The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA
Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany
Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany
Accepted 13 November 2020
After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.
Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.
Since the first attempts at treating CML with arsenic in 1865, treatment has been mostly palliative. Some modest prolongation of survival was reported with hydroxyurea and interferon alpha, for review see Hehlmann (2020) . The only curative approach was allogeneic transplantation which, however, was available only to those few patients who had a donor and could tolerate the procedure. The advent of tyrosine kinase inhibitors has profoundly changed CML management as normal survival has been achieved for most patients as seen from Table 1 [2-11]. The new goal for treating CML is now survival at good quality of life without life-long treatment: treatment discontinuation in sustained deep molecular remission (DMR) and treatment-free remission (TFR). The European LeukemiaNet (ELN) has accounted for this development with an update of its recommendations . This review summarizes the most important new developments and recommendations for treating CML including early transplantation of patients with high-risk additional chromosomal abnormalities (ACA) in early CML end-phase .
Table 1. Survival of CML patients in clinical trials: update 2020
Note: IM = imatinib, Nilo = nilotinib, Dasa = dasatinib, BOS = bosutinib, NA = not assessed
At diagnosis, ELN recommends a complete blood count with microscopic differential and a physical examination with special reference to spleen and liver size. Marrow cytology, cytogenetics for securing the Philadelphia (Ph) chromosome and a qualitative polymerase chain reaction (PCR) for BCR-ABL1 transcripts detection and typing are also recommended as well as an EKG, standard clinical chemistry and a hepatitis serology .
The preferred risk score is the new EUTOS score for long-term survival (ELTS), since it predicts death by CML better than all other scores [14, 15]. ELTS uses the same variables as the Sokal score, but with different weights. Age is much less important in the TKI era, since TKI treatment is virtually equally successful in older patients. The variables of the ELTS score and the calculation of relative risk are shown in Table 2.
Table 2. Risk assessment by ELTS14
To calculate the ELTS scores go to: http://www.leukemia-net.org/content/leukemia/cml/elts score/index_eng.html
Molecular monitoring, response milestones and deep molecular response
Molecular monitoring has replaced cytogenetics in clinical routine and is considered mainstay of treatment monitoring. Cytogenetics is still needed in the case of atypical translocations or atypical transcripts that cannot be measured by standard PCR, and in the case of failure/resistance or progression for detecting additional chromosomal abnormalities (ACA).
Quantitative real-time PCR (RT-PCR) should be performed on blood cells by standard methodology and reported as % BCR-ABL1 transcripts on the international scale (IS) [16,17]. BCR-ABL1 in %IS underlies the response milestones guiding treatment (Table 3).
Table 3. Response milestones expressed as % BCR-ABL1IS
*Loss of MMR indicates failure after treatment-free remission (TFR)
Figure 1. Benchmark times for molecular responses with imatinib (updated from Kalmanti et al.) 
Deep molecular responses (DMR; MR4 or deeper) indicate a state of disease with a very low probability of progress . They are observed in the majority of TKI treated patients.
Benchmark times for what can be expected have been determined in imatinib treated patients and are depicted in Fig. 1. Most molecular responses are stable. After 10 years, 92% of patients in MMR reached MR4.5, 88% in MR4 reached MR5. Only one of 1326 patients in MR4 progressed during a median of 3.8 years, and none of 1302 patients in MR4.5 during a median of 3 years .
Failure or intolerance (not for not-reaching MMR) in imatinib treated patients with treatment change to 2G-TKI were observed in 26.5% over 9.5 years after a median of 34 months . Changing treatment identified patients who did worse than the rest of the cohort, thus representing a poorer risk group. Most imatinib-treated patients, however, are candidates for treatment discontinuation.
At present, 4 drugs are approved for 1st line therapy in CML by EMA and FDA:
Approved in Korea only:
Generic imatinib, now available worldwide, is the cost-effective initial therapy in chronic phase (CP) CML. Dosing of generics should be the same as brand dosing. Patients should continue the same generic brand in order to avoid potential side-effects due to changes in drug structure, bioavailability and drug preparation .
Second- and higher-line treatment
Second and higher lines of treatment after intolerance or resistance to the first-line TKI usually also consist of a TKI, but may include allogeneic transplantation of hematopoietic cells (allo-HCT), see below.
Table 4. TKI drugs recommended in case of BCR-ABL1 resistance mutations
In the instance of treatment failure/resistance or progression to accelerated phase or blast crisis a mutational analysis should be initiated (Table 4) and the treatment changed. If available, next-generation sequencing (NGS) should be used for mutational analysis [12, 20]. Imatinib resistance mutations are relatively rare in CP2, but are more frequent in advanced phases.
If 2G-TKI are applied, the following comorbidities and contraindications have to be considered:
- Previous pleuro-pulmonary diseases are strong contraindications (cave pleural effusion).
- Uncontrolled hypertension, pulmonary arterial hypertension (PAH) and bleeding due to impaired platelet function (cave anticoagulation) are relative contraindications.
- Coronary heart disease, cerebrovascular accidents and peripheral arterial occlusive disease represent strong contraindications.
- Also, hypertension, diabetes mellitus, hypercholesterolemia and a history of pancreatitis may represent contraindications.
- No relevant comorbidities have been determined yet. Frequent and annoying, but mostly self-limited diarrhea occurs. Loperamide may be indicated.
- Ponatinib is a third generation (3G-)TKI and the only TKI with activity against the T315I mutation.
- Because of its cardiotoxicity dosing is critical. An initial dose of 45 mg/day should be reduced to a lower dose (15 mg/day) as soon as a response has been achieved .
Although drug therapy is clearly superior to transplantation in CP , transplantation still plays an important role in CML treatment. Indications have moved from CP to more advanced phases, accelerated phase (AP) and blast crisis (BC), but transplantation in CP has to be considered in high-risk patients. Transplantation in CP is still indicated in:
• TKI resistant disease
• Rare patients who are intolerant to all currently available TKI
• Resistance to initial 2G-TKI
• Resistance to 3G-TKI indicating high risk of progression
• End-phase CML with high-risk ACA.
Figure 2. Clinical strategies in evolving acceleration phase and blast crisis of CML
Fig. 2 illustrates the management of progression and emerging AP and BC1. Outcome of transplantation in AP and BC is worse than in CP, but transplantation provides probably the best outcome in BC. In an analysis of 786 BC patients managed by the German CML Study Group, 29 of the 40 long-term survivors (72.5%) had received a transplant .
Since earlier transplantations have better outcomes , the strategy is to recognize emerging progression to BC earlier. High-risk ACA indicate emerging progression. High-risk ACA are observed with increasing frequency in the later course of CML and have a negative impact on survival (Fig. 3). High-risk ACA are as follows [13, 24-26]:
• complex karyotypes (3 or more aberrations).
High-risk ACA are used to define CML end-phase. CML end-phase comprises early progression with emerging high-risk ACA and late progression with failing hematopoiesis and blast proliferation (Fig. 4).
Figure 4. High-risk ACA and progression to blast crisis [13, 27, 28]
Figure 5. Early versus late transplantation in CML patients with high-risk ACA 
Table 5. Benchmark times for DMR (MR4, MR4.5)
Notes: *imatinib (n=1442), **nilotinib 300 mg twice daily (n=282), imatinib 400 mg daily (n=283), ***dasatinib 100 mg once daily (n=259), imatinib 400 mg daily (n=260), ****bosutinib 400 mg once daily (n=268), imatinib 400 mg daily (n=268), NA = not available
DMR rates of these trials cannot be directly compared owing to different methods of trial evaluation.
A total of 42 patients with high-risk ACA were transplanted in CML Study IV. Transplantation in early CML end-phase with emerging high-risk ACA, but without progression to AP or BC has shown superior survival (Fig. 5), although the survival difference, due to the small numbers (n=13 without progression; n=26 with progression to AP or BC; n=3 phase unknown), has not reached statistical significance at p=0.09 .
High-risk ACA at low blast counts herald death by CML . The hazard to die with high-risk ACA compared with no ACA is increased:
• Up to 3.9-fold at blood blast levels of 1-5%;
• Up to 6.5-fold at marrow blast levels of 1-15%.
The lower the blast count, the higher is the predictive power of high-risk ACA. Low-risk ACA are associated with lesser or non-increased hazard.
Treatment discontinuation and TFR
Achievement of TFR after treatment discontinuation in sustained DMR is a new goal in the management of CML. The majority of imatinib-treated patients in CP have reached DMR (MR4 or deeper) after 3 years as seen from Fig. 1 [18, 19]. Benchmark times for DMR have been determined in long-term clinical trials for imatinib , dasatinib , nilotinib , and bosutinib  and are shown in Table 5.
After the first pioneering studies have been published by the French CML group [29,30] many more studies have followed. Table 6 shows a selection of 21 studies totaling close to 3000 patients. Rates of relapse-free remissions at 2 years range around 50% (33% to 72% at 0.5-10 years). The largest of the studies, the EURO-SKI study (n=755), reports a TFR rate of 49% at 2 years .
Duration of TFR and of TKI treatment appear to be the most important predictors of successful TFR . Loss of MMR indicates failure after TFR . After resumption of treatment, 95% of patients will regain pre-discontinuation response levels.
The ELN considers the following requirements mandatory for TKI discontinuation :
• CML in first CP only (data are lacking outside this setting);
• motivated patient with structured communication;
• accessibility to high quality quantitative PCR using the International Scale (IS) with rapid turn-around of PCR test results;
• patient agreement to more frequent monitoring after stopping treatment meaning;
• monthly for the first 6 months, every 2 months for months 6-12, and every 3 months thereafter.
Table 6. Selected TKI-discontinuation studies, update 2020
Notes: Updated from . ND = not defined; UMRD = undetectable minimal residual disease; IM = Imatinib; Nilo = Nilotinib; Dasa = Dasatinib; MR = molecular response; RFS = relapse free survival.
By 2020, survival of patients with CML has approached that of the general population. ELTS score is the preferred risk score in the TKI era. Molecular monitoring of minimal residual disease has replaced cytogenetics in routine monitoring. The four TKIs available for first-line therapy show different adverse effects profiles, but no differences in survival. Generic imatinib is the cost-effective initial treatment in chronic phase CML. Usage of second and higher-line TKI therapy is specified by mutational analysis and comorbidities. Early allogeneic hematopoietic cell transplantation is indicated in high-risk patients, e.g. with high-risk ACA. The new treatment goal is TFR. TKI discontinuation is feasible and safe. The rate of successful TFR ranges around 50% at 2 years.
Conflict of interest
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Accepted 13 November 2020