Approach

Patients with blast crisis can be treated with a tyrosine kinase inhibitor (TKI), chemotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT). The goal of treatment is to achieve a complete hematologic response.

Long-term remission is rare in blast crisis; HSCT as the sole curative treatment.

The optimal approach to managing blast crisis is unknown. Treatment should be individualized, taking into account patient characteristics and treatment factors; enrollment into a clinical trial should be encouraged for all eligible patients.

Initial treatment

Depends on the type of blast crisis (myeloid, lymphoid, or biphenotypic), any prior treatment with TKIs, and BCR::ABL1 kinase domain mutation profile.

TKI therapy combined with induction chemotherapy is recommended, both for patients with progression to blast crisis and for those with de novo blast crisis.[2][32][40]

Consider the following when beginning treatment:

  • A suitable transplant donor should be found early because the response to drug treatment is often not durable

  • The goal of initial treatment is to achieve a response sufficient to proceed to consolidation with allogeneic HSCT (e.g., return to chronic phase); transplantation in frank blast phase is not recommended

  • An alternative TKI and chemotherapy regimen should be considered in the absence of at least a partial response to initial treatment.[39]

For patients who are not candidates for allogeneic HSCT, consolidation chemotherapy and TKI maintenance is recommended for patients in remission.[2]

Myeloid blast crisis

A TKI combined with an acute myeloid leukemia (AML)-type induction chemotherapy regimen (e.g., cytarabine plus daunorubicin) is preferred for patients with myeloid blast crisis preparing for allogeneic HSCT.[2][39][41]​​​

Ponatinib with the induction chemotherapy regimen FLAG-IDA (fludarabine, cytarabine, idarubicin, and the granulocyte colony-stimulating factor filgrastim) may be an option, especially for younger patients.[39][42][43]​ In one phase 1/2 dose-finding trial, 11 (69%) of 16 evaluable patients with blast-phase CML (including myeloid, lymphoid, and mixed phenotypes) achieved hematologic or cytogenetic response after a single cycle of ponatinib-FLAG-IDA.[42]​ Four patients had dose-limiting toxicity.[42]

Less intensive regimens, such as a TKI plus a hypomethylating agent (e.g., decitabine or azacitidine), may be considered for older or less fit patients.[44][45][46]

If chemotherapy is not suitable, a TKI alone may be an alternative option.[2]

Lymphoid blast crisis

A TKI combined with high-dose acute lymphoblastic leukemia (ALL)-type induction chemotherapy (e.g., hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with cytarabine and methotrexate]) is preferred for patients with lymphoid blast crisis preparing for allogeneic HSCT.[2][39][47][48][49]

Hyper-CVAD plus dasatinib may be an option, especially for younger patients. One retrospective analysis of patients with CML-lymphoid blast phase receiving hyper-CVAD plus dasatinib found that 70% (14/20) achieved major molecular response, and 55% (11/20) complete molecular response (5-year progression-free survival 46%; 5-year overall survival 59%).[50]

​Less intensive regimens, such as a TKI plus vincristine and a corticosteroid, may be considered for older or less fit patients.[51]

​If chemotherapy is not suitable, a TKI plus a corticosteroid is recommended for patients with lymphoid blast crisis.[2]

Biphenotypic blast crisis

Patients with biphenotypic blast crisis are treated similarly to those with lymphoid and myeloid blast crisis; an ALL- or AML-type induction chemotherapy regimen can be considered alongside TKI therapy.

Patients with central nervous system (CNS) involvement

CNS involvement has been reported in some patients, most commonly in lymphoid and biphenotypic blast crisis. Guidelines recommend CNS prophylaxis (intrathecal chemotherapy) for patients with lymphoid or biphenotypic blast crisis.[2][3]​​​ Myeloid blasts are less likely to infiltrate the CNS.[52]

If CNS involvement is confirmed, it should be treated as for AML or ALL. Dasatinib, a second-generation TKI, may be an option for blast crisis with CNS involvement; there is some evidence that it may penetrate the blood-brain barrier.[2][3][53]​​​​​

TKI therapy determinants

TKIs target the BCR::ABL fusion protein associated with the Philadelphia chromosome. Choice of TKI for patients who have progressed on TKI therapy should be based on prior therapy and mutation profile.[2]

Previously untried second- or third-generation TKIs are preferred (e.g., dasatinib, nilotinib, bosutinib, ponatinib).[2][54][55][56][57]

Ponatinib should be considered for patients who have the T315I mutation. It may be an option for those without the T315I mutation who have resistance or intolerance to at least two prior TKIs.[58][59]

​​​Ponatinib is associated with a significant risk of serious vascular events, heart failure, pancreatitis, and hepatotoxicity.[60]​ Caution is required for patients with cardiovascular risk factors. Post-marketing cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported.[61]

Patients with de novo blast crisis are usually treated with a second- or third-generation TKI.[2][6]​ Imatinib may be considered for patients with contraindications to second- and third-generation TKIs; it may be less potent, but it is well-tolerated.[2]

Allogeneic stem cell transplantation

An allogeneic HSCT should be considered promptly:[2][32][39]

  • If at least a partial hematologic response or second chronic phase is achieved with initial drug therapy; and

  • A suitable donor is found.

Careful monitoring is essential during drug treatment to ensure optimal timing of HSCT; survival outcomes for allogeneic HSCT are vastly improved in patients who respond to drug treatment and have a lower disease burden.[62][63][64]

​Following allogeneic HSCT, consideration of TKI maintenance therapy is recommended for at least 1 year to reduce the risk of relapse.[2][65][66][67]​ Monitoring posttransplant for early detection of BCR::ABL1 transcripts is important to identify patients who require further treatment before relapse occurs.[2]​​​

Transplant failure or recurrence posttransplant

Options for further treatment in patients with allogeneic HSCT failure or recurrence posttransplant should be discussed with the transplant team.

A TKI, with or without donor lymphocyte infusion (DLI), may be considered.[2] One study found that imatinib combined with DLI was more effective than either treatment alone.[68] Potential complications of DLI include graft-versus-host disease and opportunistic infection due to immunosuppression.[2]

​​​​Posttransplant choice of TKI depends on prior therapy, BCR::ABL1 mutation profile, and posttransplant morbidities. Ponatinib may be an option if no other TKIs are indicated. Dasatinib may be an option for extramedullary relapse.[2][3]

Enrollment in a clinical trial with best supportive care may be an option for patients with transplant failure or recurrence posttransplant, depending on the clinical context.[2] 

Evidence for different treatment strategies is limited.

Supportive care

Should be provided throughout the course of treatment.

Granulocyte colony-stimulating factors may be used adjunctively if anemia, thrombocytopenia, or neutropenia occur during any phase of treatment. Therapy causing thrombocytopenia or neutropenia may be withheld if platelet count is <50 × 10⁹/L (<50,000/microliter) or absolute neutrophil count is <1 × 10⁹/L (<1000/microliter).

Hydroxyurea to reduce very high white blood cell counts (i.e., >100 × 10⁹/L [>100,000/microliter]), in tandem with prophylaxis for tumor lysis syndrome (e.g., with allopurinol and hydration), is given prior to TKI therapy or chemotherapy in patients with a high disease burden.

Other components of supportive care include blood transfusions and palliative care to manage symptoms.

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