Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults

INTRODUCTION — Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is a biologically and clinically distinct entity classified as ALL with t(9;22)(q34;q11.2);BCR-ABL1 in the World Health Organization (WHO) classification system (table 1) [1,2]. Expression of the BCR-ABL1 tyrosine kinase distinguishes Ph+ ALL from other types of ALL and renders this leukemia vulnerable to treatment with a BCR-ABL1 tyrosine kinase inhibitor (TKI), which is an essential component of treatment. Remission induction therapy is designed to reduce the initial leukemic burden and achieve a hematologic complete remission and a robust molecular response. This phase of treatment must be followed by post-remission therapy to enable long-term disease control and possible cure.

This topic will discuss remission induction therapy for Ph+ ALL in adults.

The following subjects are presented separately:

●Post-remission management of Ph+ ALL in adults. (See "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

●Treatment of ALL in children. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

OVERVIEW OF TREATMENT OF Ph+ ALL — Patients with Ph+ ALL should be referred to a specialty center for care or must be treated by a clinician who has the necessary experience and resources to treat with strict adherence to a contemporary published protocol. Once a treatment regimen is selected, it is important to adhere to the published protocol, rather than selecting components from different treatment protocols.

Broadly speaking, management of Ph+ ALL comprises the following phases of treatment (table 2):

●Remission induction therapy – Remission induction therapy reduces the initial leukemic burden with the goals of achieving a hematologic complete remission (CR) and a robust molecular response. Induction regimens vary in intensity and toxicity, so these goals are appropriate for patients of any age and/or fitness level. Achieving a CR reduces disease-associated symptoms, prolongs survival, and, when coupled with effective post-remission management, enables long-term disease control and possible cure.

The essential components of remission induction therapy for Ph+ ALL are discussed below. (See 'Essential components' below.)

●Post-remission management – Post-remission management is designed to eliminate leukemic cells that remain after achievement of CR. Ph+ ALL inevitably recurs unless remission induction therapy is followed by effective post-remission management.

Post-remission management of Ph+ ALL generally includes consolidation therapy (intensive treatment that follows soon after achieving CR) and maintenance therapy (prolonged treatment with a tyrosine kinase inhibitor [TKI], with or without lower-intensity chemotherapy), as discussed separately. (See "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

PRIOR TO TREATMENT — Prior to treatment, the patient should be evaluated for comorbid illnesses, neurologic findings, and critical cytopenias. The presence of BCR-ABL1 should be confirmed, medical fitness assessed, and a central venous catheter placed. Medical complications (eg, infections, hemorrhage) should be stabilized before beginning induction therapy.

Clinical/laboratory evaluation

●Clinical:

•Complications and consequences of leukemia – The patient should be evaluated for complications and consequences of anemia (eg, dyspnea, weakness), neutropenia (eg, infections), and thrombocytopenia (eg, bleeding, bruising).

•Comorbid conditions – Clinical manifestations of comorbid illnesses, including heart disease, pulmonary processes, and renal impairment should be evaluated, as they may influence the choice of induction therapy. (See 'Special populations' below.)

•Neurologic evaluation – Patients with headaches, visual changes, weakness, or other neurologic symptoms or signs (eg, cranial neuropathies, motor or sensory changes, ataxia) should undergo imaging and lumbar puncture (LP) to determine if the findings are related to leukemic involvement of the central nervous system (CNS). (See 'CNS evaluation' below.)

Note that if an LP is not performed as part of the pretreatment evaluation, a therapeutic LP to administer prophylactic intrathecal chemotherapy should coincide with the start of remission induction therapy, as described below. (See 'CNS prophylaxis' below.)

•Leukostasis – Patients with pulmonary, neurologic, or cardiac findings in the setting of hyperleukocytosis (eg, white blood cell count >200,000/microL) should be assessed for leukostasis and managed as discussed separately. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

●Laboratory:

•Complete blood count with differential, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, D-dimer.

•Serum chemistries, including electrolytes, glucose, renal and liver function tests, lactate dehydrogenase (LDH), calcium, phosphorus, uric acid, albumin and total protein.

•Serology for hepatitis B and C, herpes simplex virus (HSV), and cytomegalovirus (CMV) infection.

•Human leukocyte antigen (HLA) typing should be performed for patients who are candidates for future hematopoietic cell transplantation (HCT).

•Pregnancy test for women of child-bearing age.

●Imaging:

•Cardiac function – Baseline study of ejection fraction by echocardiogram or radionuclide ventriculogram. Management of patients with limited cardiac function (eg, ejection fraction <40 percent, significant dysrhythmias) is discussed below. (See 'Limited cardiac function' below.)

•Neurologic imaging – As mentioned above, patients with neurologic findings should undergo imaging and LP to determine if they are related to leukemic involvement of the CNS. (See 'CNS evaluation' below.)

•Other imaging should be performed as warranted to investigate infections or other consequences of the leukemia or comorbid conditions.

Pathology — Prior to initiating therapy, cytogenetic and molecular testing should be performed to distinguish Ph+ ALL from other conditions and confirm detection of BCR-ABL1 to establish a baseline for monitoring measurable residual disease (MRD).

●A bone marrow examination, including histologic evaluation by an experienced hematopathologist, cytogenetics, immunophenotype, and molecular analysis for BCR-ABL1 should have been performed at the time of diagnosis to exclude Philadelphia chromosome negative ALL, chronic myeloid leukemia (CML) in lymphoid blast phase, and other conditions in the differential diagnosis. If results are not available, bone marrow examination should be performed prior to initiating treatment. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Differential diagnosis'.)

●Real-time quantitative PCR (RQ-PCR) for BCR-ABL1 transcript should be performed to establish a baseline value for monitoring MRD.

●Mutation analysis of BCR-ABL1 is not routinely performed at the time of initiation of induction therapy.

Medical fitness — Prior to initiating therapy, we assess medical fitness based on performance status, comorbid conditions, and physiologic fitness. Importantly, age, per se, does not determine the level of fitness.

When considering comorbidities, chronic conditions should be weighted more heavily than temporary conditions caused by complications of the leukemia (eg, infection, heart failure exacerbated by anemia), which may improve with effective induction therapy and can enhance tolerance for subsequent therapy.

●Instruments for assessing fitness – We use the following tools to assess medical fitness:

•Eastern Cooperative Oncology Group (ECOG) performance status (PS) (table 3).

•Physiologic fitness (eg, comorbid conditions, activities of daily living, physical performance tests, cognition), as measured by the Charlson comorbidity index (CCI) (table 4).

●Classification of medical fitness – Following are our suggestions for classifying medical fitness:

•Medically-fit: Both ECOG PS 0 to 2 and CCI 0 to 2

•Medically-unfit, but not frail: Either ECOG PS ≥3 or CCI ≥3

•Frail: Both ECOG: ≥3 and CCI ≥3

There are no clear distinctions between these categories, and some measures of PS or physiologic fitness can apply to different categories of fitness. In selecting a category of fitness, we seek to protect frail patients from treatment that they are unlikely to survive, while not depriving others of the opportunity to achieve remission and prolonged survival.

Timing of treatment — It is important to control complications of the leukemia and stabilize the patient's medical condition before starting remission induction therapy. Several days may be needed to obtain results from cytogenetic and/or molecular studies to confirm the diagnosis of Ph+ ALL and exclude other conditions in the differential diagnosis, as discussed above. (See 'Pathology' above.)

While awaiting pathologic confirmation of the diagnosis of Ph+ ALL, we manage infections, bleeding, hyperuricemia, dehydration, renal dysfunction, anemia, thrombocytopenia, and other complications. We generally begin hydration and allopurinol to lessen the risk of hyperuricemia and its complications. If there is extreme leukocytosis (eg, >50,000 white blood cells/microL), we treat with stepwise increases of a glucocorticoid (eg, beginning with prednisone 25 mg daily) prior to initiation of induction therapy. Some centers routinely administer a glucocorticoid for three days and monitor for tumor lysis syndrome while awaiting confirmation of the diagnosis of Ph+ ALL, but a role for such prephase treatment of ALL in adults has not been firmly established.

Pretreatment management — Pretreatment management should include the following:

●Central venous access device should be inserted.

●Referral to a transplantation team to assess eligibility for HCT and initiate a search for a family or alternate donor.

●Fertility counseling and preservation.

REMISSION INDUCTION THERAPY — The patient with Ph+ ALL should either be referred to a specialty center for care or must be treated by a clinician who has the necessary experience and resources to treat with strict adherence to a contemporary published protocol. Once a treatment regimen is selected, it is important to adhere to the published protocol, rather than selecting components from different treatment protocols. We encourage participation in a clinical trial whenever possible.

Essential components — There is consensus that all remission induction regimens for Ph+ ALL must include:

●BCR-ABL1 tyrosine kinase inhibitor (TKI). (See 'A TKI is required' below.)

plus

●A glucocorticoid or chemotherapy. (See 'A TKI alone is not sufficient' below.)

In addition, all induction regimens must include central nervous system (CNS) management that is determined by the chosen induction regimen. (See 'CNS management' below.)

Evidence for the roles of the various components of remission induction therapy is discussed in the sections that follow.

TKI

A TKI is required — For remission induction therapy of Ph+ ALL, we recommend a regimen that includes a TKI rather than a regimen that does not include a TKI, based on superior response rates and long-term outcomes with little incremental toxicity when a TKI is included.

No randomized trials have directly compared specific remission induction regimens with or without a TKI. However, inclusion of a TKI in induction therapy is associated with markedly superior outcomes and little incremental toxicity, based on numerous prospective and retrospective studies [3-17]. Compared with historical controls treated with chemotherapy alone [18,19], adding a TKI is associated with higher rates of complete remission (CR; eg >90 percent versus 60 to 70 percent), superior long-term overall survival (OS; approximately 50 percent versus ≤20 percent), and a greater likelihood of proceeding to hematopoietic cell transplantation (HCT) [3,20-24].

Importantly, a TKI is an essential component of induction therapy for Ph+ ALL, but it alone is not sufficient. Because a TKI alone does not provide a deep enough and/or sustained molecular response, it must be combined with either chemotherapy or a glucocorticoid, as described below. (See 'A TKI alone is not sufficient' below.)

Choice of TKI — No specific BCR-ABL1 TKI is optimal for all patients with Ph+ ALL. The choice of a TKI is informed by the toxicity profile, comorbid illnesses, ease of administration, availability, and cost. The TKIs have not been compared head-to-head in Ph+ ALL, and different induction regimens have not been specifically tested with each TKI.

We favor dasatinib because it has an established track record in prospective studies and may have some CNS penetration, it is effective against some BCR-ABL1 mutations that do not respond to imatinib, and it is generally well-tolerated. However, we consider it acceptable to treat with a different TKI for the following reasons:

●Contraindication – For patients with a pleural effusion, pulmonary hypertension, cardiac dysrhythmias, or qualitative platelet disorders, we generally treat with imatinib, nilotinib, or ponatinib.

●Not approved – The US Food and Drug Administration (FDA) has approved dasatinib for Ph+ ALL, but it is not approved in all countries. Imatinib, which is approved by the European Medicines Agency (EMA) for initial treatment of Ph+ ALL, is an acceptable alternative.

Individual TKIs have not been compared head-to-head in Ph+ ALL. A meta-analysis and a propensity-matched score analysis showed superiority of ponatinib-based regimens over regimens containing first- or second-generation TKIs, but ponatinib is associated with substantial cardiovascular toxicity, as described below [25,26]. (See 'Ponatinib' below.)

Treatment with a TKI should begin at the time of diagnosis and continue through remission induction and post-remission management, unless there is intolerance or evidence of disease resistance. Continuous exposure to a TKI is associated with superior outcomes, compared with pulsed or intermittent administration [5,18,20,27].

Adverse effects must be managed effectively to achieve optimal patient safety, comfort, and outcomes. All TKIs are associated with certain early adverse effects, which may include rash, nausea, muscle cramps, edema, diarrhea, or fatigue. Most of these early adverse effects are modest, self-limited, and can be managed with supportive measures. Management of the early adverse effects of TKIs are described separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Common early toxicities'.)

Dasatinib — Dasatinib is a multitargeted TKI that has been widely used for Ph+ ALL. Treatment is associated with cytopenias, pleural effusions/fluid retention, QTc prolongation, and bleeding. Dasatinib should be avoided in patients with a history of bleeding, pleural effusion, or heart failure.  

●Administration – Dasatinib is administered as 140 mg by mouth daily, with or without food; tablets should not be crushed or cut. Patients should be screened by electrocardiogram (EKG) for QTc interval at baseline, and hypokalemia or hypomagnesemia should be corrected before administration of dasatinib. No initial dose adjustment is required for patients with liver or kidney impairment. Caution is advised in patients who take other products that may lead to QTc prolongation (table 5) and strong CYP3A4 inducers or inhibitors (table 6).

●Adverse effects – Most adverse effects (AE) are mild and self-limited (table 7). However, patients may experience QTc prolongation, fluid retention (grade ≥3 AEs in approximately 4 percent), exacerbation of congestive heart failure, or significant bleeding. Severe and potentially fatal CNS and gastrointestinal hemorrhages have been reported in approximately 1 and 4 percent of patients, respectively; most bleeding events were associated with severe thrombocytopenia, anticoagulants, and/or inhibitors of platelet function.

●Outcomes – In combination with chemotherapy, dasatinib is generally associated with >90 percent CR. As an example, remission induction with dasatinib plus a glucocorticoid in 63 patients achieved 98 percent CR and 29 percent molecular complete remission (molCR) [28]. High rates of CR and robust molecular response have also been reported for dasatinib combined with low-intensity chemotherapy [12], high-intensity chemotherapy [29], and various chemotherapy regimens [12,15,30].

Dasatinib is active against many BCR-ABL1 kinase domain mutations that may be present at low levels at the time of diagnosis, but it is not active against the T315I mutation (against which only ponatinib is generally effective) [31,32].

Dasatinib is approved for treatment of Ph+ ALL by the US FDA. It is approved by the EMA for Ph+ ALL with resistance or intolerance to prior therapy, including imatinib.

Imatinib — Imatinib offers the most clinical experience and longest follow-up among the TKIs, it is available as a generic medication, and it is generally less expensive than other TKIs. Compared with second and third generation TKIs, the response to imatinib is generally not as fast or deep, and it is less effective against various BCR-ABL1 kinase domain mutations. Imatinib is associated with cytopenias and edema, and it causes substantial fluid retention in some patients; we generally avoid imatinib in patients with a history of significant fluid retention or nausea.

●Administration – Initial treatment is with imatinib 400 mg once daily with a meal and a large glass of water; tablets can also be dispersed in water or apple juice. The initial dose of imatinib should be adjusted for liver or renal impairment, and concurrent use of strong CYP3A4 inducers (table 6) should be avoided.

●Adverse effects – Most AEs are mild and self-limited (table 7). The most common AEs are cytopenias, edema, nausea, diarrhea, rash, and muscle cramps; grade ≥3 AEs are reported in ≤5 percent of patients.

●Outcomes – In a study of 80 patients, treatment with imatinib plus multiagent chemotherapy was associated with 96 percent CR, with approximately 70 percent of patients achieving molCR; one-year OS and event-free survival (EFS) were 76 and 60 percent, respectively [4]. Emergence of imatinib-resistant clones due to acquired mutations in BCR-ABL1 is common.

Imatinib is approved by the US FDA and EMA for treatment of adults with Ph+ ALL [33,34].

Ponatinib — Ponatinib is the only TKI that is effective against the BCR-ABL1 T315I mutation. Some experts favor ponatinib because of the frequent emergence of the T315I mutations during treatment with other TKIs, but ponatinib is associated with a substantial risk for cardiovascular complications.

●Administration – Ponatinib is administered initially at 30 mg orally once daily, with or without food; the dose may be reduced (eg, 15 mg) after achievement of CR, to lessen toxicity.

●Adverse effects – Ponatinib carries black box warnings for potentially fatal toxicities (cardiovascular, cerebrovascular, and peripheral vascular events) and hepatotoxicity/liver failure, which may be worse when combined with chemotherapy. Common adverse effects include myelosuppression, rash, dry skin, abdominal pain, and headache.

●Outcomes – A phase 2 study that treated 76 patients with ponatinib plus intensive hyper-CVAD chemotherapy reported 70 percent three-year EFS [35]. However, 2 of the first 37 patients treated with ponatinib 45 mg daily died with a myocardial infarction; the ponatinib dose was reduced to 30 mg daily (15 mg daily after achieving a complete molecular response) and there were no further cardiovascular deaths among 39 patients.

Treatment of 86 patients with ponatinib 30 mg daily achieved 74 percent three-month molCR, according to preliminary results reported in abstract form only [36]. With median follow-up of 44 months, 71 percent of patients remained in molCR and only three relapses occurred while on ponatinib. Five-year OS and EFS were 74 and 68 percent, respectively.

Ponatinib is approved by the US FDA for Ph+ ALL that is resistant or intolerant to prior TKI therapy [37]. It is approved by the EMA for Ph+ ALL with BCR-ABL1 T315I, resistance or intolerance to dasatinib, and for patients who are not candidates for imatinib [38].

Other TKIs — Other TKIs that are acceptable in selected settings include:

●Nilotinib – Nilotinib is an acceptable TKI for patients with a contraindication or intolerance to dasatinib (eg, pleural effusion, pulmonary hypertension, cardiac dysrhythmias) or imatinib (eg, substantial edema). Nilotinib is the only TKI that must be taken twice daily and without food. It is administered 300 mg twice daily with water; patients should avoid food ≥2 hours before and ≥1 hour after taking each dose. Patients should be screened by EKG for QTc interval at baseline, and potassium and magnesium levels should be corrected. It should be used with caution when administered with other medications that can prolong QTc interval (table 5). Nilotinib is associated with cytopenias, hepatotoxicity, QTc prolongation, pancreatitis, and long-term cardiovascular complications.

Nilotinib plus chemotherapy has been associated with >90 percent CR [13,39]. In a multicenter study, treatment of 90 adults with nilotinib in combination with chemotherapy achieved 91 percent CR and 94 percent molCR; estimated two-year OS was 72 percent [13].

●Bosutinib – We do not routinely use bosutinib, because there is limited experience with its use for Ph+ ALL [40].

Additional details of TKI toxicity and management of adverse effects are provided separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Managing toxicity'.)

A TKI alone is not sufficient — As described above, a BCR-ABL1 TKI is an essential component of remission induction therapy for Ph+ ALL. However, a TKI alone is not sufficient and induction therapy must also include either chemotherapy or a glucocorticoid. Commonly used glucocorticoids include prednisone, dexamethasone, or methylprednisolone. There is no consensus regarding a preferred regimen, and choosing between a TKI plus chemotherapy versus a TKI plus a glucocorticoid is discussed below. (See 'Chemotherapy versus a glucocorticoid' below.)

Chemotherapy versus a glucocorticoid — For remission induction therapy of Ph+ ALL, we consider either a TKI plus a glucocorticoid or a TKI plus chemotherapy (which typically also includes a glucocorticoid) to be acceptable treatments. Both approaches routinely achieve excellent outcomes that enable the patient with Ph+ ALL to proceed to post-remission management, but they are associated with different toxicity profiles and may differ regarding the depth of molecular response. The choice of treatment is influenced by institutional approach, medical fitness, and patient preference.

The following should be considered when choosing a remission induction regimen for Ph+ ALL:

●Favor chemotherapy – Some experts favor a TKI plus chemotherapy because of the long experience with this approach and the potential to achieve a robust molecular response. Some studies reported that a deeper molecular response was associated with improved outcomes in patients treated with intensive chemotherapy, but this benefit may be offset by substantial morbidity and some early treatment-related deaths [41,42]. Furthermore, it is uncertain if the relationship between depth of molecular response and improved outcomes applies to patients who receive lower-intensity chemotherapy and/or subsequently undergo allogeneic HCT.

Adverse effects of chemotherapy vary according to the chosen chemotherapy regimen. The choice of a chemotherapy-containing regimen is influenced by the patient's medical fitness and preferences, as discussed below. (See 'Choice of chemotherapy regimen' below.)

●Favor glucocorticoid – Other experts favor a TKI plus a glucocorticoid because this can achieve high rates of CR with little toxicity [28], thereby enabling post-remission management with little morbidity and mortality.

Treatment with a TKI plus a glucocorticoid is suitable for patients of all levels of medical fitness, as discussed below. (See 'TKI plus a glucocorticoid' below.)

No randomized trials have compared outcomes with chemotherapy-containing regimens versus glucocorticoid-based regimens. Both approaches are associated with >95 percent CR and effectively enable the patient to proceed to post-remission management. Longer-term outcomes are difficult to compare because studies differ regarding the use of allogeneic HCT and other post-remission care. Outcomes with various regimens are discussed in the sections that follow.

TKI plus chemotherapy — As discussed above, there is no consensus regarding whether remission induction therapy of Ph+ ALL must include a TKI plus chemotherapy (which typically also includes a glucocorticoid) versus a TKI plus a glucocorticoid alone. (See 'Chemotherapy versus a glucocorticoid' above.)

Choice of chemotherapy regimen — For a chemotherapy-containing remission induction regimen for Ph+ ALL, we suggest a low-intensity or moderate-intensity chemotherapy regimen, rather than a high-intensity chemotherapy regimen. This suggestion is based on superior outcomes, less toxicity, and fewer treatment-related deaths in a trial in which patients were randomly assigned to low-intensity chemotherapy versus high-intensity chemotherapy [14].

●A phase 3 trial randomly assigned 268 adults with Ph+ ALL to either one cycle of imatinib plus low-intensity chemotherapy (vincristine) versus one cycle of a TKI plus high-intensity chemotherapy (hyper-CVAD; hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) [14]. All patients then received a cycle of infusional methotrexate and cytarabine, and those who achieved a major molecular response (MMolR; ie, 3-log response of BCR-ABL1) proceeded to allogeneic or autologous HCT.

Compared with hyper-CVAD, low-intensity therapy was associated with a higher rate of CR (98 versus 91 percent) and fewer early deaths (1 versus 7 percent) [14]. The rate of MMolR was similar in both arms (66 versus 64 percent), and there was no difference in five-year rates of EFS or OS (37 and 46 percent, respectively). There were fewer grade ≥3 adverse effects with low-intensity therapy, including neutropenia (6 versus 14 percent, respectively), thrombocytopenia (0 versus 3 percent), infectious events (37 versus 58 percent), and other toxicity (41 versus 46 percent).

●Other studies of a TKI plus low-intensity chemotherapy are consistent with these findings [20,21,27].

There is no consensus regarding the definition of low-, moderate-, and high-intensity chemotherapy regimens. Importantly, because many patients with Ph+ ALL are older and/or have significant comorbid conditions, even low-intensity regimens may be associated with significant adverse effects, as described below. (See 'Frail patients' below.)

Following are examples of chemotherapy-based regimens that have been combined with a TKI for Ph+ ALL:

Low-intensity — We consider low-intensity regimens to be those that include only a single nonmyelosuppressive chemotherapy agent (eg, vincristine) plus a glucocorticoid. These regimens are suitable for patients of any fitness level, but caution is warranted for patients who are frail or of advanced age, as vincristine can cause ileus or obstipation in older patients, especially if bedridden. The choice of a low-intensity protocol varies between institutions, but EWALL-PH-01 is an example of a low-intensity regimen:

●Dexamethasone (10 mg daily for five days), followed by dasatinib (100 mg by mouth daily), vincristine (2 mg intravenously [IV] days 1, 8, 15, 22), and dexamethasone 40 mg for two days [12]. For patients >70 years, the vincristine dose is reduced to 1 mg total and the dexamethasone dose is reduced to 20 mg daily for two days. Nonhematologic adverse events were primarily infections, edema, and peripheral neuropathy.

Treatment of 71 patients (median age 69 years) with EWALL-PH-01 was associated with 96 percent CR and 65 percent MMolR [12]. Rates of five-year OS and relapse-free survival (RFS) were 36 and 28 percent, respectively; only seven patients underwent allogeneic HCT. Among patients who ultimately relapsed, BCR-ABL1 T315I mutation was detected in three-quarters of those who were tested. Grade ≥3 adverse events included infections (37 percent) and other nonhematologic events (41 percent).

In the EWALL-PH-02 study, nilotinib (400 mg twice daily) was incorporated into the EWALL-PH-01 regimen; treatment was associated with 97 percent CR and 29 percent achieved molCR during the consolidation phase, according to preliminary findings reported in abstract form [39].

●Comparable outcomes were reported with similar low-intensity regimens [12,21,27,43].

Moderate-intensity — We consider most multiagent and/or anthracycline-containing regimens to be moderate-intensity chemotherapy. Such regimens are suitable for medically-fit patients and for selected patients who are medically-unfit, but not frail. (See 'Medical fitness' above.)

●CALGB 10701 – The CALGB 10701 regimen begins with a cycle of dasatinib plus dexamethasone, followed by systemic and intrathecal methotrexate, and for patients with >20 percent lymphoblasts in bone marrow, vincristine and daunorubicin. Preliminary results, reported in abstract form, reported 45 month median OS, 55 percent three-year OS, and 43 percent three-year disease-free survival (DFS) among 64 patients followed for median of four years [44].

●Mini-hyperCVD (a variant of hyper-CVAD [described below] that uses reduced doses of chemotherapy and does not include an anthracycline) [45] and other moderate-intensity regimens have reported similar outcomes [4,13,43,46,47].

High-intensity — High-intensity chemotherapy regimens are only suitable for medically-fit patients. Such regimens can achieve a robust molecular response, but they are associated with substantial treatment-related morbidity and possible mortality. As discussed above, we suggest treatment with low-intensity chemotherapy rather than high-intensity chemotherapy. (See 'Choice of chemotherapy regimen' above.)

Hyper-CVAD comprises eight 21-day cycles of hyperfractionated cyclophosphamide, MESNA, doxorubicin, vincristine, dexamethasone alternating with methotrexate, cytarabine, and leucovorin rescue along with a TKI (eg, ponatinib, dasatinib, or imatinib) [3,14,15,48]. Treatment of 76 patients (median age 47 years) with ponatinib plus hyper-CVAD was associated with 100 percent CR, 97 percent MMolR, 73 percent molCR, and 70 percent three-year EFS [35]. The most common grade ≥3 adverse events were infection (86 percent), increased transaminases (32 percent), increased bilirubin (17 percent), pancreatitis (17 percent), hypertension (16 percent), bleeding (13 percent), and rash (12 percent); six patients died while on study treatment, including three with infection, one from hemorrhage, and two from myocardial infarction.

TKI plus a glucocorticoid — Treatment with a TKI plus a glucocorticoid alone (ie, no systemic chemotherapy) is effective, well-tolerated, and suitable for patients with any level of medical fitness. As discussed above, there is no consensus regarding whether a TKI plus a glucocorticoid suffices as induction therapy for Ph+ ALL, or if it is necessary to add chemotherapy. (See 'Chemotherapy versus a glucocorticoid' above.)

●Administration – An example of such an induction regimen is two 28-day cycles of:

•Dexamethasone (10 mg/m²/day orally or IV on days 1 to 7)

plus

•Dasatinib 140 mg orally daily

Toxicity with this regimen is modest but may include fluid retention, hyperglycemia, hypertension, agitation, QTc prolongation, exacerbation of congestive heart failure, and bleeding or bruising.

Imatinib or another TKI is an acceptable alternative for patients with a contraindication to dasatinib (eg, bleeding history, pleural effusion, heart failure, QTc prolongation) or where dasatinib is not approved for initial treatment of Ph+ ALL. Some centers treat with prednisone, rather than dexamethasone.

A bone marrow examination should be performed after two treatment cycles to assess response and evaluate measurable residual disease (MRD).

●Outcomes – Remission induction with a TKI plus a glucocorticoid alone is associated with >95 percent CR, a high rate of proceeding to allogeneic HCT (for suitable patients), and modest toxicity, but relapses are common and BCR-ABL1 kinase domain mutations emerge frequently [9,28,44,49]. No randomized trials have directly compared a TKI plus glucocorticoid versus a TKI plus chemotherapy, but glucocorticoid-based regimens generally achieve similar outcomes with less toxicity. (See 'Chemotherapy versus a glucocorticoid' above.)

Studies that reported outcomes with a TKI plus glucocorticoid include:

•A phase 2 study of dasatinib plus a glucocorticoid achieved 98 percent CR and 29 percent molCR; consolidation therapy with blinatumomab followed, so this is a chemotherapy-free approach to treatment of Ph+ ALL [28]. Induction therapy consisted of prephase treatment with prednisone escalating to 60 mg/m² over 7 days, then continued to day 24, and tapered until day 31; dasatinib 140 mg once daily began on day 8 and continued for a total of 85 days; and intrathecal methotrexate was administered on days 14, 22, 43, 57, and 85. Induction therapy was completed by 61 of 63 patients; one patient withdrew with dasatinib-associated toxicity and one withdrew with pneumonia while in CR.

•In GIMEMA LAL-1205, treatment with dasatinib plus prednisone achieved 100 percent CR in 53 evaluable patients (median age 54 years; range 24 to 77 years) [49]. With >2-year follow-up, median OS was 31 months and 20 month OS was 69 percent. BCR-ABL1 T315I mutation was detected in 71 percent of 17 patients who later relapsed.

•Studies using a glucocorticoid plus other TKIs also reported >95 percent CR. Compared with imatinib, second and third generation TKIs are associated with deeper molecular remissions (eg, 46 percent with ponatinib, 18 percent with dasatinib, and 4 percent with imatinib), but ponatinib was associated with significant cardiovascular toxicity [9,44,49], as described above. (See 'Ponatinib' above.)

CNS MANAGEMENT — Central nervous system (CNS) management is an essential component of induction therapy, because all patients with Ph+ ALL are at risk for CNS involvement at the time of diagnosis or later relapse.

CNS evaluation — For patients with neurologic symptoms or signs, we perform the following:

●Computed tomography (CT) and/or magnetic resonance imaging (MRI) to evaluate leukemic meningitis, chloroma, or bleeding.

●Lumbar puncture (LP) – LP, including cell count, chemistries, and cytology for patients with neurologic findings. Generally, the first treatment with intrathecal (IT) chemotherapy is administered at the time of a diagnostic LP. (See 'CNS management' above.)

•CNS involvement is defined according to the presence of leukemic blasts in cerebrospinal fluid (CSF), as follows:

-CNS-1: No lymphoblasts in CSF, regardless of peripheral white blood cell (WBC) count

-CNS-2: <5 WBC/microL in CSF with lymphoblasts present

-CNS-3: ≥5 WBC/microL in CSF with lymphoblasts present

In cases where the LP was traumatic, if the CSF reveals ≥5 WBC/microL with lymphoblasts and there are leukemic cells in the peripheral blood, the ratio of WBC/red blood cell (RBC) should be compared between CSF and peripheral blood. If the WBC/RBC ratio in CSF is at least twice that of blood, the patient be should be classified as CNS-3; if not, the classification is CNS-2.

CNS treatment — If the history, physical examination, imaging, and/or LP indicate CNS involvement, treatment for leukemic meningitis should begin concurrently with induction therapy. The specific course of treatment for leukemic involvement is determined by the chosen remission induction protocol.

No specific treatment protocol has been proven to be superior for management of CNS-3 involvement. We generally treat with cranial irradiation plus IT chemotherapy. Typically, 1800 to 2400 cGy over 12 doses to the entire cranium (including the base of the brain, the back of the orbits, and the cervical spine to at least C2) plus ≥6 doses of IT methotrexate, until the CSF is clear of leukemic blasts. Some experts favor treatment with high-dose methotrexate (with or without high-dose cytarabine as in HyperCVAD, part B). However, specific protocols may call for different schedules or doses of IT chemotherapy, systemic chemotherapy, and/or cranial irradiation. (See "Treatment of leptomeningeal disease from solid tumors".)

CNS prophylaxis — For patients with Ph+ ALL and no evidence of CNS involvement by clinical, laboratory, and/or imaging evaluation, we recommend CNS prophylaxis during remission induction therapy, based on the reduced risk of CNS recurrence. The rate of CNS relapse in patients who receive tyrosine kinase inhibitor (TKI)-containing induction therapy is uncertain, but prior to the routine inclusion of a TKI, more than half of patients who did not receive prophylaxis ultimately developed CNS leukemia [50].

For patients who did not undergo LP during the pretreatment evaluation, the first prophylactic dose of IT chemotherapy should coincide with the start of induction therapy. Details of the agent, dose, and schedule of CNS prophylaxis (eg, IT methotrexate, a glucocorticoid, and/or systemic cytarabine) are determined by the remission induction protocol. (See 'CNS management' above.)

MONITORING AND RESPONSE ASSESSMENT

Monitoring during induction therapy — Patients undergoing induction therapy require daily clinical and laboratory evaluation to manage cytopenias, metabolic disturbances, and evaluation for complications of leukemia.

Most patients require hospitalization with blood product support during remission induction therapy. Occasionally, selected patients may be treated as outpatients. Daily laboratory testing should include a complete blood count and chemistries with renal function, glucose, and electrolytes. Calcium, phosphorus, and uric acid levels should be monitored until normal, and liver function tests should be assessed at least weekly.

Supportive care is a critical component of induction therapy, including management of cytopenias, infections, tumor lysis, and other complications that accompany the treatment of acute leukemia. These are discussed in more detail separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

Response assessment — The primary goal of induction therapy is achievement of an initial hematologic complete remission (CR). Subsequent management is determined by whether the patient has achieved CR versus a lesser response (ie, refractory disease).

A bone marrow examination is typically performed when the absolute neutrophil count is >1000/microL and platelet count is >100,000/microL following induction therapy. A core biopsy is required to accurately assess marrow cellularity.

●Microscopy – Hematologic CR is defined as <5 percent blasts in the bone marrow and blood and restoration of normal hematopoiesis (>25 percent cellularity and normal peripheral blood counts).

●Cytogenetics – The bone marrow and/or peripheral blood should be examined for persistence of the Philadelphia chromosome by chromosomal banding or fluorescence in situ hybridization (FISH) to document the extent of complete cytogenetic remission (CCyR). The importance of achieving a CCyR was shown in the International ALL trial, which included both Ph+ ALL and Ph-negative ALL; compared with patients who did not achieve CCyR, overall survival (OS) was superior for patients who achieved CCyR (45 versus 5 percent, respectively) [51].

●Measurable residual disease (MRD) – MRD is assessed by real-time quantitative polymerase chain reaction (RQ-PCR) for BCR-ABL1. MRD for Ph+ ALL is discussed separately. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in adults'.)

Subsequent management is determined by the response to induction therapy:

●Complete remission – For patients who achieve CR, post-remission management includes a tyrosine kinase inhibitor (TKI) plus consolidation therapy (eg, immunotherapy, chemotherapy, and/or hematopoietic cell transplantation) followed by maintenance therapy, as described separately. (See "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

●Molecular remission – Complete morphological remission plus undetectable BCR-ABL1 by quantitative reverse transcriptase polymerase chain reaction (RT-PCR).

●Refractory disease – Patients who do not achieve a CR with induction therapy are considered to have refractory disease. Management of refractory disease is discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)

SPECIAL POPULATIONS

Frail patients — Medical frailty is assessed as described above. (See 'Medical fitness' above.)

For frail patients with Ph+ ALL, we generally treat with a BCR-ABL1 tyrosine kinase inhibitor (TKI) plus either a glucocorticoid or low-intensity chemotherapy. There is no consensus regarding a preferred treatment for frail patients. The choice of treatment is influenced by comorbid conditions, convenience, and patient preference. Both approaches have a high probability of achieving a hematologic complete remission (CR), improving symptoms, and prolonging survival, but no studies have directly compared approaches in this setting.

Both glucocorticoids and low-intensity chemotherapy are generally well-tolerated, but their toxicity profiles differ. High dose glucocorticoids can cause confusion, fluid overload, hyperglycemia, and may exacerbate diabetes and heart failure. Vincristine can cause ileus or obstipation in older patients, especially if bedridden.  

Regimens and outcomes are discussed above. (See 'TKI plus a glucocorticoid' above and 'Low-intensity' above.)

Limited cardiac function — We perform an electrocardiogram and either an echocardiogram or radionuclide ventriculogram to assess ejection fraction (EF) in all patients prior to treatment of Ph+ ALL. (See 'Clinical/laboratory evaluation' above.)

Considerations for choosing induction therapy for patients with limited cardiac function include:

●When possible, we avoid treatment with dasatinib, nilotinib, and ponatinib, because of the increased risk for cardiovascular and arterial thrombotic adverse effects. However, for patients with a T315I mutation, ponatinib is the only effective BCR-ABL1 TKI. Other considerations for the selection of a TKI for patients with limited cardiac function are discussed separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Other toxicity'.)

●We generally treat with a TKI plus either low-intensity chemotherapy or a glucocorticoid, although high dose glucocorticoids may exacerbate heart failure. For patients with EF <30 percent, we avoid doxorubicin, other anthracyclines, and mitoxantrone. Options for induction therapy are described above. (See 'TKI plus a glucocorticoid' above and 'Low-intensity' above.)

The use of anthracyclines in patients with cardiac disease is discussed in detail separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

●Induction therapy may require large amounts of intravenous fluids to avoid complications from tumor lysis syndrome and hyperuricemia, which may exacerbate heart failure.

Pregnancy — Management of Ph+ ALL in pregnancy is informed by the stage of pregnancy at the time of diagnosis:

●Early in pregnancy – If Ph+ ALL is detected during the first trimester or early second trimester, we generally advise termination of pregnancy followed by treatment of the leukemia because TKIs, high dose glucocorticoids, and chemotherapy are associated with an unacceptably high incidence of fetal abnormalities and/or fetal loss [52].

●Later in pregnancy – For patients diagnosed late in the second trimester or during the third trimester, it is sometimes possible to manage patients conservatively with leukapheresis, glucocorticoids, hydroxyurea, and/or transfusions, with induction of labor and delivery as soon as possible. However, the delay of adequate ALL treatment until delivery should be carefully considered as it may increase the risk to the mother.

Benefits from use later in pregnancy may be acceptable despite the risk; in the absence of sufficient information concerning risks and benefits, personal preferences of the involved couple, with input from a hematologist and an obstetrician expert in the detection of fetal abnormalities, may influence the final decision.

CLINICAL TRIALS — Remission induction therapy is evolving rapidly as new agents are being evaluated as frontline therapy. We strongly encourage participation in a clinical trial by referral to a specialized center. In the United States, available trials are listed at: www.clinicaltrials.gov.

Investigational approaches include immunotherapy-based regimens (eg, blinatumomab, inotuzumab ozogamicin) that are used for treatment of relapsed or refractory Ph+ ALL, but we suggest not using such approaches outside of the context of a clinical trial.

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: Acute lymphoblastic 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 education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is a biologically and clinically distinct malignancy that is classified as ALL with t(9;22)(q34;q11.2); BCR-ABL1 in the World Health Organization classification system [53].

●Prior to treatment – The following should be performed prior to initiating therapy:

•Clinical and laboratory evaluation to assess cytopenias, neurologic findings, and comorbid illnesses. Patients with neurologic findings should undergo imaging and lumbar puncture to assess possible leukemic involvement. (See 'Clinical/laboratory evaluation' above.)

•Cytogenetic and molecular testing to confirm the diagnosis of Ph+ ALL, and baseline quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL1 for monitoring measurable residual disease (MRD). (See 'Pathology' above.)

•Assessment of medical fitness, based on performance status and comorbid conditions. (See 'Medical fitness' above.)

•Insertion of a central venous access device, referral to a transplantation team to assess eligibility and initiate a search for a family or alternate donor, and fertility counseling and preservation, if appropriate.

●Remission induction therapy – Patients with Ph+ ALL should be referred to a specialty center or must be treated with strict adherence to a contemporary published protocol with which the clinician has the necessary experience and resources. Once a treatment regimen is selected, it is important to adhere to the published protocol, rather than selecting components from different treatment protocols. (See 'Overview of treatment of Ph+ ALL' above.)

●Essential components of remission induction therapy – All induction regimens for Ph+ ALL must include the following (see 'Essential components' above):

•A BCR-ABL1 tyrosine kinase inhibitor (TKI)

•Either a glucocorticoid or chemotherapy (which typically also includes a glucocorticoid)

•Central nervous system (CNS) prophylaxis or treatment of leukemic involvement, informed by findings from lumbar puncture and guided by the chosen protocol

●Inclusion of a TKI – For remission induction therapy of Ph+ ALL, we recommend a regimen that includes a TKI rather than a regimen that does not include a TKI (Grade 1B), based on superior response rates and long-term outcomes with little incremental toxicity when a TKI is included. (See 'A TKI is required' above.)

No specific BCR-ABL1 TKI is optimal for all patients with Ph+ ALL. The choice of a TKI is informed by the toxicity profile, comorbid illnesses, ease of administration, availability, and cost. (See 'Choice of TKI' above.)

●Is chemotherapy required? – Treatment with a TKI is not sufficient for remission induction therapy, but there is no consensus regarding whether the TKI should be accompanied by chemotherapy versus a glucocorticoid.

We consider either a TKI plus chemotherapy (which typically also includes a glucocorticoid) or a TKI plus a glucocorticoid alone to be acceptable for induction therapy. Both approaches routinely achieve excellent outcomes that enable the patient to proceed to post-remission management, but they are associated with different toxicity profiles and they may differ regarding the depth of molecular response. Further discussion of the choice of a chemotherapy-based versus a glucocorticoid-based regimen is presented above. (See 'Chemotherapy versus a glucocorticoid' above.)

●Chemotherapy-containing regimens – For a chemotherapy-containing induction regimen for Ph+ ALL, we suggest a low-intensity or moderate-intensity chemotherapy regimen, rather than a high-intensity chemotherapy regimen (Grade 2C), based on superior outcomes, less toxicity, and fewer treatment-related deaths in a trial in which patients were randomly assigned to low-intensity chemotherapy versus high-intensity chemotherapy [14]. (See 'Choice of chemotherapy regimen' above.)

●CNS management – Patients with Ph+ ALL are at risk for CNS involvement at the time of diagnosis or later relapse.

•Neurologic findings – Patients with neurologic complaints or abnormalities on physical examination should undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) and lumbar puncture. Interpretation of findings from the lumbar puncture is presented above. (See 'CNS evaluation' above.)

-Patients with evidence of leukemic involvement should be treated as defined by the chosen protocol. (See 'CNS treatment' above.)

-Patients with no evidence of CNS involvement should be treated as described below.

•No neurologic findings – For patients with Ph+ ALL and no evidence of CNS involvement by clinical, laboratory, and/or imaging evaluation, we recommend CNS prophylaxis during remission induction therapy (Grade 1C), based on the reduced risk of CNS recurrence. Details of the agent, dose, and schedule for prophylaxis are determined by the chosen remission induction protocol. (See 'CNS prophylaxis' above.)

The first prophylactic treatment should coincide with initiation of remission induction therapy. (See 'CNS prophylaxis' above.)