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

INTRODUCTION — 

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by the proliferation of immature lymphoid cells in bone marrow, peripheral blood, and/or other organs. ALL is a heterogeneous disease, and long-term outcomes vary with clinical features and pathologic characteristics of the leukemic blasts. Patients with Philadelphia chromosome (Ph)-negative ALL lack the t(9;22)/BCR::ABL1 rearrangement, which in patients with Ph-positive ALL, is responsive to BCR::ABL1 tyrosine kinase inhibitors.

Induction chemotherapy achieves a complete remission (CR) in more than 80 percent of adults with Ph-negative ALL, but some patients have persistent leukemia cells that can be detected using sensitive immunophenotypic or molecular techniques. The residual leukemic cells in a patient with a CR are described as measurable residual disease (MRD).

Without further treatment after achieving CR, virtually all patients with Ph-negative ALL will relapse within weeks or months, whether MRD is detectable or not. The goal of post-remission therapy is to eradicate residual leukemic cells and enable long-term survival and potential cure. Post-remission management is risk-adapted, with therapy guided by the risk of relapse.

Management of Ph-negative ALL is evolving rapidly as newer immunotherapeutic agents are being incorporated into front-line therapy.

This topic reviews post-remission therapy for Ph-negative ALL in adults.

Related topics include:

●(See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

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

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

●(See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

●(See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)

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

OVERVIEW — 

Induction therapy of ALL in adults achieves complete remission (CR; <5 percent leukemic blasts in bone marrow and blood, and no extramedullary disease) in most patients. Despite a morphologic CR, most patients will relapse without post-remission treatment.

Management of ALL is informed by the presence of the t(9;22)/BCR::ABL1 rearrangement (the Philadelphia chromosome [Ph]). This topic discusses post-remission management of Ph-negative ALL. Post-remission management of Ph-positive ALL is discussed separately. (See "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management".)

CR is achieved in approximately 90 percent of adults with ALL ≤65 years old [1]. Approximately 5 percent fail to achieve CR after two induction cycles (primary resistance), and another 5 percent die early of disease- or treatment-related complications. Induction therapy for adults with Ph-negative B cell ALL is discussed separately. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults".)

Post-remission management of Ph-negative ALL is informed by the risk for relapse.

●Risk factors – Risk of relapse is influenced by clinical features (eg, age, white blood cell count), cytogenetic/molecular features of the leukemic blasts, and the presence of measurable residual disease (MRD) after initial therapy. (See 'Risk factors' below.)

●Risk stratification – Post-remission management of Ph-negative ALL is stratified according to risk for relapse, age, and medical fitness.

•Standard risk – Most adult patients with standard-risk ALL are treated with consolidation chemoimmunotherapy, followed by prolonged maintenance therapy. (See 'Standard-risk ALL' below.)

•High risk – Management of high-risk ALL is guided by the level of MRD at the end of induction therapy and eligibility for allogeneic hematopoietic cell transplantation. (See 'High-risk ALL' below.)

Central nervous system prophylaxis continues through all phases of treatment for ALL, as discussed separately. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'CNS prophylaxis'.)

Our approach to the management of adult ALL is consistent with the European LeukemiaNet (ELN) [2], the United States National Comprehensive Cancer Network (NCCN) [3], and the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL)/Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) [4].

RISK FACTORS — 

The prognosis for adults with ALL varies with clinical, cytogenetic, and molecular features at diagnosis and the level of measurable residual disease (MRD) after achieving a complete remission (CR) [5].

Clinical features — Older age is associated with inferior outcomes in adults with ALL. Other clinical features are less closely associated with outcomes in adults with ALL.

●Age – Older age is associated with inferior outcomes in ALL.

Several factors contribute to inferior outcomes in older patients with Ph-negative ALL. Older patients may receive attenuated treatment because they are less able to tolerate certain agents (eg, vincristine, asparaginase, corticosteroids) and the conditioning regimens used for allogeneic hematopoietic cell transplantation (HCT). However, less intensive HCT conditioning regimens, better donor matching, greater availability of unrelated donors, better immunosuppressive regimens, and improved supportive care have made transplantation more feasible in this population.

Older patients are also more likely to have unfavorable genetic features of leukemic blasts, as described below. (See 'Cytogenetic/molecular features' below.)

●White blood cell (WBC) count – WBC count ≥30,000/microL at diagnosis is associated with inferior outcomes.

●Time to response – No residual leukemia (ie, <5 percent blasts) by day 14 is associated with superior survival in adults and children with ALL [6-11].

Analysis of more than 400 adults with ALL treated with chemotherapy (without HCT) in prospective studies reported that favorable long-term outcomes were associated with age <30 years, WBC count <30,000/microL at diagnosis, the presence of a mediastinal mass, T cell immunophenotype, and absence of the Ph [12]. Patients with no adverse features had a 91 percent estimated three-year overall survival (OS). Survival was a continuous function of age; three-year OS was 66 percent in patients <30 years and 36 percent in patients 30 to 59 years. For patients with one, two, or three unfavorable characteristics, three-year OS was 64, 49, and 21 percent, respectively. No patient with four adverse risk factors survived >3 years.

Cytogenetic/molecular features — Outcomes in ALL are associated with cytogenetic and molecular features of the blasts.

Patients with t(4;11), complex karyotype, or low hypodiploid/near triploidy have inferior rates of OS and event-free survival (EFS) [13]. By contrast, patients with high hyperdiploidy, del(9p), or a translocation involving chromosome band 14q11-13 had better outcomes [13-15]. A small percentage of patients with adult ALL (almost all <35 years) have t(12;21) and more favorable outcomes [16].

The relationship of cytogenetic abnormalities to relapse risk in ALL is discussed in greater detail separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

Measurable residual disease — Post-remission MRD is an indicator for relapse risk. Note that the definition of MRD negative is evolving. Some studies set the threshold at 10^-3, some used 10^-4, and the threshold may decrease further with the adoption of molecular techniques (eg, patient-specific IGH rearrangement) that are more sensitive than multicolor flow cytometry.

MRD positivity at the end of induction therapy is an independent marker for a higher risk of relapse [17,18]. Detection of MRD is associated with shorter disease-free survival using conventional chemotherapy, but this appears to be therapy dependent and may be affected by post-remission therapy.

The prognostic value of MRD in adults with ALL is discussed in greater detail separately. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in adults'.)

RISK STRATIFICATION — 

Each patient with ALL is assigned a risk category based on clinical and pathologic features associated with the risk of relapse.

Prognosis in adults with Ph-negative ALL is associated with clinical factors (eg, age, level of white blood cell [WBC] count), immunologic and cytogenetic features of the leukemic blasts, and the level of measurable residual disease (MRD) at the end of induction therapy, as described above. (See 'Risk factors' above.)

We use a modification of Hoelzer risk criteria to stratify risk at diagnosis in adults with ALL [19]. In this scheme, prognostic risk is based on outcomes of patients enrolled in prospective trials and validated with other prospective studies of risk-adapted consolidation therapy.

Other models can predict relapse risk in ALL, but high-risk criteria vary, and some outcomes may be treatment-dependent [12,20-22].

●High risk – Presence of any of the following [19]:

•Older age – >60 years old.

•High WBC count at diagnosis – >30,000/microL in B cell ALL; >100,000/microL in T cell ALL.

•Clonal cytogenetic abnormalities – t(4;11), t(1;19), t(9;22), or BCR::ABL1 gene positivity.

•Ph-positive/BCR::ABL1 – This category should now be considered separately from all other cases of B cell ALL because it is highly responsive to targeted therapy with tyrosine kinase inhibitors (TKIs). The widespread use of TKIs has greatly improved outcomes in Ph-positive ALL. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

•BCR::ABL1-like (Ph-like) gene signature. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'BCR::ABL1-like (Ph-like)'.)

•Progenitor-B cell immunophenotype – Blasts that express membrane CD19, CD79a, and cytoplasmic CD22, but not CD10. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

•Time to complete remission (CR) – >4 weeks to CR.

•MRD – Post-remission bone marrow MRD ≥10^-4 using patient-specific immunoglobulin gene rearrangement [18,23]. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

●Standard risk – None of the features listed above.

The prospective MRC UKALL XII/ECOG 2993 study illustrates the difference in outcomes for standard-risk and high-risk ALL using conventional multiagent chemotherapy and transplantation. In this study, five-year overall survival was 54 percent in 533 patients with standard-risk Ph-negative ALL compared with 29 percent in 590 patients with high-risk ALL [22].

STANDARD-RISK ALL

Consolidation phase — For patients with standard-risk Ph-negative ALL in complete remission (CR) after induction therapy, we suggest consolidation using multiagent chemotherapy and blinatumomab (anti-CD19 x CD3 bispecific T cell engager) rather than chemotherapy alone, blinatumomab alone, or hematopoietic cell transplantation (HCT).

Management of Ph-negative ALL is individualized, and treatment is evolving. Post-remission management should consider age, response to induction therapy, comorbidities, institutional approach, and patient preferences.

Our approach is based on the following findings:

●A randomized trial reported that, compared with chemotherapy alone, multiagent chemotherapy followed by blinatumomab achieved superior survival with modest incremental toxicity [24]; details of this trial are presented below. Although the trial included only patients with measurable residual disease (MRD) <10^-3, we suggest this approach for all patients with standard-risk Ph-negative ALL in CR after induction therapy, regardless of MRD status.

●Some experts instead favor allogeneic HCT for transplant-eligible patients in this setting, especially when there is persistent MRD. Transplantation and consolidation chemotherapy are associated with similar long-term survival, but allogeneic HCT is associated with greater toxicity, as described in studies below.

Note that if allogeneic HCT is pursued, one or two cycles of blinatumomab may be given prior to transplantation.

●There are only limited reports of blinatumomab alone for consolidation therapy. (See 'Immunotherapy' below.)

●Consolidation chemoimmunotherapy – In adults with standard-risk ALL in MRD-negative CR, chemoimmunotherapy achieved superior survival without excessive toxicity compared with chemotherapy alone.

•In a phase 3 trial of 224 adults (30 to 70 years) with MRD-negative CR (<10^-4 percent leukemic cells by flow cytometry) after induction/intensification therapy for ALL, adding four cycles of blinatumomab sequentially to combination chemotherapy achieved superior survival compared with combination chemotherapy alone [24]. Most patients (57 percent) had one or more high-risk features for relapse. The addition of blinatumomab to multiagent chemotherapy achieved superior three-year overall survival (OS; 85 versus 68 percent; hazard ratio [HR] for death 0.41 [95% CI 0.23-0.73]) and superior three-year relapse-free survival (RFS; 80 versus 64 percent; HR for relapse or death 0.53 [95% CI 0.32-0.87]). More grade ≥3 neuropsychiatric events occurred in the blinatumomab group than with chemotherapy only (23 versus 5 percent), but other adverse effects (AEs) did not differ.

Chemotherapy components of consolidation therapy are discussed below. (See 'Chemotherapy component' below.)

Patients receive maintenance therapy after completing chemoimmunotherapy consolidation. (See 'Maintenance therapy' below.)

●Allogeneic HCT versus consolidation chemotherapy – Long-term survival is similar with allogeneic HCT and consolidation chemotherapy, but transplantation is associated with more transplant-related mortality (TRM) and late AEs.

No randomized trials have directly compared allogeneic HCT with consolidation chemotherapy or chemoimmunotherapy for adults with Ph-negative ALL. Prospective studies have used "genetic randomization," in which allogeneic HCT was assigned to patients with a human leukocyte antigen (HLA)-matched sibling donor (MSD), while those without an MSD ("no-donor") received either consolidation chemotherapy or autologous HCT (depending upon trial design). However, it should be noted that outcomes have improved with both transplantation and consolidation chemotherapy since the publication of those studies. As an example, nonrelapse mortality (NRM) decreased as supportive care improved and lower-intensity conditioning regimens were more widely used for allogeneic HCT. Also, broader application of pediatric-inspired chemotherapy regimens (eg, inclusion of asparaginase and more dose-intensive nonmyelosuppressive agents) and availability of blinatumomab have improved outcomes with consolidation chemotherapy.

Studies that compared allogeneic HCT with consolidation chemotherapy for standard-risk ALL have yielded mixed results, but long-term survival is comparable with both approaches.

•A meta-analysis of "genetic randomization" studies reported better survival with allogeneic HCT compared with either consolidation chemotherapy or autologous HCT [25]. This analysis of 2962 patients with Ph-negative ALL in first CR (CR1) reported that allogeneic HCT was associated with superior OS (HR for mortality 0.87 [95% CI 0.79-0.96]) and fewer relapses (odds ratio [OR] 0.58 [95% CI 0.52-0.65]) but more TRM (OR 2.36 [95% CI 1.94-2.86]). The survival advantage with allogeneic HCT was seen only in patients <35 years (HR 0.79 [95% CI 0.67-0.94]) because TRM was greater in older patients. The studies included both standard-risk and high-risk patients with ALL, but data were not analyzed according to risk stratification.

•In another systematic review and meta-analysis, subgroup analysis of patients with standard-risk ALL reported that allogeneic HCT in CR1 was associated with improved OS compared with autologous HCT or chemotherapy (relative risk [RR] 0.8 [95% CI 0.68-0.94]) [26].

•According to an analysis of CIBMTR (Center for International Blood and Marrow Transplant Research) data, pediatric-inspired consolidation chemotherapy was associated with better outcomes than allogeneic HCT for adults with ALL in CR1 [27]. The study compared outcomes in 422 patients who underwent allogeneic HCT with 108 age-matched patients who received pediatric-inspired consolidation chemotherapy. Consolidation chemotherapy was associated with superior four-year OS (73 versus 45 percent; HR for mortality 3.12 [95% CI 1.99-4.90]), better disease-free survival (DFS; 71 versus 40 percent), less TRM (6 versus 37 percent), and a similar rate of relapse (24 versus 23 percent).

•For standard-risk ALL, MSD allogeneic HCT (96 patients) was associated with better outcomes than autologous HCT (161 patients) in prospective cooperative group studies by the Dutch-Belgian HOVON group [28]. Allogeneic HCT was associated with better five-year DFS (60 versus 42 percent; HR 0.60 [95% CI 0.41-0.89]), fewer relapses (24 versus 55 percent; HR 0.37 [95% CI 0.23-0.60]), and a trend toward better OS (HR 0.70 [95% CI 0.46-1.05]). Five-year OS was 69 percent and five-year NRM was 16 percent with allogeneic HCT.

•Patients with standard-risk ALL in CR1 who underwent MSD allogeneic HCT (if ≤50 years; later ≤55 years) had better survival than "no-donor" patients who were randomly assigned to chemotherapy versus autologous HCT in the UKALL XII/ECOG E2993 study [29]. Allogeneic HCT was associated with better five-year OS (62 versus 52 percent) but more two-year NRM (20 versus 7 percent).

Consolidation chemotherapy is associated with pancytopenia, infection, liver toxicity, and neuropathy, but most deaths are due to disease relapse. Toxicity is generally greater for patients who undergo allogeneic HCT. One-third of 538 patients who were treated in GMALL (German Multicenter Study Group for Adult ALL) studies underwent allogeneic HCT [30]. These protocols used pediatric-inspired approaches, including prophylactic central nervous system (CNS) radiation therapy (RT), intrathecal prophylaxis, consolidation that included high-dose methotrexate and cytarabine, and maintenance therapy. For the entire study population, with median follow-up of 7.5 years, two-thirds of patients experienced comorbidities involving the neurologic system (27 percent) and endocrine system (17 percent of males and 24 percent of females), and skin conditions (including alopecia; 18 percent). Transplanted patients had more late AEs, including graft-versus-host disease (GVHD) in 47 percent, and more neurologic symptoms, fatigue, and skin and eye disorders.

●Chemotherapy versus autologous HCT – For adults with ALL in CR1, compared with consolidation chemotherapy, autologous HCT is associated with inferior survival and greater toxicity. Autologous HCT is also associated with inferior survival and a higher rate of relapse, but there are fewer treatment-related AEs compared with allogeneic HCT in this setting.

•Among "no-donor" patients with standard-risk ALL in UKALL XII/ECOG E2993, consolidation chemotherapy achieved better outcomes than autologous HCT [29]. Patients with standard-risk ALL who were randomly assigned to consolidation chemotherapy had superior five-year OS (56 versus 46 percent) and less NRM (8 versus 16 percent) compared with patients assigned to autologous HCT.

•A meta-analysis of studies that randomly assigned autologous HCT versus consolidation chemotherapy for "no-donor" adults with ALL in CR1 reported a trend toward inferior survival for autologous HCT (OR for mortality 1.18 [95% CI 0.99-1.41]) [25].

•Other studies also found no benefit for autologous HCT in CR1 compared with consolidation chemotherapy [26,31,32]. Among patients who underwent autologous HCT in EWALL (European Working Group for Adult ALL) studies, outcomes were better in MRD-negative patients compared with those with MRD ≥10^-3 [33].

Chemotherapy component — No multiagent chemotherapy regimen has proven superior for consolidation therapy of ALL, and randomized trials have not directly compared various protocols. Ideally, consolidation therapy should reflect the regimen from the published protocol that was used for induction therapy.

Some experts favor a "pediatric" approach to consolidation therapy, which involves high cumulative doses of nonmyelosuppressive agents (eg, vincristine, glucocorticoids, asparaginase) and intensive/prolonged CNS prophylaxis [34]. Most pediatric-inspired protocols are based on BFM (Berlin-Frankfurt-Munster)-like regimens, with six to nine months of intensive induction/consolidation/delayed intensification therapy, followed by prolonged maintenance therapy. By contrast, "adult" regimens typically incorporated intensive myelosuppressive agents (eg, daunorubicin, cytarabine, cyclophosphamide), often followed by allogeneic HCT in CR1.

Consolidation chemotherapy for ALL comprises various chemotherapy agents with different mechanisms of action. It is administered in several courses (separated by short intervals) that span ≥6 months. The individual drugs vary by protocol but typically include cyclophosphamide, 6-mercaptopurine, cytarabine, vincristine, methotrexate, a glucocorticoid, and doxorubicin. The goal is to deliver these agents without severe cytopenias that cause treatment delays. It is difficult to analyze the contribution of each drug or dose schedule to the ultimate outcome because these regimens have evolved empirically, and few of the individual components have been tested rigorously.

Following are examples of commonly used multiagent chemotherapy regimens for ALL in adults:

●Standard or augmented BFM [35]

●Cancer and Leukemia Group B (CALGB) 9111 [14,36]

●CALGB 10403 (adults ≤39 years) [37,38]

●Dana Farber Cancer Institute (DFCI) ALL 00-01-based [39,40]

●Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and cytarabine, with or without rituximab [38,41,42]

●French GRAALL-2003 (for younger adults) [43,44]

Immunotherapy — Blinatumomab can eradicate persistent MRD after induction therapy for ALL, but there is limited experience with blinatumomab alone for consolidation therapy in adults in CR1, and it has not been directly compared with consolidation chemotherapy or chemoimmunotherapy in a randomized trial.

The addition of blinatumomab to multiagent chemotherapy for consolidation therapy is discussed above. (See 'Consolidation phase' above.)

Studies of blinatumomab for treating MRD in ALL include:

●Among 110 patients with Ph-negative ALL in CR with persistent MRD, 78 percent had MRD <10^-3 after blinatumomab 15 mg/m²/day for 28 days; 18-month RFS was 54 percent [45]. Two-thirds of patients subsequently underwent allogeneic HCT.

●Treatment with blinatumomab converted 16 of 20 evaluable patients (20 to 77 years) with MRD ≥10^-4 to MRD negativity. Most patients subsequently proceeded to allogeneic HCT. RFS was 61 percent after 33 months [46].

Blinatumomab is approved by the US Food and Drug Administration (FDA) for Ph-negative CD19+ B cell ALL in CR1 or second CR with MRD ≥0.1 percent in adults and children >1 month; it is approved in adults for the same indication by the European Medicines Agency (EMA).

Randomized trials that evaluated rituximab for consolidation in B cell ALL reported mixed results. The addition of four cycles of rituximab to standard induction therapy achieved longer median event-free survival (EFS; HR 0.66 [95% CI 0.45-0.98]) in the GRAALL 2005 trial [44], whereas the higher three-year EFS (51 versus 44 percent; HR 0.85 [95% CI 0.69-1.06]) in the UKALL14 trial did not reach statistical significance [47].

Maintenance therapy — For adults with ALL who complete consolidation chemotherapy, we suggest low-intensity maintenance therapy, rather than no maintenance therapy.

We administer maintenance therapy for ≥2 years, but the optimal duration of therapy is not well-defined. We recognize that there are only limited data to support the duration of maintenance therapy in adults. No randomized trials have tested the need for maintenance therapy, and no maintenance regimen has proven superior. Maintenance regimens generally include a backbone of daily oral 6-mercaptopurine (6-MP) and weekly methotrexate, typically with the addition of periodic vincristine and glucocorticoids for two to three years [2].

The optimal duration of therapy is undefined. Small, observational studies that omitted or shortened maintenance therapy have reported inferior outcomes, but it is uncertain if the poor results were caused by effects of maintenance therapy or other aspects of those regimens (eg, inadequate induction and consolidation treatment) [48-50].

Dosing of 6-MP can affect treatment outcomes and toxicity. Dose reductions may be needed for patients with polymorphisms of genes involved in 6-MP metabolism (eg, thiopurine methyltransferase [TPMT]) and/or in patients who experience hepatotoxicity; conversely, dose escalation may be needed in patients who do not experience myelosuppression during maintenance therapy. Bioavailability of 6-MP is affected by age, sex, and genetic polymorphisms [51]. In patients who experience myelosuppression at standard doses of 6-MP, the TPMT and NUDT15 (nucleoside diphosphate-linked moiety X motif 15) genotype should be evaluated [52]; some clinicians routinely evaluate TPMT genotype in all patients.

Patients remain at risk for infection during maintenance phase. Fever in patients receiving chemotherapy must be evaluated and treated aggressively, especially if the patient is either neutropenic or has a central venous access device. Trimethoprim-sulfamethoxazole, dapsone, pentamidine, or atovaquone prophylaxis may be used to prevent Pneumocystis jirovecii (P. carinii) pneumonia. Patients and their household contacts should not be given live-virus immunization while receiving chemotherapy. However, influenza vaccine should be given to all patients and their family members. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Immunizations in adults with cancer", section on 'General approach' and "Immunizations in adults with cancer", section on 'Live-virus vaccines'.)

There is no evidence that maintenance therapy ≥3 years is better than two years of maintenance therapy. A meta-analysis of 42 trials that included 12,000 children with ALL who received longer versus shorter maintenance therapy found no evidence that five years of maintenance was better than three years [53]. Outcomes are better in patients who achieve myelosuppression during maintenance phase, compared with patients who have higher neutrophil counts [54].

HIGH-RISK ALL — 

For patients with high-risk ALL in first complete remission (CR1), management is stratified according to the level of measurable residual disease (MRD) after induction therapy.

MRD negative — For MRD-negative CR (ie, <10^-4) high-risk ALL, we consider either consolidation chemoimmunotherapy followed by maintenance therapy or allogeneic hematopoietic cell transplantation (HCT) acceptable. This suggestion is based on comparable survival but more relapses with the former and more morbidity and treatment-related mortality with the latter.

The approach is individualized, including consideration of fitness, patient preference, donor availability, and the heterogeneity of outcomes in patients with high-risk ALL. Some experts favor allogeneic HCT in this setting, especially for patients with certain adverse genetic features (eg, t(4;11), complex karyotype, low hypodiploid/near triploidy), TP53 mutation or loss, or very high white blood cell (WBC) count (eg, >70,000/microL).

●Transplant eligible – The choice of consolidation therapy versus allogeneic HCT is individualized and influenced by age, comorbidities, institutional approach, and patient preferences.

•Chemoimmunotherapy – Outcomes of a trial (E1910) with blinatumomab-containing consolidation chemoimmunotherapy are described above; note that more than one-half of these MRD-negative patients had high-risk features for relapse. (See 'Standard-risk ALL' above.)

Some experts favor consolidation that includes high-dose methotrexate and/or cytarabine for patients with high-risk Ph-negative ALL, although no trials have directly compared consolidation regimens in this setting.

•Allogeneic HCT – Large studies of allogeneic HCT for ALL in CR1 reported approximately 60 percent five-year overall survival (OS) [28,29]. (See 'Standard-risk ALL' above.)

Many institutions limit allogeneic HCT to patients ≤70 years without significant comorbidities, as discussed below. (See 'Allogeneic transplantation' below.)

For patients with MRD-negative high-risk ALL in CR1 who plan to proceed to allogeneic HCT, some experts treat with one or two cycles of blinatumomab prior to transplantation. (See 'Immunotherapy' above.)

A retrospective study reported that outcomes were comparable with allogeneic HCT versus no-transplant management for MRD-negative adults with high-risk ALL in CR1 [55]. Some experts favor reserving allogeneic HCT until after subsequent relapse of MRD-negative high-risk ALL because outcomes were comparable with allogeneic HCT after relapse (ie, in second CR) and with allogeneic HCT in CR1.

●Not eligible for transplantation – For patients who are not transplant-eligible, we treat with consolidation chemoimmunotherapy followed by maintenance therapy, as discussed above. (See 'Standard-risk ALL' above.)

MRD positive — Management of MRD-positive (ie, ≥10^-4) ALL in high-risk patients is guided by age, fitness, institutional approach, and patient preference.

Transplant eligible — For transplant-eligible patients with high-risk MRD-positive CR1, we suggest allogeneic HCT after treatment with one or two cycles of blinatumomab.

The choice of a conditioning regimen and graft selection for transplantation are discussed below. (See 'Allogeneic transplantation' below.)

Results of studies that compared management in MRD-positive patients have been mixed. Although some studies reported a beneficial effect of matched sibling donor (MSD) HCT versus either autologous HCT or consolidation chemotherapy, most were performed before the routine assessment of MRD, and many used adult-like (rather than pediatric-based) consolidation chemotherapy comparator arms [1].

●One study reported better outcomes with allogeneic HCT than consolidation chemotherapy for patients with persistent MRD [18]. Among 66 patients ≤55 years with MRD-positive (≥10^-3) Ph-negative B cell ALL enrolled in GRAALL (Group for Research on Adult ALL)-2003 and GRAALL-2005, 37 underwent allogeneic HCT and 29 received consolidation chemotherapy. For patients with MRD ≥10^-3, allogeneic HCT was associated with superior OS (hazard ratio [HR] 0.43 [95% CI 0.21-0.90]) and better relapse-free survival (RFS; HR 0.36 [95% CI 0.18-0.73]). However, transplantation and consolidation chemotherapy were associated with comparable outcomes for patients with MRD <10^-3, as discussed above. (See 'Standard-risk ALL' above.)

●A systematic review and meta-analysis reported that for 1364 patients in seven randomized trials, high-risk ALL (as defined by various clinical and laboratory criteria in the individual trials) was associated with a trend toward improved OS with MSD allogeneic HCT in CR1 compared with autologous HCT or chemotherapy (relative risk [RR] 0.88 [95% CI 0.76-1.01]) [26]. Another meta-analysis reported better outcomes with MSD allogeneic HCT compared with consolidation chemotherapy or autologous HCT (for "no-donor" patients), but this study did not analyze the data according to risk category [25].

●Patients with high-risk ALL had better outcomes with MSD allogeneic HCT compared with "no-donor" patients who were randomly assigned to autologous HCT versus consolidation chemotherapy in the LALA-94 study [31]. For 82 patients who underwent allogeneic HCT, five-year OS was 51 percent; by comparison, autologous HCT was associated with 29 percent five-year OS (70 patients), while five-year OS was 21 percent (59 patients) with consolidation chemotherapy. Rates of relapse and transplant-related mortality (TRM) at five years were comparable for autologous HCT versus chemotherapy.

●In the PETHEMA ALL-93 study of adults with high-risk ALL, there was no difference in outcomes with allogeneic HCT versus either consolidation chemotherapy or autologous HCT [56]. The "no-donor" patients were randomly assigned to chemotherapy (48 patients) or autologous HCT (50 patients), while 84 patients with an MSD underwent allogeneic HCT. Analysis of allogeneic HCT versus "no-donor" management found no difference in five-year OS (44 versus 35 percent). There was no difference in five-year disease-free survival between allogeneic HCT, autologous HCT, and chemotherapy (50, 55, and 54 percent, respectively).

●For patients with high-risk Ph-negative ALL, there was no difference in OS between MSD allogeneic HCT compared with "no-donor" patients who were randomly assigned to autologous HCT or chemotherapy in the UKALL XII/ECOG E2993 trial of 1913 patients (15 to 59 years) [29]. For allogeneic HCT, high rates of nonrelapse mortality (NRM; 36 percent two-year NRM compared with 14 percent for "no-donor" patients) offset the lower rates of relapse (37 versus 63 percent). By contrast, patients with standard-risk disease had a survival advantage with HCT, as discussed above. (See 'Standard-risk ALL' above.)

●A prospective study compared allogeneic HCT, autologous HCT, and consolidation chemotherapy in 1484 adults with ALL in CR1 [29,57]. Patients <55 years with an MSD were assigned to allogeneic HCT, while others were randomly assigned to autologous HCT or chemotherapy. Subset analysis reported comparable five-year OS in high-risk Ph-negative patients.

Not transplant eligible — For patients with MRD-positive CR1 who are not eligible for allogeneic HCT, we treat with consolidation chemoimmunotherapy followed by maintenance therapy, as discussed above. (See 'Standard-risk ALL' above.)

ALLOGENEIC TRANSPLANTATION — 

Allogeneic hematopoietic cell transplantation (HCT) is effective for long-term disease control/cure of Ph-negative ALL, but it is associated with substantial toxicity. Most centers limit allogeneic HCT to medically fit patients <75 years, although age restrictions vary among institutions.

The choice of allogeneic HCT versus consolidation chemoimmunotherapy in first complete remission (CR1) is discussed above. (See 'Transplant eligible' above.)

●Allogeneic HCT uses conditioning therapy (also called preparative therapy) to reduce the burden of leukemic blasts. Conditioning regimens vary in intensity and use chemotherapy, radiation therapy, and/or immunotherapy, as discussed below. (See 'Conditioning regimen' below.)

●Blood cell formation in the transplant recipient is then restored by engrafting hematopoietic stem/progenitor cells from another individual (the donor). Immunologic differences between the allogeneic graft and the host provide an important graft-versus-leukemia (GVL) effect but also cause graft-versus-host-disease (GVHD). Donor choice is discussed below. (See 'Donor selection' below.)

●The allogeneic graft can be from peripheral blood stem/progenitor cells (PBSPC) or from bone marrow. The choice of PBSPC versus bone marrow affects the degree of GVL and GVHD. The selection of a graft source is discussed below. (See 'Graft source' below.)

Further discussion of allogeneic HCT is presented separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis", section on 'Overview of allogeneic HCT'.)

Conditioning regimen — The choice between myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), or nonmyeloablative (NMA) conditioning is guided by age, comorbidities, and institutional approach.

The availability of various conditioning regimens enables allogeneic transplantation in a large population of adults with ALL. Older patients (eg, ≥55 years) and patients with significant comorbidities generally receive RIC or NMA conditioning, but the upper limit for MAC differs among transplant centers. No clinical trials have randomly assigned MAC, RIC, and/or NMA conditioning for adults undergoing allogeneic HCT for Ph-negative ALL in CR1.

One study reported comparable outcomes for RIC versus MAC HCT in 576 adults ≥45 years undergoing allogeneic HCT for ALL; one-half of patients had Ph-negative ALL [58]. In multivariate analysis, compared with RIC, MAC HCT was associated with comparable leukemia-free survival (LFS) but more nonrelapse mortality (NRM) and fewer relapses.

Donor selection — The preferred donor for patients undergoing allogeneic HCT for ALL is a human leukocyte antigen (HLA)-matched sibling donor (MSD) or a matched unrelated donor (MUD).

Only one-quarter of patients with ALL have an available MSD, but MUD grafts provide comparable outcomes [59-61]. When neither MSD nor MUD is available, a haploidentical graft (ie, from a parent, child, or other relative) or umbilical cord blood (UCB) is an acceptable option. These alternative donor sources enable allogeneic HCT in most transplant-eligible adults with ALL.

Studies that compared donor sources for allogeneic HCT for adult ALL in CR1 indicate comparable outcomes between MSD and unrelated sources. Transplant-related mortality (TRM) was reported to be 13 percent of patients receiving MSD grafts and 21 percent with unrelated donor grafts [62].

●A prospective study of allogeneic HCT in 542 patients reported that MSD and unrelated donor grafts were associated with comparable five-year overall survival (OS), LFS, relapse, and TRM [63]. Two-thirds of patients (15 to 55 years) received MSD grafts. At five years, OS was 58 percent, NRM was 20 percent (one-half from infection), and relapse occurred in one-quarter of patients.

●For 917 patients undergoing allogeneic HCT for Ph-negative ALL in CR1, four-year OS and three-year LFS were comparable between MSD, unrelated donors, and UCB grafts [60].

●Outcomes with haploidentical grafts (using post-transplant cyclophosphamide prophylaxis) were comparable with other graft sources for adults with ALL [64]. A retrospective analysis reported that OS, LFS, NRM, relapse, and acute GVHD were comparable with MSD, MUD, 7/8 antigen unrelated donor, haploidentical, and UCB grafts. However, haploidentical grafts were associated with less chronic GVHD than MSD grafts; less NRM, grade ≥3 acute GVHD, and chronic GVHD than MUD grafts; better OS and less NRM, grade ≥3 acute GVHD, and grade ≥3 chronic GVHD than 7/8 HLA antigen unrelated donors; and less NRM and grade ≥3 acute GVHD than UCB grafts.

Graft source — Most allogeneic HCT for ALL in adults uses PBSPC grafts.

Filgrastim (granulocyte colony-stimulating factor; G-CSF)-stimulated PBSPC grafts are used for most allogeneic HCT in adults with ALL [65]. Compared with bone marrow grafts, PBSPC grafts are generally associated with comparable OS and fewer relapses but more GVHD.

The choice of PBSPC versus bone marrow as a graft source is discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Adverse effects

●Short-term – Acute adverse effects (AEs) of allogeneic HCT include pancytopenia, infections, mucositis, hepatic disease, and psychosocial effects. Long-term AEs include GVHD, chronic immune suppression, cytopenias, cataracts, lung dysfunction, secondary malignancies, and infertility. (See "Early complications of hematopoietic cell transplantation" and "Long-term care of the adult hematopoietic cell transplantation survivor" and "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)

●Late AEs – Late AEs in transplanted patients may be caused by chemotherapy or radiation therapy used for conditioning therapy, chronic GVHD, and personal risk factors.

Long-term follow-up of patients treated in GMALL (German Multicenter Study Group for Adult ALL) studies reported that, compared with patients who were not transplanted, allogeneic HCT was associated with more late AEs [30]. Transplanted patients had more impairment of performance status; fatigue; GVHD; infections; and endocrine, lung, eye, skin, kidney, and neurologic complications. Patients treated for ALL are at risk for second cancers, including hematologic malignancies and solid tumors (eg, breast, thyroid, gastrointestinal, lung, skin, urogenital, brain, sarcoma). Second cancers may be related to treatment with alkylating agents, epipodophyllotoxins, central nervous system irradiation, total body irradiation (TBI)-based conditioning regimens, and personal risk factors.

SUPPORTIVE CARE — 

Supportive care is a critical component of the treatment of patients with acute leukemia.

Supportive care for patients treated for acute leukemia includes management of cytopenias, infections, tumor lysis, and other complications, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

FOLLOW-UP — 

After the completion of maintenance therapy, patients in complete clinical remission should have a final bone marrow aspiration and biopsy repeated to assess for complete remission and measurable residual disease.

We generally evaluate patients by physical examination, complete blood count, and liver function tests (until normal) every one to two months in the first year after completing therapy. There is no evidence for further bone marrow examinations unless clinically indicated.

Patients are then seen every 3 to 6 months in the second year, and every 6 to 12 months after that.

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 – Induction therapy of Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) achieves complete remission (CR) in >80 percent of adults, but most patients relapse within weeks or months without post-remission therapy.

●Risk factors – Risk for relapse is associated with increased age, elevated white blood cell (WBC) count at presentation, cytogenetic/molecular features, and the level of measurable residual disease (MRD) after induction therapy. (See 'Risk factors' above.)

●Risk stratification – Post-remission management is stratified according to risk for relapse (see 'Risk stratification' above):

•High risk

-Age >60 years

-WBC count >30,000/microL at diagnosis

-Clonal cytogenetic abnormalities – t(4;11), t(1;19)

-Ph-like (BCR::ABL1-like) gene signature

-Progenitor B cell immunophenotype

->4 weeks to achieve CR

-MRD ≥10^-4 after induction therapy

•Standard risk – No high-risk features

●Post-remission management – Management is stratified according to risk for relapse, age, and medical fitness.

●Standard-risk ALL

•Consolidation phase – For adults with standard-risk Ph-negative ALL in CR after induction therapy, we suggest consolidating with chemotherapy followed by blinatumomab, rather than chemotherapy alone, blinatumomab alone, or allogeneic hematopoietic cell transplantation (HCT) (Grade 2C). We use this approach for all patients in CR, without regard to the level of MRD. (See 'Consolidation phase' above.)

Some experts favor treating with one or two cycles of blinatumomab followed by allogeneic HCT, especially for fit patients who have persistent MRD after initial therapy.

-Chemotherapy component – No regimen has proven superior for consolidation therapy, but we favor adhering to the treatment described in the protocol chosen for induction therapy. (See 'Chemotherapy component' above.)

-Immunotherapy – Blinatumomab is an anti-CD19 x CD3 bispecific T cell engager. (See 'Immunotherapy' above.)

•Maintenance therapy – We suggest low-intensity maintenance chemotherapy after completing consolidation phase, rather than no maintenance (Grade 2C). (See 'Maintenance therapy' above.)

We administer treatment for ≥2 years but recognize the limited data to support duration of maintenance therapy. (See 'Maintenance therapy' above.)

●High-risk ALL – Management is stratified according to the level of MRD, age, and medical fitness (see 'High-risk ALL' above):

•MRD negative – For high-risk ALL with MRD <10^-4 after induction therapy, we consider either consolidation chemoimmunotherapy followed by low-intensity maintenance chemotherapy or allogeneic HCT acceptable. The choice is individualized and informed by age, comorbidities, institutional approach, and patient preferences. (See 'MRD negative' above.)

Some experts favor allogeneic HCT following one or two cycles of blinatumomab.

•MRD positive – Guided by age, medical fitness, and patient preference:

-Transplant eligible – We suggest blinatumomab followed by allogeneic HCT rather than consolidation chemoimmunotherapy (Grade 2C). (See 'Transplant eligible' above.)

We administer one or two cycles of blinatumomab prior to transplant.

-Not transplant eligible – We suggest consolidation chemoimmunotherapy followed by low-dose chemotherapy maintenance therapy rather than consolidative chemotherapy alone (Grade 2C). (See 'Not transplant eligible' above.)

●Follow-up – Patients are followed for relapse and late effects of treatment. (See 'Follow-up' above.)