Management of CML-blast crisis
Introduction
CML-blast crisis (BC) remains a challenge in the management of CML, although it develops, as a rule, under the eyes of the treating physician. Indicators are clonal evolution reaching aneuploidy levels of up to 90% [1] and mutation levels including resistance mutations to TKI treatment in up to 80% [2]. The increase of blast cells with failure of normal hemopoiesis is only the end stage of this evolution. It therefore is not surprising that the exact definition of BC (e.g. 30% blasts in the blood or marrow) is controversial [3]. Inspite of these indicators, no effective therapy exists to date, except for the occasional return to chronic phase (CP) with chemotherapy and subsequent transplantation. Prevention of BC by careful monitoring of treatment response and intensification of treatment, if response milestones are not reached remains the mainstay of management.
For the advancement of prevention and treatment several open questions and possible answers need to be addressed:
- 1.
Can we prevent progression to BC better by early treatment intensification according to response milestones? Answer: Carefully designed clinical trials could provide the answer.
- 2.
Can we identify patients at risk for progression better to improve prevention? Answer: Optimizing risk prognosticators combined with “personal” molecular markers.
- 3.
Can we define a point in the course of the disease after which treatment cannot reverse clonal evolution (point of no return)? Possible answer: by systematic aligning genetic with hematologic and clinical findings.
- 4.
What indicators precede an increase of blasts? Can we arrive at a more pathophysiologic definition of BC in the interest of better and timelier intervention? Possible answer: further dissecting more molecular pathways underlying BC with targeted intervention as proof of principle.
- 5.
Is genetic instability by BCR-ABL the single causative factor for clonal evolution, or are there other predisposing factors? Answer: Molecular techniques such as comparative whole genome sequencing may help.
In this review we present a broad overview of the diagnosis, therapy, prediction of progression and prevention of BC and our opinion of the open questions.
Section snippets
Diagnosis
To diagnose BC, complete blood and differential counts and a bone marrow analysis with cytogenetics are required. Cytogenetic evolution is the most consistent predictor of blast transformation. Flow cytometry or cytochemistry is needed to determine the type of BC (myeloid, lymphoid or mixed). Molecular genetics with mutation analysis are needed to choose the appropriate tyrosine kinase inhibitor (TKI). Consensus recommendations when to perform mutation analyses have been published on behalf of
Pathogenetic basis of therapy
Treatment of BC is guided by our understanding of BC pathogenesis. Good in-depth reviews on the biology of BC have been published [20], [21]. According to current evidence, BC is the direct consequence of continued BCR-ABL activity [20], [21], possibly via oxidative stress and reactive oxygen species [22], [23], causing DNA damage and impaired DNA repair [24] and, in a vicious circle, genomic instability by more mutations, gene doublings, translocations, and chromosomal breakages [25]. The
Intensive chemotherapy
Once BC has been diagnosed, management depends on prior therapy and type of leukemia (myeloid or lymphoid). In the late 1960s/early 1970s, attempts were made to treat BC with treatment protocols designed for acute leukemia (AL). It was observed that 30% of the patients responded to a combination of vincristine and prednisone as used for acute lymphoblastic leukemia (ALL) [27]. The cells of the responding BC frequently showed features of lymphoid morphology and were TdT+ [28]. These observations
TKI therapy
The clinical improvement with TKI treatment in parallel to BCR-ABL reduction and the postponement (or prevention) of BC in most patients with TKI (8-year incidence of BC in IRIS < 8% under standard imatinib [30]) supports the conclusion that BCR-ABL is the driving force behind disease progression. This is confirmed by the experience of the German CML Study Group which reported a decrease of 8-year BC-incidence from 70% 25 years ago to approximately 5% in CML Study IV [3] [31]. The transient
Scenario 1
If the patient has been pretreated with conventional therapy (IFN or hydroxyurea, currently the exception), imatinib 600–800 mg/d (or dasatinib 140 mg once daily or nilotinib 2 × 400 mg/d according to mutation profile) should be given and allo-SCT planned. Outcomes of trials with imatinib and other TKIs in BC have been summarized recently [32]. Imatinib and dasatinib have been approved for all phases of CML, including BC by the Food and Drug Administration and the European Medicine Agency.
Five
Dasatinib
Three studies of 400 BC patients pretreated with imatinib, including 119 with lymphoid BC, showed hematologic remission rates of 33%–61% (lymphoid BC, 36%–80%), major cytogenetic remission (MCR) rates of 35%–56%, a 1-year survival of 42%–50%, a 2-year survival of 20%–30%, and a median survival of 8–11 months [39], [40], [41].
The largest of the studies, a randomized open label phase 3 study of 214 patients with 61 in lymphoid BC, attempted to optimize the dose-schedule of dasatinib, stratified
Nilotinib
Two studies of 169 patients have been published including 40 with lymphoid BC [43], [44], reporting hematologic response rates of 60% (lymphoid BC 59%), major cytogenetic response rates of 38% (myeloid BC), and 52% (lymphoid BC), a 1-year survival of 42%, a 2-year survival of 27%, and a median survival of 10 months (7.9 months for lymphoid BC). Hyperglycemia, which is observed in up to 40% of nilotinib-treated patients, requires monitoring and may necessitate dose adjustment. Nilotinib has been
Imatinib in combination
Several small studies have focused on the combination of imatinib at 600 mg–800 mg with chemotherapy or other agents. In a phase 1/2 trial on 16 BC patients, imatinib 600 mg daily was combined with mitoxantrone/etoposide [45]. Hematologic response rate was 81% with a 1-year survival of approximately 50%, including 6 patients who had an allo-SCT. Another study combined imatinib 600 mg with decitabine in 10 patients and reported a median survival of 15 weeks [46]. The combination of imatinib
Dasatinib and nilotinib in combination
Milojkovic et al. [52] reported 4 patients who progressed to BC while on imatinib and were successfully treated with dasatinib 100 mg daily combined with fludarabine 30 mg/m2 iv days 1–5, cytosine arabinoside 2 g/m2 iv days 1–5, idarubicin 12 mg/m2 iv days 1–3 and G-CSF 300 mg/day sc days 0–6 (FLAG-IDA). All patients were alive, three after and one prior to SCT. Strati et al. treated 42 BC patients with hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone (HCVAD) plus
Bosutinib and ponatinib
Since 2012 [3], two additional TKI have been approved for CML, bosutinib and ponatinib. Bosutinib, a third second-generation TKI, shows in preliminary analyses on 48 BC-patients similar activity (CCR 29%, MMR 28%, PFS 7.8 months) as dasatinib and nilotinib [55].
The pan BCR-ABL inhibitor ponatinib shows, in addition to recognizing the T315I mutation, efficacy in BC and Ph + ALL. A phase 2 study on 449 ponatinib-treated patients included 62 patients in BC. After a median follow-up of the BC
Allo-SCT
Although allo-SCT is successful in only a minority of BC patients it probably has the best outcome in BC, if the patient can tolerate the procedure and if a donor is available after a return to CP, assuming a complete remission has been achieved. The search for a donor should be instituted as early as possible. In an overview of the European Group for Blood and Marrow Transplantation from 1980 to 2003, 2-year survival rates are 16%–22% [59]. Most patients were transplanted in the pre-imatinib
Investigational agents
A number of investigational approaches are under exploration. A selection is presented in Table 2. The approaches include activation of the tumor suppressor protein phosphatase 2A (PP2A), which shows decreased activity in BC [68] through up-regulation of its inhibitors suppressor of variegation, enhancer of zeste and trithorax (SET), and cancerous inhibitor of PP2A (CIP2A) [69] which upregulates the antiapoptotic protein BCR-XL [70]; inhibition of self-renewal of leukemia stem cells (LSCs) by
Prevention
The low progression rates of CML with TKI maintenance therapy indicate that BC can be prevented. Also, it is well known that very low or undetectable BCR-ABL transcripts after allo-SCT correlate with low relapse rates [80]. Imatinib-treated patients who have achieved MMR enjoy durable responses with virtually no current progression to AP or BC [81]. Patients who have achieved stable complete molecular remission may experience in approximately 40% of cases complete continued remission in the
Prediction of progression
At diagnosis, risk scores provide information on the likelihood of progression. The EUTOS score [83] which was developed from imatinib-treated patients, has a predictive value of not reaching a CCR by 18 months of 34% and recognizes a small group of high-risk patients (∼ 12%) with a significantly higher progression rate. The ELTS-score [84] identifies three risk groups with significantly different probabilities of death due to CML. Distinct markers such as major route ACA [6], p190BCR−ABL [85],
Conclusion
The management strategy in Table 3 gives an overview how to prevent BC or approach management after BC has evolved. Goal is the return to chronic phase or the induction of a true cytogenetic and/or molecular remission. The main form of treatment should be a TKI preferably based upon the type of remission followed quickly by allo-SCT if possible. If TKIs are not sufficient, AL-type induction therapy should be tried, cytosine arabinoside and anthracyclines for myeloid BC, vincristine and
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the Deutsche Krebshilfe (Nr. 109588), Novartis, Nürnberg, Germany, Kompetenznetz für Akute und Chronische Leukämien (BMBF 01GI0270), Deutsche José-Carreras Leukämiestiftung (DJCLS H09/01f, H06/04v, H03/01, R05/23), European LeukemiaNet (LSHC-CT-2004-503216), Roche, Grenzach-Wyhlen, Germany and Essex Pharma, München, Germany and the Cancer Research and Treatment Fund, Inc., New York, New York.
The contributions of A. Elett, G. Bartsch, S. Dean, E. Matzat, R.
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