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NCCN Flash Updates: NCCN Guidelines Updated for Chronic Myeloid Leukemia

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) and the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) for Chronic Myeloid Leukemia. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Chronic Myeloid Leukemia

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.

Updates in Version 1.2024 of the NCCN Guidelines for Chronic Myeloid Leukemia from Version 2.2023 include:

CML-1

• Workup; Bullet 3 modified: Chemistry profile, including uric acid
• Chronic phase CML; Additional Evaluation
  • Consider myeloid mutational analysis added with a category 2B designation
• Footnote a added: Hydroxyurea is the preferred option (until the initiation of TKI therapy) to lower very high white blood cell (WBC) counts. Leukapheresis is rarely indicated, except for high-risk indications (eg, persistent priapism, shortness of breath, transient ischemic attack).
• Footnote b modified: Bone marrow cytogenetics with a minimum of 20 metaphases evaluation should be done for the initial workup, to provide morphologic review, and also is useful to detect chromosomal abnormalities in addition to the Ph chromosome. The presence of major route additional chromosomal abnormalities (ACAs) in Ph-positive cells (trisomy 8, isochromosome 17q, second Ph, trisomy 19, and chromosome 3 abnormalities) may have a negative prognostic impact on survival in patients with accelerated phase. Fluorescence in situ hybridization (FISH) on the bone marrow or peripheral blood can be used if bone marrow cytogenetic evaluation is not possible.
• Footnote content moved to the algorithm: Consider myeloid mutation panel for patients with accelerated phase or blast phase.

CML-2

• Treatment considerations independent of risk score: Age added.
• Footnote f modified: If treatment is needed during pregnancy, it is preferable to initiate treatment with interferons (interferon alfa-2a; in the United States, peginterferon alfa-2a is the only interferon available for clinical use or peginterferon alfa-2a). Interferon alfa-2a/2b and peginterferon alfa-2b have been discontinued. Peginterferon alfa-2a may be substituted for other interferon preparations. TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk. See Management of CML During Pregnancy (CML-C). (also applies to CML-4A)
• Footnote i; Reference added: Kantarjian H et al. Lancet Haematol 2022;9:e854-e861. (also applies to CML-4A)

CML-3

• TKI-resistant disease; Clinical Considerations
  • Bullet 3 added: Consider bone marrow cytogenetic analysis to assess ACAs
• TKI-resistant disease; Recommendations
  • Switch to alternate TKI (CML-5) (other than imatinib)
• Possible TKI Resistance; Recommendations
  • Continue same TKI (other than imatinib)
• Footnote p added: Switching to an alternate TKI for intolerance is appropriate for patients with disease responding to TKI therapy.
• Footnote r modified: Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the 10% cutoff can continue the same dose of dasatinib, nilotinib, or bosutinib TKI for another 3 months. Continuation of imatinib 400 mg is not recommended.
• Footnote s modified: Switching from imatinib to a 2G TKI improves response, but is may be associated with increased toxicity.

CML-4

• Accelerated phase
  • The following added after treatment: Lack of response or Disease progression
• Blast phase
  • The following added after treatment: For patients in remission: Consolidation chemotherapy and TKI maintenance for non-candidates for allogeneic HCT.

CML-4A

• Footnote u modified: The presence of major route ACAs in Ph-positive cells (trisomy 8, isochromosome 17q, second Ph, and trisomy 19, and chromosome 3 abnormalities) may have a negative prognostic impact on survival. Patients who present with accelerated phase at diagnosis should be treated with a TKI at the FDA-approved dose for accelerated phase, followed by evaluation for allogeneic HCT, based on response to therapy. Consider evaluation for allogeneic HCT if response milestones are not achieved at 3, 6, and 12 months as outlined on CML-3.

CML-5

• Bullet 2 modified: Patients with disease resistant to primary treatment with bosutinib, dasatinib, or nilotinib can be treated with an alternate TKI (other than imatinib) in the second line setting, taking into account BCR::ABL1 kinase domain mutation status. Subsequent therapy with an alternate 2G TKI would be effective only in patients with identifiable BCR::ABL1 mutations that confer resistance to TKI therapy. Ponatinib is preferred for patients with no identifiable BCR::ABL1 mutations. The durability of these responses is frequently limited.
  • Ponatinib is the preferred treatment option for patients with a T315I mutation in any phase. It is also a treatment option for CP-CML with resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. (this was a previous footnote)
  • Asciminib is a treatment option for CP-CML patients with the T315I mutation and/or CP-CML with resistance or intolerance to at least two prior TKIs. (this was a previous footnote)
• Therapy: Clinical trial removed from row 5.
• Contraindicated Mutations: F359V/I/C added for asciminib.
• Footnote bb modified: Ponatinib is the preferred treatment option for patients with a T315I mutation. It is also a treatment option for CP-CML with resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. There are compound mutations (defined as harboring ≥2 mutations in the same BCR::ABL1 allele) that can cause resistance to ponatinib, but those are uncommon following treatment with bosutinib, dasatinib, or nilotinib. (also applies to CML-6)

CML-6

• Footnote cc replaced footnote bb: Ponatinib is the preferred treatment option for patients with a T315I mutation. It is also a treatment option for CP-CML with resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. Ponatinib is the preferred treatment option for patients with a T315I mutation in any phase. It is also a treatment option for patients with for CP-CML with resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. There are compound mutations (defined as harboring ≥2 mutations in the same BCR::ABL allele) that can cause resistance to ponatinib, but those are uncommon following treatment with bosutinib, dasatinib, or nilotinib.

CML-B

• Definitions of ACCELERATED Advanced Phase CML
  • Statement added: Clinical trials in the TKI era have mostly utilized the modified MDACC criteria or the IBMTR criteria. The use of the International Consensus Classification (ICC) or the World Health Organization (WHO) criteria for the diagnosis of AP-CML and BP-CML is not recommended.
  • Accelerated Phase
    • Modified MD Anderson Cancer Center (MDACC) Criteria (most commonly used in clinical trials)
• References added:
  • Gambacorti-Passerini C, le Coutre P. Chronic myelogenous leukemia In: DeVita VT, Lawrence TS, Rosenburg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology (12th edition); 2022:1773-1784.
  • Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: Integrating morphologic, clinical, and genomic data. Blood 2022;140:1200-1228.
  • Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid
    and histiocytic/dendritic neoplasms. Leukemia 2022;36:1703-1719.

CML-C 1 of 2

• TKI Therapy and Conception
  • Bullet 2 modified: TKI therapy during pregnancy in patients assigned female at birth has been associated with both a higher rate of miscarriage and fetal abnormalities. A prolonged washout period prior to pregnancy, prompt consideration of holding TKI therapy (if pregnancy occurs while on TKI therapy), and close monitoring should be considered. There are no data regarding how long a patient should be off therapy before trying to become pregnant.
  • Bullet 3 modified: Discontinuation of TKI therapy because of pregnancy in patients who were are not in DMR (≥MR4.0; ≤0.01% BCR::ABL1 IS) has only been reported in a small series of patients. Conception while on active TKI therapy is strongly discouraged due to the risk of fetal abnormalities. There are no published guidelines regarding the optimal depth of molecular response that is considered “safe” to stop TKI therapy before attempting pregnancy and the literature regarding this consists of case reports.
  • Bullet 4 modified: Prior to attempting pregnancy, patients of childbearing age and their partners should be counseled about the potential risks and benefits of discontinuation of TKI therapy, and possible resumption of TKI therapy, and treatment options during pregnancy, should the CML recur during pregnancy. Fertility preservation should be discussed with all patients of childbearing age prior to the initiation of TKI therapy. While sperm banking can be performed prior to starting TKI therapy, there are no data regarding the quality of sperm in patients with untreated CML. Referral to a CML specialty center and consultation with a high-risk obstetrician is recommended.
• Treatment and Monitoring During Pregnancy
  • Bullet 1 modified: As noted above, in patients assigned male at birth, TKI therapy need not be discontinued if a pregnancy is planned. Sperm banking can also be performed prior to starting TKI therapy, although there are no data regarding the quality of sperm in patients with untreated CML.
  • Bullet 2 modified: In patients assigned female at birth, TKI therapy should be stopped prior to natural conception, and patients should remain off therapy during pregnancy. Referral to an in vitro fertilization (IVF) center is recommended in coordination with the patient’s obstetrician. TKI should be stopped prior to attempting a natural pregnancy or oocyte retrieval, but the optimal timing of discontinuation is unknown. There are no data to recommend how long a patient should be off therapy before oocyte retrieval, although usually at least one month off therapy is recommended.
  • Bullet 3 modified: If treatment is needed during pregnancy, it is preferable to initiate treatment with interferons interferon alfa-2a; in the United States, peginterferon alfa-2a is the only interferon available for clinical use. Both interferon alfa-2a or peginterferon alfa-2a have been used during pregnancy. Most of the data using interferons during pregnancy have been reported in patients with essential thrombocythemia. If introduced earlier, the use of interferon alfa-2a or peginterferon alfa-2a can preserve molecular remission after discontinuation of TKI. Interferon alfa-2a/2b and peginterferon alfa-2b have been discontinued. Peginterferon alfa-2a may be substituted for other interferon preparations.
  • Bullet 4 modified: The use of TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk. If TKI therapy is considered during pregnancy, the potential risks and benefits must be carefully evaluated in terms of maternal health and fetal risk on an individual basis prior to initiation of TKI therapy during pregnancy.
  • Bullet 5 modified: The panel recommends against the use of hydroxyurea during pregnancy, especially in the first trimester, if possible.
  • Bullet 6 modified: Leukapheresis can be used for a rising white blood cell (WBC) count and/or platelet count, although there are no data that recommend at what levels of WBC count leukapheresis and/or platelet pheresis should be initiated.
  • Bullet 8 modified: Monthly monitoring of CBC with differential and frequent monitoring with qPCR (every 1–3 mo) and initiating treatment if the BCR::ABL1 IS increases to >1.0% is recommended would be helpful to guide the timing for initiation of TKI therapy.

CML-C 2 of 2

• Reference added: Berman E. Family planning and pregnancy in patients with chronic myeloid leukemia. Curr Hematol Malig Rep 2023;18:33-39.

CML-D

• Relapse
  • Bullet 2 modified: Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS]≤1%) – defined as an increase in BCR::ABL1 transcript to >1%

CML-E

• Bone Marrow Cytogenetics
  • Bullet 4 modified: Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase in BCR::ABL1 transcript to >1%
• qPCR using IS
  • Bullet 2 modified: Every 3 months after initiating treatment. After BCR::ABL1 (IS) ≤1% (MR2.0) has been achieved, every 3 months for 2 years and every 3–6 months thereafter
• BCR::ABL kinase domain mutation analysis
  • Bullet 1; Sub-bullet 2 modified: Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase in BCR::ABL1 transcript to >1%

 

 

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