Clonal Cells Detected by Conventional Cytogenetic Analysis Correlates with Bone Marrow Blast Percentage and Progression Free Survival Into Acute Leukemia In Myelodysplastic Syndromes

Abstract Abstract 2935 Introduction: Chromosomal abnormalities not only demonstrate the clonality of the disease, but also help to predict the outcome of the patients in MDS. While IPSS suggests conventional cytogenetic analysis as a standard method in detecting clonal abnormalities in MDS, FISH is widely used due to its ability to detect minor clones and to quantitate the clonal abnormalities. In this study, we compared the results of conventional cytogenetic analysis and FISH, and investigated their different prognostic impact in MDS. Materials and Methods: The study included 129 MDS patients composed of 10 RA, 5 RARS, 15 RCMD, 39 RAEB-1, 33 RAEB-2 and 5 MDS, U (WHO classification, 2001). A standard protocol was used to perform conventional cytogenetic analysis (G-banding). Interphase FISH was performed to detect any abnormalities of chromosomes 5, 7, 8, 20 and 1. The result was analyzed as per the manufacturer¡&hibar;s instructions and recorded according to ISCN (2005) criteria. Result: The incidence of −5/5q, −7/7q, +8, −20q and +1q were 13.2%, 14.0%, 19.4%, 7.0% and 7.8%, respectively. Among them, FISH detected occult abnormalities which were not detected in conventional cytogenetic analysis in 1.6%, 3.1%, 5.4%, 1.6% and 5.4%, respectively. Overall, FISH detected occult abnormalities in 18.6% of the patients (24/129), and IPSS grouping was changed in 4.9% (6/129: 1 Low to Int-1; 4 Int-1 to Int-2; 1 Int-2 to High). The abnormalities in −5/5q, −7/7q and +1q were more common with other chromosomal abnormalities, whereas the abnormalities in +8 and −20q were more common as a sole abnormality. The quantity of clonal cells for each chromosome detected in conventional cytogenetic analysis did not correlate with the quantity of clonal cells detected in FISH. The presence of clonal cells either in conventional cytogenetic analysis or in FISH did not correlate with prognostic factors included in IPSS. However, the clonal cell percentage detected in conventional cytogenetic analysis was higher in patients with >5% bone marrow blasts than those with <5% (79.1% vs. 57.9%, p=.013). The clonal cell percentage detected in FISH did not show any relationship with IPSS factors including bone marrow blast percentage. Multivariate analysis showed the presence of clonal cells in conventional cytogenetic analysis were independent prognostic factors in predicting progression free survival into acute leukemia in this patient group (p=.038). Conclusion: FISH is advantageous in identifying cryptic cytogenetic abnormalities which could be overlooked in conventional cytogenetic analysis, and can change the IPSS risk grouping in MDS patients. The quantity of clonal cells detected in conventional cytogenetic analysis correlates with bone marrow blast percentage, whereas the quantity of clonal cells detected in FISH does not. Blasts possess higher proliferating activity than maturing hematopoietic precursors, thus they are more likely to form metaphase required in conventional cytognetic analysis. In contrast, the FISH results performed on non-dividing, interphase cells might reflect the true quantity of clonality both in blasts and maturing hematopoietic precursors. The relationship between the quantity of clonal cells and bone marrow blast percentage, and the prognostic significance of the presence of clonality suggest the novel diagnostic utility of conventional cytogenetic analysis in MDS. Disclosures: No relevant conflicts of interest to declare.

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Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy [see comments]

Blood ◽

10.1182/blood.v83.5.1193.1193 ◽

1994 ◽

Vol 83 (5) ◽

pp. 1193-1199 ◽

Cited By ~ 169

Author(s):

DE Reece ◽

JM Connors ◽

JJ Spinelli ◽

MJ Barnett ◽

RN Fairey ◽

...

Keyword(s):

Bone Marrow ◽

Prognostic Factors ◽

Bone Marrow Transplantation ◽

Combination Chemotherapy ◽

Autologous Bone Marrow Transplantation ◽

Progression Free Survival ◽

Autologous Bone Marrow ◽

Free Survival ◽

First Relapse ◽

Autologous Bone

Abstract The optimal timing in which to use intensive chemotherapy and autologous bone marrow transplantation (BMT) in Hodgkin's disease (HD) is uncertain. In 1985, we initiated a program in which this modality was used as the initial salvage therapy in patients relapsing after combination chemotherapy. Fifty-eight patients with HD in first relapse after primary chemotherapy received conditioning with high-dose cyclophosphamide, carmustine, etoposide (VP16–213) +/- cisplatin (CBV +/- P) followed by autologous BMT. All but six of these patients were given a median of two cycles of conventional chemotherapy +/- involved field radiation therapy before CBV +/- P and autologous BMT. These measures were not used as a means for patients selection; all patients receiving such therapy ultimately were transplanted. The probability of nonrelapse mortality, progression of HD, and progression-free survival post-BMT were calculated, and prognostic factors for progression-free survival were evaluated using the Cox proportional hazards method. Treatment-related deaths occurred in only three patients. Thirteen patients have relapsed at a median 0.7 years (range 0.1 to 3.5) post- BMT. At a median follow-up of 2.3 years (range 0.4 to 7.2), the actuarial progression-free survival is 64% (95% confidence interval, 46% to 78%). In the statistical analysis, three similarly weighted but independent prognostic factors were identified: “B” symptoms at relapse, extranodal disease at relapse, and initial remission duration of less than 1 year. Patients with no risk factors had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors, and 0% in patients with all three factors. CBV +/- P and autologous BMT is highly effective salvage therapy for HD patients in a first relapse, particularly in the subset of patients with less than two adverse factors. Therapy must be improved in the future for patients with > or = 2 adverse factors.

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Classical and Molecular Cytogenetic Abnormalities in 124 Pediatric Patients with Acute Lymphocyte Leukemia.

Blood ◽

10.1182/blood.v108.11.4419.4419 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4419-4419

Author(s):

Yihuan Chai ◽

Hui Lv ◽

Jun Lu ◽

Peifang Xiao ◽

Jianqing Li

Keyword(s):

Bone Marrow ◽

Multiplex Pcr ◽

Cytogenetic Analysis ◽

Chromosomal Abnormalities ◽

Molecular Diagnostic ◽

Pcr Analysis ◽

Rt Pcr ◽

Childhood All ◽

Cytogenetic Abnormalities ◽

Conventional Cytogenetic Analysis

Abstract In childhood acute lymphocyte leukemia (ALL), cytogenetics plays an important role in diagnosis, allocation of treatment and prognosis. On base of the conventional cytogenetic analysis, molecular methods have inproved our ability to accurately and rapidly risk-stratify patient with childhood ALL in the last few years. Our aim was to assess the demography of cytogenetic abnormalities in childhood ALL. The study sample consisted of 124 newly diagnosed ALL patients younger than 16 years, who were diagnosed at the Department of Pediatric Hematology/Oncology, Soochow University Children’s Hospital. The diagnosis and FAB subtypes of ALL was determined by Wright-Giemsa-stained bone marrow smears and cytochemicalstaining. Immunophenotyping of the bone marrow samples was performed by flow cytometry. Multiplex reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed to detect the 29 most common leukemia translocations for routine molecular diagnostic hematopathology practice, and complement the information gained from conventional cytogenetic analysis. Cytogenetic analysis was successful in 112 of 124 children with ALL. Sixty-eight (60%)of them had clonal chromosomal abnormalities. Numerical imbalances consisted of hyperdipoild(>47 chromosomes, 36 cases), hypodipoild(<46 chromosomes, 14 cases), pseudodiploidy(18 cases). Chromosomal translocations were observed in 13 patients by conventional cytogenetic analysis. Three cases were found positive for t (4;11), 3 cases for t (9;22), 1 case for t (1;19) and 6 cases for other rare translocations. RT-PCR analysis detected 116 of the 124 ALL patients. Thirteen cases of TEL-AML1, 10 cases of rearrangement in the MLL gene, 4 cases of E2A-PBX1, 4 cases of E2A-HLF, 3 cases of BCR-ABL, 2 cases of TLS-ERG, 32 cases of HOX11, were detected by RT-PCR in B-lineage leukemias. SIL-TAL1 had been found in 4 of 7 of T-lineage leukemias. Sixty-eight cases of ALL show chromosomal aberrations. Multiplex PCR positivity was detected in 59(50%)of the 116 ALL patients studied. Multiplex PCR combined with chromosome analysis uncovered Chromosomal abnormalities in 95 of 124(77%) of ALL patients and supplemented each other in detecting Chromosomal abnormalities. It provides reliable evidence for the diagnosis, classification and prognosis.

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NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽

10.1182/blood.v108.11.805.805 ◽

2006 ◽

Vol 108 (11) ◽

pp. 805-805 ◽

Cited By ~ 1

Author(s):

Karsten Spiekermann ◽

Annika Dufour ◽

Gudrun Mellert ◽

Evelin Zellmeier ◽

Jan Braess ◽

...

Keyword(s):

Bone Marrow ◽

Prognostic Factors ◽

De Novo ◽

Blast Cell ◽

High Dose ◽

Bone Marrow Blast ◽

Npm1 Mutation ◽

Free Survival ◽

Cell Clearance ◽

High Dose Cytarabine

Abstract Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome. Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%). The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS. To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast <10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance. Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.

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Complex Karyotypic Abnormalities Detected by Conventional Cytogenetic Analysis More Strongly Predict Survival Than FISH, ZAP70, or IgVH Mutation Status for Previously Treated Patients with CLL.

Blood ◽

10.1182/blood.v110.11.2065.2065 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2065-2065

Author(s):

William G. Wierda ◽

S. O’Brien ◽

S. Faderl ◽

A. Ferrajoli ◽

G. Garcia-Manero ◽

...

Keyword(s):

Bone Marrow ◽

Prognostic Factors ◽

High Risk ◽

Cytogenetic Analysis ◽

Independent Predictor ◽

Alkylating Agents ◽

Mutation Status ◽

Conventional Cytogenetic Analysis ◽

Previously Treated Patients ◽

Previously Treated

Abstract Recently, several novel prognostic factors have been identified; their significance has been demonstrated in selected patient (pt) populations and retrospective analyses. As a group, previously treated pts with CLL likely have their respective, relevant prognostic factors for clinical endpoints, which may be further impacted by treatment (Rx). We prospectively evaluated the significance of newer prognostic factors: FISH abnormalities (abn) (Vysis CLL panel), IgVH mutation status, ZAP70 expression (flow & immunohistochemistry), CD38 expression (≥30%); as well as traditional factors: conventional cytogenetic analysis perfomed on bone marrow metaphases, age, sex, # prior Rx, refractoriness to alkylating agents (ALK) or fludarabine (FLU), absolute lymphocyte count (ALC), HGB, PLT, β-2 microglobulin (B2M), ALB, LDH, creatinine, and Alk Phos as independent predictors for survival in previously treated pts. The group included 473 previously treated pts seen at M.D.Anderson (10/03–8/07), who were evaluated by bone marrow sampling with conventional and FISH cytogenetic analyses, and the new and traditional prognostic factors described above. The median (range) age was 63yrs(31–87) and # prior Rx was 2(1–13). Other characteristics were: 43% Rai high-risk; 35% FLU-refractory; and 39% ALK-refractory; 74% unmutated IgVH; 54% ZAP70+ (flow); 76% ZAP70+ (IHC); and 68% CD38+. FISH results were: 22% del 17p13, 21% del 11q22, 10% +12, and 48% del 13q14 or no abn by the hierarchical classification. Conventional cytogenetic analysis of bone marrow metaphases demonstrated 25% with a complex karyotypic abn (>1 cell with >1 chromosome abn), 58% diploid, 17% with single clonal abn (>1 cell with 1 abn). Of the 100 pts with complex karyotypic abn, 50% had del 17p13, 28% del 11q22, 6% +12, 9% del 13q14, and 7% had no abn by FISH. Survival was measured from the time of prognostic factor characterization (FISH). The median follow-up time was 10mo(0–47). Univariate analyses identified the following significant (p≤.01) predictors for shorter survival: advanced age, # prior Rx, Rai high-risk, ALK- or FLU-refractory, FISH del 17p13; complex karyotypic abn (Figure 1), unmutated IgVH, high ALC, low HGB, low PLT, high B2M, low ALB, high LDH, and high Alk Phos. Multivariate analysis produced the following model with the following significant (p<.05) independent predictors for survival: ALK- (HR 2.2) or FLU-refractory (1.9), complex karyotypic abn (HR 1.8), PLT (HR 0.99), and ALB (HR 0.35). We previously reported complex karyotypic abn as a significant independent predictor for shorter survival in previously treated patients receiving chemoimmunotherapy (JCO23:4070, 2005). These data indicate that for previously treated pts with CLL, a complex karyotypic abn detected by conventional cytogenetic analysis is a strong independent predictor for survival and appears superior to FISH, and other newer prognostic factors such as IgVH mutation status and ZAP70 expression. Figure Figure

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Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy [see comments]

Blood ◽

10.1182/blood.v83.5.1193.bloodjournal8351193 ◽

1994 ◽

Vol 83 (5) ◽

pp. 1193-1199 ◽

Cited By ~ 2

Author(s):

DE Reece ◽

JM Connors ◽

JJ Spinelli ◽

MJ Barnett ◽

RN Fairey ◽

...

Keyword(s):

Bone Marrow ◽

Prognostic Factors ◽

Bone Marrow Transplantation ◽

Combination Chemotherapy ◽

Autologous Bone Marrow Transplantation ◽

Progression Free Survival ◽

Autologous Bone Marrow ◽

Free Survival ◽

First Relapse ◽

Autologous Bone

The optimal timing in which to use intensive chemotherapy and autologous bone marrow transplantation (BMT) in Hodgkin's disease (HD) is uncertain. In 1985, we initiated a program in which this modality was used as the initial salvage therapy in patients relapsing after combination chemotherapy. Fifty-eight patients with HD in first relapse after primary chemotherapy received conditioning with high-dose cyclophosphamide, carmustine, etoposide (VP16–213) +/- cisplatin (CBV +/- P) followed by autologous BMT. All but six of these patients were given a median of two cycles of conventional chemotherapy +/- involved field radiation therapy before CBV +/- P and autologous BMT. These measures were not used as a means for patients selection; all patients receiving such therapy ultimately were transplanted. The probability of nonrelapse mortality, progression of HD, and progression-free survival post-BMT were calculated, and prognostic factors for progression-free survival were evaluated using the Cox proportional hazards method. Treatment-related deaths occurred in only three patients. Thirteen patients have relapsed at a median 0.7 years (range 0.1 to 3.5) post- BMT. At a median follow-up of 2.3 years (range 0.4 to 7.2), the actuarial progression-free survival is 64% (95% confidence interval, 46% to 78%). In the statistical analysis, three similarly weighted but independent prognostic factors were identified: “B” symptoms at relapse, extranodal disease at relapse, and initial remission duration of less than 1 year. Patients with no risk factors had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors, and 0% in patients with all three factors. CBV +/- P and autologous BMT is highly effective salvage therapy for HD patients in a first relapse, particularly in the subset of patients with less than two adverse factors. Therapy must be improved in the future for patients with > or = 2 adverse factors.

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Complex Karyotype in Mantle Cell Lymphoma (MCL) Is Associated with Inferior Progression-Free Survival in Patients (pts) Receiving R-Hypercvad Followed By Autologous Stem Cell Transplant

Blood ◽

10.1182/blood.v126.23.5095.5095 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5095-5095

Author(s):

Michael Jinpyo Lee ◽

Jeffrey Switchenko ◽

Janeen S Thomas ◽

Jean L. Koff ◽

Loretta Nastoupil ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Chromosomal Abnormalities ◽

Normal Karyotype ◽

Progression Free Survival ◽

Complex Karyotype ◽

Abnormal Karyotype ◽

Free Survival ◽

The Impact

Abstract Introduction: While cytogenetic assessments are frequently utilized in many hematologic malignancies as prognostic markers, their role in MCL is less well defined. Prior studies have identified a complex karyotype (≥3 chromosomal abnormalities) in 40 - 59.2 % of patients (pts) with MCL, and it has been associated with inferior progression-free survival (PFS) in those series (Cohen et al, 2015; Sarkozy et al, 2014). Our group recently published outcomes for MCL pts at our institution, including 35 pts who received R-HyperCVAD followed by autologous stem cell transplantation (ASCT) who had an overall survival (OS) at 5-years of 74% (Nastoupil et al, 2014). We conducted an analysis of the impact of pretreatment cytogenetics on outcomes for MCL. Methods: We included all pts diagnosed with MCL at Winship Cancer Institute of Emory University between 2002 and 2014 who had available pretreatment conventional cytogenetic and clinical data. Baseline demographic, clinical, laboratory, and therapeutic variables of interest were assessed. Univariate Cox proportional hazards models were fit for each covariate, and hazard ratios are reported. Overall survival (OS) was defined as time to death or last follow-up from diagnosis, and PFS was defined as time to progression, death, or last follow-up from diagnosis. These curves were estimated via the Kaplan-Meier method, and the groups were compared using log-rank tests. We performed a similar analysis for the subset of pts initially treated with HyperCVAD and ASCT. Statistical significance was defined as α=0.05. Results: Among 184 MCL pts, 52 had pretreatment cytogenetics data available. The median age at diagnosis was 64 years (range: 32-81), 36 (69%) were male, and 37 (86%) had stage IV disease. At diagnosis, 36 pts (97%) had ECOG performance status of 0 or 1, 16 (34%) had B-symptoms, 43 (86%) had bone marrow involvement, 8 (16%) had gastrointestinal tract involvement, and 29 (71%) had splenomegaly. Initial induction therapies included R-HyperCVAD (n=27), R-CHOP (n=10), R-bendamustine (n=6), and other/unknown (n=9). Thirty pts (58%) underwent ASCT in first complete or partial remission. Five pts (10%) met criteria for a complex karyotype, 11 (21%) had 1 or 2 detectable chromosomal abnormalities, and 36 (69%) pts had a normal karyotype. Cytogenetics were assessed on nodal samples (n=7) or bone marrow/peripheral blood (n=45). Among all assessed covariates, only elevated WBC count was associated with cytogenetic abnormalities (p=0.04). Overall, there was no significant association of PFS or OS with the presence of a complex karyotype or an abnormal karyotype with < 3 abnormalities when compared to a normal karyotype. Among all assessed variables, only splenomegaly was associated with worsened PFS (p=0.02). We conducted an exploratory analysis of the 24 pts who received R-HyperCVAD followed by ASCT, of which 2 had a complex karyotype. In that subset, median PFS for pts with a complex karyotype was 35.3 months, compared to 77.9 months for those with a non-complex abnormal karyotype or a normal karyotype. Conclusion: Contrary to prior reports, a smaller percentage of pts had complex karyotype (10%) in this cohort, and pretreatment cytogenetics did not impact PFS or OS among the entire heterogeneously treated sample. However, there appears to be inferior PFS for pts with a complex karyotype in the subset who received R-HyperCVAD followed by ASCT, and a larger, multi-center series, may illuminate the impact of a complex karyotype on this subset of aggressively treated patients. Disclosures Nastoupil: AbbVie: Research Funding; Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; Janssen: Research Funding. Flowers:Infinity Pharmaceuticals: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy; Gilead Sciences: Research Funding; Millennium/Takeda: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Onyx Pharmaceuticals: Research Funding; Millennium/Takeda: Research Funding; OptumRx: Consultancy; AbbVie: Research Funding; Seattle Genetics: Consultancy; Genentech: Research Funding; OptumRx: Consultancy; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding. Cohen:Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy; BMS, Janssen: Research Funding.

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Clinical Outcome of Hypomethylating Agents in Hypocellular MDS: Mayo Clinic Experience

Blood ◽

10.1182/blood.v126.23.5254.5254 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5254-5254

Author(s):

Sonia Cerquozzi ◽

Hassan B Alkhateeb ◽

Moritz Binder ◽

Darci Zblewski ◽

Shahrukh K Hashmi ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Median Time ◽

Cytogenetic Analysis ◽

Research Funding ◽

Median Overall Survival ◽

Progression Free Survival ◽

Hypomethylating Agents ◽

Free Survival ◽

Very High

Abstract Introduction: Hypocellular myelodysplastic syndrome (h-MDS) represents only a small portion of MDS, of which, the clinical significance and outcomes are not well understood. Both laboratory and clinical evidence suggests that h-MDS shares immune-mediated pathogenic mechanisms similar to acquired aplastic anemia. As a result, immunosuppressive therapy (IST) has been the mainstay treatment. Since h-MDS is poorly understood and reported response rates to IST vary, we retrospectively reviewed the outcome of our patients with hypocellular MDS and identified the effectiveness of alternative therapy using hypomethylating agents (HMA). Methods: AllMDS patients over a 13-year period (June 1997 to May 2010) were captured after an IRB approval was obtained. Patients' demographics, labs, bone marrow aspirates and biopsies as well as cytogenetic data were collected. We used the currently accepted age-adjusted criteria to define hypocellularity as ≤ 30% in patients <70 years old, and ≤20% in >70 years old. Only patients with available response data were included in the final analysis. Survival estimates were calculated using Kaplan-Meier curves. Results: We identified 65 (8%) h-MDS patients from a cohort of 827 adult MDS. Median age was 68 years (range, 20-90), with 69% males. The largest group of patients were RAEB-1 at 9 (14%) and RAEB-2 at 14 (22%) along with RCMD at 18 (28%) and 15 (23%) MDS-U, 2 (3%) MDS 5q, 4 (6%) RARS and 2 (3%) were considered atypical. Cytogenetic analysis was normal in 17 (26%) with 7 (11%) having trisomy 8, and 11 (16%) and 14 (22%) having abnormalities of chromosome 7 and 5, respectively. IPSS-R were very low, low, intermediate, high, and very high in 4%, 30%, 28%, 21% and 17%, respectively. Leukemic transformation (LT) occurred in 6 (9%). The 4 year overall survival and progression free survival was 35% and 34%, respectively. Median overall survival and progression free survival was 30.2 and 29.7 months, respectively. Nine out 65 h-MDS patients were treated with a HMA, azacitidine (4) or decitabine (5). The median age of patients was 71 years (range, 66-85) with 6 (66%) being males. The median cellularity of the diagnostic bone marrow was 15% with the majority of patients presenting with RAEB-1 (11%) and RAEB-2 (55%) classification and 2 (22%) cases of RCMD as well as 1 (11%) case of MDS with isolated 5q. Cytogenetic analysis was normal in 3 (33%). IPSS-R were low in 1 (11%), intermediate in 4 (44%), high in 1 (11%) and very high risk in 3 (33%). The median time to initiation of a HMA from diagnosis was 5 months with response assessed at a median of 4.2 months. Two patients had received prior therapy including lenalidomide (for MDS 5q) and one had 1 cycle of trial therapy. Two patients (22%) achieved a marrow complete remission at a median time of 2.95 months; with one case of relapse at 9.8 months using HMA. Three patients (33%) had LT at a median time of 7.9 months post initiation of HMA. Median overall survival of patients with LT was 20 days. A total of 4 (44%) patients remain alive with a leukemia free survival of 67% at 2 years. In comparing to h-MDS patients without HMA treatment versus HMA treated, median OS was 28.2 vs 50.9 months (p=0.41) and PFS was 28.1 vs 40.6 months (p=0.69), respectively. Conclusions: The results from our clinical experience confirm that hypocellular MDS is a rare variant and that it is distinct from normocellular/hypercellular MDS. Two thirds of h-MDS received HMA for the treatment of higher risk disease (RAEB1-2). HMA has some efficacy in h-MDS. Further studies are warranted to better understand the clinical significance and outcomes of hypocellular MDS. Disclosures Binder: American Society of Hematology: Research Funding. Al-Kali:Celgene: Research Funding.

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IMMU-08. MODELING UPFRONT GLIOBLASTOMA SURGICAL RESECTION AND STEROID USE REVEALS IMMUNOSUPPRESSIVE CHANGES AND SUGGESTS THAT PERIPHERAL LYMPHOCYTE COUNTS ARE ASSOCIATED WITH TUMOR VOLUME AND PROGNOSIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.439 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii106-ii106

Author(s):

Balint Otvos ◽

Tyler Alban ◽

Matthew Grabowski ◽

Defne Bayik ◽

Robert Winkelman ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Surgical Resection ◽

Cd8 T Cells ◽

Tumor Volume ◽

Progression Free Survival ◽

Peripheral Lymphocyte ◽

Steroid Use ◽

Free Survival ◽

Steroid Administration

Abstract Glioblastoma (GBM) and its treatment produces systemic immunosuppression, which is being targeted by immunotherapies. However, it remains unclear how surgical resection and steroids specifically in GBM alter the immune system. To further explore this issue, immunocompetent C57Bl/6 mice were intracranially inoculated with syngeneic glioma cells (GL261 and CT-2A) and growth of tumors was evaluated by MRI. Host immune cell populations were analyzed during surgical resection and steroid administration. Mice with surgically resected tumors had a longer median survival compared to mice subjected to tumor biopsies, and had increased bone marrow sequestration of both CD4 and CD8 T cells with corresponding decreased blood lymphocytes. Furthermore, physiologic doses of dexamethasone administered perioperatively decreased tumor edema, but increased the number and proliferative capacity of both marrow and circulating MDSCs while generating no survival benefit. Independent of therapy or dexamethasone, intracranial tumor volume correlated linearly with decreased CD4 and CD8 T cells in peripheral blood, and increased T cell sequestration within the bone marrow. We validated these parameters in steroid-naïve newly diagnosed GBM patients and observed decreased lymphocytes correlated linearly with increased tumor volume. When initial lymphocyte counts in both steroid-naïve and steroid-administered patients were used in univariate and multivariate models predicting progression-free survival and overall survival, decreased initial lymphocyte counts were an independent predictor of decreased progression free survival and decreased overall survival, with steroid use and initial tumor size falling out of significance during stepwise selection. Taken together, tumor volume is linearly correlated with marrow sequestration of lymphoid cells, but both surgery and steroid administration further suppress active immune responses along lymphoid and myeloid lineages. Furthermore, decreasing peripheral lymphocyte counts at diagnosis of GBM indicate an immune system less able to mount responses to the tumor and portent a worse progression free and overall survival.

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Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study

Scientific Reports ◽

10.1038/s41598-021-96089-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Hiraoka ◽

Takashi Kumada ◽

Toshifumi Tada ◽

Joji Tani ◽

Kazuya Kariyama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Liver Disease ◽

Hazard Analysis ◽

Progression Free Survival ◽

Significant Prognostic Factor ◽

Disease Etiology ◽

Alcoholic Fatty Liver ◽

Free Survival ◽

Significant Difference

AbstractIt was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.

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Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma

npj Precision Oncology ◽

10.1038/s41698-021-00185-0 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Matthew A. Wall ◽

Serdar Turkarslan ◽

Wei-Ju Wu ◽

Samuel A. Danziger ◽

David J. Reiss ◽

...

Keyword(s):

Multiple Myeloma ◽

Chromosomal Abnormalities ◽

Transcriptional Regulatory Network ◽

Progression Free Survival ◽

Cross Sectional ◽

Free Survival ◽

Extreme Risk ◽

Transcriptional Regulatory ◽

Transcription Regulators ◽

Immunosuppressive Microenvironment

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.

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