Adult Leukemias_MDS Workbook.pdf

ADULT ACUTE LEUKEMIAS AND MYELODYSPLASTIC SYNDROMES Jill S. Bates, Pharm.D., M.S., BCOP, FASHP Oncology Precision Medicine Pharmacist University of North Carolina Medical Cen...

ADULT ACUTE LEUKEMIAS AND MYELODYSPLASTIC SYNDROMES Jill S. Bates, Pharm.D., M.S., BCOP, FASHP Oncology Precision Medicine Pharmacist University of North Carolina Medical Center Associate Professor of Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina LEARNING OBJECTIVES At the end of the presentation and after reviewing the accompanying reading materials, the participant should be able to: 1. Design an appropriate patient-specific treatment, supportive care, and monitoring plan taking into consideration efficacy and safety outcomes from clinical trials and current treatment guidelines for adults with acute leukemia or myelodysplastic syndrome. 2. Assess the prognostic impact of relevant cancer-related molecular biology testing for an adult with acute leukemia or myelodysplastic syndrome. 3. Devise and communicate appropriate plans for preventing, monitoring, and treating adverse reactions from pharmacotherapy for acute leukemia and myelodysplastic syndrome in an adult, including tumor lysis syndrome, neurotoxicity, differentiation syndrome, and cardiac toxicity from arsenic trioxide, and other agents as appropriate. 4. Determine appropriate pharmacotherapy for acute leukemia or myelodysplastic syndrome in an adult based on genomic test results. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) referenced with permission from the National Comprehensive Cancer Network® (NCCN®). To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 1  MYELODYSPLATIC SYNDROMES Patient Case #1: CJ is a 69 year-old female with no significant medical history. Despite generally enjoying good health for most of her life, she has noticed an increase in fatigue and sore throat for the last 2 weeks. When she presented to her primary care provider, her laboratory parameters revealed WBC 2300 cells/mm3 with 40% neutrophils, hemoglobin 9.1 gm/dL and platelets 138,000 cells/mm3. The patient is referred to her hematologist who finds nothing remarkable in a battery of additional tests. However, the bone marrow biopsy comes back from the hematopathologist with a reading of dysplastic changes with 4% blasts consistent with de novo MDS. Her epoetin level is reported as 157 units/L. Based upon this information, what should be done for this patient? A. Erythropoietin B. Filgrastim C. Eltrombopag D. Lenalidomide I. Etiology/Pathogenesis1-3 A. Chromosomal abnormalities underlie the molecular pathogenesis of MDS. Molecular abnormalities may include loss or gain of parts of chromosomes 3, 5, 7, 8, 11, 17 and 20. 1. Abnormalities of chromosome 5 are the most common abnormality in MDS. B. Additional cytogenetic abnormalities are necessary for progression to the leukemic phenotype. The N-ras oncogene, anti-apoptotic gene bcl-2 gene, and MLL transcription factor gene have been implicated. C. Recent data has indicated that cytogenetic patterns are not stable in MDS. A significant portion of patients will acquire additional cytogenetic changes, which is associated with increased risk of transformation to AML and worse survival. D. Gene mutations have been identified that may contribute to the biological heterogeneity of MDS. Studies have identified approximately 40 recurring genetic mutations with >80% of patients with MDS harboring at least one. Several of these mutations have been associated with adverse clinical features: 1. Complex karyotype (TP53) 2. Excess bone marrow blast proportion (RUNX1, NRAS, and TP53) 3. Severe thrombocytopenia (RUNX1, NRAS, and TP53) E. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 hold independent prognostic value and predict decreased OS in multivariate models adjusted for International Prognostic Scoring System (IPSS) and the Revised International Prognostic Scoring System (IPSS-R) risk groups. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 2 II. Risk Factors3-5 A. Previous exposure to alkylating agents, topoisomerase II inhibitors, and ionizing radiation increase the risk of MDS. 1. Alkylating agents and topoisomerase II inhibitors (individually, or in combination) are the most common causes of treatment-related MDS. a. Alkylating agent-related MDS characteristically causes mutations of chromosomes 5 and 7 or results in a complex karyotype. The median onset after therapy is 4-7 years. b. Topoisomerase inhibitor-related MDS typically causes mutations of chromosome 11q23. The median onset after therapy is 2-3 years. B. Risk factors for developing secondary AML from antecedent MDS include number of cytopenias at diagnosis, percentage of blasts in the bone marrow and cytogenetics. III. Staging6-8 A. Classification: WHO classification is current standard (2016). 1. Presence of t(15;17), t(8;21), or inv16 are classified as AML regardless of other features. B. Prognosis based on staging criteria (see Tables 1-3) IX. Prognosis of MDS based on staging criteria A. Two scoring systems are most commonly used: The IPSS and the IPSS-R , which superseded the latter.9, 10 1. Both scoring systems are based on patients with newly diagnosed MDS who received no therapy to alter the natural course of the disease. 2. Both scoring systems include analysis of peripheral cytopenias, percentage of bone marrow blasts, and cytogenetic characteristics. a. The IPSS combines risk scores for the three major variables and stratifies patients into four risk groups. 1) The IPSS score is simple to use and highly reproducible. 2) However, it is not a very precise predictor of prognosis, especially in patients with lower-risk disease. 3) Likewise, it attributes relatively little weight to cytogenetics and is insensitive to the degree of cytopenias. b. The IPSS-R score includes a new cytogenetic risk classification that divides patients into five cytogenetic categories. This system assigns patients to one of five risk groups, including an intermediate risk group. 3. The most commonly used system is still the IPSS, but it is being replaced by the IPSS-R. a. Current therapies were approved using IPSS criteria. No drug therapy has been approved using IPSS-R criteria. b. Some clinicians use IPSS to determine therapy, but use IPSS-R to determine prognosis. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 3  B. Other prognostic scoring systems used include the World Health Organization (WHO) Prognostic Scoring System (WPSS) and global M.D. Anderson Cancer Center (MDACC). These systems are more dynamic in that they can be applied beyond the point of diagnosis.11, 12 Lastly, the MDACC-lower-risk scoring system was designed to account for the heterogeneity of disease biology appreciated amongst those with lower-risk MDS.13 1. A new concept in lower-risk MDS is the concept of “poor prognosis” lower-risk MDS due to the considerable heterogeneity in outcomes within lower-risk IPSS patients.14 2. The MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) was specifically developed to further stratify patients in the lower-risk group. This system has been externally validated, but has not yet been widely applied to clinical practice. a. The following factors were independent for survival outcomes: 1) Unfavorable cytogenetics 2) Older age (≥60 years) 3) Decreased hemoglobin (≤10 g/dL) 4) Decreased platelet counts (≤200,000 cells/mm3) 5) Higher percentage of bone marrow blasts (≥4% blasts) Table 1. International Prognostic Scoring System (IPSS) for MDS9 Score Variable 0 0.5 1 1.5 2 % BM blasts 2.5 High BM = bone marrow. Republished with permission of American Society of Hematology from International scoring system for evaluating prognosis in myelodysplastic syndromes, Greenberg et al., 89, 6, 1997; permission conveyed through Copyright Clearance Center, Inc. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 4  Table 2. Revised International Prognostic Scoring System (IPSS-R) for MDS10 Score Variable 0 0.5 1 1.5 2 3 4 Very Very Cytogenetics* -- Good -- Intermediate Poor Good Poor % BM Blasts ≤2 -- >2 - 10 -- Hemoglobin ≥10 -- 8 - 4.5 – 6 13 1.6 1.4 Very High >6 10 0.8 0.7 Republished with permission of American Society of Hematology from Revised international prognostic scoring system for myelodysplastic syndromes, Greenberg et al., 120, 12, 2012; permission conveyed through Copyright Clearance Center, Inc. B. Current therapy recommendations divide patients into low-risk and high-risk groups.7, 8, 14-16 ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 5  Low risk groups High risk groups IPSS low IPSS intermediate-2 IPSS intermediate-1 IPSS high risk categories IPSS-R very low IPSS-R intermediate IPSS-R low IPSS-R high IPSS-R intermediate IPSS-R very high X. Treatment A. Goals of therapy for patients with MDS include: 1. Alteration of the natural history of the disease / delaying disease progression 2. Reducing number of red blood cell transfusions 3. Improving quality of life B. Approximately 50% of patients with newly diagnosed MDS have one or more comorbidities.8, 16 1. The presence of comorbid conditions poses potential challenges in terms of treatment tolerability and outcomes. 2. An evaluation of the presence and extent of comorbid conditions is an important aspect of management of MDS patients. C. Allogeneic hematopoietic stem cell transplantation is the only curative therapy (see chapter on Hematopoietic Stem Cell Transplantation). D. Recommended therapies8 1. Patients with lower-risk disease benefit from hematopoietic growth factors, DNA hypomethylating agents, immunosuppressive therapy and immunomodulating agents. 2. Patients with higher-risk disease are more likely to progress to AML and many benefit from DNA hypomethylating agents, intensive chemotherapy, or allogeneic hematopoietic stem cell transplant. E. Treatment of lower-risk disease 1. Therapy in this subset of patients is based on transfusion needs. Patients that are transfusion independent are typically observed until they become transfusion dependent.15 ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 6  2. Transfusion support with packed RBCs and platelets are employed as indicated.8 a. RBC transfusions (irradiated and leukocyte-reduced) for symptomatic anemia, and platelet transfusions for thrombocytopenic-related bleeding (reserve for platelets 75 years of age. c. There is little data in the use of these agents in lower-risk MDS, and neither of them have been shown to modify the natural history of this group of patients. However, they may be an appropriate option for lower-risk patients with symptomatic anemia and elevated epoetin levels who are not expected to respond to other treatment options. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 9  Table 5. Summary of common treatment strategies – hypomethylating agents in lower-risk patients Regimen Patient Results Overall Comments Population Survival Azacitidine vs BSC28 N = 191 Hematologic Median time to Further response = 60% in AML progression improvement was (Phase III trial known as “CALGB All IPSS risk patients receiving or death = 21 seen in patients who 9221”) categories of azacitidine months vs 13 received azacitidine MDS were months (p = earlier in the course included Hematologic 0.007) of disease. improvement = 5% in BSC (no responses) Alternate dosing regimens of Dose 1 (n = 50) HI = 44% vs. 45% vs. Not reported All three regimens azacitidine:30 Dose 2 (n= 51) 56% were equally well 1. “5-2-2”: 75 mg/m2/d Dose 3 (n = 50) tolerated with SQ x 5 days, 2 days rest, RBC transfusion response similar to 75 mg/m2/d SQ x 2 Most patients independence: 50% standard azacitidine days were FAB vs. 55% vs. 64% schedule. Majority 2. “5-2-5”: 50 mg/m2/d lower risk of adverse events SQ x 5 days, 2 days rest, were experienced 50 mg/m2/d SQ x 5 during early part of days therapy, suggesting 3. “5”: 75 mg/m2/d SQ x 5 improvement with days tolerance. (Phase II study) Decitabine 15 mg/m2 IV Q8H x 3 Decitabine RR = 17% vs 0% Median survival Responses in days every 6 weeks vs best (n = 89) vs BSC (p months care, range 6-24 Toxicity was INT 2) (conventional care), months), HR predominantly p = 0.003 0.58, p = 0.0001 hematologic. RBC transfusion independence = 45% (azacitidine) vs. 11% (conventional care), p < 0.0001. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 14  Azacitidine vs. allogeneic Azacitidine None reported 2 year OS = 23% Multivariate analysis transplantation40 (n = 75) vs. 39% associated ECOG score (HR 2.9/3.9, (Retrospective cohort Allogeneic P < 0.001), analysis) transplantation cytogenetics (HR (n = 103) 1.2/1.7, p < 0.001), and transplant (HR All patients had 0.3, p = 0.007) with IPSS Int-2 or improved outcomes. High-risk MDS Curves separate at 2 years, likely due to overcoming non- relapse mortality following allogeneic HSCT. Decitabine 15 mg/m2 IV Decitabine RR = 17% vs 0% Median survival Responses in Q8H x 3 days every 6 (n = 89) vs BSC (p < 0.001) was not decitabine group weeks vs best supportive (n = 81) significantly were associated with care26 9% of decitabine different transfusion All patients had pts achieved CR between the independence. (Phase III study) IPSS ≥ 0.5 patients treated 13% of decitabine with decitabine pts achieved HI and those who received Response in those supportive care with INT-2 = 12 vs 7 (14 mos vs. 14.9 months (p=0.03) mos; p = 0.636) Decitabine various doses 95 patients RR = 73% Median OS = 19 5-day IV schedule (20 mg/m2 intravenously enrolled CR = 34% months chosen on basis of daily for 5 days; 20 mg/m2 (77 MDS with dose intensity and subcutaneously daily for 5 IPSS CR = 39% in 20 response as optimal. days; or 10 mg/m2 Intermediate or mg/m2 IV arm intravenously daily for 10 High risk, 18 compared to 21- days)41 with CMML) 24% in other arms (p 5% Cellularity and morphology are not relevant Marrow CR Bone marrow ≤5% myeloblasts and decrease by ≥ 50% over pretreatment Peripheral blood: if hematologic improvement responses, they will be noted in addition to marrow complete remission Stable disease Failure to achieve at least PR Failure Death during treatment or disease progression characterized by worsening of cytopenias, increase in the percentage bone marrow blasts, or progression to an MDS FAB subtype more advanced than pretreatment Relapse after At least one of the following: CR or PR Return to pretreatment bone marrow percentage Decrement of ≥50% from maximum remission/response levels in granulocytes or platelets Reduction in hemoglobin concentration by ≥1.5 g/dL or transfusion dependence Cytogenetic Complete: Disappearance of the chromosomal abnormality without appearance of response new ones Partial: At least 50% reduction of the chromosomal abnormality Disease progression For patients with: Less than 5% blasts: ≥50% or more increase in blasts to >5% blasts 5%-10% blasts: ≥50% or more increase to >10% blasts 10% to 20% blasts: ≥50% or more increase to >20% blasts 20% to 30% blasts: ≥50% or more increase to >30% blasts And/ or any of the following: At least 50% decrement from maximum remission/response levels in granulocytes or platelets Reduction in hemoglobin by ≥2 g/dL Transfusion dependence FAB = French-American-British classification system. Republished with permission of American Society of Hematology from Report of an international working group to standardize response criteria for myelodysplastic syndromes, Cheson et al., 96, 12, 2000; permission conveyed through Copyright Clearance Center, Inc. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 18  Patient Case #2: TK is a 72-year-old male who is generally healthy but with multiple comorbidities including diabetes, hypertension, atrial fibrillation and low grade MDS. He is currently being treated with best supportive care due to a PS of 3 and consequently has received many blood transfusions. He presents with complaints of SOB and abdominal pain. The patient is taking over the counter iron supplements and vitamin C. Unfortunately, he is not a candidate for transplant; however, he does have a fairly good prognosis with respect to his MDS. Labs are as follows: WBC 3300 cells/mm3 with 45% neutrophils, hemoglobin 9 gm/dL and platelets 121,000 cells/mm3, ferritin 3100 ng/ml. What medication-related problems are present to resolve? A. Untreated iron overload B. Reactive airway disease C. Polypharmacy D. Adverse drug reaction to iron supplements XII. Iron Chelation Therapy (ICT)8, 44-49 A. Therapy for MDS may alleviate the patient’s RBC transfusion needs, but a substantial proportion of patients may not respond to treatment and may develop iron overload. 1. Retrospective and observational studies have shown that chronic iron overload is associated with an increased risk of hepatic, cardiac, and endocrine damage. a. In one study, each 500 ng/mL increase in serum ferritin above 1000 ng/mL was associated with a 40% increased risk of death. 2. A meta-analysis of 8 observational studies revealed that the use of ICT was associated with a greater median survival time than non-use of ICT, especially in low-risk MDS patients. a. The mean difference in median survival was 61.2 months. b. However, these studies may be limited by selection bias, since the decision to initiate chelation therapy may have been influenced by the patient’s clinical status. Improvements in outcomes may reflect a better clinical status and/or the potential benefits of chelation. 3. There are no prospective, randomized studies that assess the effect of iron chelation on overall survival in MDS patients. a. A recently published 5-year prospective registry enrolled 600 lower-risk MDS patients with transfusional iron overload. 1) At 24 months, chelation was associated with longer median overall survival (104.4 months vs 52.2 months, p < 0.001). 2) There was also a trend toward longer leukemia-free survival and fewer cardiac events in patients who received chelation therapy. B. If > 20 RBC transfusions have been received, consider daily iron chelation to decrease iron overload, particularly for those with >1 year lifespan (factoring in co-morbid conditions) and good prognosis (IPSS Low-risk and Intermediate-1 and for potential allogeneic HSCT candidates). Prior to commencing ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 19  iron chelation therapy, exogenous sources of iron should be discontinued. Oftentimes, vitamin C is used to increase absorption of iron supplements. This too should be discontinued. 1. Current guidelines suggest that iron chelation can be achieved with either deferoxamine or deferasirox. 2. Data from randomized, controlled clinical trials comparing ICT agents is lacking. 3. Deferasirox is contraindicated in patients with high-risk MDS due to the possibility of liver or kidney impairment and gastrointestinal bleeding. 4. Deferiprone therapy remains a controversial agent in MDS due to its potential for agranulocytosis (see Table 11). C. For patients with serum ferritin levels >2500 ng/mL, aim to decrease ferritin levels to less than 1,000 ng/mL.47 Patient Case #2 (continued): The correct answer is A. Best supportive care for low grade MDS includes support with red blood cell transfusion. TK’s signs and symptoms suggest iron overload, which is a potential problem with repeated red blood cell transfusions. Thus, the correct answer is A. TK should be started on iron chelation therapy such as deferoxamine or deferasirox. Additionally, exogenous sources of iron such as iron supplements should be discontinued. Lastly ascorbic acid increases absorption of iron and should also be discontinued. Answer B is incorrect because his shortness of breath is not associated with signs or symptoms of reactive airway disease e.g. wheezing and he has no risk factors for reactive airway disease. Answer C is incorrect because only 2 medications are mentioned and while these are inappropriate they are not too plentiful by CMS definition. Answer D is incorrect because TK’s symptoms would not be an adverse reaction to the oral iron replacement, which would not lead to iron overload when taken in normal amounts. Table 11. Summary of available iron chelating agents.50-54 Deferoxamine Deferasirox Deferasirox Deferiprone (Desferal®) (Exjade®) (Jadenu®) (Ferriprox®) Route Subcutaneous Oral Oral Oral Daily Daily 8-12 hours daily for Schedule (tablet for oral (tablet) Three times a day 5-7 days per week suspension) Infusion site reactions GI upset GI upset Major Visual changes Renal toxicity Renal toxicity Agranulocytosis adverse High-frequency Hepatic toxicity Hepatic toxicity GI upset effects hearing loss GI perforation GI perforation GI = gastrointestinal. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 20 XIII. Summary of Preferred Treatment Options8 Figure 1. Treatment of symptomatic anemia in IPSS-R Very Low, Low and Intermediate risk patients without del (5q) or other cytogenetic abnormalities. No reponse; No response - likely ≤500 mU/mL ESA ± GCSF ATG / CSA treat as per respond to INT-2 IST Serum Good [EPO] probability No response - ATG / CSA to respond see below to IST >500 mU/mL Poor Azacitidine or No Response; probability decitabine or Allo HSCT or to respond lenalidomide or clinical Trial to IST clinical trial Figure 2. Treatment of symptomatic anemia in IPSS-R Very Low, Low and Intermediate risk patients with del (5q) or other cytogenetic abnormalities. Continue Response lenalidomide Del 5q ± other cytogenetic Lenalidomide abnormalities No response See Figure 1 Figure 3. Treatment of MDS in IPSS-R Intermediate, High or Very High-risk patients. If relapse, Yes Allo HSCT azacitidine or Transplant decitabine candidate Yes and donor Azacitidine High intensity available (preferred) or therapy No decitabine or candidate Azacitidine chemotherapy or (preferrred) or No clinical trial decitabine or clinical trial ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 21  ACUTE MYELOID LEUKEMIA (AML) Patient Case #1: RO is an otherwise healthy 52-year-old female with no prior medical history who was admitted to the hospital because of a peripheral smear that is consistent with AML and without suggestion of APL. Bone marrow biopsy evaluation confirmed diagnosis of AML and cytogenetics demonstrated de novo favorable risk AML without mutated FLT3 (ITD or TKD) and is CD33 negative. Intensive remission induction chemotherapy is planned to start as soon as possible. Laboratory: WBC 42 cells/mm3 (4.3 – 10.8 cells/mm3 ) Differential: basophils 0% (0-1%) eosinophils 0% (1-3%) lymphocytes 10% (20-40%) monocytes 0% (4-8%) neutrophils bands 4% (0%) segmented 30% (40-60%) blasts 65% (0-1%) Platelets 30,000 cells/mm3 (200,000-400,000 cells/mm3) Hgb 9 gm/dl (13-18 gm/dl) HCT 27% (37-48%) Cr 1.2 mg/dl (0.5-1.4 mg/dl) Tbili 0.8 mg/dl (0.3-1.2 mg/dl) ECHO: Left ventricular ejection fraction >55% Which of the following treatments is best to use as remission induction therapy to treat RO’s AML? A. 7+3, with daunorubicin 45 mg/m2 /day B. 7+3, with daunorubicin 90 mg/m2/day C. Hyper-CVAD D. Liposomal cytarabine and daunorubicin I. Diagnosis of AML6 A. The World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia incorporates information from cytogenetics and evidence of myelodysplasia. The WHO system has replaced the prior classification system for AML defined by the French American British (FAB) system. The WHO system was most recently updated in 2016. 1. WHO separates AML and related neoplasms into five categories: 1) AML with recurrent genetic abnormalities, 2) AML with myelodysplasia-related changes, 3) Therapy-related myeloid neoplasms, 4) AML not otherwise specified (NOS), and 5) blastic plasmacytoid dendritic cell neoplasm. B. Acute promyelocytic leukemia (APL) is a distinct subtype of AML characterized by accumulation of leukemia blast cells with a 15;17 translocation [t(15;17)]. The translocated fusion protein interferes with factors required for differentiation of myeloid precursors. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 22  1. Peripheral blasts or bone marrow biopsy findings consistent with AML should be present. Greater than or equal to 20% blasts is required for diagnosis of AML per World Health Organization (WHO). However, any percentage of blasts can be considered AML if they display any of following karyotypes: a. t(8;21) b. Inversion (16) or t(16;16) c. t(15;17) II. Prognostic Factors of AML55-57 A. Patient-specific factors: 1. Age ≥ 60 years is associated with decreased overall survival due to difficulty tolerating therapy (including induction chemotherapy and possible stem cell transplant) and higher likelihood of antecedent MDS a. Performance status and comorbidities b. Total WBC at diagnosis B. AML biology-specific factors.58 AML is a heterogeneous malignancy that is associated with different outcomes depending on the biology of the cancer clone. The WHO recognizes distinct entities within the diagnosis of AML based on the presence or absence of karyotype abnormalities and molecular mutations. Specific genetic abnormalities have been identified as prognostic factors (some can also be predictive biomarkers for treatment). The prognostic impact of many abnormalities is context- dependent with prognosis influenced by the presence or absence of another aberration. Similar risk stratification systems by karyotype and/or molecular mutation have been proposed by both the National Comprehensive Cancer Network and the European Leukemia Net (ELN). 1. Karyotype (see Table 1)58-62 1) Karyotype is the strongest prognostic factor for response to induction therapy and survival. a) Favorable (a) Characterized with one (or more) of following chromosomal changes. The presence of at least one of the first three karyotypes listed (i.e. options i-ii) is called “Core- binding factor (CBF)”:63, 64 t(8;21) inv(16) or t(16;16) Technically, also includes t(15;17) into favorable; refer to “Acute Promyelocytic Leukemia” section below b) Intermediate (a) Includes normal karyotype, t(9;11) and trisomy 8 (b) Chromosomal aberrations which do not fit with other categories c) Unfavorable ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 23  (a) Any of the following karyotypes: deletion5, deletion5q, deletion7, deletion7q, abnormalities of 11q23 (e.g. MLL gene) non t(9;11), inv3, t(3;3), t(6;9), t(9;22), deletion 17p or abnormal (17p) (b) Commonly, “complex karyotype” (≥ 3 chromosomal aberrations) (c) Monosomal karyotype 2. Molecular mutations (see Table 1 below).58-62, 65, 66 Prognostic implication of molecular mutation status is an evolving area of AML. In addition to presence of molecular mutation, prognostic impact of some markers is related to allelic ratio of mutated allele. a. FMS-like tyrosine kinase (FLT)-3 1) Plays a key role in proliferation, survival and differentiation of early hematopoietic progenitor cells; all mutations lead to uncontrolled proliferation of leukemic blasts 2) FLT3-internal tandem duplication (ITD) patients do have worse outcomes. However, this is related to higher rates of relapse. Allelic ratio of FLT3-ITD is prognostic as well with higher number of copies conferring a worse prognosis. Prognostic implication of FLT3- TKD remains controversial. 3) Both prognostic and predictive biomarker associated with approved FDA companion diagnostic 4) Two types of FLT3 mutations: a) FLT3-TKD (“Tyrosine Kinase Domain”) Encountered less often and less well-studied Meta-analysis showed FLT3-TKD exhibited better survival than FLT3-ITD, which was similar to FLT3-wild type in patients with intermediate risk AML67 b) FLT-ITD i. Associated with early relapse, leading to inferior outcomes (a) Responds well to intensive remission induction chemotherapy, but confers high rate of relapse ii. FLT3-ITD is only prognostic in patients with normal karyotype AML (Table 1) (a) Minimal prognostic significance with either favorable risk or poor-risk karyotype62, 68 b. Nucleophosmin (NPM) 1 1) NPM1 mutation confers high sensitivity toward induction chemotherapy 2) In normal karyotype AML, NPM1 mutations without FLT3-ITD mutation are associated with lower relapse and greater overall survival a) Favorable feature of NPM1-positive/FLT3-ITD-negative in patients age 55-65 years was demonstrated, but not in patients age >65 years underscoring age as a significant prognostic factor.69 b) NPM1 copies are often followed throughout the disease course of AML if positive at baseline to assess minimum residual disease. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 24  c. CCAAT enhancer binding protein alpha (CEBPA) 1) Best characterized in normal karyotype.57 There are two types of CEBPA mutations: a single mutation of the gene or a double mutation of the gene. Only CEBPA double mutation is associated with an overall survival benefit. 2) Confers sensitivity to high-dose cytarabine d. Isocitrate dehydrogenase (IDH) 1 and 2 1) Predictive biomarker associated with approved FDA companion diagnostic 2) Reports of prognostic value of both IDH 1 and 2 have been inconsistent e. DNA methyltransferase 3A (DNMT3A) 1) Most commonly mutated residue is R882 2) Prognostic influence may depend on age and mutation type f. KIT gene (also called CD117) 1) Secondary genetic evaluation. Confers poor prognosis in intermediate risk AML and prognostic influence in core binding factor AML is unclear C. Response to treatment 1. Lack of complete remission after first induction therapy is associated with a poorer prognosis 2. Duration of remission < 6 months associated with a poor prognosis III. Classification of AML6, 58 A. Risk status and survival with conventional chemotherapy based upon cytogenetics and molecular mutations Table 1: National Comprehensive Cancer Network Risk Stratification65 Risk Cytogenetics Gene Mutations inv (16) Normal cytogenetics with mutated t(16;16) “Core binding factor” NPM1 without FLT3-ITD mutation Favorable t(8;21) or isolated CEBPA double mutation t(15;17) Normal cytogenetics t(8;21), inversion (16), Other non-defined t(16;16)[core binding factor]: t(9;11) with c-KIT mutation Intermediate Mutated NPM1 + FLT3-ITDhigh Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without poor risk genetic lesions) Unfavorable or Complex (≥3 clonal chromosomal abnormalities) Normal cytogenetics: Adverse Monosomal karyotype With FLT3-ITD mutation -5, -7, 5q-, 7q- TP53 mutation Abnormalities of 11q23 (MLL gene), excluding Mutated RUNX1 t(9;11) Mutated ASXL1 Inversion 3 Wild-type NPM1 and FLT3-ITDhigh t(3;3), t(6;9), t(9;22) Legend: NPM1 = Nucleophosmin 1; FLT3-ITD = Fms-like tyrosine kinase 3-internal tandem duplication; CEBPA = CCAAT/enhancer-binding protein alpha ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 25 IV. Treatment of AML A. To treat AML, most patients undergo remission induction chemotherapy followed by post-remission treatment to achieve durable remissions. There are four important predictors of outcomes in AML patients: 1. Age a. Due to worse performance status, decreased organ function, higher prevalence of unfavorable cytogenetics, likelihood of antecedent MDS, etc. b. CR rates rarely exceed 50% in patients age ≥ 60 years 2. Performance status 3. Cytogenetics a. Favorable, intermediate and adverse risk profiles identified at initial diagnosis carries through the entire treatment course in all patients b. Note: Secondary AML is automatically unfavorable risk, no matter the cytogenetics c. For unfavorable/high risk AML, it is generally accepted that allogeneic transplant is the only curable treatment available d. Evidence of pre-existing myelodysplasia 4. Duration of first CR a. CR < 6 months is poor prognosis, while CR > 12 months is more favorable B. Remission induction chemotherapy should begin immediately after a definitive diagnosis is made.70 1. Cytogenetic/biomarker information and patient history is necessary to determine treatment in the remission induction setting; however, treatment should not be significantly delayed a. Mutated FLT3 b. Treatment-related AML or AML with myelodysplasia-related changes c. The status of CD-33 expression should be determined. If the patient is CD33+ they may be a candidate for treatment with gemtuzumab ozogamicin C. Modify treatment based upon patient co-morbidities: 1. Cardiac dysfunction may either disqualify patient for intensive remission induction therapy or require using a non-anthracycline containing regimen 2. Obesity – treat with full-dose based upon actual body weight and height71-73 D. Remission induction therapy may be considered intensive or low-intensity, based upon patient characteristics.74 1. Intensive chemotherapy may be defined as chemotherapy aimed at achieving CR 2. Low-intensity chemotherapy defined as chemotherapy aimed at altering the natural course of the disease (see Table 3) E. Treat with curative intent for most patients (i.e. intensive remission induction) unless: ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 26  1. > 60-65 years old 2. Not a candidate for intensive remission induction chemotherapy F. Patients with ECOG performance status of 3 or greater and/or significant comorbidities may be considered for low-intensity chemotherapy or best supportive care, the latter of which includes: 1. Blood product transfusions as needed 2. Prophylactic antimicrobial agents 3. Hydroxyurea titrated to control leukocytosis G. Employ appropriate supportive care therapies at appropriate times throughout AML therapy H. General principles of intensive remission induction therapy: 1. The best outcomes are seen in patients < 60 years and with ECOG performance status 0-265 a. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend reserving intensive remission induction therapy for patients age < 60 years and performance status 0-2 b. However, NCCN Guidelines® state that patients ≥ 60 years with performance status 0-2 may also receive intensive remission induction therapy since there is no reliable method to determine who will or won’t benefit from intensive remission induction 2. Goal of intensive remission induction chemotherapy is to induce complete remission (CR) 3. General practice is to obtain bone marrow biopsy on or around day 14 counted from the beginning of remission induction chemotherapy for chemotherapy regimens in which this is indicated e.g. 7+375, 76 a. If evidence of AML persists and the patient still remains eligible for remission induction chemotherapy, then additional chemotherapy should be given b. Recent data have called this practice into question, partially due to the insensitivity of bone marrow evaluation around day 1477, 78 4. Consolidation therapy should begin within 2 weeks following 1) hematologic recovery after induction, and 2) confirmed bone marrow evaluation demonstrating complete remission. Consolidation therapy is typically reserved for patients who are ineligible for transplant or while preparing for transplant 5. Maintenance therapy is not recommended for AML 6. Criteria for CR:58, 76 a. Absolute neutrophil count > 1 X 109 b. Platelet count > 100 X 109 c. Patient independent of transfusions d. Bone marrow < 5% blasts e. Absence of blasts with Auer rods f. Absence of extramedullary disease ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 27  g. The disappearance of a karyotype abnormality is not required for definition of complete remission I. General principles of low-intensity remission induction therapy:65 1. May be preferential in patients 1) > 60 years and/or ECOG performance status 3 or 2) relatively unfit patients with comorbidities 2. Goal is to regain normal hematopoiesis, minimize the need for transfusion and improve quality of life. In select patients, overall survival may be increased 3. Primary metric for success is hematologic improvement or decreased transfusion requirements determined by peripheral blood counts or bone marrow biopsy results a. Success may be attained without achieving a CR 4. Low-intensity therapy generally continues until progression of disease V. Intensive remission induction therapy for newly-diagnosed AML age 59 years, ORR 43%, irrespective of blast counts Decitabine100, 108 20 mg/m2/day IV daily x 5-10 days Increased CR rate (17.8% vs. 7.8%). No difference in OS versus low-dose cytarabine or best supportive care. Gemtuzumab Remission induction: The patient population included those who were ozogamicin 92 Gemtuzumab ozogamicin 6mg/m2 elderly or unfit for intensive chemotherapy. IV on day 1 followed by 3mg/m2 IV Data from this study suggests that gemtuzumab on day 8 ozogamicin is likely most effective for patients with high CD33 expression though remains Consolidation: controversial due to results of other clinical Gemtuzumab ozogamicin 2mg/m2 trials in which gemtuzumab ozogamicin was IV on day 1 monthly for up to 8 used in combination with chemotherapy. cycles Survival benefit of gemtuzumab ozogamicin was associated with favorable or intermediate risk AML and not with unfavorable risk AML. Serious adverse events were similar when comparing gemtuzumab ozogamicin versus best supportive care in this population. Glasdegib93 Remission induction: No biomarker was found to influence response Glasdegib 100mg po daily with glasdegib + LDAC. The study met its primary Cytarabine 20mg SC BID for 10 endpoint with respect to OS and overall patients days of a 28 day cycle treated with glasdegib + LDAC achieved a 49% reduction in the risk of death relative to LDAC (median 8.8 versus 4.9 months; HR, 0.51 [80% CI, 0.39 to 0.67], p=0.0004. PK analysis in this study found that CYP3A4 inhibitors may be used safely; however, the package insert suggests modifications. Side effect profile was well tolerated with fatigue being unique to the glasdegib + LDAC arm. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 37  Venetoclax94, 109 Remission induction (28 day Overall, 67% of patients achieved CR + CRi. The cycles): venetoclax 400mg daily arm achieved a 73% CR Venetoclax 400mg po daily + CRi rate and median OS has not yet been (Ramp up: during cycle 1 is 100mg reached for this cohort. Venetoclax was well then 200mg then 400mg) Plus either: tolerated and no tumor lysis syndrome was Decitabine 20mg/m2 IV Q24h days observed in this trial. Venetoclax dosing with 1-5; or, hypomethylating agents differs from the dose Azacitidine 75mg/m2 SC Q24h used in combination with LDAC. Posaconazole days 1-7 can be used for patients receiving venetoclax after reducting the venetoclax dose by at least 75%.110 VIII. Monitoring response during remission induction A. Day 14 bone marrow biopsy: 1. Significant controversy exists related to the prognostic value of the day 14 bone marrow evaluation and a second induction treatment for residual disease. Some studies suggest that residual disease identified at day 14 bone marrow biopsy does not have prognostic significance if a patient achieves CR after 2 cycles of induction. Others demonstrate worse outcomes.111, 112 2. In the case of inadequate response to remission induction therapy based upon the day 14 bone marrow biopsy results, “booster” chemotherapy may be given as reinduction. For example, a patient who is induced with 7+3 chemotherapy and has residual AML per day 14 bone marrow biopsy may receive either another course of 7+3 or 5+2 i.e. a second induction or re-induction. B. Definition of complete remission58: 1. Normal peripheral blood count values for absolute neutrophil count >/= 1000 cells/mL and platelets >/= 100,000 cells/mL 2. Bone marrow biopsy that reveals 12 months, outcomes for salvage treatment are more favorable than if patient maintained 12 months from initial remission induction therapy, the same regimen previously used may be re-administered in patients who can tolerate based on performance status and organ function. G. No head-to-head prospective comparisons of any intensive remission induction therapy for relapsed or refractory adult AML exist. H. Enasidenib (Idhifa®) is a selective inhibitor of mutant-isocitrate dehydrogenase (IDH)2 enzymes. Enasidenib targets the IDH2 mutant variants R140Q, R172S, and R172K leading to decreased levels of 2-hydroxyglutarate (2-HG) and induced myeloid differentiation with reduced blast counts and increased percentages of mature myeloid cells. 1. In a phase I dose escalation and expansion study, enasidenib induced hematologic responses in patients with relapsed/refractory AML. 2. Enasidenib dose is 100mg po daily and should be continued until disease progression or unacceptable toxicity. 3. Its metabolism is mediated by multiple cytochrome enzymes including CYP1A2, CYP2D6 and CYP3A4 as well as multiple UGTs. It is an inhibitor of the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib also inhibits P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2. Enasidenib induces CYP2B6, and CYP3A4. 4. Overall, enasidenib was well tolerated. It was approved with a companion device to test for IDH2 mutations, the Abbott RealTime™ IDH2 assay.115 5. It has a black box warning for differentiation syndrome associated with use. In addition, enasidenib may be associated with rapid myeloid proliferation presenting as leukocytosis, which in extreme cases could be managed using a cytotoxic drug e.g. hydroxyurea. a. The most common adverse reactions included nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Differentiation induced by enasidenib did result in differentiation syndrome for some patients and deaths were reported. Management was similar to that of retinoic acid syndrome (see APL section) and consisted of drug interruption and corticosteroids. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 39  b. Elevated bilirubin was not necessarily indicative of liver toxicity and may be due to off target inhibition of UGT1A1. I. Ivosidenib (Tibsovo) is an inhibitor of isocitrate dehydrogenase 1 (IDH1) enzyme. It targets mutant enzymes that produce increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells. The most common mutant forms of IDH1 are R132H and R132C substitution mutations. Ivosidenib decreases 2- HG levels resulting in reduced blast counts and increased percentages of mature myeloid cells.116, 117 1. In a phase I dose escalation and expansion study, ivosidenib induced transfusion independence, durable remissions, and molecular remissions in some patients with relapsed/refractory AML. Trial participants had received a median of two prior therapies for their IDH1 mutated AML. 2. Ivosidenib dose is 500mg po daily with or without food (avoid high fat meal) and should be continued until disease progression or unacceptable toxicity. 3. Ivosidenib is metabolized by CYP3A4 and induces CYP3A4 but may also induce CYP2C9. 4. Overall, ivosidenib was well tolerated. It was approved with a companion device to test for IDH1 mutations, the Abbott RealTime™ IDH1 assay. 5. It has a black box warning for differentiation syndrome associated with use. a. The most common adverse reactions included fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolongation, rash, pyrexia, cough and constipation. Differentiation induced by ivosidenib did result in differentiation syndrome for some patients. Management was similar to that of retinoic acid syndrome (see APL section). However, ivosidenib was held if symptoms of differentiation syndrome did not respond to prompt initiation of hydroxyurea and corticosteroids upon the first sign or symptom of differentiation syndrome.116, 118 The differentiation syndrome treatment protocol did specify use of furosemide and leukophoresis where clinically indicated. J. Gilteritinib is a kinase inhibitor FDA approved for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation.119 1. Has an approved FDA companion diagnostic i.e. Leukostrat CDx FLT3 mutation assay 2. A phase 3 trial evaluating gilteritinib (i.e. ADMIRAL trial) is ongoing. Enasidenib Mechanism of action Small molecule inhibitor of the IDH2 enzyme. Inhibition of the IDH2 enzyme led to lower levels of 2-HG and induced myeloid differentiation in vitro and in vivo. Indications for use Treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase 2 mutation. Toxicities BBW for differentiation syndrome. Nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Drug-drug Metabolism is mediated by multiple cytochrome enzymes including interactions CYP1A2, CYP2D6 and CYP3A4 as well as multiple UGTs. It is an inhibitor of the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 40  CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib also inhibits P- gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2. Enasidenib induces CYP2B6, and CYP3A4. Ivosidenib Mechanism of action Small molecule inhibitor of the IDH1 enzyme. Inhibition of the IDH1 enzyme led to lower levels of 2-HG and induced myeloid differentiation in models of IDH1-mutated tumors. Indications for use Indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. Toxicities BBW for differentiation syndrome. QTc prologation, Guillan Barre syndrome, leukocytosis, dyspnea, fatigue, arthralgia, diarrhea, edema, nausea, mucositis, rash, pyrexia, cough, constipation, and progressive multifocal leukoencephalopathy Drug-drug Primarily metabolized by CYP3A4 so inducers or inhibitors of this interactions enzyme should warrant dose adjustment of ivosidenib. Caution should be exercised when using ivosidenib concomitantly with substrates of CYP3A4 and CYP2C9. Taking ivosidenib along with other drugs that prolong the QTc interval could have an additive effect. Gilteritinib Mechanism of action Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3) Indications for use Treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation Toxicities Myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting. Drug-drug Strong CYP 3A4 inducers with Pgp impact and strong CYP3A4 interactions inhibitors. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 41  Table 4: Intensive Remission (re)Induction Regimens for Relapsed or Refractory Adult AML59, 120 Induction Regimen Dosing and Schedule Comments 5 + 2 (or 7 + 3) Daunorubicin 45-60 mg/m2/day IV qDay Use as reinduction when: (a) results of day 14 bone Daunorubicin OR x 2 (or 3) days OR Idarubicin 12 marrow biopsy demonstrates residual leukemia, (b) Idarubicin mg/m2/day IV qDay x 2 (or 3) days residual leukemia is less than prior to initial Cytarabine Cytarabine 100 – 200 mg/m2/day remission induction therapy and (c) patient tolerates continuous continuous IV infusion qDay x 5 (or 7) further anthracycline. DFS = 35% infusion121 days Unclear if patients failing first cycle of 7+3 should receive second cycle of 7+3 or 5+2 versus alternative chemo HiDAC variant Cytarabine 2,000-3000 mg/m2/dose q 12 When employed for re-induction, no data show High-dose Cytarabine hrs x 6 days (24,000 mg/m2 total per superiority of high-dose cytarabine versus cytarabine (higher cumulative cycle) at lower doses. These regimens should be reserved dose than used for for younger patients without renal dysfunction. consolidation)122 ME(C) Mitoxantrone 8 mg/m2 IV daily x 5 days All patients relapsed or refractory. 18-24% CR rates. Mitoxantrone Etoposide 100 mg/m2 IV daily x 5 days Median OS 6.7 mo. Those with favorable Etoposide Cytarabine 1,000 mg/m2 IV daily x 5 days cytogenetics displayed trend towards greater High-dose Cytarabine benefit.123 (with or without Versus CLA, MEC demonstrated inferior OS and CR cytarabine)123, 124 rates124 There are several variations of ME and MEC with many different dosing strategies documented within the literature. Standard doses are highlighted here. FLA (± Ida) (AKA Fludarabine 30 mg/m2/day IV qDay x 5 CR rates 50-55%. Increased toxicity with idarubicin FLAG-Ida)* days without clear benefit in outcomes. Fludarabine Cytarabine 2,000 mg/m2/day IV qDay x 5 Both studies conducted in era before current High-dose Cytarabine days understanding of cytogenetics. This regimen is rarely ± ± Idarubicin 10 mg/m2/day IV qDay x 3D used with the availability of G-CLAC and CLAG Idarubicin125, 126 *Filgrastim 5mcg/kg/day SC days 0- variants. There are several dosing variations of the count recovery FLAG-Ida regimen available in the literature. G-CLAC Clofarabine 25mg/m2/day IV days 1-5 CR rate was 46% for the 46 evaluable patients who Clofarabine, Cytarabine 2,000mg/m2/day IV days 1-5 received G-CLAC (95% CI 31-60%). Timing of cytarabine and Filgrastim 5mcg/kg/day SC day 0 through cytarabine relative to clofarabine administration is filgrastim127 count recovery significant due to a theoretical efficacy advantage based on MOA. CLA (± M) (AKA Cladribine 5 mg/m /day IV on days 1-5 2 128 CR rates 38-58%. Median OS 7.4-9 months. Favorable CLAG)* (alternatively, days 2-6124) cytogenetics improved outcomes slightly. Cladribine Cytarabine 2,000 mg/m2/day IV days 1-5 Addition of mitoxantrone increased toxicity without High-dose Cytarabine ± significant improvement in outcomes. Timing of ± Mitoxantrone 10 mg/m2/day IV days 1- cytarabine relative to cladribine administration is Mitoxantrone124, 128, 3129 significant due to a theoretical efficacy advantage 129 *Filgrastim 300 mcg/day SC days 0-5 based on MOA. Note: For FLA (± Ida), G-CLAC and CLA (± Mitoxantrone), the addition of filgrastim is controversial being used in this context as “priming.” Some studies suggest benefit to priming with growth factor when used with high dose cytarabine whereas others demonstrate priming only adds to cost and toxicity.130, 131 ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 42 X. Low-intensity therapy for salvage treatment following failure of intensive remission induction therapy in relapsed or refractory AML A. Limited data exist that demonstrate utility of low-intensity therapy following relapse or refractory AML after intensive remission induction therapy. B. In select cases, may choose low-intensity if patient acquires co-morbidity or decrease in performance status from initial remission induction therapy, but goals of therapy change to non-curative and/or palliative intent. C. Gemtuzumab ozogamicin was FDA-approved for use in CD33 positive relapsed or refractory AML as monotherapy using fractionated dosing i.e. 3mg/m2 IV on days 1,4 and 7. Patient Case # 1 (continued): Following induction with 7+3 employing daunorubicin 90 mg/m2/dose, bone marrow biopsy and aspirate obtained on day 14 is hypoplastic and a repeat bone marrow biopsy and aspirate obtained on day 28 following hematopoietic recovery confirmed complete remission. It is now 10 days following recovery of peripheral blood counts and RO has an outpatient appointment with her primary hematologist to discuss post-remission therapy. Which of the following is the most appropriate post-remission therapy at this time? A. Cytarabine 3,000 mg/m2/dose IV Q12 hours on days 1,3,5 B. Cytarabine 1,000 mg/ m2/dose IV Q12 hours on days 1,3,5 C. 7+3, with daunorubicin 90 mg/ m2/dose. Cytarabine infused continuously for days 1-7 and daunorubicin IV on days 1,2,3 D. 5+2, with idarubicin 12 mg/ m2/dose. Cytarabine infused continuously for days 1-5 and idarubicin IV on days 1,2 XI. Post-remission therapy age < 60 yrs (AKA “consolidation”) A. Successfully obtaining CR with remission induction chemotherapy clears the visible signs of leukemia and restores normal hematopoiesis. However, further therapy is required to eliminate minimal disease, which persists. Without post-remission therapy, >95% of patients with AML will eventually relapse.132 B. High-dose cytarabine (HiDAC): 1. The gold-standard for post-remission therapy for those age < 60 years with favorable or intermediate risk; role in those above 60 years and/or with adverse risk is less clear and these patients should be evaluated for hematopoietic stem cell transplantation65, 85 a. Ideal post-remission therapy in patients age ≥ 60 years unknown, but HiDAC commonly employed, with modified doses (see Table 5)133 2. Subsequent analysis demonstrated that patients with core binding factor benefited the most, followed by those with normal karyotype134 3. Controversy surrounds the optimal dose and number of cycles with respect to HiDAC consolidation135 4. Primary non-hematologic toxicities: 1) cerebellar toxicity, and 2) chemical conjunctivitis (see Ocular Toxicity below) ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 43  a. Cerebellar toxicity manifests as ataxia, nystagmus and dysarthria. Occurs relatively soon upon starting high-dose cytarabine and is most associated with renal dysfunction and inconsistently associated with increased age and alkaline phosphatase136, 137 1. Neurotoxicity associated with high-dose cytarabine can lead to profound morbidity resulting in loss of gross motor ability. Oftentimes, neurotoxicity is reversible but this is not always the case and it can cause irreversible damage 2. Doses and/or frequency of cytarabine administration should be adjusted prospectively on a patient-specific basis depending on evaluation of risk factors associated with cytarabine-induced neurotoxicity138 b. Requires periodic evaluation of mental status, proprioception and cerebellar function at a carefully planned frequency typically evaluated prior to each dose of cytarabine c. Management of cerebellar toxicity: hold further doses; symptoms often improve to baseline, but permanent neuromotor damage may persist C. Re-administration of initial induction regimen: 1. Only use if initial regimen was successful 2. Caution should be exercised with anthracycline use and care taken to avoid exceeding the lifetime cumulative dose of anthracycline D. Truncated anthracycline + cytarabine continuous infusion (e.g.: “5+2” following “7+3”) may be an option; head-to-head studies against high-dose cytarabine are lacking. Table 5: Post-Remission Regimens for Adult AML Regimen Dose Regimen Comments HiDAC 3,000 mg/m2/dose IV every 12 hours on Reduce dose to 1,000-1,500 High-dose days 1, 3, 5 for total of 6 doses per cycle mg/m2/dose IV for age > 60 years139 Cytarabine85 every 28 days for 3-4 cycles (due to excess neurotoxicity) and renal dysfunction (due to impaired excretion) Recommended for all patients in CR following induction; benefit only proven in small subset of patients < 60 years and favorable cytogenetics 5+2 Idarubicin 12 mg/m2/day IV qDay x 2 NCCN Guidelines®-recommended for Idarubicin days patients who experience significant + + cytoreduction, but blasts still present Cytarabine Cytarabine 100 mg/m2/day continuous IV after intensive remission induction continuous infusion qDay x 5 days therapy infusion121 XII. Post-remission therapy age ≥ 60 yrs A. If CR obtained with induction therapy: 1. Clinical trial 2. High-dose cytarabine (dose-attenuated to 1,000 mg/m2/dose on same schedule for age) if normal karyotype with favorable cytogenetics ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 44 XIII. Selected supportive care for adults with AML A. Tumor lysis syndrome addressed in greater detail within this handout. B. Patients undergoing remission induction chemotherapy for AML have many risk factors for infectious complications:140, 141 1. Myelosuppressive chemotherapy 2. Protracted severe neutropenia (during remission induction only, if intensive regimen employed) 3. Cyclic neutropenia associated with each cycle of post-remission therapy 4. Exposure to purine analogues 5. Environmental exposure 6. Central venous catheter C. Bacterial infections:141-145 1. High-risk for febrile neutropenia. Role for antibacterial prophylaxis is controversial, due to inconclusive benefit on mortality and driving bacterial resistance. Although there is a lack of mortality benefit, NCCN Guidelines® and IDSA guidelines support antibacterial prophylaxis if anticipated duration of neutropenia is >7 days based on data that demonstrates reduced incidence of fever, probable infection and hospitalizations D. Fungal infections:143, 146-148 1. Protracted severe neutropenia during remission induction therapy mandates antifungal prophylaxis continuing until recovery from neutropenia 2. High-risk for both yeast and mold infections 3. Posaconazole improves overall survival versus fluconazole or itraconazole as prophylaxis 4. Voriconazole, echinocandins and amphotericin B products may be alternative choices for prophylaxis if barriers to posaconazole use exist E. Viral infections:141, 143 1. Protracted severe neutropenia during remission induction therapy increases risk for viral reactivation 2. Prophylaxis recommended during neutropenia following remission induction chemotherapy in patients who are herpes simplex virus seropositive or if seropositivity unknown F. Opportunistic infections following administration of fludarabine, pentostatin or cladribine requires Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole (preferred) or atovaquone, pentamidine or dapsone, if trimethoprim/sulfamethoxazole intolerant.141 G. White blood cell colony-stimulating factors:149-156 1. Primary prophylaxis following remission induction chemotherapy to shorten duration of neutropenia in not recommended in AML patients. Although neutropenia is shortened, not shown to affect overall survival. Theoretical - but unfounded - concern that a myeloid growth factor may stimulate the underlying myeloid malignancy ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 45  2. Primary or secondary prophylaxis following each cycle of post-remission (AKA consolidation) chemotherapy a. Although neutropenia is shortened and neutropenic complications reduced, not shown to affect overall survival or reduce infection-related mortality b. ASCO Guidelines state that myeloid growth factors can be used after consolidation therapy, as they may decrease infection incidence and prevent hospitalizations. The impact on neutropenia duration may also be more profound in consolidation therapy than in induction therapy for AML. Though there is no mortality benefit, decreased rates of infections and prevention of hospitalizations confers a morbidity and potential cost benefit for patients c. In vitro studies suggest use of GCSF may lead to anthracycline resistance through the postulated presence of GCSF-receptors on the cell surface, which are activated in the setting of exogenous GCSF. 3. Administration during remission induction chemotherapy as “priming” is controversial H. Ocular toxicity of high-dose cytarabine:157-161 1. Cytarabine > 1,000 mg/m2/dose IV over 1-4 hours for > 2 doses leads to corneal toxicity in over 80% of patients who do not receive eye drops, due to high water solubility and high concentrations achieved in tear glands and aqueous humor a. Case reports exist of cytarabine-induced ocular toxicity occurring in patients receiving conventional low-dose cytarabine, including subcutaneous administration 2. Symptoms of cytarabine-induced ocular toxicity include excessive tearing, pain, photophobia and sensation of foreign body a. Median onset is 2-4 days after first dose of high-dose cytarabine and lasts for up to 2-3 days following final dose, peaking 6 days from first dose of cytarabine 3. Topical deposition of cytarabine contained in tears upon corneal epithelium triggers inflammatory cascade 4. Prevention of cytarabine-induced ocular toxicity: a. Primary mechanism of action for topical eye drops appears to be related to dilution of intraocular concentration of cytarabine, but is overall unclear. It may be related to decreased replication rate induced by corticosteroids impacting DNA replication in corneal cells b. Standard of care for prevention remains unclear 1) Artificial tears 1. Studies are inconsistent when tears are compared to topical steroids. Many studies demonstrate no difference between the 2 modalities 2. May be equally effective to topical prednisolone drops when given on a rigorous schedule 2) Topical corticosteroids 1. Ocular symptoms may still occur in up to 65% of patients ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 46  2. Dexamethasone may be preferred over prednisolone due to higher potency and greater penetration into corneal epithelium (e.g. dexamethasone 0.1% instill 2 drops into both eyes every six hours) 3. Topical prevention therapies are required even if patient receiving systemic corticosteroids 3) Topical corticosteroid + topical non-steroidal anti-inflammatory 1. Application of both dexamethasone drops and diclofenac drops proved superior to dexamethasone drops alone, purportedly due to dual mechanism of action 5. Treatment of cytarabine-induced ocular toxicity: a. Discontinuation of cytarabine and frequent administration of topical corticosteroids has proven useful b. Permanent damage is rare, but may occur c. Rechallenge with high-dose cytarabine may be administered without recurrence of ocular toxicity, provided topical prophylaxis is administered Patient Case #1 Answer Which of the following is most appropriate post-remission therapy at this time? Correct answer = A The standard of care in the United States is high-dose cytarabine i.e. 3000 mg/m2/dose IV Q12 hours on days 1,3,5. While the dose of cytarabine may be debatable, the presence of NPM1-mutation and absence of FLT-ITD mutation appears to produce the optimal outcomes when high dose-intensity is utilized in patients < 60 yo with AML, so 1000 mg/m2/dose is not the best option for RO. Re-using 7+3 would only be considered if the patient was not in remission and the goal is attempt re-induction. 5+2 is sometimes employed as post- remission therapy, but predominantly in Europe and is not a preferred option based upon NCCN Guidelines®. Additionally, the choice of anthracycline should not change from remission induction to consolidation treatment. ___________________________________________________________________________________________________ ©2019 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 47  ACUTE PROMYELOCYTIC LEUKEMIA (APL) Patient Case #2: LJ is a 24-year-old male who arrives to the emergency department following a fall from a roof with excessive bleeding that would not stop with conservative measures. In the ER, a CBC with differential was obtained that was suspicious for AML. Peripheral smear evaluation revealed t(15;17) rearrangement and LJ was hospitalized for further work-up and treatment. His WBC today is 15 x 109/L with a platelet count of 10K. The decision is made to initiate therapy today based upon risk- stratification. Which of the following is best to treat LJ with at this time? A. 7+3, with daunorubicin 90 mg/m2/dose B. Midostaurin C. Tretinoin + idarubicin + arsenic D. Arsenic trioxide single-agent I. The hallmark of acute promyelocytic leukemia (APL) is translocation between promyelocytic leukemia (PML) gene on chromosome 15 and retinoic acid receptor (RAR-α) on chromosome 17, which produces the PML-RARA fusion gene that can be quantitatively monitored using PCR to document disease burden and ultimately confirm molecular remission. A. t(15;17) prevents morphologic differentiation into mature neutrophils. B. APL is clinically distinct from other subtypes of AML due to much higher 5-yr overall survival rate and sensitivity to chemotherapy and differentiating agents. C. APL can be de novo or treatment-related; however, treatment-related APL does not differ prognostically and is treated the same as de novo APL. II. Staging A. Unlike other subtypes of AML, APL is staged into high-risk, intermediate-risk and low-risk based upon WBC and platelet count upon diagnosis a