CME ARTICLE
A JH
CME Information: Chronic Myeloid Leukemia: 2016 update on diagnosis, therapy and monitoring CME Editor: Ayalew Tefferi, M.D. Author: Elias Jabbour, M.D. and Hagop Kantarjian, M.D. If you wish to receive credit for this activity, please refer to the website: www.wileyhealthlearning.com
䊏 Accreditation and Designation Statement Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to:
Manage patients with newly diagnosed CML in CP Understand the milestones and indications for switch of therapy Manage patients with resistant disease Differentiate the TKIs available Manage patients with advanced phases, including the role of allogeneic stem cell transplantation
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. CME Editor: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose. Author: Elias Jabbour, M.D. and Hagop Kantarjian, M.D. have no relevant financial relationships to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’ Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
䊏 Instructions on Receiving Credit This activity is intended for physicians. For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within one hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Additionally, up to 3 attempts and a score of 70% or better is needed to pass the post test. Follow these steps to earn credit:
Log on to www.wileyhealthlearning.com Read the target audience, educational objectives, and activity disclosures. Read the activity contents in print or online format. Reflect on the activity contents. Access the CME Exam, and choose the best answer to each question. Complete the required evaluation component of the activity. Claim your Certificate.
This activity will be available for CME credit for twelve months following its launch date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months.
C 2016 Wiley Periodicals, Inc. V
252
American Journal of Hematology, Vol. 91, No. 2, February 2016
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
AJH Educational Material
A JH
Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring Elias Jabbour* and Hagop Kantarjian Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease. C 2015 Wiley Periodicals, Inc. Am. J. Hematol. 91:253–265, 2016. V
䊏 Disease Overview Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults [1]. In 2015, it is estimated about 7,000 new CML cases will be diagnosed in the United States, and about 1,100 patients will die of CML. Since 2000, the year of introduction of imatinib, the annual mortality in CML has decreased from 10–20% down to 1–2% [1]. Consequently, the prevalence of CML in the United States, estimated at about 25-30,000 in 2000, has increased to an estimated 80–1,00,0001 in 2015, and will reach a plateau of about 1,80,000 cases by 2030 [2]. Central to the pathogenesis of CML is the fusion of the Abelson murine leukemia (ABL1) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22. This results in expression of an oncoprotein termed BCR-ABL1 [3]. BCR-ABL1 is a constitutively active tyrosine kinase that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC and STAT [4–10] This influences leukemogenesis by creating a cytokine-independent cell cycle with aberrant apoptotic signals in response to cytokine withdrawal. Until a little more than a decade ago, drug therapy for CML was limited to nonspecific agents such as busulfan, hydroxyurea, and interferonalfa (INF-a) [11]. INF-a led to disease regression and improved survival but was hindered by its modest efficacy and a multitude of toxicities. Allogeneic stem cell transplantation (allo-SCT) is curative, but carries risks of morbidity and mortality. Further, allo-SCT is an option only for patients with good performance status and organ functions, and who have an appropriate stem cell donor. The CML therapeutic landscape changed dramatically with the development of small molecule tyrosine kinase inhibitors (TKIs) that potently interfered with the interaction between the BCR-ABL1 oncoprotein and adenosine triphosphate (ATP), blocking cellular proliferation of the malignant clone. This “targeted” approach altered the natural history of CML, improving the 10-year survival rate from approximately 20% to 80–90% [1.2,12]. In this review, we will highlight the evidence supporting the use of each of the available TKIs, including how to select an agent in various circumstances and phases of the disease. Allo-SCT is an important treatment option in CML chronic phase (CP) post TKIs failure and in advanced CML phases, and its role will be discussed. Cytogenetic and molecular benchmarks for patients on therapy will be discussed. Finally, appropriate monitoring strategies for patients on various TKIs will be covered.
Department of Leukemia, the University of Texas M. D. Anderson Cancer Center, Houston, Texas
Conflict of interest: Nothing to report *Correspondence to: Elias Jabbour, MD Anderson Cancer Center, Houston, Texas, USA, Box 428, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: [email protected] Received for publication: 7 December 2015; Accepted: 9 December 2015 Am. J. Hematol. 91:253–265, 2016. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.24275 C 2015 Wiley Periodicals, Inc. V
doi:10.1002/ajh.24275
American Journal of Hematology, Vol. 91, No. 2, February 2016
253
Jabbour and Kantarjian
䊏 Manifestations and Staging About 50% of patients with CML diagnosed in the United States are asymptomatic. The disease is diagnosed often after a routine physical examination or blood tests. CML can be classified into three phases: CP, accelerated phase (AP), and blast phase (BP). Most (90– 95%) patients present in CML-CP. Common signs and symptoms of CML-CP, when present, result from anemia and splenomegaly. These include fatigue, weight loss, malaise, easy satiety, and left upper quadrant fullness or pain. Rare manifestations include bleeding (associated with a low platelet count and/or platelet dysfunction), thrombosis (associated with thrombocytosis and/or marked leukocytosis), gouty arthritis (from elevated uric acid levels), priapism (usually with marked leukocytosis or thrombocytosis), retinal hemorrhages, and upper gastrointestinal ulceration and bleeding (from elevated histamine levels due to basophilia). Leukostatic symptoms (dyspnea, drowsiness, loss of coordination, confusion) due to leukemic cells sludging in the pulmonary or cerebral vessels, are uncommon in CP despite white blood cell (WBC) counts exceeding 100 x 109/L. Splenomegaly is the most consistent physical sign detected in 40–50% of cases. Hepatomegaly is less common (less than 10%). Lymphadenopathy and infiltration of skin or other tissues are rare. When present, they favor Ph-negative CML or AP or BP of CML. Headaches, bone pain, arthralgias, pain from splenic infarction, and fever are more frequent with CML transformation. Most patients evolve into AP prior to BP, but 20% transit into BP without AP warning signals. CML-AP might be insidious or present with worsening anemia, splenomegaly and organ infiltration; CML-BP presents as an acute leukemia (myeloid in 60%, lymphoid in 30%, megakaryocytic or undifferentiated in 10%) with worsening constitutional symptoms, bleeding, fever and infections.
䊏 Diagnosis The diagnosis of typical CML is simple and consists of documenting, in the setting of persistent unexplained leukocytosis (or occasionally thrombocytosis), the presence of the Philadelphia (Ph) chromosome abnormality, the t(9;22)(q34;q11), by routine cytogenetics, or the Ph-related molecular BCR-ABL1 abnormalities by fluorescence in situ hybridization (FISH) or by molecular studies [13–15]. A FISH analysis relies on the co-localization of large genomic probes specific to the BCR and ABL genes. Comparison of simultaneous marrow and blood samples by FISH analysis shows high concordance. FISH studies may have a false positive range of 1–5% depending on the probes used. Reverse transcriptase-polymerase chain reaction (RT-PCR) amplifies the region around the splice junction between BCR and ABL1. It is highly sensitive in detecting minimal residual disease. PCR testing can either be qualitative (QPCR), providing information about the presence of the BCR-ABL1 transcript, or quantitative, assessing the amount of BCR-ABL1 transcripts. Qualitative PCR is useful for diagnosing CML; quantitative PCR is ideal for monitoring residual disease. Simultaneous peripheral blood and marrow QPCR studies show a high level of concordance. False-positive and false-negative results can happen with PCR. False-negative results may be from poor-quality RNA or failure of the reaction; false-positive results can be due to contamination. A 0.5–1 log difference in some samples can occur depending on testing procedures, sample handling, and laboratory experience [13–15]. For correlative purpose and monitoring without necessarily performing repeat marrow studies, a complete cytogenetic response (CCyR; 0% Ph-positive metaphases by cytogenetic) is equivalent to a negative FISH test (62%) and BCR-ABL1 transcripts by International Standard [IS] 1% And/or Ph1 > 0% Loss of CHR Loss or CCyR Confirmed loss of MMR CCA in Ph1 cells
doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES TABLE V. MDACC Criteria for Response/Failure and Change of Therapy Time (months) 3-6 12 Later
Imatinib MCyR; PCR10% [IS] CCyR; PCR 1% [IS] CCyR; PCR 1% [IS]
TABLE VI. Important response categories in CML
Second generation TKIs
Response
CCyR; PCR 1% [IS] CCyR; PCR 1% [IS] CCyR; PCR 1% [IS]
BCR-ABL1 10% at 6 months; CCyR later MMR
cytogenetic relapse calls for a change in therapy. Fluctuating molecular levels during continuous CCyR would only prompt closer monitoring and a compliance assessment. In several studies, the achievement of a CCyR (Ph-positive metaphases 0%; BCR-ABL1 transcripts [IS] 1%) at 12 months or later on TKI therapy was associated with significant survival benefit compared with achievement of lesser degrees of response. Achievement of CCyR is the primary endpoint of TKI therapy. Achievement of BCR-ABL1 transcripts [IS] 0.1% (MMR) was associated with modest improvements in event-free survival rates, possible longer durations of CCyR, but not with a survival benefit. The achievement of CMR (non-measurable BCR-ABL1 transcripts) offers the possibility of treatment discontinuation in clinical trials only (Table VI). Lack of achievement of MMR or of CMR should not be interpreted as a need to change TKI therapy or to consider allo-SCT. Response assessments at earlier times on frontline TKI therapy (3–6 months) have shown better outcomes with achievement of a major cytogenetic response by 3–6 months on imatinib therapy (Ph-positive metaphases 35%; BCR-ABL1 transcripts [IS] 10%). While this is interpreted to mean that a change to second TKI therapy may be considered if such outcome is not obtained, no studies have shown that changing therapy from imatinib to second TKIs has improved patients ’outcomes. When nilotinib or dasatinib are used in front-line therapy, achievement of complete cytogenetic response by 3–6 months of TKIs therapy has been associated with improved outcomes. At MDACC, our major treatment milestones are at 6 and 12 months. Patients with lack of PCyR (BCR-ABL1 transcripts [IS] > 10%) at 6 months, or without CCyR (BCR-ABL1 transcripts [IS] 1%) at 12 months, or with loss of response at any time are candidates for a switch of therapy. The choice of TKIs is based on the mutation profiles and patients comorbidities. We do not consider a change of TKI therapy in patients in CCyR but without MMR.
䊏 Management of TKI Resistance A remaining problem with the widespread use of all commercially available TKIs is increased drug resistance. A common mechanism of resistance involves point mutations in the kinase domain of BCRABL1, which impairs the activity of the available TKIs. Second generation TKIs overcome most of the mutations that confer resistance to imatinib, though novel mutations rendering the leukemia resistant to dasatinib and/or nilotinib have emerged. One important mutation, T315I known as the “gatekeeper” mutation, displays resistance to all currently available TKIs except ponatinib. Before defining a patient as having TKI resistance and modifying therapy, treatment compliance and drug-drug interactions should be assessed. Rates of imatinib adherence have been estimated to range from 75% to 90%, and lower adherence rates correlated with worse outcome [64–66]. In a study of 87 patients with CML-CP treated with imatinib 400mg daily, an adherence rate of 90% or less resulted in MMR rate of 28% compared with 94% with greater than 90% adherence rate (P 12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. The duration of TKI treatment was 8 years (range, 3–12.6 years), and median duration of MR4 before TKI cessation was 5.4 years (range, 1–11.7 years). Overall, 123 of the 200 patients remained without relapse in the first 6 months. Recurrence of CML, defined as loss of MMR, was observed in 47/114 patients (47%) treated for 8 years (P 5 0.003). The duration of MR4 >5 years vs.
A JH
CME Information: Chronic Myeloid Leukemia: 2016 update on diagnosis, therapy and monitoring CME Editor: Ayalew Tefferi, M.D. Author: Elias Jabbour, M.D. and Hagop Kantarjian, M.D. If you wish to receive credit for this activity, please refer to the website: www.wileyhealthlearning.com
䊏 Accreditation and Designation Statement Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to:
Manage patients with newly diagnosed CML in CP Understand the milestones and indications for switch of therapy Manage patients with resistant disease Differentiate the TKIs available Manage patients with advanced phases, including the role of allogeneic stem cell transplantation
䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. CME Editor: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose. Author: Elias Jabbour, M.D. and Hagop Kantarjian, M.D. have no relevant financial relationships to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’ Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.
䊏 Instructions on Receiving Credit This activity is intended for physicians. For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within one hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Additionally, up to 3 attempts and a score of 70% or better is needed to pass the post test. Follow these steps to earn credit:
Log on to www.wileyhealthlearning.com Read the target audience, educational objectives, and activity disclosures. Read the activity contents in print or online format. Reflect on the activity contents. Access the CME Exam, and choose the best answer to each question. Complete the required evaluation component of the activity. Claim your Certificate.
This activity will be available for CME credit for twelve months following its launch date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months.
C 2016 Wiley Periodicals, Inc. V
252
American Journal of Hematology, Vol. 91, No. 2, February 2016
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
AJH Educational Material
A JH
Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring Elias Jabbour* and Hagop Kantarjian Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease. C 2015 Wiley Periodicals, Inc. Am. J. Hematol. 91:253–265, 2016. V
䊏 Disease Overview Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults [1]. In 2015, it is estimated about 7,000 new CML cases will be diagnosed in the United States, and about 1,100 patients will die of CML. Since 2000, the year of introduction of imatinib, the annual mortality in CML has decreased from 10–20% down to 1–2% [1]. Consequently, the prevalence of CML in the United States, estimated at about 25-30,000 in 2000, has increased to an estimated 80–1,00,0001 in 2015, and will reach a plateau of about 1,80,000 cases by 2030 [2]. Central to the pathogenesis of CML is the fusion of the Abelson murine leukemia (ABL1) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22. This results in expression of an oncoprotein termed BCR-ABL1 [3]. BCR-ABL1 is a constitutively active tyrosine kinase that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC and STAT [4–10] This influences leukemogenesis by creating a cytokine-independent cell cycle with aberrant apoptotic signals in response to cytokine withdrawal. Until a little more than a decade ago, drug therapy for CML was limited to nonspecific agents such as busulfan, hydroxyurea, and interferonalfa (INF-a) [11]. INF-a led to disease regression and improved survival but was hindered by its modest efficacy and a multitude of toxicities. Allogeneic stem cell transplantation (allo-SCT) is curative, but carries risks of morbidity and mortality. Further, allo-SCT is an option only for patients with good performance status and organ functions, and who have an appropriate stem cell donor. The CML therapeutic landscape changed dramatically with the development of small molecule tyrosine kinase inhibitors (TKIs) that potently interfered with the interaction between the BCR-ABL1 oncoprotein and adenosine triphosphate (ATP), blocking cellular proliferation of the malignant clone. This “targeted” approach altered the natural history of CML, improving the 10-year survival rate from approximately 20% to 80–90% [1.2,12]. In this review, we will highlight the evidence supporting the use of each of the available TKIs, including how to select an agent in various circumstances and phases of the disease. Allo-SCT is an important treatment option in CML chronic phase (CP) post TKIs failure and in advanced CML phases, and its role will be discussed. Cytogenetic and molecular benchmarks for patients on therapy will be discussed. Finally, appropriate monitoring strategies for patients on various TKIs will be covered.
Department of Leukemia, the University of Texas M. D. Anderson Cancer Center, Houston, Texas
Conflict of interest: Nothing to report *Correspondence to: Elias Jabbour, MD Anderson Cancer Center, Houston, Texas, USA, Box 428, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: [email protected] Received for publication: 7 December 2015; Accepted: 9 December 2015 Am. J. Hematol. 91:253–265, 2016. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.24275 C 2015 Wiley Periodicals, Inc. V
doi:10.1002/ajh.24275
American Journal of Hematology, Vol. 91, No. 2, February 2016
253
Jabbour and Kantarjian
䊏 Manifestations and Staging About 50% of patients with CML diagnosed in the United States are asymptomatic. The disease is diagnosed often after a routine physical examination or blood tests. CML can be classified into three phases: CP, accelerated phase (AP), and blast phase (BP). Most (90– 95%) patients present in CML-CP. Common signs and symptoms of CML-CP, when present, result from anemia and splenomegaly. These include fatigue, weight loss, malaise, easy satiety, and left upper quadrant fullness or pain. Rare manifestations include bleeding (associated with a low platelet count and/or platelet dysfunction), thrombosis (associated with thrombocytosis and/or marked leukocytosis), gouty arthritis (from elevated uric acid levels), priapism (usually with marked leukocytosis or thrombocytosis), retinal hemorrhages, and upper gastrointestinal ulceration and bleeding (from elevated histamine levels due to basophilia). Leukostatic symptoms (dyspnea, drowsiness, loss of coordination, confusion) due to leukemic cells sludging in the pulmonary or cerebral vessels, are uncommon in CP despite white blood cell (WBC) counts exceeding 100 x 109/L. Splenomegaly is the most consistent physical sign detected in 40–50% of cases. Hepatomegaly is less common (less than 10%). Lymphadenopathy and infiltration of skin or other tissues are rare. When present, they favor Ph-negative CML or AP or BP of CML. Headaches, bone pain, arthralgias, pain from splenic infarction, and fever are more frequent with CML transformation. Most patients evolve into AP prior to BP, but 20% transit into BP without AP warning signals. CML-AP might be insidious or present with worsening anemia, splenomegaly and organ infiltration; CML-BP presents as an acute leukemia (myeloid in 60%, lymphoid in 30%, megakaryocytic or undifferentiated in 10%) with worsening constitutional symptoms, bleeding, fever and infections.
䊏 Diagnosis The diagnosis of typical CML is simple and consists of documenting, in the setting of persistent unexplained leukocytosis (or occasionally thrombocytosis), the presence of the Philadelphia (Ph) chromosome abnormality, the t(9;22)(q34;q11), by routine cytogenetics, or the Ph-related molecular BCR-ABL1 abnormalities by fluorescence in situ hybridization (FISH) or by molecular studies [13–15]. A FISH analysis relies on the co-localization of large genomic probes specific to the BCR and ABL genes. Comparison of simultaneous marrow and blood samples by FISH analysis shows high concordance. FISH studies may have a false positive range of 1–5% depending on the probes used. Reverse transcriptase-polymerase chain reaction (RT-PCR) amplifies the region around the splice junction between BCR and ABL1. It is highly sensitive in detecting minimal residual disease. PCR testing can either be qualitative (QPCR), providing information about the presence of the BCR-ABL1 transcript, or quantitative, assessing the amount of BCR-ABL1 transcripts. Qualitative PCR is useful for diagnosing CML; quantitative PCR is ideal for monitoring residual disease. Simultaneous peripheral blood and marrow QPCR studies show a high level of concordance. False-positive and false-negative results can happen with PCR. False-negative results may be from poor-quality RNA or failure of the reaction; false-positive results can be due to contamination. A 0.5–1 log difference in some samples can occur depending on testing procedures, sample handling, and laboratory experience [13–15]. For correlative purpose and monitoring without necessarily performing repeat marrow studies, a complete cytogenetic response (CCyR; 0% Ph-positive metaphases by cytogenetic) is equivalent to a negative FISH test (62%) and BCR-ABL1 transcripts by International Standard [IS] 1% And/or Ph1 > 0% Loss of CHR Loss or CCyR Confirmed loss of MMR CCA in Ph1 cells
doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES TABLE V. MDACC Criteria for Response/Failure and Change of Therapy Time (months) 3-6 12 Later
Imatinib MCyR; PCR10% [IS] CCyR; PCR 1% [IS] CCyR; PCR 1% [IS]
TABLE VI. Important response categories in CML
Second generation TKIs
Response
CCyR; PCR 1% [IS] CCyR; PCR 1% [IS] CCyR; PCR 1% [IS]
BCR-ABL1 10% at 6 months; CCyR later MMR
cytogenetic relapse calls for a change in therapy. Fluctuating molecular levels during continuous CCyR would only prompt closer monitoring and a compliance assessment. In several studies, the achievement of a CCyR (Ph-positive metaphases 0%; BCR-ABL1 transcripts [IS] 1%) at 12 months or later on TKI therapy was associated with significant survival benefit compared with achievement of lesser degrees of response. Achievement of CCyR is the primary endpoint of TKI therapy. Achievement of BCR-ABL1 transcripts [IS] 0.1% (MMR) was associated with modest improvements in event-free survival rates, possible longer durations of CCyR, but not with a survival benefit. The achievement of CMR (non-measurable BCR-ABL1 transcripts) offers the possibility of treatment discontinuation in clinical trials only (Table VI). Lack of achievement of MMR or of CMR should not be interpreted as a need to change TKI therapy or to consider allo-SCT. Response assessments at earlier times on frontline TKI therapy (3–6 months) have shown better outcomes with achievement of a major cytogenetic response by 3–6 months on imatinib therapy (Ph-positive metaphases 35%; BCR-ABL1 transcripts [IS] 10%). While this is interpreted to mean that a change to second TKI therapy may be considered if such outcome is not obtained, no studies have shown that changing therapy from imatinib to second TKIs has improved patients ’outcomes. When nilotinib or dasatinib are used in front-line therapy, achievement of complete cytogenetic response by 3–6 months of TKIs therapy has been associated with improved outcomes. At MDACC, our major treatment milestones are at 6 and 12 months. Patients with lack of PCyR (BCR-ABL1 transcripts [IS] > 10%) at 6 months, or without CCyR (BCR-ABL1 transcripts [IS] 1%) at 12 months, or with loss of response at any time are candidates for a switch of therapy. The choice of TKIs is based on the mutation profiles and patients comorbidities. We do not consider a change of TKI therapy in patients in CCyR but without MMR.
䊏 Management of TKI Resistance A remaining problem with the widespread use of all commercially available TKIs is increased drug resistance. A common mechanism of resistance involves point mutations in the kinase domain of BCRABL1, which impairs the activity of the available TKIs. Second generation TKIs overcome most of the mutations that confer resistance to imatinib, though novel mutations rendering the leukemia resistant to dasatinib and/or nilotinib have emerged. One important mutation, T315I known as the “gatekeeper” mutation, displays resistance to all currently available TKIs except ponatinib. Before defining a patient as having TKI resistance and modifying therapy, treatment compliance and drug-drug interactions should be assessed. Rates of imatinib adherence have been estimated to range from 75% to 90%, and lower adherence rates correlated with worse outcome [64–66]. In a study of 87 patients with CML-CP treated with imatinib 400mg daily, an adherence rate of 90% or less resulted in MMR rate of 28% compared with 94% with greater than 90% adherence rate (P 12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. The duration of TKI treatment was 8 years (range, 3–12.6 years), and median duration of MR4 before TKI cessation was 5.4 years (range, 1–11.7 years). Overall, 123 of the 200 patients remained without relapse in the first 6 months. Recurrence of CML, defined as loss of MMR, was observed in 47/114 patients (47%) treated for 8 years (P 5 0.003). The duration of MR4 >5 years vs.
