ISSN 1866-8836
Клеточная терапия и трансплантация

First- and second-line strategies in chronic phase CML including hematopoietic stem cell transplantation

Rüdiger Hehlmann, Susanne Saußele

Heidelberg University, Germany

Correspondence
Prof. Dr. Dr. h.c. R. Hehlmann, Medizinische Fakultät Mannheim der Universität Heidelberg, Pettenkoferstr. 22, 68169 Mannheim, Germany
Phone: +49 (0) 621-383-69-31, fax: +49 (0)621-383-69-32, E-mail: R.Hehlmann@urz.uni-heidelberg.de
doi 10.18620/1866-8836-2016-5-1-8-14
Submitted 12 November 2015
Accepted 18 December 2015

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Cellular Therapy and Transplantation (CTT)
Volume 5, Number 1
Contents 

Summary

Summary

The review article is dedicated to the main principles of modern therapy in chronic myeloid leukemia (CML). Current treatment options for the chronic phase (CP) CML include Imatinib at standard or high doses (400 to 800 mg/d) and second-generation tyrosine kinase inhibitors (2-G TKIs), e. g. dasatinib and nilotinib. Hematopoietic stem cell transplantation (HSCT) is generally considered second or third line. Early SCT may be an option for non-high risk patients with low transplantation risks. According to the German CML Study Group the 10-year survival in CML has continuously improved,up to 85% with imatinib introduction. Previously, the survivors after busulfan and hydroxyurea were mostly transplant recipients. CML-Study III and IIIA compared allo-SCT with the best available drug treatment. Most authors who applied TKIs in CML, used imatinib, and HSCT (in some clinical situations). According to CML- Study IV the molecular responses (MR) achieved with imatinib in MR2 situations (an analogue of complete cytogenetic remission) may reach 92% after 10 years of observations. Introduction of the 2G-TKI (dasatinib and nilotinib) is associated with more rapidly occurring and more frequent molecular responses than with imatinib at standard dose (DASISION 5-year final study results, ENESTnd 5-year update). Increased imatinib dosage to 800 mg daily provides more rapid and deep molecular responses, as shown by appropriate meta-analysis of randomized trials, being associated with a 45% higher probability of achieving MMR after 12 months with IM 800 mg or 2G-TKIs, compared to IM 400 mg (p=0,0088).

Second-line strategies

Switching to second-line TKI treatment and/or allogeneic HSCT is recommended in cases of intolerance or drug resistance. E. g., it was concluded in the ENESTcmr Study (Hughes et al., 2014) that such transition caused more molecular responses in terms of BCR-ABL than with permanent imatinib treatment (p=0,009). The best approaches with drug treatment and HSCT at different phases of CML are described in some recent works (Jiang et al., 2011; Jabbour et al., 2011, Khoury et al., 2012). A good efficacy of allo-HSCT was shown in an update of the study by Saussele et al. (2014), with a median follow-up of 78,5 months (Fig. 1). The patients were stratified by risk. In 50-70% of cases unrelated donors served as a source of transplant. The patients transplanted in 1st chronic phase electively or after resistance to TKI therapy have shown a good 5-year survival (80%). Interestingly, the survival probability of the patients transplanted early in chronic phase was similar to that of patients’ treatment with imatinib only.

Conclusion

  • Current first-line treatment includes imatinib, dasatinib and nilotinib.
  • The proportion of patients reaching MMR by 12 months is similar with optimized imatinib and second-generation TKIs.
  • SCT is an option for the 2nd-line treatment.
  • Long-term outcomes after early SCT in chronic phase is similar to the results obtained with imatinib.
  • Early HSCT may be considered in non-high risk CP CML patients with low transplantation risk.

Keywords

Tyrosine kinase inhibitors, chronic myeloid leukemia, chronic phase, therapy, hematopoietic stem cell transplantation


First-line strategies: TKI efficiency in chronic phase of CML

At present, first-line therapy options in the chronic phase of chronic myeloid leukemia (CML) include imatinib at standard or high doses (400 to 800 mg/d)and second-generation tyrosine kinase inhibitors (2 G-TKIs), i. e., dasatinib and nilotinib, especially when the treatment milestones are not reached with imatinib. Hematopoietic stem cell transplantation (HSCT) is generally considered second or third line. More recent data show that early SCT may be an option for non-high risk patients with low transplantation risk [9]. TKI at the optimal doses provide high survival rates (Table 1) .

Drug properties

Imatinib

400 mg

IM 800 mg

tolerability adapted

Nilotinib

2 x 300 mg

Dasatinib

100 mg

Efficacy

Standard treatment

Acts faster

Acts faster,

less early progressions

Acts faster,

less early progressions

Safety

Safe

Safe

Assess risks

Assess risks

Survival

84–86% after 10 years

91–94% after 5 years

94% after 5 years

91% after 5 years

Table 1. General therapeutic characteristics of tyrosine kinase inhibitors in CML

Results of the German CML Study Group show that survival of CML has continuously improved over time from 10% after 10 years when busulfan and hydroxyurea were used to 85% with imatinib (Figure 1). Long term survivors after busulfan and hydroxyurea are mostly transplant recipients. CML-Study III and IIIA compare allo-SCT with best available drug treatment. Most studies on TKI in CML have used imatinib, as seen from Table 2.

Study (reference No.)

IM-dose mg

N

Age at diagnosis, median, years

5yr survival %

8–10yr
survival %

Median observation time, years

CML-IV [11]

IM 400–800

1536

53

90

86

8 (max. 13)

IRIS [6]

IM 400

553

50

89

85 (8 years)

8

GIMEMA [18]

IM 400–800

559

52

90

NA

5

Hammersmith [5]

IM 400

204

46,3

83

NA

3,2

PETHEMA [3]

IM 400

210

44

97,5

NA

4,2

TOPS [1]

IM 400

IM 800

157319

45

48

94 (4 years)

93,4 (4 years)

NA

3,5

3,5

MDACC-2014

IM 400

M 800

70

201

8.3

NR

80

84

9,9

(min. 8)

ILTE [8]

IM NR

832

51a

98 (6 years)

95 (8 years)

5,8

ENESTnd [20]

IM 400

Nilo 600

283

282

46

47

92

94

NA

5

 

Nilo 800

281

47

96

 

 

DASISION [16]

IM 400

Dasa 100

260

259

49

46

90

91

NA

5

Median (estimate)

91

84

 

Notes: NR=not reported; yr=year; min.=minimum; max.=maxiumum; IM=imatinib; Nilo=nilotinib; Dasa=dasatinib

Notes: NR=not reported; yr=year; min.=minimum; max=maxiumum; IM=imatinib; Nilo=nilotinib; Dasa=dasatinib

Table 2. Long term results with tyrosine kinase inhibitors in CML

In some clinical situations, allogeneic HSCT is applied as seen from Table 3, according to: Barrett, Ito [2].

CML phase

Clinical situation

TKI and chemotherapy

HLA typing and donor

Immediate
allo-SCT

CP

First failure of imatinib, high risk

Second-line TKI

Yes

No

First failure of nilotinib or dasatinib

Second-line TKI

Yes

Yes

Failure to 2 TKIs

Third-line TKI

Yes

Yes

T315I mutation

Ponatinib or omacetaxine

Yes

Yes

AP

TKI naive

TKI 6 chemotherapy

Yes

Yes

 

TKI naive, without optimal response

Second-line TKI 6 chemotherapy

Yes

Yes

 

TKI pretreated

Second-line TKI 6 chemotherapy

Yes

Yes

BP

TKI naïve or pretreated

Induction chemotherapy, TKI

Yes

Yes

Table 3. Current HSCT strategies for different CML phases

According to CML- Study IV molecular responses (MR) achieved with imatinib after 10 years of observations may reach 92% for MR2 (molecular equivalent to complete cytogenetic remission), 89% for MMR, 81% for MR4, 72% for MR4.5 and 59% for MR5.

Introduction of the 2G-TKI (dasatinib and nilotinib) is associated with more rapidly occurring and more frequent molecular responses than with imatinib at standard dose (DASISION 5-year final study results, ENESTnd 5-year update).

Increasing the imatinib dose to 800 mg also achieves faster and deeper molecular responses, as seen from comparisons of imatinib 400 and 800 mg/day [4, 7, 10, 11]. Hence, dasatinib, nilotinib and dose-optimized imatinib achieve molecular responses faster than imatinib at standard dose.

Several studies were analyzed in a systematic review and meta-analysis of randomized trials [12] comparing imatinib
400 mg/d vs. imatinib 800 mg/d [1, 4, 7, 10], and imatinib 400 mg/d vs 2G-TKI in chronic phase CML [4, 16, 19, 20].

The systematic review shows a 45% higher probability of achieving MMR after 12 months with IM 800 mg compared to IM 400 mg (p=0,0088). Efficacy estimated of IM 400 vs. 800 and IM 400 vs. 2G-TKI cannot be compared directly. But given the fairly similar prognostic profiles of the patients of the different trials it can be concluded that MMR rates achieved with IM 800 and 2G-TKI might be comparable.

Second-line strategies

  • In the case of intolerance or resistance change of treatment to 2nd-line TKI or SCT is recommended (for criteria, see Table 4).
  • Switching treatment to optimize responses is recommended, if defined milestones are missed (confirmation required).

 

ELN

NCCN

3 months

Ph+ >95%

Ph+ >35%

or BCR-ABL >10%

6 months

Ph+ >35%

and / or BCR-ABL >10%

Ph+ >35%

or BCR-ABL >10%

12 months

Ph+ >0

and / or BCR-ABL >1%

Ph+ >0

or BCR-ABL >1%

Table 4. Milestones for switching of TKI - Definition of “Failure”=“Change the treatment”

Some studies tested switching of TKI to achieve time-dependent molecular targets. E.g., in the ENESTcmr Study [13], a comparison was made between imatinib treated patients in CCR switched to nilotinib (n=104), vs. imatinib continued (n=103). After 2 years 22% with nilotinib and 9% with imatinib had undetectable BCR-ABL (p=0,0087).

The TIDEL II Study [23], analyzed imatinib dose escalation to 800 mg or switching to nilotinib, if molecular targets were not reached. 73% of patients reached a confirmed MMR at 2 years.

Current best SCT practices in CML are based on several recent studies for the patients in chronic, accelerated, and blast phase of the disease [14, 15, 17 , 21, 22].

Transplantation options

A good efficacy of allo-HSCT was shown in an update of the study by Saussele et al. [22], with a median follow-up of 78,5 months (Fig. 1). The patients were stratified by risk according to the EBMT or EURO scores. In 50-70% of cases unrelated donors served as a source of transplant.

The patients transplanted in 1st chronic phase electively or after resistance to TKI therapy have shown a good 5-year survival (80%). HSCT performed in advanced phase of the disease resulted also in high survival rates. The updated matched pair analysis has a median follow-up of 87 months. The survival probability of the patients transplanted early in chronic phase was similar to that of patients with imatinib treatment (Fig. 2).


Fig. 1. Survival probabilities in groups of CML patients treated with HSCT [22].


Figure 2. Matched pair analysisof survival in chronic phase with imatinib vs. HSCT.

Conclusions

  • Current first-line treatment includes imatinib, dasatinib and nilotinib.
  • MMR at 12 months is achieved faster with dose-optimized Imatinib than with IM-400.
  • The proportion of patients reaching MMR by 12 months is similar to optimized imatinib and second-generation TKIs.
  • SCT may be considered the 1st line in selected patients.
  • SCT is an option for the 2nd-line treatment.
  • Long-term outcomes after early SCT in chronic phase is similar to the results obtained with Imatinib.
  • Early SCT may be considered in non-high risk patients with low transplantation risk.

Acknowledgements

The authors are much appreciated to Dr. Alexey B. Chukhlovin for valuable assistance with preparation of the manuscript.

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