Distribution and Impact of Comorbidities on Survival and Leukemic Transformation in Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF)

Abstract Introduction. Myelofibrosis is a disease characterized by aberrant bone marrow function with eventual fibrosis. Current widely-used disease prognostic indices, such as the Dynamic International Prognostic Scoring System (DIPSS) do not take into account comorbidities, which may have significant effects on patient survival as well as disease course. We sought to describe the comorbidity distribution in this patient population and assess the impact of comorbidities as scored by two different widely used scales in clinical practice, the Adult Comorbidity Evaluation 27 (ACE-27) and the Hematopoietic Cell Transplant Comorbidity Index (HCT-CI), on overall survival and leukemic transformation in myelofibrosis. A score of 3 on ACE-27 or ≥3 on HCT-CI generally indicates a high burden (severe) comorbidities. Methods. We conducted a retrospective study of 309 patients seen at the MPN program at the Princess Margaret Cancer Centre, with a confirmed diagnosis of myelofibrosis [primary myelofibrosis (PMF), post-essential thrombocytopenia (PET-MF) or post-polycythemia vera (PPV-MF)]. Patients were seen from 1999-2014 with a median follow-up time of 2 years. Time to death and leukemic transformation was examined from the date of first presentation to our centre. Our primary aim was to examine the impact of comorbidity scores, as assessed by ACE-27 and the HCT-CI, on overall survival. In a secondary analysis we examined the impact of comorbidity scores on leukemic transformation. Multivariable Cox proportional hazards models were constructed for the primary and secondary outcomes. A series of descriptive analyses were carried out examining the distribution of various comorbidities as captured by the two scales. Results. The most common comorbidities captured by ACE-27 were hypertension (n=92, 22.3%), diabetes mellitus (n=43, 10.4%), venous disease (n=26, 6.3%), solid tumour including melanoma (n=26, 6.3%), and angina/coronary artery disease (n=23, 5.6%). The most common comorbidities captured by HCT-CI were cardiac (n=49, 17.3%), diabetes (n=43, 15.2%), mild hepatic (n=28, 9.9%), cerebrovascular disease (n=25, 8.8%), prior solid tumour (n=24, 8.5%). The distribution of comorbidity scores as compared between scales is shown in Table 1. A total of 78 patients (25.2%) experienced the primary outcome of interest, which was all-cause death. For the primary outcome of overall survival, there were differences across groups of patients with different comorbidity scores using ACE-27 or HCT-CI, with the highest severity groups having worse outcomes (Figure 1). Progressively increasing DIPSS categories (Low, Intermediate-1, Intermediate-2, and High risk) were also associated with worse overall survival. On multivariable survival analysis, an ACE-27 score of 3 when compared to a lower score of 0-1 was associated with an almost two-fold increase in the risk of all-cause death [HR 1.95 (95% CI 1.06-3.58), p=0.03]. On multivariable analysis, an HCT-CI score of 3+ when compared with 0-1 was marginally significantly associated with an increased risk of all-cause death [HR 1.60 (95% CI 0.96-2.68), p=0.07]. Interaction terms were tested between the scores and age at presentation and no effect of age on survival across varying severities of comorbidities was found. In our secondary analysis, there was no impact of the ACE-27 or HCT-CI on leukemic transformation. Conclusions. ACE-27 picked up severe co-morbidities in 13% of patients in our cohort while HCT-CI picked up severe comorbidities in 23%. Although the incidence of severe co-morbidities was lower when assessed by ACE-27, the overall impact on survival of severe comorbidities as assessed by both scores is likely to be similar. The presence of severe comorbidities at the time of diagnosis conferred a significant survival disadvantage in patients with myelofibrosis, but had no impact on progression to leukemic transformation. Table Overall survival by ACE-27 comorbidity category, showing differences between categories of comorbidity severity (p=0.047, log rank test). Table. Overall survival by ACE-27 comorbidity category, showing differences between categories of comorbidity severity (p=0.047, log rank test). Figure Figure. Disclosures Panzarella: Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding.

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The Transcriptional Signature of Kinases Inhibited by the Multi-Targeted Kinase Inhibitor AS703569 Is Associated with Clinical Outcome in Multiple Myeloma (MM): Anti-MM Activity of AS703569 in Preclinical Studies.

Blood ◽

10.1182/blood.v114.22.730.730 ◽

2009 ◽

Vol 114 (22) ◽

pp. 730-730

Author(s):

Jake Delmore ◽

David N. Cervi ◽

Douglas McMillin ◽

Efstathios Kastritis ◽

Jana Jakubikova ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Rank Test ◽

Preclinical Studies ◽

Advisory Committees ◽

Transcriptional Signature ◽

Log Rank Test

Abstract Abstract 730 Multi-targeted kinase inhibitors, when associated with manageable toxicity, offer the therapeutically desirable option of targeting, through a single chemical entity, several pathways that may contribute to the complexity and heterogeneity of molecular lesions harbored by neoplasias such as multiple myeloma (MM). However, intractable questions often emerge while prioritizing for preclinical studies different multi-targeted agents with extensive and/or only partially overlapping of sets of known targets. We have hypothesized that the potential therapeutic relevance of a multi-targeted inhibitor may be reflected on the prognostic relevance of its targets' transcriptional signature. We applied this concept in the case of the orally bioavailable multi-targeted kinase inhibitor AS703569, which targets (with IC50 in low nM range) all 3 Aurora kinase (AK) isoforms as well as various other kinases (e.g. cSRC, FGFR1, Flt3, Fyn, Lyn, Rsk1-3, Yes, Axl, et.c.) and evaluated the transcriptional signature of AS703569 kinase targets (with IC50 <10 nM) in MM cells of patients receiving Bortezomib as part of Phase II/III trials (specifically SUMMIT/APEX). We observed that patients with high transcriptional signature of AS703569 targets had inferior progression-free and overall survival (p=0.005 and p=0.012, log-rank test) and also validated that, in a study of tandem autologous transplant, a subset of patients with high levels of this AS703569 target transcriptional signature also have inferior overall survival (p=0.032, log-rank test) compared to cases with low levels of the signature. These observations supported the notion that the kinome space targeted by AS703569 is enriched for targets associated with adverse clinical outcome in MM. In preclinical assays, we observed that AS703569 decreased the viability of MM cell lines and primary CD138+ MM tumor cells in a time- and dose-dependent manner, with IC50 values <50 nM for the majority of cell lines tested; and without evidence of cross-resistance with established anti-MM agents. Combinations of AS703569 with dexamethasone, doxorubicin, or bortezomib did not exhibit antagonism, suggesting that AS703569 can be incorporated in regimens with these established anti-MM drug classes. Interestingly, in vitro compartment-specific bioluminescence imaging (CS-BLI) assays showed that against MM cells which respond to stromal cells with increased proliferation and survival, the anti-MM activity of AS703569 is more pronounced when these MM cells are co-cultured with bone marrow stromal cells than in conventional cultures in isolation. This indicated that AS703569 is capable of overcoming the protective effects that BMSCs confer to MM tumor cells and prompted in vivo validation studies in our orthotopic SCID/NOD model of diffuse MM bone lesions established by i.v. injection of MM-1S-GFP/Luc cells monitored by whole body bioluminescence imaging. AS703569 (50 mg/kg p.o. once weekly)-treated mice had longer overall survival than vehicle-treated mice (median 50.0 days, 95% C.I. 40.3-59.7 days vs. 39.0 days, 95% C.I., 35.4-42.6 days, p=0.019, log-rank test). An alternative schedule of AS703569 at 16.7 mg/kg 3 times/week also resulted in longer overall survival (median 54.0 days, 95% C.I. 33.2-74.8 days, p=0.023, log-rank test). These data indicate that AS703569 exhibits anti-MM activity in vitro and in orthotopic in vivo MM models, and suggests that this multi-targeted inhibitor merits considerations for further preclinical studies, as well as potential clinical studies in MM, especially given the otherwise adverse outcome associated with the inhibitor's target transcriptional signature. Disclosures: Laubach: Novartis: Consultancy, Honoraria. Rastelli:EMD Serono: Employment. Clark:EMD Serono: Employment. Sarno:EMD Serono: Employment. Richardson:Millenium: (Speakers' Bureau up to 7/1/09), Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: (Speakers' Bureau up to 7/1/09), Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis : Consultancy, Honoraria; Bristol-Myers Squibb : Consultancy, Honoraria; Merck & Co: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; PharmaMar: Patents & Royalties; Amgen: Research Funding; AVEO Pharma: Research Funding; EMD Serono : Research Funding; Sunesis Pharmaceuticals: Research Funding.

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Impact Of The Proportion Of Metaphases With Isolated Del(5q) On Clinical Outcomes In Lenalidomide (LEN)-Treated Patients With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) In MDS-003 and MDS-004

Blood ◽

10.1182/blood.v122.21.1538.1538 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1538-1538

Author(s):

Aristoteles Giagounidis ◽

Alan List ◽

Eva Hellström-Lindberg ◽

Mikkael A. Sekeres ◽

Ghulam J. Mufti ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

Log Rank Test ◽

Equity Ownership ◽

Baseline Characteristics ◽

Rbc Transfusion

Abstract Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

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Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽

10.1182/blood-2021-153037 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4076-4076

Author(s):

Abi Vijenthira ◽

Xinzhi Li ◽

Michael Crump ◽

Annette E. Hay ◽

Lois E. Shepherd ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Frailty Index ◽

Secondary Analysis ◽

Advisory Committees ◽

Frail Patients ◽

The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

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Busulfan/Fludarabine- or Treosulfan/Fludarabine-Based Conditioning Regimen in Patients with Wiskott-Aldrich Syndrome Given Allogeneic Hematopoietic Cell Transplantation — an EBMT Inborn Errors Working Party and Scetide Retrospective Analysis

Blood ◽

10.1182/blood-2018-99-112394 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2175-2175 ◽

Cited By ~ 2

Author(s):

Michael H. Albert ◽

Mary Slatter ◽

Andrew Gennery ◽

Tayfun Guengoer ◽

Henric-Jan Blok ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Rank Test ◽

Unrelated Donor ◽

Advisory Committees ◽

Secondary Procedure ◽

Log Rank Test ◽

Secondary Procedures

Abstract PV and AL contributed equally Multiple studies from the EBMT registry and others have shown excellent survival rates after allogeneic haematopoietic stem cell transplantation (HSCT)for Wiskott-Aldrich syndrome (WAS) patients (Ozsahin et al, Blood 2008). The importance of myeloid engraftment for full disease correction has also been demonstrated (Moratto et al, Blood 2011). However, the vast majority of HSCTs in these studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. In 2005, the inborn errors working party (IEWP) of EBMT and ESID first recommended busulfan/fludarabine (BuFlu) or treosulfan/fludarabine (TreoFlu) based conditioning for primary immunodeficiencies such as WAS, with some centers deciding to add thiotepa (TT) to the conditioning. We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 01/01/20006 and 12/31/2016 with these two regimens. The primary objective was to compare the overall (OS) and event-free survival (EFS) after HSCT with either BuFlu±TT or TreoFlu±TT conditioning. Secondary objectives included the influence of either conditioning regimen on acute and chronic GVHD, the degree of donor chimerism, incidence of secondary procedures after HSCT (2nd HSCT, stem cell boost, DLI, gene therapy or splenectomy) and rates of disease-specific complications after HSCT. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning with a median age of 1.57 years (range 0.21-29.96) at HSCT and a median follow-up of 32.9 months (range 1.5-128.9). The donor was an HLA-matched sibling (MSD) in 30, a matched related donor (MRD) in 5, a matched unrelated donor (MUD, 9/10 or 10/10) in 105, a mismatched unrelated donor (MMUD, <9/10) in 9 and a mismatched family donor (MMFD) in 25 (18 with ex-vivo T-cell depletion). Stem cell source was bone marrow in 93 (53%), peripheral blood in 62 (36%) and cord blood in 18 (10%). Two year overall survival (OS) of the entire cohort was 88.6% (95% confidence interval 83.5%-93.6%). There was no significant difference in OS between patients treated with BuFlu±TT or TreoFlu±TT conditioning (2-year OS 88.1% vs. 89.5%; log-rank test p=0.7). Patients aged >5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; log-rank test p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (log-rank test p=0.4). Whole blood chimerism was complete (>90% donor) in 60/75 evaluable patients (80%) at last follow-up or before secondary procedure (if a patient had one), 39/40 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group. Twenty-six patients required a secondary procedure: stem cell boost in 4 patients, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. Twenty-two of these 26 (84.6%) are alive and 14 of 16 with available chimerism data have a complete donor chimerism (>90%donor) at last follow-up. The 2-year cumulative incidence (CI) of secondary procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (Gray's test p=0.017), and 2-year EFS (secondary procedure or death as event) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (log-rank test p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (100 day CI 24.4% vs. 26.3%; Gray's test p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (2 year CI 17.2% vs 6.7%; Gray's test p=0.054). The cumulative incidence of disease-specific complications occurring more than 6 months post HSCT (severe infections, bleeding, autoimmunity) was not different between the two groups (6.5% vs. 6.4%; Gray's test p=0.92). There was no malignancy reported after HSCT except for one EBV-post-transplant lymphoproliferative disorder (PTLD) 2.7 months after HSCT. In summary, HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. WAS-related complications are very rare events more than 6 months post HSCT. More patients required secondary procedures after treosulfan-based than busulfan-based conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP. Disclosures Slatter: Medac: Other: Travel assistance. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Kalwak:Sanofi: Other: travel grants; medac: Other: travel grants. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria.

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Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-126940 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1641-1641 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Kathryn G. Roberts ◽

Koji Sasaki ◽

Yaqi Zhao ◽

Chunxu Qu ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

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Cell of Origin and Treatment Impact on the Outcome of Monomorphic Post-Transplant Lymphoproliferative Disorder-Diffuse Large B-Cell Lymphoma Subtype

Blood ◽

10.1182/blood-2019-131841 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2909-2909 ◽

Cited By ~ 1

Author(s):

Francesca Montanari ◽

Changchun Deng ◽

Ahmed Sawas ◽

Jennifer Kimberly Lue ◽

Enrica Marchi ◽

...

Keyword(s):

Research Funding ◽

B Cell Lymphoma ◽

Rank Test ◽

Cell Of Origin ◽

Advisory Committees ◽

Post Transplant ◽

Oncology Research ◽

Log Rank Test ◽

Dlbcl Subtype ◽

Related Mortality

Introduction : Cell of origin (COO) determination of diffuse large B-cell lymphoma (DLBCL) is important, as it has prognostic and therapeutic relevance. Patients with germinal center (GC) like DLBCL have more favorable outcomes than those with non-GC DLBCL, when treated with standard immunochemotherapy. In monomorphic post-transplant lymphoproliferative disorder (PTLD), DLBCL subtype, the biologic significance of COO is not well established. The aims of this study were to evaluate the impact of the COO on clinical presentation, outcome and response to different treatment regimens. Methods : We conducted a retrospective review of all monomorphic PTLD of the DLBCL subtype diagnosed and treated at Columbia University from 2000-2018. COO classification into GC and non-GC subtype was determined by immunohistochemistry using the Hans algorithm. In situ hybridization for Epstein-Barr encoded small RNAs (EBER) was performed to evaluate for EBV infection of the neoplastic lymphocytes. Outcomes according to therapeutic regimens were assessed using the revised response criteria for malignant lymphoma (2007). Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log rank test. Results : Cell of origin: Biopsy material for COO subtyping was available for 49 monomorphic PTLD-DLBCL diagnosed during the study period. By immunohistochemistry 20/49 cases (40.8%) were GC and 29/49 cases (59.2%) were non-GC. Median age of presentation was 52 years (range 3-72) and 55 years (range 3-75), for the GC and non-GC respectively. Median time from transplant to PTLD onset was 3 years, range 7 months-25 years vs. 6 years, range 2 months-24 years for GC vs non-GC respectively. There was no significant difference in the incidence of EBV positivity, immunosuppressive therapy, organ transplanted, stage, LDH, ECOG and IPI between the 2 groups. Of note, extranodal involvement, specifically of the gastrointestinal tract was extremely common in both subtypes (16/20 [80%] in GC and 25/29 [86%] in non-GC). While acknowledging the heterogeneity of therapies administered, a trend suggesting better prognosis for the GC type was noted, although not statistically significant. The median PFS was 151.0 months for GC vs 17.0 months in non-GC (p= 0.1095), while the median OS was 151.0 months for GC vs 36.7 months for non-GC (p=0.1006) (Figure 1A, 1B). Impact of Treatment: Of the 49 cases, 44 were adults (age≥18). The two most common first line therapies administered were R-EPOCH (25) and R-CHOP (9). Ten patients received 6 other therapies including Rituximab monotherapy (3), CHOP (2), palliative care (2), RCEOP (1), EPOCH (1), and radiation (1). When focusing on patients who received R-CHOP or R-EPOCH as initial therapy, no significant differences in age, stage, LDH, extranodal disease, ECOG, IPI, immunosuppressive therapy and COO was identified between the 2 groups. The complete response (CR) rate for R-CHOP was 6/9 (66.6%) vs. 21/25 (84%) for R-EPOCH (p= 0.2701). Primary refractory disease was present in a third of the patients receiving R-CHOP vs. (4/25) 16% of the patients treated with R-EPOCH (p=0.2701). Treatment related mortality was low in both groups (1/9 (0.1%) vs 1/25 (0.04%) patients died during first line therapy with RCHOP vs REPOCH respectively). No difference was seen in terms of PFS and OS in the 2 groups. Median PFS and OS for RCHOP was 80.0 and 83.9 months respectively, the medians for R EPOCH were not reached (log-rank test p= 0.5430, 0.2855 for PFS and OS, respectively) (Figure 1C-1D). When the OS and PFS curves for RCHOP and REPOCH were analyzed based on COO, again no difference was noted. Conclusions : Non-GC subtype is more common than GC in monomorphic PTLD DLBCL. Clinical characteristics, EBV infection and time of onset post transplant is not different in the 2 subtypes. There is a trend suggesting better PFS and OS of PTLD DLBCL GC subtype, although not statistically significant, mirroring the outcome of GC vs non-GC COO in DLBCL of immunocompetent patients. With regard to therapy, R-EPOCH did not improve OS or PFS when compared to R-CHOP, but did not result in increased toxicity or treatment related mortality, which in our series was extraordinarily low for both therapies (<=0.1%). Given the retrospective nature of our analysis, further studies of a larger cohort of patients is ongoing to validate these observations. Disclosures Sawas: Seattle Genetics, Gilead, Daiichi Sanko: Consultancy; Affimed: Research Funding. Lue:Kymera Therapeutics: Honoraria; Astex Pharmaceuticals: Honoraria. Marchi:Spectrum Pharmaceuticals, Verastem Oncology: Research Funding. Radeski:Corvus Pharmaceuticals: Research Funding. O'Connor:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Other: Travel Support, Research Funding; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding.

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Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial

Cancers ◽

10.3390/cancers13010140 ◽

2021 ◽

Vol 13 (1) ◽

pp. 140

Author(s):

Renaud Sabatier ◽

Jean-Yves Pierga ◽

Hervé Curé ◽

Rakan Abulnaja ◽

Eric Lambaudie ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Neoadjuvant Treatment ◽

Complete Response ◽

Rank Test ◽

Significant Prognostic Factor ◽

Log Rank Test ◽

The Impact

The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75–22.06), p = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17–10.52), p = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR (p = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19–12.67); p = 0.68 for OS and HR = 2.76; 95%CI (0.60–12.61); p = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.

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Results of a Phase I-II Clinical Trial of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab (OFAR) Combination Therapy In Patients with Aggressive, Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Richter Syndrome (RS)

Blood ◽

10.1182/blood.v116.21.923.923 ◽

2010 ◽

Vol 116 (21) ◽

pp. 923-923 ◽

Cited By ~ 2

Author(s):

Apostolia Maria Tsimberidou ◽

William G. Wierda ◽

Sijin Wen ◽

William Plunkett ◽

Susan O'Brien ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Clinical Outcomes ◽

Median Survival ◽

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Rank Test ◽

Advisory Committees ◽

Log Rank Test

Abstract Abstract 923 Background: To enhance the response rate with a decrease in myelosuppression that were observed with oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) (Tsimberidou et al, J Clin Oncol, 2008;26:196), the daily dose of oxaliplatin was increased from 25 to 30mg, the daily dose of Ara-C was decreased from 1 g/m2 to 0.5 g/m2 and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: OFAR2 consisted of oxaliplatin 30mg/m2 D1-4; fludarabine 30mg/m2; Ara-C 0.5g/m2; rituximab 375mg/m2 D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2-3 (level 1) D2-4 (level 2) or D2-5 (level 3) every 4 weeks. Tumor lysis, DNA virus, and PCP prophylaxis was administered. A “3+3” design was used (Phase I) and and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results: Overall 102 patients (rel. CLL 67, RS 35) were treated. Twelve patients were treated in the Phase I portion of the study. Dose-limiting toxicities were noted in 2/3 patients at level 3 (G4 diarrhea and G4 sepsis). Level 2 was the maximum tolerated dose. Ninety patients (CLL, 60; RS, 30) were treated in Phase II portion of the study (age > 60 years 67%, 17p del 37.5%, 11q del 15%, 13q del 18%, +12, 17%; neg. 12.5%; unmutated IgVH 81.5%, ZAP70-positive 77%, and CD38 30%, 63%). Response in 80 of 90 patients (Phase II) is shown in Table (too early, n=10). The overall response rates in patients (Phase II) with 17p deletion and 11q deletion were 29% and 41%, respectively. Twenty-nine patients underwent SCT after OFAR2 (response status to OFAR2 at the time of SCT: CR, n=3; nPR, n=2; 15; no response, n=9). With a median follow-up of 20.8 months, the median survival was 19 months (95% CI, 13–37+) and the median FFS was 6 months (95% CI, 3.4 – 8.2). Overall, 238 cycles were administered. G3-4 neutropenia, thrombocytopenia, and anemia were noted in 67%, 74%, and 44% of patients (51%, 64%, and 25% of cycles); and G3-4 infections in 19% of patients. Clinical outcomes of OFAR2 were compared with those of OFAR1. In patients with RS, the overall response rate was 41% (11/27) with OFAR2 and 50% (10/20) with OFAR1 (p = 0.57, Fisher's test); the median survival with OFAR2 and OFAR1 was 8.3 months and 18+ months, respectively (p = 0.92, log-rank test); and the respective median FFS was 3.0 months and 4.1 months (p = 0.40, log-rank test). In patients with CLL, the overall response rate was 55% (29/53) with OFAR2 and 33% (10/30) with OFAR1 (p = 0.36, Fisher's test); the median survival with OFAR2 was 21.4 months and 13.8 months with OFAR1 (p = 0.19, log-rank test); and the respective median FFS was 6.6 months and 4.9 months (p = 0.69, log-rank test). Conclusion: OFAR2 induced response in 41% of patients with RS and 55% of patients with relapsed/refractory CLL in the phase II study. Antileukemic activity was also noted in patients with 17p deletion. Although the numbers of patients are small, OFAR1 was associated with a trend towards superior clinical outcomes in patients with RS compared to OFAR2; and OFAR2 was associated with a trend towards superior clinical outcomes compared to OFAR1 in patients with relapsed/refractory CLL. Disclosures: Tsimberidou: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; ASCO: Career Development Award, Research Funding. Off Label Use: Drug: Oxaliplatin. Oxaliplatin combined with fludarabine, cytarabine, and rituximab has antileukemic activity in patients with relapsed/refractory Chronic Lymphocytic Leukemia and Richter Syndrome. Wierda:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Micromet: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Abbott Laboratories: Research Funding. O'Brien:Biogen Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Kipps:Sanofi Aventis: Research Funding. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

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Bendamustine in Monotherapy and in Combination Regimens in the Treatment of Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma – a Retrospective Analysis

Blood ◽

10.1182/blood.v120.21.4602.4602 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4602-4602

Author(s):

Iwona Hus ◽

Dariusz Jawniak ◽

Magdalena Gorska-Kosicka ◽

Aleksandra Butrym ◽

Justyna Dzietczenia ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Lymphocytic Leukaemia ◽

Cell Lymphoma ◽

Aggressive Lymphoma ◽

Rank Test ◽

Indolent Lymphoma ◽

Advisory Committees ◽

Log Rank Test ◽

Combination Regimens

Abstract Abstract 4602 Purpose: In this study, we carried out a retrospective analysis of the efficacy and toxicity of bendamustine in patients with B-cell lymphoproliferative diseases. Methods: Bendamustine was administered both in monotherapy and combined protocols in 111 patients, including 81 patients with chronic lymphocytic leukaemia (CLL), 20 patients with indolent lymphoma, and 10 patients with aggressive lymphoma (8 mantle cell lymphoma and 2 diffuse large B-cell lymphoma). Median age of patients was 61 years (range: 44 – 87 years). Almost all patients, except 3 previously untreated patients with CLL had relapsed (78 patients) or refractory disease (30 patients). 60.4% of patients were treated with bendamustine plus rituximab, while 28.2% received bendamustine in monotherapy, and 31.4% received other combined regimens. Results: Overall response rate (ORR) was 65.8%, including 20.7% of complete response (CR) and 45.1% of partial response (PR). In CLL patients, ORR was 59.3% with 16% of CR and 43.2% of PR. In patients with indolent NHL, ORR was 80%, including 30% of CR and 50% of PR. In patients with aggressive lymphoma, OR and CR rates were respectively: 90% and 40%. In patients with CLL, a likelihood of response was significantly lower in patients with ZAP-70 expression (p=0.006) and 17p deletion (p=0.009). Median overall survival (OS) for all patients was 11.5 months (range 1–40). For CLL patients, median OS was 11 months (range 1–40), for patients with indolent lymphoma 15.5 months (range 5–29 ) and for patients with aggressive lymphoma - 10 months (6–38). Median OS was significantly longer in patients responding to therapy as compared to non-responders (15 months vs. 8 months; p=0.0001). Median progression-free survival (PFS) in all patients was 6 months (0–38), including 4 months (0–38) for CLL patients, and 8.5 months (0–33) for patients with both aggressive and indolent lymphoma. Among pre-treatment parameters, β2-microglobulin (RR=1.234; p=0.002), haemoglobin level (RR=0.803; p=0.03) and PLT count (RR=1.005; p=0.03) significantly influenced survival. Also, the higher number of bendamustine cycles was associated with longer overall survival (RR=0.715; p=0.003). In patients with CLL, 17p deletion was associated with reduced overall survival (p=0.021; log-rank test). OS was significantly longer in patients who received ≤ 2 lines of previous therapies as compared to > 3 lines (p=0.018; log-rank test), and who received ≥ 4 courses of therapy (p=0.02; log-rank test). In patients with NHL, both OS and PFS were significantly longer in patients with lactate dehydrogenase level <250 U/l (p= 0.01; p=0.02; respectively), and who received ≥ 4 cycles of treatment (P= 0.03). Toxicity was predominantly haematological, including grade III/IV neutropenia in 32%, thrombocytopenia in 15% and anaemia in 16% of patients. Conclusion: Bendamustine, both in monotherapy and combination regimens, is an effective therapy with a favourable toxicity profile even in heavily pretreated patients. Disclosures: Hus: Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Glaxosmithkline: Consultancy. Off Label Use: In Europe bendamustine is indicated for first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate and indolent non-Hodgkin's lymphomas as monotherapy in patients who have progressed during or within 6 months following treatment with rituximab or a rituximab containing regimen. Wiktor-Jedrzejczak:Genzyme: Speakers Bureau; Celgene: Speakers Bureau; Genopharm: Speakers Bureau; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy; Janssen-Cilag: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Walewski:Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dmoszynska:Millenium Pharmaceuticals: Consultancy; Celgene: Consultancy; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Analyzing Patient Characteristics Who Received (DA) EPOCH-R for High Risk Diffuse Large B-Cell Lymphoma: MD Anderson Cancer Center Experience

Blood ◽

10.1182/blood.v128.22.4208.4208 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4208-4208 ◽

Cited By ~ 1

Author(s):

Kristin A. Simar ◽

Vishwanath Sathyanarayanan ◽

Amir K Issa ◽

Mohamed Amin Ahmed ◽

Mansoor Noorani ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Neutropenic Fever ◽

Rank Test ◽

Cancer Center ◽

P Value ◽

Outpatient Therapy ◽

Advisory Committees ◽

Log Rank Test ◽

The Difference

Abstract Background: Due to ~50% risk of relapse with standard therapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP), an increasing number of patients with high risk diffuse large B-cell lymphomas (DLBCL) are being treated with dose-adjusted (DA) EPOCH-R (rituximab, etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide). DA-EPOCH-R contains a 96-hour continuous infusion can be delivered either in the inpatient or outpatient setting, via use of ambulatory infusion pumps. Potential advantages of outpatient therapy include reduced inpatient burden for routine chemotherapy, less exposure to resistant bacterial infections, increased patient satisfaction, and reduced cost. The ability to administer outpatient DA-EPOCH-R is dependent on the ability of the healthcare facility to administer the regimen safely while maintaining dose adjustments and schedule. We hypothesize that patients who receive DA-EPOCH-R as an outpatient have similar outcomes and toxicity rates as patients who receive the regimen as an inpatient. We further hypothesize that there is a significant cost benefit for patients to receive DA-EPOCH-R as an outpatient. Methods: This was a retrospective database analysis of newly diagnosed consecutive DLBCL patients ≥ 18 years of age who received DA-EPOCH-R chemotherapy at MD Anderson Cancer Center between 2010 and 2014. Patients with double hit lymphoma defined as having a MYC and BCL2 or BCL6 translocation were excluded due to their aggressive nature. We descriptively analyzed demographic variables in this population including, age, gender, international prognostic index (IPI)) and outcome (overall response rates (ORR), complete response (CR), progression free survival (PFS), overall survival (OS), and hospital admission for neutropenic fever events). Additionally, we evaluated the number of outpatient cycles received in relation to survival outcomes and neutropenic fever events. Statistical analysis was done using Fisher's exact test or Chi-square test to evaluate the association between two categorical variables and Wilcoxon rank sum test was used to evaluate the difference in a continuous variable between patient groups. Kaplan-Meier method was used for time-to-event analysis including overall survival and progression free survival. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Results: A total of 196 patients had data available for analysis, with 138 patients (70.4%) receiving all cycles as an inpatient, while 58 patients (29.6%) received at least 1 outpatient cycle of DA-EPOCH-R (Table 1). Compared with patients who received no outpatient cycle, the patients who received any outpatient therapy were younger, had a lower proportion of high IPI, and experienced fewer episodes of febrile neutropenia. The median OS and PFS for the entire population has not been reached, with a median follow-up time for the censored observations of 2.78 years (range: 0.24 - 8.64 years). The difference in OS between the patients who had any outpatient therapy and no outpatient therapy was not significant by the log-rank test (p-value=0.11). The difference in PFS between the patients who had any outpatient therapy and no outpatient therapy was marginally significant for OS by the log-rank test (p-value=0.07). Our cost analysis for 6 cycles of inpatient DA-EPOCH-R is estimated to be ~$88K, or $14.6K/cycle. The cost savings incurred for chemotherapy only expenses for each outpatient cycle is at least $3.3K/cycle or $19.8K for a total of 6 cycles. Conclusion: DA-EPOCH-R is a highly effective regimen for treating aggressive DLBCL which can be administered in an outpatient setting safely, efficaciously, and in a cost-effective manner without any apparent effect on outcome or rate of admission for neutropenic fever. There can be savings of about of nearly $20K per patient for a 6-cycle course of therapy. In our series, patients who received outpatient therapy were younger and may have had greater social support, which could potentially confound results. This retrospective analysis supports the use of outpatient DA-EPOCH-R, but additional studies are warranted to evaluate which patients may benefit most. Disclosures Oki: Novartis: Research Funding. Nastoupil:Janssen: Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Research Funding; Celgene: Honoraria; AbbVie: Research Funding. Fowler:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Wang:Asana BioSciences: Research Funding; Acerta: Consultancy, Research Funding; Dava Oncology: Honoraria; BeiGene: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding. Westin:Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees.

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