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

INTRODUCTION — Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, and long-term outcomes vary widely. More than 80 percent of adult patients attain complete remission (CR) with intensive induction chemotherapy, but virtually all will relapse without additional therapy.

Induction therapy aims to reduce the total body leukemia cell population from approximately 10¹² cells to <10⁹ cells (the cytologically detectable level of disease). Despite a clinical and morphologic CR at the end of induction, a substantial burden of leukemia cells (measurable residual disease [MRD]) remains and will lead to relapse within weeks or months without further treatment. By contrast, adults with standard-risk ALL who receive post-remission therapy may expect five-year survival rates up to 60 percent.

The goal of post-remission therapy is to eradicate residual disease using a risk-adapted approach that offers more intensive therapy to patients with a higher risk of relapse.

This topic reviews post-remission therapy for Philadelphia chromosome-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".)

RISK FACTORS — ALL is a heterogeneous disease. Outcomes in adults vary by clinical, cytogenetic, and molecular features at diagnosis and remission status at the time of first complete remission (CR1) [1].

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 unfavorable genetic features. (See 'Cytogenetic/molecular features' below.)

Older patients are also less able to tolerate the treatments used for ALL (eg, vincristine, asparaginase, corticosteroids), and doses are often reduced or eliminated. Older adults are also less able to tolerate myeloablative conditioning regimens used for allogeneic hematopoietic cell transplantation (HCT), but less intensive conditioning regimens, better donor matching, availability of unrelated donors, and better immunosuppressive agents and supportive care strategies have made transplantation more feasible in this population.

●White blood cell (WBC) ≥30,000/microL count at diagnosis.

●Time to CR1 – Achievement of CR by day 14 is associated with superior survival in adults and children with ALL [2-7].

Analysis of more than 400 adults with ALL treated on prospective clinical trials that used chemotherapy without transplantation as post-remission therapy identified more favorable long-term outcomes with age <30 years, WBC <30,000/microL at diagnosis, the presence of a mediastinal mass, T cell immunophenotype (with or without myeloid markers), and the absence of the Ph chromosome [8]. Patients with no adverse features had a 91 percent estimated three-year overall survival. Survival was a continuous function of age; three-year overall survival 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 overall survival was 64, 49, and 21 percent, respectively. None of the patients with four adverse risk factors survived >3 years.

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

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

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 measurable residual disease (MRD) is an independent marker of high-risk ALL.

MRD ≥10^-4 or ≥10^-3 at the end of induction therapy is an independent marker of high-risk disease [13,14]. Detection of MRD is associated with shorter disease-free survival using conventional chemotherapy, but this appears to be therapy dependent. MRD does not discriminate perfectly, and outcomes in patients with MRD can 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 — Adults are assigned a risk category based clinical features, tumor characteristics, and end of induction measurable residual disease (MRD). Risk factors for outcomes are described above. (See 'Risk factors' above.)

We use a modification of Hoelzer risk criteria to stratify risk in adults with ALL [15]. This risk stratification system was developed from analysis of prognostic factors in patients enrolled on prospective trials. Many of these characteristics have been used in other prospective trials that tested risk-adapted consolidation therapy. Other clinical models to predict relapse risk have been developed, but the high-risk subset varies somewhat from study to study and is in part treatment dependent [8,16-18].

●High risk – Any of the following features:

•Older age – >60 years old.

•High white blood cell count (WBC) 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 (the prognostic value of t(1;19) in adult ALL is less clear than in pediatric ALL [12]).

•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 – Time from start of induction therapy to attainment of complete remission >4 four weeks is of lesser importance.

•MRD – Post-remission bone marrow MRD ≥10^-3 using patient-specific Ig/TCR gene rearrangement [14,19]. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

●Standard risk – None of the features listed above.

OVERVIEW OF APPROACHES — There is no consensus for post-remission management of ALL in adults, and practices vary among institutions. Post-remission management is risk stratified and may include:

●Consolidation chemotherapy – Nonmyeloablative chemotherapy has a low treatment-related mortality rate (<5 percent). Common, major side effects are generally short-term and include pancytopenia, infection, hepatic impairment, and neuropathy.

●Immunotherapy – Bispecific antibodies (eg, blinatumomab) or immunoconjugates (eg, inotuzumab ozogamicin). These agents are approved for relapsed/refractory ALL and are moving into front-line therapy, particularly for patients with measurable residual disease (MRD) following remission induction.

●Cellular therapies – Autologous anti-CD19 chimeric antigen receptor T cells are approved for adults with relapsed/refractory ALL and are under investigation in front-line therapy for high-risk disease. Retrospective studies suggest that these agents are more effective when used in low-burden, MRD-positive disease rather than at overt relapse [20,21].

●Allogeneic hematopoietic cell transplantation (HCT) – Allogeneic HCT combines intensive (sometimes myeloablative) chemotherapy with a graft-versus-leukemia effect to effectively treat ALL, but it is associated with substantial toxicity. Adverse effects (including graft-versus-host disease, chronic cytopenias, and second cancers) and treatment-related mortality (approximately 10 to 20 percent) vary with age, comorbid conditions, other patient-related factors, and transplantation technique. (See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults", section on 'Quality of life'.)

Autologous HCT is rarely used in this setting because it doesn't improve outcomes compared with consolidation chemotherapy. (See 'Chemotherapy versus autologous transplant' below.)

Our approach is consistent with the European LeukemiaNet (ELN), the National Comprehensive Cancer Network (NCCN), and other expert groups [22,23].

CONSOLIDATION PHASE

Standard-risk disease — There is no clear consensus regarding the optimal consolidation therapy for patients with standard-risk ALL. Consolidation chemotherapy produces four-year survival rates of 40 to 60 percent. Common, major side effects include pancytopenia, infection, liver toxicity, and neuropathy. Most deaths are due to relapsed disease, and long-term treatment-related complications are rare. Alternatively, allogeneic hematopoietic cell transplantation (HCT) results in a lower relapse rate but higher rates of treatment-related mortality and morbidity resulting in similar rates of long-term survival. By contrast, autologous HCT does not appear to improve on the results seen with consolidation chemotherapy or allogeneic HCT in this population.

There have been no randomized trials directly comparing consolidation chemotherapy with allogeneic HCT. Comparative analyses have had mixed results with some suggesting that allogeneic HCT may result in higher long-term overall survival and others reporting that it does not. Given this uncertainty, all patients should be encouraged to participate in clinical trials. We offer the following guidance for the treatment of patients who are either not candidates for clinical trials or choose not to participate.

For most patients with standard-risk ALL in first complete remission (CR1), we suggest the use of consolidation chemoimmunotherapy rather than either allogeneic or autologous HCT. This preference places a relatively high value on avoiding the higher short-term mortality and long-term morbidity associated with HCT and a low value on the potential, but uncertain, ability of the more intensive transplant therapy to eliminate residual disease.

Chemotherapy — Consolidation chemotherapy for ALL consists of a variety of chemotherapy agents with different mechanisms of action administered in combinations over several courses at short intervals that span a total of approximately seven months. The individual drugs used vary by protocol but typically include cyclophosphamide, 6-mercaptopurine, cytarabine, vincristine, methotrexate, prednisone or dexamethasone, and doxorubicin. Central nervous system prophylaxis with either intrathecal chemotherapy or cranial radiation therapy is incorporated as well. The goal is to deliver high doses of these agents without causing severe cytopenias that lead to treatment delays. Blinatumomab has been approved for patients in CR1 with positive measurable residual disease (MRD).

These regimens have evolved empirically with few of the individual components tested rigorously in randomized trials. Thus, it is difficult to analyze critically the absolute contribution of each drug or dose schedule to the ultimate outcome. Numerous nonrandomized trials have attempted to answer these questions, but multiple alterations in study design between sequential trials have made it difficult to assess the exact merit of each modification.

Several nonrandomized studies strongly suggest a benefit from intensive multiagent post-remission chemotherapy. By contrast, prospective studies evaluating even more intensive chemotherapy regimens have not demonstrated improved outcomes [16,17,24-28]. The following are examples of the most commonly used chemotherapy regimens for ALL in adults:

●Cancer and Leukemia Group B (CALGB study 9111) ALL regimen [10,29].

●Cancer and Leukemia Group B (CALGB study 10403) ALL regimen for adolescents and young adults up to age 39 [30,31].

●Dana Farber Cancer Institute (DFCI) ALL regimen based on DFCI Protocol 00-01 [32,33].

●Standard or augmented Berlin-Frankfurt-Munster (BFM) [34].

●Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) alternating with high-dose methotrexate and cytarabine with or without rituximab [31,35,36].

●French GRAAL-2003 regimen for younger adults [37]. The design of the GRAALL-2005 study was similar to the GRAALL-2003 trial, with the addition of randomized evaluation of hyperfractionated cyclophosphamide during induction and late intensification, as well as randomized evaluation of rituximab in patients with CD20-positive, Ph-negative ALL (n = 209; median age, approximately 40 years; range, 18 to 59 years) [37,38].

None of these regimens has been directly compared in a prospective randomized trial. As such, there is no single best regimen for post-remission therapy. In general, the consolidation chemotherapy regimen should be consistent with the induction regimen that was chosen at the time of diagnosis. This choice should be made based upon the physician's comfort with administration and patient characteristics. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Chemotherapy'.)

Immunotherapy — The bispecific antibody blinatumomab has been approved for the treatment of relapsed CD19+ B-lineage ALL as well as for post-remission therapy in frontline regimens [39]. Similarly, the anti-CD22 immunoconjugate inotuzumab ozogamicin has also been approved for relapsed or refractory B-lineage ALL, and it is now being evaluated as post-remission therapy for adults with ALL.

Chemotherapy versus allogeneic transplantation — Consolidation chemotherapy has not been directly compared with allogeneic HCT in randomized trials. Instead, investigators in prior studies have relied on a "genetic randomization" in which patients are assigned to treatment with or without allogeneic HCT based on the presence or absence of a human leukocyte antigen (HLA)-matched sibling donor. Patients without an HLA-matched sibling are assigned to treatment with either chemotherapy alone or autologous HCT, depending upon the trial design. Results are then evaluated by an intention-to-treat analysis for "donor" and "no donor" (available) treatment groups. As with randomized trials, not all patients in the "donor" group ultimately receive an allogeneic HCT, but they would still be included in the "donor" group for the statistical analysis.

There is clearly more treatment-related mortality as well as later morbidity after allogeneic HCT than after chemotherapy alone. However, the relapse rate is reduced by allogeneic transplantation. Younger age (<35 years), better transplantation methods, and availability of an optimal donor may favor allogeneic HCT in CR1. This is discussed in more detail separately. (See 'Allogeneic transplant versus chemotherapy' below.)

Allogeneic transplantation is more fully described below. (See 'Allogeneic transplantation' below.)

Chemotherapy versus autologous transplant — Autologous HCT is rarely performed but has been used experimentally for patients with ALL who are not candidates for allogeneic HCT. It is associated with fewer treatment-related complications, largely due to the lack of graft-versus-host disease (GVHD). In addition, developments in technology and supportive care have made autologous HCT available for larger numbers of patients, including older adults. However, autologous HCT does not have a graft-versus-leukemia (GVL) effect, which is a key component of the transplantation process. As described above, prospective randomized trials have reported that event-free and overall survival rates with autologous HCT are either similar or inferior to those obtained with consolidation chemotherapy [40-47]. (See 'Chemotherapy versus allogeneic transplantation' above.)

As an example, in the French LALA-87 trial described above, patients 15 to 40 years of age who lacked an HLA-identical sibling and those 40 to 50 years of age and still in CR1 after two courses of consolidation chemotherapy were randomly assigned to autologous HCT or to maintenance chemotherapy [40,41]. There were no differences in overall survival (34 versus 29 percent in the chemotherapy arm) or in survival in either the high-risk (16 versus 11 percent) or standard-risk (49 versus 40 percent) subgroups.

The main cause for failure after autologous HCT for ALL is a high relapse rate. The factors implicated in this process include the inefficiency of the conditioning regimen in eradicating leukemia, the lack of GVHD/GVL, and the contamination of the stem cell graft by leukemic cells. Data indicate that the autograft can be the source of recurrent ALL cells in some cases [48]. However, it is equally likely that many relapses arise from residual disease in the subject not from graft contamination. This may be the main reason why purging bone marrow in vitro has no detectable impact on relapse [49].

Maintenance chemotherapy has not commonly been used after autologous HCT, although one study reported a probability of survival of 53 percent at 10 years when autologous HCT was followed by two years of maintenance chemotherapy for adults in CR1 [47]. On the other hand, a randomized trial evaluating interleukin 2 (IL-2) after autologous HCT showed no benefit [46].

High-risk disease — Patients with high-risk disease, as defined above, do poorly when treated with consolidation chemotherapy alone after attainment of a CR1; rates of 10-year overall survival with this approach are approximately 10 percent. By contrast, treatment with allogeneic HCT provides an additional GVL effect together with myeloablative chemotherapy, resulting in superior survival rates of approximately 45 percent at 10 years.

For young patients with high-risk ALL in CR1 who have an HLA-matched donor, we recommend allogeneic HCT rather than consolidation chemotherapy or autologous HCT. Unfortunately, many patients achieving a CR are excluded from HCT due to early relapse, comorbid medical conditions, lack of insurance, or lack of a suitable HLA-matched donor. Alternative hematopoietic stem cell sources such as umbilical cord blood or haploidentical donors should be considered. For patients with high-risk ALL in CR1 who are not eligible for allogeneic HCT because of older age or comorbidities, we suggest consolidation chemotherapy rather than autologous HCT. Alternatively, these patients may be considered for reduced-intensity allogeneic HCT as part of a clinical trial [50].

For some older adults with high-risk ALL in CR1, allogeneic transplantation, when compared with standard chemotherapy, offers the advantage of an intensive therapy administered over a shorter period of time with a more rapid recovery of blood counts from the donor's normal hematopoietic progenitor cells. This compares with two to three years of continuous immunosuppression required for standard chemotherapy to have a good chance of curing their leukemia. Thus, some older patients may benefit from an allogeneic transplant in CR1 while they are otherwise healthy and well-nourished with minimal residual disease rather than attempt a transplant later after a relapse when they are sicker and may have more refractory disease present. Nevertheless, transplantation has morbidities that are not present with chemotherapy, such as GVHD, which, if it occurs, can be difficult for older patients to survive. Less intensive conditioning regimens, better donor matching and availability of unrelated donors, and better immunosuppressive agents and supportive care strategies have extended the transplant eligibility age to greater than 70 years.

Patients with Philadelphia chromosome-positive ALL require specialized therapy; this is discussed in more detail separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Allogeneic transplantation — When used for young adults with high-risk disease, allogeneic HCT results in 10-year overall survival rates of approximately 45 percent [51,52]. Short-term morbidities include pancytopenia, infections, mucositis, hepatic disease, and psychosocial effects. Long-term complications include GVHD, chronic immune suppression, cytopenias, cataracts, lung dysfunction, secondary malignancies, and infertility. (See "Hematopoietic support after hematopoietic cell transplantation" and "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".)

For patients >60 years who may not be eligible for myeloablative conditioning, reduced-intensity conditioning may be an acceptable approach [53]. Details related to allogeneic transplantation in adults with ALL, including donor selection, preparative chemoradiotherapy regimens, and the GVL effect are presented separately. (See "Hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) in adults".)

Outcomes with allogeneic HCT compared with chemotherapy are presented in the following section.

Allogeneic transplant versus chemotherapy — Consolidation chemotherapy has not been directly compared with allogeneic HCT in randomized trials. Instead, investigators have relied on a "genetic randomization" in which patients are assigned to treatment with or without allogeneic HCT based on the presence or absence of an HLA-matched sibling donor. Patients without an HLA-matched sibling are assigned to treatment with either chemotherapy alone or autologous HCT, depending upon the trial design. Results are then evaluated by an intention-to-treat analysis for "donor" and "no donor" (available) treatment groups. As with randomized trials, not all patients in the "donor" group ultimately receive an allogeneic HCT, but they would still be included in the "donor" group for the statistical analysis. Similarly, some patients in the "no donor" group will go on to receive a matched unrelated allogeneic HCT, but they would still be included in the "no donor" group for statistical analysis.

These donor versus no donor comparisons have had conflicting results. The following are examples of some of the largest donor versus no donor comparisons:

●The French LALA-87 trial investigated the use of allogeneic HCT, autologous HCT, or consolidation chemotherapy for 436 patients with ALL in CR1 [40,41]. Patients aged 15 to 40 years underwent HLA-typing, and 116 had an HLA-identical sibling, 98 of whom underwent a matched sibling HCT. Those without an HLA-identical sibling and patients 40 to 50 years old were randomly assigned treatment with either autologous HCT (95 patients) or chemotherapy (96 patients). All patients over 50 years were treated with chemotherapy alone (58 patients). In a donor versus no donor comparison of the transplant-eligible group, there was no significant difference in median disease-free survival (24 versus 22 months) or overall survival (51 versus 30 months) for those patients with or without sibling donors [54]. On subgroup analysis of the 161 patients with standard-risk ALL, there was no significant difference in median survival (not reached versus 56 months) or disease-free survival (27 versus 30 months) for those who did or did not have a matched sibling. On subset analysis, however, allogeneic HCT was associated with a significant survival advantage (44 versus 11 percent in controls) in the high-risk patients defined as Ph+ ALL, null or undifferentiated immunophenotype, or common ALL with either age greater than 35 years, white blood cell (WBC) >30,000/microL, or time to achieve CR greater than four weeks.

●An international (MRC/ECOG) ALL trial was a collaborative prospective, randomized trial that compared these same three consolidation strategies in 1484 adults with ALL in CR1 [42,43]. Patients younger than 55 years who had an HLA-matched sibling donor were assigned to allogeneic HCT. Other patients were randomly assigned to autologous HCT or chemotherapy for 2.5 years. At a median follow-up of five years, the following results were reported:

•Evaluation of the 1031 patients who were younger than 55 years found that patients with a donor had a significantly higher five-year overall survival rate (53 versus 45 percent). However, this difference did not retain its significance in a subset analysis of the high-risk patients without the Ph chromosome (41 versus 35 percent). This was likely due to a higher two-year nonrelapse mortality rate among the high-risk patients with a donor when compared with the standard-risk patients with a donor (36 versus 20 percent). On a subset analysis of the 562 standard-risk patients, patients with a donor had a significantly lower relapse rate at 10 years (24 versus 49 percent), a higher nonrelapse mortality rate at two years (19.5 versus 6.9 percent), and a higher overall survival rate (62 versus 52 percent) when compared with those without a donor.

•Patients randomized to receive chemotherapy had significantly improved rates of five-year event-free (41 versus 32 percent) and overall (46 versus 37 percent) survival when compared with those who were randomized to autologous HCT.

●A Dutch-Belgian prospective trial that included 288 patients younger than age 55 with standard-risk ALL in CR1 assigned therapy based on the availability of a sibling donor [55]. Patients with a donor were assigned allogeneic HCT while those without a donor were assigned autologous HCT. Patients who had a donor demonstrated a significantly lower incidence of relapse (24 versus 55 percent), superior disease-free survival (60 versus 42 percent), and improved overall survival (69 versus 49 percent) at five years.

●A 2013 meta-analysis included individualized data from 2962 patients with Philadelphia chromosome-negative ALL in CR1 enrolled in 13 trials with "genetic randomization" to allogeneic HCT [56]. The identification of a matched sibling donor was associated with the following outcomes:

•Fewer relapses (odds ratio [OR] 0.58; 95% CI 0.52-0.65).

•Higher treatment-related mortality (OR 2.36; 95% CI 1.94-2.86).

•Superior overall survival (hazard ratio [HR] 0.87; 95% CI 0.79-0.96).

•High-risk ALL was defined by a WBC count at diagnosis >30,000/microL in B-ALL or >100,000/microL in T-ALL. For patients classified as having high-risk disease, overall survival was not significantly improved for those with a matched sibling (HR 0.90; 95% CI 0.71-1.14).

•The survival benefit was most apparent in patients <35 years (HR 0.79; 95% CI 0.67-0.94) and was not demonstrated in patients ≥35 years (HR 1.01; 95% CI 0.81-1.26). This appeared to be due to a decreased treatment-related mortality in patients <35 years (32 versus 19 percent in those with donors).

●An evidence-based review concluded that allogeneic HCT offers a survival benefit in selected patients with ALL [57]. There are consensus recommendations and standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for younger adult ALL, resulting in higher remission rates and overall survival. This, in turn, has increased the equipoise around decision making for ALL in CR1 when there is no MRD at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy and immunotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

There is clearly more treatment-related mortality as well as later morbidity after allogeneic HCT than after chemotherapy alone. However, the relapse rate is reduced by allogeneic transplantation. Younger age (<35 years), higher-risk ALL (such as Ph-like ALL), better transplantation methods, and availability of an optimal donor may favor allogeneic HCT in CR1.

MAINTENANCE THERAPY — Remission maintenance therapy is a standard component of the management of ALL and is given for two to three years after consolidation therapy. In general, maintenance therapy is not used after allogeneic hematopoietic cell transplantation (HCT), although a tyrosine kinase inhibitor (eg, imatinib, dasatinib) is sometimes offered after allogeneic HCT as maintenance to patients who had Philadelphia chromosome-positive disease. This is discussed in more detail separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Most standard maintenance regimens consist of daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine and prednisone (ie, prednisone or dexamethasone plus vincristine, methotrexate, and 6-mercaptopurine [POMP]) or dexamethasone. Yet, the efficacy of maintenance therapy in adults has not been assessed via a randomized trial. Trials omitting or shortening maintenance therapy appear to produce inferior results than those obtained with maintenance. In addition, longer maintenance may not improve on results seen with two years of maintenance. The optimal duration and timing for maintenance treatment is unknown.

Two prospective studies that omitted maintenance treatment following the completion of consolidation therapy are notable for short disease-free survival times when compared with historical controls:

●In CALGB study 8513, in which all treatment was completed after 29 weeks, the median remission duration was only 11 months [58]. This was markedly shorter than the 21-month remission duration seen in the earlier CALGB study 8011 in which three years of therapy were administered [24]. Median survival was also inferior in the group that received shorter therapy (19 versus 30 months).

●ECOG studies 2483 and 3486 treated a total of 336 patients with induction followed by intensive 12-month consolidation but no maintenance therapy. The median disease-free survivals were only 9 and 11 months, respectively [25].

It is unclear if the poor results seen in these studies of shortened therapy are due to inadequate initial induction and consolidation treatment or the lack of prolonged maintenance therapy.

A meta-analysis of 42 trials that included 12,000 children with ALL who received longer versus shorter maintenance therapy reported that there was no evidence that five years of maintenance was better than three years [59]. However, when compared with those who received two years of maintenance, patients given three years of maintenance had lower combined rates of relapse or death (23 versus 28 percent).

For patients who are still in complete remission after completing consolidation chemotherapy, we recommend two to three years of maintenance chemotherapy. The most commonly used regimen is POMP, administered for three years.

During maintenance therapy, patients remain at risk for infection. Fever in patients who are 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'.)

If there is unexpectedly severe or prolonged myelosuppression in patients taking 6-mercaptopurine, the medication should be stopped and an analysis obtained for thiopurine methyltransferase activity, if this had not already been assayed at initial diagnosis. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

If symptoms or routine neurologic examination suggest any weakness in cranial nerves, a lumbar puncture and evaluation for central nervous system leukemia should be performed [60].

SUPPORTIVE CARE — Supportive care is a critical component to the treatment of patients with acute leukemia. This includes the management of cytopenias, infections, tumor lysis, and other complications that accompany the treatment of acute leukemia. These are discussed in more detail separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

FOLLOW-UP — After the completion of maintenance therapy, patients in complete clinical remission have a final bone marrow aspiration and biopsy repeated to assess for residual or relapsed disease. It is uncertain whether periodic surveillance bone marrow examination leads to better overall outcomes than monitoring for changes in the circulating blood counts. This is discussed in more detail separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Evaluation for relapse or resistance'.)

Long-term survivors of ALL can develop late adverse effects related to treatment, including central nervous system impairment, peripheral neuropathy, cardiotoxicity, infertility, avascular necrosis of bone, and an increased incidence of secondary cancers, as well as an overall decreased health status due to such factors as neurocognitive dysfunction, depression, fatigue, and anxiety. The occurrence of specific complications depends upon the patient's age and the type and intensity of therapy with which they were treated. These long-term side effects are discussed in more detail separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Late effects' and "Long-term care of the adult hematopoietic cell transplantation survivor".)

YOUNGER ADULTS — Retrospective data supporting the use of regimens developed by pediatric cooperative groups that emphasize more aggressive central nervous system prophylaxis, increased use of antimetabolites, and repeated administration of nonmyelosuppressive agents, including vincristine and asparaginase, have led to ongoing studies assessing such approaches in previously untreated patients with ALL up to age 40 [34,61]. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

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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 – Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, and outcomes vary by clinical, cytogenetic, and molecular features. Although >80 percent of adult patients attain a first complete remission (CR1) with intensive induction chemotherapy, most will relapse within a few weeks or months if they do not receive post-remission therapy.

●Risk factors – Age, other patient-related factors, cytogenetic features, and persistent measurable residual disease (MRD) are associated with outcomes in adult ALL. (See 'Risk factors' above.)

●Risk stratification – We classify adults with ALL according to clinical, cytogenetic/molecular features, and MRD status at the end of induction therapy, as discussed above. (See 'Risk stratification' above.)

●Post-remission treatment options – Most clinicians use a risk-adapted approach to post-remission management, but there is no standard post-remission therapy for all adults with ALL. Options for consolidation phase include (see 'Overview of approaches' above):

•Consolidation chemotherapy

•Immunotherapy – Bispecific antibodies or immunoconjugates

•Cellular therapies – Anti-CD19 chimeric antigen receptor T cells

•Allogeneic hematopoietic cell transplantation (HCT)

●Standard risk – For most patients with standard-risk ALL in CR1, we suggest consolidation chemotherapy rather than allogeneic HCT (Grade 2B). (See 'Standard-risk disease' above.)

●High risk – For patients with high-risk ALL in CR1 who are candidates for allogeneic HCT, we suggest allogeneic HCT rather than chemotherapy (Grade 2B).

For patients with high-risk ALL who are not transplant eligible, we treat with consolidation chemotherapy.

●Maintenance therapy – For patients who remain in CR1 after completing consolidation chemotherapy, we recommend two to three years of maintenance chemotherapy rather than observation (Grade 1B). (See 'Maintenance therapy' above.)

●Follow-up – Patients are followed for signs and symptoms of relapsed disease or late effects of treatment. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Evaluation for relapse or resistance' and "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Late effects'.)