scholarly journals Residual Clonal Plasma Cells Detected By Flow Cytometry at 10-4level within Autologous Stem Cell Grafts Is Associated with Significantly Less Overall Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3438-3438
Author(s):  
Guldane Cengiz Seval ◽  
Klara Dalva ◽  
Sule Mine Bakanay ◽  
Mustafa Merter ◽  
Ugur Sahin ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Hematopoietic Cell Transplantation ◽  
Plasma Cells ◽  
High Dose ◽  
Statistical Tool ◽  
Aberrant Expression ◽  
Post Transplant ◽  
Flow Cytometric ◽  
The Impact

Abstract Introduction:High-dose Melphalan followed by autologous hematopoietic cell transplantation (ASCT) compared to conventional chemotherapies has been shown to improve survival and progression free survival (PFS) in eligible patients with multiple myeloma (MM). However cells that are resistant to the high-dose therapy and remaining in the patient and/or PBSC grafts may eventually lead to relapse. Over the past decade, data have been published on the role of circulating plasma cells (CPCs) as a poor prognostic feature at the time of diagnosis and prior to auto HSCT. But these studies have not sought this issue exclusively in PBSC grafts. The aim of this study was to analyze the impact of flow cytometric measurement of residual clonal cells within the apheresis products on outcome following ASCT. Materials and Methods:Patients with a diagnosis of MM who underwent auto HSCT at our center between January 2008- Mart 2018 were prospectively analyzed. PBSC grafts were tested for the presence of abnormal PCs (APC) and the number of normal PCs (NPC) by multi-parameter flow cytometry (FCM). Standard panel was set up with CD138FITC/CD38PE/CD45ECD/CD56PC5, CD45-CD56+PCs were identified as APC if any aberrant expression (including; CD20(loss)CD27(loss)CD28(gain)CD33(loss)CD34(gain)CD81(loss) CD117(gain)) is detected at diagnosis, the corresponding antibody was also added to the panel. Since maintenance was not an approved treatment in myeloma most patients did not receive any. Outcome was determined as response to transplant, PFS and overall survival (OS) in months by Kaplan-Meier analysis using SPSS (IBM SPSS Statistics 21; IBM Corp., Chicago, IL) statistical tool kit. Results: A total of 209 patients with MM with routine assessment for APC in the apheresis product were included in the analysis. Of these patients, 195 who underwent ASCT, met the predetermined criteria for inclusion. There were 81 (41.5%) female and 114 (58.5%) male patients. The median age at diagnosis of MM was 56 years (range, 31-71 years). The interval from the time of diagnosis to ASCT was median 7 months and median follow-up from ASCT was 49 months (range, 3-198 months). Among 195 patients, 36 (18.5%) had evidence of APC contamination in the PBSC grafts ranging between 1x10-4-12.8 x10-4of total cells. Subtypes of MM were similar among those w/wo APC. Seventy-four patients had pre and post ASCT PET-CT imaging done with 28.2% still active lesions post-ASCT. There was no correlation between PET-CR and absence of APC in grafts. Neither was there a statistically significant association between disease response <VGPR at mobilization and the number of APC in the apheresis product. Post-transplant responses were closely associated with pre-transplant responses. A total of 25 and 57 patients relapsed/progressed in respectively 6 and 12 months after ASCT. Post-transplant response was significantly associated with relapse at 6 months (≥VGPR vs. <VGPR; 37.5% vs. 62.5%, p=0.000). Estimated median OS was significantly different between patients w/o APC contamination; 20.4±8.1 and 63.3±3.8, respectively (p=0.000) (Figure 1). There were no differences in OS among the patients achieving VGPR/CR at the time of mobilization and also two months after the ASCT. We performed a subgroup analysis of patients in grouping together VGPR/CR or only CR and among those patients presence of APC was correlated with worse OS (Figure 1). PFS at 2 years were 60.3±4.3% and 75.6±9.7% in patients receiving APC free PBSC grafts compared with grafts with evidence of APC contamination, respectively (p=0.595). Discussion:PostASCT immune response was predictive for OS only when combined with APC results. Our study provides new insight suggesting a survival advantage value of residual APC detected by FCM, even at a low sensitivity level, on OS but not PFS following ASCT. The impact of such analysis may be more relevant on PFS with better assessment of residual APC with next generation flow cytometric/sequencing approaches while taking into account maintenance. Disclosures Ilhan: Roche: Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Celgene: Speakers Bureau.

scholarly journals Bortezomib and High Dose Melphalan (Bor-HDM) Compared to HDM Conditioning for the Treatment of Transplant Eligible Multiple Myeloma: Report from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3189-3189
Author(s):  
Victor H Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Ahsan Chaudhry ◽  
Marcia Culham ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
High Dose Melphalan ◽  
The Impact

Abstract Introduction Preclinical and clinical data suggest that bortezomib in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve the quality of response for MM patients undergoing auto-SCT. In the present study, we aimed to assess the impact of Bor-HDM conditioning on ORR, and MRD negativity for MM patients undergoing single auto-SCT at our Institution. Methods All consecutive patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2004 to 06/2015 using Bor-HDM or HDM as conditioning regimen were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. MRD negativity was assessed by multiparameter flow cytometry. All patients received induction chemotherapy before undergoing auto-SCT. Bortezomib was administered intravenously at 1-1.3 mg/m2 on days −5, −2, 1, and 4, while melphalan was given at 200 mg/m2 on day −1. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results Two-hundred and fifty-eight consecutive patients receiving Bor-HDM or HDM alone were evaluated. A total of 85 patients received Bor-HDM conditioning and 173 received HDM. Clinical characteristics and chemotherapy induction regimens are listed in Table 1. At day-100 post auto-SCT a ³VGPR was seen in 83.3% in the Bor-HDM group compared to 67.6% for HDM patients. The CR/nCR rate was higher in the Bor-HDM group (47.6% vs 23.6%) as well as MRD negativity assessed by flow cytometry (30.9% vs 9.7%, p=0.0001). Median OS in the Bor-HDM group was NR compared to 95 months for HDM alone (p=0.572), while median PFS was 39.3 months for Bor-HDM compared to 27 months for HDM (p=0.1). Median OS was shorter in the HR cytogenetic group regardless of the type of conditioning regimen employed (39 months vs NR for SR cytogenetics). In addition, patients who achieved MRD negativity, exhibited a longer OS (NR vs 78 months, p=0.007). Transplant-related mortality (TRM) was similar between both groups (p0.5). In conclusion, Bor-HDM is a safe and efficacious conditioning regimen able to increase the nCR/CR and MRD negativity rates compared to HDM. Further studies are warranted to explore this regimen, especially when other upfront therapies are employed, with special view on the high-risk MM patients where response rates are good but sustainability remains an issue. Table 1. Clinical Characteristics Characteristic Bor/HDM, N=85 HDM alone, N=173 Age (median) 58 59 GenderMaleFemale 51 (60%)34 (40%) 113 (65.3%)60 (34.7%) Hb (g/L) 112 117 Calcium (µmol/L) 2.25 2.29 Creatinine (µmol/L) 85 80 B2microglobulin (µmol/L) 3.3 2.79 Albumin (g/L) 31 35 Stage IStage IIStage III 154723 617333 M-spike (g/L) 34 30 LDH (IU/L) 194 180 BMPC (%) 40 33 Heavy chain:IgGIgAIgDFLC onlyBiclonalIgM 491811511 1142403210 Light chain:KappaLambdaBiclonal 50351 124471 High riskStandard risk 2263 36135 InductionCyBorDVDDexamethasoneRVD 4524016 16544315 Figure 1. Overall Survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 1. Overall Survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 2. Progression-Free survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 2. Progression-Free survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 3. Overall Survival for patients with MM undergoing single auto-SCT according to MRD negativity assessed by flow cytometry Figure 3. Overall Survival for patients with MM undergoing single auto-SCT according to MRD negativity assessed by flow cytometry Disclosures Jimenez-Zepeda: Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding.

Residual Disease Detection by Flow Cytometry Predicts Risk of Relapse and Overall Survival in Patients with Acute Myeloid Leukemia Following Reduced Intensity- and Myeloablative- Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4098-4098
Author(s):  
Charlotte Ann Bradbury ◽  
Janice Ward ◽  
Paresh Vyas ◽  
Nigel H. Russell ◽  
Grimwade David ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Cell Transplantation ◽  
Disease Burden ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Hematopoietic Cell ◽  
Post Transplant ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Abstract 4098 Relapse after allogeneic hematopoietic cell transplantation (HCT) is usually incurable for acute myeloid leukemic (AML) patients. Residual disease (MRD) monitoring pre- and post-HCT may improve relapse prediction, allowing the targeted implementation of post-HCT interventions to at risk patients when disease burden is sufficiently low for these to be effective. Previous studies have shown that MRD detection by multiparameter flow cytometry (MRD MFC) at either pre- (Leung et al 2012, Walter et al 2011) or post- transplant (Yan et al 2012) timepoints is prognostic for myeloablative HCT outcome in AML. Quantification of hematopoietic populations enriched for leukemic stem cells such as CD34+CD38low or lymphoid-primed multi-potential progenitor-like (LMPP-like) (Lin-CD34+CD38lowCD90-CD45RA+) (Goardon et al 2011) may improve the specificity of MFC MRD assays. In this study we retrospectively evaluated the predictive value of MRD MFC at both pre- and post- HCT timepoints in a cohort of unselected AML/high risk myelodysplasia (MDS) patients (n=44) who underwent reduced intensity conditioning (RI n= 32, median age 59, range 34–70) or myeloablative (MA n=12, median age 28, range 19–47) HCT between June 2010 and November 2011 (Table 1). MFC MRD was assessed both by detection of standard leukemic- aberrant-immunophenotypes (LAIPs) (identified at presentation and/or relapse) and quantification of CD34+CD38low and LMPP-like progenitors (LSC-enriched progenitors, LSC-EP). Pre HCT, 37 patients (MA = 11, RI = 26) were assessable for MFC MRD. 15 (41%) were MRD positive (LAIP MRD+) and 47% (7/15) (MA = 37.5%, 3/8; RI = 57%, 4/7) of these relapsed post HCT compared to 8% (MA = 0%, RI = 9%) of MRD negative patients (LAIP-MRD-), (Fig 1 p 0.03). Post HCT, 34 patients (MA = 9, RI =25) were assessable for MFC MRD. 10 (37%) had detectable LAIP MRD positivity between 2 and 9 months post HCT. 80% of these relapsed (MA = 60%; RI = 100%) with a median disease free survival (DFS) post HCT of 5 months (MA = 4 months; RI = 5 months); there were no relapses in the 17 patients who remained LAIP MRD- at a median follow-up of 20 months (range 9–26). (p=0.0006, Figure 2a). Presence of MRD post-transplant was associated with significantly poorer overall survival (p=0.005). Although 1 patient with high MRD (in CR, LAIP >1%, LSC-EP +) pre HCT relapsed <3 months post HCT, in 8 of 9 other relapses MRD positivity detected at ≥ 2 months post HCT preceded clinical relapse by >1 month (median time to relapse from MRD detection of 1.5 months, range 1–6; OS, median 4 months, range 1 - not reached). CD34+CD38low progenitors (34+38low) were < 0.03% of bone marrow nucleated cells in the majority of patients. Detectable 34+38low were mainly CD45RA+ so in most cases correlated with LMPP-like quantitation. Pre HCT, 34+38low were detectable in 40% of patients who went on to relapse and in only 9% of those who have not yet relapsed. Post HCT, 34+38lowpositivity preceded frank relapse by ≥1 month in 60% of patients who relapsed. Only 6% of patients who have not yet relapsed had detectable 34+38low. LSC-LEP positivity appears prognostic for DFS and OS (Figure 2b) but for a lower frequency of relapses compared to LAIP MRD positivity (60% v 80%). Conclusions: These data suggest that post HCT MFC detection of LAIP MRD is predictive of relapse in RI as well as MA HCT. LSC-LEP quantitation may be prognostic in a subset of patients. Pre HCT MRD might be more predictive of relapse in RI than MA HCT. However, post HCT MRD positivity precedes most clinical relapses by a time window which may be sufficient for interventions such as azacytidine or donor lymphocyte infusion (DLI) when disease burden is still low. These results provide a basis for the use of MFC residual disease detection pre and post HCT to inform treatment decisions in reduced intensity as well as myeloablative HCT. Disclosures: No relevant conflicts of interest to declare.

Effect of Pre and Post-Transplantation Responses on Outcome of Multiple Myeloma Patients: CR and near-CR Should Not Be Considered as Equivalent Prognostic Markers. Results of a PETHEMA/Gem Prospective Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 161-161
Author(s):  
Juan José Lahuerta ◽  
Maria Victoria Mateos ◽  
Joaquin Martínez-López ◽  
Laura Rosinol ◽  
Anna Sureda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Plasma Cells ◽  
High Dose ◽  
Cell Transplant ◽  
Post Transplantation ◽  
Post Transplant ◽  
Post Induction ◽  
The Impact ◽  
Response Post

Abstract To achieve CR is an important goal in the treatment of most Hematological malignancies. In Multiple Myeloma (MM) although there is evidence demonstrating an association between CR and long-terms outcomes, some trials have failed to find such a correlation. In addition, it is not clear whether different responses categories, such as CR, near-CR (nCR) o Very Good Partial Response represent different prognostic subgroups or include an homogeneous group of patients with similar outcomes. Therefore, the confirmation of a possible association between different responses categories and long-term outcomes is required. We evaluated the prognostic influence on EFS and OS of pre- and post-transplant responses in newly diagnosed MM patients. Patients and Methods: We analyzed 632 patients who had been included in the prospective GEM2000 trial. All were uniformly treated with VBCMP/VBAD induction followed by high-dose therapy and autologous stem cell transplant and maintenance therapy with interpheron plus prednisone. Disease response was assessed post-induction and post-transplant using EBMT criteria, modified to include nCR. CR required at least 6 weeks of negative immunofixation (IFx) in serum and urine plus less than 5% plasma cells in BM. nCR was defined as electrophoresis-negative but IFx-positive. Partial response (PR) required greater than 50% reduction in M-protein and Stable disease (SD) included patients with minimal response and no change by EBMT criteria. Results: Probability of achieving CR post-transplant was significantly higher among patients achieving nCR versus PR (p= 0.004) versus SD or PD (p= 0.0003) pre-transplant. Patients achieving nCR or PR post-induction had similar outcomes, and both response categories showed a trend to have inferior EFS and OS as compared to patients in CR. After transplant, only borderline differences in EFS were detected upon comparing nCR with PR (nCR: median 40 months; PR median 34 months, p=0.07), by contrast the EFS of CR patients (median 61 months) was significantly longer than that of nCR or PR categories (both comparisons p&lt;10−5). OS was longer among patients achieving CR post-transplant (median NR) compared with patients achieving nCR (median NR, p= 0.01) or PR (61 months, p &lt; 10−5); it should be noted that nCR patients had longer OS than PR patients (p = 0.04). The multivariate analysis showed that achieving CR was associatted with significantly better EFS and OS while the EFS/OS influence of nCR was no statistically different from PR or SD. Within nCR patients, outcomes were significantly worse among those who achieved nCR post-induction and remained in nCR post-transplant compared with those who upgraded to nCR post-transplant after PR or SD post-induction. EFS and OS, and influence of response, were similar among elderly (65–70 years) and younger (&lt;65 years) patients. (both comparisons p&lt;10). Conclusions: Our results confirm that the degree of response is highly associated with final survival, with higher benefit for patients achieving CR by IFx, which should not be pooled with the nCR patients. Although the impact in survival is more evident for the responses measures after HDT/SCT it is also evident after induction therapy, moreover, the quality of response post-induction clearly influences response post-transplant. Finally, patients between 65 and 70 years should not be completely discouraged from HDT/SCT.

scholarly journals BAFF signaling drives interstitial transformation of mouse renal tubular epithelial cells in a Pin1-dependent manner

2021 ◽  
Author(s):  
Haiyan Xu ◽  
Dan Song ◽  
Renfang Xu ◽  
Xiaozhou He
Keyword(s):  
Flow Cytometry ◽  
Epithelial Cells ◽  
Biological Activities ◽  
High Dose ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Aberrant Expression ◽  
Renal Tubular

AbstractAberrant expression of B cell–activating factor belonging to TNF superfamily (BAFF) and its receptors results in abnormal biological activities in hematopoietic and non-hematopoietic cells and is closely associated with the occurrence and development of various diseases. However, the biological significance and potential mechanisms underlying BAFF signaling in renal tubular epithelial cells (RTECs) remain unknown. This study aimed to investigate the biological role of BAFF signaling in RTECs. Mice primary RTECs were applied. The proliferation status and apoptotic rates were examined by MTS assay and flow cytometry, respectively. The expression of BAFF and its receptors was analyzed via flow cytometry and sodium ion transport function, and cytokeratin-18 expression was detected through immunofluorescence staining. In addition, Pin1 was knocked down via siRNA and its expression was assessed through reverse transcription PCR. Lastly, western blotting was performed to analyze E-cadherin, ɑ-SMA, and Pin1 expression. Results suggested that BAFF-R was significantly upregulated upon IFN-γ stimulation, and enhancement of BAFF signaling promoted cell survival and reduced their apoptotic rate, while simultaneously reducing the epithelial phenotype and promoting the interstitial transformation of cells. Furthermore, Pin1 was significantly increased, along with the upregulation of BAFF signaling in the RTECs, and participated in interstitial transformation induced by BAFF signaling. Collectively, the present results elucidate the potential mechanism of loss of normal function of RTECs under long-term high dose of BAFF stimulation provides a potential therapeutic target for renal interstitial fibrosis, and underlining mechanisms of shortening of long-term outcomes of kidney allografts via augmenting of BAFF signaling.

Immunophenotypic Study of Basophils by Multiparameter Flow Cytometry

2008 ◽  
Vol 132 (5) ◽  
pp. 813-819
Author(s):  
Xiaohong Han ◽  
Jeffrey L. Jorgensen ◽  
Archana Brahmandam ◽  
Ellen Schlette ◽  
Yang O. Huh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Myelogenous Leukemia ◽  
Multiparameter Flow Cytometry ◽  
Color Flow ◽  
Aberrant Expression ◽  
Flow Cytometric ◽  
Hla Dr

Abstract Context.—The immunophenotypic profile of basophils is not yet fully established, and the immunophenotypic changes in chronic myelogenous leukemia are not fully characterized. Objective.—To establish a comprehensive immunophenotypic spectrum of normal basophils and to assess the range of immunophenotypic aberrations of basophils in chronic myelogenous leukemia. Design.—Using 4-color flow cytometry, we compared the immunophenotypic profile of basophils in peripheral blood or bone marrow samples from 20 patients with no evidence of neoplasia to basophils from 15 patients with chronic myelogenous leukemia. Results.—Basophils in control cases were all positive for CD9, CD13, CD22, CD25 (dim), CD33, CD36, CD38 (bright), CD45 (dimmer than lymphocytes and brighter than myeloblasts), and CD123 (bright), and were negative for CD19, CD34, CD64, CD117, and HLA-DR. Basophils in all chronic myelogenous leukemia patients possessed 1 to 5 immunophenotypic aberrancies. The most common aberrancies were underexpression of CD38, followed by aberrant expression of CD64 and underexpression of CD123. CD34 and CD117 were present in cases with basophilic precursors. Myeloblasts showed a distinct immunophenotypic profile, as they typically expressed CD34 and CD117, showed dimmer expression (compared with basophils) of CD38, CD45, and CD123, and lacked expression of CD22. Conclusions.—Flow cytometric immunophenotyping can identify immunophenotypic aberrations of basophils in chronic myelogenous leukemia, and discriminate basophils from myeloblasts.

Impact of Consolidation Radiotherapy in Patients With Advanced Breast Cancer Treated With High-Dose Chemotherapy and Autologous Bone Marrow Rescue

1999 ◽  
Vol 17 (3) ◽  
pp. 887-887 ◽  
Author(s):  
Dennis L. Carter ◽  
Lawrence B. Marks ◽  
Joseph M. Bean ◽  
Gloria Broadwater ◽  
Atif Hussein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Overall Survival ◽  
Advanced Breast Cancer ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
Advanced Breast ◽  
High Dose ◽  
Autologous Bone ◽  
The Impact

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994, 425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT−). The assignment of RT was not randomized. The RT+ and RT− groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT− patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT− groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT− groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.

A Complete Remission (CR) Is Not a Prerequisite for Prolonged Survival after Autotransplants for Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 926-926 ◽  
Author(s):  
Guido Tricot ◽  
Maureen Reiner ◽  
Jeffrey Sawyer ◽  
John Crowley ◽  
Bart Barlogie
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Tumor Burden ◽  
Time Dependent ◽  
Prolonged Survival ◽  
P Value ◽  
High Dose ◽  
Cytogenetic Abnormalities ◽  
Variate Analysis ◽  
The Impact

Abstract In acute leukemia prolonged survival is impossible without obtaining a CR. Based on the acute leukemia model, myeloma therapy has gradually been intensified with the aim to increase the CR rate as a first important step to improve overall survival (OS). Although patients with abnormal metaphase cytogenetics have a significantly inferior outcome in terms of event-free and overall survival, the CR rate is similar for patients with and without cytogenetic abnormalities, indicating that CR may not be a good prognostic indicator of ultimate outcome. To address the importance of obtaining a CR for OS, we analyzed our Total Therapy I (VADx3-high dose cyclophosphamide 6g/m2 with stem cell collection-EDAP-melphalan-based tandem transplants-α interferon maintenance) data in those patients who had not received any treatment prior to enrollment (N=155), received at least one transplant (N=135) and were alive one year after the first transplant (N=132). Kaplan-Meier curves were generated using a 1 year landmark to compensate for the guaranteed time of CR patients, but thereby excluding patients who died within the first year after the first autotransplant (N=3). The 1-year landmark was chosen because the large majority of CR patients (75%) had achieved their CR at 1 year after the first transplant. In addition, a time-dependent co-variate analysis for CR was performed, including the 135 patients. The median follow-up of these patients was 10.5 years. The 9 year OS after the landmark, i.e., 10 years after the first transplant, was 41% (95% confidence interval: 26, 55) for CR patients versus 37% (26, 47) for no CR patients (i.e., PR and <PR) with a logrank p value of 0.71 (Figure 1). Using a time-dependent co-variate analysis for CR, achieving a CR was not significantly related to OS (Hazard Ratio: 0.83; p value 0.39). Only the presence of metaphase cytogenetic abnormalities (HR: 2.0; p=0.005), LDH > 190 U/L (upper limit of normal) (HR: 2.0; p=0.01) and CRP >4.0mg/L (HR: 1.6; p=0.03) were significant for OS. When the importance of CR was assessed separately for patients with (N=43) and without (N=84) abnormal cytogenetic (cytogenetic information was missing on 5 patients), no survival benefit for CR patients was seen in either subgroup (p values 0.52 and 0.32, respectively) and similarly, using the time-dependent co-variate analysis for CR, there was no significant benefit for OS of attaining a CR in either group (p value: 0.7 and 0.5, respectively). We conclude that prolonged survival (>10 years) is observed in a substantial proportion of myeloma patients receiving a tandem autotransplant-based regimen, irrespective of the completeness of response to tandem transplants. The inherent genetic features of the myeloma and the impact on the micro-environment of the myeloma cells appear to be more important than the absolute tumor burden reduction accomplished by tandem transplants. Our findings may also be a reflection of the insensitivity of CR as an assessment of remaining tumor burden in myeloma and a new definition of CR may be required. Figure Figure

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3090-3090 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Rima M. Saliba ◽  
Marilyn S. Davis ◽  
Floralyn L. Mendoza ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Cell Transplantation ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Significant Difference ◽  
Preparative Regimen ◽  
The Impact

Abstract Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC >500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Myeloid Dyspoiesis as Determined by Flow Cytometry Is a More Powerful Predictor of Post-Transplant Relapse with MDS Than the Marrow Myeloblast Count.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1656-1656
Author(s):  
Denise A. Wells ◽  
Bart L. Scott ◽  
Wendy M. Leisenring ◽  
Michael R. Loken ◽  
H. Joachim Deeg
Keyword(s):  
Flow Cytometry ◽  
Hematopoietic Cell Transplantation ◽  
International Prognostic Scoring System ◽  
Initial Report ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Myeloid Antigens ◽  
Increased Risk ◽  
Good Risk ◽  
Risk Of Relapse

Abstract We showed previously that the presence of aberrant marrow myeloblasts, as determined by flow cytometry immediately pre-transplant had predictive value for post-transplant outcomes in patients undergoing hematopoietic cell transplantation (HCT) for Myelodysplastic Syndrome (MDS). The characteristics of phenotypically abnormal myeloblasts in MDS include decreased expression of CD45, presence of non-lineage lymphoid antigens including CD56, and differences in the intensity of various myeloid antigens in comparison to healthy controls. In the present study, the bone marrow aspirates of 156 patients with MDS were analyzed before HCT for the presence of abnormal myeloblasts with the aim of determining whether myeloid dyspoiesis by flow cytometry was predictive of post-transplant outcomes, specifically in patients who were considered good risk by currently accepted criteria. All patients received ”myeloablative” conditioning, which in most patients (78%) consisted of busulfan (targeted) and cyclophosphamide followed by HLA-identical related (52%), HLA-matched unrelated (39%), or alternative donor (9%) stem cell infusions. In agreement with our initial report, patients with severe flow scores (≥4) had an increased hazard of relapse (HR=2.7, 95% CI_1.1–6.3, p=0.017) in comparison to patients with normal flow scores. In addition, even among patients with less than 5% marrow myeloblasts, dyspoietic characteristics of the blasts, as assessed by flow cytometry criteria were associated with an increased hazard of relapse (HR=4.0, 95% CI 1.4–12.1, p=0.013) as compared to patients without dyspoiesis by flow. The cumulative incidence of relapse in MDS patients with flow cytometrically normal marrow myeloblasts was 11.7%, compared to 28.1% in patients with less than 5% but phenotypically aberrant myeloblasts; the latter was not different from a relapse incidence of 31.4% in patients with 5% or more abnormal marrow myeloblasts. Furthermore, patients with intermediate-1 risk disease by the International Prognostic Scoring System, who showed flow cytometric aberrancies were at significantly increased risk of relapse (HR=4.2, p=0.01) in comparison to patients with intermediate-1 risk disease and no or mild dyspoiesis by flow cytometry. Thus, the presence of dyspoietic changes was more relevant than the proportion of marrow myeloblasts in predicting the risk of relapse, suggesting that flow cytometry is a powerful tool to select high risk patients from cohorts of patients who by established criteria would be considered to have good risk MDS.

Sign in / Sign up

Export Citation Format

Share Document