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Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults

Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults
Literature review current through: Jan 2024.
This topic last updated: Mar 30, 2021.

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.

The goal of post-remission therapy in Ph+ ALL is to eradicate residual leukemia cells after achieving a hematologic complete remission (CR) with remission induction therapy. Although >90 percent of adults with Ph+ ALL achieve CR, virtually all will relapse within months without post-remission therapy. Post-remission therapy comprises:

Consolidation therapy – Intensive treatment that follows soon after achievement of hematologic CR.

Maintenance therapy – Prolonged lower-intensity treatment that includes a BCR-ABL1 TKI, with or without chemotherapy.

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

The following subjects are presented separately:

Induction therapy for Ph+ ALL in adults. (See "Induction 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".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.

(See "COVID-19: Considerations in patients with cancer".)

PRETREATMENT EVALUATION — Prior to selecting post-remission therapy, the following evaluations should be performed:

Medical fitness — Medical fitness may have changed since the time of diagnosis and remission induction therapy. Medical fitness should be re-evaluated prior to post-remission therapy because, for some patients, medical fitness improves with achievement of remission, whereas for others, fitness may have declined due to complications of treatment or the underlying leukemia. Evaluation of medical fitness is described separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Medical fitness'.)

Transplant consultation — We obtain consultation regarding eligibility for transplantation for all patients, except those who are frail.

We do not consider age a barrier to obtaining transplantation consultation. Although age limits vary, many institutions restrict allogeneic hematopoietic cell transplantation (HCT) for Ph+ ALL to patients ≤60 years. Transplant eligibility also requires no severe lung, heart, liver, or kidney disease; a suitable graft source; and adequate social supports. Further details of eligibility for allogeneic HCT are presented separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

MRD assessment — Measurable residual disease (MRD) should be evaluated upon completion of remission induction therapy. MRD for Ph+ ALL is assessed by real-time quantitative polymerase chain reaction (RQ-PCR) for BCR-ABL1 of a bone marrow specimen, as discussed separately. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'Ph+ ALL'.)

MRD status informs the choice and timing of components of post-remission therapy for Ph+ ALL. (See 'Pretransplant management by MRD status' below and 'Choices for HCT-ineligible patients' below.)

CONTINUATION OF TKI AND CNS THERAPY — The same BCR-ABL1 tyrosine kinase inhibitor (TKI) that was given during remission induction therapy should be continued through post-remission therapy for Ph+ ALL. Selection of a BCR-ABL1 TKI and management of patients with intolerance or resistance to a TKI are discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Choice of TKI'.)

The TKI may be withheld during the period of hematologic engraftment after transplantation or immunotherapy, as discussed below. (See 'Resumption of TKI' below and 'Immunotherapy' below.)

Central nervous system (CNS) management during post-remission therapy is governed by the remission induction protocol and evidence of CNS involvement, based on neurologic symptoms or signs, imaging, and/or presence of lymphoblasts in cerebrospinal fluid (CSF), as described separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'CNS management'.)

CONSOLIDATION THERAPY — We strongly encourage enrollment in a clinical trial. Treatment of Ph+ ALL continues to evolve with the introduction of new agents and approaches to therapy; participation in a clinical trial is the best way to ensure safe and effective treatment.

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.

Indications and exceptions — For most patients with Ph+ ALL, we suggest consolidation therapy, rather than maintenance therapy alone or observation only. Consolidation therapy offers the greatest likelihood of long-term survival for patients with Ph+ ALL, but is associated with adverse effects that vary with the chosen approach. No randomized trials have compared consolidation therapy versus maintenance therapy alone or observation only and it is difficult to compare different studies because of various selection criteria and measures of outcomes. Most studies with maintenance therapy alone involved frail or less-fit patients or were from the pre-tyrosine kinase inhibitor (TKI) era. Observation alone is associated with relapse within months in virtually all patients. Selection of consolidation therapy is discussed below. (See 'Choices for transplant candidates' below and 'Not a transplant candidate' below.)

Possible exceptions to treatment with consolidation therapy include:

Selected patients with undetectable measurable residual disease (MRD):

Transplant-eligible – For patients with undetectable MRD who are candidates for allogeneic hematopoietic cell transplantation (HCT), some experts favor proceeding directly to maintenance therapy, whereas others favor allogeneic HCT, as discussed below. (See 'MRD not detected (molCR)' below.)

Not a transplant candidate – For patients with undetectable MRD who are not candidates for allogeneic HCT, we proceed directly to maintenance therapy, as discussed below. (See 'Choices for HCT-ineligible patients' below.)

Frail patients – For frail patients, we proceed directly to maintenance therapy because the toxicity of consolidation therapy in this population may outweigh the benefits. (See 'Maintenance therapy' below.)

Choices for transplant candidates

Preference for allogeneic HCT — For most patients with Ph+ ALL who are eligible for transplantation, we suggest consolidation with allogeneic HCT rather than autologous HCT, chemotherapy, or immunotherapy. Allogeneic HCT is associated with the most favorable long-term outcomes for Ph+ ALL, but this benefit must be weighed against substantial toxicity and treatment-related mortality (TRM), which vary with patient age and transplantation technique [3-9]. It is uncertain if the favorable balance of benefits and toxicity of allogeneic HCT applies to patients who have undetectable MRD after remission induction therapy. The role of MRD status on decisions about transplantation, timing of HCT, and pretransplant management are described below. (See 'Pretransplant management by MRD status' below.)

Studies that compared allogeneic HCT with other approaches generally used "genetic randomization," in which allogeneic HCT is offered to patients with a human leukocyte antigen (HLA)-matched donor, while other patients received either autologous HCT or chemotherapy.

In one study, 254 patients in hematologic complete remission (CR) underwent allogeneic HCT (if they had a matched donor) versus autologous HCT (if no suitable donor was available) [3]. Allogeneic HCT was performed in 161 patients (76 matched sibling donors, 72 matched unrelated donors, 13 umbilical cord blood) and autologous HCT in 35 patients. Compared with autologous HCT, allogeneic HCT was associated with more favorable overall survival (OS; hazard ratio [HR] 0.64; 95% CI 0.44-0.93) and relapse-free survival (RFS; HR 0.69; 95% CI 0.49-0.98). However, OS or RFS did not differ between treatment arms among patients who achieved major molecular response (MMolR; BCR/ABL1 <10-3 [MR3]) prior to transplantation. Allogeneic HCT was associated with more nonrelapse mortality (NRM; 26 versus 6 percent).

A multicenter study that used genetic randomization of 83 patients (median age 44 years) who achieved CR or CR with incomplete hematologic recovery (CRi) reported that patients who underwent allogeneic HCT (41 patients) followed by TKI maintenance therapy had superior 12-month RFS (83 percent) compared with patients who proceeded directly to two years of maintenance therapy with a TKI, prednisone, and vincristine [10].

A retrospective study reported that for patients who received intensive chemotherapy plus a TKI, outcomes were similar for patients who subsequently underwent allogeneic HCT versus those who received indefinite TKI maintenance therapy [11]. Compared with maintenance therapy alone, those who underwent HCT had similar OS at one, two, and three years and RFS at three years.

For patients who decline allogeneic HCT because they place greater weight on the adverse effects than on long-term disease control, the choice of consolidation therapy is described below. (See 'Choices for HCT-ineligible patients' below.)

Pretransplant management by MRD status — Our approach to management prior to HCT is influenced by MRD status.

Detectable MRD — We favor maximizing the depth of response prior to allogeneic HCT, because deeper molecular responses are associated with more favorable outcomes. However, it has not been proven that treatment to enhance the depth of response prior to transplantation will alter the outcome.

For patients with detectable MRD (eg, <MR4.5; BCR/ABL1 >10-4.5), we favor treatment to deepen the response prior to transplantation (algorithm 1). Treatments that can enhance the molecular response in patients with persistent MRD include:

Blinatumomab is available – Treat with blinatumomab to achieve undetectable MRD (ie, ≥MR4.5) and then proceed to allogeneic HCT. If one or two cycles of blinatumomab does not achieve undetectable MRD, further treatment is unlikely to provide additional benefit.

Blinatumomab is approved for treatment of MRD by the US Food and Drug Administration (FDA), but not by the European Medicines Agency (EMA).

Blinatumomab is not available:

Patient is receiving imatinib – For patients who received imatinib during remission induction therapy, we treat for one to two months with a second-generation TKI (eg, dasatinib) or ponatinib; a decision to change the TKI must consider the toxicity profile and the individual's comorbid illnesses. Some centers also treat with high-dose methotrexate (HD-MTX) during this period. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Choice of TKI'.)

Patient is not receiving imatinib – For patients who were treated with a second- or third-generation TKI during remission induction therapy, we treat with HD-MTX before proceeding to allogeneic HCT; the preferred regimen and duration of HD-MTX therapy varies between centers. Some centers proceed directly to allogeneic HCT without HD-MTX.

MRD not detected (molCR) — For patients with a complete molecular CR (molCR; ie, ≥MR4.5; BCR/ABL1 ≤10-4.5), we generally proceed directly to HCT (algorithm 1). We judge that the risk of relapse (ie, approximately one-quarter of patients with molCR who do not undergo HCT) [8,12,13] outweighs transplant-related toxicity and TRM. However, some experts favor omitting HCT for patients with a molCR, because they place greater weight on limiting toxicity for patients in whom an incremental benefit from transplantation cannot be demonstrated (ie, because BCR/ABL1 is not measurable). Instead, they reserve allogeneic HCT for the possibility of a future relapse. The decision to omit HCT in a patient with a molCR is influenced by individual preference and should weigh the physical and emotional burden of allogeneic HCT against the greater uncertainty of outcomes without transplantation.

Donor source — An HLA-matched related donor or matched unrelated donor is preferred because they are associated with the most favorable outcomes with allogeneic HCT. (See "Donor selection for hematopoietic cell transplantation".)

Alternative donor sources (eg, single-antigen mismatched related or unrelated donor, haploidentical donor, or umbilical cord blood) are acceptable for selected patients, but the possibility of increased graft-versus-host disease (GVHD) or other adverse effects must be weighed against the benefits of transplantation.

Conditioning regimen — Myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) are associated with similar outcomes for allogeneic HCT in Ph+ ALL. The preferred conditioning regimen varies between centers. Selection of a conditioning regimen is discussed separately. (See "Preparative regimens for hematopoietic cell transplantation".)

A retrospective multicenter study of 197 patients with Ph+ ALL reported similar three-year OS for patients who received MAC versus RIC (35 and 39 percent, respectively), but one-year TRM was lower with RIC (13 versus 36 percent) [14]. Other studies have reported similar findings [8,15,16].

Resumption of TKI — The TKI is generally withheld at the time of HCT. We resume the TKI as soon as possible after recovery of blood counts, recognizing that gastrointestinal or hematopoietic toxicity or drug interactions may delay initiation of TKI [17,18]. No studies have defined an optimal period for withholding the TKI, but the interruption is generally 30 to 60 days.

Not a transplant candidate — For patients with Ph+ ALL who are not candidates for allogeneic HCT, the following options can be considered for consolidation therapy:

Chemotherapy plus a TKI. (See 'Chemotherapy plus a TKI' below.)

Immunotherapy. (See 'Immunotherapy' below.)

Autologous HCT – We generally restrict autologous HCT to selected patients with undetectable MRD. (See 'Choices for HCT-ineligible patients' below.)

Choices for HCT-ineligible patients — For patients with Ph+ ALL in CR who are ineligible or decline allogeneic HCT, our approach is influenced by the level of MRD (algorithm 2):

MRD detected in HCT-ineligible patients — For patients who have detectable MRD (ie, <MR4.5; BCR-ABL1 >10-4.5), we treat with blinatumomab (two to five cycles), where available, followed by maintenance therapy. The TKI should be withheld during immunotherapy to reduce the risk of cytopenias and it should be resumed upon initiation of maintenance therapy. If blinatumomab is not available, we treat with a TKI plus combination chemotherapy followed by maintenance therapy. We consider that toxicity associated with autologous HCT outweighs the benefits in this setting. (See 'Chemotherapy plus a TKI' below and 'Immunotherapy' below.)

MolCR in HCT-ineligible patients — For patients with undetectable MRD (molCR), we proceed directly to maintenance therapy. Blinatumomab is not approved for treatment of molCR, and we consider that the toxicity of autologous HCT or a TKI plus combination chemotherapy is not warranted for patients in whom an incremental benefit from consolidation therapy cannot be demonstrated. However, some experts offer autologous HCT in this setting. No studies have compared outcomes and toxicity with these strategies and the preferred approach differs between centers. (See 'Immunotherapy' below and 'Maintenance therapy' below.)

Chemotherapy plus a TKI — Treatment with TKI plus combination chemotherapy is an acceptable option for patients with Ph+ ALL who are medically ineligible for allogeneic HCT, but we generally reserve it for patients with detectable MRD (algorithm 2), as discussed above. (See 'Choices for HCT-ineligible patients' above.)

No protocol for a TKI plus combination chemotherapy has proven to be superior, and there is no consensus regarding a preferred regimen [19-25]. Consolidation with a TKI plus chemotherapy can achieve deep molecular remissions, but the durability is uncertain and it is not clear if this approach can routinely cure Ph+ ALL. Most studies of combination chemotherapy consolidation for Ph+ ALL did not routinely include a TKI, and it is unclear how inclusion of TKIs in remission induction therapy and post-remission therapy will impact long-term outcomes.

No randomized trials have compared a TKI plus combination chemotherapy versus allogeneic HCT, autologous HCT, or immunotherapy. Retrospective studies of TKI plus chemotherapy were generally small, included patients who were medically ineligible for allogeneic HCT, and/or had short follow-up. Inherent differences in patient populations make it difficult to compare these studies with studies of patients who underwent allogeneic HCT.

A prospective study of 71 adults (median age 69 years, most of whom had high comorbidity scores) reported 36 percent OS at five years in patients who were treated with dasatinib plus asparaginase, methotrexate, and cytarabine consolidation for six months [19]. Favorable performance status and achievement of a deep molecular response during consolidation were associated with prolonged RFS.

Immunotherapy — Consolidation with blinatumomab (bispecific anti-CD3 and anti-CD19 antibody) is a promising approach and in some settings may enable chemotherapy-free treatment of Ph+ ALL. Blinatumomab is approved by the US FDA for patients with detectable MRD in first CR.

A phase 2 study of 63 patients that used chemotherapy-free induction therapy (dexamethasone plus dasatinib) and consolidation therapy (two to five cycles of blinatumomab) reported 95 percent OS and 88 percent disease-free survival (DFS), with median follow-up of 18 months [26]. At the end of the second cycle of blinatumomab, 60 percent of patients had achieved molCR. There were 21 grade ≥3 adverse events (primarily neutropenia or cytomegalovirus [CMV] reactivation or infection). BCR-ABL1 mutations were detected in six patients who had increasing MRD during induction therapy, but all clones with mutated BCR-ABL1 were cleared by blinatumomab. Relapses occurred in 8 percent of patients and a total of 24 patients received allogeneic HCT; there was one death related to transplantation.

Autologous HCT — Autologous HCT has a limited role for consolidation therapy in Ph+ ALL. Autologous HCT is generally limited to patients with undetectable MRD who are not candidates for allogeneic HCT and who place greater emphasis on potential prolongation of survival than on the associated toxicity. (See 'Choices for HCT-ineligible patients' above.)

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 with autologous HCT are considerably lower than with allogeneic HCT. Studies that compared autologous versus allogeneic HCT are discussed above. (See 'Preference for allogeneic HCT' 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 [4,27,28]. For patients who achieve MMolR (>MR3; BCR-ABL1 <10-3) after induction therapy, autologous HCT can achieve outcomes that are comparable to allogeneic HCT [3]. A prospective study from the European Group for Blood and Marrow Transplantation (EBMT) 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 NRM [29]. A prospective study reported that autologous HCT achieved molCR in nine patients and minimal BCR-ABL1 positivity in four patients, but some patients relapsed with clones that carried a BCR-ABL1 T315I mutation while maintained on imatinib [4,30].

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

MONITORING — The schedule for response monitoring and surveillance for relapse of Ph+ ALL should be guided by the published treatment protocol and modified as warranted by clinical needs and concerns of the clinician and patient.

Clinical and laboratory evaluation – For the first year after completing consolidation therapy, the patient should be seen every one to 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, but the schedule of visits should be adjusted as warranted by measurable residual disease (MRD) status, cytopenias, complications of treatment, and other clinical needs.

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 the patient's age and the type and intensity of therapy. 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'.)

Measurable residual disease Some experts perform bone marrow examination, including morphology and measurement of MRD, at 1, 3, 6, and 12 months after completion of consolidation therapy. Others reserve bone marrow evaluation for patients with unexpected changes in blood counts. We do not routinely test for BCR-ABL1 mutations unless there is evidence of relapse.

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.

No evidence of relapse – Patients with stable or declining MRD and no clinical evidence of relapse should proceed to maintenance therapy. (See 'Maintenance therapy' below.)

Possible relapse – For evidence of relapsing disease in peripheral blood, bone marrow morphology, or increasing levels of MRD, the patient should be treated for relapsed disease. If an increasing level of MRD is the only evidence of relapse, we generally repeat MRD testing two to four weeks later to confirm the finding. Management of relapsed disease is discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Philadelphia chromosome positive ALL'.)

MAINTENANCE THERAPY — Maintenance therapy for Ph+ ALL refers to prolonged treatment with a BCR-ABL1 tyrosine kinase inhibitor (TKI), with or without low-intensity chemotherapy.

For patients with Ph+ ALL who are in remission after completing consolidation therapy, we suggest maintenance therapy with a BCR-ABL1 TKI, with or without low-intensity chemotherapy, rather than chemotherapy alone or observation, based on the potential for reducing relapse and only modest toxicity.

Administration

Patients – Extrapolating from its proven benefit in Ph-negative ALL, maintenance therapy should be given to all patients, regardless of the type of consolidation therapy (eg, transplantation, chemotherapy, immunotherapy, or no consolidation because of frailty) and level of measurable residual disease (MRD), unless there is evidence of relapse. (See 'Monitoring' above.)

Selection of regimen – The maintenance regimen should be guided by the treatment protocol that was chosen for prior induction and consolidation therapy. The same TKI should be given, unless there was unacceptable intolerance or emergence of a BCR-ABL1 mutation that is not sensitive to that TKI. For some protocols, maintenance comprises a TKI alone, whereas other protocols include a TKI plus periodic low-intensity chemotherapy (eg, vincristine, methotrexate, mercaptopurine).

Timing of initiation – Maintenance therapy should begin promptly after remission is documented following consolidation therapy (or after remission induction for patients who did not receive consolidation). For patients who underwent hematopoietic cell transplantation (HCT), the TKI should be resumed as soon as possible after recovery of blood counts, as discussed above. (See 'Resumption of TKI' above.)

Duration – The optimal duration of TKI maintenance therapy is not well-established, but we generally treat for at least two years, unless there is unacceptable intolerance or evidence of TKI resistance.

The duration of treatment may be influenced by the level of MRD:

>MR4 – For >MR4 (ie, BCR-ABL1 <10-4) we treat for at least two years. For patients who have undergone allogeneic HCT, some experts treat for one to two years after transplantation [31-33].

≤MR4 – For ≤MR4 (ie, BCR-ABL1 ≥10-4), we continue the TKI indefinitely. If MRD subsequently declines to >MR4 in two successive examinations, we treat for at least one year longer (minimum two years total).

Our approach to maintenance therapy is consistent with the position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation [31].

Outcomes — The benefit of maintenance therapy for Ph+ ALL is unproven because most long-term studies of maintenance therapy reflect treatment before the routine use of TKIs. No randomized trials have compared maintenance using a TKI with or without chemotherapy or TKI maintenance versus chemotherapy.

After HCT:

A systematic review of 17 studies reported that TKI maintenance therapy after allogeneic HCT was associated with improved overall survival (OS) [34]. Limited data suggested that, compared with imatinib, second-generation TKIs (eg, dasatinib) were associated with better OS, especially in patients with MRD-positive status.

In a multicenter phase 3 trial, 55 patients who underwent allogeneic HCT were randomly assigned to receive maintenance imatinib for one year versus starting imatinib only at the time of MRD detection [32]. After median follow-up of 30 months, there was no difference in estimated five-year OS (77 percent), sustained complete remission (CR; 83 percent), or disease-free survival (DFS; 69 percent). However, 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).

TKI maintenance may even be clinically useful after allogeneic HCT in patients who were MRD negative prior to transplantation [35]. TKI maintenance was associated with improved progression-free survival (PFS).

TKI plus chemotherapy consolidation:

The multicenter EWALL-PH-01 study reported 36 percent long-term OS in older patients treated with lower-intensity therapies for Ph+ ALL [19]. Remission induction was dasatinib plus low-intensity therapy, consolidation included dasatinib plus chemotherapy, and maintenance included dasatinib and vincristine/dexamethasone over 18 months, followed by dasatinib until relapse or death.

RELAPSED DISEASE — 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'.)

INVESTIGATIONAL TREATMENTS — Frontline post-remission management of Ph+ ALL continues to evolve, with investigation of immunotherapy as an alternative to chemotherapy and/or transplantation. Promising agents in this setting include blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor engineered T (CAR-T) cells, as discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Salvage (rescue) therapy'.)

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 5th to 6th 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 10th to 12th 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

The goal of post-remission therapy in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is to eradicate residual disease after achieving a hematologic complete remission (CR) with remission induction therapy. Virtually all adults who achieve CR will relapse within months if they do not receive post-remission therapy. Post-remission therapy for Ph+ ALL generally includes both:

Consolidation therapy – Intensive treatment that follows soon after achievement of hematologic CR.

Maintenance therapy – Prolonged lower-intensity treatment that includes a BCR-ABL1 tyrosine kinase inhibitor (TKI), with or without chemotherapy.

Pretreatment evaluation – Prior to selecting post-remission therapy, eligibility for allogeneic hematopoietic cell transplantation (HCT) should be determined in all but frail patients, without regard to age. The level of measurable residual disease (MRD) in bone marrow should be assessed upon completion of remission induction therapy. (See 'Pretreatment evaluation' above.)

Tyrosine kinase inhibitor – The same BCR-ABL1 TKI that was given during remission induction therapy should be continued through all phases of treatment for Ph+ ALL, but it may be withheld during the period of hematologic engraftment after transplantation or during treatment with immunotherapy. (See 'Continuation of TKI and CNS therapy' above.)

Consolidation therapy – For most patients with Ph+ ALL, we suggest consolidation therapy rather than maintenance therapy alone or observation (Grade 2C). Consolidation therapy offers the greatest likelihood of long-term survival for patients with Ph+ ALL, but it is associated with adverse effects that vary with the chosen approach. Possible exceptions include frail patients and selected patients with undetectable MRD, as described above. (See 'Indications and exceptions' above.)  

Choice of consolidation therapy – We strongly encourage participation in a clinical trial whenever possible. Outside of a clinical trial, the choice of approach is influenced by eligibility for allogeneic HCT, level of MRD, availability of treatments, and patient preference. (See 'Consolidation therapy' above.)

Candidate for transplantation – For most patients with Ph+ ALL who are eligible for transplantation, we suggest consolidation with allogeneic HCT rather than autologous HCT, chemotherapy, or immunotherapy (Grade 2C). Allogeneic HCT is the approach that is best proven to achieve long-term disease control/cure, but this must be balanced against substantial toxicity. (See 'Preference for allogeneic HCT' above.)

Pretransplant management is informed by the level of MRD (algorithm 1) (see 'Pretransplant management by MRD status' above):

-Detectable MRD – For patients with detectable MRD (ie, <MR4.5; BCR/ABL1 >10-4.5), we favor maximizing the depth of the response prior to allogeneic HCT. Methods to deepen the molecular response (eg, blinatumomab, change of TKI, or high-dose methotrexate) are discussed above. (See 'Detectable MRD' above.)

-Undetectable MRD (molecular CR [molCR]) – For patients with undetectable MRD (ie, ≥MR4.5; BCR/ABL1 ≤10-4.5) we generally proceed directly to allogeneic HCT. However, some experts omit HCT in this setting and proceed directly to maintenance therapy, as discussed above. (See 'MRD not detected (molCR)' above.)

Not a transplant candidate – For patients with Ph+ ALL who are ineligible or decline allogeneic HCT, our approach is influenced by the level of MRD (algorithm 2) (see 'Choices for HCT-ineligible patients' above):

-Detectable MRD – For patients with detectable MRD (ie, <MR4.5; BCR/ABL1 >10-4.5) who are not candidates for transplantation, we favor blinatumomab, where available. Otherwise, a TKI plus combination chemotherapy is an acceptable option; we consider that the toxicity of autologous HCT outweighs its benefits in this setting. (See 'Chemotherapy plus a TKI' above and 'Immunotherapy' above.)

-Undetectable MRD – For patients with undetectable MRD (≥MR4.5; BCR/ABL1 ≤10-4.5) who are not candidates for transplantation, we favor proceeding directly to maintenance therapy. Some experts offer autologous HCT in this setting, as described above. (See 'Immunotherapy' above and 'Maintenance therapy' above.)

Maintenance therapy – For patients with Ph+ ALL who are in remission after completing consolidation therapy, we suggest maintenance therapy with a BCR-ABL1 TKI, with or without low-intensity chemotherapy, rather than chemotherapy alone or observation (Grade 1C), based on the potential for reducing relapse and only modest toxicity.

Details of administration and outcomes with maintenance therapy for Ph+ ALL are discussed above. (See 'Maintenance therapy' above.)

  1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017.
  3. Chalandon Y, Thomas X, Hayette S, et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood 2015; 125:3711.
  4. Wetzler M, Watson D, Stock W, et al. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica 2014; 99:111.
  5. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial. Blood 2002; 100:2357.
  6. Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 2009; 113:4489.
  7. Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am 2000; 14:1353.
  8. Cassaday RD, Alan Potts D Jr, Stevenson PA, et al. Evaluation of allogeneic transplantation in first or later minimal residual disease - negative remission following adult-inspired therapy for acute lymphoblastic leukemia. Leuk Lymphoma 2016; 57:2109.
  9. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111:1827.
  10. Ravandi F, Othus M, O'Brien SM, et al. US Intergroup Study of Chemotherapy Plus Dasatinib and Allogeneic Stem Cell Transplant in Philadelphia Chromosome Positive ALL. Blood Adv 2016; 1:250.
  11. Chang J, Douer D, Aldoss I, et al. Combination chemotherapy plus dasatinib leads to comparable overall survival and relapse-free survival rates as allogeneic hematopoietic stem cell transplantation in Philadelphia positive acute lymphoblastic leukemia. Cancer Med 2019; 8:2832.
  12. Ravandi F, Jorgensen JL, O'Brien SM, et al. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol 2016; 172:392.
  13. Short NJ, Jabbour E, Sasaki K, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2016; 128:504.
  14. Bachanova V, Marks DI, Zhang MJ, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia 2014; 28:658.
  15. Mohty M, Labopin M, Volin L, et al. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood 2010; 116:4439.
  16. Marks DI, Wang T, Pérez WS, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood 2010; 116:366.
  17. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood 2014; 123:843.
  18. Ribera JM, Oriol A, González M, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica 2010; 95:87.
  19. Rousselot P, Coudé MM, Gokbuget N, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood 2016; 128:774.
  20. Mizuta S, Matsuo K, Yagasaki F, et al. Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia. Leukemia 2011; 25:41.
  21. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006; 24:460.
  22. Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood 2015; 126:746.
  23. Slayton WB, Schultz KR, Kairalla JA, et al. Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622. J Clin Oncol 2018; 36:2306.
  24. Yoon JH, Yhim HY, Kwak JY, et al. Minimal residual disease-based effect and long-term outcome of first-line dasatinib combined with chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann Oncol 2016; 27:1081.
  25. Wieduwilt MJ, Yin J, Wetzler M, et al. A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Transplantation for Adults with Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Final Results of Alliance/CALGB Study 10701. Blood (ASH Annual Meeting Abstracts) 2018; 132:309.
  26. Foà R, Bassan R, Vitale A, et al. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med 2020; 383:1613.
  27. Shin HJ, Chung JS, Cho GJ. Imatinib interim therapy between chemotherapeutic cycles and in vivo purging prior to autologous stem cell transplantation, followed by maintenance therapy is a feasible treatment strategy in Philadelphia chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant 2005; 36:917.
  28. Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol 2010; 28:3644.
  29. Giebel S, Labopin M, Gorin NC, et al. Improving results of autologous stem cell transplantation for Philadelphia-positive acute lymphoblastic leukaemia in the era of tyrosine kinase inhibitors: a report from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Eur J Cancer 2014; 50:411.
  30. DeBoer R, Koval G, Mulkey F, et al. Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665. Leuk Lymphoma 2016; 57:2298.
  31. Giebel S, Czyz A, Ottmann O, et al. Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer 2016; 122:2941.
  32. Pfeifer H, Wassmann B, Bethge W, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia 2013; 27:1254.
  33. Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 2007; 109:2791.
  34. Warraich Z, Tenneti P, Thai T, et al. Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblast Leukemia: A Systematic Review. Biol Blood Marrow Transplant 2020; 26:e55.
  35. Saini N, Marin D, Ledesma C, et al. Impact of TKIs post-allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive ALL. Blood 2020; 136:1786.
Topic 16841 Version 21.0

References

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