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

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.

References

Baccarani M, Druker BJ, Branford S, Kim DW, Pane F, Mongay L, Mone M, Ortmann CE, Kantarjian HM, Radich JP, Hughes TP, Cortes JE, Guilhot F. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the tyrosine kinase inhibitor optimization and selectivity (TOPS) study. Int J Hematol. 2014; 99 (5): 616-624.
Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century. Blood. 2015; 125 (21): 3230-3235.
Cervantes F, Lopez-Garrido P, Montero MI, Jonte F, Martinez J, Hernandez-Boluda JC, Calbacho M, Sureda A, Perez-Rus G, Nieto JB, Perez-Lopez C, Roman-Gomez J, Gonzalez M, Pereira A, Colomer D. Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica. 2010; 95 (8): 1317-1324.
Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim DW, Pane F, Pasquini R, Goldberg SL, Kalaycio M, Moiraghi B, Rowe JM, Tothova E, De Souza C, Rudoltz M, Yu R, Krahnke T, Kantarjian HM, Radich JP, Hughes TP. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. Clin Oncol. 2010; 28 (3): 424-430.
de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26 (20): 3358-3363.
Deininger M, O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, Radich JP, Hatfield AK, Mone M, Filian J, Reynolds J, Gathmann I, Larson RA, Druker BJ. et al. International randomized study of Interferon Vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with Imatinib. Proc. ASH 2009. Abstr. #1126.
Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E, Emanuel PD, Tallman M, Wadleigh M, Larson RA, Lipton JH, Slovak ML, Appelbaum FR, Druker BJ. Imatinib 800 mg daily induces deeper molecular responses than Imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol. 2014; 164 (2): 223-232.
Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D’Emilio A, Stagno F, le Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Valsecchi MG, Kim DW. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011; 103 (7): 553-561.
Gratwohl A, Pfirrmann M, Zander A, Kroeger N, Beelen D, Novotny J, et al. for the SAKK and the German CML Study Group. Long-term outcome of patients with newly diagnosed chronic myeloid leukemiaFA randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2015 Oct 14. doi: 10.1038/leu. 2015.281.
Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Mueller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011; 29 (12): 1634-1642.
Hehlmann R, Mueller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einssele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saussele S, Hochhaus A. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014; 32 (5): 415-423.
Hoffmann VS, Hasford J, Hehlmann R. Systematic Review and Meta-Analysis of Randomized Trials Comparing Imatinib 400 Mg/d Vs. Imatinib 800 Mg/d, and Imatinib 400 Mg/d Vs. Second Generation TKIs in Chronic Phase CML-Patients. Proc. ASH, 2015. Abstract # 2787
Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood 2014; 124 (5): 729-736.
Jabbour E, Cortes J, Santos FP, Jones D, O’Brien S, Rondon G, Popat U, Giralt S, Kebriaei P, Jones RB, Kantarjian H, Champlin R, de Lima M. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood 2011; 117 (13): 3641-3647.
Jiang Q, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, Jiang H, Chen H, Chen YH, Han W, Zhang XH, Wang Y, Qin YZ, Liu YR, Lai YY, Huang XJ. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011; 117 (11): 3032-3040.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362 (24): 2260-2270.
Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora M, Gupta V, Rizzieri DA, George B, Keating A, Gale RP, Marks DI, McCarthy PL, Woolfrey A, Szer J, Giralt SA, Maziarz RT, Cortes J, Horowitz MM, Lee SJ. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib era: a CIBMTR analysis. Bone Marrow Transplant. 2012; 47 (6): 810-816.
Palandri F, Castagnetti F, Alimena G, Testoni N, Breccia M, Luatti S, Rege-Cambrin G, Stagno F, Specchia G, Martino B, Levato L, Merante S, Liberati AM, Pane F, Saglio G, Alberti D, Martinelli G, Baccarani M, Rosti G. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica 2009; 94 (2): 205-212.
Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, Paietta E, Wadleigh M, Larson RA, Emanuel P, Tallman M, Lipton J, Turner AR, Deininger M, Druker BJ. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012; 120 (19): 3898-3905.
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010; 362 (24): 2251-2259.
Saussele S, Lauseker M, Gratwohl A, Beelen DW, Bunjes D, Schwerdtfeger R, Kolb HJ, Ho AD, Falge C, Holler E, Schlimok G, Zander AR, Arnold R, Kanz L, Dengler R, Haferlach C, Schlegelberger B, Pfirrmann M, Mueller MC, Schnittger S, Leitner A, Pletsch N, Hochhaus A, Hasford J, Hehlmann R; German CML Study Group. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 2010; 115 (10): 1880-1885.
Saussele S, Lauseker M, Mueller MC, Gratwohl A, Beelen DW, Bunjes D, Schwerdtfeger R, Kolb, H-J, Ho AD, Falge Ch, Holler E, Schlimok G, Zander AR, Arnold R, Kanz L, Dengler R, Haferlach C, Schlegelberger B, Schnittger S, Kalmanti L, Proetel U, Hanfstein B, Hasford J, Hochhaus A, Pfirrmann M, and Hehlmann R for the German CML-Study Group. Allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia after imatinib failure; updated results of the German CML Study IV. Proc. ASH 2014. Abstr. # 155.
Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of Imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015; 125 (6): 915-923.

Volume 5, Number 1

03/01/2016

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doi 10.18620/1866-8836-2016-5-1-8-14

Submitted 12 November 2015
Accepted 18 December 2015

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