Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management

INTRODUCTION — Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by the t(9;22)(q34;q11.2);BCR::ABL1 rearrangement. Expression of the BCR::ABL1 tyrosine kinase renders this leukemia vulnerable to BCR::ABL1 tyrosine kinase inhibitors (TKIs).

TKI-based remission induction therapy achieves hematologic complete remission (CR) in >90 percent of adults with Ph+ ALL. Despite morphologic CR in blood and bone marrow, a subset of patients has measurable residual disease (MRD) that can be detected by highly sensitive molecular studies for BCR::ABL1. MRD is a useful prognostic factor, but virtually all patients, whether MRD positive or MRD negative, will relapse within months unless they receive TKI-based post-remission therapy.

The goal of post-remission therapy for Ph+ ALL is to enable long-term survival and possible cure by eradicating residual leukemia cells. Post-remission care is complex, intensive, and prolonged. To achieve optimal long-term outcomes, the treatment protocol that was chosen for remission induction therapy of Ph+ ALL should also guide post-remission management; remission induction and post-remission management from different protocols should not be mixed and matched. Post-remission management is informed by whether MRD is detectable and the level of medical fitness.

This topic discusses post-remission management of Ph+ ALL in adults.

Related topics include:

●(See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

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

EVALUATION — Post-remission management for Ph+ ALL requires the evaluation of medical fitness and assessment of BCR::ABL1 measurable residual disease (MRD).

Clinical features, evaluation, and diagnosis of Ph+ ALL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

Medical fitness — The patient's level of fitness should be re-evaluated prior to post-remission therapy because it may have changed since diagnosis. For some patients, medical fitness improves with the achievement of remission, while for others, fitness declines due to the complications of treatment or the underlying leukemia.

Medical fitness is assessed by clinical evaluation, laboratory studies, other testing, and performance status (table 1), as discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Medical fitness'.)

We request a consultation from transplantation specialists for all patients, except those who are frail. We do not consider age a barrier to obtaining transplantation consultation. Although age limits vary, some institutions may restrict allogeneic hematopoietic cell transplantation (HCT) for Ph+ ALL to patients ≤75 years. Transplant eligibility also requires no severe lung, heart, liver, or kidney disease; a suitable graft source; and adequate social support. Further details of eligibility for allogeneic HCT are presented separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Measurable residual disease testing — MRD is an important prognostic factor in Ph+ ALL, and it influences post-remission treatment decisions.

MRD should be assessed using standardized methodology. The preferred specimen for MRD testing is the first small volume (eg, ≤3 mL) pull of a bone marrow aspirate.

Important variables for MRD testing include:

●Timing – MRD should be assessed at presentation (using the initial diagnostic specimen) to establish a baseline value, repeated using the bone marrow specimen that documented complete remission (CR), and assessed again after initial consolidation therapy (ie, within 90 days of diagnosis) [1].

Post-remission management of Ph+ ALL is stratified according to the level of MRD after initial consolidation therapy, as described below. (See 'Repeat measurable residual disease testing' below.)

●Method – MRD assessment for Ph+ ALL generally uses next-generation sequencing (NGS) or real-time quantitative polymerase chain reaction (RQ-PCR) for BCR::ABL1. Multicolor flow cytometry can be used if these molecular techniques are not available, but it is less sensitive and specific than molecular techniques.

●Sensitivity – Sensitivity for the detection of MRD varies among methods. While flow cytometry can generally detect MRD at the level of 10^-4 (ie, 1 malignant cell among 10,000 nucleated cells), RQ-PCR and NGS are more sensitive.

●Threshold – We consider BCR::ABL1 ≤10^-4 (molecular response [MR] 4) to be MRD negative [1]. All the methods described above can achieve this level of sensitivity.

Prognosis in Ph+ ALL is associated with the level of MRD; each log level of increase in MRD is associated with a shorter time to subsequent hematologic relapse [1-3].

A meta-analysis reported that patients who were MRD positive prior to transplantation had higher rates of relapse than those who were MRD negative [4]. MRD testing after initial consolidation phase treatment was identified as the most prognostically relevant time for predicting relapse [2]. While MRD testing during remission induction can identify patients with a very favorable prognosis [5], testing after the patient has been exposed to all relevant chemotherapy agents is more likely to identify those with chemotherapy resistance.

OVERVIEW — More than 90 percent of adults with Ph+ ALL achieve hematologic complete remission (CR) with tyrosine kinase inhibitor (TKI)-based induction therapy. However, virtually all will relapse without post-remission management. Remission induction therapy of Ph+ ALL in adults is discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Despite hematologic CR, many patients with Ph+ ALL have measurable residual disease (MRD) that can be detected by sensitive molecular or immunophenotypic techniques. MRD is an important prognostic feature in Ph+ ALL, but whether MRD is detectable or not, virtually all patients with Ph+ ALL in hematologic CR will relapse unless they receive post-remission treatment.

Post-remission management of Ph+ ALL is complex, intensive, and prolonged, but it is associated with long-term survival/cure for many patients. No single treatment strategy has proven superior for all adults with Ph+ ALL, and details of management differ among research groups. However, adherence through all phases of treatment to the protocol that was chosen at diagnosis is associated with optimal outcomes for adults with Ph+ ALL; it is important to avoid a "mix-and-match" strategy that combines remission induction therapy with post-remission management from a different protocol.

Ph+ ALL management in the post-remission period is informed by medical fitness and the burden of residual disease, as assessed by MRD. Post-remission management includes some or all of the following:

●Consolidation phase – Consolidation therapy (also called intensification phase) begins soon after achieving CR. Details of therapy vary among protocols, but consolidation generally includes combinations of drugs that were used for the induction phase, including methotrexate, cytarabine, glucocorticoids, asparaginase, and others.

We initiate consolidation therapy soon after achieving CR and then repeat MRD testing after one or two cycles of consolidation therapy. The presence of MRD and its trajectory after achieving CR inform post-remission management. (See 'Repeat measurable residual disease testing' below.)

●Allogeneic HCT – Allogeneic hematopoietic cell transplantation (HCT) is the only approach that is proven to achieve long-term disease control/cure with Ph+ ALL, but it is associated with substantial toxicity. Allogeneic HCT is generally restricted to fit patients ≤75 years, but eligibility criteria vary among institutions.

The decision to pursue allogeneic HCT is discussed below. (See 'Transplant eligible' below.)

Important aspects of allogeneic HCT are discussed below. (See 'Allogeneic hematopoietic cell transplantation' below.)

●Maintenance phase – The maintenance phase refers to prolonged (generally years-long) treatment that includes a TKI, with or without low-intensity chemotherapy. The doses and schedules of drugs used for maintenance therapy, and the duration of maintenance therapy, are guided by the chosen protocol.

The maintenance phase for adults with Ph+ ALL is discussed below. (See 'Maintenance phase' below.)

●Other components of post-remission management

•MRD – Details of MRD testing are discussed above. (See 'Measurable residual disease testing' above.)

•TKI – TKI therapy continues through the entire course of treatment, as discussed below. (See 'Tyrosine kinase inhibitor' below.)

•CNS management – Central nervous system (CNS) prophylaxis continues through post-remission management of Ph+ ALL because patients remain at risk for CNS relapse, and a TKI alone is not sufficient to eliminate all infiltrating leukemia cells from the cerebrospinal fluid. Details of CNS prophylaxis vary among protocols, and the prophylaxis regimen should adhere to that used in the chosen protocol.

CNS management for adults with Ph+ ALL is discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'CNS management'.)

Our approach to the management of Ph+ ALL in adults is consistent with those of the European LeukemiaNet (ELN) and the United States National Cancer Center Network (NCCN) [1,6].

POST-REMISSION MANAGEMENT — The following sections address the management of adults with Ph+ ALL who achieved hematologic complete remission (CR) with remission induction therapy.

Remission induction therapy for Ph+ ALL in adults is discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Tyrosine kinase inhibitor — For Ph+ ALL, we recommend the inclusion of a tyrosine kinase inhibitor (TKI) through all phases of treatment based on improved outcomes and little toxicity.

In general, Ph+ ALL is treated using a second-generation TKI or a third-generation TKI, rather than imatinib because they provide faster, deeper responses and are more likely to be effective against various ABL1 kinase domain (KD) mutations. The TKI used for the induction therapy of Ph+ ALL is generally continued through the entire course of treatment unless it must be changed due to intolerable adverse effects (AEs) or emerging resistance. However, the TKI is often temporarily held during and immediately after allogeneic hematopoietic cell transplantation (HCT) and restarted when blood counts recover (eg, day 30 to 60); temporarily holding the TKI during allogeneic HCT may hasten hematopoietic engraftment, and it avoids drug-drug interactions with the numerous agents used in this period. Changing a TKI for emerging resistance is discussed below. (See 'Measurable residual disease unchanged or rising' below.)

No randomized trials have directly compared treatment with or without a TKI, but TKI-based treatment is associated with markedly superior outcomes, greater likelihood of proceeding to allogeneic HCT, and little incremental toxicity. Compared with chemotherapy alone, with which long-term survival was generally <20 percent, prospective and retrospective studies have demonstrated the benefit of including a TKI in various phases of treatment and with numerous treatment protocols [7-22].

Initial consolidation therapy — For adults with Ph+ ALL in CR after remission induction therapy, we suggest treatment with one or two cycles of consolidation therapy, followed by an assessment of measurable residual disease (MRD). This approach enables stratification of treatment according to MRD status, and it avoids the toxicity of allogeneic HCT in some patients.

The consolidation phase generally begins soon after blood counts recover from remission induction therapy. In some protocols, consolidation comprises a TKI plus immunotherapy (eg, blinatumomab), while other protocols treat with a TKI plus multiagent chemotherapy. Drug doses/schedules and the timing of MRD testing (ie, after one versus two cycles of consolidation) should adhere to the approach described in the chosen treatment protocol; the mixing and matching of induction therapy and consolidation therapy from different protocols has not been proven to be beneficial.

Less-fit patients who cannot tolerate consolidation therapy should proceed directly to maintenance phase, as discussed below. (See 'Maintenance phase' below.)

Repeat measurable residual disease testing — MRD is assessed after one or two cycles of consolidation, as specified in the chosen treatment protocol. (See 'Initial consolidation therapy' above.)

Post-remission management of Ph+ ALL is stratified according to the level of MRD after initial consolidation therapy.

Measurable residual disease positive — For patients with persistent MRD (ie, BCR::ABL1 >10^-4; molecular response [MR] ≤4), we assess the trajectory of MRD levels. We compare the MRD level after initial consolidation therapy with the level at the time of CR (ie, upon recovery from remission induction therapy) and at diagnosis. (See 'Measurable residual disease testing' above.)

Management is informed by the MRD trajectory, as described in the following sections.

Measurable residual disease declining — For a level of MRD that is lower after initial consolidation therapy compared with the time that CR was achieved, further treatment is guided by medical fitness.

The management of patients with stable or increasing MRD is discussed below. (See 'Measurable residual disease unchanged or rising' below.)

Transplant eligible — For transplant-eligible patients who are MRD positive, we suggest allogeneic HCT rather than other post-remission approaches. Allogeneic HCT is associated with superior long-term survival, but this must be weighed against transplant-related toxicity and some early treatment-related mortality (TRM). In the era of potent TKIs and immunotherapy, the advantage of allogeneic HCT in early first CR is controversial.

The decision to proceed to allogeneic HCT is individualized, with the consideration of age, fitness, institutional approach, and patient preference. Allogeneic HCT is generally restricted to medically fit patients ≤75 years, but eligibility criteria vary among institutions. The management for patients who are judged ineligible or decline transplantation is discussed below. (See 'Not transplant eligible' below.)

We continue consolidation therapy while awaiting the availability of the allogeneic graft, but there is no consensus for optimal timing of transplantation. If the level of MRD continues to decline, we generally continue consolidation therapy until the patient is MRD negative before transplantation rather than transplanting while the patient is MRD positive.

If the level of MRD plateaus or rises during consolidation therapy, we manage as described below. (See 'Measurable residual disease unchanged or rising' below.)

No randomized trials have directly compared allogeneic transplantation with other contemporary approaches, but allogeneic HCT is associated with better long-term outcomes than no-transplantation approaches. Allogeneic HCT is associated with long-term survival in more than two-thirds of patients overall, but outcomes vary with age, fitness, and transplantation technique [8,23-28]. Allogeneic transplantation was clearly superior before TKIs were widely available [25,29-31], but the benefit is less certain in the era of second-generation and third-generation TKIs. Some prior studies have used "genetic randomization," in which allogeneic HCT is offered to patients with a human leukocyte antigen (HLA)-matched donor, while those without an HLA-matched donor received either autologous HCT or chemotherapy. Although immunotherapy using blinatumomab is associated with robust molecular responses in patients with Ph+ ALL, follow-up is limited, and it is unclear if this will translate into long-term disease control.

The following studies compared allogeneic HCT with other post-remission management, but these studies did not stratify treatment according to MRD status.

●Allogeneic HCT versus autologous HCT or consolidation chemotherapy – Allogeneic HCT is associated with better long-term survival than autologous HCT or multiagent consolidation chemotherapy.

•In one study, 254 patients with Ph+ ALL in CR underwent allogeneic HCT if they had a matched donor and autologous HCT if no suitable donor was available [8]. Allogeneic HCT was performed in 161 patients (76 matched sibling donors [MSD], 72 matched unrelated donors [MUD], 13 umbilical cord blood), and autologous HCT was performed in 35 patients. Compared with autologous HCT, allogeneic HCT was associated with a better overall survival (OS; hazard ratio [HR] 0.64; 95% CI 0.44-0.93) and better relapse-free survival (RFS; HR 0.69; 95% CI 0.49-0.98) but more nonrelapse mortality (NRM; 26 versus 6 percent). However, subgroup analysis reported no difference in OS or RFS between treatment arms among patients who had a major molecular response (MMR; BCR::ABL1 <10^-3 [MR 3]) prior to transplantation.

•A prospective study (CALGB 10701) that used dasatinib plus dexamethasone induction therapy reported outcomes in 65 patients (a median age of 60 years) [32]. The five-year OS with reduced-intensity conditioning (RIC) HCT was 62 percent compared with a 57 percent five-year OS with autologous HCT and a 46 percent five-year OS with multiagent consolidation chemotherapy; relapse occurred in 25, 57, and 36 percent of patients, respectively. Among six patients who did not receive any of these approaches, only one remained alive and in remission at five years.

•In a retrospective single-institution study of 70 patients with Ph+ ALL, there was no difference in three-year OS after allogeneic HCT (76 percent) compared with a TKI plus chemotherapy consolidation therapy (71 percent) [33].

●Allogeneic HCT versus maintenance therapy – Survival is better after allogeneic HCT compared with maintenance therapy alone.

•Among 83 patients with Ph+ ALL (age 18 to 60 years) who achieved CR after remission induction therapy, 41 patients with a suitable graft donor underwent allogeneic HCT (plus indefinite dasatinib maintenance therapy), while others received two years of maintenance therapy with vincristine and prednisone plus indefinite dasatinib [34]. For the entire patient population, the three-year OS, event-free survival (EFS), and RFS were 69, 55, and 62 percent, respectively. At 12 months, transplanted patients had an 87 percent OS and 71 percent RFS. Landmark analysis at 175 days reported that OS and RFS were longer with transplantation than with maintenance therapy.

•In the phase 2 GRAAPH-2003 study of Ph+ ALL in adults (a median age of 45 years), allogeneic HCT was associated with better survival than maintenance therapy without transplantation [9,35]. Allogeneic HCT was performed in 24 patients in CR who had an available MSD graft, while 9 patients in CR without a donor received imatinib-based maintenance therapy. The four-year OS was superior with allogeneic HCT (76 versus 33 percent).

Graft donor and sources, conditioning regimens, and other aspects of allogeneic HCT are discussed below. (See 'Allogeneic hematopoietic cell transplantation' below.)

Maintenance therapy after allogeneic HCT is discussed below. (See 'Maintenance phase' below.)

Not transplant eligible — For MRD-positive patients who are not transplant eligible, we consider consolidation therapy with either a TKI plus blinatumomab (where available) or with a TKI plus multiagent chemotherapy acceptable.

For patients who are not medically fit for consolidation therapy, we proceed directly to maintenance therapy. (See 'Maintenance therapy regimens' below.)

No randomized trials have directly compared outcomes of consolidation therapy using a TKI plus immunotherapy versus a TKI plus multiagent chemotherapy.

●Blinatumomab – Long-term outcomes are not yet available for patients who received consolidation therapy with a TKI plus blinatumomab.

•Consolidation therapy with two to five cycles of blinatumomab was given to 63 patients after remission induction therapy with dexamethasone plus dasatinib [36]. At the end of remission induction therapy, 29 percent of patients were MRD negative, whereas 60 percent were MRD negative after the second cycle of blinatumomab. There were few grade ≥3 AEs; primarily neutropenia or cytomegalovirus (CMV) reactivation or infection. Blinatumomab cleared MRD in six patients who had increasing MRD during the induction phase in association with KD mutations. One-half of the patients enrolled in this study later proceeded to allogeneic HCT.

●Multiagent chemotherapy – Outcomes using multiagent consolidation chemotherapy vary among protocols, but no regimen has proven superior [37-42]. Outcomes of studies that compared a TKI plus multiagent chemotherapy versus allogeneic HCT are presented above. (See 'Transplant eligible' above.)

•A prospective study of 71 adults (a median age of 69 years, most of whom had high comorbidity scores) reported a 36 percent OS at five years in patients who received six months of consolidation therapy using dasatinib plus asparaginase, methotrexate, and cytarabine [10]. Prolonged RFS was associated with a favorable performance status and an achievement of a deep MR during consolidation.

•A Korean study of consolidation therapy using nilotinib plus multiagent chemotherapy reported a 72 percent two-year OS and RFS [11].

Prospective studies are evaluating inotuzumab ozogamicin for Ph+ ALL with CD22-positive blasts.

Monitoring disease status after consolidation therapy is discussed below. (See 'Surveillance' below.)

Maintenance therapy after consolidation therapy is discussed below. (See 'Maintenance phase' below.)

Measurable residual disease unchanged or rising — For MRD levels that rose between CR and after initial consolidation therapy, and for unchanged MRD levels, we perform BCR::ABL1 KD mutation analysis by next-generation sequencing (NGS) [43].

Further management is guided by the results of NGS testing:

●BCR::ABL1 KD mutation detected – The TKI should be changed if a KD mutation is found that is not sensitive to the current TKI. The selection of a TKI is guided by the specific KD mutation and comorbidities, as discussed separately. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Initial management'.)

We reassess MRD after two and four months of treatment with the new TKI.

•For MRD levels that decline within four months of treatment with a new TKI (including patients who convert to MRD negative), we manage as described above. (See 'Measurable residual disease declining' above.)

•For persistent or rising MRD, we manage as refractory disease. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)

●No actionable mutation detected – If no actionable KD mutation is identified in a patient with stable or rising MRD, we manage as refractory disease. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)

Measurable residual disease negative — For patients who are MRD negative after initial consolidation therapy, we consider it acceptable to complete consolidation therapy (per protocol) or to proceed to early allogeneic HCT or autologous HCT. Survival is similar with each of these approaches in MRD-negative patients, but HCT is associated with more short-term and long-term AEs.

Some experts favor allogeneic HCT for fit patients who have a suitable graft donor because it is the only proven cure for Ph+ ALL. RIC HCT is an option for older patients and those with comorbid conditions that might increase TRM; some experts offer autologous HCT in this setting based on similar survival in this setting. (See 'Autologous hematopoietic cell transplantation' below.)

Details of consolidation therapy (ie, a TKI plus either multiagent chemotherapy versus immunotherapy) are guided by the chosen protocol.

●There was no demonstrated survival advantage associated with allogeneic HCT in a retrospective multicenter study of adults with MRD-negative Ph+ ALL [44]. Among 230 patients who were MRD negative within 90 days of diagnosis, 98 underwent allogeneic HCT and 132 received consolidation therapy. There was no difference in OS or RFS, but HCT was associated more NRM (HR 2.59; 95% CI 1.37-4.89) and fewer relapses (HR 0.32; 95% CI 0.17-0.62).

●A prospective study reported similar outcomes with autologous HCT versus allogeneic HCT in patients who achieved MMR [8]. That study and others that compared autologous HCT versus allogeneic HCT are discussed above. (See 'Transplant eligible' above.)

●Approximately one-quarter of patients with Ph+ ALL who are MRD negative after consolidation therapy later relapse [27,45,46].

Repeat measurable residual disease testing after consolidation or hematopoietic cell transplantation — MRD testing is repeated soon after the completion of consolidation therapy and/or upon hematologic recovery from HCT.

Further post-remission management is guided by findings from this evaluation:

●MRD negative – Proceed to maintenance phase, as described below. (See 'Maintenance phase' below.)

●Persistent or rising MRD – For patients with persistent or rising MRD, we perform NGS for BCR::ABL1 KD mutation status. Further management is guided by the results from NGS testing, as described above. (See 'Measurable residual disease unchanged or rising' above.)

Maintenance phase

Maintenance therapy after transplantation — For patients who undergo either allogeneic HCT or autologous HCT, we suggest the continuation of a TKI for at least one year rather than shorter intervals based on improved outcomes.

The duration of TKI maintenance therapy is specified in the chosen protocol, but some protocols continue the TKI for several years.

Studies of TKI maintenance after transplantation include:

●In a phase 3 trial, 55 patients who underwent allogeneic HCT were randomly assigned to maintenance imatinib for one year versus starting imatinib only at the time of MRD detection [12]. There was no difference in the estimated five-year OS, sustained CR, or disease-free survival, but patients who received maintenance imatinib were more likely to remain MRD negative at four years (46 versus 27 percent, respectively) and had a longer median duration of sustained MRD negativity (27 versus 7 months).

●A systematic review of 17 studies reported that TKI maintenance therapy after allogeneic HCT was associated with an improved OS [47].

●In a single-institution study, TKI maintenance after transplantation was associated with improved outcomes in both patients who were MRD negative before transplantation and in patients who were MRD positive prior to transplantation [48].

Maintenance therapy after consolidation therapy — For patients who did not undergo HCT, we suggest a TKI plus lower-intensity chemotherapy rather than a TKI alone.

Maintenance therapy should adhere to the regimen in the chosen treatment protocol. No randomized trials have compared maintenance regimens with a TKI alone versus a TKI plus chemotherapy, and long-term benefits with TKI-containing maintenance therapy are limited because most studies with a long follow-up reflect the management from before the routine use of TKIs.

The EWALL-PH-01 study reported a 36 percent long-term OS in older patients who received dasatinib plus lower-intensity remission induction and consolidation therapies followed by maintenance therapy with dasatinib and vincristine/dexamethasone for 18 months and continued dasatinib until relapse or death [10].

SURVEILLANCE — The schedule for response monitoring and surveillance is guided by the treatment protocol, but it may be modified according to measurable residual disease (MRD) status and/or as warranted by clinical needs and concerns of the clinician and patient.

●Clinical and laboratory evaluation – For the first year after completing consolidation therapy or transplantation, the patient should be seen every one or two months for clinical evaluation and routine laboratory studies. The interval can be increased to every three or more months in the second to fifth years.

The schedule of visits may be adjusted as warranted by MRD status, cytopenias, complications of treatment, and other clinical needs.

We do not routinely test for BCR::ABL1 kinase domain mutations unless there is evidence of relapse. (See 'Measurable residual disease unchanged or rising' above.)

●MRD monitoring – There is no consensus schedule for MRD monitoring.

Some experts perform a bone marrow examination, including morphology and measurement of MRD, at 1, 3, 6, and 12 months after the completion of consolidation therapy. Others reserve a bone marrow evaluation for patients with unexpected changes in blood counts.

Although not as sensitive as using bone marrow, monitoring MRD in peripheral blood can be done more frequently and less expensively and is an alternative to bone marrow examinations.

Long-term survivors of ALL can develop late treatment-related complications, including neurocognitive dysfunction, cardiotoxicity, infertility, secondary cancers, depression, fatigue, and anxiety. The occurrence of specific complications is influenced by age and the type and intensity of therapy. The long-term monitoring and evaluation of late adverse effects are discussed separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Late effects'.)

TREATMENTS

Consolidation regimens — Details of consolidation therapy for Ph+ ALL vary among treatment protocols, but all include a tyrosine kinase inhibitor (TKI) plus either immunotherapy or multiagent chemotherapy. Consolidation therapy should adhere to the regimen described in the protocol that was chosen for remission induction therapy.

Blinatumomab — Blinatumomab is a CD3/CD19 bispecific T cell-engager antibody that comprises a peptide connecting two single-chain immunoglobulin variable region fragments that simultaneously bind CD19 on lymphoblasts and CD3 on T cells. After binding to its CD19 target, blinatumomab activates T cells and leads to polyclonal expansion of cytotoxic CD8+ T cells, T cell activation, and cell lysis of CD19+ lymphoblasts due to the release of cytokines and cytotoxic granules.

●Administration – Blinatumomab is usually given as a 28-day continuous infusion. The dose is 9 mg/day for the first week of induction, followed by 28 mg/day thereafter.

Dexamethasone prophylaxis is often given for patients with a high disease burden. It is also used to treat symptoms of cytokine release syndrome (CRS), which may occur during the first days of blinatumomab infusion.

We treat with one or two cycles of blinatumomab. If the patient remains MRD positive after two cycles of blinatumomab, further treatment is unlikely to provide additional benefit.

TKIs are generally not withheld during blinatumomab infusion.

Blinatumomab is approved by the US Food and Drug Administration (FDA) for the treatment of CD19+ ALL in first or second complete remission (CR) with measurable residual disease (MRD) ≥0.1 percent and for relapsed ALL. Blinatumomab is approved by the European Medicines Agency (EMA) for adults with CD19+ Ph+ ALL who have failed treatment with ≥2 TKIs and have no alternative treatment options.

●Toxicity – The major adverse effects (AEs) of blinatumomab are CRS and neurotoxicity.

Grade ≥3 CRS was reported in 2 to 6 percent of patients and grade ≥3 neurotoxicity in 7 to 14 percent [49]. The incidence of these AEs generally decreases after the first treatment cycle.

Multiagent consolidation chemotherapy — The choice of a multiagent chemotherapy regimen for consolidation therapy is guided by the chosen protocol.

Optimal outcomes are seen when treatment adheres strictly to that described in the published report; it is important to avoid mixing and matching induction therapy and consolidation therapy from different protocols.

Consolidation therapy using a TKI plus multiagent chemotherapy includes combinations of drugs that were used during the remission induction phase. Methotrexate, cytarabine, 6-mercaptopurine, cyclophosphamide, vincristine, corticosteroids, and asparaginase are frequently incorporated into consolidation therapy. No consolidation chemotherapy regimen has proven to be superior, and there is no consensus regarding a preferred regimen [10,11,50-54].

Consolidation therapy using a TKI plus multiagent chemotherapy can achieve deep molecular remissions, but the durability is uncertain, and it is not clear if this approach can routinely cure Ph+ ALL. Studies of Ph+ ALL with the longest follow-up did not routinely include a TKI through all phases of therapy, and it is unclear how the inclusion of TKIs will impact long-term outcomes.

Maintenance therapy regimens — TKI-containing maintenance therapy is offered to all patients with Ph+ ALL, including those who underwent hematopoietic cell transplantation (HCT), patients who received consolidation therapy with multiagent chemotherapy or immunotherapy, and those who did not receive consolidation treatment. (See 'Maintenance phase' above.)

Various maintenance therapy regimens have not been directly compared in randomized trials, but attempts to omit the maintenance phase were associated with inferior outcomes [55,56]. Long-term drug exposure is probably needed to eradicate MRD [56], and insufficient maintenance therapy has been associated with inferior survival [55,57].

Methotrexate and 6-mercaptopurine are the main drugs used in maintenance therapy; some protocols also include periodic treatment with a glucocorticoid and vincristine [55,57-60]. Maintenance therapy generally lasts for 2 to 2.5 years, and central nervous system prophylaxis with intrathecal chemotherapy continues during this time.

Individuals who inherit a nonfunctional variant allele of the TPMT gene are at an increased risk for hematopoietic toxicity (especially severe neutropenia) after treatment with 6-mercaptopurine [61]. Testing for a TPMT polymorphism should be done in patients who will receive 6-mercaptopurine to avoid severe cytopenias.

Transplantation

Allogeneic hematopoietic cell transplantation — Allogeneic HCT is the only approach proven to provide long-term disease control/cure with Ph+ ALL, but it is associated with substantial toxicity. Allogeneic HCT is generally restricted to fit patients ≤75 years, but eligibility criteria vary among institutions. The decision to pursue allogeneic HCT is discussed below. (See 'Transplant eligible' above.)

Aspects to consider when pursuing allogeneic HCT include:

●Donor source – A human leukocyte antigen (HLA)-matched related (sibling) donor or matched unrelated donor is preferred because they are associated with the most favorable outcomes with allogeneic HCT.

Long-term outcomes are less well defined using alternative donor sources, such as haploidentical donors, umbilical cord blood, or an HLA-mismatched related or unrelated donor. Donor selection is discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

●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 'Adults'.)

●Conditioning regimen – The choice of myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) is individualized and is influenced by age, comorbidities, and institutional approach. The selection of a conditioning regimen is discussed separately. (See "Preparative regimens for hematopoietic cell transplantation".)

A retrospective multicenter study of transplantation in 197 patients with Ph+ ALL reported a similar three-year overall survival (OS) for patients who received MAC versus RIC (35 and 39 percent, respectively), but one-year transplant-related mortality was lower with RIC (13 versus 36 percent) [62]. Other studies have reported similar findings [27,63,64].

●TKI – The TKI is generally held at the time of HCT to enable optimal engraftment and to avoid drug-drug interactions. We resume the TKI as soon as possible after the recovery of blood counts, recognizing that gastrointestinal or hematopoietic toxicity or drug interactions may delay the reinitiation of a TKI [13].

Autologous hematopoietic cell transplantation — Autologous HCT has a limited role for the post-remission management of Ph+ ALL.

Autologous HCT uses MAC, but the reconstituted autologous immune system does not provide a graft-versus-leukemia effect, as occurs with allogeneic HCT. The toxicity and TRM associated with autologous HCT are considerably lower than with allogeneic HCT.

Autologous HCT is generally restricted to MRD-negative patients who are not eligible for allogeneic HCT and who place greater emphasis on the potential prolongation of survival than on the associated toxicity. (See 'Measurable residual disease negative' above.)

Autologous HCT can achieve long-term deep molecular remissions in some patients, but it is not yet clear whether it can routinely cure Ph+ ALL [14,23,65]. A prospective multicenter study reported that at three years, autologous HCT was associated with 57 percent OS, 52 percent leukemia-free survival, 45 percent relapse rate, and 3 percent nonrelapse mortality [66]. Studies that compared autologous HCT with allogeneic HCT or consolidation therapy are presented above. (See 'Transplant eligible' above and 'Measurable residual disease negative' above.)

Eligibility for autologous HCT is discussed separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

RELAPSED/REFRACTORY PH+ ALL — The management of patients with relapsed Ph+ ALL is discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Philadelphia chromosome positive ALL'.)

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

●Description – Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is associated with t(9;22)(q34;q11.2);BCR::ABL1, which renders it susceptible to tyrosine kinase inhibitors (TKIs). TKI-based remission induction therapy achieves hematologic complete remission (CR) in >90 percent of adults, but virtually all relapse within months without post-remission therapy.

●Evaluation

•Medical fitness – Clinical evaluation, performance status (table 1), and transplant eligibility should be reassessed before beginning post-remission management, as fitness may have changed since diagnosis. (See 'Medical fitness' above.)

•Measurable residual disease – Measurable residual disease (MRD) is associated with prognosis and is used to stratify post-remission management in Ph+ ALL. The details of assessing BCR::ABL1 MRD by next-generation sequencing or real-time quantitative polymerase chain reaction are discussed. (See 'Measurable residual disease testing' above.)

●Overview – Post-remission management includes one or more of the following treatment phases: consolidation, allogeneic hematopoietic cell transplantation (HCT), and/or maintenance treatment. (See 'Overview' above.)

●TKI – For Ph+ ALL, we recommend the inclusion of a TKI through all phases of treatment (Grade 1B). (See 'Tyrosine kinase inhibitor' above.)

●Initial consolidation – We suggest initial post-remission management with one or two cycles of consolidation therapy, followed by assessment of MRD (Grade 2C). The details of initial consolidation therapy are guided by the protocol selected for induction therapy. (See 'Initial consolidation therapy' above.)

●MRD-positive patients – Management is guided by the trajectory of MRD levels after achieving CR:

•MRD declining – Informed by medical fitness:

-Transplant eligible – For transplant-eligible patients, we suggest allogeneic HCT rather than other post-remission approaches (Grade 2C). Consolidation therapy (ie, a TKI plus either chemotherapy or immunotherapy) may yield similar results, but it is not proven to cure Ph+ ALL. The decision to pursue allogeneic HCT is individualized based on age, fitness, institutional approach, and patient preference. (See 'Transplant eligible' above.)

-Not transplant eligible – We consider consolidation therapy with either a TKI plus blinatumomab (where available) or a TKI plus multiagent chemotherapy acceptable (Grade 2C). (See 'Not transplant eligible' above.)

•MRD rising/unchanged – Perform BCR::ABL1 kinase domain mutation analysis (see 'Measurable residual disease unchanged or rising' above):

-Actionable mutation – Change the TKI based on specific mutation(s), toxicity, and comorbidities, and then monitor response by MRD. The choice of a TKI is extrapolated from the treatment of chronic myeloid leukemia. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Initial management'.)

-No actionable mutation – Manage as refractory disease. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)

●MRD negative – For patients who are MRD negative after initial consolidation therapy, we consider it acceptable to complete consolidation therapy or proceed to early allogeneic HCT or autologous HCT (Grade 2C). (See 'Measurable residual disease negative' above.)

●Repeat MRD testing – MRD is repeated after completing consolidation therapy or transplantation. (See 'Repeat measurable residual disease testing after consolidation or hematopoietic cell transplantation' above.)

●Maintenance therapy

•Transplantation – After either allogeneic or autologous HCT, we suggest continuing the TKI for ≥1 year rather than shorter intervals (Grade 2C). (See 'Maintenance therapy after transplantation' above.)

•No transplantation – For patients who did not undergo transplantation, we suggest a TKI plus lower-intensity chemotherapy rather than a TKI alone (Grade 2C). The TKI generally continues for 24 to 30 months, and the chemotherapy component is guided by the chosen protocol. (See 'Maintenance therapy after consolidation therapy' above.)

●Surveillance – Response monitoring and surveillance for relapse and adverse effects are described. (See 'Surveillance' above.)

●Treatments – Details of components of care are provided:

•(See 'Consolidation regimens' above.)

•(See 'Maintenance therapy regimens' above.)

•(See 'Transplantation' above.)

●Relapsed/refractory disease – Discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)