A Comprehensive Analysis of Cytogenetic Abnormalities in Myeloma: Results of the FISH Analysis of 1000 Patients Enrolled in the IFM99 Trials.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 622-622 ◽  
Author(s):  
Herve Avet Loiseau ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Catherine Charbonnel ◽  
Frederic Garban ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Mononuclear Cells ◽  
Chromosomal Abnormalities ◽  
Prospective Trial ◽  
High Dose ◽  
Fish Analysis ◽  
Therapeutic Trial ◽  
Prognostic Impact ◽  
The Impact

Abstract Because cytogenetics has been demonstrated to be the most powerful prognostic factor in many hematopoietic malignancies, we hypothesized that chromosomal abnormalities may also predict outcome in MM, as previously suggested by several reports. In order to test this hypothesis, we analyzed the main chromosomal abnormalities in a large series of 1000 patients with newly diagnosed MM, enrolled in the IFM 99 therapeutic trial. This trial enrolled 1083 patients under the age of 65, between May 2000 and December 2003. Briefly, the patients were treated by an induction therapy (4 VAD courses), followed by 2 courses of high-dose melphalan. In patients with less than 2 poor-prognosis factors (del(13) and b2m>3), a maintenance therapy was randomized (none vs pamidronate vs pamidronate + thalidomide). For all the patients, a fresh bone marrow specimen was shipped overnight to the central laboratory in Nantes. After separation of the mononuclear cells, malignant plasma cells were sorted using magnetic beads coated with an anti-CD138 monoclonal antibody. All the analyzed specimens presented a plasma cell purity > 90%. The patients were then analyzed by FISH for the following abnormalities: del(13q14), t(4;14), t(11;14), del(17p13), MYC rearrangements, hyperdiploidy (assessed by interphase FISH as previously reported), and 1q21 gains (CKS1B). Abnormalities were observed in 45%, 14%, 21%, 11%, 13%, 40%, and 40%, respectively, in agreement with previously reported incidences. We then looked at the prognostic impact of these chromosomal abnormalities, analyzing both the overall survival (OS) and the event-free survival (EFS). With a median follow-up of 32 months, t(11;14) and MYC rearrangements were not significant for both OS and EFS, and hyperdiploidy was marginally significant (p=.03, and .02 for EFS and OS, respectively, with a longer survival for hyperdiploid patients). In contrast, del(13), t(4;14), del(17p) and 1q gains significantly negatively impacted both EFS and OS (p<10−5, p=10−7, p<10−6, and p=10−3, respectively for EFS, and p<10−5, p=10−7, p=10−7, and p<10−3, respectively for OS). Further statistical analyses showed significant associations between del(13) and t(4;14) (p<10−12), and between del(17p) and del(13) (p<10−4), but not between del(17p) and t(4;14). Gains of 1q did not represent an independent prognostic factor in the multivariate analysis. A multivariate analysis including the chromosomal abnormalities, b2m, albumin, and CRP levels lead to a model with 3 factors: t(4;14), del(17p), and b2m>3. Three groups of patients can be identified with highly different outcomes: patients with b2m<3, without t(4;14) or del(17p) (35% of the patients), presenting very long OS, patients with either t(4;14) or del(17p), and b2m>3 (15% of the patients) with a median OS < 2 years, and the other patients (half of the cohort) presenting an intermediate prognosis. This analysis, performed on a very large cohort of patients treated in a prospective trial, strengthens the impact of chromosomal analysis in the prediction of survival for patients under the age of 65 treated with high-dose therapy. An updated analysis will be presented at the meeting.

Patients Under 50 Years of Age Do Not Present Specific Prognostic Characteristics: An IFM Study in 1897 Patients Under 65 Years of Age.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2837-2837
Author(s):  
Virginie Roland ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Claire Mathiot ◽  
Catherine Charbonnel ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Board Of Directors ◽  
Prognostic Value ◽  
Young Age ◽  
High Dose ◽  
Prognostic Impact ◽  
Prognostic Parameters ◽  
Advisory Committees ◽  
High Dose Melphalan ◽  
The Impact

Abstract Abstract 2837 Poster Board II-813 Age is a critical prognostic factor in many hematological malignancies. The reasons for this major prognostic impact are not univocal. For a large part, its prognostic value is in fact related to the therapy intensity tolerated by the patients. Because of frequent renal, hepatic, cardiac impairments, intensive therapies are not tolerated after 60 or 65 years, leading physicians to dramatically reduce treatment intensity in elderly patients. The question of a specific prognostic value of age in a more homogeneous population is an unresolved issue. In myeloma, it has been suggested that patients under 50 years of age presented more favorable features, explaining the better outcome observed in these patients (Ludwig et al., Blood 2008). However, the population was highly heterogeneous, treated both with conventional and intensive therapeutic strategies. In order to address this question, we reviewed the files of 1897 patients under 65 years of age, homogeneously treated within the IFM with high-dose melphalan, from 2000 to 2007. The median age was 56 years (range=23-65), the sex-ratio male/female was 54%. We addressed the issues of the prognostic impact of young age (<50), but also of older patients (60 to 65). The following prognostic parameters were tested: b2-microglobuline, high creatinine (>177 μmol/l), hypercalcemia, low hemoglobin (<10 g/dl), thrombocytopenia (<130 G/l), ISS, del(13), t(4;14), and del(17p). In the first comparison (<50 vs others), the only statistically different parameters were b2-microglobuline (p=.009) and ISS distribution (p=.004). All the other parameters were not significantly different. Similar results were observed in the second comparison (<60 vs 60-65). Only b2-microglobuline values (p=.0001) and ISS distribution (p<.0001) were different. These differences in b2-microglobuline levels probably reflect the decrease of glomerular filtration with age. We then looked at the impact of age on outcome. We found that patients under 50 years of age displayed a better overall survival than patients between 50 and 65 (p=.007), with no difference in PFS. We also found that patients between 60 and 65 presented a poorer outcome than younger patients (OS, p=0.002, EFS, p=0.01). However, when patients under 50 were compared with those between 50 and 60, no difference was observed, both for OS and EFS. Thus, in conclusion, young age is not a prognostic factor in multiple myeloma. In contrast, older age (60 to 65) remains an adverse prognostic parameters, even in patients treated with high-dose melphalan. Disclosures: Attal: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Integrated Glasgow Prognostic- and Cytogenetic Risk Score (CytoGPS) at Diagnosis Is a Strong and Independent Predictor of Survival in Transplant-Eligible Patients with Multiple Myelom

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4509-4509
Author(s):  
Hanno Maximilian Witte ◽  
Harald Biersack ◽  
Armin Riecke ◽  
Bastian Bonorden ◽  
Svenja Kopelke ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Clinical Outcome ◽  
Risk Stratification ◽  
Independent Predictor ◽  
Prognostic Score ◽  
High Dose ◽  
Prognostic Impact ◽  
Group I ◽  
The Impact

Abstract Abstract Introduction: Immunity and inflammatory response impact tumor microenvironment and progression of malignancies. Metabolic and inflammatory parameters of the peripheral blood, and ratios of the latter, correlate with outcome in cancer patients. There exist several established inflammation-based scores of prognostic significance including the Glasgow-prognostic-score (GPS; integrating serum-CRP (>10 mg/L: 1pt) and albumin (< 35g/L: 1 pt). Methods: In this retrospective multi-center study we investigated the prognostic capabilities of an integrated scoring system including GPS and information on cytogenetic high-risk aberrations as determined by FisH (CytoGPS) in transplant-eligible MM patients as a complementary resource for risk-stratification. Patients with MM admitted to our institutions between January 2000 and July 2017 were screened and established prognostic factors were assessed. CytoGPS was calculated as conventional GPS score plus one additional point for high-risk cytogenetics. Statistical evaluation resulted in three significantly divergent groups in terms of clinical outcome (Group I: 0-1 pts.; group II. 2 pts.; III: 3 pts.). Characteristics significantly associated with OS or PFS were included in a proportional-hazard-model. The study was approved by the local ethics committee. Results: Following initial assessment we identified 212 eligible and fully evaluable as well as transplant eligible patients. Centralized review of pathology and cytogenetic reports was conducted and central hematopathology assessment was performed in 163/212 (76.9%) cases. All patients included in the study proceeded to high-dose melphalan and subsequent autologous stem cell transplantation. Median age at diagnosis was 59 years (range 35 - 76 years) with a median follow-up of 76 months. Mean GPS was 0.849, with a mean CytoGPS of 0.472. Multivariate analysis revealed ISS (HR = 1.677, 95% CI = 1.035 - 2.716, p = 0.036) and CytoGPS but not R-ISS to be the only independent predictors of OS and CytoGPS constituted the only independent predictor of PFS (OS: HR = 2.172; 95% CI = 1.607 - 2.936 p = 0.001; PFS: HR = 1.517; 95% CI = 1.174 - 1.960, p = 0.001). The impact of CytoGPS on OS and PFS is presented in Figure 1. Discussion: There is growing evidence stating a drastic impact of systemic inflammatory scores and cytogenetic data on clinical outcome in various malignancies including lymphoma and solid tumors. Our data show that baseline CytoGPS, integrating both these aspects, correlates with rates of relapse and refractory disease across all primary stages of MM in transplant-eligible patients. Upon multivariate analysis these effects were preserved with prognostic impact beyond established prognosticators. CytoGPS constitutes a promising means of risk-stratification in MM requiring further validation. Acknowledgments The authors would like to thank Mr. Jan Kroenke (ASH-Member) for the sponsorship of this abstract. Figure 1: Overall and Progression-free Survival in transplant-eligible Multiple Myeloma patients according to CytoGPS (Log-rank: A: p < 0.0001, B: p = 0.0001). Disclosures No relevant conflicts of interest to declare.

scholarly journals Impaired Nodal Shrinkage and Apoptosis Lacking Define the Adverse Independent Clinical Outcome of NOTCH1 mutated Chronic Lymphocytic Leukemia (CLL) Patients in the Age of Targeted Agents (TA)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1744-1744
Author(s):  
Giovanni Del Poeta ◽  
Annalisa Biagi ◽  
Annalisa Chiarenza ◽  
Luca Laurenti ◽  
Federico Pozzo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Clinical Outcome ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Real Life ◽  
Independent Prognostic Factor ◽  
Prognostic Impact ◽  
The Impact

The advent of agents inhibiting the BCR-associated kinases (ibrutinib and idelalisib) and the antiapoptotic protein Bcl-2 (venetoclax) has dramatically changed treatments algorithms of CLL as well as the role of different adverse prognosticators. The marked benefit of these new drugs has been investigated in the context of NOTCH1 mutations (M). In fact, NOTCH1 M were significantly correlated with CD49d overexpression identifying CLL with reduced lymphocytosis and inferior nodal response (Tissino, 2018). Moreover, NOTCH1 M were characterized by overexpression and increased activity of the NF-kB pathway genes, promoting tumor cell proliferation and survival (Benedetti, 2017). The primary aims of our clinical research were: i) to correlate NOTCH1 M with CD49d expression and bax/bcl-2 ratio in ibrutinib-treated patients; ii) to verify the impact of NOTCH1M on the peripheral lymphocytes redistribution and on the nodal response calculated as percentual reduction from baseline (SPD); iii) to evaluate the impact of NOTCH1 M on overall response rate (ORR), progression free survival (PFS) and overall survival (OS); iiii) finally, to assess NOTCH1 M as an independent prognostic factor. Therefore, we evaluated the efficacy of ibrutinib as single agent, in a real-life contest, on 180 patients recruited from three independent cohorts from Italy, median age 69 years (36-90), median number of previous regimens 2 [range 0-4; 26 patients (14.4%) previously untreated]. Noteworthy, 24/64 (37.5%) TP53 mutated patients were treated in first line with ibrutinib (p<0.0001). Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Median follow up on TA was 25 months. NOTCH1 M were investigated with next generation sequencing (NGS) method. CD49d antigen was evaluated by flow cytometry and the threshold of positivity was set >30%. Bax/bcl-2 ratio, evaluated in 113 patients, was calculated by flow cytometry, dividing mean florescence intensity (MFI) of bax by MFI of bcl-2 on CLL cells. The threshold of positivity was set at the median value >1.5 (range 0.41-5.10). Sixty-five patients were NOTCH1 M (36.11%). NOTCH1 M were strongly correlated both with CD49d >30% (51/65; p=0.0001) and bax/bcl-2 ratio <1.5 (34/38; p=0.00007). Absolute lymphocyte counts (ALCs) were collected at days ranging from 30 to 90 on ibrutinib. NOTCH1 M were correlated with significant lower median ALCs than all other patients (10.7 x 106/ml vs 31.0 x 106/ml; p=0.0003). Moreover, the median SPD, calculated at 3-6 months on ibrutinib, was lower in NOTCH1 M patients (53% vs 80%; p<0.0001), confirming a significant poor nodal response. ORR was 90% [complete response (CR): 18%, partial response (PR): 28%, PR with lymphocytosis (PR-L): 44%]. The estimate 2-year PFS and OS were 80% and 84%, respectively. Sixty nine patients (39%) discontinued ibrutinib either for progression (n=38) or for adverse events (n=31). With regard to clinical outcome, NOTCH1 M were significantly correlated with PR and PR-L (30/65 and 22/65, respectively; p=0.00002). Moreover, NOTCH1M were significantly associated with disease recurrence (23/38; p=0.0005). Significant shorter PFS and OS were observed in NOTCH1 M patients (36% vs 84% and 58% vs 84% at 3 years, respectively; p<0.0001 and p=0.00075; Figure 1A and 1B). Thirty-seven patients underwent subsequently venetoclax [13 for toxicity (grade 3 or 4 WHO) and 24 for progression]. OS for this subgroup was 70% at 3 years (Figure 1C). In multivariate analysis of PFS, including previous chemotherapy regimens, NOTCH1, TP53 and IGHV status, NOTCH1 was confirmed as an independent prognostic factor (p=0.0002) together with TP53 (p=0.003). On the other hand, in multivariate analysis of OS, NOTCH1 remained as an independent prognostic factor (p=0.009) together with previous therapy (p=0.013) and TP53 (p=0.019). In conclusion, NOTCH1M are characterized by resistance to apoptosis, lower peripheral lymphocytosis and lower nodal shrinkage, all responsible for partial responses, subsequent relapses, shorter PFS and OS under ibrutinib treatment. The prognostic impact of NOTCH1 M on patients treated subsequently with venetoclax is unclear due to the low number of our cases (Roberts, 2019). Probably the therapeutic answer for NOTCH1 M patients could come either from TA combination approaches or from new gamma-secretase inhibitors or also from new antibodies targeting NOTCH1. Disclosures No relevant conflicts of interest to declare.

Time to Post-Remission Therapy (PRT) Is an Independent Prognostic Factor for Relapse and Overall Survival in Adults with Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1883-1883 ◽  
Author(s):  
Anjali Advani ◽  
Tao Jin ◽  
Ramon Tiu ◽  
Giridharan Ramsingh ◽  
Christopher Lowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Univariate Analysis ◽  
Independent Prognostic Factor ◽  
High Dose ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Poor Risk ◽  
The Impact

Abstract Only 30% of adults with ALL are cured. The identification of modifiable prognostic factors is important in designing future treatment paradigms, and improving the outcome of patients. PRT is integral in the treatment of ALL, and eradicates minimal residual disease (MRD) after complete remission (CR) has been achieved with induction chemotherapy (IC). Decreasing the time from the start of IC to the initiation of PRT may improve prognosis by eradicating MRD at an earlier stage, and preventing the development of resistant leukemic clones. The goal of this study was to retrospectively evaluate the impact of time from the start of IC to PRT, and determine whether or not this affects progression-free survival (PFS) and overall survival (OS). Methods: We retrospectively evaluated adults with newly diagnosed ALL treated at CCF between the years 1996–2005. 116 patients with ALL were seen. 57 patients were newly diagnosed and received IC and PRT. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, OS, relapse after remission, and PFS. Only variables significant in the univariate setting were included in multivariate analysis. Results were summarized as the hazard ratio (HR) with 95% confidence intervals (CI). The following variables were used in the analysis: pre-treatment characteristics (age, WBC, cytogenetic (CG) risk group, LDH), time to WBC recovery (time from the initiation of IC to an ANC of 500 after IC), CD20 expression, and time from the initiation of IC to start of PRT. CG risk was defined by CALGB criteria. Results: Characteristics at diagnosis: median age of 38 years [range 16–72], median LDH 673 U/L [112–5753], and median WBC 17.8 × 103/L [1.2–364]. 33.6% of patients had poor risk CG, 22.4% normal CG, 15% miscellaneous, and 29% unknown. Most patients received a vincristine/prednisone based IC (88%). However, 12% received high dose cytarabine/mitoxantrone IC. The CR rate was 75.3% for patients age < 60, and 60% for age ≥ 60. Median disease-free survival was 20.2% at 5 years. The median time from IC to PRT was 7.0 weeks [4.1–17.0]. On univariate analysis, increased age and increased time to WBC recovery were associated with a lower CR rate. Age and time from IC to PRT (per week increase (PWI)) [HR 1.17(CI 1.04–1.32), p=0.009] were significant predictors for relapse after remission. Increased age, poor risk CG, and time from IC to PRT (PWI) [HR 1.13(1.02–1.25), p=0.024] predicted decreased PFS. All of these factors (including time to WBC recovery) predicted decreased OS, with time from IC to PRT (PWI) having a HR of 1.11[(1.01–1.23), p=0.039]. On multivariate analysis, there was a trend for longer time from IC to PRT (PWI) [HR 1.53(0.92–2.54, p=0.10] predicting decreased OS and increased chance of relapse (PWI) [HR 1.12(0.98–1.29), p=0.09]. When patients age > 60 and poor risk CG were excluded, time from IC to PRT (PWI) was the only factor associated with decreased OS [HR 1.34(1.08–1.67), p=0.009], PFS [HR 1.27(1.04–1.55, p=0.019)], and an increased chance of relapse [HR 1.26(0.99–1.61), p=0.06]. Conclusions: Strategies to improve the prognosis of ALL are needed. Time from IC to PRT is an independent prognostic factor for treatment outcome, and administering PRT on time may improve our outcomes in adult patients with ALL.

High-Resolution Genomic Profiles Identify Novel Genes and/or Chromosomal Regions with Prognostic and Oncogenic Significance in Myeloma Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 657-657
Author(s):  
Herve Avet Loiseau ◽  
Nikhil C. Munshi ◽  
Cheng Li ◽  
Florence Magrangeas ◽  
Wilfried Gouraud ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chromosomal Abnormalities ◽  
Global Analysis ◽  
Copy Number Variations ◽  
Response To Therapy ◽  
High Dose ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Free Survival ◽  
The Impact

Abstract Despite major improvements in the treatment of myeloma over the last decade, disease course is variable due to genetic heterogeneity. Even though cytogenetics is a difficult art in myeloma, chromosomal abnormalities are present in 100% of the patients. In order to define the spectrum of unbalanced chromosomal abnormalities in myeloma, we studied a cohort of 200 patients ≤ 65 years of age, homogeneously treated with high dose chemotherapy in the IFM 99 trials, using the Affymetrix 500K SNP arrays. Bone marrow was obtained at diagnosis, and plasma cells were sorted using anti-CD138-coated magnetic beads. In all cases, a plasma cell suspension with a purity > 90% was obtained, and DNA was extracted using standard methods. After labeling, DNA was hybridized on the two Nsp and Sty chips, containing 260,000 SNP each. As expected, copy number variations were observed in all the cases. The most frequently involved chromosomes were chromosomes 13, 16, 1, 8 and 6. We then performed a prognostic analysis to correlate survival and chromosomal abnormalities. Many previously unreported chromosomal regions were identified; for example, 89 deleted chromosomal regions as well as 53 regions present in > 2.5 copies were associated with a survival < 3 years. Among the deleted regions with prognostic impact, the most frequent were 1p, 12p, and 4q. The most frequently gained regions associated with overall survival were 1q, 8q, and chromosomes 7 and 21. A similar analysis was performed for association with event free survival (EFS). Losses at 11q, 4q, and 12p were highly predictive of a short EFS, whereas gains of chromosome 15 predicted a longer EFS. Global analysis revealed a marked heterogeneity in the gains observed in hyperdiploid karyotypes, explaining the inconsistency in the literature regarding the prognostic value of hyperdiploidy. A more detailed analysis identified more than 80 genes presenting a double deletion, suggesting their role as putative tumor suppressor genes. This study represents the largest cohort of patients analyzed with such high-density arrays, enabling the description of a highly confident landscape of chromosomal abnormalities in myeloma. Moreover, since all the 200 patients were treated with a similar high-dose regimen, it allows powerful statistical analysis of the impact of chromosomal gains and losses on response to therapy, event free survival and overall survival. Finally, since all the patients were also annotated for other prognostic parameters such as t(4;14) or beta2-microglobulin, a multivariate prognostic model will be presented.

Deletion 13, Detected by Metaphase Analysis, Is Not a Significant Prognostic Indicator In Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2980-2980
Author(s):  
Fiona M. Ross ◽  
Laura Chiecchio ◽  
GianPaolo Dagrada ◽  
William J Tapper ◽  
Zoe J Konn ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Poor Prognosis ◽  
Conflicts Of Interest ◽  
Phase Iii ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Abnormal Karyotype ◽  
Randomized Controlled ◽  
The Uk ◽  
The Impact

Abstract Abstract 2980 Introduction: Deletion of chromosome 13, detected by conventional chromosome analysis (CC), has been suggested to be an independent indicator of poor prognosis in myeloma (MM). With the exception of a single study using conventional therapy this has not been confirmed in multicenter randomized controlled trials which have mostly used FISH analysis. We set out to assess the prognostic value of del(13) and compare its detection by FISH and CC. Methods: We have examined the effect of del(13) in a large multicenter randomized controlled phase III trial, MRC Myeloma IX (ISRCTN68454111), which tested the effect of induction therapy with a thalidomide combination in both an intensive (CTD vs CVAD prior to single HDM plus ASCT) and a non-intensive (CTDa vs MP) setting. From June 2003 to November 2007 samples from newly presenting MM patients were sent from hospitals throughout the UK to a central laboratory where CD138 purification for FISH was performed, with conventional cytogenetic culture(s), using unpurified cells, being set up wherever possible. Results: 1960 evaluable patients were entered into the trial (1111 intensive, 849 non-intensive) of which 1036 were evaluable for del(13) by FISH (613 intensive, and 423 non-intensive); del(13) was seen in 45% (470/1036) with a similar incidence in both pathways. With a median follow up of 3.7 years del(13) detected by FISH was associated with impaired OS (median, 42 vs 52 mo, p=0.004). The effect was stronger in the non-intensive pathway (median OS 25 vs 37 mo, p=0.001) than in the intensive one (median 58 mo vs not reached, p=0.095). However, this adverse prognostic impact was negated when the strong association of del(13) with the bad prognosis IGH translocations t(4;14), t(14;16) and t(14;20) (bad IGH) was taken into account. In comparison, 639 patients were evaluable for CC results (378 intensive, 261 non-intensive) with an overall abnormality rate of 35% (224/639). We note that the impact of detecting any abnormal karyotype was not significantly different from a normal/failed karyotype irrespective of intensive or non-intensive treatment being used (whole trial p=0.213, intensive p=0.249, non-intensive p=0.252) suggesting that the capacity to generate abnormal metaphases alone is not an adverse prognostic factor. Del(13) was seen in 45% of abnormal karyotype cases (102/224) and 16% of all cases tested for CC. Overall the detection of del(13) by CC was associated with an adverse prognostic effect on OS (median 34 vs 47 mo, p=0.039). However, the entire effect was in the non-intensive pathway (median 20 vs 34 mo, p=0.018) (Fig1A), with no detectable effect in the intensive pathway (median 69 vs not reached, p=0.679) (Fig1B). We addressed the impact of the treatment used, and in a comparison of the thalidomide and non-thalidomide regimes for all del(13) CC patients there was no significant impact on OS (p=0.538). However, in the non-intensive pathway there was a significant improvement in favour of thalidomide (median 33 vs 18 mo p=0.03). Multivariate analysis of the prognostic impact of genetic factors within abnormal metaphases showed that bad IGH (p=0.001), gain of 1q (p=0.001) and deletion of 17p (p=0.001) were the only independent prognostic factors. In further analyses including all FISH-detected abnormalities, the markers bad IGH (p<0.001) and 1q gain (p<0.001) retained statistical significance when ISS, performance status and age were added into the model. Conclusions: We demonstrate that in a large multicenter trial carried out across the UK del 13 detected by FISH does not have adverse prognostic impact if its association with the poor prognosis translocations is taken into account. Similarly del(13) detected by CC is not an independent prognostic factor when bad IGH and gain of 1q are taken into acount. The trial shows that thalidomide improves the outcome for del(13) by CC in patients treated with conventional dose therapy. However, this beneficial effect of thalidomide is not enough to account for the lack of independent significance of this marker across the study. On the basis of these results we cannot recommend the use of conventional cytogenetic testing methods as a routine for patients entered into multicenter clinical trials. Disclosures: No relevant conflicts of interest to declare.

Secondary Chromosomal Abnormalities Appear to Be Less Prognostic for Children with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with Intensified Imatinib and Chemotherapy: Results of the Children's Oncology Group (COG) Study AALL0031.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2606-2606
Author(s):  
Andrew J. Carroll ◽  
Nyla A. Heerema ◽  
Meenakshi Devidas ◽  
W. Paul Bowman ◽  
Chenguang Wang ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Board Of Directors ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
High Dose ◽  
Unrelated Donor ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
The Impact

Abstract Abstract 2606 Poster Board II-582 Background: Secondary chromosomal aberrations at diagnosis occur frequently in both pediatric and adult patients with Ph+ ALL. Several studies have shown that the presence of additional cytogenetic abnormalities is a major negative prognostic factor among children and adults with Ph+ ALL. A Japanese study in adults with Ph+ ALL indicated that the adverse prognostic significance of secondary rearrangements was seen even in patients treated with imatinib-combined chemotherapy including consolidation with blood and marrow transplantation (BMT) (Haematologica 92:287, 2008). Two-year EFS in that study was 48.5±5.7%, and the 50 patients with secondary chromosomal abnormalities had a 35% - 40% lower EFS than those with t(9;22) only (p=0.003). COG AALL0031 treated children with imatinib in combination with intensive chemotherapy. This study had an overall 3 year EFS of 80±11% for those receiving chemotherapy only, an outcome similar to those receiving allogeneic BMT. We evaluated the impact of secondary chromosomal abnormalities in children and adolescents receiving this regimen. Methods: Children and adolescents (age 1–21 years) with Ph+ ALL enrolled on AALL0031 after completing 3- or 4-drug induction therapy. Imatinib was given at 340mg/m2/day for an increasing number of days in combination with an intense chemotherapy backbone. Cohort 4 received imatinib for 126 (N=12) and cohort 5 for 280 continuous days (N=50) prior to maintenance therapy. The first two cycles of the intensive chemotherapy included ifosfamide and etoposide (cycle 1) and high dose (HD) methotrexate and HD cytarabine (cycle 2). Patients were non-randomly assigned to an HLA-identical related donor BMT, if a donor was available, or to an intensive chemotherapy regimen that continued for approximately 2.2 years. Unrelated donor BMT was not allowed; these patients were taken off protocol but included in survival evaluation by an intent-to-treat evaluation. Results: Satisfactory cytogenetic results were available for 71 (76%) of 93 enrolled children. Secondary aberrations were present in 46 (65%) patients. The most frequent secondary aberrations were +der(22) (N=21), =50 chromosomes (N=14), −7/del(7p) (N=11), abnormal (9p) (N=7), and +8 (N=5). The overall 3 year CCR was 79±6% for patients in cohorts 4/5, including those with non evaluable cytogenetics (N=55). When outcome analyses were limited to Ph+ ALL patients in cohorts 4/5 (N=43), three-year CCR for patients with Ph+ alone (N=14) was 86±10% versus 71±9% for those with Ph+ and secondary abnormalities (N=29) (p=0.19). Conclusions: In this study, the lower 3 year CCR seen in patients with Ph+ ALL with secondary chromosomal abnormalities was not significantly different than for children with Ph+ alone possibly reflecting small patient numbers. The lower 3 year CCR for Ph+ ALL with secondary chromosomal abnormalities in those treated on AALL0031 (∼15% lower) appeared to be less than that seen in the previous adult trial (∼35%). This may be the result of the addition of imatinib to intensified chemotherapy reducing the poor prognostic significance of additional chromosome abnormalities seen in previous studies. Larger patient numbers and longer follow-up will be necessary to answer this question. Disclosures: Schultz: DOR Biopharma: Membership on an entity's Board of Directors or advisory committees; Genzyme Canada: Membership on an entity's Board of Directors or advisory committees.

Detection of 13q14 Deletion by FISH Is Not Sufficient to Define a Group of Good Prognosis Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2332-2332
Author(s):  
Virginie Eclache ◽  
Vincent Levy ◽  
Fanny Baran-Marszak ◽  
Remi Letestu ◽  
Florence Cymbalista
Keyword(s):  
Prognostic Markers ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Large Cohort ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Trisomy 12 ◽  
Conventional Cytogenetics ◽  
The Impact ◽  
13Q Deletion

Abstract Abstract 2332 Poster Board II-309 Deletion of a 13q14.3 region is by far the most common genomic alteration in CLL. In a large cohort of CLL patients, the presence of deletion 13q as sole anomaly detected by FISH was predominantly found in Binet stage A CLL and associated with a favorable outcome (Dohner et al., N Engl J Med 2000). Further studies have evidenced some heterogeneity among CLL cases with 13q deletion, such as the size of the clone carrying the deletion, the existence of mono versus biallelic deletions, and the presence of other concomitant genetic aberrations. Therefore, we aimed at analysing the impact of this heterogeneity on the prognostic value of 13q14 deletion (del13q) in CLL. Patients and methods In a cohort of 329 previously untreated newly diagnosed stage A CLL, we detected del13q by FISH in 172 patients (52%) using the D13S319 probe. Conventional cytogenetics was performed in the 105 cases with del13q followed in our institution. The other important prognostic markers ( ZAP70, IgVH, CD38, proliferation markers) and clinical progression were also available for all patients. Results We first studied the large cohort of stage A patients and found that deletion 13q had no prognostic impact on PFS. When considering more specifically the presence of deletion 13q as sole anomaly (n=143), PFS was not significantly different from that of patients with no aberration detected by FISH analysis (del 13q, del11q, del17p and trisomy 12) (n=98). Moreover, the distribution of prognostic factors (ZAP70, sTK, mutational status, CD38 expression, lymphocytosis) was not statistically different among these two groups. We aimed at deciphering further these del13q cases through analysis of the percentage of deleted cells, the presence of mono versus biallelic deletions, and the presence of additional aberrations as detected by FISH and conventional cytogenetics in the 105 del13q cases followed in our institution. The size of the del13q clone, as reflected by the percentage of del13q cells by FISH, was highly variable, ranged from 7 to 90 %, and had no prognostic significance on PFS. Monoallelic deletions were present in 77 cases, fully biallelic deletions in 9 cases, and concomitant bi and monoallelic deletions in 19 cases. The 9 cases with biallelic deletions had a significantly shorter PFS and were associated with other unfavorable prognostic markers. As biallelic deletions are most likely to represent progression from monoallelic cases, it is understandable that no clear prognostic impact was evidenced between cases with monoallelic deletions and with concomitant variable amount of bi and monoallelic deleted cells. Twenty cases (20 monoallelic and 6 biallelic) were further studied by array-CGH. Minimal deleted region (MDR) was included in all deletions but the size of the deletion was variable and in most cases much larger than MDR. Among the 6 bi allelic cases, one of the deletions was restricted to the MDR in all cases, pointing out to the importance of the level of miRNA expression. Additional aberrations were found in 44/105 del13q cases. In 17 patients, one or more alterations were detected by FISH techniques : del11q (n=8), trisomy 12 (n=8) or del17p (n=5). By conventional cytogenetic all these aberrations were also detected, as well as other rare ones in 16 additional cases, either isolated or associated in a complex karyotype in 5 cases. Presence of additional aberrations had a significant unfavourable impact on PFS, even when excluding del11q, del17p and tri12, and considering the non recurrent aberrations that were detected by conventional cytogenetics only. Conclusion Presence of 13q deletion should not be considered as a good prognostic marker by itself among stage A patients. Moreover, del13q cases are highly heterogeneous, and the presence of deletion 13q should not be interpreted without considering both alleles or the presence of concomitant genetic alterations. Disclosures: No relevant conflicts of interest to declare.

The Interaction of Response and FISH-Based Risk Stratification to Better Define Clinical Outcome in Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1823-1823
Author(s):  
Kevin D Boyd ◽  
Fiona M Ross ◽  
Mark T Drayson ◽  
Roger G Owen ◽  
Alex J Szubert ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Factor ◽  
Induction Therapy ◽  
Response Rates ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Important Prognostic Factor

Abstract Abstract 1823 Background: The achievement of a complete response (CR) is an important prognostic factor in myeloma. The international staging system (ISS) and tumor genetic lesions detected by FISH also impact survival. It is not known whether response rates are adversely affected by these factors, whether achieving CR overcomes the adverse prognosis associated with these factors, or if achievement of CR is more important in a specific biological subgroup. We have examined the importance of CR in the context of these other prognostic factors in the intensive arm of a phase III randomized trial, MRC Myeloma IX, in which all patients were planned to proceed to autologous stem cell transplant (ASCT) after induction. Patients and Methods: Patients were randomized to a conventional or thalidomide-based induction regimen followed by ASCT, with a second randomization to maintenance thalidomide versus no maintenance. Response was assessed after completion of induction therapy and 100 days post-ASCT. iFISH was performed on diagnostic bone marrow samples and genetic lesions associated with adverse progression free survival (PFS) were defined as t(4;14), t(14;16), t(14;20), +1q and 17p-. Results: To confirm that CR was prognostically important in the data set, patients with a CR at 100 days post-ASCT (N=355) were compared to non-CR (N=344) (comprising VGPR, PR and SD). CR was strongly associated with improved PFS (median 30.8 months vs 38.7 months, P<0.001) but was not associated with improved OS at median follow-up of 3.7 years. Response rates were assessed in the context of other prognostic factors. Interestingly, the presence of high risk FISH lesions was not associated with impaired CR rates following induction therapy (P=0.584) or following ASCT (P=0.314). Patients without adverse genetic lesions had a CR rate of 11.1% post-induction which improved to 48.3% post-ASCT. In comparison, patients with adverse FISH lesions had a 13.3% CR rate, rising to 44.9% post ASCT. Similarly, there was no correlation between ISS stage and response. The absence of adverse FISH lesions (hazard ratio (HR) 2.68 (1.94-3.70) P<0.001) and achievement of CR (HR 1.58 (1.15-2.17) P=0.005) were independently associated with improved PFS in multivariate analysis. The prognostic impact of achieving CR was assessed in various prognostic groups. CR was associated with improved PFS in patients with no adverse FISH lesions (N=179)(median PFS 58.4 vs 37.1 months, P=0.031), and in ISS I (N=182)(median PFS 51.2 vs 33.2 months, P=0.008). In patients with adverse FISH lesions, and in ISS II and III, there was a trend towards improved PFS with CR that was not significant. For patients achieving CR as their maximum response (N=398), in a multivariate analysis including the ISS, the presence of high risk FISH lesions was the most significant factor associated with impaired PFS and OS. Patients with more than 1 adverse FISH lesion were associated with an especially high risk of progression or death (PFS HR 6.63 (3.23-13.53) P<0.001; OS HR 5.35 (1.98-14.45) P=0.001). Conclusion: These data show that attainment of CR is an important prognostic factor associated with improved PFS in patients treated with ASCT, and this benefit was most significant in patients with favorable prognostic factors such as lack of adverse FISH lesions and ISS I. The presence of t(4;14), t(14;16), t(14;20), +1q or 17p- was also strongly associated with PFS, and the impaired outcome associated with these adverse genetic lesions was not overcome by achievement of CR, within the context of the therapies used in this trial. The presence of more than 1 adverse FISH lesion identified a patient group with an especially poor prognosis, despite achieving CR. However, CR rates within these high risk patients were similar to patients without adverse genetic features, showing that they were sensitive to chemotherapy, but progressed quickly after therapy was stopped. The implication of these data is that it may be possible to improve the poor outcome of this genetically-defined high risk group with an alternative treatment strategy aimed at maintaining these responses. Disclosures: Gregory: Celgene: Honoraria. Child:Celgene: Honoraria.

High-Risk Cytogenetics and Persistent Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) Predict Unsustained Complete Response (CR) After Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 630-630
Author(s):  
Bruno Paiva ◽  
Norma C. Gutierrez ◽  
Laura Rosiñol ◽  
María-Belén Vidriales ◽  
María-Angeles Montalbán ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Fish Analysis ◽  
Fish Cytogenetics ◽  
Cytogenetic Abnormalities ◽  
High Risk Disease ◽  
Standard Risk

Abstract Abstract 630 The achievement of CR after high-dose therapy/ASCT (HDT/ASCT) is a surrogate for prolonged survival in MM. While this is well accepted, the long-term clinical outcome of MM patients achieving CR is still heterogeneous and a small fraction of patients unexpectedly lose their CR status early on after HDT/ASCT and experience a dismal survival. In fact, survival of patients with unsustained CR is even poorer than that of those not achieving CR. Herein we sought to identify prognostic markers predictive of unsustained CR after HDT/ASCT. The study included a total of 241 patients achieving CR at day+100 after HDT/ASCT treated in two consecutive GEM/PETHEMA trials: GEM2000 (VBMCP/VBAD, n=140) and GEM2005<65y (randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; N=101). All cases were referred for MRD assessment by MFC at day+100 after HDT/ASCT; baseline FISH analysis were available in 110 of the 241 patients. We first investigated which of the most relevant disease characteristics had prognostic influence in patients in CR at day+100 after HDT/ASCT. In this cohort some markers with consistent influence in unselected MM populations such as patient age, ISS stage, serum β2-microglobulin, BMPC burden and % of PC in S-phase were not significantly predictive. In contrast, the presence of baseline anemia was a significant prognostic marker for OS (P=.01). Regarding cytogenetics, 16% of CR patients were considered with high-risk disease at presentation and showed a significantly inferior TTP (3-years, 40% vs 79%; P=.001) and borderline OS (3-years, 73% vs 96%; P=.07) compared to cases with standard-risk. In addition, MFC immunophenotyping showed persistent MRD in 87 of the 241 (36%) CR patients, and the failure to achieve an immunophenotypic CR at day+100 after HDT/ASCT resulted in significantly inferior TTP (3-years, 58% vs 85%; P<.001) and OS (3-years, 80% vs 90%; P=.001). In the multivariate analysis, the best combination of independent predictive parameters for TTP were immunophenotypic CR status (P<.001;HR=7.1) and FISH cytogenetics (P<.001;HR=5.6); in turn, for OS immunophenotypic CR status (P=.001;HR=7.7), FISH cytogenetics (P=.01;HR=5.1) and age ≥60 years (P=.03;HR=3.4) were selected. We further explored the clinical impact of the immunophenotypic CR in the context of standard-risk and high-risk disease. The best prognosis was for patients with both standard-risk cytogenetics and in immunophenotypic CR (3y: TTP, 92%; OS, 100%), while the worst outcome occurred in cases with both high-risk disease and persistent MRD (3y: TTP, 0%; OS, 32%). The two other categories had an intermediate prognosis, although it was better for patients with high-risk cytogenetics achieving an immunophenotypic CR (3y: TTP, 69%; OS, 100%) than for patients with standard-risk disease but failing to achieve an immunophenotypic CR after HDT/ASCT (3y: TTP, 57%; OS, 90%). We then investigated the parameters that could help to identify patients in CR at risk of early relapse after HDT/ASCT. Of the 241 patients, 30 (12%) progressed within 1 year after HDT/ASCT (unsustained CR) and this subgroup showed a dismal outcome, with a median OS of only 39 months (P<.001). Patients with unsustained CR showed significantly higher incidence of anemia at baseline (48% vs 24%, P=.01), advanced ISS stage 2 or 3 (86% vs 55%, P=.003), high-risk cytogenetics (40% vs 10%, P=.005) and persistent MRD by MFC (63% vs 32%, P=.001) compared with the remaining cases. At the multivariate analysis, only cytogenetic abnormalities (P=.002;HR=12.5) and the immunophenotypic CR status at day+100 after HDT/ASCT (P=.001;HR=8.8) emerged as independent predictive markers for unsustained CR. Based on these two variables, we established a predictive index by assigning one point for each adverse factor. Accordingly, 3 risk groups of patients in CR after HDT/ASCT were defined, with significantly (P<.001) different rates of disease progression within the first year after HDT/ASCT for patients with none, one, or both risk factors (7%, 20% and 100%, respectively; Figure). Our results show that the baseline evaluation of cytogenetic abnormalities combined with response assessment by MRD after HDT/ASCT can discriminate a subset of CR patients with a dismal outcome who should be candidates for novel treatment strategies after HDT/ASCT. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria.

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