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

INTRODUCTION — Over 80 percent of adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) will attain a complete remission (CR) with intensive induction chemotherapy. However, without additional cytotoxic therapy, virtually all of these patients will relapse within a few weeks or months. In contrast, patients who receive post-remission therapy may expect five-year survival rates up to 60 percent in adults with standard-risk disease.

Induction therapy aims to reduce the total body leukemia cell population from approximately 10¹² to below the cytologically detectable level of about 10⁹ cells. It is generally assumed, however, that a substantial burden of leukemia cells persists undetected in patients in initial clinical and morphologic CR (ie, "minimal residual disease"), leading to relapse within a few weeks or months if no further therapy were administered.

The primary aim of post-remission therapy (eg, consolidation, intensification) is to eradicate this minimal residual disease. There are three basic options for post-remission therapy (in order of increasing intensity): consolidation plus maintenance chemotherapy, autologous hematopoietic cell transplantation (HCT), or allogeneic HCT. The choice among these for an individual patient depends upon a number of factors, including:

●Expected rate of relapse with consolidation chemotherapy alone (influenced strongly by the patient and tumor characteristics)

●Expected morbidity and mortality associated with treatment options (as determined by patient characteristics such as age and comorbidities)

●Salvage (or rescue) therapies available for the treatment of relapsed disease

In general, a risk-adapted treatment approach is used that offers more intensive therapy to patients with a higher risk of relapse. This topic review will discuss the post-remission therapy for Philadelphia chromosome negative ALL in adults. The following related subjects are presented separately:

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

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

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

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

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

●The clinical and pathologic features and diagnosis of ALL in adults. (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".)

RISK STRATIFICATION — ALL is a heterogeneous disease and outcomes vary by clinical, cytogenetic, and molecular features. Patients should be evaluated at the time of first complete remission (CR1) to determine their expected risk of relapse [1].

Identifying high-risk disease — In general, patients are categorized as having standard or high-risk disease based on a combination of clinical features and tumor characteristics. There is increasing evidence regarding the prognostic importance of end-of-induction measurable residual disease (MRD, also called minimal residual disease) level. While MRD measurement is not available at all centers, it should be incorporated into this assessment when available.

While many variations in risk stratification have been proposed, we use the following risk stratification system (ie, a modification of the Hoelzer risk criteria) [2].

Patients with any of the following characteristics are considered to have high-risk disease:

●High white blood cell count at diagnosis (ie, >30,000/microL in B-ALL or >100,000/microL in T-ALL).

●Clonal cytogenetic abnormalities – t(4;11), t(1;19), t(9;22), or BCR-ABL gene positivity. The prognostic value of t(1;19) in adult ALL is less clear than in pediatric ALL [3].

●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 (eg, blasts expressing membrane CD19, CD79a, and cytoplasmic CD22, but not CD10). (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

●Length of time from start of induction therapy to attainment of CR greater than four weeks is of lesser importance.

●Older age – >60 years old is high risk, 30 to 59 years old is intermediate risk.

●MRD – A post-remission bone marrow MRD level ≥10^-3 using patient-specific Ig/TCR gene rearrangement [4]. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

In comparison, patients with none of the above characteristics are generally considered to have standard-risk disease. This risk stratification system was developed based upon analyses of prognostic factors in patients enrolled on prospective trials and many of these characteristics have been used in other prospective trials that have tested a risk-adapted approach to consolidation therapy.

While MRD after induction can define a group of patients with ALL at high risk for relapse, the following caveats must be considered:

●Detection of MRD is predictive of shorter disease-free survival using conventional treatment regimens. Its importance is likely therapy-dependent and may change as better therapies are developed.

●There are no randomized trials evaluating the efficacy of altering treatment based on MRD after induction in adults with ALL. The detection of MRD may simply identify ALL that will not respond well to any intervention, standard or novel.

●Some patients with MRD after induction have appeared to be cured with conventional chemotherapy and without escalation of therapy. Thus, this laboratory measurement does not discriminate perfectly.

●Some patients with MRD after conventional chemotherapy have converted to MRD negative status after prolonged infusions of blinatumomab, a bispecific anti-CD19/anti-CD3 antibody, but the long-term efficacy of this intervention has not been test in a randomized trial.

The effect of these clinical features on relapse risk is described below. The effect of cytogenetic abnormalities on relapse risk is described separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

Clinical features — As mentioned above, numerous clinical models of relapse risk have been developed [5-8]. The high-risk subset varies somewhat from study to study and is in part treatment-dependent. However, older age and the presence of the Philadelphia (Ph) chromosome have been universally identified as markers of poor prognosis. Post-remission therapy for Ph chromosome positive ALL is presented separately. (See "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

As an example, an analysis of more than 400 adults with ALL treated on prospective clinical trials that principally used chemotherapy without transplantation as post-remission therapy identified the following clinical and biologic features, which correlate with favorable long-term outcome: age <30 years, white blood cell count <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 [5]:

●Patients with no adverse features had a 91 percent estimated probability of survival at three years (95% CI 66-98 percent).

●Survival was a continuous function of age. The three-year survival rates were 66 and 36 percent for patients less than 30 and those 30 to 59 years old, respectively.

●The estimated three-year survival rates of patients with one, two, or three unfavorable characteristics (as defined above) were 64, 49, and 21 percent, respectively. None of the patients with four adverse risk factors survived more than three years.

Studies in children and adults with ALL have also identified the time to initial complete remission (CR) as a marker of prognosis; those patients who achieve CR by day 14 have superior survival rates [9-14]. As an example, a controlled trial of 2090 children with ALL randomly assigned to receive either standard or intensified therapy reported that the blast percentage on day eight of therapy was a significant predictor of prognosis [9]. Patients with 25 percent or fewer bone marrow blasts on day eight had higher rates of progression-free survival at three years (eg, 74 versus 62 percent, respectively).

Although not available at all centers, a post-remission minimal residual disease (MRD, also called measurable residual disease) level ≥10^-4 or ≥10^-3 is an independent marker of high-risk disease [4,15]. The prognostic value of MRD in this setting is discussed in detail separately. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in adults'.)

Patients with Ph+ ALL, t(4;11), t(8;14), complex karyotype, or low hypodiploid/near triploidy have inferior rates of event-free and overall survival [16]. In contrast, patients with high hyperdiploidy, del(9p), or a translocation involving chromosome band 14q11-13 had a significantly improved outcome [16-18]. A small percentage of patients with adult ALL, almost all under 35 years of age, have t(12;21) and a favorable outcome [3].

Older age — As described above, older age has been a determinant of outcome in adult ALL chemotherapy series for several decades. This is largely due to two factors:

●Unfavorable genetic features are more common in older adults (more Ph+ cases; fewer cases of T cell ALL) – The impact of these unfavorable genetic features is likely to change as the prognosis for Ph+ ALL has improved with the use of tyrosine kinase inhibitors in combination with less intensive chemotherapy. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults" and "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

●Older patients do not tolerate as well the intensive and prolonged chemotherapy used in younger adults – Mainstays of ALL treatment, such as vincristine, asparaginase, and corticosteroids, are not well tolerated by older adults, and doses are often reduced or eliminated. Older patients also cannot tolerate myeloablative conditioning regimens prior to allogeneic hematopoietic cell transplantation. Less intensive conditioning regimens, better donor matching and availability of unrelated donors, and better immunosuppressive agents and supportive care strategies have made transplant more feasible in this population.

As such, it is important to remember that "risk factors" are always relative to available treatments, and fortunately these are improving, both for chemoimmunotherapy for ALL and for allogeneic transplantation. Chronological age alone is probably not a high risk factor but only a surrogate for inability to tolerate curative treatment for subtypes of ALL that are biologically relatively resistant to conventional chemotherapy.

CONSOLIDATION AND INTENSIFICATION

Overview — As mentioned above, the three main options for consolidation therapy (in order of increasing intensity) are:

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

●Autologous hematopoietic cell transplantation (HCT) – Autologous HCT allows the use of myeloablative chemotherapy and is not associated with graft-versus-host disease (GVHD), but does not provide the graft-versus-leukemia (GVL) effect seen with allogeneic HCT. Treatment-related morbidity and mortality are relatively low (≤6 percent). 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.

●Allogeneic HCT – Allogeneic HCT targets cancer cells both by administering intensive and sometimes myeloablative chemotherapy and by harnessing a GVL effect. Treatment-related mortality is high on average (approximately 20 percent), but varies in individuals according to patient-related transplantation risk factors (eg, age, comorbid conditions). In addition, allogeneic HCT can result in significant morbidity associated with GVHD, chronic cytopenias, second malignancies, cataracts, and sterility. (See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults", section on 'Quality of life'.)

There is great variability in practice and it remains controversial how intensive post-remission therapy should be, but most clinicians use a risk-adapted treatment approach where patients with disease at high risk for relapse are treated with more aggressive therapy (eg, allogeneic HCT) than patients at standard risk for relapse. This approach minimizes exposure to potentially toxic therapies in patients expected to respond well to conventional chemotherapy while providing maximum antitumor activity for patients with more difficult-to-treat disease.

The following sections describe our approach to the treatment of standard- and high-risk disease. Patients with Philadelphia chromosome positive ALL require specialized therapy and this is discussed in more detail separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

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. The majority of deaths are due to relapsed disease and long-term complications from therapy are rare. Alternatively, allogeneic HCT results in a lower relapse rate, but higher rates of treatment-related mortality and morbidity resulting in similar rates of long-term survival. In 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. Other 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 CR1, we suggest the use of consolidation chemotherapy 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, and doxorubicin. Central nervous system prophylaxis with either intrathecal chemotherapy or 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.

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 postremission chemotherapy. In contrast, prospective studies evaluating even more intensive chemotherapy regimens have not demonstrated improved outcomes [6,7,19-23]. 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 [17,24]

●Standard or augmented Berlin-Frankfurt-Munster (BFM) [25]

●Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) alternating with high-dose methotrexate and cytarabine [26]

●French GRAAL-2003 regimen for younger adults [27]

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 treatment of relapsed CD19+ B-lineage ALL. It is now being evaluated as post-remission therapy in frontline regimens. Similarly, the anti-CD22 immunoconjugate inotuzumab ozogamicin has also been approved for relapsed or refractory B-lineage ALL, and it too is now being evaluated as post-remission therapy for adults with ALL.

Chemotherapy versus allogeneic transplant — 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.

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.)

Chemotherapy versus autologous transplant — Autologous HCT 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 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 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 [28-35]. (See 'Chemotherapy versus allogeneic transplant' 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 [28,29]. 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 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 [36]. 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 [37].

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 auto-HCT was followed by two years of maintenance chemotherapy for adults in CR1 [35]. On the other hand, a randomized trial evaluating interleukin (IL)-2 after autologous HCT showed no benefit [34].

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".)

High-risk disease — Patients with high-risk disease, as defined above, do poorly when treated with consolidation chemotherapy alone after attainment of a complete remission (CR1); rates of 10-year overall survival with this approach are approximately 10 percent. In 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 candidates 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 [38].

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 when 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 graft–versus-host disease, which, if it occurs, can be quite 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 up to about 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. 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 >45 years who may not be eligible for myeloablative conditioning, reduced intensity conditioning may be an acceptable approach [39]. Details related to allogeneic transplantation in adults with ALL, including donor selection, preparative chemoradiotherapy regimens, and the graft-versus-leukemia 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 first complete remission (CR1) [28,29]. 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 [40]. 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, 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 [30,31]. Patients younger than 55 years who had an HLA-matched sibling donor were assigned to allogeneic HCT. Other patients were randomly assigned to auto-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 non-relapse 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 non-relapse 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 [41]. 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 [42]. 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 0.87; 95% CI 0.79-0.96).

•High-risk ALL was defined by a white blood cell 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 (hazard ratio 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 TRM in patients <35 years (32 versus 19 percent in those with donors).

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.

Treatment of younger adults — Retrospective data supporting the use of regimens developed by pediatric cooperative groups that emphasize more aggressive central nervous system prophylaxis, use of anti-metabolites, and repeated administration of non-myelosuppressive agents including vincristine and asparaginase have led to ongoing studies assessing such approaches in previously untreated patient with ALL up to age 40 [25]. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

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 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, POMP). As 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 [43]. 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 [19]. 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 nine and 11 months, respectively [20].

It is unclear if the poor results seen in these studies of shortened therapy are due to inadequate initial induction and consolidation treatment or to 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 [44]. 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 (prednisone or dexamethasone plus vincristine, methotrexate, and 6-mercaptopurine) 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 neurological examination suggest any weakness in cranial nerves, a lumbar puncture and evaluation for CNS leukemia should be performed [45].

FOLLOW-UP — After the completion of maintenance therapy, patients in complete clinical remission usually have a bone marrow aspiration and biopsy repeated periodically to assess for residual or relapsed disease. Whether surveillance bone marrow examination leads to better overall outcomes than monitoring for changes in the circulating blood counts is uncertain. 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, cardiotoxicity, infertility, 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".)

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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

●Over 80 percent of adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) will attain a first complete remission (CR1) with intensive induction chemotherapy. However, without additional cytotoxic therapy, virtually all of these patients will relapse within a few weeks or months. In contrast, patients who receive post-remission therapy may expect five-year survival rates up to 60 percent in young and middle-age adults with standard-risk disease. (See 'Introduction' above.)

●ALL is a heterogeneous disease, and outcomes vary by clinical, cytogenetic, and molecular features. Patients should be evaluated at diagnosis to determine if they have standard- or high-risk disease as this will affect the choice of post-remission therapy. (See 'Risk stratification' above.)

●There is no standard post-remission therapy for patients with ALL. Most clinicians use a risk-adapted treatment approach where patients with disease at high risk for relapse are treated with more aggressive therapy (eg, allogeneic hematopoietic cell transplantation [HCT]) than patients at standard risk for relapse. (See 'Overview' above.)

●For most patients with standard-risk ALL in CR1, we suggest the use of consolidation and maintenance chemotherapy rather than either allogeneic or autologous HCT (Grade 2B). This preference places a relatively high value on avoiding the higher short-term mortality and long-term morbidity associated with allogeneic HCT and a low value on the potential, but uncertain, ability of the more intensive transplant therapy to eliminate residual disease. Autologous HCT appears no more effective than consolidation chemotherapy. (See 'Standard-risk disease' above.)

●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 (Grade 1B). For patients with high-risk ALL in CR1 who are not candidates for allogeneic HCT, we suggest consolidation chemotherapy rather than autologous HCT (Grade 2B). Patients with Philadelphia chromosome positive ALL require specialized therapy and this is discussed in more detail separately. (See 'High-risk disease' above and "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

●For patients who are still in CR1 after completing consolidation chemotherapy, we recommend two to three years of maintenance chemotherapy rather than observation (Grade 1B). The most commonly used regimen is daily 6-mercaptopurine given in the evening, weekly methotrexate, and monthly pulses of vincristine and prednisone (ie, POMP) or dexamethasone administered for three years. (See 'Maintenance therapy' above.)

●Patients are followed after the completion of maintenance therapy 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'.)