scholarly journals Kinetics of bone marrow blasts during induction and achievement of complete remission in acute myeloid leukemia

Haematologica ◽  
2008 ◽  
Vol 93 (8) ◽  
pp. 1263-1265 ◽  
Author(s):  
M. Yanada ◽  
G. Borthakur ◽  
F. Ravandi ◽  
C. Bueso-Ramos ◽  
H. Kantarjian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Kinetics Of ◽  
Bone Marrow Blasts ◽  
Acute Myeloid

Kinetics of Bone Marrow Blasts during Remission Induction Course in Acute Myeloid Leukemia: Effect on Complete Remission and Relapse-Free Survival.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1852-1852
Author(s):  
Masamitsu Yanada ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Persistent Disease ◽  
Bone Marrow Blasts ◽  
Acute Myeloid

Abstract Achievement of complete remission (CR) is crucial to prolong survival in acute myeloid leukemia (AML). The definition of CR has been well established; however, there are no objective measures for deciding when the probability of achieving CR has become so low that a patient’s disease can be considered resistant to therapy. In particular, it can be difficult to distinguish patients with resistant disease from those with persistent disease but who subsequently will enter CR, a distinction that underlies the decision to start a second course or change therapy. We attempted to facilitate this decision by examining the relation between the % marrow blasts 21 days, and later, after start of course 1 of initial induction therapy and the subsequent probability of CR on course 1. Our database consisted of the 593 adults with AML (≥20% blasts, acute promyelocytic leukemia excepted) who had bone marrow examined 21 days after beginning induction therapy including cytarabine at cumulative dose of 5–6 g/m2 at M. D. Anderson Cancer Center from 1995 to 2004. 340 of the 593 patients had an additional bone marrow examination between day 22 and day 28 (day 22–28) of course 1; similarly, day 29–35 marrows were done in 185 patients, day 36–42 marrows in 89 patients and so on. Bone marrows were categorized as morphologic leukemia-free state (MLFS; <5% blasts), persistent disease (PD; ≥5% blasts), or too few cells to count (TFTC). 197 of the 593 patients (33%) had an MLFS on day 21. This conferred a 94% probability of CR on course 1, independent of cytogenetic group. 275 patients (47%) had PD on day 21 and 57% of these 275 entered CR on course 1, with the probability of subsequent CR being predictable from the combination of cytogenetics, day 21 bone marrow blasts, and day 21 platelet and neutrophil counts. Patients with PD on day 21, but who achieved an MLFS on day 28 were highly likely to enter CR (40/47). However, those with PD beyond day 28 were very unlikely to enter CR on course 1, and no CR was observed in patients with PD after day 43. 121 patients (20%) had a TFTC marrow on day 21, with this finding associated with a CR rate of 72% on course 1 (p<0.001 vs MLFS, and p<0.001 vs PD). Not surprisingly given the respective CR rates, patients with MLFS on day 21 had significantly longer survival than patients with PD and patients with TFTC marrow (p<0.001). However, Relapse-free survival was not different among the 3 groups (p=0.109), which was also confirmed by multivariate analysis accounting for cytogenetics, antecedent hematologic disorder, and age. These results appear useful in management of AML, and recommend that bone marrow be examined on day 28, in patients with PD on day 21 and a <50% probability of subsequent CR and in patients with TFTC on day 21. Should PD persist on day 28, and especially on day 35, a second course should be started or new therapy instituted.

Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.

1994 ◽  
Vol 12 (10) ◽  
pp. 2138-2145 ◽  
Author(s):  
P J Shaw ◽  
M E Bergin ◽  
M A Burgess ◽  
L Dalla Pozza ◽  
S J Kellie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Survival Rate ◽  
Complete Remission ◽  
Relapse Rate ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Free Survival ◽  
Acute Myeloid

PURPOSE To report the impact of bone marrow transplantation (BMT) with busulfan/cyclophosphamide (BuCy) as end consolidation in a cohort of consecutively diagnosed children with acute myeloid leukemia (AML). PATIENTS AND METHODS Between May 1987 and November 1992, 43 patients were diagnosed with AML. Tissue typing at diagnosis determined whether patients would proceed to autologous or allogeneic BMT as end consolidation after six cycles of chemotherapy. Conditioning for BMT was with BuCy, followed by allogeneic or unpurged autologous marrow infusion. RESULTS Of 37 patients who received chemotherapy, 35 achieved remission (95%) after one to six courses of treatment and 34 (92%) were transplanted. Five relapsed before BMT, four were subsequently transplanted in second complete remission (CR2) (n = 3) or untreated first relapse (n = 1), and one failed to respond to further therapy. All other patients proceeded to BMT in first complete remission (CR1). Eleven patients received allografts: one relapsed and one died of graft-versus-host disease (GvHD), for a leukemia-free survival rate of 90% at a median of 41 months after BMT (range, 3 to 60). For 23 autografts, there were two toxic deaths and eight relapses, with a leukemia-free survival rate of 61% at a median of 11 months after BMT (range, 0 to 66). The high relapse rate following autologous BMT led us to escalate the dose of Bu from 16 mg/kg to 600 mg/m2 using a single daily dose of Bu. CONCLUSION With modern supportive therapy, most newly diagnosed children with AML will enter remission and are eligible for intensification therapy. BuCy is well tolerated in children, which allowed us to escalate the dose of Bu in recent patients. Further follow-up is needed to determine whether this has an impact on the relapse rate following autologous BMT.

Plasma Exosomes As Markers of Residual Disease in Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2357-2357
Author(s):  
Michael Boyiadzis ◽  
Chang Sook Hong ◽  
Theresa L Whiteside
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Protein Content ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Molecular Profile ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract Background: Exosomes are virus-size (30–100 nm in diameter) membrane-bound microvesicles that are formed within the endocytic compartments and via fusion of multivesicles bodies are released into extracellular space. The exosomal cargo includes proteins/glycoproteins expressed on the cell membrane as well as molecules and soluble factors present in the cytosol of parental cells. While exosome secretion occurs under physiologic conditions, and all cells are capable of their release, tumor cells are avid exosome producers. Patients newly diagnosed with acute myeloid leukemia (AML) prior to any therapy have higher levels of exosomes compared to normal controls (NC). We hypothesize that the molecular content of isolated exosomes, which are thought to mimic that of leukemic blasts, could be informative about the presence in the bone marrow of leukemic blasts that might avoid detection by conventional hematopathological assays. Methods: Samples of venous blood (20-50 mL) were obtained from patients newly diagnosed with AML prior to any treatment (n=13), after completion of initial induction chemotherapy in patients who achieved complete remission (n=8), during consolidation therapy and age-matched healthy volunteers. Exosome fractions were isolated from plasma by exclusion chromatography on Sephadex G50 columns followed by ultracentrifugation. Exosome protein content was determined and expressed in µg protein/mL plasma. Isolated exosomes were characterized by western blots for expression of classical exosomal markers and for expression of novel myeloid cell surface markers associated with AML, interleukin-3 receptor a chain (CD123) and C-type lectin-like molecule-1 (CLL-1). Results: The exosome fractions isolated from AML patients’ plasma at diagnosis had a considerably greater mean protein content (81.5 ± 10.8 μg protein/mL plasma) than did exosome fractions isolated from the plasma of NC (13.1 ± 2.4 μg protein/mL plasma) with p < 0.005. The molecular profile of exosomes isolated from plasma of AML patients at diagnosis was distinct from that of exosomes isolated from plasma of NC. In addition to classical exosomal markers (MHC class I molecules, LAMP-1, CD81) exosomes isolated from AML patients at diagnosis contained CD34, CD117, CD123 and CLL-1. The exosome fractions isolated from the patients’ plasma who achieved complete remission (n=8) remained elevated, similar to the levels at the time of AML diagnosis (78.5 vs 77.5 μg protein/mL plasma). Exosomes in AML patients who achieved complete remission and in patients receiving consolidation therapy when leukemic blasts are undetectable in the bone marrow by conventional hematopathological methods contained CD123 and CLL-1. Conclusions: Exosomes in AML patients have a unique and distinctive molecular profile. The exosomal profile suggest the presence of residual disease in patients considered to have achieved complete remission by conventional hematopathologic assays. Disclosures No relevant conflicts of interest to declare.

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2637-2644 ◽  
Author(s):  
Teresa Padró ◽  
Sandra Ruiz ◽  
Ralf Bieker ◽  
Horst Bürger ◽  
Martin Steins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Microvessel Density ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P < .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P < .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P < .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

Effect of Complete Remission Achievement on Survival In Acute Myeloid Leukemia of the Elderly.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1048-1048
Author(s):  
Felicetto Ferrara ◽  
Cira Riccardi ◽  
Salvatore Palmieri ◽  
Tiziana Izzo ◽  
Antonella Carbone
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Loading Dose ◽  
Refractory Disease ◽  
Bone Marrow Blast ◽  
Blast Count ◽  
Acute Myeloid

Abstract Abstract 1048 The achievement of complete remission (CR) is considered an essential prerequisite for cure in acute myeloid leukemia (AML). Notwithstanding, in older AML patients recent data suggest that, at least for patients receiving new compounds such as hypomethilating agents Azacytidine and Decitabine, the benefit on survival can be independent from CR achievement, namely in patients with low bone marrow blast count (< 30%) at diagnosis. In this study we evaluated the impact of CR achievement on overall survival from a series of 140 patients aged over 60 years; all patients received a therapeutic program including continuous infusion of fludarabine (F) and cytarabine (ARA-C) as induction and consolidation, followed whenever possible by autologous stem cell transplantation (Ferrara et al, Haematologica, 2005). Briefly, F was administered at a loading dose of 10 mg/m2 over 15 min at day 0 followed 6 hours and half later by continuous infusion (c.i.) of 20 mg/m2/24 hours for 72 hours (days 0–2); ARA-C was given at a loading dose of 390 mg/m2 three hours and half after F and then as c.i. over 96 hours at 1440 mg/m2/24 hours (days 0–3). G-CSF was added at day +15 at a dose of 5 μg/kg. A second identical course was planned for patients obtaining partial response, defined as less than 5% blasts in peripheral blood and less than 30% of blasts in the bone marrow. Patients achieving CR, established as less than 5% blasts in the bone marrow, normal blood count and differential and absence of extramedullary leukemia, were programmed to receive an additional identical course as consolidation, reduced of one day (i.e. two days c.i. of F and three days c.i, of ARA-C). The effect of CR was separately analyzed according to karyotype, bone marrow blast count and, in patients with normal karyotype, NPM1 and FLT3 positivity. Of note, patients dead in induction were excluded from survival benefit evaluation. The median age was 69 years (range 61–82). Cytogenetic analysis was successfully in 134/140 patients (96%). Among these 89 (66%) were found as having normal karyotype (NK) and 45 (34%) with different chromosomal abnormalities, mostly complex or involving chromosomes 5 and/or 7, classified as unfavorable (UK). Overall 94 patients (67%) achieved CR; the CR rate was 77 % in NK and 47% in unfavorable karyotype (p:<0.001). Of note, rates of either death in induction (22% vs 14%) or primary refractory disease (33 % vs 8%) were significantly higher in patients with adverse cytogenetics. The median survival for the whole patient population was 10 months; survival was significantly influenced by cytogenetics at diagnosis (12 months for NK vs 7 months for UK), p:<0.001). The median duration of CR was 11 months (16 months for patients with NK as opposed to 7 months for those with UK). The overall impact of CR achievement on survival was remarkable and remained statistically significant after exclusion of patients dead in induction (18 months vs. 6 months, p:< 0.001). The advantage of achieving CR was found in patients with NK, independently from molecular assessment at diagnosis, i.e. NPM1+/FLT3-, NPM1-FLT3-, NPM-FLT3+, NPM+/FLT3+). Of interest, no difference was found as bone marrow blast count at diagnosis, i.e. more or less than 30 %, was concerned in the rate of CR achievement, CR duration and impact of CR on survival either in univariate or multivariate analysis. By separately analyzing patients with UK, the advantage of CR achievement was found only when patients dead in induction were excluded and was limited to 4 months (11 months for remitters vs. 7 months for refractory patients, p:0.04). We conclude that older AML patients with unfavorable karyotype have lower CR rates following conventional chemotherapy, because of higher mortality in induction and more frequent refractory disease; in addition, CR is shorter when compared to patients with normal karyotype and has limited impact on survival. Accordingly, even when clinically eligible for aggressive chemotherapy, such patients should be included into therapeutic programs based on experimental programs including agents with alternative mechanisms of action. Disclosures: No relevant conflicts of interest to declare.

Rapid Rate of Peripheral Blood Blast Clearance Accurately Predicts Complete Remission in Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3551-3551
Author(s):  
Vladimir Vainstein ◽  
Sarah A. Buckley ◽  
Shukron Ofir ◽  
Elihu H. Estey ◽  
Janis L Abkowitz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Peripheral Blood ◽  
Clearance Rate ◽  
Myeloid Leukemia ◽  
Decay Curve ◽  
Secondary Aml ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 3551 Background: With intensive chemotherapy, many acute myeloid leukemia (AML) patients will enter complete remission (CR). Empirically, the bone marrow is typically examined 14 days after initiating induction therapy, and re-treatment is commonly considered if significant residual blasts remain. However, many patients receiving single induction will enter CR without additional therapy despite substantial amounts or residual marrow blasts on day 14, leaving considerable uncertainty about the value of early marrow assessments. An emerging alternative approach to predict the efficacy of induction therapy includes the assessment of peripheral blood blast (PBB) dynamics. Rapid clearance of PBB, determined either by review of manual differential counts or flow cytometry is predictive of CR (likelihood of 76–90%) and overall survival. We investigated whether mathematical modeling of early PBB dynamics using automated complete blood cell (CBC) counts and the manual differential could further refine our ability to predict CR. Patients and Methods: We identified 111 adult patients with circulating PBB who underwent curative-intent, single-cycle induction chemotherapy for newly diagnosed AML between April 1999 and December 2011. Therapy regimens included “7+3”-like (56.8%), and regimens of similar/higher (29.7%) or lower (13.5%) intensity. PBBs were quantified as WBC count from the automated CBC times percentage of blasts by manual differential (100 cells). Cytogenetic abnormalities, NPM1/Flt3 status, day 14 and recovery bone marrow data were extracted from patient records. In the 62 patients with >3 measurable PBB counts, the rate of PBB clearance was calculated by fitting an exponential decay curve to the data points of absolute PBB counts, starting on day 1 of chemotherapy. This subgroup of patients had similar baseline parameters as the whole group, including age, WBC count at diagnosis, cytogenetic risk, percent of secondary AML, therapy regimens were similar, and CR rates were identical (69 vs. 68%). Results: An exponential decay curve [N(t) = N0×e-xt, with x=decay constant] resulted in an excellent goodness of fit of early PBB dynamics (mean r2=0.93). Rapid PBB clearance was highly predictive of CR achievement, with an optimal cut-off of x=1.4 (corresponding to a 4.2-log reduction in tumor burden if maintained over the course of a weeklong chemotherapy) based on the receiver operating characteristic (ROC) curve. All but 1 of the 27 patients with x>1.4 achieved CR (positive predictive value [PPV]=96%) the only non-responder with x>1.4 had a combination of negative prognostic factors including secondary AML, unfavorable cytogenetics, older age, and lower intensity treatment. PPV of PBB clearance rate of 96% for predicting CR compared favorably to alternative previously published approaches such as day of PBB clearance or percentage of day 14 bone marrow blasts (84 and 85% respectively in our study). Day 14 marrow assessments did not add prognostic information in 26/27 patients who had fast PBB clearance rate (x>1.4). In univariate analyses, CR achievement was significantly correlated with a higher PBB clearance rate, younger age, primary AML, more favorable cytogenetics, and treatment intensity. In multivariate analyses including age, primary vs. secondary AML, cytogenetics, type of therapy, and PBB clearance rate (57 patients), only the PBB clearance rate remained statistically significantly associated with CR achievement. Importantly, information from CBC differentials is routinely available in most institutions and associated costs are low. Unlike determination of the exact day of PBB clearance that coincides with profound cytopenia, the PBB clearance rate is measured while PBB are still abundant, rendering the latter method less prone to sampling and observer errors. Conclusion: our findings suggest that early marrow assessment may not be necessary in AML patients who experience rapid PBB clearance upon induction treatment initiation as they have an almost 100% chance of achieving CR. Disclosures: Vainstein: Neumedicines Inc: Employment.

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