Molecular remission in PCR-positive acute myeloid leukemia patients with inv(16): role of bone marrow transplantation procedures

Martinelli, Giovanni; Ottaviani, Emanuela; Testoni, Nicoletta; Visani, Giuseppe; Terragna, Carolina; Amabile, Marilina; Trabacchi, Elena; Montefusco, Vittorio; Tura, S

doi:10.1038/sj.bmt.1701963

Cited by 6 publications

(7 citation statements)

References 16 publications

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“…12,17,18 It is thought that some of these patients may be considered cured. This report on a large series of patients with inv(16) AML examines what, to our knowledge, is the longest clinical, cytogenetic, and molecular follow-up thus far published.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16] Most patients with inv(16) AML treated in our institute achieved long-term CR. 17,18 However, several groups have reported persistence of the chimeric transcript even after allogeneic bone marrow transplantation (BMT). 12,[19][20][21] These considerations prompted us to investigate whether it is possible to predict relapse among patients who have achieved CR, and under what conditions patients can be considered in a curable state.…”

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confidence: 99%

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Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state

Buonamici

Ottaviani

Testoni

et al. 2002

Blood

130

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The inv(16) cytogenetic subtype of acute myeloid leukemia (AML) has a relatively good prognosis. Many patients achieve complete remission (CR). The prognostic uncertainty of negative qualitative reverse transcription-polymerase chain reaction (RT-PCR) assays suggests the need to identify prognostically significant critical thresholds by real-time RT-PCR. A reliable and sensitive (10 ؊5 ) real-time RT-PCR assay was set up for the evaluation of relevant CBF␤-MYH11/ABL transcript ratios and was applied to the 21 patients with inv(16) AML routinely referred for cytogenetic and molecular monitoring in Serà gnoli Institute (Bologna, Italy) since 1990. Among the 18 patients who underwent ablative chemotherapy, all achieved CR with a 3-year disease-free survival probability of 63% (95% CI, 40%-87%) and no recorded events after 26 months. Five patients had relapses; 2 died of disease and 3 entered second CR. Analysis of the 125 bone marrow (or peripheral blood) samples studied by real-time RT-PCR showed that transcript ratios of samples taken during CR at any time before a relapse were always greater than 0.12%, whereas those of samples taken during first or second CR from patients who did not subsequently have relapses were always less than 0.25%. This suggests that transcript ratios greater than 0.25% may correspond to high risk for relapse, whereas ratios below 0.12% might indicate the patient is in a curable state. IntroductionInversion of chromosome 16, inv(16)(p13q22), and its related translocation, t(16;16)(p13;q22), are recurrent rearrangements found in a subset of patients with acute myeloid leukemia (AML), particularly the M4Eo subtype. [1][2][3][4] Inv(16) is associated with relatively good long-term, disease-free survival (DFS). 5,6 It generates a chimeric mRNA transcript, CBF␤-MYH11, by fusing the CBF␤ gene located on band q22 of chromosome 16 7,8 and the MYH11 gene, which encodes a heavy chain of the smooth-muscle myosin protein, located at the p13 breakpoint. 9,10 Messenger RNA analysis by reverse transcription-polymerase chain reaction (RT-PCR) can help define leukemic subsets and provide potentially valuable diagnostic and prognostic information. 11 Qualitative RT-PCR reveals the presence of detectable levels of minimal residual disease (MRD) in patients in complete clinical remission (CR) after induction chemotherapy. 12 Introduction of real-time RT-PCR 13 should allow routine quantitation of the transcript. The 5Ј-3Ј nuclease activity of the Taq polymerase cleaves an internal fluorogenic probe specific for the target sequence, causing the emission of a fluorescent signal that can be detected during amplification. This allows rapid quantitation of specific RT-PCR products with a dynamic detection range of more than 5 orders of magnitude. Several groups have used real-time RT-PCR with TaqMan technology to quantitate MRD with leukemia-specific chromosome aberrations such as t(9;22), t(l5;17), and t(8;21). [14][15][16] Most patients with inv(16) AML treated in our institute achieved long-term CR. 17,18 Ho...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state

Buonamici

Ottaviani

Testoni

et al. 2002

Blood

130

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“…1,2 In these entities most patients achieve a complete remission (CR); however, 10% to 30% finally have a relapse. 1,[3][4][5][6][7][8][9][10] The corresponding leukemia-specific fusion transcripts, PML-RARA, CBFB-MYH11, and AML1-ETO, can be targeted by polymerase chain reaction (PCR)-based methods at diagnosis and to detect minimal residual disease (MRD). [11][12][13] Thus, the presence of residual PML-RARA ϩ cells strongly predicts relapse and therefore is an important parameter for treatment decisions.…”

Section: Introductionmentioning

confidence: 99%

New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts

Schnittger¹,

Weisser²,

Schoch³

et al. 2003

Blood

199

179

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To evaluate the prognostic significance of quantitative PML-RARA, AML1-ETO, and CBFB-MYH11 fusion transcript expression, real-time polymerase chain reaction was used to analyze bone marrow samples of 349 such patients at diagnosis and 522 samples of 142 patients also during therapy (total analyses, n ‫؍‬ 859; median number of follow-up samples, 4/patient; median duration of assessment, 12 months). Lower expression levels at diagnosis correlated with better overall and event-free survival in all 3 leukemia subtypes. By combining the median expression ratio after consolidation therapy and the 75th percentile of the expression ratio at diagnosis, a new score was established that separates a group with 100% EFS from a significantly worse group (P < .0001) in each of the 3 acute myeloid leukemia subgroups. Eight patients showed increasing levels of expression during follow-up and all had relapse. In conclusion, patients at high risk for treatment failure can be identified by high levels of fusion gene expression at diagnosis or less than 3 logs of tumor reduction during the first 3 to 4 months of therapy. By combining the transcription ratios at these 2 checkpoints, a new powerful prognostic score has been established. (Blood. 2003;102:2746-2755

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“…Similar to t(8;21) AML, the inv (16) AML studies reported to date have limitations consisting of small numbers of patients analyzed and lack of standardized RT-PCR assays. However, the collective analysis of these data supports the notion that molecular remission is achievable and is likely to be predictive of CCR in this subgroup of AML patients (Table 3) (12,13,(46)(47)(48)(49)(50)(51)(52)(53).…”

mentioning

confidence: 56%

“…In some cases, in fact, the detection of MRD during CR is not indicative of impending relapse, and chimeric transcripts have been found in patients with long‐term clinical remission and in normal healthy individuals (8–10). Similarly, a BM or blood sample deemed negative for MRD on the basis of an undetectable fusion transcript has not been invariably predictive of long‐term remission (11–13). These data support the notion that distinct molecular subgroups of AML may have a diversified biology, and that in some cases, persistence of chimeric clones following aggressive treatment is compatible with normal hematopoiesis.…”

Section: Monitoring Minimal Residual Disease In Acute Myeloid Leukemiamentioning

confidence: 99%

Core binding factor (CBF) acute myeloid leukemia: is molecular monitoring by RT–PCR useful clinically?

Marcucci

Caligiuri

Bloomfield

2003

European J of Haematology

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Clonal chromosomal abnormalities are the most important prognostic indicators in acute myeloid leukemia (AML). Two of the most prevalent cytogenetic subtypes of adult primary AML, t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), are characterized by disruption of the AML1(CBFA2, RUNX1) and CBFbeta genes, respectively, which encode subunits of core binding factor (CBF), a regulator of normal hematopoiesis. At the molecular level, t(8;21) and inv(16)/t(16;16) result in the creation of novel fusion genes, AML1/ETO and CBFbeta/MYH11, respectively, which encode fusion transcripts readily detectable by the reverse transcription-polymerase chain reaction (RT-PCR). Although the detection of t(8;21) or inv(16)/t(16;16) in adult patients with primary AML represents a favorable independent prognostic indicator for achievement of cure following intensive chemotherapy or stem cell transplantation, a substantial number of these patients (i.e. 40-50%) relapse and eventually die of their disease. Therefore, timely identification and therapeutic stratification of those patients deemed at high risk for disease relapse could ultimately result in a further improvement of clinical outcome within these cytogenetic subgroups of AML. As relapse is likely to occur as the result of failure of treatment to completely eradicate leukemic blasts, the detection of the AML1/ETO and CBFbeta/MYH11 fusion transcripts using sensitive RT-PCR assays has been utilized as a surrogate marker for resistant disease and, in turn, to predict disease recurrence during remission. The purpose of this paper is to review the applicability of this strategy to the clinical management of t(8;21) and inv(16)/t(16;16) primary AML, here collectively referred to as CBF AML.

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Molecular remission in PCR-positive acute myeloid leukemia patients with inv(16): role of bone marrow transplantation procedures

Cited by 6 publications

References 16 publications

Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state

Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state

New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts

Core binding factor (CBF) acute myeloid leukemia: is molecular monitoring by RT–PCR useful clinically?

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