BRAF mutation as a pejorative marker in metastatic melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8555-8555 ◽  
Author(s):  
Sophie Brissy ◽  
Caroline Gaudy-Marqueste ◽  
Stéphanie Mallet ◽  
Sandrine Monestier ◽  
Sylvie Hesse ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Metastatic Melanoma ◽  
Distant Metastasis ◽  
Braf Mutation ◽  
Cox Model ◽  
Primary Melanoma ◽  
Wild Type ◽  
Significant Difference ◽  
Braf Mutant

8555 Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p<0.05) were histopathologic subtype (SSM), high mitotic rate (≥1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, p=0.016), truncal location and location on occasionally exposed at sun site.The interval from diagnosis of first ever melanoma to first distant metastasis was not significantly different in BRAF-mutant and wild-type patients. The median overall survival (OS) from diagnosis of primary melanoma was 6.5 years for BRAF wild-type patients. Median OS was not reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, but also in those not treated (p=0.24, and p=0.06 for treated BRAF-mutant vs BRAF wild-type). The overall survival from diagnosis of first distant metastasis was not significantly different (p=0.75). These results remained unchanged in a multivariate analysis. Conclusions: Our results confirm the characteristics of BRAF-mutant metastatic patients, and the efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is per se a pejorative predictive marker.

Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma

2011 ◽  
Vol 29 (10) ◽  
pp. 1239-1246 ◽  
Author(s):  
Georgina V. Long ◽  
Alexander M. Menzies ◽  
Adnan M. Nagrial ◽  
Lauren E. Haydu ◽  
Anne L. Hamilton ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Distant Metastasis ◽  
Braf Mutation ◽  
Braf Inhibitor ◽  
Primary Melanoma ◽  
Age At Diagnosis ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutation Status ◽  
Braf Mutant

Purpose To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome. Patients and Methods Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Results Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor. Conclusion V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.

scholarly journals Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma?

2019 ◽  
Vol 11 ◽  
pp. 175883591984887 ◽  
Author(s):  
Lorena Incorvaia ◽  
Giuseppe Badalamenti ◽  
Gaetana Rinaldi ◽  
Juan Lucio Iovanna ◽  
Daniel Olive ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Survival Rate ◽  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Primary Melanoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Enzyme Linked Immunosorbent Assay ◽  
Melanoma Patients ◽  
Infiltrating Lymphocytes

Background: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate. Patients and Methods: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma. Results: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients’ overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs. Conclusions: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a BRAF mutation at the time of diagnosis.

scholarly journals 7 Assessing melanoma BRAF status through ddPCR of cfDNA

2019 ◽  
Vol 95 (1130) ◽  
pp. 686.4-687
Author(s):  
Lauren Passy ◽  
Shobha Silva ◽  
Ian Brock ◽  
Greg Wells ◽  
Angela Cox ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Limit Of Detection ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutation Status ◽  
Gapdh Gene ◽  
Fractional Abundance ◽  
Significant Difference ◽  
Tissue Specimens ◽  
Braf Mutant

IntroductionTreatment of recurrent and metastatic melanoma has been revolutionised by targeted therapy. Inhibitors of mutant BRAF are a systemic treatment offered for patients with stage III/IV melanoma who are known to carry a mutation in BRAF. Currently patients’ BRAF mutation status is assessed through molecular analysis of tissue specimens.Cell-free DNA (cfDNA) released from tumours can be used to non-invasively detect active disease and predict survival in melanoma. cfDNA also provides a method for detecting BRAF mutations. This project aimed to ascertain BRAF mutation status in cfDNA through digital droplet PCR (ddPCR) of plasma samples from patients with melanoma. We aimed to assess the relationship between cfDNA BRAF positivity and disease relapse and progression.MethodsPlasma from 100 patients with active or recently resected melanoma was obtained during previous work. 85 samples had cfDNA extracted. Tissue BRAF status was known for 57 samples. cfDNA was extracted from 1–2 ml plasma with the QIAamp circulating nucleic acid kit (QIAGEN®) following manufacturer protocol, eluting cfDNA into 100µL. cfDNA was quantified with SYBR green quantitative real-time PCR (Life Technologies), based on an 87bp GAPDH gene amplicon. ddPCR™ was performed using the Bio-Rad QX200 Droplet Generator™ and Droplet Reader as per manufacturer protocol. Analysis was performed with Bio-Rad QuantaSoft Version 1.7.4.ResultsMedian yield of cfDNA extracted from 85 samples was 1.97 ng/ml when eluted into 100µL. This was well-correlated with previous cfDNA extraction yields from this sample set (Pearson’s r=0.6687, p<0.0005), where a 200µL elution volume was used. 74 samples yielded >10,000 droplets and were included for analysis. 12 samples contained BRAF mutant positive droplets. A 74% concordance rate between tissue BRAF mutation status and the presence/absence of cfDNA BRAF mutant positive droplets was found. 7/18 tissue BRAF mutant samples contained BRAF mutant droplets, in comparison to 2/32 tissue BRAF wild-type samples. The presence of BRAF mutant positive droplets was significantly different between the tissue BRAF mutant and tissue BRAF wild-type groups (χ2 8.3145, p=0.004).Fractional abundance of BRAF mutant droplets in the samples containing mutant droplets ranged from 0.07–0.74%. When comparing BRAF mutant droplet-containing samples and samples without BRAF mutant droplets, there was no significant difference in rate of relapse (χ2 0.0948, p=0.758), nor mortality rate (χ2 3.3959, p=0.654).Conclusion cfDNA provides a non-invasive snapshot of the tumour genome and any potential therapeutic targets held within. This work demonstrates that a very low volume of cfDNA can be used to detect BRAF mutations in patients with melanoma through ddPCR.Previous work assessing BRAF status in cfDNA has used larger volumes of cfDNA. Though our concordance rates are comparable with other studies, it is possible that using a smaller amount of cfDNA in our ddPCR has resulted in some samples being below the limit of detection for ddPCR.Longitudinal study is warranted to monitor cfDNA BRAF status and mutant fractional abundance, and whether this better correlates with relapse of disease and disease progression.

Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 413-413
Author(s):  
T. Yokota ◽  
T. Ura ◽  
N. Shibata ◽  
D. Takahari ◽  
K. Shitara ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Clinicopathological Features ◽  
Wild Type ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Braf Mutant

413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p<0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p<0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2. Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.

Analysis of Kohne's prognostic index in KRAS wild-type patients with metastatic colorectal cancer (mCRC) treated with salvage-line cetuximab-based regimen: HGCSG0901.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 634-634
Author(s):  
Ayako Doi ◽  
Satoshi Yuki ◽  
Yasushi Tsuji ◽  
Takahide Sasaki ◽  
Hiraku Fukushima ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Prognostic Impact ◽  
Wild Type ◽  
Free Survival ◽  
Significant Difference

634 Background: In the treatment for mCRC, it is essential for understanding the prognosis of each individual patient. Köhne’s index (KI) based on performance status, white blood cell count, alkaline phosphatase and number of metastatic sites has been previously proposed. However, in the salvage setting, the validity of KI has not been reported in patients treated by cetuximab-based chemotherapy. Methods: 269 patients with mCRC treated by cetuximab contained chemotherapy were retrospectively registered from 27 centers in Japan. This analysis was included in the KRAS wild-type patients who were refractory to or intolerant for 5-FU/irinotecan/oxaliplatin and were never administered anti-EGFR-antibody. Univariate and multivariate analysis for overall survival were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. The analysis was also designed to determine whether the Köhne’s classification could be extended to other endpoints such as progression-free survival. Results: All data were available for prognostic categorization in 127 patients. Median overall and progression-free survival was 9.8 and 4.2 months. The distribution and median survival / progression-free survival for KI were as follows: low risk (L) (n = 40; 13.1/5.1 months), intermediate risk (I) (n = 17; 9.6/3.5 months), and high risk (H) (n = 70; 7.6/4.1 months). For overall survival, there was significant difference between L and H (p = 0.004), but not between L and I (p = 0.213), and between I and H (p = 0.321). For progression-free survival, there was tended to difference between L and H (p = 0.083), but not between L and I (p = 0.392), and between I and H (p = 0.630). In Cox multivariate analysis, KI showed an independent prognostic impact (HR 1.370, p = 0.010), but not predictive impact (HR 1.147, p = 0.212). Conclusions: In this analysis, KI might be a prognostic factor in salvage treatment with cetuximab-based regimen, but no effect predicted impact. Moreover, the prospective evaluation is needed for the further validation.

SP6.1.11 The Effect of the Enhanced Recovery Programme for Liver Surgery on Long Term Survival

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Kalaiyarasi Arujunan ◽  
Abdulwarith Shugaba ◽  
Harmony Uwadiae ◽  
Joel Lambert ◽  
Georgios Sgourakis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Postoperative Complications ◽  
Liver Surgery ◽  
Patient Survival ◽  
Enhanced Recovery ◽  
Readmission Rates ◽  
Term Survival ◽  
Significant Difference

Abstract Aims The Enhanced Recovery Programme for Liver Surgery (ERPLS) has been shown to promote functional recovery and reduce hospital stay. However, its effect on long term survival has yet to be established. The aim of this study was to determine the effect of the ERPLS on 5-year patient survival. Methods This was a retrospective study of patients who underwent liver resection for colorectal liver metastasis (CRLM) between January 2011 and December 2016 at a regional hepatobiliary centre. The cohort comprised of 60 pre-ERPLS and 60 post-ERPLS patients. The primary outcome was 5-year patient survival. The secondary outcomes were length of stay (LOS), postoperative complications and 90-day readmission rates. Multivariate analysis was performed to identify independent predictors of overall survival. Results There was no significant difference in the age (p = 0.960), gender (p = 0.332) and type of resection (p = 0.198) between both groups. ERPLS was not an independent predictor for overall survival (Gehan Wilcoxon Test, p = 0.828). There was no significant difference in the LOS (p = 0.874) and 90-day readmission rates (p = 0.349). Major postoperative complications (&gt;3a Clavien-Dindo classification) were significantly less in the ERPLS group (p = 0.02). On multivariate analysis, positive resection margins and major postoperative complications were independent predictors for overall survival. Conclusions ERPLS does not seem to have an effect on long term patient survival. However, it appears to reduce the rate of major postoperative complications. LOS and 90-day readmission rates were not influenced by ERPLS.

Overall survival based on MSI and BRAF mutation status for stage II/III colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 132-132
Author(s):  
Sophiya Karki ◽  
Rashna Madan ◽  
Sarah Schmitt ◽  
Ziyan Y. Pessetto ◽  
Andrew K. Godwin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Median Survival ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Stage Ii ◽  
Age At Diagnosis ◽  
Mutation Status ◽  
Braf Mutant

132 Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. Some of the poor prognostic factors for metastatic CRC (mCRC) include BRAF V600E mutation and microsatellite instability (MSI) that result from mutation or loss of mismatch-repair genes. While the prognostic value of MSI-high CRC for early-stage patients treated with resection and adjuvant chemotherapy is favorable, the prognostic value of BRAF mutation is still unclear. Furthermore, the impact of BRAF mutation with concurrent microsatellite instability on overall survival has not been well investigated. Methods: Here, we collected BRAF mutation status and MSI status of stage II/III CRC patients (n=106) treated at the University of Kansas Cancer Center between September 2009 and July 2020 and compared overall survival between 4 subtypes:MSI-H/BRAF mutant (n=16), MSS/BRAF mutant (n=4), MSI-H/BRAF WT (n=17) and MSS/BRAF WT (n=69), further stratifying patients by age at diagnosis and tumor location. Molecular data were obtained from molecular oncology laboratory as PCR or IHC-based or acquired from outside records. Subgroup analyses were done for stage II and stage III cancers. Results: Table shows the patient characteristics. From our preliminary analysis, MSI-H CRC was found to be primarily a right-sided tumor (MSI-H/BRAF mutant: 94% and MSI-H/BRAF WT 76%). On the contrary, MSS CRC had a more heterogenous localization, spanning left colon, right colon and rectum. In our patient cohort, median survival was not reached for stage II patients whereas for stage III patients, BRAF mutation was associated with poor median survival irrespective of MSI status (MSS/BRAF mutant: 27 months and MSI-H/BRAF mutant 29 months). Median overall survival was found to be 87 months, not reached, 27 months and 29 months for MSS/BRAF WT, MSI-H/BRAF WT, MSS/BRAF mutant and MSI-H/BRAF mutant, respectively. Although associated with poor survival, MSI-H/BRAF mutant displayed later age at diagnosis (mean age 73) compared to MSS/BRAF mutant (mean age 60, p-value<0.029). Conclusions: Our finding suggests that BRAF mutation has poor prognosis even at earlier stages of the disease and that MSS/BRAF mutation, in particular, has the worst prognostic features. These findings highlight the need for BRAF-targeted therapy for CRC at any stage. Due to small sample size, however, our results warrant validation in a larger cohort. [Table: see text]

scholarly journals STMO-11 CLINICAL EFFICACY OF AWAKE SURGERY: ANALYSIS OF 335 CASE ON EXTENT OF RESECTION AND SURVIVAL TIME

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii20-ii20
Author(s):  
Atsushi Fukui ◽  
Yoshihiro Muragaki ◽  
Takashi Maruyama ◽  
Taiichi Saito ◽  
Masayuki Nitta ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
General Anesthesia ◽  
Extent Of Resection ◽  
Awake Surgery ◽  
Significant Prognostic Factor ◽  
Glioma Surgery ◽  
Long Term Outcome ◽  
Significant Difference ◽  
Eloquent Area

Abstract INTRODUCTION Awake craniotomy (AS) with intraoperative mapping can be compatible to obtain maximal resection and preserve neurological function for glioma surgery. However, there is less evidence to improve overall survival for glioma patients. We compared the long-term outcome of glioma resection during AS and general anesthesia (GA). METHODS Continuous 335 patients with newly diagnosed glioma of WHO grade2 (G2) or higher who underwent surgery with intraoperative MRI between 2000 and 2013 were reviewed. Three-dimensional volumetric tumor measurements before and after operation were made. Multivariate analysis was used to evaluate the effect of awake surgery on overall survival (OS). RESULTS The mean age of all cases was 46 years, male: female 199: 136, mean preoperative tumor volume (PTV) 44.5cc, mean extent of resection (EOR) 88.31%, and median survival (MST) 82.6 months. MST of G4 was significantly longer in the AS group (AS 38.9 months vs. GA group 22.0 months: p = 0.03), while multivariate analysis showed that age and KPS was a significant prognostic factor, but AS was not. There was no significant difference in the EOR of G3 (AS group 80.1% vs. general anesthesia 84.2%: p = 0.365), and MST was also not significantly different (AS group 134.8 months vs. GA group 117.9 months: p = 0.338). G2 also had no significant difference in the EOR (AS group 84.6% vs. GA group 86.7%; p = 0.92), and MST was also not significantly different (AS group 152.9 months vs. GA group 135.1 months: p = 0.235). Analysis of G2 or G3 showed no significant differences in PTV, KPS, and age at the surgery between two groups. CONCLUSION Even if a glioma is located close to or within the eloquent area, AS can lead to EOR and OS equivalent to the removal of the non-eloquent area under GA.

Maintenance Thalidomide May Improve Progression Free but Not Overall Survival; Results from the Myeloma IX Maintenance Randomisation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 656-656 ◽  
Author(s):  
Gareth J Morgan ◽  
Graham H Jackson ◽  
Faith E Davies ◽  
Mark T Drayson ◽  
Roger G Owen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Recovery Time ◽  
Cell Clone ◽  
Cox Model ◽  
Continuous Variable ◽  
Hazard Ratio ◽  
High Dose ◽  
Prognostic Features ◽  
Significant Difference ◽  
The Impact

Abstract The role of maintenance therapy for the long term control of the plasma cell clone in patients induced into response with either intensive or conventional treatment is an important outstanding question. We addressed this in the MRC Myeloma IX study which incorporates intensive and non-intensive pathways selected according to PS and age. In the intensive pathway patients were randomised to either CTD or CVAD induction, followed by High Dose Melphalan (HDM) before being randomised to either thalidomide or no maintenance. In the non-intensive pathway patients were randomised to either MP or attenuated CTD prior to the maintenance randomisation. For patients randomised to thalidomide it was initiated at d100 following HDM or at the end of induction in the non-intensive arm with the aim of delivering 100mg daily until relapse. A dose reduction algorithm for side effects was used. Between the years of 2003–8, 820 patients were entered into the maintenance randomisation, median age 64 (intensive 59, non-intensive 73), median follow-up 32 months. Prognostic features were evenly distributed between the arms. FISH and cytogenetics were done using standard methods. Response was assessed by IWG criteria. For overall survival (OS) there was a non-significant trend in favour of the no maintenance arm, which enables us, by calculating confidence limits on the hazard ratio, to make the assertion that no maintenance could be up to 7% worse than thalidomide at 5 years (p=.005). Further analysis showed that there was no significant difference in OS in either the intensive or the non-intensive arm. The duration of time on thalidomide maintenance appeared to make no difference to OS. There was a non-significant improvement in progression free survival (PFS) across the maintenance randomisation as a whole and in the intensive pathway a significant benefit of maintenance was seen in the patients achieving less than a VGPR post initial induction therapy prior to HDM, (hazard ratio 1.9, p=.007). This PFS difference did not translate into a survival benefit because the survival after progression in the PR patients receiving maintenance thalidomide was poor (p=.002). In addition we looked at the time spent off thalidomide, the recovery time, (the time between stopping thalidomide and progression) as a possible predictor of survival after progression. Treated as a continuous variable in the Cox model this showed a trend for longer survival after relapse in those with longer recovery time (p=.056). In the non-intensive pathway a similar but less pronounced effect of thalidomide maintenance on PFS was seen. These results are consistent with a consolidation rather than a maintenance effect for thalidomide in this setting. The impact of maintenance in different cytogenetic subgroups was also determined [17p-, 13q-, 14q abnormalities including t(4;14), t(14;16), t(6;14), t(14;20) and t(11;14)]. For the 17p- group, the difference in OS between no thalidomide and thalidomide is large (HR = 4.55, p=.02) with the thalidomide patients faring worse, although this is based on only 30 patients. For the non 17p- group there is no difference in PFS (HR = 1.24, p=.37), in the 17p- group, however, the PFS is worse. In addition, of the 22, 17p- patients receiving CTD or CTDa as initial therapy, the 10 who received no thalidomide maintenance are all still alive, whereas 9/12 of those who went on to receive thalidomide maintenance have died. It seems that thalidomide given at induction and again in maintenance, may be particularly detrimental in 17p- patients. Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS. It is important to identify 17p- in order to exclude these patients from receiving thalidomide maintenance.

Circulating Plasma Cells By Routine Complete Blood Count Identify Patients With Similar Outcome As Plasma Cell Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5356-5356 ◽  
Author(s):  
Rupin A Shah ◽  
Satyajit Mohite ◽  
Veerabhadran Baladandayuthapani ◽  
Sheeba K. Thomas ◽  
Donna M. Weber ◽  
...  
Keyword(s):  
Overall Survival ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Blood Count ◽  
Plasma Cells ◽  
Complete Blood Count ◽  
Cox Model ◽  
Cell Leukemia ◽  
Who Criteria ◽  
Significant Difference

Abstract Introduction Plasma cell leukemia (PCL) is a plasma cell dyscrasia that predicts for a shortened survival. World Health Organization (WHO) criteria require the presence of ≥20% circulating plasma cells (CPC) in the peripheral blood, and an absolute plasma cell count ≥2,000/µl (microliter). These criteria for PCL were established by Noel and Kyle in 1974, but subsequent studies to further validate this cut off are lacking. Since the presence of any plasma cells in the peripheral blood is now known to be a poor-risk feature, we sought to compare the overall survival of patients (pts) with any CPC observed on routine complete blood count (CBC) and differential with those that meet the WHO criteria of PCL. Methods We evaluated pts that received hyper-CVAD (cyclophosphamide /vincristine/doxorubicin/dex); CBAD (cyclophosphamide/bortezomib/doxorubicin/ dex), and DT-PACE (dexamethasone/thalidomide/ cisplatin /etoposide / doxorubicin/ cyclophosphamide) chemotherapy at The University of Texas M. D. Anderson Cancer Center for multiple myeloma from 2003-2012. We included pts with circulating blasts, plasma cells, or plasmacytoid cells regardless of the percentage (%) and absolute count. Pts were excluded if blasts or plasma cells were seen transiently in the setting of leukopheresis, growth factor support, or during severe sepsis. Overall survival (OS) was defined from the first detection of CPC until death due to any cause. We treated the % of plasma cells in the CBC as a continuous variable in the range from 1% to 20%. Pts with plasma cells below the cut off were defined as the “low” group and their survival was compared to the pts with plasma cells above the cut off that was defined as the “high” group. We conducted a log rank test for difference in survival curves between the two groups for each cut off, and the results were verified with a Cox model and both results were identical. Results 85 pts were identified with presence of any CPC or PCL diagnosed based on WHO criteria; 19 had primary PCL (pPCL) and 66 pts had secondary PCL (sPCL). At the time of diagnosis, 83 (2 with unknown values) pts had a median CPC of 4% and median absolute plasma cells of 178/µL. 73 pts had cytogenetic abnormalities by florescence in situ hybridization studies, including deletion/monosomy 13 in 32 pts, IgH gene rearrangement in 24 pts and TP53 deletions in 12 pts. 17/19 pts with pPCL received bortezomib based therapy and 14/19 underwent stem cell transplant. 26 pts met the WHO criteria of PCL at some point during their disease, including 11 who met criteria when plasma cells were first detected, and 15 who had CPC < 20% initially, but subsequently met WHO criteria.  Of the remaining 57 pts that did not meet the WHO criteria for presence of both absolute plasma cell count and % plasma cells, 13 met one of the criteria during the course of their disease. 44 pts had CPC but did not meet either of the WHO criteria. Survival data were available for 79/85 pts. Pts with pPCL (either by CPC or met at least one of the WHO criteria) had a median OS of 18.5 months. pPCL pts who only had CPC and did not meet either of the WHO criteria (n=5) had a median OS of 19 months; pPCL patients who met either or both of the WHO criteria (n=13) had a median OS of 18 months.  Pts with sPCL (either by CPC or met at least one of the WHO criteria) had a median OS of 5 months (n=61). sPCL pts who only had CPC and did not meet either of the WHO criteria (n=39) had a median OS of 5 months; sPCL patients who met either or both of the WHO criteria (n=22) had a median OS of 4 months. Based on evaluating plasma cell %  as a dichotomous factor with cut-off ranging  from 1% to 20%, there was no significant difference in overall survival based on specific levels of plasma cell percent, and verified with a Cox model, however with many cut-offs, the sample size was small potentially limiting analysis. Conclusion In our analysis of OS of pts having plasma cells in their peripheral blood, we did not find any statistically significant difference based on their degree of % plasma cells or absolute plasma cells at the time of diagnosis. This supports the hypothesis that, irrespective of quantity, the presence of any plasma cells in the CBC is a poor prognostic indicator, with a similar natural history and a uniformly poor OS. While these findings will need to be validated in a larger, independent dataset, we would propose that these initial data support redefining the diagnostic criteria of PCL to include any pt with CPC observed in a routine CBC. Disclosures: No relevant conflicts of interest to declare.

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