatinib therapy were associated with treatment failure. On logistic regression, only a prolonged duration between diagnosis and starting imatinib was an independent predictor of failure. The study aims to help identify patients at higher risk of imatinib treatment failure so they can be considered for
This document discusses immunotherapies for hepatocellular carcinoma (HCC). It begins by explaining that HCC typically develops in the context of chronic liver disease and cirrhosis. For early-stage HCC, surgical resection and liver transplantation can be curative, while radiofrequency ablation and transarterial chemoembolization are common local therapies for intermediate-stage HCC. Systemic therapies were historically ineffective for advanced HCC, but tyrosine kinase inhibitors like sorafenib were found to provide a survival benefit. More recent immunotherapies like nivolumab, pembrolizumab, and combinations with ipilimumab have shown response rates of 15-31% in advanced HCC
Inotuzumab ozogamicin is an antibody-drug conjugate being studied for the treatment of acute lymphoblastic leukemia (ALL) in adults. The INO-VATE ALL study compared inotuzumab ozogamicin to standard chemotherapy for adults with relapsed or refractory ALL. The primary objectives were to demonstrate higher rates of complete remission and longer overall survival with inotuzumab ozogamicin. Complete remission, safety, and overall survival were evaluated. If shown to be effective, inotuzumab ozogamicin could provide a new treatment option for adults with relapsed/refractory ALL.
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Advances in immunotherapy, including checkpoint inhibitors targeting CTLA-4 and PD-1, have significantly improved outcomes for patients with metastatic melanoma. Combination immunotherapy with nivolumab and ipilimumab produces response rates over 60%, compared to around 40% for nivolumab alone and 11% for ipilimumab alone. Many patients receiving the combination immunotherapy continue to respond even after stopping treatment, achieving a state of treatment-free survival. While combination immunotherapy is more toxic than single-agent treatments, the toxicities are often manageable. Ongoing research continues to explore optimizing combination immunotherapy regimens to improve outcomes while reducing toxicity.
This document discusses improvements in treatment and outcomes for acute lymphoblastic leukemia (ALL) in children. It notes that the cure rate for ALL has increased from less than 10% in the 1960s to around 90% currently due to several factors: large randomized clinical trials to test chemotherapy regimens more effectively; understanding of genetic subtypes to tailor treatment intensity; monitoring of minimal residual disease to identify high-risk patients; and introduction of new targeted drugs like imatinib for resistant ALL subtypes. The success of the pediatric approach relies on high enrollment in collaborative multi-center studies to continually refine treatment protocols.
This document provides information about Dr. Jason Westin, an assistant professor at MD Anderson Cancer Center whose research focuses on improving therapy and outcomes for patients with lymphoma. His specific research interests include diffuse large B-cell lymphoma, developing systems to identify optimal therapeutic combinations for individual patients, drug synergy and antagonism, scale free networks in cancer therapy, and developing sensitive disease monitoring methods. The document also summarizes several of Dr. Westin's presentations on novel targeted therapies in T-cell lymphoma from 2014, including studies on drugs such as brentuximab, mogamulizumab, lenalidomide, alisertib, selinexor, romidepsin, panobinostat, and inhibitors of the
This document summarizes a presentation on the management of metastatic colorectal cancer (mCRC) in 2017. It discusses several key points:
1) Patient stratification is important in determining treatment approach for mCRC, taking into account factors like disease extent and symptoms.
2) A multidisciplinary team approach is mandatory for developing optimal treatment plans.
3) Assessment of predictive biomarkers like RAS mutations helps determine which first-line treatments may be most effective.
4) Tumor location (right vs left-sided colon cancer) can impact treatment outcomes and response to certain drugs like anti-EGFR therapies.
5) Multiple clinical trials over time have led to improved survival outcomes and more
This document provides an overview of the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). For AML, it discusses pre-treatment evaluation, induction therapy including various chemotherapy regimens, post-remission consolidation therapy stratified by risk factors, and management of relapsed or refractory disease. It also covers special situations in AML including differentiation syndrome, tumor lysis syndrome, and hyperleucocytosis. For CML, it outlines prognostic scoring, treatment goals, available tyrosine kinase inhibitors and their dosing and side effects, monitoring response levels, and options for treatment discontinuation or allogeneic stem cell transplant.
- Renal cell carcinoma (RCC) incidence has increased in recent years, with 20-50% of localized cases progressing to metastatic cancer.
- Several risk stratification models (UISS, SSIGN, Leibovich) are used to predict survival and guide surveillance and treatment eligibility.
- Early adjuvant trials of VEGF TKIs like sunitinib and sorafenib showed minimal improvement in disease-free survival at significant cost of toxicity.
- The KEYNOTE-564 trial showed significant improvement in disease-free survival for high-risk RCC patients treated with adjuvant pembrolizumab compared to placebo.
This document provides an overview of chronic myelogenous leukemia (CML) for primary care physicians. It discusses the epidemiology, clinical manifestations, molecular pathophysiology, natural history, diagnosis, and treatment of CML. Key points include: CML represents 15-20% of adult leukemias, with the median age of onset being 45-55 years. The Philadelphia chromosome, resulting from a translocation, produces a Bcr-abl fusion gene that drives uncontrolled proliferation. CML progresses through chronic, accelerated, and blast phases if left untreated. Tyrosine kinase inhibitors like imatinib revolutionized treatment by targeting the Bcr-abl protein. Imatinib induces high rates of remission but side effects can include
Stem Cell Transplantation in Hodgkin’s Lymphoma Past, Present and FutureAmir Abbas Hedayati Asl
Treatment for HL has improved significantly since the ABVD chemotherapeutic combination was invented over 30 years ago .
Despite using the same ABVD regimen in most patients treated in the first line, we now have a much better understanding of disease biology and the late side effects of therapy, and we have moved toward a personalized, risk-adapted approach.
This approach promises to deliver low toxicities and high cure rates for lower risk patients while reserving aggressive regimens for those high risk patients who really need them.
For the minority of patients who fail first-line therapy, novel drugs like the antibody-drug conjugate BV and immunotherapies with nivolumab and pembrolizumab have produced high response rates and durability of benefit.
Further research is needed to determine whether these novel drugs could make life better for both patients with HL who are undergoing treatment and for the growing cohort of HL survivors.
This document discusses the management of triple negative breast cancer (TNBC). It begins with an overview of the three main subtypes of breast cancer and their associated treatments. It then focuses on the characteristics and treatment challenges of TNBC, including its aggressiveness, younger patient population, and lack of targeted therapies. Current treatment options for metastatic TNBC are discussed, including various chemotherapy regimens. The document also touches on neoadjuvant and adjuvant systemic therapy approaches as well as ongoing research into better understanding the biology of TNBC to revolutionize outcomes.
1) The study evaluated the impact of a fasting mimicking diet (FMD) as an adjunct to neoadjuvant chemotherapy for breast cancer patients. 2) 131 patients were randomized to receive either an FMD or regular diet for 3 days prior to each chemotherapy cycle. 3) Results showed that patients who adhered more closely to the FMD experienced higher rates of tumor response according to pathological criteria and were less likely to have triple negative tumors, suggesting the FMD may reinforce the effects of chemotherapy.
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Thrombophilia test- when and what to do?
Thrombophilia is not a disease itself but a manifestation of several conditions leading to increased tendency for thrombosis. Since long it has been a grey area in thrombophilia with a lot of who, when, why and what regarding testing for this condition. As a result, the tests are being done very indiscriminately without knowing what to do with the result, whether positive or negative. Many family-screening are also commonly done simultaneously in many cases unnecessarily.
The inherited thrombophilias are mutation of factor V Leiden (FVL) or prothrombin gene and deficiency of protein C (PC), protein S (PS) or antithrombin (AT). The acquired conditions are anti-phospholipid syndrome (APS), paroxysmal nocturnal hemoglobinuria (PNH) and myeloproliferative neoplasms (MPN). Various malignancies, drugs (e.g., oral contraceptives, chemotherapy), pregnancy, trauma and surgery also increase the risk of thrombosis. In clinical point of view immobility and central venous access devises (CVAD) also add fuel to the flame (Virchow’s triad).
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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Upfront treatment of CML:How to select TKI?.pptx
1. Upfront treatment of CML:
How to select TKI?
Dr Pritish Chandra Patra
Associate Professor
Dept. of Clinical Hematology
IMS & SUM Hospital, Bhubaneswar
Which one to choose?
RED pill or BLUE pill
2. Epidemiology: SEER Database
1 to 2 new cases of CML are diagnosed per 100,000 people annually1
With the success of TKI therapy, the prevalence of CML is increasing annually2,3
1. Baccarani M, et al. Ann Oncol. 2009;20(suppl 4):iv105-iv107.
2. Rohrbacher M, Hasford J. Best Prac Res Clin Haematol. 2009;22(3):295-302.
3. Huang X, Cortes J, Kantarjian H. Cancer. 2012;118(12):3123-3127.
3. • ICON (Indian Cooperative Oncology Network) in 2010.
• 8115 patients data was presented and 18 centers.
• CML is one of the commonest adult leukemia in Indian population accounting for 30% to 60% of all adult
leukemias.
• Incidence of CML cases varied from 70% of all leukemia cases at IGIMS, RCC, Patna to 16.6% GCRI, Gujarat.
• This huge difference in incidence of CML cases:
• not population-based registries
• different cancer populations they cater to.
Indian data
Bansal S, Prabhash K, Parikh P. Chronic myeloid leukemia data from India. Indian J Med Paediatr Oncol. 2013 Jul;34(3):154-8.
4. • 2 decades back, managing CML was simple !
• Start Imatinib
• If it fails, Allogeneic Transplant !
• Now we have 6 TKI s, namely Imatinib, Nilotinib, Dasatinib, Bosutinib, Ponatinib and Asciminib
• Which one to choose as first Line ?
The journey so far
5. Overview
• Two decades of experience with imatinib and later-generation BCR::ABL1 TKIs in Ph+ve CML
• Important to discuss
• established guidelines on treatment options
• frontline CML therapy
• treatment aims
• response monitoring
• significance of the response milestones: ELN and NCCN
6. Targeted Therapy in the Post-Imatinib Era
Approved treatment
Imatinib
(Gleevec®/Glivec®)
FDA approval of imatinib
for all phases
of Ph+ CML1
2001
ENESTnd study meets its
primary endpoint; nilotinib
demonstrates superiority
over imatinib4,5
2009
1. Gleevec (imatinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
2. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2012.
3. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
4. Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259.
5. Saglio G, et al. Blood. 2009;114(22) [abstract LBA-1].
6. Bosulif (bosutinib) [package insert]. New York, NY; Pfizer; 2012.
7. Iclusig (ponatinib) [package insert]. Cambridge, MA: Ariad Pharmaceuticals, Inc; 2012.
8. Synribo (omacetaxine mepesuccinate) [package insert]. North Wales, PA: Teva Pharmaceuticals, Inc; 2012.
9. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-scemblix-asciminib-patients-philadelphia-
chromosome-positive#:~:text=On%20October%2029%2C%202021%2C%20the,for%20adult%20patients%20with%20Philadelphia
Initial FDA
approval of
dasatinib2,a
2006
FDA approval of nilotinib for patients
resistant to or intolerant of prior therapy,
including imatinib3,a
2007
Dasatinib
(Sprycel®)
Nilotinib
(Tasigna®)
Nilotinib approved for first-
line use in patients with Ph+
CML-CP3,a
2010
Dasatinib approved for
first-line use in
patients with Ph+
CML-CP2,a
2010
2012
FDA approval of
bosutinib,6,a
ponatinib,7,a and
omacetaxine8,b for
patients resistant to
or intolerant of prior
therapy
Bosutinib
(Bosulif®)
Ponatinib
(Iclusig®)
2000 2010
Omacetaxine
(Synribo®)
2021
FDA approval of Asciminib for patients
with CML CP previously treated with >2
TKI and with T315I mutation9
2021
Asciminib
(Scemblix®)
Olverembatinib
7. Front line therapy
Primary aim
• To improve survival so that it matches that of a
normal population
Second aim
• Achievement of a durable deep molecular
response (DMR)
• Allow treatment discontinuation and potentially a
treatment-free remission (TFR) status
CCyR MMR DMR TFR
2 log reduction or
≤1 % on IS
MR3 or 3 log reduction or
≤0.1 % on IS
MR4 or 4 log reduction or ≤ 0.01% on IS
MR4.5 or < 0.0032% on IS
However, it is no indication that CML
has been eliminated !
8. Molecular response for CML
Vivian G. Oehler; First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?. Hematology Am Soc Hematol Educ
9. Available options
Imatinib Nilotinib
Dasatinib Bosutinib
Patients comply with the treatment
Monitored optimally
Minimal interruptions
Managed well at earliest signs of resistance
4 approved TKI for 1st line
All TKI near normal QoL and life expectancy
10. Established treatment goals and their significance
1. Hughes TP, et al. Blood 2014;123:1353-1360; 2. Jabbour E, et al. Blood 2014;123:494-500; 3. Hanfstein B, et al. Leukemia 2012;26:2096-2102; 4. Gambacorti-Passerini C, et al. Blood.
2017;130 [abstract 896]; 5. Baccarani M, et al. Blood. 2013;122:872-884; 6. Hochhaus A et al. Ann Oncol 2017;28:iv41-iv51; 7. Larson RA, et al. Blood. 2014;124 [abstract 4541]; 8. Hochhaus A,
et al. Leukemia. 2016;30:1044-1054; 9. Cortes JE, et al. J Clin Oncol. 2016;34:2333-2340; 10. Cortes JE, et al. J Clin Oncol. 2018;36:231-237.
• EMR is associated with higher rates of MR4.5 and improved OS and PFS1-3
• Rates of EMR (BCR-ABL1IS ≤ 10% at 3 months) are higher with 2G TKIs vs imatinib in 1L1,2,4
Early
Molecular
Response
• MMR at 12 months is considered to be an optimal response per treatment recommendations5,6
• Rates of MMR are higher with 2G TKIs vs imatinib in 1L4,7-10
MMR at
12 months
• Frequency of progression to AP/BC is lower with 1L nilotinib vs imatinib7; numerically fewer
patients have disease progression with 1L dasatinib vs imatinib9
Disease
Progression
• OS rates are high with all 1L TKIs4,8,9
• 2G TKIs are associated with fewer deaths due to disease progression than imatinib in 1L4,8,9
• Deaths due to CVEs are rare with imatinib and dasatinib8,9
• More deaths due to infections are seen with 1L dasatinib vs imatinib9
Overall
Survival
11. Overview of the 2020 ELN Recommendations
Key Updates Since the 2013 ELN Recommendations
CML, chronic myeloid leukemia; DMR, deep molecular response; ELN, European LeukemiaNet; TFR, treatment-free remission.
Hochhaus A, et al. Leukemia. 2020 Mar 3 [Epub ahead of print].
• Achievement of stable DMR and TFR to avoid life-long treatment is now considered
a treatment goal
CML Treatment Goals
• All target response milestones are now defined based on molecular response
levels
• Target response milestones are now the same for 1L and 2L therapy
• For patients aiming to achieve TFR, the optimal response at any time is now defined
as BCR-ABL1IS ≤ 0.01% (MR4)
Target Response Milestones
• The ELN has proposed contraindications for some TKIs
Recommendations Regarding Treatment Selection
• For the first time, the ELN has proposed criteria for attempting TFR outside of
clinical trials
TFR
12. Target Response Milestones for Frontline and Second-Line TKI Therapy
Optimal
BCR-ABL1IS Level
Warning
BCR-ABL1IS Level
Failure
BCR-ABL1IS Level
Baseline NA High-risk ACA, high-risk ELTS score NA
3 months ≤ 10% > 10%
> 10% if confirmed within 1 to 3
months
6 months ≤ 1% > 1-10% > 10%
12 months ≤ 0.1% (MMR) > 0.1-1% > 1%
Any time ≤ 0.1%a,b > 0.1-1%,
loss of MMRc
> 1%, resistance mutations, high-
risk ACA
ACA, additional chromosome abnormalities in Ph+ cells; BCR-ABL1IS, BCR-ABL1 transcript level on the International Scale; ELTS, European Treatment
Outcome Study Long Term Survival; MMR, major molecular response equivalent to BCR-ABL1IS ≤ 0.1%; NA, not applicable; Ph+, Philadelphia chromosome-
positive; TKI, tyrosine kinase inhibitor.
a For patients aiming to achieve TFR, the optimal response at any time is BCR-ABL1IS ≤ 0.01% (MR4).
b A change of treatment may be considered if MMR (BCR-ABL1IS ≤ 0.1%) is not achieved by 36-48 months.
c Loss of MMR indicates failure following TFR.
Hochhaus A, et al. Leukemia. 2020 Mar 3 [Epub ahead of print].
All target response milestones are now defined based on
molecular response levels
rather than cytogenetic or hematologic response
Key updates
since 2013
NCCN
Guidelines
2024
ELN
2020
13. Comparison of TKIs: which is the BEST?
Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Elias Jabbour, Hagop Kantarjian. Am J Hematol. 2022;97:1236–1256.
14. How to choose ?
Aim of therapy: survival or TFR
• Elderly: survival > TFR- Imatinib may be better
• Young: TFR > survival- 2G TKI
Cost of therapy & affordability
• Imatinib
• Generics
Co-morbidities
• Lung disease
• DM, HTN
• Hepatic or renal dysfunction
• Pancreatitis, enterocolitis, VOE
CML risk category
• Sokal or ELTS
• HR- 2G TKI > Imatinib
• LR- Imatinib > 2G TKI
• Advance disease
Management of chronic myeloid leukemia in 2023- common ground and common sense. J. Senapati et al. Blood Cancer Journal (2023) 13:58.
15. Scoring systems to guide!
Sokal Hasford
EUTOS ELTS
• Several risk scores help predict outcomes.
• Low- or intermediate-risk disease- expected to have optimal responses with
imatinib, dasatinib, nilotinib, or bosutinib.
• High risk disease- 2G TKI as frontline therapy may be more beneficial.
• Higher risk disease- a lower likelihood of achieving the early milestones of
CCyR and MMR and, particularly, higher risks of disease transformation to
AP-CML or BP-CML.
• Any of the TKIs currently approved for frontline CML therapy may be
selected.
• While 2G TKIs have demonstrated superiority over imatinib in relation to
early surrogate markers, imatinib is still highly effective in most patients with
CML.
Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Elias Jabbour, Hagop Kantarjian. Am J Hematol. 2022;97:1236–1256.
• Kinase domain mutation profile plays no role in selecting an initial TKI.
16. TKI resistance
• Incidence of primary resistance to frontline TKI therapy is 10%, and of secondary resistance 30%.
• German CML IV trial-
• 1551 pts, CML-CP, Imatinib, median follow up 10 yrs, 10yr OS 82%, relative survival rate 92%, , BP incidence 5.2%, 26.5% changed TKI:
10% due to, rest for toxicities
• MDACC-
• Dasatinib 50mg, median follow up 5yrs, 5yr OS 98%, AP/BP incidence 0%, primary or secondary resistance <5% (defined as BCR::ABL1
transcripts [IS] > 1% any time after 12 months of therapy)
• MDACC-
• Dasatinib 100 vs Imatinib trial in frontline-
• In our long-term frontline TKI therapy experience, the estimated 15-year OS rate (including any death,
regardless of cause) is about 75%. The CML-specific survival rate (considering only deaths from CML or
treatment complications) is >90% [33].
• Thus, frontline therapy with the existing TKIs achieves the primary endpoint of survival normalization for
most patients with CML.
Management of chronic myeloid leukemia in 2023- common ground and common sense. J. Senapati et al. Blood Cancer Journal (2023) 13:58.
17. Achievement of TFR
DMR: BCR::ABL1 transcripts- 0% or MR4 or MR4.5
Discontinuing the TKI after a sustained DMR of >2 years 3-year TFR rates- 40%–50%.
Discontinuation of TKI after a DMR of ≥5 years 5-year TFR rates- >80%.
Achievement of TFR has been estimated to be about 25–30%.
Management of chronic myeloid leukemia in 2023- common ground and common sense. J. Senapati et al. Blood Cancer Journal (2023) 13:58.
18. Special situation: Pregnancy
• Must be individualized.
• TKI should be discontinued in the first trimester, as soon as pregnancy is confirmed.
• Fetal ultrasonography should be performed immediately.
• Options of continuing or discontinuing treatment and continuation of pregnancy or not should
be exhaustively discussed.
• Teratogenicity of TKI is due to off-target- PDGFR inhibition during organogenesis.
• All TKIs are contraindicated throughout pregnancy.
• Although imatinib has been used safely in the second and third trimesters, insufficient
experience.
• More advance disease- termination of the pregnancy is considered.
• Low WBC count- CML treatment may not be required before delivery.
• Thrombocytosis- Aspirin and/or LMWH.
• Leucapheresis and/or IFNα are safe throughout gestation.
• Low-level secretion of TKI in breast milk contraindicates their use during breast-feeding.
19.
20. How to select TKI?
Vivian G. Oehler; First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?. Hematology Am Soc Hematol Educ Program 2020;
21. How to select TKI?
Vivian G. Oehler; First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?. Hematology Am Soc Hematol Educ Program 2020;