Minimal Residual Disease (MRD) Analysis in Non-MRD Based ALL IC-BFM 2002 Protocol for Childhood ALL: Is It Possible To Omit Minimal Residual Disease in Risk Stratification?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2271-2271
Author(s):  
Eva Fronkova ◽  
Smadar Avigad ◽  
Ki Wai Chik ◽  
Luis Castillo ◽  
Manor Sigal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hong Kong ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Risk Group ◽  
Univariate Analysis ◽  
Response To Treatment ◽  
Molecular Response ◽  
Childhood All ◽  
Minimal Residual

Abstract More than 800 children with acute lymphoblastic leukaemia (ALL) are treated every year according to ALL IC-BFM 2002 protocol, which was designed by the International-BFM Group as a parallel to MRD-based ALL/AIEOP BFM 2000 study. The ALL-IC BFM 2002 risk group stratification comprises blast proportion in peripheral blood (PB) after 7 days of prednisone and one IT-MTX (prednisone response) and bone marrow (BM) morphology evaluation at days 15 and 33 of therapy together with age, initial WBC and presence of BCR/ABL and MLL/AF4 fusion. One of the aims of the ALL IC-BFM 2002 study is the comparison of this risk group assessment to the MRD-based criteria used in ALL-BFM 2000. We analyzed a total of 203 patients treated according to the ALL IC-BFM 2002 in the Czech Republic, Israel, Hong Kong and Uruguay for the presence of clonal antigen receptor rearrangements. MRD was evaluated in 175 patients at several time-points of therapy including mandatory points at week 5 and 12, which are used in the ALL/AIEOP BFM 2000 stratification. In total, 654 follow-up BM specimens and 80 PB samples were tested. In the univariate analysis, a good molecular response defined as MRD negativity at both week 5 and 12 was associated with the age of 1–6 years (p=0.0001), WBC<20,000/mm3 (p=0.0002), non-T immunophenotype (p<0.0001), good prednisone response (p=0.0006), presence of TEL/AML1 fusion (p=0.003) and non-M3 morphology (≤25% blasts in BM) at day 15 (p=0.02). There was no significant association of MRD negativity with sex and hyperdiploidy; non-M3 BM morphology at day 8 was significant only when analyzing non-T ALL (p=0.02). Patients with BCP ALL had significantly lower MRD levels at day 15 (p=0.03) and at day 33 (p=0.001) than T-ALL patients; the difference was no more significant at week 12. Patients stratified to standard risk group (SRG) according to the ALL IC-BFM 2002 criteria had a significantly better molecular response defined as MRD negativity at week 5 and 12 than intermediate risk group (IRG) patients (p=0.009). However, in 24 of 69 SRG patients (34.7%), MRD positivity at week 5 and/or at week 12 was observed (ranging from borderline positivity to 1.5x10(-2)), thus identifying patients who would not qualify to MRD-based SRG in ALL/AIEOP BFM 2000. Within ALL IC SRG, patients with slow molecular response did not differ significantly from those with good MRD response in age, sex, WBC, BM morphology at day 15 and presence of hyperdiploidy or TEL/AML1 fusion. The only difference was in a higher proportion of M3 BM at day 8 in MRD slow-responders (p=0.04). Our findings revealed a significant divergence between the stratification results of ALL IC-BFM 2002 and ALL-BFM 2000. A fast morphological response to treatment (M1 or M2 bone marrow at day 15) together with other low-risk features does not necessarily correspond with rapid MRD clearance. Supported by MSM0021620813, Israel Cancer Association and Children’s Cancer Foundation Hong Kong.

Importance of Minimal Residual Disease Testing During the Second Year of Therapy for Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (4) ◽  
pp. 704-709 ◽  
Author(s):  
Glenn M. Marshall ◽  
Michelle Haber ◽  
Edward Kwan ◽  
Ling Zhu ◽  
Daniella Ferrara ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Maintenance Chemotherapy ◽  
Childhood All ◽  
Second Year ◽  
Minimal Residual

Purpose: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. Patients and Methods: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. Results: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. Conclusion: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.

Single Immunophenotypical Evaluation of Minimal Residual Disease before Autotransplantation of Non-Cryopreserved Bone Marrow Is Insufficient for Prediction of Outcome in High Risk Adult Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4439-4439
Author(s):  
Beata M. Stella-Holowiecka ◽  
Krystyna Jagoda ◽  
Aleksandra M. Holowiecka-Goral ◽  
Tomasz Czerw ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Long Term Results ◽  
Color Flow ◽  
Childhood All ◽  
Minimal Residual

Abstract For high-risk adult ALL patients alloHCT is a preferable option. However, a significant proportion of those not having a suitable donor may be successfully treated with autotransplantation (autoHCT). Based on our experience this treatment ensures low transplant related mortality below 3% and a reasonable overall survival and disease free survival of 60% and 45% respectively. The status of the disease before transplantation is an important factor for long term results. In childhood ALL most studies suggest that the level of minimal residual disease (MRD) after induction evaluated immunophenotypically or with bio-molecular methods is predictive for outcome after different treatments including chemotherapy, alloHCT and autoHCT. The results in adult ALL are more controversial. Patients selection. Among 1205 haematopoetic cell transplantations performed in our institution 224 (147 autologous, 77 allogeneic) were performed in 205 adults with ALL. For this study we selected an uniform group of 81 patients fulfilling following criteria’s: Ph (-) ALL, status CR1, evaluable MRD, strictly defined autoBMT procedure performed until the end of 2003. Methods. MRD was tested before autoBMT (median interval 10 days) using 2 ore 3-color flow-cytometry, as appropriate. The atypical immunophenotypes were evaluated using the “quadrans” analysis in all cases and since 2002 also the “empty spaces” technique. The sensitivity equals at least 0.0001. For all autoHSCT bone marrow was used as a source of stem cells. The CAV conditioning regimen consisted of cyclophosphamide 60mg/kg on d. -3, -2, cytarabine 2 g/m2 d. -3, -2, -1, etoposide 800 mg/m2 d. -3, -2. Bone marrow was not cryo-preserved after collection but stored in 40 C and re-transplanted after 72h. Results. In 41 patients; age med. 26 y (15–53), F/M=12/29, the MRD level was &lt;0,001: the MRD (−) group. In 40 patients; age med. 29 y (16–53), F/M=18/22, the MRD was detected at the level =/&gt; 0,001; MRD+ group. The ALL-immunophenotypes of MRD−/MRD+ groups were as follows; proB 4/7, preB 2/6, Common 18/19, B 0/1, preT 5/2, T 12/1). The interval from DGN to BMT was similar in both groups. The probability of LFS and OS at 10y calculated with median follow up time of 5y equaled; in the MRD(−) group 47% and 62% and in the MRD+ one 48% and 57% respectively (p=ns). The main reason of failure in both groups was a relapse which occurred after a median time of 277 days in the MRD(−) group and 134 days in MRD+ one (p=0.19). Conclusion and comment. Based on this observation we conclude that a single evaluation stratifying patients before autoBMT according to MRD level below or above 0.001 is not predictive for DFS and OS, because it informs only about the current amount of the disease but not about its opportunistic nature. In this respect a repeatedly confirmed MRD positivity should be more significant. Taking into consideration that the main reason of failures were relapses, this finding suggests also that in patients with chemotherapy-responsive ALL confirmed by stabile CR, the myeloablative CAV regimen is sufficiently strong to eliminate the residual disease at the level ranging 0.01–0.001. It may be speculated only that the 72h lasting incubation of bone marrow product before re-transplantation has also some kind of purging effect for leukemic blasts.

scholarly journals Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

2021 ◽  
Author(s):  
Meera Mohan ◽  
Samantha Kendrick ◽  
Aniko Szabo ◽  
Naveen K Yarlagadda ◽  
Dinesh Atwal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Clinical Relapse ◽  
Landmark Analyses ◽  
Minimal Residual

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next generation flow cytometry (sensitivity of 10-5 cells) at 3 to 6 months intervals. With a median follow up of 9.9 years from diagnosis (range, 0.4 - 30.9), 61% of patients maintained MRD negativity, while 39% experienced MRD conversion at a median of 6.3 years (range, 1.4 - 25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95%vs. 84%; P = 0.001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 year (range, 0 - 4.9). However, 27% of MRD conversion positive patients had not yet experienced a clinical relapse with a median follow-up of 9.3 years (range, 2.2 - 21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared to patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

Bone Marrow Fibrosis Evaluation in Childhood Acute Lymphoblastic Leukaemia: Correlation to Biological Factors and Treatment Response.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2280-2280
Author(s):  
Ulrika Norén-Nyström ◽  
Goran Roos ◽  
Anders Bergh ◽  
Ingrid Thörn ◽  
Gudmar Lonnerholm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Myeloproliferative Disorders ◽  
Prognostic Impact ◽  
Childhood All ◽  
Modal Chromosome Number ◽  
Minimal Residual

Abstract Fibrosis may complicate bone marrow (BM) disease and in its advanced stage negatively affect the outcome of the patients due to BM failure, particularly in myeloproliferative disorders. Studies of the potential importance of BM fibrosis are rare in childhood acute lymphoblastic leukemia (ALL). We have previously shown a prognostic impact of BM fibrosis measured as reticulin fibre density (RFD) at diagnosis in childhood ALL. To further investigate the consequence of BM fibrosis in childhood ALL in relation to immunophenotype, cytogenetic findings and minimal residual disease (MRD) we retrospectively evaluated the RFD in 139 diagnostic BM biopsies from patients with a total mean follow up time of five years and eight months from two childhood oncology centers in Sweden. Patients with pre-B-ALL showed a higher mean RFD (19.1%) compared to patients with T-ALL (11.4%, p < 0.001). This was true also when comparing high-risk (HR) pre-B-ALL patients (18.1%) with the T-ALL patients (p = 0.002). RFD correlated inversely with the white blood cell count in the HR group (r = −0.41, p = 0.009), probably reflecting our finding of low degree of fibrosis in T-ALL. The cytogenetic analysis revealed that for patients with a hyperdiploid ALL (modal chromosome number: 51–61, n: 41) in the low-risk (LR) group, mean RFD was higher for relapsed patients (22.6%) compared to patients in continuous complete remission (17.2%, p = 0.019). The probability of disease free survival for the same group using RFD cutoff of 21.1%, representing the upper third of the material, was 85%±8% for patients with hyperdiploid ALL and low RFD compared to 51%±14% for patients with hyperdiploid ALL and high RFD (p = 0.01, Figure 1). Data for 32 of the patients demonstrated an association between high RFD at diagnosis and high minimal residual disease (MRD) on day 29 after start of treatment. Patients with FACS-MRD > 10−3 day 29 displayed higher mean RFD at diagnosis (21.2%) compared to patients with FACS-MRD < 10−3 (16.7%, p = 0.027, Figure 2). When analyzing the PCR-MRD data day 29 the findings were similar. We conclude that RFD is higher in pre-B-ALL compared to T-ALL, that RFD has prognostic impact in LR patients with hyperdiploid ALL and that high RFD at diagnosis is associated to high MRD on treatment day 29. All these findings are to our knowledge novel, suggesting that evaluation of BM fibrosis at diagnosis is a potentially new therapy stratifying factor and support the need of further research on BM fibrosis in childhood ALL and expanded use of BM biopsy at diagnosis. Figure 1 Figure 1. Figure 2 Figure 2.

Assessment of Minimal Residual Disease (MRD) In Relapsed CLL Patients Treated with Fludarabine and Cyclophosphamide with or without Rituximab (REACH)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1390-1390
Author(s):  
Annika Dufour ◽  
S. K Bohlander ◽  
Karsten Spiekermann ◽  
Stephanie Schneider ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
Small Sample ◽  
Patient Specific ◽  
Molecular Response ◽  
Igh Rearrangement ◽  
Minimal Residual

Abstract Abstract 1390 Introduction: Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher et al. Leukemia, 2009). Patients who remain MRD positive after treatment have a higher risk of relapse. Eradication of MRD is therefore a desirable clinical endpoint of treatment. We were interested to assess this correlation in REACH, a randomized international clinical study in previously treated CLL patients, randomized 1:1 for treatment with rituximab, fludarabine and cyclophosphamide© R-FC (276 patients) or FC alone (276 patients); (Robak et al. JCO 2010). Methods: While MRD quantification by flow cytometry requires an identifiable stable phenotype and fresh blood samples, PCR based methods can be performed centrally on frozen samples. We have therefore developed a Realtime Quantitative (RQ) PCR method, using patient-specific IgVH (immunoglobulin variable heavy chain) gene rearrangements as targets. Briefly, genomic DNA was isolated from CD19 sorted B-cells. ASO (allele-specific oligonucleotide) primers were designed matching the hypervariable N-D-N region of the patient-specific leukemic clone and used with reverse consensus primers and hydrolysis probes annealing to the family-specific joining region of the IGH rearrangement (Brüggemann et al., Leukemia, 2004). Maximum sensitivity and quantitative range were defined for every RQ-PCR. Patients were categorized as molecular responders (MRD negative) if there was no detectable clonal IgH rearrangement, using a sensitivity cut-off of 1×10-4. Molecular response was assessed at the time of CR confirmation and 6 months later (if CR was maintained). Results: Among the 103 patients who achieved CR during the study, 86 patients had at least one MRD assessment in peripheral blood, 92 patients in bone marrow. Since many patients had a CR confirmation at different time points during the follow-up period, we initially analyzed the MRD levels only in patients who had achieved confirmed complete response at end of treatment +/−3 month (“EOT - period”). The rate of MRD negativity in blood (22 pts: 5(15) FC, 6(7)R-FC) at EOT was 33% for patients treated with FC, and 86% for patients treated with R-FC (p=0.06); In bone marrow at the EOT (61 patients: 5(27) FC, 20(34) R-FC) the rates were 19% and 59%, respectively (p= 0,02), indicating higher efficacy of the Rituximab containing regimen in eradication of residual disease; This is in line with the previously reported results using FACS analysis of MRD in the CLL8 trial; the differences in the detection rate in blood versus bone-marrow, suggest a higher sensitivity for detection of MRD in bone marrow. We therefore compared the levels of MRD negativity in samples from blood and bone marrow in patients where both samples were taken at the same time point. Results were concordant in 8/9 patients, one patient had a positive result in bone marrow with no detectable signal in blood. This supports the notion that assessment of MRD in bone marrow of CLL patients may be more sensitive than assessment in blood only. However, for a definitive statement larger sample size would be needed. We then correlated MRD status at EOT, regardless of treatment arm, with PFS: In line with previous reports, there was a clear trend to longer PFS in patients who had reached MRD negativity (median PFS not reached), while patients with residual disease had shorter PFS; however, due to small sample numbers, statistical significance could not be reached. We also analyzed the correlation of MRD negativity reached at any time during and after treatment with PFS, bearing in mind that this sample set is inherently biased, since patients with early progression will be lost from the analysis; the results are consistent with the EOT findings. Summary: ASO IgVH RQ-PCR is a powerful method to detect residual levels of disease in CLL patients with clinical complete response and undetectable MRD correlates with longer PFS. Among patients in REACH achieving clinical CR on either study arm, a higher percentage achieved MRD negativity on the R-FC arm, consistent with the increased efficacy shown for the Rituximab treatment arm by the REACH clinical data. Disclosures: Mundt: Roche: Employment. Smith:Roche: Employment. Lin:Genentech: Employment. Barrett:Roche: Employment. Hurst:Genentech: Employment. Geisler:Roche: Research Funding, Speakers Bureau. Hiddemann:Roche: Research Funding.

Standardized 4 Color Flow Cytometric Minimal Residual Disease Detection Failed To Overcome Regeneration Problems but Identifies Early Blast Clearence Predictive of Molecular Remission after Induction in Childhood B Lineage Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1842-1842 ◽  
Author(s):  
Ester Mejstrikova ◽  
Eva Fronkova ◽  
Drago Batinic ◽  
Klara Dubravcic ◽  
Flora Kiss ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Univariate Analysis ◽  
Molecular Response ◽  
Color Flow ◽  
Time Points ◽  
Flow Cytometric ◽  
Therapeutic Decisions ◽  
B Lineage ◽  
Minimal Residual

Abstract Several studies showed a good correlation between minimal residual disease (MRD) obtained by flow cytometry (FC) and by PCR (Ig/TCR rearrangements). However, before FC is widely applied for therapeutic decisions we need exact and standardized criteria. Therefore, we pre-defined B-lineage cell subsets using 4 or 3-color FC and we established background levels for each subset in pre-defined time-points on therapy. Methods. Children with ALL were treated by ALL IC BFM2002 protocol. This international flow cytometric trial MiniMini contained 4 laboratories (Croatia 36 patients, Israel 48, Hong Kong 33 and Czechia 136). 442 samples were measured simultaneously by PCR and 4color FC. Pre-defined subsets (28 values) were measured at 5 time points (d0, d8, d15, d33 and week 12). Cut off for positivity and negativity of individual subpopulations were assessed as follows: 1) negative samples by PCR for respective time point were randomly divided into training and testing cohort 2) 98.5 percentile of individual subpopulation in training cohort was selected as a cut off for positivity and negativity 3) cut off values were tested on testing cohort and PCR positive samples (total 337 samples), sample was considered positive when having at least one value above cut off (when more values were above cut off, highest value was considered as MRD). Results. When all time points were analyzed together, sensitivity of FC MRD was 82% and specificity 88% There are no negative patients at day 8 in bone marrow by FC or by PCR. 5 samples at day 15 were positive by PCR (<=10^−4) and negative by FC, no sample was false positive by FC, sensitivity was 98%, no sample was negative by both methods. At day 33 and at week 12, sensitivity dramatically dropped to 34 and 13%, specificity was 80% and 100%. We next asked whether the early blast clearance assessed by FC MRD predicts positivity by PCR after induction. Univariate analysis showed that the blast clearance by FC both at days 8 and 15 predicts the PCR-based molecular response at day 33 and/or week 12. Patients with PCR-positive MRD at day 33 and at week 12 had more often over 50% blasts at day 8 BM (Fischer test p=0.0013 and p=0.04) and/or more than 5% blasts at day 15 by FC (p=0.0015 and p=0.0036). Conclusion. With a minimized subjective bias and exact background values set for each cellular subset and timepoint, we did not reach satisfactory sensitivity at day 33 and at week 12. The FC-assessed leukemia clearance at days 8 and 15 predicts MRD by PCR at day 33 and at week 12. Since a non leukemic background influences sensitivity of FC MRD at day 33 and at week 12, complex approach using 6 and more color combinations is needed for precise distinction between leukemic and non leukemic B cells.

Minimal Residual Disease in Acute Myeloid Leukemia (AML) and Hematopoietic Stem Cell Transplantation (HSCT) - A Retrospective Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4469-4469
Author(s):  
Maura Valerio Ikoma ◽  
Vergílio Antônio Rensi Colturato ◽  
Camila Marques ◽  
Marcimara Penitenti ◽  
Anderson João Simione ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Cord Blood ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Minimal Residual

Abstract Abstract 4469 Minimal Residual Disease (MRD) is an important criterion to define risk of relapse in Acute Leukemia (AL). The most powerful methods for MRD characterization are PCR, and flow cytometry (FCM). Although PCR is more sensible that FCM, respectively 10−4 and 10−3 logs, FCM is more applicable than PCR, usually more than 80% versus less than 50% to PCR. In patients eligible for HSTC, the value of MRD is being studied and some results showed implications both in overall survival (OS) as in event free survival (EFS). The RCI seems to be influenced by the presence or absence of MRD, as well. Nowadays the most important factor that influences survival is the relapse. Then, the earlier relapse detection has a potential to improve the therapeutic results. We presented the results of MRD before and after HSTC and its prognostic significance. Other evaluated factors were: age, acute and chronic GVHD (aGVHD and cGVHD), cell source (bone marrow, peripheral blood, cord blood), ATG use, myeloablative conditioning or not, related (RD) and unrelated donor (UD), donor gender and disease status. Bone marrow of 112 AML patients were analyzed by FCM, since January/ 2008 until April / 2011. The evaluation was made in irregular period of time with variable number of samples by patients. They were from 1 to 61 years old. It was considered for analysis the patients that had MRD > 0,1% and < 5%. It was considered as negative result MRD < 0,1%. A dual laser FACSCalibur™ flow cytometer was used to data acquisition and analysis. Four color panels of monoclonal antibodies were chosen according the initial disease phenotype. Cell Quest Software was used for acquisition data and PAINT-A-GATE PRO and Infinicyt ™ for FMC analysis. It was done a live gate in reference markers and it was acquired a minimum of 500000 total events in each tube. Statistical analysis were performed by Kaplan Meier curves for OS e EFS and Cox regression. It was observed statistical significance in univariate analysis related to OS the following factors: RD (64%) × UR (42%) (p = 0,002), no ATG use (64%) × ATG use (44%) × (p = 0,003%), no aGVHD (63%) (p = 0,016) × aGVHD II to IV (50%), age > 40 years old (yo) (70%), 20 to 40 yo (59%) and < 20 yo (46%) (p = 0,048), MRD after HSCT <0,1% (77%) and > 0,1% (36%) (p=0,001) (fig 1). The other factors did not show statistical significance with a negative tendency to cord blood use (p = 0,079). To RCI, the significance was observed in: patient age < 21 yo (52%), 21 to 40 yo (30%) and > 40 yo (21%) (p=0,015); and MRD after TCTH > 0,1% (73%) × MRD < 0,1% (15%) (p = 0,000). Exerted statistical tendency: MRD < 0,1% before HSCT (p = 0,06), 1st remission (p = 0,07) and cGVHD (p = 0,08). The group of 44 patients that did not has MRD neither before or after HSCT showed OS of 85% in three years and 11% of RCI. The five morphologic relapses observed in this group suggest that a regular monitorization of MRD must be done. The only factor that kept statistical significance in multivariate analysis was MRD > 0,1% after TCTH in RCI (p = 0,001 HR = 9,93) and for OS (p = 0,001 HR = 3,77) (Tables 1 and 2). In conclusion, the presence of MDR > 0,1% was the only independent prognostic factor for survival and relapse in AML patients after HSCT. Disclosures: No relevant conflicts of interest to declare. Table 1:OS multivariate analysis Table 2:RCI multivariate analysis Figure 1: OS of patients after HSCT P = 0,000

scholarly journals Angiogenesis and Minimal Residual Disease in Patients with Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Pardis Nematollahi ◽  
Azar Baradaran ◽  
Zahra Kasaei Koopaei ◽  
Hamidreza Sajjadieh
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Response To Treatment ◽  
Bone Marrow Biopsies ◽  
The Mean ◽  
Minimal Residual ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is the most prevalent acute leukemia in adults. Bone marrow angiogenesis is crucial for pathogenesis of leukemia, and increasing bone marrow Mean Vascular Density (MVD) and level of angiogenesis factors are seen in patients with AML. Higher level of bone marrow MVD is associated with poor prognosis of AML according to previous studies. The present study aimed to compare bone marrow MVD in AML patients and controls and evaluate the relation between bone marrow MVD and number of residual blast cells after AML treatment. Materials and Methods: This study is a longitudinal study on AML patients who were admitted to Omid hospital. The bone marrow biopsies of patients with AML and patients with normal diagnosis –as control group- were taken from archives of pathology laboratory. Immunohistochemistry staining was used for all specimens by using thrombomodulin markers for calculating MVD. Flow cytometry findings of AML patients were assessed for percent of minimal residual disease (MRD) after AML treatment in AML patients group.                                                                 Results: In this study, 27 AML patients and 24 healthy individuals with mean age of 40.92±15.13 years were evaluated, of whom 56.86% were male. The mean bone marrow MVD was significantly higher in AML patients than controls. The mean bone marrow MVD was significantly higher in males and there was insignificant reverse correlation between bone marrow MVD and MRD. About 59.3% of AML patients had response to treatment and there was no significant relationship between MVD and response to treatment.                      Conclusion: Bone marrow MVD was higher in AML patients than controls and there was no remarkable relationship between bone marrow MVD and MRD and response to treatment.

Plasma Alemtuzumab Levels at End of Treatment Correlate with Response and Response Duration in Patients with CLL Receiving Treatment for Residual Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2109-2109
Author(s):  
William G Wierda ◽  
Thomas J Kipps ◽  
Michael J Keating ◽  
Jennifer R Brown ◽  
John G Gribben ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Response Duration ◽  
Response To Treatment ◽  
Color Flow ◽  
Median Response ◽  
End Of Treatment ◽  
Minimal Residual

Abstract We conducted a phase II trial with alemtuzumab self-administered, subcutaneously (SQ) to eliminate residual disease after chemotherapy or chemoimmunotherapy for patients (pts) who were in partial remission (PR) or pts in complete remission (CR) with 2-color flow cytometry evidence of disease. Pts received alemtuzumab SQ 3mg, 10mg, 30mg on days 1,2,3 then 30mg thrice weekly for a total of 12 doses, including rampup. After the 12th dose, pts with residual disease could receive a second course of 12 additional doses. Responding pts were pts in PR who converted to nodular PR (NPR) or CR by NCI-WG ‘96 criteria or pts in CR who remained in CR and had no evidence of disease by 2-color flow cytometry. There were 26 pts enrolled in PR, 5 pts in CR. 7 pts received a second course of alemtuzumab. End of treatment plasma alemtuzumab levels were measured by a flow cytometry-based assay (Rebello and Hale, J Immunol Methods, 2002). The response rate in the intent-to-treat population was 74%. We retrospectively evaluated patients’ bone marrow for minimal residual disease by 4-color flow cytometry. A disappointing 18% of pts evaluated was MRD-negative in bone marrow by this method. Responding pts had mean plasma alemtuzumab level of 8μg/ml verses 3μg/ml for non-responders (p=.003). The median plasma alemtuzumab level for responders was 6μg/ml. Responders with end of treatment plasma alemtuzumab level greater than 6μg/ml had a significantly longer median response duration of 21.2 months versus 8.9 months for pts with less than 6μg/ml (p=.048). End of treatment plasma alemtuzumab level correlated with response to treatment and response duration for patients treated with alemtuzumab SQ. Future studies to optimize dose and schedule for alemtuzumab SQ as treatment for CLL, including for residual disease, should include measurement of end of treatment plasma alemtuzumab levels and evaluation of bone marrow for minimal residual disease by 4-color flow cytometry. Furthermore, consideration of these results should be given to optimize the effective duration of treatment with alemtuzumab SQ.

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