The U.S. National Comprehensive Cancer Network (NCCN) has published new guidelines for the treatment of chronic myelogenous leukemia (O’Brien and colleagues. J Natl Compr Canc Netw 2014;12:1590-1610). The NCCN is one of two groups (the other is the European LeukemiaNet, or ELN) that provides recommendations on the best way to manage CML.
The recommended initial treatments for chronic-phase CML are Gleevec (400 mg once-daily), Tasigna (300 mg twice-daily) or Sprycel (100 mg once-daily). The initial treatment choice can be maintained indefinitely if a person responds well to the medication. For those with accelerated-phase CML, a more aggressive approach is needed because of the higher risk of disease progression. So the preferred starting therapies are higher doses of Gleevec (600 mg once-daily), Tasigna (400 mg twice-daily), or Sprycel (140 mg once-daily), or treatment with Bosulif (500 mg once-daily). Blast-crisis CML needs to be treated with a course of chemotherapy, plus a TKI, and followed by a stem-cell transplant, if a donor is available.
The goal of treatment is to achieve certain milestones, as determined by cytogenetic or molecular testing. Cytogenetic testing looks at the number of abnormal cells (containing the Philadelphia chromosome [Ph+]) in a sample obtained from bone marrow or blood. A cytogenetic response is categorized as minor (more than 35% of cells are Ph+), partial (1-35% of cells are Ph+), or complete (no Ph+ cells). Molecular assessments are more sensitive and use polymerase chain reaction (PCR) testing to look at the number of proteins produced by the CML gene (called BCR-ABL; the proteins are called BCR-ABL transcripts), which provides a measure of the presence and activity of this cancer gene. A major molecular response (MMR) is when the number of transcripts is reduced to 1/1000th (also referred to as 0.1% or a 3-log reduction). A complete molecular response (CMR) is when transcripts are no longer detectable (a minimum 4.5-log reduction). [The ELN no longer uses the term, “complete molecular response”; its preferred term is molecularly undetectable leukemia.]
In the updated NCCN guidelines, the goal of treatment for people with chronic-phase CML is to achieve at least a partial cytogenetic response or a 1-log reduction (i.e. transcripts reduced to 10%) by three months. This 3-month milestone is the same in the most recent version of the ELN guidelines (Baccarani and colleagues. Blood 2013;122:872-884).
The NCCN uses the same milestone (partial cytogenetic response or 1-log reduction) at six months. In contrast, the ELN considers this level of response to be a warning sign. The ELN’s 6-month milestone is achieving a complete cytogenetic response (CCyR) or a 2-log reduction.
The NCCN is also less aggressive than the ELN when it comes to the 12-month milestone. After one year on treatment, the NCCN considers CCyR to be sufficient (i.e. a 2-log reduction), whereas the ELN considers MMR (a 3-log reduction) to be the optimal response.
If a person doesn’t achieve any of these treatment milestones, both the NCCN and ELN recommend switching to another medication to see if the response can be improved. For those starting on Gleevec, the options are to switch to a more potent TKI (either Tasigna, Sprycel or Bosulif). For those who don’t have a good enough response to Tasigna or Sprycel, the best strategy is to switch to a TKI that hasn’t been tried yet (either Tasigna, Sprycel, Bosulif or Iclusig). If three attempts at TKI treatment aren’t successful, the NCCN recommends either Synribo, a clinical trial (where available) of a new agent, or stem cell transplantation. Synribo (omacetaxine) was recently approved by the Food and Drug Administration for people who have not responded to at least two TKIs (tyrosine kinase inhibitors). Synribo is administered by injection under the skin twice-daily for 14 days in a month (later reduced to 7 days in a month).
To access the NCCN’s free booklet on CML, go to www.nccn.org/patients/guidelines/cml/ (requires Adobe Flash Player).