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Clinical use of measurable residual disease detection in acute lymphoblastic leukemia

Clinical use of measurable residual disease detection in acute lymphoblastic leukemia
Authors:
Wendy Stock, MD
Zeev Estrov, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Mar 07, 2022.

INTRODUCTION — Most children and up to half of adults with newly diagnosed acute lymphoblastic leukemia (ALL) attain a complete remission after induction chemotherapy and experience prolonged disease-free survival. Nevertheless, some will relapse because of residual leukemic cells that are below the limits of detection using conventional morphologic and cytogenetic assessment; such levels of residual leukemia are termed measurable residual disease (MRD; formerly called minimal residual disease). The presence of MRD is an important prognostic factor for survival in both children and adults with ALL and it may guide the use of targeted agents or immunotherapy to increase the proportion of MRD-negative responses and improve survival rates.

This topic reviews the clinical use of MRD in ALL.

Methods for detecting MRD in ALL are described separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

Detection and clinical use of MRD in acute myeloid leukemia and chronic myeloid leukemia are covered separately. (See "Overview of the treatment of chronic myeloid leukemia", section on 'Monitoring response' and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)

GENERAL CONSIDERATIONS — MRD is an important prognostic factor for outcomes in both children and adults with ALL and MRD testing is routinely incorporated into ALL management.

MRD testing is performed at various points during and after treatment in contemporary ALL protocols. Interpretation of test results involves both the level of MRD at specified time points and the trajectory/rate of decline of MRD levels. In some protocols, this is used to determine whether therapy intensity should be escalated or reduced for an individual patient. The method for detecting MRD in ALL varies according to immunophenotypic and molecular features of the leukemia and the timing for testing varies according to the treatment protocol. Methods for MRD detection in ALL are described separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

Bone marrow (BM) has long been considered standard for measuring MRD, but the level of MRD in peripheral blood (PB) is closely correlated with MRD in BM [1]. If MRD, using next generation sequencing (NGS), is negative in both BM and PB, we consider that monitoring for relapse with blood alone is satisfactory. In other settings, we await additional studies before routinely substituting PB MRD for BM MRD. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)

A prospective study reported a strong correlation between MRD levels in PB and BM [1]. MRD was measured by NGS in adults with ALL receiving allogeneic hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapies. Among the 126 paired specimens, the correlation between PB and BM MRD was 0.87; compared with BM MRD, the sensitivity and specificity of PB MRD were 87 and 90 percent, respectively. PB MRD became detectable in the PB in 100 percent of patients who subsequently relapsed following HCT (median 90 days from MRD+ to clinical relapse) and in 85 percent of patients who relapsed following CAR-T cell therapy (median 60 days to clinical relapse).

Not all patients with detectable MRD will relapse clinically; in some cases, ALL cells persist after treatment but they do not progress to clinical disease. Conversely, some patients relapse despite MRD-negative results, perhaps because the recurrent disease manifests different immunophenotypic or molecular markers or because of clonal evolution.

A meta-analysis comprising 13,637 patients in 39 studies reported that for MRD-negativity, the hazard ratio (HR) for overall survival (OS) in pediatric patients was 0.28 (95% Bayesian credible interval [BCI] 0.19-0.41) and for adult patients was 0.28 (95% BCI, 0.20-0.39) [2]. The corresponding HR for event-free survival (EFS) in pediatric patients was 0.23 (95% BCI 0.18-0.28) and 0.28 (95% BCI, 0.24-0.33) for adults. The favorable prognostic association was consistent across therapies, methods of and times of MRD assessment, threshold levels, and subsets of ALL [2].

MRD IN CHILDREN

Prognostic value — Depending on the method used, up to 70 percent of children with ALL will have MRD detectable immediately following the completion of induction therapy [3,4], with levels declining in most patients during the first six months of treatment [5]. Multiple studies have shown that patients with detectable MRD have significantly higher relapse rates [5-14]. The timing of MRD disappearance and reappearance appears to affect its prognostic value.

Polymerase chain reaction (PCR)-based techniques and multicolor flow cytometry are sufficiently sensitive, specific, and reproducible for MRD assessment in most patients. More robust techniques using multiplex PCR with deep sequencing and next-generation flow cytometry are under investigation. Multicolor flow cytometry is most commonly used in the United States. The ideal test is unknown and likely differs depending on the ALL subtype and the clinical scenario. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

Published studies of MRD testing in children using PCR have had variable results, which may be ascribed to a number of factors:

●PCR testing at different times during the treatment cycle

●Differences in PCR methodologies, use of different cutoff values

●Differing sample sources (eg, fresh bone marrow versus archival material)

●Considerable variation in treatment regimens

Large, prospective studies of MRD in pediatric ALL have conclusively demonstrated that the probability of long-term relapse-free survival (RFS) is directly related to the level of residual disease, both early in the course of treatment [6,8,12,15-23], and at later time points [15,16,20,24].

With conventional therapy — Large, independent prospective studies have conclusively demonstrated that children with detectable MRD have decreased disease-free survival (DFS) and overall survival (OS) and that the level of detectable MRD correlates with relapse [16,17,25-27]. In addition to its potential to impact treatment decisions (discussed in more detail below), MRD analysis may allow for modifications in the treatment response assessment. As an example, the prognostic value of MRD status at the end of induction (using a cutoff threshold of 0.01 percent) provides independent and predictive information and thus allows for the elimination of day 14 bone marrow examinations in the vast majority of children with ALL.

The following studies illustrate the prognostic value of MRD measurements in children treated with conventional chemotherapy:

●An initial study used flow cytometry of bone marrow samples to evaluate MRD in 158 children with ALL [25]. Samples were collected after induction therapy and during weeks 14, 32, and 56 of continuation therapy, and again at 120 weeks (end of therapy). Leukemia cells were detectable in 23, 17, 5, and 4 percent of patients after remission induction and at weeks 14, 32, and 56, respectively. None of the 65 samples examined at the completion of therapy (week 120) showed evidence of disease. At all time points, MRD detection was associated with a significantly higher rate of relapse.

●Another study measured MRD by PCR on day 46 in 455 children with B cell lineage ALL treated with contemporary regimens [13]. MRD was undetectable in 58 percent; <0.001 percent in 11 percent; 0.001 to <0.01 percent in 14 percent; and 0.01 percent or greater in 17 percent. The five-year cumulative incidence of relapse (CIR) was higher among those with MRD of 0.01 percent or greater versus MRD of <0.01 percent or undetectable MRD (23 versus 6 percent). Furthermore, the five-year CIR was higher among those with MRD 0.001 to <0.01 percent versus MRD <0.001 percent or undetectable (13 versus 5 percent). These results suggest a prognostic impact for MRD detected below the conventional threshold of 0.01 percent.  

●In a large collaborative European study (AIEOP-BFM 2000 study), 3184 children with Philadelphia chromosome negative B cell lineage ALL were risk stratified by MRD status (PCR sensitivity ≤0.01 percent) at day 33 (end of induction) and day 78 (start of consolidation with significantly different event-free survival [EFS] and OS at five years) [28]:

•Standard risk (42 percent): Those with MRD ≤0.01 percent at both time points had EFS and OS of 92 and 98 percent, respectively.

•Intermediate risk (52 percent): Those with MRD >0.01 percent at either time point (and <0.1 percent on day 78) had EFS and OS of 78 and 93 percent, respectively.

•High risk (6 percent): Those with MRD ≥0.1 percent on day 78 had EFS and OS of 50 and 60 percent, respectively.

●In an analysis of 7430 children enrolled on Children's Oncology Group (COG) studies, evaluation of MRD by flow cytometry on day 29 was highly predictive of patient outcomes [29]. Estimated DFS at five years was significantly higher among patients who were MRD negative (89 versus 72 percent, respectively). Among patients who were MRD negative, five-year DFS was similar regardless of whether they had morphologic evidence of disease on a day 14 bone marrow (89 versus 91 percent). Similarly, patients who had no morphologic evidence of disease on day 14, but were MRD positive on day 29, had similar five-year DFS as those who had detectable disease at either time (77 versus 72 percent). These results suggest that MRD status using a threshold of 0.01 percent at the end of induction obviates the need for analysis at day 14.  

●In another study, MRD remained detectable in the bone marrow by flow cytometry in nearly half of children on day 19 of induction therapy and was associated with a higher chance of relapse (five-year CIR 33 versus 6 percent) [19]. These results suggest that MRD status has prognostic value even when measured before the end of induction therapy.

These and other studies have demonstrated that either semi-quantitative PCR or flow cytometry may be used to assess MRD in childhood ALL. However, these data were derived from prospective clinical trials where special expertise was available in central research laboratories, and individual patients submitted both pretreatment and post-treatment samples. A broader discussion comparing PCR and flow cytometry for MRD detection is presented separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

In the setting of transplantation — MRD studies have demonstrated prognostic value when measured before and after allogeneic hematopoietic cell transplantation (HCT).

Patients with MRD prior to allogeneic HCT are more likely to relapse than those without detectable MRD [30-32]:

●A study of 64 children and adolescents with ALL in morphologic remission reported two-year EFS rates of 17 and 73 percent for those with and without MRD prior to allogeneic HCT, respectively [30]. While prognostic, some patients with MRD prior to HCT will have long-term DFS and some patients without detectable MRD prior to HCT may ultimately relapse.

●A study of children undergoing allogeneic HCT for ALL (64 patients) or acute myeloid leukemia (58 patients) confirmed that MRD status prior to HCT is associated with RFS and OS after HCT [32]. Five-year survival rates increased as pre-HCT MRD levels decreased being 29, 52, and 68 percent for patients with high, low, and no MRD. These results suggest that more than half of patients with low levels of MRD prior to HCT will have long-term survival after the procedure and that detection of MRD alone should not eliminate HCT as a treatment option.

Several studies have also demonstrated an increased rate of relapse among those found to be MRD positive after allogeneic HCT [33-37]:

●In the prospective ALL-BFM-SCT 2003 trial, 113 children with relapsed ALL had MRD testing of the bone marrow by quantitative real-time PCR prior to and on days +30, +60, +90, +180, and +365 post-HCT [37]. Among those with MRD ≥10-4 leukemic cells at one of these time points, the estimated cumulative incidence of relapse at three years was 38, 50, 75, 100, 100, and 100 percent, respectively. In contrast, approximately one-quarter of consistently MRD-negative patients relapsed within three years. These results suggest that MRD positivity at day +60 or beyond is highly predictive of subsequent relapse.  

●A study of 71 children reported that those who exhibited MRD during the first three months following allogeneic HCT had a ninefold higher relapse rate when compared with MRD-negative patients [33]. Only 1 of 35 patients in complete remission had MRD detectable more than six months following transplant.

It is not yet known how best to use MRD status to facilitate treatment decisions in patients who have undergone or are about to undergo allogeneic HCT for ALL. Potential uses include using these levels to determine the best timing of HCT, to modulate immunosuppressive therapy after HCT, or guide the use of donor lymphocyte infusions after HCT. (See 'Using MRD to escalate therapy' below.)

At relapse — Among children with relapsed ALL who achieve a complete remission, MRD assessment may predict the risk of a second relapse:

●In a study of 35 children who experienced a second morphologic complete remission after reinduction therapy for relapsed disease, MRD ≥0.01 percent by flow cytometry was associated with an increased risk of relapse (two-year CIR 70 versus 28 percent) [38].

●In another study of 60 children with high-risk ALL who relapsed within 30 months of initial diagnosis, MRD status measured three to five weeks after starting reinduction therapy was highly predictive of EFS [39]. The estimated EFS rate at three years was 73, 45, and 19 percent among those with no MRD, MRD <0.01 percent, and MRD ≥0.01 percent, respectively.

Using MRD to escalate therapy — Patients with detectable MRD have an increased risk of relapse after conventional therapy. The absolute risk varies depending on a number of factors including the timing of MRD evaluation, the sensitivity of the method used to evaluate MRD, and baseline characteristics of the patient and tumor. Given this increased rate of relapse, prospective trials have attempted to decrease this risk by escalating therapy in those demonstrating MRD [40-42].

In the UKALL 2003 trial, 533 patients clinically identified as having standard-risk or intermediate-risk ALL at diagnosis and who had MRD in the bone marrow at the end of induction therapy were randomly assigned to receive standard or augmented post-remission therapy [40]. The augmented therapy included additional doses of pegylated asparaginase, vincristine, and methotrexate. Augmented therapy was associated with more adverse events including hypersensitivity, pancreatitis, and mucositis/stomatitis. After a median follow-up of 70 months, augmented therapy resulted in superior EFS at five years (90 versus 83 percent) and a trend toward improved survival at five years (93 versus 89 percent). These results suggest that escalating care in patients with MRD at the end of induction therapy improves clinical outcome.

In another prospective trial of 208 children with intermediate-risk ALL as determined by bone marrow morphology at diagnosis, consolidation therapy was assigned based on MRD status after induction [41]. Those with an MRD level <10-3 were assigned to receive conventional consolidation and maintenance therapy. In contrast, for patients with MRD ≥10-3, related or unrelated HLA-matched allogeneic HCT was recommended as consolidation. In this group, 83 percent had appropriate donors and underwent HCT, while 17 percent received chemotherapy without HCT because no donor was available. EFS was higher for patients receiving HCT versus those receiving chemotherapy alone (64 versus 24 percent). These results suggest that consolidation with allogeneic HCT may mitigate some of the risk associated with MRD.

Using MRD to minimize therapy — As long-term survival in childhood ALL improves, more children experience late adverse effects including central nervous system impairment, decreased linear growth, cardiotoxicity, infertility, and an increased incidence of secondary cancers. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Late effects'.)

Given these late effects, researchers have tried to identify a group of ALL patients that may be treated with less intensive therapy without compromising survival. Ongoing trials are evaluating whether patients who demonstrate a rapid clearance of tumor cells during induction therapy resulting in no detectable MRD may be candidates for less intensive consolidation [42,43]. At this point it is unknown whether the good outcomes seen in this patient group are dependent on the use of standard induction, consolidation, and maintenance, or if they may be curable with less intensive therapy.

As an example, a multicenter randomized trial of over 3000 consecutive children and young adults (≤25 years) with newly diagnosed ALL examined the use of MRD measurements obtained after induction and consolidation therapy to minimize maintenance therapy [43]. Clinical criteria were initially used to classify the disease as standard-, intermediate-, or high-risk, then MRD measurements following induction and before interim maintenance were used to further revise this classification. Patients with standard or intermediate clinical risk who achieved MRD negativity were randomly assigned to receive one or two delayed intensification treatments. When compared with those assigned to the standard two delayed intensification treatments, those assigned to a single intensification had a similar estimated EFS (94.4 versus 95.5 percent), OS (97.9 versus 98.5 percent), and rate of relapse (4.2 versus 2.3 percent) at five years. Our confidence in the ability of this evaluation to detect a difference in outcome, if present, is limited by the low event rate and short follow-up.

Long-term surveillance — It is unknown whether interventions based on the serial analysis of MRD after the completion of therapy will affect clinical outcomes. Theoretically, all clinically evident relapses should be preceded by the appearance of previously undetectable MRD or a rise in amount of measurable MRD [44]. However, the length of time between detection of potential relapse with MRD testing and the clinical detection of relapse with standard methods is not known. In addition, not all patients with detectable MRD will ultimately relapse. As such, the value of serial, quantitative measurements of MRD in long-term survivors is unknown.

Despite the finding that the presence of residual disease following completion of combination chemotherapy or allogeneic transplant portends relapse, other studies suggest that not all patients with MRD are destined to relapse:

●In one study, approximately 20 percent of patients with an MRD level greater than 10-2 had not yet relapsed at a median follow-up of 38 months [16].

●MRD has been detected in bone marrow samples obtained as long as nine years following completion of therapy for ALL without clinical relapse [45].

●A highly sensitive quantitative PCR assay demonstrated MRD in 15 of 17 children with ALL who remained in remission 2 to 35 months after completion of all treatment [46].

●Long-term persistence of MRD without clinical relapse has also been described in patients with p210 BCR::ABL-positive ALL and in children with t(1;19) ALL.

It is clear that the leukemic clone can establish a prolonged "dormancy." As an example, in one study, bone marrow samples obtained at relapse in 8 of 12 children who relapsed more than 10 years after the diagnosis of ALL, demonstrated the identical immunoglobulin heavy chain (IgH) or T cell receptor (TCR) gene rearrangement as that present in the diagnostic bone marrow specimen [47]. This suggests that the leukemic cells, or clonal precursors, survived for more than a decade.

While it is unclear whether the identification of MRD should lead to subsequent therapy, the presence of a persistently positive MRD result should trigger preparation for potential disease relapse in the future. As an example, a search for potential donors may be undertaken for patients who have not yet undergone allogeneic HCT.

MRD IN ADULTS — MRD detection and monitoring is an important aspect of treatment for adults with Philadelphia chromosome positive (Ph+) and Philadelphia chromosome negative (Ph-) ALL.

Effect on prognosis — Depending on the method used, up to 80 percent of adults with ALL will have MRD detectable immediately following the completion of induction therapy. Multiple studies have shown that patients with detectable MRD have significantly higher relapse rates.

MRD is most commonly detected using polymerase chain reaction (PCR)-based techniques and multicolor flow cytometry. Reverse transcriptase PCR (RT-PCR) can be used to detect leukemia-specific fusion mRNA, such as BCR::ABL resulting from t(9;22). More robust techniques using multiplex PCR with deep sequencing and next-generation flow cytometry are under investigation. The ideal test is unknown and likely differs depending on the ALL subtype and the clinical scenario. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

Identifying patients with persistent MRD who are at highest risk for relapse may enable post-remission therapies with novel agents, such as inotuzumab ozogamicin, blinatumomab, and CD19-directed chimeric antigen receptor T (CAR-T) cells, all of which have been shown to be effective in achieving MRD negativity, even in patients with relapsed or refractory disease [48,49].

Ph+ ALL — The BCR::ABL fusion gene associated with the Philadelphia (Ph) chromosome, t(9;22), which occurs in up to 30 percent of adults with ALL, is a marker of poor prognosis. Such patients are routinely treated with allogeneic hematopoietic cell transplantation (HCT) after remission induction. It is currently unclear if MRD status can be used to alter the therapy of such patients.

RT-PCR can be used to detect and monitor the BCR::ABL fusion gene [50]. There are two main fusion gene variants. Approximately 70 percent of patients have the p190 subtype. The p210 subtype (present in the vast majority of patients with chronic myeloid leukemia) accounts for 25 to 30 percent of ALL cases [51]. (See "Molecular genetics of chronic myeloid leukemia" and "Cellular and molecular biology of chronic myeloid leukemia", section on 'BCR-ABL1'.)

Detection of MRD by RT-PCR analysis of BCR::ABL predicts early relapse [50,52]. As an example, one study reported that MRD status at the time of first complete remission was not prognostic, but that MRD status at three months and beyond predicted survival [52]. Whether these patients can be cured without allogeneic HCT is unknown. (See "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Several studies of MRD status following allogeneic or autologous HCT in patients with Philadelphia chromosome positive ALL suggest that MRD positivity may identify patients who are likely to relapse [50,53-55]. In the largest series, the relative risk for relapse was significantly higher for those patients with a detectable BCR::ABL transcript following HCT, in comparison with those without detectable BCR::ABL (relative risk 5.7, p = 0.025) [50]. The median time from detection of a positive PCR result to clinical relapse was 94 days.

Ph(-) ALL — Prospective studies that have evaluated serial, quantitative measurements of residual disease in adults with ALL have demonstrated that the measurement of MRD can predict those destined to relapse and those who will remain in remission [15,44,56-63]. The following are examples of studies that have indicated that MRD positivity at various time points after the initiation of treatment is a strong factor predicting for relapse in adults with ALL:

●Low-level MRD was an independent prognostic factor in 112 adults who were tested for immunoglobulin/T-cell receptor (TCR) rearrangements during early consolidation treatment for BCR::ABL1-negative ALL [64]. MRD was categorized as complete molecular response (CMR), positive/non-quantifiable (MRDnq), and positive/quantifiable (MRDq). Rates of five-year overall survival (OS) for CMR, MRDnq and MRDq at week 11 were 74, 42, and 35 percent, respectively. MRDnq before the first and second consolidation blocks had a comparable negative effect on survival as MRDq.

●A prospective trial of adults with standard-risk ALL used tumor-specific PCR probes to measure residual disease at treatment days 11 (mid-induction I), 24 (end of induction I), and week 16 (prior to consolidation II) [15]. MRD assessment was able to categorize 196 patients into three risk categories:

•Low risk (10 percent) – No patients with MRD <10-4 at both days 11 and 24 had relapsed by three years.

•High risk (23 percent) – Of those patients with MRD >10-4 at both day 24 and week 16, 94 percent had relapsed by three years.

•Intermediate risk (67 percent) – Of those patients not meeting criteria for low- or high-risk MRD, 47 percent had relapsed by three years.

●Another prospective study of 102 adolescent and adult patients with ALL that used multiparameter flow cytometry to define MRD reported [57]:

•For patients in morphologic complete remission at day 35, MRD >0.05 percent was associated with worse median relapse-free survival (RFS) times (16 versus 42 months).

•The 12 patients with MRD <0.03 percent by day 14 had a projected RFS rate of 90 percent at five years.

•Of those achieving morphologic complete remission after day 35, all with MRD >0.1 percent had relapsed by two years.

●Another prospective study of 116 patients with Philadelphia chromosome negative ALL used flow cytometry to identify MRD [58]:

•Among patients with precursor B cell ALL, those with MRD <0.1 percent after induction therapy had a significantly lower relapse rate (26 versus 81 percent) and higher rate of leukemia-free survival (LFS; 61 versus 17 percent) at three years. This advantage could not be demonstrated for patients with T cell ALL.

•There was a nonsignificant trend toward improved clinical outcomes among those patients without MRD after consolidation therapy.

•Patients less than 35 years old who presented with a white blood cell count <30,000 and a favorable immunophenotype (not pro-B or T cell) who achieved MRD negativity (<0.1 percent) after a single course of induction had three-year RFS and LFS rates of 9 and 71 percent, respectively.

●The MLL::AF4 fusion gene resulting from t(4;11)(q21;q23) is associated with a poor prognosis in both adults and children with ALL. A prospective analysis of quantitative RT-PCR MRD monitoring in 25 patients with the MLL/AF4 transcript reported that patients with continued MRD positivity and those who initially attain a clinical remission but then convert from negative to positive MRD have a high relapse rate [65]. In contrast, patients who remained PCR negative during the first three to six months following diagnosis appeared to enjoy prolonged disease-free survival (DFS). Further, PCR negativity following transplantation is highly predictive for longer RFS [66-68]. MRD testing appears to be prognostic in this group of patients.

MRD for treatment stratification — MRD is detected in up to one-half of adults who achieve a hematologic remission with frontline treatment of ALL and the presence of MRD is associated with increased risk for relapse.

As an example of the use of MRD in this setting, adults with MRD (≥10-3) after induction therapy for Ph(-) ALL were treated with one cycle of the bispecific T cell engager antibody, blinatumomab; 78 percent of 113 evaluable patients achieved a complete MRD response after treatment [69]. Compared with non-responders, patients who became MRD-negative had longer OS (39 versus 13 months) and longer RFS (24 versus 6 months). (See "Post-remission therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults".)

MRD can be used to stratify subsequent management:

●In the ALL-HR-11 study, patients (15 to 60 years) with high-risk ALL had MRD assessed by eight-color flow cytometry at the end of induction and consolidation phases of treatment [70]. Patients with MRD <0.1 percent after induction and <0.01 after early consolidation were assigned to receive delayed consolidation and maintenance therapy for up to two years, while the remaining patients were assigned to allogeneic HCT because of higher levels of MRD; by intention-to-treat, 218 patients were assigned to chemotherapy and 106 to HCT. Five-year rates of OS, relapse, and event-free survival (EFS) were similar, whether patients received chemotherapy because they had satisfactory levels of MRD versus allogeneic HCT.

●A prospective study of 142 adults with ALL who had completed consolidation therapy reported that MRD was negative, positive, or not assessable by RT-PCR in 58, 54, and 30 patients, respectively [71]. Patients who were MRD negative were given maintenance therapy and had 75 percent five-year OS and 72 percent five-year DFS. Patients who were MRD positive underwent allogeneic HCT (if a donor was available) or autologous HCT (if a donor was not available) and had DFS and OS rates at five years of 33 and 14 percent, respectively.

●A prospective study (PETHEMA ALL-AR-03) evaluated MRD monitoring to modify treatment in adults with high-risk Ph(-) ALL [72]. Patients with a good early morphologic response (<10 percent bone marrow blasts at day 14 of induction) and MRD <5 x 10-4 by flow cytometry at the end of consolidation were assigned to receive delayed consolidation and maintenance therapy. Patients with poor early cytogenetic response or positive MRD at the end of consolidation were assigned to allogeneic HCT. Estimated OS and DFS for patients assigned HCT were 37 and 32 percent, respectively; corresponding outcomes for patients assigned to chemotherapy were 59 and 55 percent, respectively. These results suggest that a subset of patients who attain MRD negativity may have long-term disease control without HCT.

In the setting of transplantation — Detection of MRD after allogeneic HCT is associated with increased risk for relapse in patients with Ph(-) or Ph+ ALL.

The following studies included post-hoc analyses regarding the impact of HCT on those with detectable MRD after induction therapy:

●In the GRAALL-2003/2005 trials, 522 young adults (age 15 to 55 years) with at least one conventional high-risk feature were treated with pediatric-inspired intensive chemotherapy with plans to proceed to HCT in first remission if a donor was available [62]. HCT was performed in 282 patients. Post-induction MRD results were available for 259 patients, and 19 additional patients had evidence of overt residual disease after induction. While RFS did not differ by HCT status in the group as a whole, receipt of HCT was associated with superior RFS (hazard ratio [HR] 0.40; 95% CI 0.23-0.69) and OS (HR 0.41; 05% CI 0.23-0.74) in those with MRD ≥10-3.  

●Another prospective study (GMALL 07/2003) of 580 patients with Philadelphia chromosome negative ALL who attained a morphologic complete response (CR) after two induction phases used tumor-specific PCR probes with a sensitivity of better than 10-4 to measure MRD [59]. MRD negativity was attained in 76 percent by week 16 after consolidation. When compared with those patients with measurable MRD, patients who attained MRD negativity had a higher rate of continuous morphologic CR (69 versus 26 percent) and OS (80 versus 42 percent) at five years. Among those with measurable MRD, when compared with those treated with chemotherapy alone, patients who underwent allogeneic HCT in first morphologic CR were more likely to retain morphologic CR at five years (66 versus 12 percent).

Other studies have also examined the prognostic value of MRD for patients with Ph(-) or Ph+ ALL [50,56,73,74].

Relapsed disease — The prognosis of adults with relapsed or refractory ALL is poor, and the prognosis depends on the response to salvage therapies [75].

A phase 2 study reported that 69 percent of patients with ALL achieved MRD negativity by PCR; MRD negativity was associated with superior OS (odds ratio for death 0.33) [76]. Phase 3 trials reported efficacy of blinatumomab and inotuzumab ozogamicin (a CD22 antibody conjugate) for achieving MRD-negativity with relapsed ALL [77,78]. Among 109 patients treated with inotuzumab ozogamicin, 81 percent achieved a complete response and 78 percent became MRD negative [78].

Surveillance — It is unknown whether clinical outcomes can be improved by interventions based on the serial analysis of MRD after the completion of therapy. While all clinically evident relapses should be preceded by the appearance of previously undetectable MRD or a rise in the amount of measurable MRD, it is unknown whether all cases that become MRD positive ultimately relapse. As such, the value of serial, quantitative measurements of MRD in long-term survivors is unknown. "Molecular relapse" does not always predict subsequent clinical relapse, nor does a negative result guarantee leukemia-free survival.

Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission. As yet, the significance of the reappearance of ALL detected only by MRD analysis is uncertain.

It is unknown whether serial testing of MRD in patients who are MRD negative after the completion of therapy may detect relapses at an earlier, more curable stage. In a prospective study, 105 adult patients with standard-risk ALL who were in hematologic remission following the first year of chemotherapy and who had tested MRD negative prior to study entry, were followed with serial MRD testing for a median of 16 months [79]:

●Twenty-two of the original 105 patients relapsed after the first year of therapy. MRD was detected prior to clinical relapse in 17 of these patients (77 percent). The median interval between MRD positivity and clinical relapse was 9.5 months.

●Of the 77 patients who were consistently MRD negative, only five (6 percent) have subsequently relapsed.

The long-term outcome of patients with continuous complete remission but positive MRD testing is not known. Serial quantitative measurements in such patients may be helpful, as increasing values for MRD may identify patients at a higher risk of relapse [16,80-82]. However, residual disease is a dynamic process, with the numbers of residual leukemic cells fluctuating over time [46,83]. Although levels of residual disease may fall below the detection limit of even highly sensitive molecular assays shortly after therapy, the leukemic cells do not necessarily disappear when the patient enters into clinical remission. They may subsequently increase until clinically overt disease recurs, or they may fall below the threshold of detection again. A "positive" to "negative" to "positive" pattern of PCR results is commonly seen. As such, therapeutic decisions on whether to continue therapy or begin salvage therapy cannot at present be based solely on a single positive MRD result. However, if a positive MRD result persists, efforts should be made to prepare for potential disease relapse in the future. As an example, a search for potential donors may be undertaken for patients who have not yet undergone allogeneic HCT.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY

●Measurable residual disease (MRD) refers to residual leukemia cells that are detectable with sensitive immunophenotypic or molecular techniques, which are below the limits of detection using conventional morphologic and cytogenetic evaluation. These persistent residual leukemia are responsible for most relapses after initial disease response.

●Prognostic importance of MRD – Despite achieving a hematologic remission, 70 percent of children and 80 percent of adults with acute lymphoblastic leukemia (ALL) have detectable MRD after completing induction therapy. Patients with detectable MRD have higher relapse rates and the timing of MRD disappearance and reappearance appears to affect its prognostic value. (See 'Prognostic value' above.)

●Clinical applications of MRD with ALL – MRD assays are routinely used in the clinical care of children and increasingly in adults with ALL. Ongoing trials are evaluating the escalation of therapy intensity in MRD-positive cases and the reduction of therapy intensity in MRD-negative cases. (See 'Using MRD to escalate therapy' above and 'MRD for treatment stratification' above.)

  1. Muffly L, Sundaram V, Chen C, et al. Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia. Blood Adv 2021; 5:3147.
  2. Berry DA, Zhou S, Higley H, et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol 2017; 3:e170580.
  3. Goulden NJ, Knechtli CJ, Garland RJ, et al. Minimal residual disease analysis for the prediction of relapse in children with standard-risk acute lymphoblastic leukaemia. Br J Haematol 1998; 100:235.
  4. Kuang S, Gu L, Dong S, et al. Long-term follow-up of minimal residual disease in childhood acute lymphoblastic leukemia patients by polymerase chain reaction analysis of multiple clone-specific or malignancy-specific gene markers. Cancer Genet Cytogenet 1996; 88:110.
  5. Foroni L, Coyle LA, Papaioannou M, et al. Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response. Leukemia 1997; 11:1732.
  6. Madzo J, Zuna J, Muzíková K, et al. Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study. Cancer 2003; 97:105.
  7. Steenbergen EJ, Verhagen OJ, van den Berg H, et al. Rearrangement status of the malignant cell determines type of secondary IgH rearrangement (V-replacement or V to DJ joining) in childhood B precursor acute lymphoblastic leukemia. Leukemia 1997; 11:1258.
  8. Brisco MJ, Condon J, Hughes E, et al. Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. Lancet 1994; 343:196.
  9. Gruhn B, Hongeng S, Yi H, et al. Minimal residual disease after intensive induction therapy in childhood acute lymphoblastic leukemia predicts outcome. Leukemia 1998; 12:675.
  10. Wasserman R, Galili N, Ito Y, et al. Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia. J Clin Oncol 1992; 10:1879.
  11. Eckert C, Biondi A, Seeger K, et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 2001; 358:1239.
  12. Patel B, Rai L, Buck G, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol 2010; 148:80.
  13. Stow P, Key L, Chen X, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 2010; 115:4657.
  14. Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol 2015; 16:465.
  15. Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006; 107:1116.
  16. Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339:591.
  17. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352:1731.
  18. Nyvold C, Madsen HO, Ryder LP, et al. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood 2002; 99:1253.
  19. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 2002; 100:52.
  20. Gameiro P, Moreira I, Yetgin S, et al. Polymerase chain reaction (PCR)- and reverse transcription PCR-based minimal residual disease detection in long-term follow-up of childhood acute lymphoblastic leukaemia. Br J Haematol 2002; 119:685.
  21. Zhou J, Goldwasser MA, Li A, et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 2007; 110:1607.
  22. Karsa M, Dalla Pozza L, Venn NC, et al. Improving the identification of high risk precursor B acute lymphoblastic leukemia patients with earlier quantification of minimal residual disease. PLoS One 2013; 8:e76455.
  23. Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2012; 120:5173.
  24. Schrappe M. Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient. Hematology Am Soc Hematol Educ Program 2012; 2012:137.
  25. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 1998; 351:550.
  26. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232. Blood 2015; 126:964.
  27. Willemse MJ, Seriu T, Hettinger K, et al. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 2002; 99:4386.
  28. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115:3206.
  29. Borowitz MJ, Wood BL, Devidas M, et al. Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children's Oncology Group study (abstract 10001). J Clin Oncol 2013; 31:613s.
  30. Knechtli CJ, Goulden NJ, Hancock JP, et al. Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood 1998; 92:4072.
  31. Uzunel M, Mattsson J, Jaksch M, et al. The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 2001; 98:1982.
  32. Leung W, Pui CH, Coustan-Smith E, et al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood 2012; 120:468.
  33. Knechtli CJ, Goulden NJ, Hancock JP, et al. Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol 1998; 102:860.
  34. Radich J, Ladne P, Gooley T. Polymerase chain reaction-based detection of minimal residual disease in acute lymphoblastic leukemia predicts relapse after allogeneic BMT. Biol Blood Marrow Transplant 1995; 1:24.
  35. Dominietto A, Pozzi S, Miglino M, et al. Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood 2007; 109:5063.
  36. Elorza I, Palacio C, Dapena JL, et al. Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia. Haematologica 2010; 95:936.
  37. Bader P, Kreyenberg H, von Stackelberg A, et al. Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial. J Clin Oncol 2015; 33:1275.
  38. Coustan-Smith E, Gajjar A, Hijiya N, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 2004; 18:499.
  39. Paganin M, Zecca M, Fabbri G, et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed 'high-risk' acute lymphoblastic leukemia. Leukemia 2008; 22:2193.
  40. Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 2014; 15:809.
  41. Eckert C, Henze G, Seeger K, et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol 2013; 31:2736.
  42. Pieters R, de Groot-Kruseman H, Van der Velden V, et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 2016; 34:2591.
  43. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 2013; 14:199.
  44. Nizet Y, Van Daele S, Lewalle P, et al. Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction. Blood 1993; 82:1618.
  45. Potter MN, Steward CG, Oakhill A. The significance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia. Br J Haematol 1993; 83:412.
  46. Roberts WM, Estrov Z, Ouspenskaia MV, et al. Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. N Engl J Med 1997; 336:317.
  47. Vora A, Frost L, Goodeve A, et al. Late relapsing childhood lymphoblastic leukemia. Blood 1998; 92:2334.
  48. Short NJ, Jabbour E. Minimal Residual Disease in Acute Lymphoblastic Leukemia: How to Recognize and Treat It. Curr Oncol Rep 2017; 19:6.
  49. Jabbour E, Ravandi F, Kebriaei P, et al. Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial. JAMA Oncol 2018; 4:230.
  50. Radich J, Gehly G, Lee A, et al. Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 1997; 89:2602.
  51. Westbrook CA, Hooberman AL, Spino C, et al. Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762). Blood 1992; 80:2983.
  52. Ravandi F, Jorgensen JL, Thomas DA, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood 2013; 122:1214.
  53. Bachanova V, Marks DI, Zhang MJ, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia 2014; 28:658.
  54. Pfeifer H, Wassmann B, Bethge W, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia 2013; 27:1254.
  55. Wetzler M, Watson D, Stock W, et al. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica 2014; 99:111.
  56. Mortuza FY, Papaioannou M, Moreira IM, et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol 2002; 20:1094.
  57. Vidriales MB, Pérez JJ, López-Berges MC, et al. Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value. Blood 2003; 101:4695.
  58. Holowiecki J, Krawczyk-Kulis M, Giebel S, et al. Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study. Br J Haematol 2008; 142:227.
  59. Gökbuget N, Kneba M, Raff T, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood 2012; 120:1868.
  60. Brüggemann M, Raff T, Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood 2012; 120:4470.
  61. Caye A, Beldjord K, Mass-Malo K, et al. Breakpoint-specific multiplex polymerase chain reaction allows the detection of IKZF1 intragenic deletions and minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia. Haematologica 2013; 98:597.
  62. Dhédin N, Huynh A, Maury S, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 2015; 125:2486.
  63. Nagafuji K, Miyamoto T, Eto T, et al. Monitoring of minimal residual disease (MRD) is useful to predict prognosis of adult patients with Ph-negative ALL: results of a prospective study (ALL MRD2002 Study). J Hematol Oncol 2013; 6:14.
  64. Šálek C, Folber F, Froňková E, et al. Low levels of minimal residual disease after induction chemotherapy for BCR-ABL1-negative acute lymphoblastic leukaemia in adults are clinically relevant. Br J Haematol 2022; 196:706.
  65. Cimino G, Elia L, Rapanotti MC, et al. A prospective study of residual-disease monitoring of the ALL1/AF4 transcript in patients with t(4;11) acute lymphoblastic leukemia. Blood 2000; 95:96.
  66. Cimino G, Elia L, Rivolta A, et al. Clinical relevance of residual disease monitoring by polymerase chain reaction in patients with ALL-1/AF-4 positive-acute lymphoblastic leukaemia. Br J Haematol 1996; 92:659.
  67. Hilden JM, Frestedt JL, Moore RO, et al. Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4; 11)(q21; q23). Blood 1995; 86:3876.
  68. Janssen JW, Ludwig WD, Borkhardt A, et al. Pre-pre-B acute lymphoblastic leukemia: high frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission. Blood 1994; 84:3835.
  69. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. Blood 2019; 133:2625.
  70. Ribera JM, Morgades M, Ciudad J, et al. Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia. Blood 2021; 137:1879.
  71. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009; 113:4153.
  72. Ribera JM, Oriol A, Morgades M, et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol 2014; 32:1595.
  73. Ding Z, Han MZ, Chen SL, et al. Outcomes of Adults with Acute Lymphoblastic Leukemia After Autologous Hematopoietic Stem Cell Transplantation and the Significance of Pretransplantation Minimal Residual Disease: Analysis from a Single Center of China. Chin Med J (Engl) 2015; 128:2065.
  74. Spinelli O, Peruta B, Tosi M, et al. Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica 2007; 92:612.
  75. Gökbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 2012; 120:2032.
  76. Zugmaier G, Gökbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood 2015; 126:2578.
  77. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376:836.
  78. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med 2016; 375:740.
  79. Raff T, Gökbuget N, Lüschen S, et al. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood 2007; 109:910.
  80. Krauter J, Wattjes MP, Nagel S, et al. Real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21)-positive AML patients. Br J Haematol 1999; 107:80.
  81. Muto A, Mori S, Matsushita H, et al. Serial quantification of minimal residual disease of t(8;21) acute myelogenous leukaemia with RT-competitive PCR assay. Br J Haematol 1996; 95:85.
  82. Tobal K, Yin JA. Monitoring of minimal residual disease by quantitative reverse transcriptase-polymerase chain reaction for AML1-MTG8 transcripts in AML-M2 with t(8; 21). Blood 1996; 88:3704.
  83. Estrov Z, Freedman MH. Detection of residual disease in acute lymphoblastic leukemia of childhood. Leuk Lymphoma 1999; 33:47.
Topic 4519 Version 32.0

References

1 : Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia.

2 : Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis.

3 : Minimal residual disease analysis for the prediction of relapse in children with standard-risk acute lymphoblastic leukaemia.

4 : Long-term follow-up of minimal residual disease in childhood acute lymphoblastic leukemia patients by polymerase chain reaction analysis of multiple clone-specific or malignancy-specific gene markers.

5 : Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response.

6 : Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study.

7 : Rearrangement status of the malignant cell determines type of secondary IgH rearrangement (V-replacement or V to DJ joining) in childhood B precursor acute lymphoblastic leukemia.

8 : Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction.

9 : Minimal residual disease after intensive induction therapy in childhood acute lymphoblastic leukemia predicts outcome.

10 : Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia.

11 : Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia.

12 : Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993.

13 : Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia.

14 : Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.

15 : Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.

16 : Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group.

17 : Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood.

18 : Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome.

19 : Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.

20 : Polymerase chain reaction (PCR)- and reverse transcription PCR-based minimal residual disease detection in long-term follow-up of childhood acute lymphoblastic leukaemia.

21 : Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01.

22 : Improving the identification of high risk precursor B acute lymphoblastic leukemia patients with earlier quantification of minimal residual disease.

23 : Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia.

24 : Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient.

25 : Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia.

26 : Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.

27 : Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL.

28 : Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study.

29 : Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children's Oncology Group study (abstract 10001)

30 : Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia.

31 : The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia.

32 : Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

33 : Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia.

34 : Polymerase chain reaction-based detection of minimal residual disease in acute lymphoblastic leukemia predicts relapse after allogeneic BMT.

35 : Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia.

36 : Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia.

37 : Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial.

38 : Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

39 : Minimal residual disease is an important predictive factor of outcome in children with relapsed 'high-risk' acute lymphoblastic leukemia.

40 : Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial.

41 : Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group.

42 : Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group.

43 : Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

44 : Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction.

45 : The significance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia.

46 : Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia.

47 : Late relapsing childhood lymphoblastic leukemia.

48 : Minimal Residual Disease in Acute Lymphoblastic Leukemia: How to Recognize and Treat It.

49 : Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial.

50 : Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation.

51 : Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762).

52 : Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy.

53 : Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

54 : Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia.

55 : Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance).

56 : Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia.

57 : Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value.

58 : Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study.

59 : Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.

60 : Has MRD monitoring superseded other prognostic factors in adult ALL?

61 : Breakpoint-specific multiplex polymerase chain reaction allows the detection of IKZF1 intragenic deletions and minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia.

62 : Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

63 : Monitoring of minimal residual disease (MRD) is useful to predict prognosis of adult patients with Ph-negative ALL: results of a prospective study (ALL MRD2002 Study).

64 : Low levels of minimal residual disease after induction chemotherapy for BCR-ABL1-negative acute lymphoblastic leukaemia in adults are clinically relevant.

65 : A prospective study of residual-disease monitoring of the ALL1/AF4 transcript in patients with t(4;11) acute lymphoblastic leukemia.

66 : Clinical relevance of residual disease monitoring by polymerase chain reaction in patients with ALL-1/AF-4 positive-acute lymphoblastic leukaemia.

67 : Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4; 11)(q21; q23).

68 : Pre-pre-B acute lymphoblastic leukemia: high frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission.

69 : Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531.

70 : Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia.

71 : Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).

72 : Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial.

73 : Outcomes of Adults with Acute Lymphoblastic Leukemia After Autologous Hematopoietic Stem Cell Transplantation and the Significance of Pretransplantation Minimal Residual Disease: Analysis from a Single Center of China.

74 : Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia.

75 : Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation.

76 : Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment.

77 : Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia.

78 : Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia.

79 : Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials.

80 : Real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21)-positive AML patients.

81 : Serial quantification of minimal residual disease of t(8;21) acute myelogenous leukaemia with RT-competitive PCR assay.

82 : Monitoring of minimal residual disease by quantitative reverse transcriptase-polymerase chain reaction for AML1-MTG8 transcripts in AML-M2 with t(8; 21).

83 : Detection of residual disease in acute lymphoblastic leukemia of childhood.

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