Extreme Regression: A Statistical Technique for Finding Good or Poor Prognostic Groups, Illustrated Using Myeloma Patient Data from Intergroup Trial S9321.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5202-5202 ◽  
Author(s):  
John J. Crowley ◽  
Jason McCoy ◽  
Michael LeBlanc ◽  
Bart Barlogie
Keyword(s):  
Median Survival ◽  
Survival Data ◽  
Poor Prognosis ◽  
Risk Group ◽  
Staging System ◽  
Statistical Technique ◽  
High Dose ◽  
Prognosis Group ◽  
Intergroup Trial ◽  
One Year

Abstract Extreme Regression (LeBlanc, Moon and Kooperberg, manuscript submitted) is a statistical technique for finding patient subsets with either very good or very poor prognosis. In contrast to Cox regression, which generates predictions based on linear combinations of variables, Extreme Regression results in groups based on intersections or unions of simple statements involving single covariates (eg sb2m > 3.5 and albumin < 3.5; sb2m > 3.5 or LDH > ULN). Thus, Extreme Regression is similar in spirit to tree-based regression methods, except that the goal is not to develop a complete staging system (like the new International Staging System, ISS, for myeloma, which was derived using tress-based methods) but rather to define subsets of a given size (eg 10%) with extreme prognosis. Here prognosis may be defined in terms of any type of outcome such as response, one-year mortality, overall survival, etc. To illustrate we use survival data from the Intergroup Trial S9321, which tested high dose therapy with melphalan and TBI versus a standard dose regimen of VBMCP (both after VAD induction) for newly diagnosed patients with multiple myeloma. We used as potential predictors serum beta-2 microglobulin (sb2m), LDH, albumin and creatinine as measured at baseline. There were 682 eligible patients with complete data on these four covariates. We asked the algorithm to identify roughly 10% of the patients representing a poor prognosis group, and then another 25% representing a good prognosis group. The results are shown in Figure 1, along with the intermediate group of all other patients. The poor risk group comprised 77 patients (11% of the total) and was defined by those patients with sb2m > 9 and LDH > ULN; or patients with creatinine > 5; or patients with albumin < 2. These patients had a median survival of 19 months, a one year survival of 66%, and a five year survival of 19%. The good risk group included 181 patients (27%) defined by LDH <= 67% of ULN and creatinine <= 2 and albumin >= 3.5. This group had a median survival of 67 months, a one year survival of 96%, and a five year survival of 57%. Extreme regression appears to be a promising exploratory tool when the goal is the identification of simple, interpretable subsets of patients with extreme prognosis. Figure Figure

Prognostic Performance of the Cytogenetic Risk Classification Defined by the German-Austrian Myelodysplastic Syndromes (MDS) Study Group and Its Contribution to the International Prognostic Scoring System (IPSS) and the World Health Organization-Based Prognostic Scoring System (WPSS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4005-4005
Author(s):  
Benet Nomdedeu ◽  
Meritxell Nomdedeu ◽  
Arturo Pereira ◽  
Dolors Costa ◽  
Anna Carrió ◽  
...  
Keyword(s):  
Median Survival ◽  
Poor Prognosis ◽  
Risk Group ◽  
Good Prognosis ◽  
High Risk Group ◽  
Risk Classification ◽  
Prognostic Performance ◽  
The Poor ◽  
Prognosis Group ◽  
Good Prognosis Group

Abstract Abstract 4005 Background and objective: the cytogenetic risk classification defined by the 1997 IPSS remains the most widely used to assess the prognostic impact of karyotype in the MDS. Recently, the German-Austrian MDS Study Group (Haase, Ann Hematol 2008; 87:515) has proposed a new, more comprehensive cytogenetic risk classification. Our aim was to assess the prognostic performance of the Haase's cytogenetic classification, as compared to that defined by the IPSS, and what would be its contribution to the IPSS and WPSS. Methods: MDS patients seen at our center after 1986 were eligible for inclusion if they had a cytogenetic study performed at diagnosis that could be scored according to both the IPSS and the Haase's criteria. The prognostic performance was assessed by the Harrell's concordance index and the R2 explained variation (the closer both statistics to 1 the better the prognostic performance). Results: 327 out of 494 patients seen after 1986 met the eligibility criteria. Median age was 73 (range: 16–97) years and 55% were women. The 2001 WHO categories were refractory anemia (RA, 6%), RA with ringed sideroblasts (RARS, 2%), refractory cytopenia with multilineage dysplasia (RCMD, 54%), RCMD with ringed sideroblasts (RCMD-RS, 11%), RA with excess of blasts (RAEB-1, 11%; RAEB-2, 14%), and del(5q) (2%). According to the IPSS cytogenetic classification, 232 (71%) patients were in the low risk group, 46 (14%) in the intermediate, and 49 (15%) in the high risk group. According to Haase's criteria, 239 (73%) patients were in the good prognosis group, 26 (8%) in the int-1, 25 (8%) in the int-2, and 37 (11%) in the poor prognosis group. Agreement between both karyotype-based risk classifications was high (Kendall's tau=0.92; Kruskal's gamma=0.99). At the study closing date, median survival for the whole series was 4.1 years, 160 (49%) patients had died and 27 (8%) were lost to follow-up. Median survival (95% CI) in years according to the IPSS cytogenetic classification was 5.2 (4.2-6.4) for the low risk group, 3.8 (1.7-5.0) for the intermediate, and 0.9 (0.7-1.1) for the high risk group. Median survival (95% CI) in years according to Haase's criteria was 5.2 (4.1-6.4) for the good prognosis group, 3.9 (1.6-not reached) for the int-1, 3.1 (0.9-3.8) for the int-2, and 0.8 (0.6-1.9) for the poor prognosis group. There was no statistically significant difference in survival between the int-1 and Int-2 groups. Grouping the Int-1 and Int-2 into a single intermediate risk category yielded a median survival of 3.5 (1.7-4.4) years, which was significantly different from that of good and poor risk groups (p=0.014 and p=0.0001, respectively). The figure shows the concordance and R2 statistics for both cytogenetic classifications as well as those of the IPSS and the WPSS had they been based on the Haase's score, as compared to the standard ones. For this latter analysis, the Haase's int-1 and int-2 categories were grouped together. Conclusion: The new cytogenetic risk classification was comparable to that defined by the IPSS with regard to prognostic performance and did not improve the discriminatory power of the IPSS or the WPSS. Disclosures: No relevant conflicts of interest to declare.

Adaptation of chemotherapy to the decline tumor markers in patients with poor prognosis nonseminomatous germ cell tumors:Real-world French experience.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 385-385
Author(s):  
Marion Rolland ◽  
Sara Faouzi ◽  
Leonor Chaltiel ◽  
Clement Dumont ◽  
Lionnel Geoffrois ◽  
...  
Keyword(s):  
Germ Cell ◽  
Tumor Marker ◽  
Tumor Markers ◽  
Poor Prognosis ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
French Experience ◽  
Prognosis Group

385 Background: Personalized chemotherapy based on tumor marker decline is the new standard in poor prognosis germ-cell tumor in Europe since 2014 (GETUG 13, Lancet, Fizazi et al). The purpose of this study was to analyze the reproducibility of the princeps study in patients not selected in clinical routine between 2014 and 2018. Methods: Patients (pts) were eligible if they had at least one criteria of IGCCCG classification for poor prognosis group. They had to be treated according the study terms of GETUG 13 study and did not received prior treatment. They had to received 1 BEP (Bleomycin, Etoposide, Cisplatin). Tumor markers (HCG and AFP) were dosed between day 18 and 21. Then, they received 3 additional BEP if they had favorable tumor marker decline or intensive chemotherapy if they had unfavorable decline. Results: This retrospective study included 104 patients in 14 french centers treated between 2013 and 2018: 22,1 % (n = 23) in the favorable group (Fav), 77,9 % (n = 81) in the unfavorable group (Unfav). Thirty-two pts had PS ≥ 2. In Unfav, there were more pts with HCG > 50 000 UI/L (44,2 % vs 13 %, p = 0,0067), neutrophil-to-lymphocyt ratio was also higher (median 6,4 vs 4,5, p = 0,0199). At cycle 1, all pts received BEP in Fav and 87,5 % (n = 70) in Unfav. After chemotherapy and surgery, 65,2 % in Fav and 41,3 % in Unfav obtained complete response. At 30 months (median follow-up), Fav-OS was 80,5 % (IC95% 55,8 – 92,2) and Unfav-OS was 64,4 % (IC95% 52 – 74,4). At 30 months, rates were 69,6 % (IC95% 46,6 -84,2) and 63.5 % (IC95% 51,9 – 73) respectively. In GETUG 13 study, 3-years OS was 84 % in Fav and 73 % on Unfav; 3-years PFS was 70 % and 59 % respectively. Seven pts died because of toxicity in Unfav (No one in Fav). Neuropathy, anemia and thrombopenia were more frequent in Unfav. Salvage high-dose chemotherapy with stem-cell transplant was required in 4 (66,7 %) pts in Fav and 8 (36,4 %) pts in Unfav. Conclusions: This study showed a reproducibility of the princeps study in terms of PFS and OS. Toxicity seemed more important in real world. For the congress, results will be reported with 50 additional pts.

Genetic Polymorphisms Associated with Clinical Outcome in the Intergroup Trial S9321, Comparing High Dose Therapy with Standard Dose Therapy for Myelomaon, on Behalf of ECOG, SWOG, CALGB, and the Bank on a Cure.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1495-1495
Author(s):  
Rafael Santana-Davila ◽  
John Crowley ◽  
Brian Durie ◽  
Bart Barlogie ◽  
Philip Greipp ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Genetic Polymorphisms ◽  
Median Survival ◽  
Dose Regimen ◽  
Standard Dose ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Intergroup Trial

Abstract Genetic variations in patient populations likely contribute to disease progression and therapeutic outcomes. We have begun a systematic approach to examine the association of genetic variations (ie. functional, single nucleotide polymorhisms, SNPs) involved in myeloma growth promotion, metabolic events, drug responses, and DNA repair on clinical outcome in the intergroup trial S9321. This trial tested a single high dose regimen with autologous stem cell support against a conventional dose regimen, with further randomization of responders to maintenance with interferon or not, in newly diagnosed patients with multiple myeloma. ECOG, CALGB and SWOG enrolled 899 patients with newly diagnosed MM to receive VAD induction x 4 cycles followed by randomization to PBSC-supported high dose therapy (HDT) versus standard dose therapy (SDT) of VBMCP, using CTX 4.5 g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or HDT were randomized to IFN or no maintenance. Specimens were distributed through ECOG for biologic correlative studies, including candidate SNP analysis. SNP assays have been developed using the Sequenom Mass-extend platform for functional SNPs in IL-6, IL-1, IL-RA, IL-10, TNF, Lta, TGFb, MDR1, MPO, CYP3A4, GST (M, P, T), ERCC2 and XRCC1, and are being evaluated on 803 DNA samples prepared from patients enrolled in S9321. Preliminary findings (n=135) demonstrate functional genetic variants of IL-10 (position -1082), IL-1 (position +3953), TGFb (postion -509), and TNFa (position -308) are showing trends associated with differences in progression free survival; and variants in IL-6 (position -174) are associated with response. Median survival of the IL-10 variants was 31 months for A/A low producer alleles versus 19 months for the G/G high producer alleles (p=.5). For TNFa, 2 cases with the high producer A/A alleles died within a year, while the median survival for the lower producer G/G alleles was 2 years (p=.04). For patients with the high producer C/C/ allele of IL-1 (n=67), median survival was 2 years, versus 5 patients with the T/T low producer alleles that had a median survival greater than 5 years (preliminary p=.29). While these preliminary results are now only suggestive of trends in genetic polymorphisms associated with clinical outcome, completion of the full SNP panel on the entire sample base should provide a extensive association study, and analysis of potential differences in therapy arms of the trial. The full panel and association studies will be presented.ααββααα

scholarly journals Staging of chronic lymphocytic leukemia

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1191-1196
Author(s):  
M Baccarani ◽  
M Cavo ◽  
M Gobbi ◽  
F Lauria ◽  
S Tura
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Survival ◽  
Lymphocyte Count ◽  
Death Rate ◽  
Risk Group ◽  
Young Patients ◽  
Staging System ◽  
High Risk Group ◽  
Lymphocytic Leukemia ◽  
Standard Risk

One-hundred and eighty-eight patients with chronic lymphocytic leukemia were analyzed for prognosis based on Rai's staging system. It was found that stages I and II were not homogeneous as to prognosis. Stage II patients presenting with isolated splenomegaly had a long survival and were pooled with stage 0 patients (low risk group, 30% of cases, relative death rate 0.24, median survival greater than 10 yr). Stages I and II patients with a lymphocyte count higher than 40 x 10(9)/liter had a short survival and were pooled with stages III and IV patients (high risk group, 39% of cases, relative death rate 1.91, median survival 3.3 yr). Stages I and II patients with a lymphocyte count lower than 40 x 10(9)/liter made up an intermediate or standard risk group (31% of cases, relative death rate 1.00, median survival 6.2 yr). This modified staging system applied successfully to both old and young patients (more and less than 60 yr old, respectively).

Validation of International Staging System (ISS) for Multiple Myeloma: A Retrospective Analysis of 487 Patients at 8 Brazilian Centers.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5069-5069
Author(s):  
Vania T.M. Hungria ◽  
Angelo Maiolino ◽  
Gracia Martinez ◽  
Gisele Colleoni ◽  
Luciana Oliveira ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Median Survival ◽  
Staging System ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
High Dose ◽  
International Staging System ◽  
New System

Abstract Introduction: The survival of patients with multiple myeloma varies from a few months to more than 10 years. This heterogeneity is related to the characteristics of the myeloma itself and of the host. The identification of the factors which influence the prognosis is very important to predict the result, assist in the choice of the treatment and adequately stratify the patients in clinical studies. Many prognostic factors have been identified in patients with multiple myeloma, such as anemia, renal failure, ß2 microglobulin, albumin and chromossomic alterations. Some authors have combined prognostic factors and proposed various systems of staging. However, none of them have yet substituted the Durie-Salmon staging system. Recently, the International Myeloma Working Group, with the objective of developing a simple and reliable staging system, which can be internationally applied to classify and stratify patients with multiple myeloma, identified 3 risk groups. This new system of staging, the “International Staging System” (ISS), consists of stage I: ß2 microglobulin < 3.5 mg/L plus albumin ≥ 3.5 g/dL (median survival: 62 months); stage II: neither I nor III (median 44 months); stage III: ß2 microglobulin > 5.5 mg/L (median 29 months). This study included sites in North America, Europe and Asia, but the sites in Latin America were not included. Objective: To validate the ISS in patients with multiple myeloma at Brazilian centers. Patients and Methods: Four hundred and eighty-seven patients with the diagnosis of multiple myeloma within the period of 1998 to 2004 at Santa Casa de São Paulo, Hospital Universitário Clementino Fraga Filho do Rio de Janeiro, Hospital das Clínicas de São Paulo, Hospital São Paulo, Hospital das Clínicas de Ribeirão Preto, HEMOPE, Hospital Prof. Edgar Santos de Salvador and Hospital de Clínicas de Porto Alegre, with available data on albumin and ß2 microglobulin, were stratified according to the ISS. A total of 339 patients received standard therapy and 148 received high-dose therapy as initial therapy. The survival was estimated using the Kaplan-Meier method with differences in survival examined using the logrank test. Results: The median age of the patients was 60 years, 52% male and 48% female. In Stage I (n=104), the global median survival was not reached, the survival at 60 months was 60%, in stage II (n=264), the global median survival was 61 months and in stage III (n=119), 19 months (p<0.001). Conclusion: The new system of staging for multiple myeloma (ISS) is simple, based on variables easy to be applied and was possible to be validated in patients with multiple myeloma in Brazilian centers.

scholarly journals Effect of neoadjuvant chemotherapy in patients with resectable colorectal liver metastases.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14523-e14523 ◽  
Author(s):  
Jianmin Xu ◽  
Dexiang Zhu ◽  
Yunshi Zhong
Keyword(s):  
High Risk ◽  
Neoadjuvant Chemotherapy ◽  
Liver Metastases ◽  
Median Survival ◽  
Survival Data ◽  
Survival Benefit ◽  
Colorectal Liver Metastases ◽  
Risk Group ◽  
Low Risk ◽  
Significant Difference

e14523 Background: Whether patients with resectable colorectal liver metastases (CRLM) receive a survival benefit from neoadjuvant chemotherapy prior to hepatectomy remains controversial. Methods: We retrospectively analyzed 466 consecutive patients with resectable CRLM between 2000 and 2010. Patient and tumor characteristics, surgical procedure and survival data were recorded. Results: The patients were divided into two groups: one group with neoadjuvant chemotherapy (group NC, n=121) and one group without (group WN, n=345). There was no significant difference in the median survival (60.0 m vs. 53.9 m) or 5-year survival (52% vs. 48%) between the two groups. No significant differences were identified between the two groups in terms of 30-day mortality (1.7% vs. 1.2%) or morbidity (33.9% vs. 25.8%). A primary tumor at stage T4, ≥ 4 liver metastases, the largest liver metastasis ≥ 5 cm in diameter, and a serum CEA level ≥ 5 ng/ml were independent prognostic factors for the surgical patients. By assigning one point to each of above factors, all of the patients were divided into a low-risk group (0-2) and a high-risk (3-4). The patients in the low-risk group received no survival benefit from neoadjuvant chemotherapy, whereas those in the high-risk group received a survival benefit (median survival, 38.9 m vs. 28.4 m; 5-year survival, 39% vs. 33%, P=0.028). Conclusions: Preoperative neoadjuvant chemotherapy did not significantly increase mortality or complications. Not all resectable patients (only those with more than 2 independent risk factors) receive a survival benefit from neoadjuvant chemotherapy.

scholarly journals Staging of chronic lymphocytic leukemia

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
M Baccarani ◽  
M Cavo ◽  
M Gobbi ◽  
F Lauria ◽  
S Tura
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Survival ◽  
Lymphocyte Count ◽  
Death Rate ◽  
Risk Group ◽  
Young Patients ◽  
Staging System ◽  
High Risk Group ◽  
Lymphocytic Leukemia ◽  
Standard Risk

Abstract One-hundred and eighty-eight patients with chronic lymphocytic leukemia were analyzed for prognosis based on Rai's staging system. It was found that stages I and II were not homogeneous as to prognosis. Stage II patients presenting with isolated splenomegaly had a long survival and were pooled with stage 0 patients (low risk group, 30% of cases, relative death rate 0.24, median survival greater than 10 yr). Stages I and II patients with a lymphocyte count higher than 40 x 10(9)/liter had a short survival and were pooled with stages III and IV patients (high risk group, 39% of cases, relative death rate 1.91, median survival 3.3 yr). Stages I and II patients with a lymphocyte count lower than 40 x 10(9)/liter made up an intermediate or standard risk group (31% of cases, relative death rate 1.00, median survival 6.2 yr). This modified staging system applied successfully to both old and young patients (more and less than 60 yr old, respectively).

High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma.

1993 ◽  
Vol 11 (10) ◽  
pp. 1846-1851 ◽  
Author(s):  
J M Vose ◽  
J R Anderson ◽  
A Kessinger ◽  
P J Bierman ◽  
P Coccia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Poor Prognosis ◽  
Prognostic Model ◽  
High Dose Chemotherapy ◽  
Good Prognosis ◽  
High Dose ◽  
The Poor ◽  
Prognosis Group ◽  
Good Prognosis Group

PURPOSE To evaluate clinical and tumor characteristics in patients receiving high-dose chemotherapy and autologous peripheral stem-cell transplantation (PSCT) or bone marrow transplantation (ABMT) for relapsed or primary refractory non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS One hundred fifty-eight patients with NHL received high-dose chemotherapy and ABMT or PSCT. A multivariate analysis of characteristics was performed for comparison of the long-term failure-free survival (FFS) rate. RESULTS Using a multivariate analysis, a prognostic model was constructed with patients in the good-prognosis group being those without a mass > or = 10 cm at the time of transplant, and no more than one of the following characteristics: three or more prior chemotherapy regimens, lactate dehydrogenase (LDH) level above normal, and chemotherapy resistance. Patients in the poor-prognosis group had a mass > or = 10 cm, or two of the other characteristics noted. The poor-prognosis group had a 3-year FFS rate of 10%, compared with a 45% 3-year FFS in the good-prognosis group (P < .001). Within the prognostic groups, there was no difference in the 3-year FFS rate of the poor-prognosis patients who received ABMT versus PSCT (10% v 12%; not significant). However, in the good-prognosis group, patients who received ABMT had a 3-year FFS rate of 32%, compared with 70% for those who received PSCT (P < .008). CONCLUSION This prognostic model can identify patients with good and poor prognoses following high-dose chemotherapy and ABMT or PSCT for aggressive NHL. In good-prognosis patients, those who received PSCT had a superior FFS rate.

Mitoxantrone, Vinblastine, and Lomustine (MVC): Long-Term Follow-Up of Patients Treated for Hodgkin’s Disease (HD).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1312-1312 ◽  
Author(s):  
Doru T. Alexandrescu ◽  
Sirisha Karri ◽  
Janice P. Dutcher ◽  
Peter H. Wiernik
Keyword(s):  
Median Survival ◽  
Poor Prognosis ◽  
De Novo ◽  
Response Duration ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Mixed Cellularity ◽  
Median Response

Abstract Advanced-stage or relapsed/refractory HD has a poor prognosis despite aggressive chemotherapy regimens and the use of high dose therapy with autologous support. Sixty seven patients with HD(23 newly diagnosed and 45 with relapsed/refractory disease, one patient treated twice) were treated with the MVC regimen (mitoxantrone 8mg/m2/day IV days 1–3, vinblastine 8m/m2/day days 1 and 22, and CCNU 100 mg/m2 on day 1, repeated at 6 to 8 wks) in a single-arm Phase II study. This regimen combines the most effective chemotherapeutic agents of previous regimens for poor prognosis HD, and eliminates marginally active agents with unnecessary toxicities. Median age at treatment was 35 years (16–71), with 42 males and 25 females. 23 patients had previously untreated (PU) disease, staged as II (7), III (7), IV (9), and subtypes consisted of nodular sclerosis (21), mixed cellularity (1), and lymphocyte depletion (1). 45 patients were previously treated (1st relapse-20, 2nd relapse-13, 3rd relapse-12) and had relapsed after chemotherapy alone (17), radiotherapy alone (4), or combined modality treatment (24). 39 patients were relapsed and 6 refractory to treatment. This refractory/relapsed (R/R) group at diagnosis was staged II (11), III (10), IV (22), unknown (2), with 34 nodular sclerosis, 3 mixed cellularity, 1 anaplastic large cell, 1 lymphocyte predominant, 2 lymphocyte depleted, 4 unknown. All patients responded to treatment in the newly diagnosed group (OR 100%). The median response duration was 57.2 mos, and the median survival 108.1 mos. 11 complete responses are ongoing at 39+ to 189+ mos. In the prior treated patients, 41 responded to MVC (OR 91%). The median response duration for this group was 11 mos, and the median survival was 82.1 mos. Grade 3 and 4 treatment-related toxicities included neutropenia (89%), thrombocytopenia (73%), infection (40%), bleeding (20%), and two (2.9%) deaths (related to granulocytopenia and infection). Three secondary myeloid leukemias occurred, two in the de-novo, and one in the relapsed/refractory group, at a median follow-up of 16 years. In conclusion, MVC regimen for HD is very active, for both de novo and relapsed/refractory disease, with high response rates and survival that compare favorably with the results obtained by high-dose therapy with stem-cell transplantation. Although significant, the toxicities associated with this regimen were manageable. Group OR CR PR Overall median response Overall survival CR median response CR median survival NR* = not reached, range 8.2-189+ mos PU 100% 83% 17% 57.2 mos 108 mos NR* 186 mos R/R 91% 44% 47% 11 mos 82 mos 15 mos 168 mos

scholarly journals Low Expression of the CIITA Gene Predicts Poor Outcome in Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2948-2948 ◽  
Author(s):  
Matias Autio ◽  
Kirsi Jäntti ◽  
Alejandra Cervera ◽  
Sampsa Hautaniemi ◽  
Sirpa Leppä
Keyword(s):  
Differentially Expressed Genes ◽  
Research Funding ◽  
Poor Prognosis ◽  
B Cell Lymphoma ◽  
Exon Array ◽  
Differentially Expressed ◽  
High Dose ◽  
Poor Survival ◽  
Large B Cell Lymphoma ◽  
Prognosis Group

Abstract Background Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients still experience relapse with a dismal prognosis. To identify biological correlates for poor survival, we compared differentially expressed genes between high-risk DLBCL patients, who had relapsed or remained in remission after dose-dense chemoimmunotherapy. Design and methods We performed genome-wide exon array analysis (Affymetrix Human Exon 1.0 ST) with 38 de novo high-risk (aaIPI>1) DLBCL patients less than 65 years old. The patients were treated in a Nordic phase II protocol with six courses of R-CHOEP-14 followed by systemic central nervous system prophylaxis with one course of high dose methotrexate and high dose cytarabine. We quantified the expression data by MEAP (Multiple Exon Array Preprocessing) algorithm and identified differentially expressed genes between the patients, who relapsed (n=9; poor prognosis group) or remained in long-term remission (n=29; good prognosis group). RNA sequencing and oligonucleotide-based microarray data from 92 (Cancer Genome Characterization Initiative, CGCI) and 233 (Lymphoma/Leukemia Molecular Profiling Project, LLMPP) DLBCL patients were utilized for validation. In both validation cohorts, the patients were treated with chemoimmunotherapy. Results Gene expression profiling (GEP) identified 215 differentially expressed genes (DEGs) between the good and poor prognosis groups. Of these, 41% were upregulated and 59% suppressed in the patients with poor prognosis. Pathway analyses indicated that the DEGs were enriched in many immune response related processes, such as the antigen processing and presenting pathway. Of note was the observation that major histocompatibility complex class II transactivator (CIITA) and selected human leucocyte antigen- (HLA) genes were significantly suppressed in the poor prognosis group. A correlation between CIITA and HLA gene expression levels was also observed. In Cox univariate analysis with continuous variables, low CIITA expression predicted poor overall survival (OS; p = 0.035). Five-year OS rates were 89% and 50% for the patients with high and low CIITA mRNA levels, respectively (p = 0.007). The prognostic impact of CIITA expression on survival was confirmed in independent CGCI (OS; p = 0.020, PFS; p = 0.002) and LLMPP validation cohorts (OS; p = 0.002, PFS data not available). In the CGCI cohort, the association of CIITA expression with survival was independent of IPI. Consistent with previous data, suppression of certain HLA-genes was also associated with poor outcome. Conclusions The results demonstrate that low CIITA expression is a novel independent predictor of poor survival in patients with DLBCL. The loss of CIITA offers, through the loss of MHC class II expression, a mechanism of immune escape and treatment resistance. Disclosures Leppä: Amgen: Research Funding; CTI Life Sciences: Honoraria; Janssen: Research Funding; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel Expenses, Research Funding; Mundipharma: Research Funding; Bayer: Honoraria, Research Funding.

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