Chronic myeloid leukemia-blast phase: Diagnosis and treatment

INTRODUCTION — 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm in which cells of the granulocytic lineage predominate in bone marrow and peripheral blood. CML is associated with the t(9;22)(q34;q11) rearrangement (the Philadelphia chromosome), which generates the BCR::ABL1 fusion gene. This acquired genetic rearrangement produces BCR::ABL1, a constitutively active tyrosine kinase that is susceptible to tyrosine kinase inhibitors (TKIs).

Most patients with CML present with the relatively indolent chronic phase (CP) of CML (CML-CP), but some patients present with more advanced disease. In less developed countries, a higher proportion of patients have advanced disease. Blast phase (BP) of CML (CML-BP) manifests with increasing blasts in blood, bone marrow, or extramedullary sites accompanied by worsening anemia or thrombocytopenia, constitutional symptoms (ie, fever, sweats, weight loss), or increasing splenomegaly.

Most cases of BP arise from the transformation of CML-CP while a patient is being treated with a BCR::ABL1 TKI. Less often, BP arises de novo (ie, it is the initial presentation of CML). Most patients with BP manifest predominantly myeloid blasts, while one-third have predominantly lymphoid blasts. All cases of CML-BP require treatment with a TKI, but there are important differences in the management of myeloid BP versus lymphoid BP.

Evaluation, diagnosis, and treatment of CML-BP are discussed in this topic.

Related topics include:

●(See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Overview of the treatment of chronic myeloid leukemia".)

●(See "Chronic myeloid leukemia in chronic phase: Initial treatment".)

●(See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

●(See "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment".)

CLINICAL PRESENTATION — 

BP of CML is an advanced form of CML that manifests as acute leukemia and is associated with poor prognosis. Most cases of CML-BP emerge from the chronic phase (CP) of CML (CML-CP) through clonal evolution during treatment with a BCR::ABL1 tyrosine kinase inhibitor. A minority of cases present as de novo CML-BP (ie, no prior diagnosis of CML).

Presentation of CML-BP may include symptoms related to cytopenias (eg, bleeding/bruising, infection), extramedullary collections of blasts (myeloid sarcoma), organomegaly, and/or constitutional symptoms (eg, fevers, drenching sweats).

EVALUATION — 

Evaluation of clinical, laboratory, and cytogenetic/molecular findings.

Clinical and laboratory

●Clinical evaluation – History of constitutional symptoms (unexplained fevers, sweats, weight loss); bleeding/bruising; abdominal pain, fullness, or anorexia associated with progressive splenomegaly.

For patients with a previous diagnosis of CML, prior treatment with tyrosine kinase inhibitors (TKIs) should be documented.

Physical examination may demonstrate hepatosplenomegaly, bleeding/bruising, evidence of infections, and tumor masses (myeloid sarcoma).

●Laboratory

•Hematology – Complete blood count with differential, review of blood smear, including percentage of circulating blasts and other immature forms.

Note that circulating blasts can be used for mutation analysis (described below).

•Serum chemistry – Comprehensive metabolic panel, including liver and kidney function tests, uric acid.

●Clinical tests

•Chest radiograph.

•Electrocardiogram (ECG), including QT interval.

•Echocardiogram or radionuclide ventriculography to assess cardiac function.

•Lumbar puncture (LP) – Patients with lymphoid BP or unexplained neurologic findings should have an LP to assess possible central nervous system (CNS) involvement. An LP is not performed for neurologically asymptomatic patients with myeloid BP.

●Bone marrow examination – Includes:

•Microscopy – Bone marrow morphology, including percentage of blasts.

•Immunophenotype – Flow cytometry and/or cytochemistry to classify the blasts as myeloid or lymphoid lineage. (See 'Determine blast lineage' below.)

•Cytogenetics – Chromosomal banding for karyotype to identify additional cytogenetic abnormalities (ACAs), in addition to t(9;22) rearrangement (ie, Philadelphia chromosome).

Fluorescence in situ hybridization (FISH) for t(9;22) alone is not sufficient in this setting because it does not identify the many possible ACAs.

Additional details of bone marrow examination for CML are presented separately. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Bone marrow'.)

●Molecular analysis – Mutation analysis of the BCR::ABL1 kinase domain is important for selecting a TKI for patients in BP.

•Kinase mutation analysis – Next-generation sequencing (NGS) to detect BCR::ABL1 kinase domain mutations can be done using blood or bone marrow.

Specific mutations are associated with resistance to specific TKIs, as discussed below. (See 'Tyrosine kinase inhibitor selection' below.)

•Additional mutations – Mutations in ASXL1, RUNX1, and/or TP53 may have prognostic value, but they are not clinically actionable at present. NGS for additional mutations can be done using blood or bone marrow.

Additional details of molecular analysis of CML are presented separately. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Cytogenetics'.)

Medical fitness — We assess functional status and fitness for transplantation.

●Performance status (table 1).

●Eligibility for allogeneic hematopoietic cell transplantation (HCT) – All but medically frail patients should be referred promptly to determine eligibility for allogeneic HCT and to initiate a donor search. Human leukocyte antigen typing should be performed without delay for potential transplant candidates.

Many centers limit allogeneic HCT to patients ≤70 years, although the age threshold varies among institutions. Eligibility requires adequate organ function (eg, heart, lung, kidney, liver), performance status, and social supports, as described separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

DIAGNOSIS — 

CML-BP should be suspected in a patient with previously diagnosed CML who develops new or progressive symptoms, worsening laboratory abnormalities, and/or an inadequate response or loss of response while being treated with a BCR::ABL1 tyrosine kinase inhibitor (TKI). CML-BP should also be suspected in a patient with newly diagnosed CML who has lymphoblasts in blood or bone marrow and in patients with no prior diagnosis of CML who present with myeloid blasts plus other circulating immature myeloid cells.

Diagnostic criteria — CML-BP is defined by t(9;22)(q34;q11) (Philadelphia chromosome [Ph]) or BCR::ABL1 plus at least one of the following:

●≥20 percent blasts in blood or bone marrow

●Extramedullary proliferation of blasts (not including splenomegaly)

●Increased lymphoblasts in blood or bone marrow

The above criteria are used by the International Consensus Classification (ICC) [1] and the World Health Organization 5^th edition (WHO5) [2]. Note that the ICC distinguishes between myeloid BP (MBP) and the accelerated phase (AP) of CML (CML-AP; 10 to 19 percent blasts in blood or bone marrow) [1]. By contrast, WHO5 eliminated AP as a distinct category [2].

Note that CML-BP is defined as ≥30 percent blasts in some clinical trials and by the European LeukemiaNet (ELN), International Blood and Marrow Transplant Registry (IBMTR), and MD Anderson Cancer Center (MDACC) [3-5].

Differential diagnosis — BP must be distinguished from chronic phase (CP) CML (CML-CP) and CML-AP. Clinical and pathologic features of BP that arise in a patient with known CP can resemble acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

●CML-CP and CML-AP – CML-BP is distinguished from other phases of CML by blasts ≥20 percent in blood or bone marrow. (See 'Diagnostic criteria' above.)

●Acute myeloid leukemia – CML-BP is distinguished from AML with BCR::ABL1 (diagnosis requires ≥20 percent blasts) by the presence of immature cells beyond the blast phase and/or detection of BCR::ABL1 in nonmyeloid lineages [1,2].

●Acute lymphoblastic leukemia – Detection of BCR::ABL1 in blood granulocytes by fluorescence in situ hybridization (FISH) can distinguish de novo CML-BP from de novo Ph-positive ALL.

Determine blast lineage — The lineage of blasts must be determined because the management of MBP differs from that of lymphoid BP (LBP).

Lymphoid blasts and/or mixed lineage blasts are found in one-third of patients with BP [6]. Neither the ICC nor WHO5 provides a threshold for defining LBP [1,2], but the detection of any lymphoblasts by morphologic and/or immunophenotypic findings should raise suspicion of LBP.

Flow cytometry is preferred for lineage classification. However, immunohistochemical stains can be used if a bone marrow aspirate cannot be obtained (ie, "dry tap") or if there are insufficient blasts in peripheral blood.

●Myeloid BP – MBP is manifest as neutrophilic, monocytic, megakaryocytic, eosinophilic, basophilic, and/or erythroid blasts, along with other immature myeloid forms. Myeloid blasts commonly have an undifferentiated morphology.

•Flow cytometry – Myeloid blasts often express CD33, CD13, CD14, CD11b, CD11c, CD117 (KIT), CD15, CD41, CD61, and/or glycophorin A and C [6]. In some cases, blasts may also express lymphoid-related antigens [7].

•Immunohistochemistry – Myeloid blasts may have strong, weak, or no myeloperoxidase activity.

●Lymphoid BP – Most blasts in LBP are of precursor B cell origin, but rare cases have markers of T or natural killer (NK) lineage.

•Flow cytometry – B lineage blasts express B cell-related antigens, including CD19, CD20, CD10, CD79a, and PAX5. T lineage blasts express CD3, CD2, CD5, CD4, CD8, and/or CD7.

•Immunohistochemistry – Most cases express terminal deoxynucleotidyl transferase (TdT).

OVERVIEW OF MANAGEMENT — 

The goals of treatment of CML-BP are to control disease manifestations and symptoms, improve quality of life, and extend survival. For medically fit patients with BP, potential cure using allogeneic hematopoietic cell transplantation may be an option.

We encourage participation in a clinical trial, when possible.

Following are key aspects of management of CML-BP:

●Remission induction – The initial treatment of CML-BP is stratified according to the predominant lineage of blasts:

•Myeloid blasts (see 'Myeloid BP' below)

•Lymphoid blasts (see 'Lymphoid BP' below)

●Tyrosine kinase inhibitor selection – All cases of BP require treatment with a suitable tyrosine kinase inhibitor (TKI).

Selection of a TKI is individualized according to prior TKI treatment (if applicable), BCR::ABL1 kinase domain mutation analysis, toxicity, and comorbidities, as described below. (See 'Tyrosine kinase inhibitor selection' below.)

●Response assessment – Patients require close monitoring and supportive care for cytopenias, infections, and other complications during remission induction therapy.

Response assessment includes hematologic, cytogenetic, and molecular parameters. (See 'Response assessment' below.)

●Post-remission management – Post-remission management is informed by medical fitness and blast lineage:

•Myeloid BP – (See 'Myeloid BP' below.)

•Lymphoid BP – (See 'Lymphoid BP' below.)

●Monitoring – Patients are monitored for possible relapse and adverse effects of therapy. (See 'Response assessment' below.)

REMISSION INDUCTION — 

Remission induction therapy differs for patients with myeloid BP (MBP) versus lymphoid BP (LBP).

Myeloid BP — For patients with MBP, we suggest a tyrosine kinase inhibitor (TKI) plus induction chemotherapy, rather than a TKI alone or induction chemotherapy alone (algorithm 1), based on superior survival and a higher likelihood of proceeding to allogeneic hematopoietic cell transplantation (HCT).

Cytarabine, which is commonly used to treat MBP, has synergism with TKIs [8-11], and combining a TKI with chemotherapy is associated with improved outcomes, including longer survival [8-13]. By contrast, TKIs alone generally achieve only short-lived remissions in patients with BP [14,15]; as an example, the median survival was eight months for the treatment of CML-BP with dasatinib alone, and most patients experienced early relapse. Intensive myeloid leukemia induction therapy without a TKI can achieve a rapid initial response, but most patients relapse within weeks to months [16,17]. Patients with MBP who cannot tolerate induction chemotherapy can benefit from palliative treatment with a TKI alone.

No prospective trials have directly compared induction regimens for MBP. Some experts favor intensive acute myeloid leukemia (AML)-like induction therapy when possible, while others favor less-intensive induction therapy (eg, a hypomethylating agent plus venetoclax), particularly in older patients. Intensive AML induction chemotherapy and less-intensive regimens are discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Induction therapy' and "Acute myeloid leukemia: Management of medically unfit adults", section on 'Treatments'.)

Selection of a TKI is discussed above. (See 'Tyrosine kinase inhibitor selection' below.)

The following studies report outcomes with a TKI plus chemotherapy for MBP:

●Treatment with a TKI plus chemotherapy was associated with better outcomes than a TKI alone or intensive chemotherapy (IC) alone in a single-institution study of 104 patients with MBP (88 percent with transformed MBP) [12]. Treatments included a TKI plus IC (20 patients), a TKI plus a hypomethylating agent (HMA; 20 patients), a TKI alone (56 patients), and IC alone (8 patients). All patients who received a TKI plus IC received a second-generation (2G) or a third-generation (3G) TKI, whereas 65 percent of patients treated with a TKI plus an HMA received a 2G/3G TKI, and 52 percent treated with a TKI alone received a 2G/3G TKI. The five-year overall survival (OS) was superior for patients who received a TKI plus IC (30 percent) or a TKI plus an HMA (28 percent) compared with a TKI alone (13 percent) or IC alone (0 percent). Among patients who received a 2G or 3G TKI, treatment with a TKI plus IC, a TKI plus an HMA, and a TKI alone was associated with five-year OS rates of 30, 38, and 8 percent, respectively. More patients treated with a TKI plus IC or an HMA proceeded to HCT than those treated with a TKI alone (33 versus 11 percent), but 60-day mortality was higher (13 versus 2 percent).

●Treatment with ponatinib plus FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin) was an effective bridge to transplantation in a small study [18]. One cycle of therapy was associated with a return to chronic phase (CP) in two-thirds of 16 evaluable patients, including major molecular response (MMR) in one-third. The median OS was 12 months, and 41 percent of patients were alive at three years, but long-term survival depended on successful transplantation; there was no apparent benefit from a second cycle of ponatinib plus FLAG-IDA.

●Small prospective and retrospective studies have reported outcomes with a TKI plus an HMA [19-22] and a TKI plus an HMA plus venetoclax [23].

In general, responses are more common in patients presenting with de novo BP than in those who transform from previously treated CP.

The assessment of response to induction therapy is discussed below. (See 'Response assessment' below.)

Lymphoid BP — Induction chemotherapy for LBP is like that for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), which generally includes a TKI plus multiagent chemotherapy or a TKI plus immunotherapy rather than any of these treatments alone (algorithm 1).

Preferred Ph+ ALL regimens vary among experts, and no prospective studies have directly compared induction regimens for LBP. A TKI plus hyper-CVAD/IMAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine) is the best-studied induction regimen in this setting, but it is associated with substantial toxicity, and it is generally suitable only for medically fit patients <65 years. In older or less-fit patients, treatment with a TKI plus lower-intensity Ph+ ALL-like induction therapy or a TKI plus glucocorticoid is acceptable, but such regimens are less effective for LBP compared with Ph+ ALL. Treatment with a TKI plus either blinatumomab [24] or inotuzumab [25] may also be considered in patients with LBP. Regimens used to treat Ph+ ALL are discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Selection of a TKI is discussed below. (See 'Tyrosine kinase inhibitor selection' below.)

Outcomes of treatment for LBP include:

●TKI plus hyper-CVAD/IMAC

•Treatment of 42 patients with LBP (median age 53 years) using dasatinib plus hyper-CVAD was associated with complete hematologic remission (CHR) in 90 percent, complete cytogenetic remission (CCyR) in 58 percent, and complete molecular remission (CMR) in 25 percent (table 2) [26]. The median OS was 17 months and median duration of remission (DOR) was 14 months. Hematologic toxicity was reported in 100 percent and infectious complications in 59 percent, but <10 percent of patients required treatment discontinuation.

•In a study that included 23 patients with LBP, dasatinib plus hyper-CVAD was associated with CHR or complete remission with incomplete hematologic recovery in 82 percent, CCyR in 85 percent, and CMR in 55 percent [27]. The five-year OS was 59 percent, but it was 88 percent in patients who proceeded to allogeneic HCT.

●TKI plus blinatumomab

•Treatment of LBP with ponatinib plus blinatumomab in six patients was associated with an 83 percent response rate, including a 33 percent CMR [28]. Grade ≥3 infections were reported in one-third of 72 patients with various Ph+ leukemias in the study, and there were no treatment-related deaths.

•All three patients with LBP treated with ponatinib or dasatinib plus blinatumomab achieved a response with undetectable BCR::ABL1 [24].

•Treatment with ponatinib plus blinatumomab in a patient who relapsed with LBP after hyper-CVAD achieved MMR and enabled subsequent allogeneic HCT [29].

●TKI plus inotuzumab ozogamicin – One of two patients with LBP treated with bosutinib plus inotuzumab ozogamicin had a response [25].

Further studies are needed before routinely implementing TKI plus immunotherapy for LBP.

TYROSINE KINASE INHIBITOR SELECTION — 

BCR::ABL1 tyrosine kinase inhibitors (TKIs) are essential components of treatment for all patients with CML-BP.

Selection of a TKI is based on prior TKI therapy (if applicable), BCR::ABL1 kinase domain (KD) mutation status, toxicity considerations, and comorbidities. TKI choice is not affected by the blast lineage. Analysis of BCR::ABL1 KD mutations is discussed above. (See 'Clinical and laboratory' above.)

The treatment of CML-BP almost always uses a second-generation (2G) TKI or a third-generation (3G) TKI. We generally exclude imatinib for the treatment of BP because it is ineffective against many mutations associated with BP, and it is slower than the other agents for achieving remission. Imatinib should be used to treat BP only when all other TKIs are contraindicated. Administration and toxicity of imatinib are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Imatinib'.)

The TKI is given continuously during remission induction and post-remission therapy, but it may be held temporarily during allogeneic hematopoietic cell transplantation (HCT). The TKI dose should not be adjusted for cytopenias in patients with a robust response to remission induction therapy; rather, the TKI dose should be maintained while the patient receives necessary blood product support.

BCR::ABL1 T315I — For patients with BCR::ABL1 T315I, we suggest treatment with ponatinib rather than other TKIs (which have limited or no activity against this mutation).

For patients with significant cardiovascular comorbidities, the dose of ponatinib can be reduced if remission is achieved. Asciminib has activity against T315I but has little track record for the treatment of CML-BP.

Treatment, toxicity, and outcomes with ponatinib are presented below. (See 'Ponatinib' below.)

Other kinase domain mutations — For patients with BP who do not have T315I mutation, we select a TKI based on BCR::ABL1 KD mutations.

The TKI that was being used at the time transformed BP arose is contraindicated because, by definition, the disease was resistant to that agent. The TKI that is chosen should have activity against the KD mutation(s) that are found, and toxicities and comorbidities should be considered.

We generally avoid TKIs that are ineffective against specific KD mutations [5], as follows:

●A337T – Avoid asciminib

●E255K/V – Avoid nilotinib

●F317L – Avoid bosutinib

●F317L/V/I/C – Avoid dasatinib, nilotinib

●F359V/I/C – Avoid asciminib

●G250E – Avoid bosutinib

●P465S – Avoid asciminib

●V299L – Avoid bosutinib, dasatinib

●Y253H – Avoid nilotinib

●T315I – Discussed above (see 'BCR::ABL1 T315I' above)

POST-REMISSION MANAGEMENT — 

Post-remission management of CML-BP is guided by eligibility for hematopoietic cell transplantation (HCT).

The management of patients who are not transplant-eligible is stratified according to the myeloid BP (MBP) versus lymphoid BP (LBP). (See 'Less fit' below.)

Transplant eligible — For patients with either MBP or LBP who achieve remission with induction therapy, we suggest allogeneic HCT rather than a tyrosine kinase inhibitor (TKI) plus consolidation chemotherapy (algorithm 1) because it offers the best opportunity for long-term survival.

The decision to proceed with allogeneic HCT should be individualized according to the availability of a suitable graft, comorbidities, and patient preference. Eligibility for allogeneic HCT is discussed above. (See 'Medical fitness' above.)

●Outcomes with allogeneic HCT

•Myeloid BP

-In a single-institution study, among patients with MBP who achieved hematologic remission, outcomes were better for 19 patients who underwent allogeneic HCT compared with 22 patients who were not transplanted [12]. The five-year overall survival (OS) after HCT was 58 percent, and the five-year OS without HCT was 22 percent, but four of the patients who were not transplanted survived >5 years. Other outcomes from this study are discussed above. (See 'Myeloid BP' above.)

-HCT using fludarabine-based reduced-intensity conditioning (RIC) in 64 patients with advanced CML who were not eligible for myeloablative conditioning (MAC) was associated with 33 percent five-year OS and 20 percent five-year progression-free survival [30]. Transplant-related mortality was 33 percent at 100 days, 39 percent at two years, and 48 percent at five years.

•Lymphoid BP

-In a study that used a TKI plus hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) induction therapy for LBP, 18 of 42 patients underwent allogeneic HCT [26]. Compared with patients who were not transplanted, HCT was associated with a longer OS (median 93 versus 9 months) and longer duration of response (not reached after 15 months median observation versus 7 months).

●Timing of HCT – No prospective trials have evaluated the optimal timing of transplantation in patients with BP, but remissions are often short-lived, there is a low likelihood of achieving a second remission, and outcomes are generally better when patients are transplanted in remission than with active disease.

Prior TKI therapy does not compromise outcomes after allogeneic HCT or increase transplant-related toxicity [31-36].

●Conditioning regimen – The preferred conditioning regimen varies with patient age and institutional approach, but RIC or nonmyeloablative (NMA) conditioning is acceptable for older (eg, >55 years) or less-fit patients who are not candidates for MAC [30,37-40].

●Donor source – Human leukocyte antigen (HLA)-matched sibling donors (MSD) or matched unrelated donors (MUD) are preferred [41,42], but haploidentical donors or umbilical cord blood are acceptable when matched donors cannot be identified rapidly.

●Graft source – The choice of a peripheral blood stem/progenitor cell graft versus a bone marrow graft is discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Allogeneic HCT for malignancies'.)

●TKI use during transplantation – The TKI may be held during and immediately after allogeneic HCT and restarted when blood counts recover (eg, day 30 to 60). Temporarily withholding the TKI potentially avoids drug interactions with the numerous agents that are given in this period and may hasten hematopoietic engraftment.

Less fit — Post-remission management in patients who are not eligible for allogeneic HCT is guided by the predominant lineage of the blasts.

Myeloid BP — For patients with MBP who are not transplant-eligible, we suggest a TKI plus consolidation chemotherapy followed by indefinite TKI maintenance therapy (algorithm 1).

Consolidation chemotherapy in this setting is like that for acute myeloid leukemia (AML), with the addition of a TKI. Consolidation chemotherapy regimens for AML are discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Intermediate-risk disease'.)

For patients who are not sufficiently fit for consolidation therapy or who decline it, we treat with a TKI until relapse.

Lymphoid BP — For patients with LBP who are not transplant-eligible, we suggest a TKI plus consolidation/intensification chemotherapy followed by maintenance therapy.

Management in this setting includes:

●TKI – Patients should continue the TKI throughout post-remission management.

●Consolidation – Consolidation/intensification is like that for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), but the preferred regimen varies among experts.

●Maintenance – For patients who are not fit for consolidation therapy or who decline it, we proceed to maintenance chemotherapy, including the continuation of the TKI along with other drugs (eg, methotrexate, 6-MP, vincristine, prednisone), as specified by the chosen protocol. Maintenance therapy is usually given for at least five years after consolidation therapy. Long-term data in this setting are sparse.

Post-remission management of Ph+ ALL is discussed separately. (See "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management".)

MONITORING

Response assessment — Patients treated for CML-BP require close monitoring of disease status.

●Clinical monitoring – We monitor blood counts and clinical status frequently until a hematologic response is achieved, but the schedule of visits varies with the intensity of the induction regimen and clinical status. Patients frequently need care for cytopenias and often require transfusions of red blood cells and/or platelets. Note that post-transfusion platelet increments are often compromised by splenomegaly in patients with BP.

●Bone marrow examination – For patients with a clinical response to induction therapy (eg, reduced/absent circulating blasts, improving splenomegaly), we perform a bone marrow examination approximately four weeks after the initiation of therapy.

●Response milestones – Optimal response milestones for the treatment of BP have not been defined. We apply definitions of hematologic, cytogenetic, and molecular responses (table 2) used in chronic phase (CP). Treatment response is discussed in greater detail separately. (See "Overview of the treatment of chronic myeloid leukemia".)

•We monitor BCR::ABL1 by quantitative polymerase chain reaction (PCR) in peripheral blood every three months for two years and every three to six months thereafter:

-If PCR remains negative, we continue the TKI as maintenance therapy for at least one year [43-45].

-If PCR becomes positive, we retest BCR::ABL1 mutation status and adjust the choice of TKI accordingly. We encourage enrollment in a clinical trial. Further management is discussed below. (See 'Relapsed/refractory BP' below.)

Surveillance — Following the completion of post-remission management, we monitor patients for relapse and treatment-associated adverse effects.

The schedule of clinical evaluation and laboratory testing is individualized according to clinical status and concerns of the clinician and patient.

TREATMENTS — 

BCR::ABL1 tyrosine kinase inhibitors (TKIs) are essential components of treatment for all patients with CML-BP.

The selection of a TKI for the treatment of CML-BP is discussed above. (See 'Tyrosine kinase inhibitor selection' above.)

We do not use imatinib to treat BP because many mutations in this setting are resistant to it and imatinib is associated with slower responses that other TKIs [46-49]. The administration and toxicity of imatinib are discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Imatinib'.)

The management of TKI-related adverse effects (AEs) is discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

Bosutinib — Bosutinib is a second-generation (2G) TKI that should be avoided in patients with liver or kidney dysfunction, diarrhea, and heart failure. It is associated with cytopenias, diarrhea, abnormal liver function, and fluid retention (table 3).

●Administration – Bosutinib 500 mg once daily by mouth with food is used for BP.

The dose should be reduced in patients with moderate kidney impairment. Kidney and liver function tests should be monitored during treatment.

Caution is advised when bosutinib is given with CYP3A inhibitors.

Avoid bosutinib in patients with BCR::ABL1 F317L, G250E, T315I, and V299L. (See 'Other kinase domain mutations' above.)

Bosutinib is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of CML-BP in adults with resistance or intolerance to prior therapy.

●Toxicity – Most AEs of bosutinib are mild and self-limited. Diarrhea is very common if patients are initiated on full doses. If time is available, a lower dose should be started, and then the dose can be escalated over two to three weeks to the full dose.

●Outcomes – Treatment with bosutinib in 36 patients who previously received only imatinib included a 50 percent major cytogenetic response (MCyR), 37 percent complete cytogenetic response (CCyR) (table 2), and 28 percent overall survival (OS) after a 48-month median follow-up [50]. For patients previously treated with imatinib followed by dasatinib or nilotinib, bosutinib treatment in 28 patients was associated with a 21 percent MCyR, 17 percent CCyR, and 17 percent OS after a 48-month follow-up.

Additional details of bosutinib administration, toxicity, and outcomes are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Bosutinib'.)

Dasatinib — Dasatinib is a 2G TKI associated with cytopenias, pleural effusions, fluid retention, QT prolongation, platelet dysfunction, and bleeding. We avoid dasatinib in patients with a bleeding history, pleural effusion, and heart failure, when possible, and it should not be given to patients with hypokalemia, hypomagnesemia, or who have or may develop prolongation of the QTc interval (table 3).

●Administration – Dasatinib 140 mg once daily is used for BP.

Dose adjustment may be needed when dasatinib is used concurrently with CYP3A4 inhibitors and inducers. The drug is best absorbed in an acid milieu, so proton-pump inhibitors should be avoided.

Avoid the use of dasatinib in patients with BCR::ABL1 F317L/V/I/C, T315I/A, and V299L. (See 'Other kinase domain mutations' above.)

Dasatinib is approved by the FDA and EMA for the treatment of BP in adults with resistance or intolerance to prior therapy.

●Toxicity – Dasatinib can cause cytopenias, bleeding, fluid retention, cardiovascular toxicity (including prolongation of the QT interval), pulmonary arterial hypertension, Stevens-Johnson syndrome, and embryo-fetal toxicity.

●Outcomes

•Treatment with dasatinib 140 mg daily in 61 patients with lymphoid BP (LBP) was associated with an 18 percent complete hematologic remission (CHR), 43 percent MCyR, 34 percent CCyR, and 21 percent OS with a 24-month median follow-up [14]. The treatment of 149 patients with myeloid BP (MBP) was associated with a 17 percent CHR, 26 percent MCyR, 17 percent CCyR, and 24 percent OS with a 24-month median follow-up.

•Treatment with dasatinib 70 mg twice daily (total 140 mg daily) in 48 patients with LBP was associated with a 26 percent CHR, 43 percent CCyR, and five-month median OS [51,52]. The treatment of 109 patients with MBP was associated with a 26 percent CHR, 43 percent CCyR, and 12-month median survival.

Additional details of dasatinib administration, toxicity, and outcomes are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Dasatinib'.)

Nilotinib — Nilotinib is a 2G TKI that must be taken twice daily without food. Nilotinib is associated with cytopenias, hepatotoxicity, QT prolongation, pancreatitis, and long-term cardiovascular complications (table 3).

●Administration – Nilotinib 400 mg twice daily (approximately 12 hours apart) by mouth is used for treatment of advanced-phase CML. Food should be avoided for ≥2 hours before and ≥1 hour after treatment. Food increases the bioavailability, and excessive blood levels may occur.

The dose should be adjusted for patients with prolonged QT interval. Drugs that prolong the QT interval and strong CYP3A4 inhibitors should be avoided.

Avoid nilotinib in patients with BCR::ABL1 E255K/V, F317L/V/I/C, T315I, and Y253H. (See 'Other kinase domain mutations' above.)

Nilotinib is not approved by the FDA or EMA for the treatment of CML-BP.

●Toxicity – Most AEs are mild and self-limited, but pancreatitis and rare sudden deaths have been reported. Later effects include cardiac, cerebral, and peripheral artery disease; liver disease; and hyperglycemia.

●Outcomes

•Treatment with nilotinib 400 mg twice daily in 31 patients with LBP was associated with a 59 percent major hematologic response (MHR), 52 percent MCyR, 32 percent CCyR, and 10 percent OS after a 24-month median follow-up [53]. The treatment of 105 patients with MBP was associated with a 60 percent MHR, 38 percent MCyR, 30 percent CCyR, and 32 percent OS after a 24-month median follow-up.

•In 137 patients with CML accelerated phase (AP), nilotinib was associated with a 31 percent CHR, 32 percent MCyR, 70 percent two-year OS, and 33 percent two-year progression-free survival (PFS) [54].

Ponatinib — Ponatinib is a third-generation (3G) TKI that is effective against BCR::ABL1 T315I and when no other TKI is indicated. (See 'BCR::ABL1 T315I' above.)

Ponatinib is associated with potentially fatal arterial occlusive events, venous thromboembolism, heart failure, and hepatoxicity (table 3).

●Administration – Treatment should begin with ponatinib 45 mg orally once daily by mouth, with or without food.

The dose may be adjusted as the patient responds to therapy, using the lowest dose that prevents disease progression. Ponatinib 15 mg daily was reported to successfully maintain remission in a patient with BP [55] and in patients with chronic phase (CP) [56].

Some clinicians treat patients receiving ponatinib with low-dose aspirin, especially in those with a history of thromboembolic events.

Ponatinib is approved by the FDA and EMA for adults with BCR::ABL1 T315I and in patients for whom no other TKIs are indicated.

●Toxicity – Ponatinib has a boxed warning regarding the risk of vascular occlusion, heart failure, and liver toxicity. Additional AEs include hypertension, pancreatitis, neuropathy, ocular AEs, hemorrhage, fluid retention, heart arrhythmias, myelosuppression, impaired wound healing, gastrointestinal perforation, and rare cases of reversible posterior leukoencephalopathy syndrome.

●Outcomes – The phase 2 PACE study of ponatinib included 62 patients with MBP or LBP [57]. Treatment was associated with an 84 percent one-year OS, 55 percent one-year PFS, 31 percent MHR, 23 percent MCyR, and 18 percent CCyR. Serious cardiovascular, cerebrovascular, and peripheral vascular events occurred in 7, 4, and 5 percent of patients, respectively. Most patients with vascular events had at least one vascular risk factor (eg, hypertension, diabetes, hypercholesterolemia, obesity) and, of patients who continued ponatinib after a vascular event, 36 percent had subsequent events. AEs led to the discontinuation of therapy in 11 percent of patients. One death was thought to be related to ponatinib-related gastric hemorrhage.

Additional details of administration, toxicity, and outcomes with ponatinib for CML are presented separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor", section on 'Ponatinib' and "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment", section on 'Ponatinib'.)

Asciminib — Asciminib is an allosteric inhibitor that targets the ABL myristoyl pocket of BCR::ABL1 (rather than the adenosine triphosphate [ATP] binding that is bound by other TKIs).

Asciminib is effective against BCR::ABL1 T315I at high doses, but it has little track record in the treatment of BP.

●Administration – For patients with T315I mutation, asciminib 200 mg is taken by mouth twice daily.

Asciminib is an inhibitor of CYP2C9, and it increases the plasma concentration of other drugs that are CYP2C9 substrates.

Asciminib is contraindicated for patients with BCR::ABL1 A337T, F359V/I/C, and P465S. (See 'Other kinase domain mutations' above.)

Asciminib is approved by the FDA and EMA for adults with CP with resistance or intolerance to ≥2 prior TKIs or with T315I.

●Toxicity – Asciminib can cause myelosuppression, pancreatitis, cardiovascular toxicity, and hypertension.

●Outcomes – There are no reports of asciminib for the treatment of BP. Studies of asciminib for the treatment of CML-CP with BCR::ABL1 T315I or patients with resistance/intolerance to 2G TKIs [58,59] are discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

CENTRAL NERVOUS SYSTEM INVOLVEMENT — 

Involvement of the central nervous system (CNS) by CML-BP has been described in case reports [60-65].

Dasatinib [66], bosutinib [67], nilotinib [68], and ponatinib [69] can cross the blood-brain barrier, but there are limited clinical data to guide the choice of a tyrosine kinase inhibitor (TKI) for the treatment of CNS involvement. The choice of a TKI is guided by mutation analysis, comorbidities, and prior therapy, as discussed above. (See 'Tyrosine kinase inhibitor selection' above.)

Other aspects of management, such as intrathecal chemotherapy and/or high-dose methotrexate, are the same as the treatment of CNS involvement by acute lymphoblastic leukemia or acute myeloid leukemia. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'Central nervous system involvement' and "Acute myeloid leukemia: Involvement of the central nervous system".)

RELAPSED/REFRACTORY BP — 

Relapsed/refractory CML-BP carries a very unfavorable prognosis. We strongly encourage participation in a clinical trial when possible.

BCR::ABL1 kinase domain testing should be repeated, with the choice of a tyrosine kinase inhibitor guided by mutation analysis. (See 'Tyrosine kinase inhibitor selection' above.)

Management must be individualized according to medical fitness, prior treatments, and patient preferences.

Options include:

●For patients who previously underwent allogeneic hematopoietic cell transplantation (HCT), donor lymphocyte infusion (DLI) can achieve remission in patients with relapsed BP, but it is associated with graft-versus-host disease, infections, and immunosuppression. Efficacy of DLI for relapsed BP is less than with earlier phases of CML. In some instances, a second HCT may be considered [70].

●For patients who were not previously transplanted, allogeneic HCT may be considered, based on age and fitness.

●Immunotherapy or chemotherapy, as used for relapsed/refractory acute lymphoblastic leukemia or acute myeloid leukemia, may provide transient disease control. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults" and "Treatment of relapsed or refractory acute myeloid leukemia".)

●Palliative treatments and supportive care are appropriate for most patients with relapsed/refractory CML-BP.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic myeloid leukemia".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Chronic myeloid leukemia (CML) in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with t(9;22)(q34;q11) and BCR::ABL1. Most patients present with relatively indolent chronic phase (CP) CML, but some patients present with advanced disease.

Blast phase (BP) is an aggressive phase of CML that presents with features of acute leukemia. Most cases arise in patients with a prior diagnosis of CML (transformed BP), but occasional patients present de novo with CML-BP. Two-thirds of BP cases have predominantly myeloid blasts, while one-third have predominantly lymphoid blasts.

●Presentation – Constitutional symptoms, progressive splenomegaly, extramedullary mass, cytopenias, and other findings of acute leukemia. (See 'Clinical presentation' above.)

●Diagnosis – BP should be suspected in patients with CML and progressive splenomegaly, constitutional symptoms, or circulating blasts. It may also be suspected in patients with a similar presentation who have t(9;22). (See 'Diagnosis' above.)

•CML-BP is diagnosed with t(9;22) and ≥20 percent blasts in blood or bone marrow, extramedullary collections of blasts, or increased lymphoblasts in blood/bone marrow. (See 'Diagnostic criteria' above.)

•BP must be distinguished from other phases of CML and from acute leukemias. (See 'Differential diagnosis' above.)

•The lineage of blasts is determined by flow cytometry. (See 'Determine blast lineage' above.)

●Tyrosine kinase inhibitor (TKI) selection – Selection of a TKI is guided by kinase domain (KD) mutation status (see 'Tyrosine kinase inhibitor selection' above):

•T315I – We suggest ponatinib (Grade 2B). (See 'BCR::ABL1 T315I' above.)

•Other mutations – For patients who do not have T315I mutation, we select a TKI based on BCR::ABL1 KD mutation(s), toxicity, and comorbidities; if applicable, the TKI that was taken when BP emerged is contraindicated. Sensitivity of specific mutations to individual TKIs is presented above. (See 'Other kinase domain mutations' above.)

The TKI is combined with myeloid or lymphoid induction therapy, according to the blast immunophenotype.

●Myeloid BP

•Myeloid BP remission induction – For myeloid BP, we suggest a TKI plus induction chemotherapy, rather than a TKI alone or induction chemotherapy alone (algorithm 1) (Grade 2C). The preferred induction chemotherapy regimen varies among experts, as discussed above. (See 'Myeloid BP' above.)

•Myeloid BP post-remission – Based on medical fitness (algorithm 1):

-Transplant eligible – We suggest allogeneic hematopoietic cell transplantation (HCT) rather than a TKI plus consolidation chemotherapy (Grade 2C). (See 'Transplant eligible' above.)

-Less fit – We suggest a TKI plus consolidation chemotherapy, followed by TKI maintenance therapy (Grade 2C). (See 'Myeloid BP' above.)

●Lymphoid BP

•Lymphoid BP remission induction – For lymphoid BP, we suggest a TKI plus either induction chemotherapy or immunotherapy (algorithm 1) (Grade 2C). The preferred induction regimen varies among experts, as discussed above. (See 'Lymphoid BP' above.)

•Lymphoid BP post-remission – Based on medical fitness (algorithm 1):

-Transplant eligible – We suggest allogeneic HCT rather than a TKI plus consolidation chemotherapy (Grade 2C). (See 'Transplant eligible' above.)

-Less fit – We suggest a TKI plus consolidation chemotherapy, followed by TKI maintenance therapy (Grade 2C). (See 'Lymphoid BP' above.)

●Response assessment – Monitor hematologic and molecular status, and adverse effects, and perform a bone marrow examination after four weeks of treatment. Other aspects of monitoring are discussed above. (See 'Response assessment' above.)

●Treatments – Treatment with TKIs is discussed above. (See 'Treatments' above.)

●Refractory disease – Options include a clinical trial, change of TKI based on mutation(s), HCT, donor lymphocyte infusion (for patients post-HCT), lineage-guided salvage palliative chemotherapy, and palliative treatments. (See 'Relapsed/refractory BP' above.)