ID1 Expression Correlates with CEBPA Mutational Status and Is Not An Independent Risk Factor in Cytogenetically Normal AML,

Abstract Abstract 3554 Background: Acute myeloid leukemia with normal karyotype (CN-AML) is a heterogenous disease. During the last years, mutations in several genes (e.g. NPM1, FLT3, CEBPA, WT1, IDH1, IDH2) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Moreover, deregulated expression of genes such as MN1, BAALC, ERG and WT1 was demonstrated to be predictive of outcome in CN-AML. Recently, high expression of the ID1 gene was described as a negative prognostic factor in AML (Tang et al. Blood 2009, 114:2993–3000). Aims: We have shown that C/EBPα, a transcription factor encoded by the CEBPA gene, binds to a regulatory element in the promoter region of the ID1 gene and regulates ID1 expression in leukemic cells (Wagner et al. Proc Natl Acad Sci USA 2006, 103:6338–6343). Therefore, we wanted to analyze the prognostic impact of ID1 expression in CN-AML in the context of other molecular markers, in particular CEBPA mutations. Methods: ID1 expression was quantified normalized to ABL by real time RT-PCR in 269 patients (age 16–60 years) with CN-AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations in the genes NPM1, FLT3, CEBPA, WT1, IDH1 and IDH2. Median follow up was 79 months. Results: Expression of ID1 varied over a 3-log range. High expression of ID1 (ID1high, defined as > median expression level) was significantly associated with the presence of a FLT3 -ITD or an IDH2 mutation and WT1 wildtype. Moreover, ID1 expression was closely associated with CEBPA mutational status. Altogether, 41 patients (15%) harboured a CEBPA mutation (24 monoallelic and 17 biallelic mutations). ID1 expression in the CEBPA wildtype patients was significantly higher than in patients with monoallelic CEBPA mutations and these patients had a significantly higher ID1 expression compared to patients with biallelic CEBPA mutations (p = 0.001). ID1high patients had a trend to a lower complete remission (CR) rate (74% vs. 84%; p = 0.07), but in multivariate analysis only blast clearance on day 15 after induction 1, age and WT1 SNP rs16754 were independent predictors for the achievement of CR. In univariate analysis, ID1high patients had an inferior overall survival (OS) compared to patients with low expression (median OS 29 vs. 78 months, 5 year OS 39% vs. 53%, p = 0.026). ID1high status was an independent negative prognostic factor in multivariate analysis when analyzed together with NPM1, FLT3 -ITD, WT1, IDH1, IDH2, extramedullary disease and platelet counts (HR 1.51; 95% CI 1.06–2.19). However, when also CEBPA mutational status was entered into the model, ID1 expression lost its prognostic impact and the only independent prognostic factors were age, platelets, CEBPA mutations, NPM1 /FLT3 -ITD risk group and WT1 SNP rs16754. Likewise, ID1high patients had a trend to an inferior relapse-free survival (RFS; HR 1.36, 95% CI 0.96–1.93, p = 0.086) in univariate analysis. However, in multivariate analysis including CEBPA mutational status, ID1 expression had no impact on RFS and the only prognostic factors for RFS were NPM1 and CEBPA mutations and WT1 SNP rs16754. In CEBPA wildtype patients, ID1 expression had no impact on CR-rate, OS or RFS in univariate or multivariate analysis. Conclusions: CEBPA mutations seem to deregulate ID1 expression in CN-AML. Therefore, ID1 expression is not an independent prognostic factor in CN-AML. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Genomic Aberrations Dramatically Improve The Strong Prognostic Impact Of IGHV Mutational Status In Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.1370.1370 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1370-1370

Author(s):

Giovanni Del Poeta ◽

Dario Ragusa ◽

Francesco Buccisano ◽

Michele Dal Bo ◽

Luca Maurillo ◽

...

Keyword(s):

Prognostic Factors ◽

Sanger Sequencing ◽

Conflicts Of Interest ◽

Direct Sequencing ◽

Univariate Analysis ◽

Intermediate Stage ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Mutational Status ◽

Genomic Aberrations

Abstract CLL is a heterogeneous disease with patients (pts) experiencing rapid disease progression and others living for years without requiring treatment. Recently, next generation sequencing has revealed new molecular alterations, targeting the NOTCH1 and BIRC3 genes which occur in about 10% CLL at diagnosis and correlate with poor outcome. Given the possibility of targeting NOTCH1 and BIRC3 with drugs currently under development, the primary endpoints of our research were: 1) to determine overall survival (OS) upon IGHV, NOTCH1, TP53 and BIRC3 in univariate analysis; 2) to correlate these genomic aberrations with other biological or clinical prognostic factors, and finally 3) to confirm NOTCH1, BIRC3 and TP53 as independent prognostic factors. We investigated 475 pts with a median age of 65 years (range 33-89), whose 160 had low Rai stage, 301 intermediate stage and 14 high stage. NOTCH1 mutations (mut) were studied by ARMS PCR for c.7544-7545delCT and by Sanger sequencing of NOTCH1 exon 34. Mutations of TP53 were analysed by DNA direct sequencing, while BIRC3 disruption (disr) was studied by Sanger sequencing for mutations and by interphase FISH for deletions. All these alterations were studied at diagnosis or before any chemotherapeutic approach. NOTCH1mut and TP53mut pts were 52 (10.9%) and 36/475 (7.6%), respectively. Thirty four patients were BIRC3mut (7.2%) and 26 BIRC3 deleted (5.5%) for a total of 46 cases (9.7%) BIRC3disr. NOTCH1, TP53 and BIRC3 alterations were mutually exclusive. There were significant correlations between NOTCH1 (P<0.00001), TP53 (P=0.004), BIRC3 status (P=0.00004) and IGHV mutations. Concerning FISH cytogenetics (460 patients), a significant correlation (P<0.0001) was found between NOTCH1mut and trisomy 12 (20/62; 32%). TP53mut were strictly associated with del17p (15/25; 60%; P<0.0001), while BIRC3disr was found mainly within 11q22-q23 deletions subset (22/46;49%; P<0.0001). With regard to clinical outcome, 30 (83%) of 36 TP53mut pts (P=0.00009), 47 (90%) of 52 NOTCH1mut (P<0.00001) and 40 (87%) of 46 BIRC3disr pts had received chemotherapy at the time of analysis. Twenty nine NOTCH1mut (56%), 15 TP53mut (42%) and 18 BIRC3disr (39%) pts underwent at least two lines of treatment (P<0.0001). Noteworthy, shorter OS was observed in IGHV unmutated (UM) patients (12% vs 80% at 18 years, P<0.00001), in NOTCH1mut pts (12% vs 71% at 16 years, P<0.00001), in TP53mut pts (9% vs 76% at 14 years, P<0.00001) and in BIRC3disr pts (29% vs 65% at 16 years, P=0.00001). To further explore the prognostic impact of NOTCH1mut, TP53mut and BIRC3disr, we investigated them within the UM (153 pts) IGHV subset, notoriously at worst prognosis. As a matter of fact, NOTCH1mut (16% vs 45% at 14 years, P=0.012), TP53mut (0% vs 43% at 13 years, P=0.002) and BIRC3disr (0% vs 57% at 11 years, P=0.011) pts showed significant shorter OS [Figure]. Within the mutated IGHV subgroup we obtained similar results. In multivariate analysis of OS, TP53mut (HR 5.2, P<0.00001), age >60 years (HR 3.8, P=0.00002), IGHV UM status (HR 0.30, P=0.0001), intermediate/high Rai stages (HR 2.8, P=0.0002), NOTCH1mut (HR 2.6, P=0.001), and BIRC3disr (HR 2.5, P=0.005) were confirmed to be independent adverse prognostic factors. Noteworthy, here, we demonstrated that genomic aberrations are able to improve the historical prognostic ability of the IgHV mutational status. In conclusion, genomic aberrations, particularly TP53mut, NOTCH1mut and BIRC3disr should be considered as novel important prognostic parameters in CLL and therefore they have to be necessarily considered in updated scoring prognostic systems. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Comprehensive Genetic Screening of Chronic Myelomonocytic Leukemias (CMML)

Blood ◽

10.1182/blood.v120.21.3811.3811 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3811-3811

Author(s):

Raphael Itzykson ◽

Olivier Kosmider ◽

Aline Renneville ◽

Margot Morabito ◽

Céline Berthon ◽

...

Keyword(s):

Multivariate Analysis ◽

Conflicts Of Interest ◽

Gene Dosage ◽

Univariate Analysis ◽

Continuous Variable ◽

Prognostic Impact ◽

Gene Dosage Effect ◽

Disease Evolution ◽

Mutational Status

Abstract Abstract 3811 Background: A large number of genes have been found mutated in CMML including 18 encoding signaling molecules (CBL, N/KRAS, JAK2, FLT3, KIT), epigenetic regulators (TET2, IDH1/2, DNMT3A, ASXL1, EZH2) transcription (RUNX1, NPM1) and splicing (SRSF2, SF3B1, U2AF1, ZRSR2) factors. We report the genotypic patterns, clinical correlates and prognostic impact of mutations in those 18 genes in a large cohort of CMML patients (pts). Methods: Bone marrow or peripheral CD14+ cells from 224 CMML pts from a non interventional study (n=186) or a phase II decitabine trial (n=38; Braun Blood 2011) were genotyped by mutation specific techniques and Sanger sequencing for up to 18 genes (depending on available material): TET2, IDH1, IDH2, DNMT3A, CBL, NRAS, KRAS, JAK2V617F, FLT3, KIT, NPM1, RUNX1, ASXL1, EZH2, SF3B1, SRSF2, U2AF1 and ZRSR2. The number of TET2 alleles with a functional Cystein Rich (CysR) domain (Delhommeau NEJM 2009) was predicted based on mutation type and zygosity, assuming that double mutations affect independent alleles. Overall (OS) and AML-free (AMLFS) survival were analyzed from the date of genotyping. Results: 224 CMML pts (152M/72F, median age 75y) were genotyped at diagnosis (37%) or after a median of 7.2 months of evolution (none had received hypomethylating agents [HMA] before genotyping); WHO diagnosis was CMML-1/2 in 78%/22%, 70% pts had normal karyotype, 22% had extramedullary disease (EMD); 13 pts had autoimmune manifestations (AIM). The most frequently mutated genes were TET2 (58%), SRSF2 (47%) and ASXL1 (38%). Mutations in RUNX1, CBL and NRAS were found in 14%, 11% and 10% of pts, respectively (resp). All other genes were mutated in <10% of pts. Only 5% pts lacked any mutation, and 70% had ≥2 mutated genes; TET2, IDH1 and IDH2 mutations, present in 64% of pts, were mutually exclusive. Mutations in splice and signaling genes were present in 63% and 35% of pts, with 2 mutated genes within each group in 3% and 2% pts, resp. ASXL1 mutations were less frequent in the presence of TET2 mutations (P<.0001). Significant mutual associations included ASXL1/RUNX1, ASXL1/NRAS, TET2/SRSF2, RUNX1/SRSF2 and U2AF1/IDH2. In multivariate analysis accounting for those interactions, TET2 status was the only independent predictor of hemoglobin values (median 10.2 vs 11.9 g/dL in wildtype [wt] vs mutated pts, P<.0001) with a gene dosage effect (P=.0003). Platelet counts were higher in JAK2V617F pts, and lower in pts with RUNX1, TET2 or SRSF2 mutations. WBC and monocyte counts were higher in pts with ASXL1 and NRAS mutations. EMD was associated to ASXL1, CBL, KRAS and JAK2 mutations. EMD, CMML-2 and abnormal karyotype were less frequent in TET2 mutated pts. All 13 pts with AIM had at least one mutated gene, with no specific genotype spectrum. With a median follow-up of 25.4 months, median OS and AMLFS were 32.2 and 28.0 months resp. In univariate analysis, OS was decreased in pts with IDH2 mutations (P=.04), and AMLFS was shorter in pts with NRAS (P=.04), RUNX1 (P=.03) and SRSF2 (P=.04) mutations. ASXL1 mutations markedly reduced OS (median 18.5 vs 35.7 months in wt pts) and AMLFS (median 12.5 vs 34.7 months, both P<.0001), with similar results in the 74 pts who received HMA during follow-up. In the 224 pts, there was no significant effect of overall TET2 status (wt vs mutated) on OS or AMLFS (both P=.09) but median OS was 29.3, 35.7 months and not reached in pts with 2 (57%), 1 (30%) and 0 (13%) TET2 alleles with a putatively functional CysR domain (P=.01). Similar differences were noted for AMLFS (P=.008). In multivariate analysis including peripheral blood counts, WHO classification, cytogenetics, disease evolution and therapy, ASXL1 was the only gene whose mutations independently predicted inferior OS (HR: 2.44, 95% CI: 1.36–4.37, P=.003)and AMLFS (HR: 2.54, 95% CI: 1.46–4.42, P=.001); SRSF2 mutations only predicted inferior AMLFS (HR: 2.05, 95% CI: 1.15–3.65, P=.02). The total number of mutated genes as a continuous variable, which was higher in ASXL1 mutated pts (mean 3.0 vs 1.8, P<.0001), was the only genetic variable to retain prognostic value when added to those models (OS and AMLFS both P<.0001). Conclusion: TET2, SRSF2 and ASXL1 are the most frequent mutated genes in CMML. The number and location of TET2 mutations may impact CMML presentation and outcome. The total number of mutated genes has the strongest prognostic relevance, but ASXL1 mutational status provides a robust surrogate prognostic marker for daily practice. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v118.21.1823.1823 ◽

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.

Download Full-text

FLC Assay and Multiparameter Flowcytometry Based Clonal Plasma Cell Measurement Are Independent but Complementary in Assessing the Treatment Response in Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.2969.2969 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2969-2969

Author(s):

Hiroki Sugihara ◽

Kenji Tsuda ◽

Tomotaka Ugai ◽

Yuki Nishida ◽

Masayuki Yamakura ◽

...

Keyword(s):

Prognostic Factor ◽

Partial Response ◽

Plasma Cell ◽

Cox Regression ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Response To Treatment ◽

Rank Test ◽

Multiparameter Flow Cytometry ◽

Prognostic Impact

Abstract Abstract 2969 Purpose: Although stringent complete response (sCR) defined by paraprotein negativity on immunofixation and serum free light chain (sFLC) ratio normalization are considered deeper responses in the IMWG criteria, recent report indicated that Multiparameter flow cytometry (MFC)-dased immunophenotypic response (IR) is a more relevant prognostic factor in MM patients. However, data on the prognostic impact of IR and sFLC ratio (sFLCκ/λ) normalization are still scarce. We investigated the prognostic impact of IR and sFLCκ/λ normalization in MM patients treated with novel agents. Patients and Methods: A total of 124 consecutive patients (M:F=68:56; median age, 71 yr) were treated by chemotherapy regimens containing at least one novel agent (thalidomide, bortezomib, lenalidomide)from April 2005 to May 2012. Treatment responses were assessed using the IMWG criteria, and the best response to treatment during the clinical course was assessed by simultaneous serum immunofixation, sFLC measurements, and MFC analysis of bone marrow (BM) plasma cells. Normalization of sFLCκ/λ was defined 2 consecutive normal sFLCκ/λ apart from at least 4 weeks. MFC-defined minimal residual disease (MRD) was evaluated by single-tube 6-color MFC, CD45-CD38 gating strategy, and combination CD19, CD56, and cytoplasmic κ-λ analysis. Clonal plasma cell (PC) negativity by MFC (MFC-negative) was defined as <10−4 neoplastic PCs in BM samples on MFC. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan–Meier (K-M) method and differences between curves were calculated by two-sided log-rank test. Univariate analysis was used to assess the impacts of factors on sFLCκ/λ normalization and MFC negativity (age, Durie–Salmon stage, ISS stage, LDH, hemoglobin, serum albumin, serum creatinine, FISH at diagnosis). The Cox regression proportional hazard model (stepwise regression) was used to explore the independent effects of these variables on PFS and OS. Results: At a median follow-up of 25.8 months, 3- and 5-year OS of all patients were 61.0% and 42.4%, respectively. CR was obtained in 25% (31/124), very good partial response (VGPR) in 33.5% (41/124), partial response (PR) in 30.5% (38/124), and stable disease or less (SD) in 11% (14/124). Normal sFLCκ/λ was achieved in 81% of CR, 56% of VGPR, 13% of PR, and 0% of SD or less response of patients. K-M estimated 3- and 5-year OS were 100% in CR patients; these were significantly better than in VGPR (75.8% and 43.2%, respectively) and PR patients (63% and 26.7.%, respectively). There were no significant differences in 3- or 5-year OS between VGPR and PR patients. Normal sFLCκ/λ and MFC negativity were achieved in 25 (81%) and 18 (58%) of 31 CR patients, respectively. Among 25 CR patients with normal sFLCκ/λ (stringent CR), 15 (60%) were MFC-negative and 10 (40%) were MFC-positive; three of 6 CR patients (50%)without normal sFLCκ/λ were MFC-positive. Twenty-three of 41 VGPR patients (56%) obtained normal sFLCκ/λ, while only 5 (12%) became MFC-negative; all 5 MFC-negative patients also obtained normal sFLCκ/λ. Among 52 patients with less than PR, only 5 (9.6%) obtained normal sFLCκ/λ and none achieved MFC negativity. Patients with MFC-negative CR showed significantly better PFS than patients with MFC-positive CR (p<0.05). Although patients in stringent CR with MFC-negative showed slightly better PFS compared to patients in stringent CR with MFC-positive, difference between the curves were not significant. Within the group of VGPR, PFS and OS were significantly longer in normal sFLCκ/λ patients than abnormal sFLCκ/λ(P<0.001). Univariate analysis showed that hemoglobin 10.0 g/dl>, age >70 yr, and abnormal LDH had negative prognostic impacts on attaining normal sFLCκ/λ, but none of these factors remained significant on multivariate analysis. Cox analysis showed that sFLCκ/λ normalization was an independent prognostic factor for longer PFS and OS in patients with CR, VGPR and PR (P=0.001). Conclusions: This study confirmed that magnitude of CR and VGPR response defined by IMWG criteria was heterogeneous in terms of sFLCκ/λ normalization and MFC negativity. Although MFC and sFLC analysis frequently gave discrepant results among patients with CR and VGPR, both analyses appeared to give important complementary information for assessing the depth of CR and VGPR category. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

ABCA3 Expression Predicts Response to Gemtuzumab Ozogamicin in AML

Blood ◽

10.1182/blood.v128.22.3946.3946 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3946-3946 ◽

Cited By ~ 1

Author(s):

Antony Ceraulo ◽

Aminetou Mint-Mohamed ◽

Delphine Maucort-Boulch ◽

Etienne Paubelle ◽

Xavier Thomas ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Relapse Rate ◽

Small Sample Size ◽

Univariate Analysis ◽

Gemtuzumab Ozogamicin ◽

Small Sample ◽

Control Group ◽

Prognostic Impact ◽

Significant Difference

Abstract Background. The ATP binding cassette transporter 3 (ABCA3) has been recently found to induce a significant reduction in cytotoxicity following exposure to anthracyclines, mitoxantrone, etoposide, Ara-C, vincristine, and rituximab. ABCA3 acts through the modulation of multivesicular bodies (MVB) and contributes to drug sequestration in late endosomal organelles, i.e. MVB and lysosomes. Studies having investigated the prognostic impact of ABCA3 expression in AML have yielded conflicting results as ABCA3 expression has both been reported to exert unfavorable or neutral effects on patient outcomes. In addition, the small sample size of these studies precluded the use of multivariate analyses. Methods. Our goal was to investigate the prognostic impact of ABCA3 expression in adult patients with AML treated with IC with or without gemtuzumab ozogamicin (GO). To this end we investigated the relationship between ABCA3 expression and EFS in a representative series of 221 AML homogeneously treated in the ALFA-0701 trial. qRTPCR amplification of conserved ABCA3 mRNA sequences, as identified with FasterDB database, was performed with GUS and ABL as reference genes. Primer sets were complementary to conserved ABCA3 exons 6-7 and exon 19-20 junctions. Patients were given a 3+7 induction course without (control group, n=110) or with fractionated intravenous GO (n=111) (Castaigne S, Lancet 2012; 379:1508-1516). Results. Among the 278 randomized patients, 221 had available bone-marrow diagnostic samples with high-quality RNA. The same benefits associated with GO were observed in the 221 patients from the present study as in the entire trial population. Overall, median age, CR rate, relapse rate, median follow-up, 3-years EFS were 62.1 years, 76.5%, 66%, 47.45 months, 28±3%, respectively. There was no significant difference in the level of ABCA3 expression between responders and non-responders. In the 169 responders, ABCA3 expression at diagnosis was more than 3-fold higher in the 111 remitters who subsequently relapsed than in the 58 patients who remained in persistent CR (p=0.033). The level of ABCA3 expression was significantly lower in ELN favorable group than in intermediate and adverse risk AML (p= 0.004) and negatively correlated with CD33 expression (R=-0.272, p<10-4). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±3 vs 45±7 % p=0.002). Multivariate analysis identified age, treatment arm, and ELN risk group as independent prognostic factors for EFS. In the control group, there was no significant association between ABCA3 expression and CR rate, relapse rate, and EFS. In the 111 patients within the GO arm, there was no significant difference in the level of ABCA3 expression between responders and non-responder whereas in the 89 responders, ABCA3 expression at diagnosis was more than 7-fold higher in the 53 remitters who subsequently relapsed than in the 36 patients who remained in persistent CR (p=0.006). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±5 vs 64±9 % p=0.0002). Multivariate analysis identified ABCA3 expression, cytogenetics, CD33 expression, and ECOG as independent prognostic factors for EFS (Figure 1). Conclusion. WhileABCB1 has been previously found to attenuate GO-induced cytotoxicity in AML cells (Walter RB, Blood 2003; 102:1466-1473), present results indicate that higher ABCA3 expression independently predicts poor outcome in AML patients treated with fractionated GO and intensive chemotherapy (IC). GO is an anti-CD33 antibody carrying a toxic calicheamicin derivative that, after hydrolytic release within lysosomal vesicles, induces DNA strand breaks, apoptosis, and cell death. Whether the clinical effect of ABCA3 expression relies on the modulation of CD33 internalization, calicheamicin release or combination thereof is under investigation. Finally our results encourage inhibiting ABCA3, such as with indomethacin, in order to overcome drug resistance in AML treated with GO-IC. Figure 1 Figure 1. Disclosures Thomas: Pfizer: Consultancy.

Download Full-text

Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors

Blood ◽

10.1182/blood.v100.4.1177.h81602001177_1177_1184 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1177-1184 ◽

Cited By ~ 375

Author(s):

David G. Oscier ◽

Anne C. Gardiner ◽

Sarah J. Mould ◽

Sharron Glide ◽

Zadie A. Davis ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Clinical Stage ◽

Univariate Analysis ◽

Prognostic Significance ◽

P53 Gene ◽

Early Stage Disease ◽

Cd38 Expression ◽

Mutational Status ◽

Chromosome 11Q23

This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVHgene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutatedIGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutatedIGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVHgenes, unmutated IGVH genes, and loss or mutation of thep53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.

Download Full-text

Incidence and Prognostic Impact of Gene Mutations in Older Patients with AML Treated in the ALFA-9801 Study.

Blood ◽

10.1182/blood.v112.11.1525.1525 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1525-1525

Author(s):

Aline Renneville ◽

Sylvie Castaigne ◽

Sylvie Chevret ◽

Laura Llopis ◽

Nathalie Philippe ◽

...

Keyword(s):

Multivariate Analysis ◽

Older Patients ◽

Gene Mutations ◽

Significant Prognostic Factor ◽

Prognostic Impact ◽

Npm1 Mutation ◽

Younger Patients ◽

Mutational Status ◽

Cebpa Mutations ◽

The Impact

Abstract Introduction: The impact of gene mutations, i.e. poor-prognosis FLT3 internal tandem duplications (ITDs) and good-prognosis NPM1 or CEBPA mutations, has been welldocumented in several recent reports dealing with younger patients with acute myeloid leukemia (AML). As these mutations were associated with cytogenetically normal (CN) AML, most of these reports focused on CN-AML patients. Both FLT3-ITD and NPM1 mutations were also associated with higher WBC. The objective of the present study was to evaluate the incidence, correlations, and prognostic value of these mutations in older patients with the disease. Methods: The French ALFA group has screened a total of 583 patients, including 333 younger patients (15–50 years) treated in the ALFA-9802 trial and 250 older patients (50–70 years) treated in the ALFA-9801 trial. The older ALFA-9801 trial included 468 patients with previously untreated de novo AML and studied the role of idarubicin (IDA) as compared to high-dose daunorubicin (DNR) as well as interleukine-2 as a maintenance therapy (C. Pautas et al. ASH 2007, abstract #162). Comparison between the 250 patients tested for mutations in that trial and the 218 patients not tested showed no differences in age, sex ratio, FAB classification, bone marrow blasts percentage, randomization arm, and performance status at entry in the study. There was, however, a higher rate of patients with intermediate cytogenetics (p=.01) or increased WBC (p=.01) in the former subgroup. Results: Median age of the 250 patients tested was 60 years. Cytogenetics was studied in 232 patients (12 favorable, 174 intermediate, 46 unfavorable). One hundred twenty-two patients (49%) had CN-AML. CR rate was 67.5% and estimated 4-year OS was 26% (95% CI, 20–33). Incidences of FLT3-ITD, NPM1, and CEBPA mutations were 37/250 (15%), 64/249 (26%), and 20/249 (8%), respectively. These incidences were very similar than in the younger ALFA-9802 population [50/329 (15%), 76/321 (24%), and 24/316 (8%), respectively]. In these older AML patients, the correlation between increased WBC and FLT3-ITD (p<.001) or NPM1 mutation (p<.001) was still observed. Conversely, NPM1 mutations only (p<.001), but not FLT3-ITDs (p=.10) or CEBPA mutations (p=.99), were significantly associated with CN-AML. In the whole group of 249 patients with either normal or abnormal karyotype tested for all mutations, 46 were NPM1+/FLT3-ITDwt, 19 FLT3-ITD+/NPM1wt, 18 FLT3-ITD+/NPM1+, and 166 NPM1wt/FLT3-ITDwt. CR rate was 87%, 84%, 56%, and 75% and median OS was 20.5, 18.6, 6.0, and 14.6 months, respectively. In the 20 CEBPA+ patients, CR rate was 80% and median OS was 22.8 months. In the group of 122 CN-AML patients tested for all mutations, 36 were NPM1+/FLT3-ITDwt, 8 FLT3-ITD+/NPM1wt, 15 FLT3-ITD+/NPM1+, and 63 NPM1wt/FLT3- ITDwt. CR rate was 92%, 87.5%, 60%, and 78% and median OS was 20.5, 16.9, 7.0, and 16.8 months, respectively. In the 10 CEBPA+ patients, CR rate was 80% and median OS was not reached. In multivariate analysis including age, WBC, cytogenetics (favorable versus others), and gene mutational status (NPM1+ or CEBPA+ if FLT3-ITDwt versus others), a pejorative effect of age (p=.02) and WBC (p<.001), but a protective effect of mutational status (HR= 0.66, p=.05) and favorable cytogenetics (HR=0.43, p=.06) was observed in the whole patient population. Nevertheless, estimated 4-year OS was only 37% (95% CI, 23–50) in patients with a favorable mutational status. In those with CNAML and a favorable mutational status, estimated 4-year OS reached only 40% (95% CI, 23–56). In this subgroup of patients with CN-AML, WBC was the only significant prognostic factor identified in multivariate analysis (p<.001). Conclusion: This study conducted in a large cohort of patients aged 50 to 70 years and prospectively treated in the same trial showed that gene mutational status still affect the outcome of older patients with AML. Mutation incidences are in the same range than in younger patients. Nevertheless, their impact on OS appeared to be less marked than in younger patients, probably due to the worse general outcome observed in these older patients.

Download Full-text

MicroRNAs in Intermediate Risk Cytogenetic Acute Myeloid Leukemia Add Relevant Prognostic Information to Molecular Categorization

Blood ◽

10.1182/blood.v118.21.235.235 ◽

2011 ◽

Vol 118 (21) ◽

pp. 235-235

Author(s):

Marina Díaz-Beyá ◽

Alfons Navarro ◽

Tania Díaz ◽

Marta Pratcorona ◽

Maria Rozman ◽

...

Keyword(s):

Multivariate Analysis ◽

Mirna Expression ◽

Conflicts Of Interest ◽

Detection System ◽

Intensive Therapy ◽

Molecular Characteristics ◽

Prognostic Impact ◽

Intermediate Risk ◽

Prognostic Information ◽

Mutational Status

Abstract Abstract 235 The prognosis of AML patients within the intermediate cytogenetics category is mainly determined by the mutational status of some relevant genes, such as NPM1 mutations (NPMmut), or biallelic CEBPA mutations (CEBPAmut), associated with a favorable outcome, and with the presence of FLT3 internal tandem duplication (FLT3-ITD), which correlates with an adverse prognosis. Nonetheless, additional biological features such as microRNA (miRNA) expression pattern might contribute to refine prognosis and guide therapy in this setting. The aim of the present study is to investigate whether miRNA expression is associated with molecular characteristics and clinical outcome in intermediate-risk AML patients (IR-AML). We have analyzed samples from 85 IR-AML patients (median age, 52 [range, 18–71]; 52% males) who received intensive therapy from 1994 to 2009. Forty-three patients (51%) harbored NPMmut, 37 (44%) harbored FLT3-ITD (including 23 with NPMmut), and 11 (13%) harbored CEBPAmut, including 7 with biallelic mutations. The expression of 670 mature miRNAs was analyzed by multiplex Real Time PCR using TaqMan Human MicroRNA Arrays (Applied Biosystems). All PCR reactions were performed using an ABI 7900 HT sequence detection system. miRNA expression data was analyzed by the 2−DDCt method, using RNU48 as endogenous control. Statistical analysis was performed with BRB Array Tools, SPSS version 15.0.1 and R software version 2.9.0. Supervised analysis by means of t-test based on multiplex permutations (class comparisons analysis, p<0.001) revealed a distinctive miRNA signature in patients with NPMmut, with overexpression of miR-10a, miR-10a*, miR-10b and miR-196b, and downregulation of miR-126, miR126*, miR-424, miR-424* and miR-335, as well as patients with biallelic CEBPAmut, characterized by downregulation of miR-196b and upregulation of miR-181a. Response rate in this series of patients was 84%, with 5-year survival of 43±11% and relapse incidence (RI) of 55±14%. Multivariate analysis for overall survival(OS) including NPM status, FLT3-ITD status, age, WBC, and Log Rank OS significant miRNAs (miR-632, miR-23b, miR-409-3p, let-7a*, miR-565 and miR-196b) identified age, absence of NPMmut, and FLT3-ITD as unfavorable variables together with low expression of miR-409-3p (p<0.001; HR=3.3, 95% CI: 1.7–6.4), and increased level of let-7a* (p=0.026; HR=5.1, 95% CI: 1.21–21.5) and miR-196b (p=0.056; HR=7.27, CI: 0.95–55.6). Concerning risk of relapse (RR), multivariate analysis including NPM status, age, FLT3-ITD, WBC, and Log Rank RR significant miRNAs (miR-632, miR-155*, miR-135a, miR-409-3p, miR-150, miR-23a* and miR-363) the absence of NPMmut, FLT3-ITD and increasing leukocyte count were associated with a higher RI. Remarkably, decreased miR-409-3p expression (p=0.011; HR=3.3, 95% CI: 1.3–8.2) and miR-135a (p=0.02; HR=4.2, 95% CI: 1.2–14.2), together with higher levels of miR-23a* (p<0.001; HR=6.2, 95% CI: 2.61–14.7) were independently associated with a higher relapse risk. Of note, a decreased miR-409-3p level retained its adverse prognosis value in the subgroup of patients without favorable molecular markers (i.e., wild-type NPM1 and CEBPA and/or FLT3-ITD;p=0.001) together with low miR-361-3p (p=0.013, HR= 2.4, CI: 1.2–5.1). On the contrary, let-7a* levels segregated subgroups of patients in the category of favorable genotype (i.e., mutated NPM1 without FLT3-ITD p=0.027). In this series of patients of intermediate-risk cytogenetic AML, measurement of expression levels of several miRNAs such as miR-409-3p, miR-135a, let-7a* or miR-23a* showed independent prognostic value, and contribute to predict the outcome within specific molecular subgroups. Nonetheless, confirmation of the prognostic impact of these miRNAs and investigation of possible underlying mechanisms account for this effect require future studies. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Daunorubicin or Not During the Induction Treatment of Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): The Randomized Fralle 2000-A Protocol

Blood ◽

10.1182/blood.v120.21.135.135 ◽

2012 ◽

Vol 120 (21) ◽

pp. 135-135

Author(s):

Andre Baruchel ◽

Arnaud Petit ◽

Thierry Leblanc ◽

Gérard Michel ◽

Yves Perel ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Fusion Transcript ◽

Induction Treatment ◽

Secondary Neoplasms ◽

Bone Marrow Morphology

Abstract Abstract 135 From December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1–9 years, WBC<50 G/L, CNS-, no MLL rearrangement, no BCR-ABL, no Down syndrome) were included in the FRALLE 2000-A multicenter protocol. At a MFU of 60 months, 1195 patients are evaluable. An ETV6-RUNX1 fusion transcript was documented in 28% of the pts (329 out of 1173 evaluable pts). Induction regimen: prednisone prephase +IT MTX, dexamethasone (DEX) 6 mg/m2/d, vincristine (VCR), native E.coli L-asparaginase ASPA: 6000 IU/m2 × 9 infusions). Response was assessed at D8 (blood, good if < 1000 blasts/mm3), D21 (bone marrow morphology, good if less than 5% blasts, so-called M1) and end of induction D35 (bone marrow morphology and DNA-based PCR for Ig/TCR rearrangements MRD). A D21 M1 marrow was observed in 1132 pts (94.7%). Out of these, 1128 pts were randomized to receive daunorubicin (DNR; 40 mg/m2 at D22 and D29) [560 DNR(+) pts] or not [568 DNR(-) pts]. Pts with D21 M2/M3 marrow (n= 61; 5%) were not randomized and received two infusions of DNR. Two pts died before D21. Pts with D21 M1 marrow (A1 group) received after induction a 12 week-consolidation based on VCR, DEX, mercaptopurine (6-MP) and oral methotrexate (MTX), followed by a 1st delayed intensification (reduced “Protocol II”, including a total of 75 mg/m2 of doxorubicin), an interphase therapy (VCR, DEX, 6-MP, MTX), and a triple drug only-2nd delayed intensification (DI°2) (VCR, MTX 100 mg/m2, ASPA 20000 IU/m2; 4 cycles). A 24-month maintenance was then applied, including 12 VCR-DEX pulses the first year. A total of 18 intrathecal injections of MTX was given. Only the rare patients with D21 M3 marrow and/or EOI MRD level ≥1% (n= 47, 4%)(A3 group) received an intensified treatment after CR with 3 block-consolidation, intensified interphase with 6 cycles of MTX 5 g/m2 and a second DI (“reduced protocol II”). No pt received CNS irradiation. Results: 1. Overall efficacy: No leukemic induction failure was observed; 4 induction deaths (0.3%) occurred leading to a 99.7% CR rate. Only 30 out 1097 evaluable pts (2.7%) had a decisional EOI MRD ≥ 1%. Eighty-two relapses have been observed (BM: 47, CNS+: 24, BM+CNS: 9, testis: 2). For the whole population 5-year EFS is 91.5% (95%CI: 89.8–93.3), 5-year OS is 97.4% (95%CI: 96.4–98.4). 5-yr EFS and OS for the A1 and A3 groups are 93.1% vs. 61.2% (p<0.0001), and 98.3% vs. 84.2% respectively (p<0.0001). Five-year DFS of the 30 pts with MRD ≥1% is 58.8% (95%CI: 41.7–82.8). Five-year EFS of the children with ETV6-RUNX1 fusion transcript is 96.6% (95%CI: 94.4–98.8). 2. Overall toxicity: 5 non leukemic deaths have been observed after CR (0.4%). Other main toxicities were attributable to ASPA (CNS thrombosis: 1.5%, grade 3–4 pancreatitis: 0.8%, allergic reaction-all grades- during DI °2: 70%). Six cases of secondary neoplasms were observed (AML: 5 pts, astrocytoma: 1 pt). 3. Randomization: 5y EFS and OS from randomization was 92.9% and 97.2% for D21 M1 pts DNR(+) versus 93.3% and 98.2% for D21 M1 DNR(-) pts (p= 0.89 and p= 0.85, respectively). Interestingly EOI MRD levels in the two arms were not different at the sensitivity cut-off of 10−2 (p=0.93) or 10−3(p= 0.74). 4. Prognostic factors: For the whole population, age < 6 years, WBC < 20.000/mm3, ETV6-RUNX1 positivity, as well as D21 marrow M1 and EOI MRD levels of 10−2 and 10−3 were all associated to EFS in univariate analysis. In multivariate analysis remain only WBC < 20.000/mm3 (p=.001), ETV6-RUNX1 positivity (p=.02), EOI MRD levels ≤ 10−3 (p=1.4×10−5). Considering only randomized pts (D21M1 pts) age <6 (p=.004), WBC < 20.000/mm3 (p=.04), ETV6-RUNX1 positivity (p=.01), EOI MRD levels ≤ 10−3(p=.002) remain as independent prognostic factors in multivariate analysis. Conclusions: Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

What Is the Appropriate Dose Attenuation System of RCHOP for Elderly DLBCL Patients? - A Single Institutional Analysis in 115 Cosecutive Patients From Japan -

Blood ◽

10.1182/blood.v120.21.3639.3639 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3639-3639

Author(s):

Akira Tanimura ◽

Risen Hirai ◽

Atsushi Sato ◽

Miki Nakamura ◽

Masataka Takeshita ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Elderly Patients ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Age Related

Abstract Abstract 3639 Background: The combination therapy of RCHOP [rituximab (R), cyclophosphamide (CY), doxorubicin (DOX), vincristine (VCR), and prednisone (PSL)] is a standardized treatment for diffuse large B-cell lymphoma (DLBCL). However, its clinical outcome is worse in elderly patients because of comorbidities, age-related decrease in organ function, and impaired drug metabolism. If possible, the dose of RCHOP in elderly patients and patients with comorbidities should be adjusted appropriately. Since 2005, we have used a unified dose attenuation system for RCHOP according to the age and comorbidities of patients. This study retrospectively verified this system. Patients/Methods: We analyzed 115 consecutive DLBCL patients treated at our institute from September 2001, when rituximab was approved in Japan, to December 2010. From September 2001 to August 2005, 33 patients received dose adjustment of RCHOP according to the physician's discretion (PHY group). From September 2005, 82 patients received RCHOP according to the unified dose attenuation system (UNI group). In the UNI group, patients younger than 60 years received the standard RCHOP dose [R, 375 mg/m2; CY, 750 mg/m2; DOX, 50 mg/m2; VCR, 1.4 mg/m2 (max 2.0 mg/body); PSL, 100 mg/m2]. In patients older than 60 years, the doses of CY, DOX, VCR, PSL, and R were attenuated as shown in Table 1. In addition to age, the doses of CY, DOX, and VCR were adjusted according to organ functions (Table 2). The two groups were compared statistically. Results: The median age of patients was 70 years (range, 38–91), with 70.4% of patients classified as stage III or IV DLBCL, 40.4% with an international prognostic index (IPI) score of 0–2, and 70.2% with a ECOG performance status (PS) of 0 or 1. Low serum albumin levels (under normal range) were observed in 50.5% patients, and a high Charlson comorbidity index (CCI) score of >1 was found in 58.3%. The characteristics of the patients in the two groups were almost similar. The UNI system was completed in 94% of patients. The complete response (CR) rate was 63% in all patients (UNI group, 73%; PHY group, 39%; P = 0.0006). Univariate analysis revealed that better prognostic factors for CR were a low IPI score, better PS, and the UNI group. In the multivariate analysis, only the UNI group was a significantly better prognostic factor for CR. With a median follow-up of 26 months, the 5-year event-free survival (EFS) and overall survival (OS) were 39.3% and 68% in all patients, 43% and 72% in the UNI group, and 27% and 59% (5-year EFS; P = 0.0083, 5-year OS; P = 0.16) in the PHY group, respectively. Multivariate analysis showed that better prognostic factors for EFS were a low IPI score, a low CCI score, and the UNI group, and that for OS were low IPI and low CCI scores. In elderly patients aged >70 years (N = 59), the CR rates were 81% and 13% in the UNI and PHY groups, respectively (P = 0.0004), with OS in the UNI group being longer than that in the PHY group (72% vs. 59%; P = 0.02; Fig.1). In the UNI group, patient age did not affect the CR rate (<70, 71% vs. 70–79, 83% vs. >79, 79%; P = 0.56) or 5-year OS (<70, 76% vs. 70–79, 70% vs. >79, 66%; P = 0.58). The actual dose of CY, DOX, and VCR compared with the standard RCHOP dose was 64% and 26%, 63% and 16%, and 63% and 21% in the UNI and PHY groups, respectively. Disease progression during treatment, discontinuation of therapy, and death during treatment were observed in 10% and 15%, 5% and 24%, and 5% and 3% in the UNI and PHY groups, respectively. Nineteen patients (23%) from the UNI group died over a median follow-up of 15 months, while 15 patients (45%) of the PHY group died over a median follow-up period of 29 months. Lymphoma-related deaths were 12 (14%) in the UNI group and 8 (24%) in the PHY group. Five secondary primary malignancies (SPM) were observed (1 colon cancer and 1 breast cancer in the PHY group, and 1 lung cancer and 2 myelodysplastic syndrome in the UNI group). Four deaths were related to SPM. Conclusion: The unified dose attenuation system determined by the patients' age and comorbidities may achieve an effective dose level and better prognosis in elderly DLBCL patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text