Minimal residual disease (MRD)

A strong predictor of relapse in acute lymphoblastic leukemia in children and adults.

Defined as the amount of residual leukemic cells that remain in the bone marrow and/or circulating in the peripheral blood after treatment.

Also referred to as measurable residual disease.
The level of MRD reflects the response to achieve primary induction and consolidation therapies, as well as immunological effects that have the potential to counteract relapse.
Flow cytometry is commonly used for measuring MRD, as is PCR, but next generation DNA sequencing is being more broadly applied.
Next generation flow cytometry and allele specific oligo nucleotide quantitative PCR are also available to evaluate MRD status.
With bone marrow sampling NGS can reach sensitivity of 10 to the -6.
MRD is a standard test for patients with ALL.
In  ALL MRD appears to be the most important factor guiding treatment decisions
MRD in ALL  has been shown that MRD negative response to frontline therapies is an independent predictor of overall outcome, whereas persistence of MRD is associated with higher rates of relapse and worse survival.

An MRD threshold of 10-4th leukemia cells has been recognized in several studies as the cut off that can differentiate between patients and higher risk of relapse and those with a lower but non-negligible risk of relapse for ALL.

In all studies of acute lymphoblastic leukemia shown to be prognostic in every point time including during or after induction, and early in consolidation.

Flow cytometry is based on the quality of the bone marrow sample and the laboratory performing the study and requires a sufficient number of cells and should be taken from the first pull of bone marrow aspiration.

The flow cytometry laboratory essay should be at least 10 to the -4th sensitivity.

Flow cytometry is a corner stone for ALL MRD analysis as it provides important information about the cells.

MRD is the most important prognostic factor in the management of ALL.
The persistence of MRD is associated with a higher relapse rates and worse disease free survival and overall survival in several leukemia‘s including CML, CLL, and acute lymphoblastic leukemia, and AML.

In ALL a pre-transplant positive MRD is a significant negative predictive relapse free survival, event free survival, and overall survival.

After induction therapy it is the most important prognostic factor for outcome of children with acute lymphoblastic leukemia.

In studies of both pediatric and adult populations with ALL, MRD negativity uniformly correlates with significant better outcomes in all studies.
Achieving an MRD negative status of less than 10 to the -4th° is a critical milestone that should be pursued in all patients with ALL.

10 year event free survival within the first three cycles of chemotherapy was 64% for adult achieving MRD- negative status versus 21% in those with MRD positive disease.

Children’s Oncology Group indicates MRD at the end of induction may be the most useful for predicting 5-year event free survival.

In ALL  patients who have MRD positive disease should be converted to MRD negative prior to transplant.

Measurement of MRD in the peripheral blood at day 8 provides information by identifying patients with acute lymphoblastic leukemia with low risk of relapse.

Recognition of MRD in patients with ALL that is BCR/ABL positive after initiation of therapy with T KI and chemotherapy can establish which patients would benefit from stem cell transplant at the time of first remission.

MRD impacts on progression free survival and overall survival in allogeneic hematopoietic transplant patients with AML and in a similar degree in first and second remission.

Presently can be utilized in acute promyelocytic leukemia.

MRD may be useful in evaluating post remission treatment in AML to decide whether allogeneic hematpoetic stem cell transplant should be considered.

In multiple myeloma flow cytometry and gene sequencing can determine the presence of minimal residual disease, detecting as few as 1 myeloma cell among millions of normal cells.

MRD in myeloma is associated with prolonged remissions.

For a patient with Philadelphia chromosome positive ALL the most common method of disease monitoring his BCR-ABL fusion gene quantification my PCR. PCR.
In multiple myeloma the evaluation of residual disease present utilizes to techniques commonly: next generation sequencing and next generation flow cytometry.
Next generation sequencing of the immunoglobulin gene within myeloma cells allows detection of malignant plasma cells present at one abnormal cells per million normal cells( 10th to the -6th).
In myeloma next generation sequencing analyzes immunoglobulin genes  can establish a rearrangement pattern and identification, and PCR amplification of the immunoglobulin loci.
In CLL MRD status at the end of chemoimmuno therapy treatment correlates with better survival.
In CLL IGHV  mutation and undetectable MRD at the end of six cycles of FCR have the best outcomes in terms of progression free survival.
MRD negative status of less than 10 to minus 4, is associated with better clinical outcomes.
In CLL levels below a sensitivity threshold of 10 to the -4th at the end of therapy can expect similarly good outcome regardless of whether they have a complete remission or a partial remission, and mild residual lymphadenopathy or splenomegaly often reflects non-residual disease activity but rather residual tissue scars.
End of treatment MRD status strongly associated with progressive free survival in CLL.
FCR therapy is associated with a 30%-57% undetectable MRD in CLL.
In CLL undetectable MRD has better outcomes in terms of progression free survival and overall survival, regardless of whether a partial or complete remission is achieved.
Ibrutinib  continuous therapy in CLL only has an undetectable MRD of 5% with a significantly longer progressive free survival and overall survival suggesting BTK inhibitors can effectively modulate disease without reducing MRD in CLL.

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