Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Walter, Roland B.; Gooley, Ted; Wood, Brent L.; Milano, Filippo; Fang, Min; Sorror, Mohamed L.; Estey, Elihu H.; Salter, Alexander I.; Lansverk, Emily; Chien, Jason W.; Gopal, Ajay K.; Appelbaum, Frederick R.; Pagel, John M.

doi:10.1200/jco.2010.31.8121

Cited by 358 publications

(315 citation statements)

References 31 publications

Supporting

Mentioning

285

Contrasting

Unclassified

Order By: Relevance

“…39 Minimal residual disease detected using up to 10-color multidimensional flow cytometry has been shown to predict relapse in MAC allo-HCT settings in adults or in children. 40,41 Our study did not find that patients with lower blast counts had favorable outcome compared with those with higher blast counts, while still being in morphologic CR. This suggests that the quantity of non-leukemic myeloblasts has no influence on outcome.…”

Section: Discussioncontrasting

confidence: 61%

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Üstün

Wiseman

DeFor

et al. 2013

Bone Marrow Transplant

View full text Add to dashboard Cite

Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3-10.3, P ¼ 0.01) and decreased survival (HR: 2.9; 95% CI: 1.3-6.4, Po0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre-allo-HCT bone marrow (BM) blast count (that is, 0-4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation. Keywords: allogeneic hematopoietic cell transplantation; reduced-intensity conditioning regimen; AML; relapse; minimal residual disease; CR INTRODUCTIONAllogeneic hematopoietic SCT (allo-HCT) remains the most effective treatment for most patients with AML. 1 The two main mechanisms by which allo-HCT can cure AML are through the immunologically based GVL effect and leukemic cell cytoreduction by HCT conditioning. 2-5 Reduced-intensity conditioning (RIC) was introduced to allo-HCT more than a decade ago for patients who are older, had significant co-morbid conditions or poorer performance status. [6][7][8] The anti-neoplastic potency of these RIC HCT regimens relies primarily on the GVL effect rather than ablating all residual leukemic disease. 9 It is clear that patients with active leukemia had more relapse and worse OS after allo-HCT regardless of donor type or patient age. [10][11][12][13][14][15] Following allo-HCT, 40-60% of AML patients in CR1 enjoy long-term OS, whereas o20% of refractory or relapsed AML patients survive. 1,11 Yet even for allo-HCT during CR, relapse remains the most frequent complication of allo-HCT. 16 As relapse has been reported more frequently after RIC allo-HCT compared with myeloablative conditioning (MAC) allo-HCT in patients with AML, this suggests heterogeneity in the interpretation of a CR, which may be more important after RIC allo-HCT. [17][18][19][20][21][22][23] The CR definition updated in 2003 24 clearly requires no evidence of leukemia by flow cytometry in addition to the morphologic remission as reported: 'The presence of a unique phenotype (by flow cytometry) identical to what was found in the pretreatment specimen (for example, CD34, CD7 coexpression) should be viewed ...

show abstract

Section: Discussioncontrasting

confidence: 61%

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Üstün

Wiseman

DeFor

et al. 2013

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…2). Walter et al have reported that MPFC detectable MRD prior to HCT is independently associated with relapse after HCT [17]. Since MRD prior to HCT reflects ineffectiveness of chemotherapy prior to HCT these results suggest that ineffective chemotherapy begets ineffective HCT, although the effect pre HCT of a given increment in MPFC detectable MRD seems greater, at least in children, in ALL than in AML [18].…”

Section: Minimal Residual Disease (Mrd)mentioning

confidence: 99%

Acute myeloid leukemia: 2013 update on risk‐stratification and management

2013

Self Cite

View full text Add to dashboard Cite

Disease overviewAcute myeloid leukemia (AML) results from accumulation of abnormal blasts in the marrow. These cells interfere with normal hematopoiesis, can escape into the peripheral blood, and infiltrate CSF and lung. It is likely that many different mutations, epigenetic aberrations, or abnormalities in micro RNA expression can produce the same morphologic disease with these differences responsible for the very variable response to therapy, which is AMLs principal feature.DiagnosisThis rests on demonstration that the marrow or blood has > 20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry, with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated.Risk StratificationTwo features determine risk: the probability of treatment‐related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics, with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogentic finding is a normal karyotype(NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics (inv 16 or t[8;21]) (60–70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30–40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Increasing evidence indicates that other mutations and abnormalities in microRNA (miRNA) expression also affect resistance as do post treatment factors, in particular the presence of minimal residual disease. These newer mutations and MRD are discussed in this update.Risk‐adapted therapyPatients with inv (16) or t(8;21) or who are NPM1+/FLT3ITD—can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m2 will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m2 (for example bid X 6 days), as opposed to the more commonly used 3 g/m2. Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. This update discusses results with newer agents: quizartinib and crenolanib, gemtuzumab ozogamicin, clofarabine and cladribine, azacitidine and decitabine, volasertib, and means to prevent relapse after allogeneic transplant.The diagnosis of AML essentially is made as it was in 2012. Thus this review will emphasize new developments in risk stratification and treatment using as references many papers published in 2012. Am. J. Hematol. 88:318–327, 2013. © 2013 Wiley Periodicals, Inc.

show abstract

“…18 The impact of MRD evaluation performed before allogeneic, either related or unrelated hematopoietic stem cell transplantation has been reported in patients with ALL and acute myeloid leukemia and found to be associated with outcomes. 19,20 In order to verify whether MRD determination before the allograft has prognostic significance in patients given UCBT, we conducted a retrospective analysis on children with ALL transplanted from an unrelated cord blood donor and reported to the Eurocord registry.…”

Section: Introductionmentioning

confidence: 99%

Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP–EBMT analysis

et al. 2012

View full text Add to dashboard Cite

To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR) ¼ 0.4, P ¼ 0.01) and for those transplanted in CR1 and CR2 (HR ¼ 0.3, P ¼ 0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P ¼ 0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR ¼ 2, P ¼ 0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation. Approaches that may decrease relapse incidence in children given UCBT with positive MRD should be investigated to improve final outcomes.

show abstract

Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Abstract: These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.

Cited by 358 publications

References 31 publications

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Acute myeloid leukemia: 2013 update on risk‐stratification and management

Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP–EBMT analysis

Contact Info

Product

Resources

About