Haploidentical Transplantation Using T-Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors Is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of A Prospective Phase II Trial

Abstract Abstract 889 Introduction: Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for nearly all patients to benefit from HSCT when a human leukocyte antigen (HLA) genotypically matched donor is not available. Initial approaches to mismatched allografting using ex-vivo T-cell depletion and intense preparative regimens were associated with high rates of graft rejection, severe graft-versus-host disease (GVHD) and infectious complications, resulting in an unacceptable treatment-related morbidity and mortality. More promising outcomes have been recently demonstrated by a new approach to haploidentical transplantation, utilizing a nonmyeloablative preparative regimen, followed by a T cell-replete bone marrow infusion and post-transplantation immunosuppression with high dose Cyclophosphamide (Cy), tacrolimus, and mycophenolate mofetil (MMF). However, relapse represents the major cause of treatment failure in these patients, particularly with high-risk myeloid malignancies. Methods: In order to decrease relapse risk in patients with high-risk malignancies, we initiated a trial between January 2009 and March 2011, of haploidentical allografting using a myeloablative preparative regimen and peripheral blood stem cells (PBSC) instead of bone marrow as the graft source. Eligibility was limited to patients perceived to be at prohibitively high risk of relapse following nonmyeloablative haploidentical BMT. Initial conditioning (n=5) consisted of Fludarabine 30 mg/m2 on days −7 to −2, IV Busulfan 130 mg/m2 on days −7 to −4, and Cy 14.5 mg/kg on days −3 and −2 followed by an unmanipulated PBSC infusion in all patients. In response to increased rates of mucositis, fludarabine and busulfan doses were decreased by 30% and 15%, respectively, in subsequent patients. Post-grafting immunosuppression consisted of Cy 50mg/kg/day on days 3 and 4, MMF, and tacrolimus. Results: A total of twenty patients were enrolled in the study: median age 44 years (25–56); diagnoses AML=12, ALL= 2, HD=1, CML=3, CLL=1, NHL=1; allograft from 5/10 locus matched (n=14), 6/10 locus matched (n=2), 7/10 locus matched (n=3), or 8/10 locus matched (n=1). CIBMTR disease risk-high risk =7 (35%), intermediate risk = 4 (20%) or low risk = 9 (45%). Of the 9 low risk patients, seven were cytogenetically poor-risk AML and/or required ≥2 induction cycles to induce complete response. Donor engraftment occurred in all 20 patients, with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. All evaluable patients achieved complete donor T cell and myeloid chimerism by Day +30. The cumulative incidence of grades II–IV and grades III–IV aGVHD was 30% and 20%, respectively. The cumulative incidence of cGVHD at one year was 42%. Non-relapse mortality (NRM) at 100 days and 1 yr was 10% for all patients and 0% for low-risk patients. Non-infectious fever (median tmax 103.9; 101.2–106.8), possibly related to cytokine release from proliferating alloreactive cells, developed in 90% of patients within a median of 2.5 days (1–5) of transplant and resolved by day 6 (5-7) following post-transplant Cy. BK virus-associated cystitis occurred in 75% of patients, and was severe (requiring hospital admission for bladder irrigation and/or pain management) in 35%. Other severe infections were not seen at increased frequency compared to conventional donor myeloablative transplants at our center. With a median follow-up of 14 months, the estimated 1 year overall and disease-free survival was 74% and 51%, respectively for all patients; 100% and 76%, respectively for low-risk patients. Conclusion: HLA haploidentical HSCT using this myeloablative regimen with T-cell replete PBSC and post-transplant Cy is associated with excellent rates of engraftment, GVHD, NRM and DFS, it is therefore a valid option in patients with high-risk malignancies who lack timely access to a conventional donor. Disclosures: Sizemore: Otsuka America Pharmaceuticals, Inc.: Research Funding. Bashey:Otsuka America Pharmaceuticals, Inc.: Research Funding. Sanacore:Otsuka America Pharmaceuticals, Inc.: Research Funding. Manion:Otsuka America Pharmaceuticals, Inc.: Research Funding. Holland:Otsuka America Pharmaceuticals, Inc.: Research Funding. Morris:Otsuka America Pharmaceuticals, Inc.: Research Funding. Brown:Otsuka America Pharmaceuticals, Inc.: Research Funding. Solomon:Otsuka America Pharmaceuticals, Inc.: Research Funding.

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Five Gene Probes Carry Most Of The Discriminatory Power Of The 70-Gene Risk Model In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.125.125 ◽

2013 ◽

Vol 122 (21) ◽

pp. 125-125

Author(s):

Christoph Heuck ◽

Pingping Qu ◽

Frits van Rhee ◽

Sarah Waheed ◽

Saad Z Usmani ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Risk Model ◽

Progression Free Survival ◽

Dna Probes ◽

Low Risk ◽

Free Survival ◽

The Us ◽

Risk Patients ◽

Total Therapy

Abstract Gene expression profiling (GEP) reliably predicts overall and progression free survival in multiple myeloma. Driven by the concept that therapy will reveal biology, we applied the GEP70 risk model to 56 patients enrolled in Total Therapy 6 (TT6), a phase 2 trial for previously treated patients. One year survival estimates were 62% vs.97%, p<0.0001, Figure 1A). To investigate whether fewer than the 70 genes could predict this difference in outcomes, the probe sets of the GEP70 risk model were ranked by p-values, based on univariate Cox regression analysis for OS. The five probe sets with the smallest P values (corresponding to genes ENO1, FABP5, TRIP13, TAGLN2, and RFC4) were combined to create a continuous score (Figure1B). Association of several of these genes with different cancers has previously been reported by others. We re-trained this 5 gene model (GEP5) on a dataset of 275 uniformly treated patients on Total Therapy 3A (TT3A) and identified a new optimal cutoff of 10.68. We validated this new cutoff with patients enrolled in Total Therapy 2 (TT2) (n=351) and Total Therapy 3B (TT3B) (n=166). For TT2 patients, the dataset from which the GEP70 model was developed, clinical outcomes of the GEP5defined low risk patients were very similar to the GEP70 defined low risk patients. Survival estimates were higher for GEP5-defined high risk than for GEP70 high risk patients (5-year estimated OS: 40%, GEP5; 28%, GEP70; 5-year estimated PFS: 26%, GEP5; 15%, GEP70) (Figure 2A and 2B). This was also seen in both TT2 treatment arms. For the second validation cohort (TT3B), GEP5 and GEP70 risk distinction were similar to the TT3A discovery cohort (Figures 2C and 2D). On multivariate analysis, the GEP5-defined high-risk designation was the most adverse variable for PFS, with an estimated hazard ratio of 3.44 (95% CI: 2.02-5.86), whereas the GEP70 model was selected first for OS. (Table 1).Table 1.Multivariate stepwise Cox regression analysis performed on the TT3B validation setOverall survivalProgression-free survivalVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueMultivariateGEP70 high-risk36/159 (23%)4.45 (2.47, 8.02)<.001B2M > 5.5 mg/L49/159 (31%)1.73 (1.01, 2.95)0.045GEP5 high-risk42/159 (26%)3.44 (2.02, 5.86)<.001 Applied to the publicly available dataset from the HOVON group, GEP5 identified a high risk group with a 3-year estimate OS survival of 52% compared to 75% for the low risk group (p<0.001). TT4 and TT5 are phase 2 trials for previously untreated GEP70 defined low-risk and high-risk patients, respectively. GEP5 identified in TT4 a subset (17/303) of high risk patients with significantly worse 3-year estimated OS (69% vs. 86%, p=0.03), and in TT5 GEP5 identifies a low-risk subset (22/57) of patients with significantly better 3-year estimate OS (94% vs. 59%, p=0.01). Recently a large-scale proteomics experiment involving 85 patients with MM identified ENO1, FABP5, and TAGLN2 among a set of 24 proteins that are associated with short OS. It was further shown that gene expression levels correlated closely with protein abundance. In summary, we have identified 5 genes that have the greatest influence on GEP defined risk. The GEP5 score maintains prognostic power even in patients who have been risk stratified using other risk models. The correlation of expression at both mRNA and protein levels indicate that the genes identified in GEP5 are not simply an artifact of the microarray methodology, but rather supports their biologic relevance. This simplified risk model with a reduced number of genes has the potential to open molecular risk testing to a larger audience. Figure 1. Figure 1. Overall Survival in TT6 according to A) GEP70 risk score and B) GEP5 risk score Figure 2. Figure 2. Overall survival (left panels) and progression-free survival (right panels) according to GEP5 risk score in A) TT3A training set set, B) TT2 test set and C) a second test set TT3B Figure 3. Figure 3. Overall survival (left panels) and progression-free survival (right panels) according to GEP5 in A) the publicly available HOVON dataset B) TT4, for previously untreated GEP70 defined low-risk myeloma and C) TT5, for previously untreated GEP70 defined high-risk myeloma Disclosures: van Rhee: Jansen & Jansen: Research Funding. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Epstein:University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties. Zhang:University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; Myeloma Health, LLC: Patents & Royalties.

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A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22031075 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1075

Author(s):

Luca Bedon ◽

Michele Dal Bo ◽

Monica Mossenta ◽

Davide Busato ◽

Giuseppe Toffoli ◽

...

Keyword(s):

Machine Learning ◽

Hepatocellular Carcinoma ◽

High Risk ◽

Progression Free Survival ◽

Low Risk ◽

Functional Enrichment ◽

Free Survival ◽

High Risk Patients ◽

Risk Of Progression ◽

Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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T Cell Reconstitution in First 200 Days Post Transplantation Predicts Long Term Survival in Allogeneic Hematopoetic Progenitor Cell Transplantation (HPCT).

Blood ◽

10.1182/blood.v108.11.3224.3224 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3224-3224 ◽

Cited By ~ 1

Author(s):

Laura Vann ◽

Milcah Larks ◽

Christopher Flowers ◽

Sagar Lonial ◽

Jonathan Kaufman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

High Risk ◽

Immune Cells ◽

Conditioning Regimen ◽

Low Risk ◽

Myeloablative Conditioning ◽

Post Transplant ◽

Risk Patients ◽

Study Population

Abstract Background: Successful reconstitution of cellular immunity following allogeneic HPCT reduces the risk of relapse and confers protection against opportunistic infections. We performed an IRB-approved retrospective analysis of patients who underwent allogeneic HPCT and in whom the content of immune cells were measured in the graft and in post-transplant blood samples. Methods: The study population consisted of 122 patients with hematologic disorders (71 acute leukemia; 14 chronic leukemia; 18 lymphoma, 12 MDS; 3 aplastic anemia; and 4 other) who underwent HPCT with a non-T cell depleted graft from an HLA matched related (73) or unrelated (49) donor. 47 patients had low risk disease (AA, ALL CR1, AML CR1, CML CP1), while 75 had high risk disease (all others). The conditioning regimen was non-myeloablative in 38 (31%), included ATG in 18 (15%), and included TBI in 54 (44%). Peripheral blood was drawn at a median of 101 days post-HPCT and analyzed for T-cell subsets, B-cells, NK cells, and dendritic cells. Subjects were divided into three strata based upon the maximal value for the content of each cell subset in the blood. Univariate and multi-variable stepwise logistic regression analyses were performed to test the association of pre-transplant clinical factors, the cells in the graft, and the numbers of immune cells in the blood post-transplant with overall survival. Results: The estimated three-year survival for all subjects was 53%, with death in 49/122 patients (40%) due to progressive disease (37%), infection (29%), GVHD (20%), and other causes (14%). Univariate factors associated with death included high risk, age, the use of reduced intensity conditioning regimen, the use of TBI, the use of ATG during conditioning and the measurement of lower numbers of total T-cells, CD4+ T-cells, CD8+ T-cells, γδ T-cells, DC1 and DC2 in the peripheral blood during the first 200 days post-transplant. A multi-variable Cox model identified non-myeloablative conditioning (HR 2.2, 95% CI 1.2–3.9), TBI (HR 1.9, 95% CI 1.1–3.3), transplant risk strata (HR 1.9, 95% CI 1.0–3.6), and a blood CD3+ T-cell count of less than 600 cells/mcL (HR 1.8, 95% CI 1.2–2.5) as independent risk factors for post-transplant death. The presence of acute GVHD (all grades) or graft constituents was not significantly associated with survival. Limiting the study population to those subjects who survived at least 100 days showed that blood CD3+ T-cells, non-myeloablative conditioning, the use of TBI remained significantly associated with survival. Conclusions: Higher CD3+ counts in the early post-transplant period predict better survival. Patients who fail to achieve a blood CD3+ T-cell count of >600/mcL in the first 200 days post-transplant may be appropriate subjects for adoptive cellular immunotherapy. Low Risk Patients Low Risk Patients High Risk Patients High Risk Patients

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Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial.

Blood ◽

10.1182/blood.v114.22.100.100 ◽

2009 ◽

Vol 114 (22) ◽

pp. 100-100 ◽

Cited By ~ 3

Author(s):

Ralf Trappe ◽

Sylvain Choquet ◽

Stephan H.K. Oertel ◽

Veronique Leblond ◽

Daan Dierickx ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Risk Stratification ◽

Disease Progression ◽

Early Treatment ◽

Interim Analysis ◽

Research Funding ◽

Low Risk ◽

Sequential Treatment ◽

Risk Patients

Abstract Abstract 100 Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression. Methods: An ongoing prospective, multicenter, international phase II trial was initiated in January 2003. Initially patients were treated with a fixed sequence of rituximab at days 1, 8, 15 and 22 (4R) followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab (sequential treatment, ST). Based on the results of an earlier interim analysis showing that the response to rituximab predicts OS the trial was amended in 2007 introducing risk stratification according to the response to 4R (risk stratified sequential treatment, RSST). In RSST patients achieving a complete remission after 4R (low risk) continue with four 3-weekly courses of rituximab monotherapy while patients in PR, SD or PD (high risk) are followed by four cycles of R-CHOP-21 + G-CSF. Results: This is a scheduled interim analysis after inclusion of a total of 104 patients. The median follow up is 34.0 months for ST (64 pts.) and 9.1 months for RSST (40 pts.). 61 ST and 35 RSST patients were diagnosed with monomorphic PTLD, 3/5 with polymorphic PTLD. 27/23 patients were kidney, 3/0 kidney+pancreas, 15/8 liver, 13/6 heart, 6/3 lung or heart+lung transplant recipients. Median age at diagnosis of PTLD was 53/60 years (mean age: 48/56 years). 59%/58% of patients had an advanced stage of disease (Ann Arbor III/IV) and 49%/47% of tumors were EBV positive. 75%/75% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 71%/64% of patients, respectively. The overall response rate (ORR) to 4 initial courses of rituximab monotherapy (4R, N=104) was 54% with a CR-rate of 32% and the subsequent completion of treatment with CHOP or R-CHOP allowed a clear increase of the response (p<0.0001, Fig. 1). With ST the final ORR was 89% (CR rate: 69%). 86%, 75% and 75% of patients were without disease progression at one, two and three years, respectively (Fig. 2a). Disease free survival was 87%, 78% and 70% at one, two and three years. There were 6 early treatment associated deaths (9%) resulting from infections (1 from CMV-colitis, 1 from PcP-pneumonia, 1 from fulminant hepatitis, 3 from sepsis) and 2/64 patients died from refractory PTLD. Two further patients died due to hemorrhage during treatment. With RSST the ORR was 90% and 73% achieved a complete remission. 90% of patients were without disease progression at one year (Fig. 2a). There was one early treatment related death due to infection (2.5%). This patient died from sepsis secondary to intestinal perforation in response to R-CHOP treatment. 2/40 patients died from refractory PTLD. With 1 event in 16 patients in both, the ST and the RSST-arms, subsequent consolidation with rituximab monotherapy (RSST) seems not to be inferior to consolidation with 4 cycles of CHOP (ST) in patients with a CR after 4R. Up to now there is no difference in toxicity between CHOP and R-CHOP in ST/RSST. Patients failing to achieve a complete remission with 4R (72 patients) seem to benefit from the subsequent escalation from CHOP to R-CHOP (Fig. 2b). Conclusions: This is the largest prospective study in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective with a treatment related mortality of less than 10% and an efficacy of up to 90%. In comparison to historic series of rituximab monotherapy, significantly more patients achieve a CR with sequential treatment and time to progression (TTP) is very much prolonged. In comparison to historic series of CHOP, sequential treatment is much better tolerated. This may result from a lower tumor burden and a better patient fitness at the time chemotherapy is applied. Introduction of risk stratification according to the response to 4 courses of rituximab monotherapy might further improve these results restricting chemotherapy related toxicity to high risk patients while these data suggest that low risk patients can effectively be treated with extended rituximab monotherapy. Thus, risk stratified sequential treatment (RSST) might further improve OS in this difficult to treat disease. Disclosures: Trappe: Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmbH: Research Funding. Choquet:Hoffmann La Roche Ltd.: Consultancy, Honoraria. Oertel:Hoffmann La Roche Ltd.: Employment, Equity Ownership. Leblond:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Ekman:Hoffmann La Roche Ltd.: Honoraria. Dührsen:Hoffmann La Roche Ltd.: Honoraria, Research Funding. Salles:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Morschhauser:Hoffmann La Roche Ltd.: Honoraria. Riess:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmBH: Consultancy, Honoraria, Research Funding.

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Rituximab Maintenance Benefits Less for Follicular Lymphoma Patients with Low Risk of the Follicular Lymphoma International Index

Blood ◽

10.1182/blood-2021-147114 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3544-3544

Author(s):

Tingyu Wang ◽

Ru Li ◽

Rui Lv ◽

Ying Yu ◽

Jiawen Chen ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Progression Free Survival ◽

Risk Groups ◽

Low Risk ◽

Control Group ◽

Intermediate Risk ◽

Free Survival ◽

Rituximab Maintenance ◽

Risk Patients

Abstract Background Follicular lymphoma (FL) is an incurable indolent disease with a heterogeneous course. The Follicular Lymphoma International Prognostic Index (FLIPI) is the most commonly used prognostic system to predict survival. Rituximab-based immunochemotherapy is now the standard choice for the first-line therapy of FL, followed by rituximab maintenance (RM) in patients with response, which prolongs the progression-free survival (PFS). However, the role of RM in different FLIPI risk groups has never been studied as we know. In this study, we aimed to illustrate the effect of RM in FLIPI risk groups. Methods Newly diagnosed FL patients at our center were enrolled in this analysis. All the patients received the rituximab-based chemoimmunotherapy induction regimens. Response assessments were determined according to Lugano's 2014 criteria. Patients who didn't respond to induction were excluded. Categorical variables were compared using Fisher's exact test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results From May 2003 to September 2020, 203 newly diagnosed FL were included. 192 patients (95.0%) achieved remission (complete response, CR/partial response, PR) after immunochemotherapy induction, of whom 96 patients continued rituximab maintenance therapies every 3 months for 1-2 years (RM group) (median 7 times，range 4 to 12). 96 patients received no maintenance or fewer than 4 times (control group) (median 0 times, range 0-3). There were no significant differences in baseline characteristics other than the Ann Arbor stage and pathological grade. The RM group patients were more likely to be at low grade (71.8% vs 54.9%, P = 0.042) and advanced stage (90.6% vs 78.7% , P = 0.027) (Table 1). After a median follow-up of 36.4 months (95% confidence interval [CI], 32.2 to 40.6), median OS and PFS were not reached. The 5-year OS rates and PFS rates were 95.1% (95%CI, 90.2%-100%) and 83.0% (95%CI, 75%-91%)(Fig 1). And RM significantly prolonged the PFS, with 5-year PFS rates 92.2% (95%CI, 85.1%-99.3%) and 70.3%(95%CI, 55%-85.6%) (P = 0.0003) (Fig 2). According to FLIPI risk stratification, patients were classified into low-risk, intermediate-risk, and high-risk groups. The 5-year PFS rates were 97.7% (95%CI, 93.2%-100%), 84.7% (95%CI, 70.4%-99%), and 67.8% (95%CI, 49%-86.6%), respectively (Fig 3). For low-risk patients, there was no significant difference in PFS for the RM group vs the control group. However, for both intermediate risk and high-risk patients, PFS was significantly longer in the RM group compared to the control group (P < 0.0001). The PFS rates at 5 years in intermediate-risk patients were 100% and 77.8% (95%CI, 40.8%-92.6%), for the RM group vs control group, high risk 76.4% (95%CI, 54.3%-98.5%), and 54.9% (95%CI, 21.6%-88.2%), respectively (Fig 4). Conclusion Standard rituximab maintenance significantly prolongs progression-free survival in FLIPI intermediate risk and high-risk patients with FL, but not in the FLIPI low risk group. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

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A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽

10.1182/blood-2018-99-114620 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2872-2872 ◽

Cited By ~ 2

Author(s):

Farheen Mir ◽

Andrew Grigg ◽

Michael Herold ◽

Wolfgang Hiddemann ◽

Robert Marcus ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Model ◽

Low Risk ◽

Prognostic Variables ◽

Advisory Committees ◽

High Risk Disease ◽

Risk Patients ◽

Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

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Oncogenetic Risk Classification Based on NOTCH1/FBXW7/RAS/PTEN Mutation Profiles Improves Outcome Prediction in Pediatric T-Cell Acute Lymphoblastic Leukemia, Treated According the Fralle 2000 T Guidelines

Blood ◽

10.1182/blood.v128.22.1083.1083 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1083-1083 ◽

Cited By ~ 1

Author(s):

Arnaud Petit ◽

Amélie Trinquand ◽

Sylvie Chevret ◽

Paola Fabiola Ballerini ◽

Jean-Michel Cayuela ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Low Risk ◽

Study Cohort ◽

Risk Patients ◽

Cell Acute Lymphoblastic Leukemia ◽

Wbc Count ◽

Risk Of Relapse

Abstract Background: Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is crucial to drive treatment decisions. Since patients with induction failure or relapse are often refractory to further treatment, identifying high risk patients up-front will allow improved treatment. While minimal residual disease (MRD) is the strongest prognosis risk factor used after complete remission (CR), NOTCH1/FBXW7 (N/F) and RAS/PTEN (R/P) mutation profiles at diagnosis have recently been identified to predict outcome in adult T-ALL. Objective: to test whether an oncogenetic classifier using N/F and R/P mutations could improve the detection of children with T-ALL at risk of relapse. Methods: 405 patients with T-ALL aged from 1 to 14 years were treated according to FRALLE T guidelines (FRALLE Study group) between 2000 and 2010. Among them, 220 patients, for whom biological material at diagnosis was available, were tested retrospectively for N/F and R/P mutations. These study cohort patients were representative of overall FRALLE 2000 T-ALLs. CR was achieved in 213 patients. MRD (IgH-TCR markers) tested at CR (day 35) was available for 191 patients. MRD was <10-4 for 114 patients (60%) and ≥10-4 for 77 patients. Patients with N/F mutation and R/P germline (GL) were defined as oncogenetic low risk (LoR), while N/F GL and R/P GL or mutation and N/F mutation and R/P mutation were defined as high risk (HiR). Results: 111 patients were classified as LoR and 109 as HiR. Five-year-CIR and DFS were respectively 35.5% (95% CI, 26.7-44.3) and 59% (95%CI, 50.2-69.6) for HiR versus 13% (95% CI, 6.8-19.2) and 86.8% (80.5-93.5) for the LoR group (Figures A and B). HiR patients were significantly associated with MRD ≥ 10-4 (p=0.0004) and higher risk of relapse (p=0.00002). Among patients with MRD ≥ 10-4, HiR feature worsened the risk of relapse: 5-year-CIR and DFS were respectively 42.8% (95% CI, 28.9-56.7) and 71.1% (95%CI, 56.0-90.2) in HiR versus 28.9% (95% CI, 11.7-46.1) and 50.9% (95%CI, 38.4-67.6) in the LoR group. Among patients with MRD <10-4, 5-year-CIR and DFS were respectively 28.9 % (95% CI, 15.0-42.8) and 71.0% (95%CI, 58.4-86.3) in HiR group versus 4.4% (95% CI, 0-9.2) and 95.5% (95%CI, 90.7-1.00) in LoR group (Figures C and D). As such, the classifier allowed identification of 63% of very low risk patients amongst the MRD<10-4 population. Prognostic values of new oncogenetic risk factors were then analyzed with conventional factors. By univariate analysis, factors identified to predict relapse were male gender (p=0.036), WBC count ≥ 200 G/L (p=0.023), chemoresistance at day 21 (p=0.007), MRD ≥10-4 (p=0.0006) and oncogenetic HiR (p<0.0001). A multivariable cox model including these variables selected the classifier together with WBC count, day 21 chemo-sensitivity and MRD. Based on a stepwise selection procedure, the three most discriminating variables were classifier, WBC count and MRD. The cause specific Hazard Ratio (HR) was 3.22 (95% CI, 1.64-6.28) for oncogenetic HiR versus LoR (p=0.0006), 2.30 (95% CI, 1.26-4.20) for MRD≥10-4 versus MRD<10-4(p=0.0070) and 1.85 (95% CI, 1.01-3.37) for WBC≥200G/L versus <200 G/L (p=0.0456). Based on these three parameters, 8 subsets of patients were defined according to the estimated 5-year CIR. The 58 patients (30%) associating WBC count < 200G/L, classifier LoR and MRD<10-4 were at very low risk of relapse, with a 5-y-CIR of 1.7%. Patients harboring at least one of: WBC count ≥200G/L, classifier HiR or MRD>10-4, demonstrated an increasing CIR, up to 45.8% if all three were associated. Conclusion: in childhood T-ALL, oncogenetic classification using N/F and R/P mutation profiles is an independent predictor of relapse. When combined with MRD and WBC count ≥200 G/L, it significantly improved relapse prediction, particularly amongst the 60% of T-ALLs with MRD <10-4 at day 35. Appropriate integrating these 3 factors, will help optimize treatment. Figure Figure. Disclosures No relevant conflicts of interest to declare.

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The NCCN-IPI Score Is Prognostic of Survival in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified

Blood ◽

10.1182/blood-2018-99-113187 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5363-5363

Author(s):

Brady E. Beltrán ◽

Denisse A. Castro ◽

Yesenia M. Huerta- Collado ◽

Eduardo Sotomayor ◽

Jorge J. Castillo

Keyword(s):

Overall Survival ◽

T Cell ◽

High Risk ◽

Research Funding ◽

Cell Lymphoma ◽

Low Risk ◽

T Cell Lymphoma ◽

Score Distribution ◽

Peripheral T Cell Lymphoma ◽

Not Otherwise Specified

Abstract Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) accounts for 15-20% of NHL and is characterized by a poor survival. The IPI and PIT scores are prognostic factors in survival in B-cell and T-cell lymphomas, but not without limitations. The aim of this study is to evaluate the prognostic value of the NCCN-IPI score in patients with PTCL-NOS. Methods: We included patients with a pathological diagnosis of PTCL-NOS who were diagnosed and treated at our institution between 1997 and 2017. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists at our institution to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratios (HR) for overall survival (OS). Results: A total of 173 patients with diagnosis of PTCL-NOS were included in this analysis. The median age at diagnosis was 58 years (range 18-91 years) with a male predominance (58%). Clinically, 47% of patients were 60 or older, 52% presented with ECOG >1, 82% had elevated serum LDH, 74% had extranodal disease, and 34% had stage I/II and 66% had stage III/IV. IPI score distribution was low-risk in 55% of patients, low-intermediate in 36%, high-intermediate in 48% and high-risk in 33%. PIT score distribution was low-risk in 53%, low-intermediate in 67%, high-intermediate in 38% and high-risk in 14%. NCCN-IPI score distribution was low risk in 40%, low-intermediate in 56%, high- intermediate in 63% and high risk in 11%. 22% of patients received CHOEP, 23% received CHOP, and 55% received other regimens. The overall response rate was 59%; 47% had a complete response and 12% had a partial response. The 5-year overall survival (OS) rate was 32% with a median OS of 12 months. PTCL-NOS patients with low, low-intermediate, high-intermediate and high-risk NCCN-IPI had 5-year OS rates of 46%, 36%, 26% and 0%, respectively (p<0.001). When compared with patients with low-risk NCCN-IPI, patients with low-intermediate (HR 3.2, 95% CI,1.1-9.5; p=0.044) and high-intermediate /high risk NCCN-IPI (HR 6.0, 95% CI 2.1-17; p=0.001) had worse OS. Conclusions: We have validated the NCCN-IPI score as a prognostic tool in patients with PTCL-NOS. This work can serve to address future prospective designs that allow selection of groups of patients at greater risk and thus lead to more individualized therapy. Figure. Figure. Disclosures Castillo: Janssen: Consultancy, Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Beigene: Consultancy, Research Funding.

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Real-World Treatments and Thrombotic Events in Polycythemia Vera Patients: A Retrospective Analysis between 2018-2019 in US Population

Blood ◽

10.1182/blood-2020-142549 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Srdan Verstovsek ◽

Ariel Han ◽

Karin Chun Hayes ◽

Tracy Woody ◽

Frank Valone ◽

...

Keyword(s):

High Risk ◽

Real World ◽

Blood Cells ◽

Initial Treatment ◽

Research Funding ◽

Treatment Initiation ◽

Low Risk ◽

High Risk Patients ◽

Risk Patients

BACKGROUND Polycythemia Vera (PV) is a rare myeloproliferative neoplasm associated with an increased production of red blood cells, white blood cells, and platelets. Most frequent treatment includes phlebotomy, hydroxyurea, interferon, and ruxolitinib. Current NCCN guideline recommends managing HCT levels to below 45%. The objective of this study was to determine real-world standards of care and patient characteristics, and to observe how treatment decisions vary by HCT level and thrombosis risk. METHODOLOGY We conducted a retrospective study using Symphony Health's longitudinal transactional healthcare claims database that includes prescription, medical and hospital claims across > 4,900 US payers representing 86% of US lives. Eligible patients had at least one ICD-10 diagnosis code for PV and at least one of the treatments including phlebotomy, hydroxyurea, busulfan, interferon, and ruxolitinib between Jan 1, 2018 and Dec 31, 2019 (index period). For eligible patients, all prior treatment history initiated as far back as January 2010 was used to report therapy changes. Patients were also required to have at least one PV diagnosis within a year of treatment initiation and at least 2 HCT lab results during the index period. PV treatment changes and characteristics were studied. RESULTS Out of 28,306 patients with PV, 4,264 patients had HCT lab data for 2 years (index period). Median duration of follow-up was 854 days (range 98-3,373days). Patient therapy duration was from 1 to 9 years. Median patient age was 65 (range 11-94), with 1,451 (34%) patients aged less than 60, 2,813 (66%) 60 years or older, and a substantial male predominance (62% vs 38%). 1,247 (29%) patients were classified as Low Risk (age< 60 with no TE history) and 3,017 (71%) patients as High Risk. Within the High-Risk group, 2,224 (52%) were age>60 without prior TE, 204 (5%) were age<60 with prior TE and 589 (14%) were age>60 with prior TE. For Low Risk patients' initial treatment was phlebotomy alone (85%) and a total of 73% of all Low Risk patients remained on phlebotomy alone. For High Risk patients' initial treatment was phlebotomy alone (60%) and 43% all of High-Risk patients remained on phlebotomy alone (Figure 1). The median HCT prior to treatment initiation was 52.9% and 48% during treatment. 936 (22%) patients achieved NCCN treatment guidelines with HCT levels always remaining under 45%, and 1,226 (29%) patients had HCT levels controlled between 45% and 50%. However, 2,102 (49%) patients had some or all HCT levels> 50% (Figure 2). With the most recent lab test, 2,180 (51%) of patients still had HCTs above 45% and 804 (19%) were still above 50%. In a sub-cohort of 653 High Risk patients with a prior TE and up to 5 years of follow up, 236 (36%) had at least one other TE; for the 1,774 High Risk patients who did not have the history of thrombosis, 161(9%) had at least one TE (Table 2). The most common TE since treatment began in patients with prior TE were deep vein thrombosis (n= 92 patients, 14%) and stroke (n= 95 patients, 15%). Among High Risk patients (n=397) who had another thrombotic event, 180 (45%) were treated by phlebotomy only and never switched to any other therapies. CONCLUSIONS Despite currently available treatments in US, patients' HCT level after treatment were higher than recommended as per guidelines. Failure to maintain HCT less than 45% increases the risk of future thrombotic events as shown by 36% of patients with prior TE experiencing another TE within the next 5 years. Disclosures Verstovsek: Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; CTI Biopharma Corp: Research Funding. Han:Protagonist Therapeutics: Consultancy. Chun Hayes:Protagonist: Consultancy. Woody:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Gupta:Protagonist: Current Employment.

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