scholarly journals Bone Marrow Aspirates Alone without a Trephine Biopsy May be Insufficient for the Detection of Residual Leukemia Following Intensive Chemotherapy for the Treatment of Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2336-2336
Author(s):  
Lalit Saini ◽  
Robert Turner ◽  
Loree Larratt ◽  
Joseph Brandwein ◽  
Marlene Ann Hamilton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Intensive Chemotherapy ◽  
Trephine Biopsy ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background: The diagnosis of acute myeloid leukemia (AML), response to treatment and disease recurrence are most commonly assessed with bone marrow studies. Recommendations from leading experts (Bain, 2001) and guidelines of the European LeukemiaNET (Dohner, 2010) and the National Comprehensive Cancer network (O’Donnell, 2012) suggest that only the bone marrow aspirate (BMA) is necessary to assess residual disease while the trephine biopsy (TB) is necessary only when an aparticulate BMA is obtained. In contrast, guidelines of the International Council for Standardization in Hematology (Lee, 2008) suggest that BMA and the TB should be routinely performed together as they provide complementary information. Due to these conflicting recommendations we sought to determine whether the TB provides additional sensitivity for the detection of residual leukemia following intensive chemotherapy for AML. Methods: A single centre retrospective chart review was conducted of bone marrow studies of all AML patients who had received intensive chemotherapy from 2004 – 2013. Those lacking a TB were excluded. Residual disease was assessed by morphological examination of the BMA and TB +/- immunostaining but minimal residual disease (MRD) analysis was not performed. Results: 598 bone marrow studies from 227 patients were evaluated. The median age of the patients was 54.6 (range 18 -77) with 70% age < 60. Forty-four percent were female. Cytogenetics were favorable in 30 (13%), intermediate in 146 (64%), high-risk in 44 (19%) and failed in 7 (3%) of the patients. Of the 598 bone marrow samples 198 (33%) were interim marrows performed 14 days following initiation of induction or re-induction chemotherapy (D14 marrow), 251(42%) were recovery marrows following induction/re-induction chemotherapy (EOI marrow) and 149 (25%) were during follow-up. The BMA was considered to be acellular/hypocellular in 31%, hemodilute in 16.4% and aparticulate/pauciparticulate in 27.3% of samples. As per guidelines > 200 cells were counted in 99.8% of the aspirate samples to ascertain remission status. The median length of the TB segments was 1.85 cm (0.2 – 7.0 cm) and it was considered inadequate in 12.7%, of good or excellent quality in 24.9% and adequate for residual disease assessment in the remainder of cases. Approximately 19 % of TB samples had mild to significant hemorrhagic artifact. The bone marrow cellularity could not be assessed in 1.2% of samples but was patchy in 0.5%, aplastic in 2.8%, hypocellular in 36%, normocellular in 23.6%, hypercellular in 23.2%, packed in 6% and was not described in 6.7% of the cases. Residual leukemia was identified in 33.1% of BMA and in 33.3% of TB samples. The BMA and the TB findings were concordant in 562 of 598 (94%) of cases. In 3.5% (21) of cases residual leukemia was seen in the TB but not the BMA whereas in 2.5% (15) of cases the BMA detected residual disease but the TB failed to do so. The TB led to a change in diagnosis from ‘No Leukemia’ to ‘Residual Disease’ in 5.1% of D14 marrows, 3.6% of EOI marrows and in 1.3% of follow-up marrows with no statistically significant difference between the groups (p=0.178). There was no relationship between a change in diagnosis and whether patients received an anthracycline or a non-anthracycline based chemotherapy regimen (4.4% vs. 3.2%, p=1.0). The TB, however, led to a change in diagnosis more commonly in patients with favorable risk karyotype relative to those with intermediate risk karyotype (20% vs. 6.2%, p= 0.02) but not relative to those with unfavorable risk karyotype (20% vs. 13.6%, p=0.53). Hemodilute bone marrow samples were more likely to have a TB related change in diagnosis relative to undilute samples (8.2% versus 2.6%, p=0.01) as were aparticulate/pauciparticulate samples relative to particulate samples (8% vs. 1.9%, p=0.00046). However, in multivariate analysis, only an aparticulate/pauciparticulate sample was associated with TB related change in diagnosis (p=0.015, OR = 3.6). Conclusions: Our data demonstrate that, following intensive chemotherapy, the BMA alone may fail to identify residual leukemia particularly when the BMA is aparticulate/pauciparticulate. In these situations the TB provides additional sensitivity for the detection of residual disease. Further studies are required to evaluate the need for the TB in particulate samples when combined with MRD analysis. Disclosures No relevant conflicts of interest to declare.

Multidrug-Related Protein 1 (MRP1) Polymorphisms rs129081, rs212090, and rs212091 Predict Survival In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2580-2580 ◽  
Author(s):  
Desiree Kunadt ◽  
Christian Dransfeld ◽  
Maria Schmiedgen ◽  
Michael Kramer ◽  
Christoph Röllig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Significant Influence ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Npm1 Mutation ◽  
Significant Difference ◽  
Impact On Treatment ◽  
Acute Myeloid

Abstract Background ABCB1 (=MDR1, multidrug resistance protein 1) single nucleotide polymorphisms (SNPs) were shown to have a significant impact on therapy outcome in patients with acute myeloid leukemia (AML). Furthermore, an independent significant impact on treatment response and patient survival of SNPs in the genes for ABCC4 (MRP4), ABCC5 (MRP5) and ABCC11 (MRP8) related SNPs has also been demonstrated. In contrast, therapeutic strategies trying to modulate the anthracycline efflux of these transporters have failed in most clinical trials so far. Recently, higher dosages of daunorubicin used during induction chemotherapy have been associated with a better outcome in certain subgroups of AML patients. Hence, in times of individual diagnostic genetic analyses available as point-of-care diagnostics, the goal of this study was to further investigate whether SNPs in ABC-transporter genes, which are responsible for anthracycline efflux, have an independent impact on treatment outcome. Patients and Methods DNA samples were obtained from bone marrow aspirates of 160 Caucasian patients with newly diagnosed AML as part of the prospective AML2003 trial (NCT00180102). The cohort solely consisted of patients with a normal karyotype, based on conventional G-banding, minimizing false results in case of gain or loss of chromosomal material. All patients received double induction chemotherapy with daunorubicin and cytarabine. After DNA extraction, quantitative real time PCR was performed, using a total of 49 SNP assays investigating SNPs of seven different ABC genes. The identification of the corresponding SNPs was performed in an in silico analysis using the NIH dbSNP database and HapMap while statistical univariate and multivariate analyses were performed using SPSS. Results We detected three ABCC1 (MRP1) SNPs: rs129081 (CACCCC[C/G]ACTCCA), rs212090 (TTACTG[A/T]TCCCAC), and rs212091 (ACCTTA[A/G]AGAACA) with a significant influence on disease-free survival (DFS) or overall survival (OS), respectively. Patients carrying the homozygous rs129081 GG-SNP had a significant longer 5-year OS and 5-year DFS compared to the homozygous wildtype CC and heterozygous CG patients (OS: 68% [GG] vs. 40% [CC] vs. 64%, [CG], p=.035; DFS: 64% vs. 35% vs. 50%, p=.01). SNP rs212090 revealed a statistically significant difference in DFS when comparing homozygous alleles TT and AA (wildtype), 40% vs. 68%, p=.021. SNP rs212091 showed a significant difference concerning OS, with homozygous SNP GG leading to worse OS (0% vs. wildtype AA 64% vs. heterozygous AG 59%, p=.006). Again, there was a significant difference in DFS between both homozygous alleles AA (wildtype) and GG (55% vs. 0%, p=.018). Furthermore, there were no significant differences of standard clinical and laboratory baseline characteristics, FLT3-ITD mutation, or NPM1-mutation status, or chemotherapeutic toxicities. In order to exclude false positive findings of SNPs conferred as a result of leukemic transformation, we obtained saliva germline DNA from patients in complete remission who were treated by chemoconsolidation and performed a confirmatory analysis with the investigated SNPs, including rs129081, rs212090, and rs212091. Here, all SNPs were shown to be expressed in germline DNA in remission and bone marrow samples at diagnosis alike. The multivariate models for rs129081, rs212090 (TT), rs212091(AG), and rs212091(AA) revealed significances of p=.024, p=.029, p=.042, and p=.017 respectively for DFS but not for OS (except for rs212091[AA]). After adjustment for a false discovery rate of 5% still a trend towards the association of the SNPs and DFS could be seen. Therefore, more research is necessary to strengthen this evidence. Conclusion In this study we found a significant influence of rs129081, rs212090, and rs212091 SNPs (ABCC1, MRP1) on survival in AML in univariate analyses. Interestingly, these polymorphisms were not associated with other AML specific characteristics at diagnosis and were shown to be expressed in germline DNA and AML DNA alike. Hence, we suggest a prognostic effect of these SNPs which might be responsible for differential anthracycline susceptibility. Disclosures: No relevant conflicts of interest to declare.

The Initial Level of MLL-PTD Affects the Prognosis of Patients with Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5241-5241
Author(s):  
Jun Kong ◽  
Hao Jiang ◽  
Yazhen Qin ◽  
Xiaosu Zhao ◽  
Hong-Hu Zhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Initial Level ◽  
Low Level ◽  
High Level ◽  
Level Group ◽  
Acute Myeloid

Abstract Genetic alterations of the mixed-lineage leukemia (MLL) gene are commonly implicated in the development of acute leukemia. In acute myeloid leukemia (AML), a partial tandem duplication (PTD) of MLL occurs in about 5%-11% of patients, mainly in adults and rarely inchildren( Meyer C et al Leukemia 2013) .It is not known whether the initial expression level of MLL-PTD affects the prognosis of AMLs. Therefore, we analyzed the clinical data of 36 AML patients with MLL-PTD treated in our institute from January 2014 to January 2016, and tried to investigate whether the initial level of MLL-PTD has an impact on the prognosis of AML patients. MLL-PTD is present in adult non-leukemichematopoiesisand observed in bone marrow and peripheral blood of adult healthy individuals. In order to identify the threshold of MLL-PTD for AML patients, a control group of bone marrow samples from 29 normal adult donors were tested. The median value of MLL-PTD was 0.046(0.014¡«0.080)%. Patients with AML were considered MLL-PTD positive if their expression level was higher than 0.08%. 430 patients were newly diagnosed AML and treated in institute between January 2014 and January 2016. Among these AML patients, AML patients with MLL-PTD were selected as the subject patients. The following inclusion criteria were applied: (1) more than 16 years old; (2)Bone marrow MLL-PTD/ABL£¾0.08%; (3)receivedmore than 2 cycles of chemotherapy. Our study was approved by the Ethics Committee of Peking UniversityPeople¡¯s Hospital.All patients offered signed informed consent to participate in the study.The cutoff date for follow-up was Match 31, 2016. Of the 430 de novo AML patients, 36(8.4%) patients were MLL-PTD positive. The median age was 48(22¡«72) years. 28 cases were diagnosed M2, and the others included 4 cases of M4, 2 cases of M5 and 2 cases of M6. 5 cases were FLT3-ITD mutation+, 2 cases were NPM1 mutation+,7cases were double-CEBPA mutation+. The complete remission (CR) rate after first induction chemotherapy was 58.3%, the total CR rate after second chemotherapy was 66.7%, 1 case achieved CR after third chemotherapy, and 1 case achieved CR withsorafenibtreatment. 2 cases receivedallo-HSCT. In the 26 cases who achieved CR1, 7 cases relapsed at a median of 5 months. The median follow-up was 4.8 (2¡«17.2) months, and 10 cases were died. According to Hans B. Ommenetal¡äs study (Ommen HB et al Br J Haemato2014), ROC analysis was performed to determine the potential optimal MLL-PTD cutoff level to predict the incidence of CR after second induction chemotherapy. We established MLL-PTD ¡Ý1% as the cut of value. 19 cases were MLL-PTD £¼1% as the low level group and 17 cases were MLL-PTD ¡Ý1% as the high level group. Distribution of FAB type (M2 incidence 100% vs. 53%, P=0.003) and biallelic CEBPA mutation incidence (37% vs. 0%, P=0.008) were significantly different between the two groups. (Table 1) The CR rate after first induction chemotherapy (78.9% VS 35.3%, P=0.008) and CR rate after second induction chemotherapy (84.2% VS 47.1%,P=0.001) were also significantly different between the two groups.(Table 2) Logistic regression analysis showed that high level of MLL-PTD was the only independent risk factor of CR rate after second induction chemotherapy (OR=0.16, P=0.024). There were 5 patients died in each group. The 15-month estimated OS between low-level and high-level groups was not significantly different (51.5% vs .67.2%, P=0.607). Our data indicates that the initial level of MLL-PTD in patients with AML affects clinical prognosis, and patients with high initial level MLL-PTD have a lower CR rate. Low level of MLL-PTD may not play a part in the development of acute leukemia. And it needs further observation to identify the effect of initial MLL-PTD level on survival. Kong Jun and Jiang Hao contributed equally to this work Disclosures No relevant conflicts of interest to declare.

Predictors for requiring re-induction chemotherapy in acute myeloid leukemia patients with residual disease on day 14 bone marrow assessment

2017 ◽  
Vol 63 ◽  
pp. 56-61 ◽  
Author(s):  
Victoria R. Nachar ◽  
Anthony J. Perissinotti ◽  
Gianni B. Scappaticci ◽  
Dale L. Bixby ◽  
Bernard L. Marini
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Acute Myeloid

Minimal Residual Disease in Patients with Acute Myeloid Leukemia Quantified by Multiparameter Flow Cytomety and Quantitative RT-PCR Is an Independent Prognostic Parameter.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 319-319 ◽  
Author(s):  
Wolfgang Kern ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Daniela Voskova ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
Minimal Residual ◽  
Acute Myeloid

Quantification of minimal residual disease (MRD) is becoming increasingly important to guide therapy in patients with acute myeloid leukemia (AML). While MFC can be applied to more patients with AML than QPCR, the latter has the advantage of a higher sensitivity in many cases. We compared data obtained by both methods in parallel in bone marrow samples in 160 patients at diagnosis and at 469 follow-up checkpoints. MFC was applied at diagnosis with a comprehensive panel of antibodies to identify leukemia-associated aberrant immunophenotypes (LAIP) useful for MRD monitoring. QPCR targeted on the leukemia-specific fusion transcripts AML1-ETO, AML1-EVI1, CBFB-MYH11, MLL-AF10, MLL-AF6, MLL-AF9, MLL-ELL, MLL-ENL, and PML-RARA as well as overexpression of EVI1, length mutations of FLT3, and partial tandem duplications of MLL. In order to adjust for differences in the percentages of bone marrow cells covered by the respective LAIP by MFC at diagnosis and for the heterogeneity of transcript levels detected by QPCR at diagnosis, the logarithmic difference (LD) was calculated for each follow-up sample in comparison to the diagnostic sample. There was a significant correlation between MFC and QPCR with regard to the LD from diagnosis to follow-up checkpoint (r=0.645, p=0.000001). Concordant results with regard to negativity between QPCR (no signal) and MFC (<0.01% positive cells) was found in 301/469 (64.2%) samples (both methods positive, 270 (57.6%); both methods negative, 31 (6.6%)). In 44 samples (9.4%) QPCR detected positivity and MFC negativity while in 124 samples (26.4%) MFC detected positivity and QPCR negativity (sensitivity of QPCR was lower than 1:100,000 in some cases). In 133 patients clinical follow-up data was available allowing the analysis of the prognostic impact of MRD levels. Cytogenetics were favorable, intermediate, and unfavorable in 86, 30, and 17 cases, respectively. Median age was 46 years (range, 17–83). Median event-free survival (EFS) was 22.1 months, overall survival (OS) at three years was 77%. The median LDs for MFC and QPCR at the checkpoint 1 (up to day 21), 2 (day 22–60), 3 (day 61–120), 4 (day 121–365), and 5 (after day 365) were 2.40 and 0.62, 2.05 and 1.55, 2.51 and 3.34, 2.71 and 3.70, and 2.60 and 3.45, respectively. Separating patients according to these median LDs resulted in a better EFS and OS for cases with higher LDs at all five checkpoints for each method. Significant differences in EFS were observed at checkpoints 2 (MFC, 22.1 vs. 12.6 months, p=0.0379; QPCR, median not reached vs. 9.9, p=0.0081), 3 (QPCR, 30.9 vs. 14.1 months, p=0.0011), 4 (MFC, median not reached vs. 16.9 months, p=0.0007; QPCR, median not reached vs. 15.1 months, p=0.0102), and 5 (QPCR, median not reached vs. 17.2, p=0.0008). Cox regression analysis taking into consideration cytogenetics, age, WBC count, and bone marrow blast count at diagnosis identified the LD at checkpoint 4 determined by MFC and the LD at checkpoints 2 and 5 determined by QPCR as independent prognostic factors. The results of our analyses confirm that both MFC and QPCR are highly sensitive methods capable of quantifying MRD in AML. While data are concordant for both methods in many cases, either of the two has advantages in distinct cases depending on the individual MRD marker. Clinical trials should consider MRD monitoring by both methods in order to prove their respective roles in risk prediction and treatment stratification.

Prognostic Significance of FLT3/ITD Mutation in AML1/ETO-Associated Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3493-3493 ◽  
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Nam Kim ◽  
Il-Kwon Lee ◽  
Soo-Mee Bang ◽  
Deog-Yeon Jo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Npm1 Mutation ◽  
Response To Chemotherapy ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background: AML1-ETO fusion gene in acute myeloid leukemia (AML) usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. An internal tandem duplication of the FLT3 gene (FLT3/ITDs) is known to be associated with poor outcome after standard induction chemotherapy in AML patients with normal cytogenetics. However, this mutation is reported to be rarely found in cases with AML1/ETO positive and it remains a matter of debate as to whether these mutations play an independent role in the prognosis of AML patients with AML1/ETO fusion gene. Aims: To determine the prevalence and the prognostic role of FLT3/ITD in patients with AML1/ETO positive AML. Methods: FLT3/ITD and NPM1 mutation status was evaluated by performing DNA polymerase chain reaction assays on 39 bone marrow samples obtained at initial diagnosis from the patients with AML1/ETO fusion gene positive AML. GeneScan analysis was performed to confirm the FLT3/ITD mutation and to measure mutant levels. Results: Of total 39 patients, 11 patients (28.2%) demonstrated the aberrant FLT3/ITD mutations. The median age of patients was 40 years (range, 17–75 years). There were 24 males (61.5%) and 15 females (38.5%). There was no statistically significant difference in age, gender, leukocyte count, hemoglobin level, platelet count and percentage of peripheral or bone marrow blasts between the patients with or without FLT3/ITD. No NPM1 mutation was found in these AML Patients. To analyze the response to or outcome of therapy, we evaluated 34 patients who received intensive induction chemotherapy containing cytarabine. In univariate analysis, there was no significant difference in complete response rate (FLT3/ITD+: 100% vs. FLT3/ITD−: 95.6%, p = 0.48). However, the presence of FLT3/ITD was associated with higher relapse rate in these patients (FLT3/ITD+: 72.7% vs. FLT3/ITD−: 27.3%, p = 0.01).Significant shorter leukemic-free survival (LFS) was observed in patients with FLT3/ITD compared with those without FLT3/ITD (6.9±1.0 ms vs. 18.9±10.9 ms, p = 0.01), but there was no statistical significance in overall survival (OS) (10.6±0.6 ms vs. 16.5± NA ms, p = 0.56). Conclusions: This study demonstrates that the presence of FLT3/ITD mutations is a significantly higher relapse rate and shorter LFS in AML1/ETO positive patients. Therefore, a stratified treatment plan such as stem cell transplantation may be warranted for the AML1/ETO positive AML harvoring FLT3/ITD mutation.

Azacitidine Alone Or The Combination With Valproic Acid As a Bridge Therapy For Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes Before Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2812-2812
Author(s):  
Cristina Calderón Cabrera ◽  
Jose F Falantes ◽  
Marina Gómez ◽  
Rocío Parody ◽  
Francisco J Márquez Malaver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Valproic Acid ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Refractory Anemia ◽  
Intensive Chemotherapy ◽  
Bone Marrow Blast ◽  
Acute Myeloid

Abstract Introduction Intensive chemotherapy (IC) followed by allogeneic stem cell transplantation (AlloSCT) is standard of care for intermediate and high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). However, morbidity and lack of response are common with IC. Retrospective data have shown similar outcomes with azacitidine (AZA) when compared to IC. Moreover, the combination of AZA with other epigenetic modifiers such as HDAC inhibitors seems to improve quality of responses. Aim Evaluate response, toxicity and feasibility of AlloSCT after AZA alone or the combination with valproic acid (VPA) as a bridge strategy in MDS and AML. Patients Nineteen consecutive patients (pts) receiving azacitidine alone (n=11) or in combination with valproic acid (VPA) (n=8) were analyzed. Median age of the cohort was 57 years (18-67). Diagnosis by WHO classification included: RAEB-2 (n=10/19; 52.6%), RAEB-1 (n=2; 10.5%), RCMD (n=2; 10.5%) and AML (n=5; 26.3%). Four out of 5 AML pts had bone marrow blast count >30% at diagnosis. In MDS patients, according to International Prognostic Scoring System (IPSS): 1 intermediate-1 (7%), 3 intermediate-2 (21.5%) and 10 high-risk (71.5%) and by IPSS-revised (IPSS-R): 1 intermediate (7%), 4 high (29%) and 9 very high (64%). Regarding karyotype, in MDS: 5 good (35.7%), 2 intermediate (14.3%), 6 poor (43%) and 1 insufficient metaphases (7%) whereas in AML Patients 1 intermediate (20%) and 4 adverse (80%). Eleven out of 19 pts (58%) received AZA as frontline therapy. The remaining 8 pts experienced disease relapse after intensive chemotherapy (IC) or had primary refractory AML, and subsequently received AZA plus VPA as salvage therapy. Median courses of previous IC were 2 (1-4). For pts receiving AZA/VPA, median bone marrow blast % and leukocyte were 31% (2-60) and 1.9x10e9/L (0.3-4.2) when therapy started. Most of these pts had refractory or relapsed disease (n=6/8; 75%) with 4 pts displaying poor karyotype. Treatment schema was AZA (75 mg/m2, 7d/4w) and VPA (20-25 mg/kg/d, 10 days). Results At analysis, 17/19 pts are evaluable for response. Median courses of AZA: 5 (2-53). Overall response (ORR) at 4 courses: 59% (CR=4/17; 23.5%, CRm=5/17; 29.5% and PR=1/17; 6%). For pts receiving AZA/VPA (Table 1, n=8), ORR: 83% (CR=1/6; 17% and CRm=4/6, 66%) in 6 evaluable pts. Median courses to response were 2. Among pts achieving CR/CRm/PR/SD at 4 courses (n=12), 2 pts lost response prior to AlloSCT. Most frequent toxicity was hematological (58% grade 3-4) with no treatment related mortality attributable to AZA/VPA. Eleven out of 19 pts (58%) received AlloSCT (matched related=5, matched unrelated=5, haploidentical=1). Causes for not proceeding to AlloSCT: Disease progression (n=4; 50%), infection (n=1; 12.5%), pending evaluation after 2 courses (n=2; 25%) and 1 pt (12.5%) scheduled for matched unrelated AlloSCT. Conditioning regimen: Reduced intensity (9/11) and myeloablative (2/11). Tacrolimus/sirolimus (50%) and cyclosporine/MMF (40%) as GVHD prophylaxis. With a median follow-up of 4 months after AlloSCT (1-26), only 1 pt developed acute GVHD, 1 had early relapse postransplant and 9 patients continue in CR at last follow up. Conclusions AZA alone and particularly the combination AZA/VPA prior to AlloSCT is a well-tolerated and highly effective schema even in pts with poor prognostic features and refractory to prior IC. Adequate selection of pts (leukocyte <10x10e9/L) and larger prospective studies are needed to assess the role of this strategy. AML; Acute myeloid leukemia, RAEB-2; Refractory anemia with excess blasts type 2, RAEB-1; Refractory anemia with excess blasts type 1, IM; Insufficient metaphases, IC; Intensive chemotherapy, CR; Complete response, CRm; marrow CR, NA; Not assessable (pending bone marrow evaluation). 1Refractory to IC. 2Relapsed after IC. aBone marrow evaluation after 2 and 4 courses of therapy Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Prospective Clinical Study of the Efficacy and Adverse Reactions of Azacitidine Combined with IA Regimen As the Induction Treatment of Newly Diagnosed AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4408-4408
Author(s):  
Lifen Kuang ◽  
Juan Li
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Objective: This single-arm prospective research (ChiCTR2100044731) aimed to evaluate the efficacy and safety of azacitidine combined with IA regimen in the induction treatment of newly diagnosed acute myeloid leukemia (AML), with a view to further improving the efficacy of acute myeloid leukemia with poor prognosis. Methods: Newly diagnosed AML (non-M3) patients who received azacitidine combined with IA regimen induction chemotherapy in the Department of Hematology of the First Affiliated Hospital of Sun Yat-sen University from November 2019 to February 2021 were enrolled, and the efficacy and side effect were analyzed. Results: A total of 33 patients were enrolled. The median age of the enrolled patients was 43.36 years (17-63), including 16 males (48.5%) and 17 females (51.5%). According to NCCN risk stratification, there were 3 patients (9.1%) in the favor group (9.1%) ,13 cases (39.4%) in the intermediate group and 17 cases (51.5%) in the poor group.The CR rate of one cycle of azacitidine combined with IA regimen was 66.7%, with a PR rate of 12.1% and a NR rate of 21.2%. After propensity score matching with the newly diagnosed AML patients who received IA regimen as induction chemotherapy in our center, a paired study was carried out. The results showed that there was no significant difference between the 2 groups in the treatment CR rate (66.7% for azacitidine combined with IA vs 54.5% for IA, P=0.592, Fig1). Subgroup analysis (table 1) showed combination of azacitidine with IA significantly improved the CR rate of patients with a ratio of blasts in the bone marrow greater than 67% (83.3% vs 30.8%, P=0.014) and patients in the intermediate NCCN risk group (100.0% vs 37.5%, P=0.001).The duration of agranulocytosis in the azacitidine combined with IA chemotherapy group was longer than that in the IA group (21 days vs 19 days, P=0.045). There was no significant difference in the number of platelet transfusions and the number of red blood cell transfusions between the two groups, and there was no significant difference in the incidence of infection between the two groups (table 2). Conclusions: The remission rate of induction chemotherapy for azacitidine combined with IA regimen and IA regimen in newly diagnosed non-M3 AML patients is comparable. Patients with a ratio of immature cells in bone marrow greater than 67% and patients in the intermediate NCCN risk group may benefit from azacitidine combined with the IA regimen. The combination of azacitidine with IA regimen aggravated granular bone marrow suppression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Prognostic Significance of ABCB1 (MDR1) Gene Polymorphisms in De Novo Acute Myeloid Leukemia with t(8;21) or inv(16).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4271-4271
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Nam Kim ◽  
Il-Kwon Lee ◽  
Soo-Mee Bang ◽  
Deog-Yeon Jo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Gene Polymorphisms ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Abcb1 Gene ◽  
Cytogenetic Abnormalities ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background: Reciprocal translocations like t(8;21) or inv(16) in acute myeloid leukemia (AML) usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. MDR1/Pgp, the gene product of MDR1, is recognized as an important class of proteins for regulating pharmacokinetics. Several reports showed the effects of ABCB1 (mutidrug resistance 1 gene, MDR1, PgP) genotypes such as single nucleotide polymorphisms (SNPs) on pharmacotherapy in various malignancies including AML. However, it remains to be clarified that these SNPs of ABCB1 gene play an significant role in the treatment outcome of AML patients with favorable cytogenetics especially t(8;21) or inv(16). Aims: To determine the prevalence and the prognostic role of ABCB1 polymorphisms in de novo AML patients with t(8;21) or inv (16). Methods: Twenty ABCB1 gene polymorphisms (SNP numbers: rs1055302, rs1002205, rs4148750, rs7779562, rs6980101, rs1922242, rs2235013, rs4728702, rs1922240, rs1922241, rs4148734, rs6950978, rs10256836, rs1202172, rs17327442, rs7802773, rs13229143, rs4148732, rs1978095, rs10264856) were evaluated by performing DNA polymerase chain reaction assays on 49 bone marrow samples obtained at initial diagnosis from the AML patients with t(8;21) or inv(16). DNA sequencing and GeneScan analysis was performed to confirm the the genotyping results. All patients received one round of intensive induction chemotherapy consisting of 3 days of idarubicin and 7 days of cytarabine. Results: Of total 49 patients, 39 (79.6%) were AML with t(8;21) and 10(20.4%) were AML with inv(16). The median age of patients was 37 years (range, 17–69 years). There were 29 males (59.2%) and 20 females (40.8%). There was no statistically significant difference in age, gender, leukocyte count, and percentage of peripheral or bone marrow blasts in the patients according to the ABCB1 polymophisms or cytogenetic abnormalities. However, there was significant difference in complete response (CR) rate according to the zygocities of SNPs in the intron of ABCB1 gene such as rs6980101 (genotype C/C: 68.4% vs. C/T: 100%, p=0.03), rs10256836 (G/G: 91.3% vs. G/C: 50%, p=0.03), rs17327442 (T/T: 88.9% vs. T/A: :40%, p=0.01), rs4148732 (A/A: 95.8% vs. A/G: 50%, p=0.00). CR rates were not significantly influenced by cytogenetic abnormalities. There was no significant difference in relapse rate, leukemia-free survival and overall survival between homo- and heterozygote groups in these polymorphsims. Conclusions: This study revealed an association between ABCB1 SNPs and the treatement outcomes for AML patients with t(8;21) or inv(16). Further study is needed to reach the definite conclusion on these associations. However, a stratified treatment plan in remission induction chemotherapy such as augmentation or addition of other chemotherapeutic agents may be warranted for the AML with t(8;21) or inv(16) harvoring such ABCB1 polymophrisms.

scholarly journals Re-Induction Therapy Decisions Based on Day 14 Bone Marrow Biopsy in Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3590-3590
Author(s):  
Tod A. Morris ◽  
David A. Rizzieri ◽  
Carlos M de Castro ◽  
Louis F. Diehl ◽  
Jon P. Gockerman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Treatment Decisions ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3590 Purpose: Treatment decisions for early re-induction of patients with de novo acute myeloid leukemia (AML) based on sub-optimal cytoreduction as seen on day 14 bone marrow (BM) biopsy is laden with controversy. The aim of our review was to correlate results of the day 14 BM biopsy to overall outcomes of induction therapy. Methods: Between November 1995 and July 2008, medical records for patients treated for de novo AML were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on day 14 BM biopsies. Of all patients treated during that period, 100 patients were categorized as de novo AML, and were treated with standard induction chemotherapy. Seventy-four (n=74) of these patients had paired BM biopsy reports. Response to therapy was based purely on morphology noted by the pathologist on the day 14 BM in this analysis, with indeterminate response (IR) defined as a hypocellular marrow (HM) with moderate increase in blasts above 5% in which the reviewing pathologist could not rule out the possibility of persistent leukemia. Residual disease (RD) was defined by the reviewing pathologist as grossly elevated percentages of abnormal populations of persistent blasts by morphology alone definitively consistent with residual disease (i.e. no flow cytometric or molecular adjuncts). Otherwise, the patients were classified as appropriate response with a HM and less than 5% blasts with no evidence of residual leukemia. Results: Day 14 BM biopsies of the 74 patients (median age = 42 years, range 18 to 77) undergoing standard induction chemotherapy revealed that 45 patients (61%) had a HM with less than 5% blasts. Eleven patient's (15%) BM biopsies were classified as IR. Eighteen patients (24%) had morphologically definitive RD. In all, 29 patients (39%) had a sub-optimal response (SOR) to induction chemotherapy (IR+RD=SOR). The 45 patients with HM and low blast percentage were observed until count recovery as is the usual practice. However, 16 of 29 patients with SOR received re-induction chemotherapy (1 IR and 15 RD) of which 10 patients attained a morphologic CR (9 RD and 1 IR). The 13 remaining patients (3 RD and 10 IR) were observed without any re-induction therapy, and re-evaluated with a follow-up BM biopsy between days 21 and 42 of initial induction. Interestingly, 11 of these 13 patients had a morphologic CR on follow-up biopsy, including 2 of 3 patients initially categorized as RD. Analysis of the paired results from nadir to recovery for the 58 observed patients in this cohort revealed a positive predictive value (PPV) and negative predictive value (NPV) for the day 14 BM biopsy review of 15% and 93% respectively. Conclusions: Our data suggests that those patients with an IR on day 14 may not necessarily require re-induction chemotherapy, and may actually benefit from careful observation by avoiding the risks of reinduction and prolonged cytopenias. Thus, while the day14 BM is an important tool for the evaluation of response in AML patients undergoing induction therapy, it is not always a reliable test for residual leukemic burden, as illustrated by its low PPV. As such, future treatment decisions should be weighted by, but not based solely on this parameter. Our future plans are to evaluate this question prospectively in a larger cohort of de novo AML patients receiving induction therapy with centralized pathologic review, and also to look at the effect of cytogenetic and molecular mutation analysis at day 14 on treatment decision making and outcomes. Disclosures: No relevant conflicts of interest to declare.

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