Measurable/Minimal residual disease (MRD) · 2020. 10. 14. · Measurable/Minimal residual disease (MRD) Source of cells MRD analyses can be performed on BM aspirate specimens or

Measurable/Minimal residual disease

(MRD)

residual leukemic cells that remain following the

achievement of "complete" remission, but are below

the limits of detection using conventional morphologic

assessment.


(MRD)


(MRD)

Difficulties in the

defining CR

Hematogones

Sampling error

Detection limits


(MRD)

Source of cells

MRD analyses can be performed on BM aspirate

specimens or PB. BM is preferred, especially in cases of

B-lineage ALL.

A 2 to 5 mL sample from the first bone marrow aspirate

usually provides sufficient numbers of bone marrow

cells to achieve adequate sensitivity.

For T-lineage ALL, PB and BM may yield similar MRD

assessments.

PB is not a sensitive measure of MRD in B-lineage ALL.


(MRD)

Methods for detecting MRD

cytogenetics

cell culture systems

fluorescence in situ hybridization (FISH)

Southern blotting

multicolor flow cytometry

polymerase chain reaction (PCR)

deep sequencing


(MRD)

Methods for detecting MRD In order to apply these techniques for MRD detection, they

must demonstrate three salient characteristics :

Specificity – The ability to discriminate between malignant

and normal cells

Sensitivity – The ability to detect one malignant cell in a

background of at least 1000 normal cells

Reproducibility and applicability – The techniques must be

standardized and reproducible, and results

must be available in a timely manner


(MRD)

The preferred method depends at least in part on the

impact the results will have on patient care

To identify patients at high risk of relapse

flow cytometry is often preferred

To identify patients with a low risk of relapse

PCR is often preferred


(MRD)

Response defined

Complete MRD response – No MRD is detected

MRD persistence – Presence of a continuously quantifiable MRD positivity measurable at at least two time points with at least one relevant treatment element in between.

MRD reappearance – Conversion from MRD negativity to quantifiable MRD positivity

Negative MRD

As commonly used "MRD negative" implies to ≤10-4

residual disease was found.


(MRD)

Prognostic value

conventional chemotherapy:

An study used flow cytometry of BM samples to

evaluate MRD in 158 children with ALL. Samples were

collected after induction therapy and during weeks 14,

32, and 56 of continuation therapy, and again at 120

weeks (end of therapy).

At all time points, MRD detection was associated with a

significantly higher rate of relapse.


(MRD)

conventional chemotherapy:

Another study measured MRD by PCR on day 46 in 455 children with B cell lineage ALL.

MRD was undetectable in 58 percent; <0.001% , in 11 percent; 0.001 to <0.01% in 14 percent; and 0.01 percent or greater in 17 percent.

The five-year cumulative incidence of relapse was higher among those with MRD of 0.01 percent or greater versus MRD of <0.01 percent or undetectable MRD.

These results suggest a prognostic impact for MRD detected below the conventional threshold of 0.01 percent..


(MRD)

conventional chemotherapy:In AIEOP-BFM 2000 study, 3184 children with Philadelphia chromosome negative B cell lineage ALL were risk stratified by MRD status (PCR sensitivity ≤0.01%) at day 33 and day 78 with significantly different event-free survival [EFS] and OS at five years

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

•Intermediate risk (52 percent): Those with MRD >0.01% 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% on day 78 had EFS and OS of 50 and 60 percent, respectively.


(MRD)

In an analysis of 7430 children enrolled on COG studies, evaluation of MRD by flow cytometry on day 29 was highly predictive of patient outcomes.

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.

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.

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.


(MRD)

In the setting of transplantation

MRD studies have demonstrated prognostic value when

measured before and after allogeneic HCT.

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.


(MRD)


Five-year survival rates in ALL and AML increased as

pre-HCT MRD levels decreased being 29, 52, and 68

percent for patients with high, low, and no MRD.


(MRD)


In the prospective ALL-BFM-SCT 2003 trial, 113 children with relapsed ALL had MRD testing of the BM by RT PCR prior to and on days +30, +60, +90, +180, and +365 post-HCT.

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.


(MRD)


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.

Only 1 of 35 patients in complete remission had MRD

detectable more than six months following transplant.


(MRD)


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.


(MRD)

At relapse In a study of 35 children who experienced a second

morphologic complete remission after reinduction therapy for relapsed disease, MRD ≥0.01% by flow cytometry was associated with an increased risk of relapse

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 reinductiontherapy was highly predictive of EFS.

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.


(MRD)

Using MRD to escalate therapy

Patients with detectable MRD have an increased risk of relapse after conventional therapy.

UKALL 2003 trial : 533 patients who had MRD in the bone marrow at the end of induction therapy were randomly assigned to receive standard or augmented post-remission therapy.

Augmented therapy resulted in superior EFS at five years and a trend toward improved survival at five years.

These results suggest that escalating care in patients with MRD

at the end of induction therapy improves clinical outcome.


(MRD)

Using MRD to escalate therapy

In 208 children with ALL consolidation therapy was assigned based on MRD status after induction.

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 .


(MRD)

Using MRD to minimize therapy :

As an example, a trial of over 3000 children with newly

diagnosed ALL examined the use of MRD measurements to

minimize maintenance therapy.

MRD measurements following induction and before interim

maintenance were used to classification.

Patients who achieved MRD negativity were randomly

assigned to receive one or two delayed intensification.

Both group had a similar estimated EFS, OS and rate of

relapse at five years.


(MRD)

Long-term surveillance :

Approximately 20% of patients with an MRD level greater

than 10-2 had not yet relapsed at a median follow-up of 38 months.

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

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.

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.


(MRD)

Long-term surveillance :

As such, the value of serial, quantitative measurements of MRD in long-term survivors is unknown

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)

Specific questions regarding MRD testing that remain include:

What is the best test to measure MRD?

What number of abnormal cells should be used to define MRD status?

At what time in the disease/treatment course should MRD be measured?

Should treatment be intensified or HSCT be recommended for patients with MRD positivity?


(MRD)

How does the information gained from MRD testing

differ among various ALL subtypes (eg, T cell versus

B cell ALL or Philadelphia chromosome positive ALL)?

Must the leukemic clone be completely eliminated in

order to achieve long-term survival?

Documents

Measurable/Minimal residual disease (MRD) · 2020. 10. 14. · Measurable/Minimal residual disease (MRD) Source of cells MRD analyses can be performed on BM aspirate specimens or