NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-21-002-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/89184; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: January 10, 2021; Expiration date: January 10, 2022
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Acute Myeloid Leukemia
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Acute Myeloid Leukemia
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Martin S. Tallman, MD, Panel Chair, has disclosed that he receives grant/research support from AbbVie, Inc., Orsenix, Biosight, Glycomimetics, Rafael Pharmaceuticals, and Amgen; is a scientific advisor for AbbVie, Inc., Orsenix, Biosight, Daiichi-Sankyo Co., KAHR, Novartis Pharmaceuticals, and Innate Pharmaceuticals; and receives royalty from UpToDate.
Daniel A. Pollyea, MD, MS, Panel Vice Chair, has disclosed that he is a scientific advisor for AbbVie, Inc., Amgen Inc., Bristol-Myers Squibb Company, Celgene Corporation, Genentech, Inc., GlycoMimetics, Inc., Karyopharm Therapeutics, Novartis Pharmaceuticals Corporation, Kiadis, Syndax, Syros Pharmaceuticals, and Takeda Pharmaceuticals North America, Inc.
Vijaya Raj Bhatt, MBBS, Panel Member, has disclosed that he receives grant/research support from AbbVie, Inc., Incyte Corporation, Jazz Pharmaceuticals Inc., Tolero, and Pfizer Inc.; consulting fees from AbbVie, Inc., Genentech, Inc., Incyte Corporation, Omeros, Rigel, and Takeda Pharmaceuticals North America, Inc.; and other financial benefit from Oncoceutics.
Dale Bixby, MD, PhD, Panel Member, has disclosed that he has no relevant financial relationships.
Alexander Perl, MD, Panel Member, has disclosed that he is a scientific advisor for AbbVie, Inc., Astellas Pharma US, Inc., Celgene Corporation, Daiichi-Sankyo Co., Genentech, Inc., Actinium Pharmaceuticals, Loxo, Sumitomo Dainippon, and Syndax; receives grant/research support from AbbVie, Inc., Astellas Pharma US, Inc., Daiichi-Sankyo Co., and Fujifilm Corporation; receives consulting fees from AbbVie, Inc., Astellas Pharma US, Inc., Daiichi-Sankyo Co., BeatAML LLC, Forma Therapeutics, Sumitomo Dainippon, and Syndax; and receives honoraria from AbbVie, Inc., Astellas Pharma US, Inc., Celgene Corporation, Daiichi-Sankyo Co., Genentech, Inc., Actinium Pharmaceuticals, Loxo, and Syndax.
Ndiya Ogba, PhD, Oncology Scientist/Senior Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics.
Overview
Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common form of acute leukemia among adults and is characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow (BM), and/or other tissues. In the United States, an estimated 19,940 people will be diagnosed with AML in 2020, and 11,180 patients will die of the disease.1 AML is a disease of older adults, with approximately 54% of patients diagnosed at age ≥65 years,2 and a median age at diagnosis between 68 and 71 years of age.1,3 In addition, AML can be subclassified into several categories, including acute promyelocytic leukemia (APL). Recently a new category of myeloid neoplasms with germline disposition was suggested, given that data increasingly demonstrate a link between inherited or de novo germline mutations and myeloid neoplasms, including AML and myelodysplastic syndromes (MDS).4
Treatment of AML is divided into initial remission-induction chemotherapy, postremission or consolidation therapy, and, recently, maintenance therapy, using oral azacitidine for patients who are unable to complete intensive curative therapy.5 Although obtaining a remission is the first step in controlling the disease, it is also important for patients to emerge from the induction phase in a condition that allows them to tolerate subsequent, sometimes more intensive, treatments to achieve durable disease control or cure. Current pretreatment factors, such as age, cytogenetics, and the presence of specific gene mutations, are used to estimate posttreatment risk of relapse.6–8 Increasing evidence suggests that the evaluation of measurable or minimal residual disease (MRD) is an important part of refining posttreatment risk stratification.9,10
In addition, advances in sequencing techniques have broadened our understanding of the molecular basis of AML,11 which has increased the number of treatment options, including new targeted agents, like venetoclax, and alternative formulations of existing therapies.6,12 As the use of these novel treatment options increase, it is important to understand and monitor for associated adverse effects to ensure that timely supportive care is implemented. In addition, individualization of treatment and supportive care is an essential component of oncology, and may involve tailoring treatment plans according to a patient’s preference.
Familial Genetic Alterations in AML
Background
Relative to sporadic cases of AML and MDS, the prevalence of known familial acute leukemia and MDS is considered rare; but with increasing recognition of germline mutations associated with predisposition to developing AML/MDS, identifying these syndromes is important for optimal management of patients and their relatives.13–16 Evaluation for an underlying familial syndrome in a patient with acute leukemia or MDS should involve a screening history, focused physical examination, and diagnostic genetic testing.13,17 In particular, the screening evaluation should determine whether the patient has a family history of hematologic malignancies (including AML, acute lymphoblastic leukemia [ALL], or aplastic leukemia) or unexplained leukopenia, anemia (eg, aplastic anemia, macrocytic anemia), and/or thrombocytopenia within 2 generations.13,14,18,19 In addition, other guidelines recommend that the screening evaluation should determine whether the patient has signs or symptoms indicative of a hereditary condition (including Li Fraumeni syndrome) that predisposes them to developing myeloid neoplasms.20
Familial AML with mutated CEBPA is one of the most common inherited syndromes associated with AML.13,21,22 Several reports have noted that all individuals who carry this germline mutation developed AML between 2 and 59 years of age.13,21,23,24 Other familial AML syndromes include germline mutations in DDX41,13,25,26 which are relatively common, and germline mutations in MBD4,27 which are rare; syndromes with platelet abnormalities, including familial platelet disorder with mutated RUNX113,17,28; or syndromes associated with organ system manifestations, including familial AML/MDS with mutated GATA2.13,17
NCCN Recommendations
Based on these emerging data, the NCCN AML Panel recommends that patients with a family history of leukemia, or of other hematologic cancers or abnormalities, should be evaluated for an inherited predisposition syndrome (see AML-A 2 and 3 of 3, pages 18 and above, respectively). The panel also strongly recommends that patients with a variant allele frequency (VAF) of 40% to 60% of genes associated with a predisposition syndrome be referred for germline testing. However, there is no consensus on optimal management of individuals diagnosed with familial acute leukemia or MDS, so management must be individualized.13,17
Management of Low-Risk APL: Is a Postinduction BM Needed?
Background
In the previous version of the NCCN Guidelines for AML, patients with low-risk APL who were induced with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) were recommended to undergo a BM aspirate and biopsy to document morphologic remission at day 28 to 35, before proceeding with consolidation. During this update, the panel discussed whether a BM aspirate after induction should be optional in patients with low-risk APL, given high complete remission (CR) rates observed in this subgroup.29–31
In several studies focused on the management of newly diagnosed low-risk APL, after induction with ATRA and ATO-containing regimens a BM aspirate was performed to document whether hematologic remission was achieved, although the time frame to achieving CR can vary.29–33 In a study by Estey et al30 among patients with low-risk APL who were treated with ATRA and ATO, weekly BM assessments were performed beginning 25 to 28 days after induction. If the marrow showed <5% blasts and no abnormal promyelocytes, treatment was withheld until CR.
In a phase III randomized trial from the Italian-German Cooperative Group, induction with ATRA + ATO was compared with the AIDA regimen (ATRA + idarubicin) in patients with newly diagnosed, low-, or intermediate-risk APL (n=162).31 Patients in arm A received ATRA + ATO daily until CR or for a maximum of 60 days, then ATO 5 days per week for 4 weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks every 4 weeks for a total of 7 courses. Patients in arm B received standard AIDA induction until CR or for a maximum of 60 days, followed by consolidation with 3 cycles of anthracycline-based consolidation combined with ATRA and then maintenance comprising low-dose chemotherapy and ATRA.34 In both arms, if CR was not achieved by day 60, the patients were taken off study. Among evaluable patients (n=156), CR rates were not different between arms A and B (100% vs 95%). After a median follow-up of 34.4 months, the 2-year event-free survival (EFS) rate was significantly higher in arm A compared with arm B (97% vs 86%; P<.001 for noninferiority; P=.02 for superiority). The 2-year overall survival (OS) probability was also significantly higher in arm A compared with arm B (99% vs 91%; P=.02).31
In the randomized phase III AML17 trial, ATRA + ATO was also compared with AIDA in a cohort of patients with APL and without cardiac/pulmonary comorbidities (n=235).29 ATRA was given to both groups until remission or day 60, after which patients were treated 2 weeks on, then 2 weeks off.29 The AIDA group received 4 cycles of consolidation consisting of idarubicin and mitoxantrone.29 The ATRA + ATO consolidation treatment entailed ATO on days 1 through 5 in the first week, twice weekly in weeks 2 through 8 in course 1, and then twice weekly in weeks 2 through 4 during courses 2 through 5. High-risk patients could receive an initial dose of gemtuzumab ozogamicin (GO) at 6 mg/m2 for cytoreduction. Comparison between the ATRA + ATO group and the AIDA group showed a higher 4-year EFS (91% vs 70%; P=.002) and lower 4-year cumulative incidence of morphologic relapse (1% vs 18%; P=.0007) for ATRA + ATO compared with AIDA, although no statistically significant difference in 4-year survival was seen (93% vs 89%; P=.25).29
NCCN Recommendations
If a patient is cytopenic after induction, one reason for assessing the BM after induction is to differentiate BM myelosuppression from persistent disease. Nonetheless, some panel members questioned the utility of a BM biopsy in this context if the peripheral blood counts have recovered to normal. Based on these data and discussion, during this update the panel decided to revise the guidelines to clarify that if a patient is cytopenic on days 28 through 35, BM biopsy and aspirate are recommended to document blast clearance and to assess whether the marrow is suppressed, and to determine whether ATRA and ATO should be held to allow count recovery (see APL-2, opposite page). If, however, blood counts have recovered by this time point, a BM biopsy may be considered to document remission but is optional (see APL-2, opposite page).
Postremission Therapy for CBF-AML: Consideration of KIT Versus MRD
Background
After response to induction chemotherapy, postremission therapy is based on risk status defined by cytogenetics and molecular abnormalities in patients with AML aged <60 years. In the previous version of the NCCN Guidelines for AML, for patients with favorable-risk features and core-binding factor AML (CBF-AML) without KIT mutations, postremission treatment recommendations included participation in a clinical trial and intermediate- or high-dose cytarabine (iDAC or HiDAC, respectively) ± GO.35
In some studies in which patients with CBF-AML received postremission therapy with HiDAC, the presence of KIT mutations resulted in poorer outcomes, particularly in patients with t(8;21).36,37 One multicenter study that enrolled patients with CBF-AML (n=67) into intensive chemotherapy protocols that involved HiDAC postremission therapy36 showed that at 24 months, a KIT mutation in the tyrosine kinase domain (TKD) at codon 816 (TKD816) in patients with t(8;21) was associated with a significantly higher incidence of relapse (90% vs 35.3%; P=.002) and lower OS (25% vs 76.5%; P=.006) compared with patients with wild-type KIT.36 In patients with CBF-AML with inv(16), TKD816 did not result in a significant difference in relapse incidence and OS.36 The prognostic influence of TKD816 and other mutations in exon 17 (mutKIT17) versus other recurrent KIT mutations in CBF-AML, such as exon 8 (mutKIT8), have been investigated.37,38
In an analysis of adult patients aged <60 years with CBF-AML treated with intensive chemotherapy on CALGB trials (n=110), KIT mutations (mutKIT17 and mutKIT8) among patients with inv(16) were associated with a higher cumulative incidence of relapse at 5 years (56% vs 29%; P=.05) and a decreased 5-year OS rate (48% vs 68%) compared with those with wild-type KIT; in multivariate analysis, the presence of KIT mutations remained a significant predictor of decreased OS in the subgroup with inv(16). In patients with t(8;21), KIT mutations were associated with a higher incidence of relapse at 5 years (70% vs 36%; P=.017), but no difference was observed in 5-year OS (42% vs 48%).37 The CALGB trial also included 4 courses of monthly maintenance chemotherapy with daunorubicin and subcutaneous cytarabine after the consolidation phase; however, only 55% of patients in CR received maintenance chemotherapy following HiDAC consolidation.39 Subsequent clinical trials have eliminated this form of maintenance therapy after postremission therapy. However, the impact of KIT mutations in CBF-AML is unclear. A meta-analysis of 11 studies examining the effect of KIT mutations on CR, OS, and relapse rates in patients with CBF-AML determined that KIT mutations did not affect CR rates.40 In patients with t(8;21) AML, KIT mutations were associated with an increased risk of relapse and shorter OS rates compared with patients with inv(16) AML.40
Some studies suggest that after induction, relative to KIT mutations, MRD may be a more relevant prognostic factor for CBF-AML risk stratification.6,41–43 In a prospective study, adult patients with CBF-AML (aged 18–60 years; n=198) were randomized to receive a reinforced induction course (arm A) or standard induction course (arm B), followed by 3 HiDAC consolidation courses.42 Arm A consisted of a first sequence with daunorubicin (60 mg/m2/d by a 30-minute intravenous infusion) on days 1 and 3 and cytarabine (500 mg/m2 continuous infusion) from days 1 to 3, followed by a second sequence at day 8 with daunorubicin (35 mg/m2/d by a 30-minute intravenous infusion) on days 8 and 9, and cytarabine (1,000 mg/m2 every 12 hours by a 2-hour infusion) on days 8 and 10.42 Arm B consisted of cytarabine (200 mg/m2 continuous infusion) for 7 days combined with daunorubicin (60 mg/m2) for 3 days. In arm B, at day 15 a peripheral blood and BM evaluation was performed followed by a second sequence of chemotherapy in patients who experienced CR.42 In addition, MRD levels were serially monitored for RUNX1-RUNX1T1 and CBFB-MYH11 by real-time quantitative PCR in BM samples before the first, second, and third consolidation courses. In this study, both treatment arms demonstrated similar efficacy. After first consolidation, higher WBC count, KIT and/or FLT3 gene mutations, and a <3-log MRD reduction were associated with a higher specific hazard of relapse, but MRD was the only prognostic factor in multivariate analysis.42 At 36 months, the cumulative incidence of relapse and relapse-free survival were 22% and 73%, respectively, in patients who achieved 3-log MRD reduction versus 54% (P<.001) and 44% (P<.001), respectively, in other patients.42
NCCN Recommendations
Based on these data and discussion, during this update the NCCN AML Panel revised the risk category from “CBF-AML without KIT mutation” to “CBF-AML and MRD-negative” to note the emerging significance of MRD in this risk group (see AML-4, page 21). There are insufficient data to evaluate the use of allogeneic hematopoietic cell transplantation (HCT) in first remission for patients with AML who are MRD-negative and have favorable-risk cytogenetics outside of a clinical trial.44 Data suggest that the response to treatment is similar regardless of whether the favorable-risk cytogenetics are de novo or treatment-related.44 However, outcomes for patients with t(8;21) and KIT mutations may be less favorable than for those with wild-type KIT or inv(16) AML with KIT mutations. In the Jourdan et al42 study described earlier, patients with a <3-log MRD reduction of the RUNX1-RUNX1T1 transcript level between diagnosis and after 2 cycles of consolidation had a higher rate of relapse. The implications of this suggest that patients with favorable-risk cytogenetics who are above this transcript level after 2 cycles of consolidation may require alternative therapies, including allogeneic transplantation or a clinical trial, but optimal timing is not yet established.
Principles Surrounding Use of Venetoclax-Based Therapies
Background
During the 2021 guidelines update, the panel discussed some comments related to venetoclax use in AML treatment, specifically focused on understanding dose adjustments and potential drug interactions. Given the increasing use of venetoclax-based therapies in AML (eg, venetoclax with hypomethylating agents [HMAs] or low-dose cytarabine [LDAC]), and the fact that these therapies may be given for an indefinite duration as long as patients experience response or derive hematologic benefit from the therapies, the panel reviewed the literature and developed guidelines that can inform ways to optimize use of these therapies.
NCCN Recommendations
Based on existing literature and clinical practice, the panel developed a new section in the guidelines to address the use of venetoclax-based therapies (see AML-J 1 and 2 of 2, pages 22 and 23). For patients with newly diagnosed disease, the panel notes that venetoclax with HMA or LDAC should be given concomitantly. The addition of a third targeted agent to these combinations is not recommended outside the context of a clinical trial. Prior to administering therapy, it is important to achieve a WBC count of <25,000/mcL with hydroxyurea, or leukapheresis if needed.45 It is worth noting that the data supporting a beneficial role for leukapheresis in this context is limited.46 In addition, venetoclax is a substrate of CYP3A4, and therefore dose adjustments of venetoclax are recommended when using it concurrently with strong CYP3A4 inhibitors, most commonly the azole class of antifungal agents.47 Reductions in duration of venetoclax and HMAs or LDAC may be considered in the setting of cytopenias. If during treatment there is a need to discontinue any of the agents or a consideration to continue maintenance on single-agent venetoclax, the panel recommends referral to a tertiary care or academic medical center.
To minimize the development of tumor lysis syndrome (TLS)—which is uncommon in this setting45—during the first cycle of treatment, inpatient treatment is strongly recommended, especially through dose escalation. The intrapatient dose escalation for venetoclax with HMA is 100, 200, and 400 mg given daily on days 1 to 3; and the intrapatient dose escalation for venetoclax with LDAC is 100, 200, 400, and 600 mg given daily on days 1 to 4.45 To minimize and avert further risk of TLS, the panel recommends aggressive monitoring of blood chemistries, monitoring and managing electrolyte imbalances, and treatment with allopurinol or other uric acid–lowering agent.45
Venetoclax and HMAs have been shown to induce prolonged cytopenias even after achieving remission, and neutropenia is a dominant treatment-related toxicity associated with this combination of agents.48 During the first cycle, the panel recommends continuing treatment regardless of cytopenias until a response assessment is made,47 with aggressive transfusion support and supportive care as needed. The panel also recommends withholding growth factors until after the first cycle response assessment.45 However, granulocyte colony-stimulating factors (G-CSFs) should be considered for patients with neutropenia who are in morphologic remission but whose counts have not recovered. A BM biopsy is necessary for response assessment on days 21 through 28 of the first cycle,45 perhaps on the early end of this range for patients who receive the combination of venetoclax + decitabine.
If blasts are <5% during the first cycle, in the setting of cytopenias all treatment should be held and the following measures should be considered: growth factor support, if indicated, and a treatment-free interval for up to 14 days. When counts have recovered to a clinically significant threshold (ideally to CR or CR with incomplete hematologic recovery), the next cycle of treatment can begin.45 If counts have not recovered to a clinically significant threshold, a repeat BM biopsy should be considered. If morphologic remission is ongoing, therapy can continue to be held or a second cycle can proceed with adjustments to dose or schedule of venetoclax and HMA or LDAC.45
During the second and subsequent cycles of treatment, if remission was observed after the first cycle, sequential cycles should continue with up to 14-day interruptions between cycles for count recovery and/or growth factor support.45 If there is no evidence of disease after the first cycle, and assuming no unexpected changes in blood counts occur, the BM biopsy can be repeated at 3- to 6-month intervals, or as needed based on clinical suspicion for relapse, depending on the goals of the patient. If count recovery worsens over time, relapsed disease should be ruled out with a repeat BM biopsy.45 If morphologic remission is ongoing with worsening blood counts, decreasing the duration, and/or dose, of venetoclax and/or HMA or LDAC should be considered. However, if there is no morphologic remission after the second cycle, enrollment in a clinical trial should be considered if available. If no clinical trial is available, and patient has had some response with manageable toxicity, therapy may be continued as long as it is tolerated.
If venetoclax and HMA or LDAC are being given to patients with relapsed/refractory AML, the panel recommends antifungal prophylaxis.48 Other recommendations for TLS, intrapatient dose escalation, BM biopsies, and cytopenia mitigation plans are similar to considerations that have been described.
Considerations for Patients With AML Who Prefer Not to Receive Blood Transfusions
Background
During this update, the AML panel considered a set of comments proposing that guidance should be offered to clinicians with patients who would prefer not to receive blood transfusions as part of their care. There is no established treatment of AML that does not require use of blood and blood products for supportive care, and with limited data, providing guidelines or recommendations for AML management in this context is challenging. However, the panel recognizes that this is a significant issue faced in a narrow spectrum of clinical settings. In this context, the panel reviewed the existing literature and collective experience with this issue and summarized some considerations to guide treatment and supportive care in a new section (see AML-D, opposite page). However, it is important to note that the panel believes that in many cases, good outcomes from these strategies are rare.
NCCN Recommendations
At the outset, it is important to discuss the goals of care with the patient and establish an understanding of the complications that can arise without transfusions. In addition, it will be helpful to ascertain whether the patient will accept certain blood products (eg, cryoprecipitate) and stem cells (either autologous or from another donor source). To mobilize peripheral blood stem cells and/or raise hemoglobin levels prior to peripheral blood stem cell transplantation, some treatment centers have used erythropoietin-stimulating agents, G-CSF, and thrombopoietin mimetics.49–51 However, before using this strategy, the potential risks, benefits, and uncertainties of using these agents in this context should be thoroughly discussed. Consider referring patients to centers with expertise in bloodless autologous transplant.50,51 In addition, for patients who are Jehovah’s Witnesses and therefore refuse blood transfusions, the United States branch of the Christian Congregation of Jehovah’s Witness has Hospital Liaison Committees that may provide helpful information about bloodless medicine.
Regarding treatment options, the panel recommends considering less myelosuppressive induction, including dose reduction of anthracyclines and use of nonintensive chemotherapy.52–56 Some of these options may include targeted agents guided by testing for actionable mutations rather than intensive chemotherapy, especially in a noncurative setting. However, the panel notes that chemotherapy dose reductions without transfusion support in patients with AML are associated with a lower rate of remission and a high mortality rate due to severe anemia, and are unlikely to result in durable remissions.55 During treatment, measures should be taken to minimize blood loss and decrease the risk of bleeding, including use of pediatric collection tubes, avoiding concomitant medications or procedures that increase the risk of bleeding or myelosuppression, use of oral contraceptive pills or medroxyprogesterone acetate in menstruating women, or administration of proton pump inhibitors, as indicated.50,57 Vitamin K may be considered as an adjuvant to improve coagulopathy.50,57 In patients at risk for bleeding (eg, when platelet counts decrease to <30,000/mcL), aminocaproic or tranexamic acid may be considered to manage bleeding.50,57 In patients with elemental or vitamin deficiencies, iron, folate, and vitamin B12 supplementation should be considered.50,57 In patients with severe anemia, bed rest and supplemental oxygenation should be considered.50,57
Conclusions
The goal of any therapeutic strategy is to achieve durable CR and minimize treatment-related toxicities. During the 2021 update of the NCCN Guidelines for AML, the panel addressed some of these issues by adding new sections to the guidelines. One section highlights the importance of screening patients and their families for germline mutations that characterize hereditary myeloid malignancy syndromes.17 Other sections offer recommendations on optimal use of venetoclax-based therapies45 and considerations for patients who prefer not to receive blood products during care. Regarding risk-stratification, in patients with low-risk APL treated with ATRA + ATO induction therapy, the panel clarified that a BM assessment should be optional if blood counts have recovered by day 28.
Once a patient is in remission, physicians must decide whether to continue treatment with allogeneic HCT to prevent relapse, and relying solely on pretreatment factors may be inadequate.58 To note the emerging significance of MRD relative to KIT mutations in posttreatment risk assessment, the panel also revised the guidelines to state that patients who have CBF-AML and are MRD-negative after induction may proceed to postremission treatment that does not involve allogeneic HCT. Ongoing studies are evaluating the impact of interventions based on MRD,9 and emerging data will continue to inform the panel’s recommendations in the NCCN Guidelines for AML.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
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