Min­i­mal Resid­ual Dis­ease: A Prog­nos­tic Fac­tor Mov­ing the Nee­dle in Pa­tient Care

As tech­nol­o­gy ad­vances, in­no­v­a­tive di­ag­nos­tic tools that may help guide ther­a­peu­tic de­ci­sion-mak­ing are be­com­ing avail­able to more and more health­care pro­fes­sion­als (HCPs).

In the past, blood can­cers like acute lym­phoblas­tic leukemia (ALL) were pri­mar­i­ly eval­u­at­ed un­der a mi­cro­scope to de­tect re­main­ing can­cer­ous cells dur­ing and af­ter treat­ment. Now, there are more pre­cise tools to iden­ti­fy minute amounts of can­cer, known as mea­sur­able or min­i­mal resid­ual dis­ease (MRD), present at con­cen­tra­tions that less sen­si­tive tests, such as mi­croscopy, could not de­tect.¹

Tests for MRD have shown to bet­ter as­sess drug re­sponse and re­lapse risk than stan­dard tech­niques, the re­sults of which will equip HCPs with more ac­cu­rate in­for­ma­tion about which pa­tients may re­quire fur­ther in­ter­ven­tion and which can be spared ad­di­tion­al ther­a­py.¹

“Over the last 20 years we have made sig­nif­i­cant ad­vance­ments not on­ly in the sci­ence of MRD de­tec­tion, but in its po­ten­tial im­pact as it re­lates to treat­ment of pa­tients liv­ing with cer­tain blood can­cers,” said David M. Reese, M.D., se­nior vice pres­i­dent, Trans­la­tion­al Sci­ences and On­col­o­gy, Am­gen.

“The tech­nol­o­gy has ad­vanced to the point where we def­i­nite­ly need to re­de­fine what our goals of ther­a­py are, and for every pa­tient with a blood can­cer we should be striv­ing to achieve an MRD neg­a­tive re­mis­sion,” said Aaron Lo­gan, M.D., PhD. hema­tol­o­gist.

MRD is usu­al­ly eval­u­at­ed in one of two ways. The first, called flow cy­tom­e­try, us­es cell-sur­face pro­tein mark­ers to dif­fer­en­ti­ate be­tween cells that are nor­mal and those that are can­cer­ous.²MRD can al­so be test­ed through DNA-based meth­ods that can iden­ti­fy ge­net­ic al­ter­ations and over-ex­pressed genes re­spon­si­ble for caus­ing can­cer.²

Com­pared to con­ven­tion­al test­ing meth­ods that de­tect can­cer cells in the bone mar­row or blood with a sen­si­tiv­i­ty of about 1 in 20, these MRD test­ing meth­ods have im­proved de­tec­tion to sen­si­tiv­i­ties of 1 in 10,000 cells or bet­ter.^2,3

Re­gard­less of the method used to mea­sure MRD, a neg­a­tive sta­tus has been shown to cor­re­late with im­proved clin­i­cal out­comes.⁴Ac­cord­ing to Dr. Lo­gan, MRD sta­tus is “an ex­treme­ly im­por­tant prog­nos­tic fac­tor for pre­dict­ing whether a pa­tient is like­ly to re­lapse af­ter achiev­ing re­mis­sion.”

Be­cause MRD is a quan­tifi­ca­tion of dis­ease bur­den, it can al­so be lever­aged at sev­er­al points in time, not just af­ter the achieve­ment of re­mis­sion.^1,4

“There’s a grow­ing in­ter­est in us­ing MRD not on­ly for risk strat­i­fy­ing pa­tients and to pre­dict their out­comes, but al­so to iden­ti­fy strate­gies for in­ter­ven­ing up­on resid­ual dis­ease,” said Dr. Lo­gan.

When used dur­ing treat­ment, MRD lev­els can in­di­cate a pa­tient’s re­sponse to ther­a­py, as Dr. Lo­gan ex­plains.¹De­spite the im­pact MRD can play on risk strat­i­fi­ca­tion for pa­tients, Dr. Lo­gan notes not all labs are able to de­tect MRD at lev­els sen­si­tive enough to un­der­stand the true im­pact.

How­ev­er, he adds, “aware­ness of the im­por­tance of MRD is in­creas­ing. I do think more and more providers who see ALL pa­tients are go­ing to be find­ing ways to con­duct MRD as­sess­ments on their pa­tients.”

Be­yond ALL, MRD test­ing has been used across a va­ri­ety of hema­to­log­ic ma­lig­nan­cies, in­clud­ing oth­er types of leukemia, cer­tain lym­phomas, and mul­ti­ple myelo­ma.⁵Clin­i­cal re­search con­tin­ues to ex­plore the sig­nif­i­cance of MRD in these can­cers.

“We still have a ton of work to do to,” Dr. Lo­gan ex­plains, “to in­ves­ti­gate in all of these blood can­cers what is the thresh­old at which we should change ther­a­py, what are the most ef­fec­tive ther­a­pies and then once you achieve an MRD-neg­a­tive re­mis­sion, what do you do then to main­tain that re­mis­sion?”

Ul­ti­mate­ly, Dr. Lo­gan be­lieves that the field is head­ing in a di­rec­tion that will lead to bet­ter de­ci­sion mak­ing.

Out­side of the lab, the path ap­pears to be mov­ing quick­ly. Ac­cord­ing to a 2017 analy­sis by the U.S. Food and Drug Ad­min­is­tra­tion, near­ly 40 per­cent of new drug and bi­o­log­ics li­cense ap­pli­ca­tions sub­mit­ted to the Di­vi­sion of Hema­tol­ogy Prod­ucts be­tween 2014 and 2016 in­clud­ed MRD da­ta.⁶

“At Am­gen, we have been able to take what we are see­ing in the lab af­ter ex­am­in­ing resid­ual can­cer cells and ap­ply these learn­ings to our clin­i­cal de­vel­op­ment pro­grams,” said Reese. “As test­ing for MRD con­tin­ues to ad­vance and be­comes more com­mer­cial­ly avail­able, there is every ex­pec­ta­tion that treat­ment ap­proach­es will evolve to help bet­ter care for these pa­tients.”

For more in­for­ma­tion on MRD and oth­er ad­vance­ments in on­col­o­gy, please vis­it www.AmgenOn­col­o­gy.com.

Ref­er­ences:

1. Paeit­ta E. Bone Mar­row Trans­plant. 2002;29:459-465.
2. Brügge­mann M, et al. Blood. 2012;120:4470-4481.
3. Gök­buget N, et al. Blood. 2012;120:1868-1876.
4. Berry D, et al. JA­MA On­col. 2017; 3:e170580.
5. van der Velden VH, et al. Leukemia. 2003;17:1013-1034.
6. Gorm­ley N, et al. J Clin On­col.2017;35:(sup­pl; ab­str 2541)

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