Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with heterogeneous presentation, ranging from indolent disease courses to aggressive diseases similar to acute myeloid leukemia ...(AML). Approximately 90% of MDS patients harbor recurrent mutations , which – with the exception of mutated SF3B1 –have not (yet) been included into the diagnostic criteria or risk stratification for MDS. Accumulating evidence suggests their utility for diagnostic workup, treatment indication and prognosis. Subsequently, in patients with unexplained cytopenia or dysplasia identification of these mutations may lead to earlier diagnosis. The acquisition and expansion of additional driver mutations usually antecedes further disease progression to higher risk MDS or secondary AML and thus, can be clinically helpful to detect individuals that may benefit from aggressive treatment approaches. Here, we review our current understanding of somatic gene mutations, gene expression patterns and flow cytometry regarding their relevance for disease evolution from pre-neoplastic states to MDS and potentially AML.
Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases ...and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.
Although the presence of
-ITD, as well as levels of the
-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the
-ITD allelic ratio ...impacts patients' outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed 118 patients (median age at diagnosis 58.3, range 14.3-82.3 years) harboring
-ITD, of whom 94 patients were consolidated with an allogeneic HSCT and included in outcome analyses. A high
-ITD allelic ratio was associated with a higher white blood cell count, higher blood and bone marrow blasts, and worse ELN2017 risk at diagnosis. Patients with a high
-ITD allelic ratio more often had
mutations, while patients with a low allelic ratio more often had
-TKD mutations. Patients with a high
-ITD allelic ratio were less likely to achieve a measurable residual disease (MRD)-negative remission prior to allogeneic HSCT and had a trend for a shorter time to relapse. However, there was no distinct cumulative incidence of relapse, non-relapse mortality, or overall survival according to the
-ITD allelic ratio in transplanted patients. While co-mutated
-TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high
-ITD allelic ratio, comparative studies are needed to evaluate which
-ITD mutated patients benefit from which consolidation strategy.
The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute ...lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the "MRD-target", time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional-potentially toxic-therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences.
For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, ...high expression of the AML-associated genes
BAALC
(brain and acute leukemia, cytoplasmic) and
MN1
(meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic
BAALC/ABL1
and
MN1/ABL1
copy numbers in 302 AML patients. High
BAALC/ABL1
and
MN1/ABL1
copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high
BAALC
and
MN1
expression are mitigated by allogeneic HSCT. But preHSCT
BAALC
/
ABL1
and
MN1
/
ABL1
assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic
BAALC
or
MN1
expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.
Introduction
Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free ...light chain (iFLC) is of potential prognostic value.
Methods
This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV).
Results
After a median number of two (range 1–5) BPV cycles, the majority of pts (
n
= 86; 93%) responded with either sCR (
n
= 21), CR (
n
= 1), nCR (
n
= 25), VGPR (
n
= 20), or PR (
n
= 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (
p
= 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (
p
> 0.05).
Conclusion
These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment.
Red blood cell distribution width (RDW) is calculated in every blood count test and reflects variability in erythrocyte size. High levels mirror dysregulated erythrocyte homeostasis and have been ...associated with clonal hematopoiesis as well as higher mortality in several conditions.
We aimed to determine the impact of preprocedural RDW levels on functional outcomes after transcatheter aortic valve implantation (TAVI).
In this single-center retrospective study, we analyzed 176 consecutive patients receiving TAVI between 2017 and 2021. RDW upper limit of normal was < 15 %. Patients were stratified according to preprocedural RDW as having normal or elevated values. We assessed all-cause-mortality and a composite endpoint comprising cardiovascular/ valve-related mortality and cardiovascular, valve-related and heart failure hospitalization at 1 year.
43 patients (24.4 %) had RDW ≥ 15 %. There were significant baseline differences between groups (Society of Thoracic Surgeons – Predicted Risk of Mortality score 3.18 %interquartile range 1.87–5.47 vs. 6.63 %4.12–10.54 p < 0.001; hemoglobin 13.2 g/dL11.8–14.1 vs. 10.4 g/dL9.8–12.2, p < 0.001, RDW-normal vs. RDW-high, respectively). Age was not distinct (80.2 years 77.5–84.1 vs 81.271.3–84.7, p = 0.78). 1-year-all-cause mortality was not different (7.9 % vs. 9.4 %, p = 0.79). The RDW-high group showed markedly higher NT-proBNP levels after 1 year (647 ng/ml283–1265 vs. 1893 ng/ml744–5109, p = 0.005), and experienced more clinical endpoints (hazard ratio 2.571.28–5.16 for the composite endpoint, p = 0.006). RDW remained an independent predictor of the composite endpoint when accounting for all baseline differences in multivariable regression.
Elevated preprocedural RDW identifies patients at risk for impaired functional outcome after TAVI and may represent a useful low-cost parameter to guide intensity of outpatient surveillance strategies.
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