Attainment Of Complete Remission Research Articles

A novel approach to induce early remission in high-risk primary membranous nephropathy.

This prospective single-arm trial with historic controls evaluated the efficacy and safety of treatment based on a combination of rituximab, intravenous cyclophosphamide, and corticosteroids (RCP) administered at lower cumulative doses for the induction of early remission in primary membranous nephropathy (PMN). We prospectively enrolled 30 high-risk PMN patients with persistent nephrotic syndrome (NS) and elevated antibodies to the phospholipase A2 receptor who underwent RCP therapy. We compared the effectiveness of RCP with that of historic controls who received rituximab-based therapy (RTX, n=15) or cyclosporine+corticosteroids (CSA, n=42). The primary outcomes were complete remission (CR) and overall remission (OR) by month 12 and the time to remission. In the RCP group, the OR and CR rates by 12 months (97% and 60%) were higher than those in the RTX group (60% and 7%, P≤0.009) and the CSA group (50% and 24%, P≤0.003). The median time to OR (2.8 (1.6-3.9) months) was shorter compared to RTX (7.1 (3.4-17.5) months, P=0.008) and CSA (7.3 (6.0-13.6) months, P<0.001). In adjusted Cox regression, hazard ratios for OR and CR attainment for RCP versus other treatments were 5.2 (95% CI: 2.8-9.6) and 4.8 (95% CI: 2.2-10.3), respectively. Propensity score-matched group analyses confirmed these results. One serious adverse event occurred in the RCP group in the follow-up of 56 patient-years. RCP therapy is considered effective and safe for inducing early remission in high-risk PMN patients.

Abstract P25: Identification of biological components and novel clinical subsets of NPM1-mutated AML using an integrated, multi-omics approach

Abstract P25: Identification of biological components and novel clinical subsets of <i>NPM1</i>-mutated AML using an integrated, multi-omics approach

Serum thymidine kinase 1 activity as a prognostic biomarker in dogs with chemotherapy-treated diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is frequently treated with chemotherapy incorporating cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), which induces remission in 80% to 95% of cases. However, not all dogs derive meaningful benefit from CHOP, and prognostic factors for dogs with DLBCL are poorly defined. Serum thymidine kinase 1 (TK1) activity, a marker of tumour cell proliferation, has shown promising initial results as a prognostic biomarker in dogs with multicentric lymphomas. The purpose of this study was to determine if baseline serum TK1 activity is associated with clinical outcome in dogs with CHOP-treated DLBCL. Baseline serum TK1 activity was measured in banked sera from 98 dogs with CHOP-treated DLBCL using a commercially available ELISA kit. Data on other potential prognostic factors were abstracted retrospectively from electronic medical records. Multivariable statistical methods were used to identify associations between TK1 and other potential prognostic factors with progression-free survival (PFS) and attainment of complete remission. TK1 activity at baseline was not associated with PFS (p=.299) or attainment of complete remission (p=.910) following CHOP chemotherapy. Of the other prognostic factors analysed, only purebred (vs. mixed breed) status (HR 8.81, 95% CI 1.68-46.30, p=.010), attainment of complete (vs. partial) remission (HR 0.09, 95% CI 0.02-0.49, p=.006), and baseline serum C-reactive protein concentration (HR 1.19, 95% CI 1.07-1.32, p=.001) were independently associated with PFS. Based on these findings, baseline serum TK1 activity does not appear to be a useful prognostic biomarker in dogs with CHOP-treated DLBCL.

Intravenous cyclophosphamide induces remission in children with difficult to treat steroid resistant nephrotic syndrome from minimal change disease

BackgroundSteroid resistant nephrotic syndrome (SRNS), while uncommon in children, is associated with significant morbidity. Calcineurin inhibitors (CNIs) remain the first line recommended therapy for children with non-genetic forms of SRNS, but some children fail to respond to them. Intravenous (IV) cyclophosphamide (CTX) has been shown to be effective in Asian-Indian children with difficult to treat SRNS (SRNS-DTT). Our study evaluated the outcome of IV CTX treatment in North American children with SRNS-DTT.MethodsRetrospective review of the medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. Data abstracted included demographics, histopathology on renal biopsy, prior and concomitant use of other immunosuppressive agents and serial clinical/laboratory data. Primary outcome measure was attainment of complete remission (CR).ResultsEight children with SRNS-DTT received monthly doses (median 6; range 4–6) of IV CTX. Four (50%) went into CR, 1 achieved partial remission and 3 did not respond. Three of the 4 responders had minimal change disease (MCD). Excluding the 1 child who responded after the 4th infusion, the median time to CR was 6.5 (range 0.5–8) months after completion of IV CTX infusions. Three remain in CR at a median of 8.5 years (range: 3.7–10.5 years) after completion of CTX; one child relapsed and became steroid-dependent. No infections or life-threatening complications related to IV CTX were observed.ConclusionsIV CXT can induce long term remission in North-American children with MCD who have SRNS-DTT.

Overexpression of BRD4 Is an Adverse Prognostic Factor in Acute Myeloid Leukemia

Background:Bromodomain containing protein 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) protein family, has been implicated in the pathogenesis of a number of hematological and solid tumors. BRD4 is an epigenetic reader that plays a central role in transcriptional regulation, cellular growth control, and cell cycle progression. As a consequence, BET inhibitors elicit anticancer activity in numerous malignant contexts. While deregulation of BRD4 activity has been shown to be essential for the maintenance of AML, its expression profile and prognostic value in AML have not been investigated. Additionally, how BRD4 is regulated in cancer cells remains largely unknown.Methodology: We therefore evaluated the level of BRD4 expression using Reverse Phase Protein Array (RPPA) technology in marrow and blood samples from 511 newly diagnosed AML patients, and determined a correlation between BRD4 expression and clinical characteristics and overall survival in AML patients. We also correlated expression of BRD4 with 232 other proteins (encompassing signal transduction, metabolism, apoptosis and cellular proliferation pathways) that were included in RPPA. Potential role of molecular chaperone heat shock protein 90 (Hsp90) in regulating BRD4 protein stability was also investigated.Results: BRD4 expression was similar in peripheral blood and bone marrow and expression was found to be higher at diagnosis than at relapse (P = .035). Compared with normal bone marrow derived CD34+ cells, BRD4 expression in AML was higher in 28% of patients and that higher BRD4 levels significantly predicted shorter overall survival (P = .002). There was no significant difference in BRD4 expression on the basis of age, sex, or performance status, antecedent malignancies, and previous chemotherapy and/or radiotherapy. BRD4 expression levels were not strongly correlated with French-American-British classification (FAB), although levels were slightly higher in M5 subtype. BRD4 levels were found to be significantly higher in patients with NPM1 mutation (P = .003) or FLT3-ITD (P = .057) or between those with both FLT3-D835F and NPM1 mutation (P = .01). BRD4 levels were not associated with the attainment of complete remission (CR), although rates were somewhat lower for those with high. However, patients with high levels of BRD4 had significantly inferior remission duration (25.9 vs 50 weeks; P = 0.03) compared with those with normal levels of BRD4. The overall survival (OS) of patients with higher levels of BRD4 was significantly inferior compared with those with normal levels of BRD4 (28.3 vs 55.3 weeks; P = .002). Patients with unfavorable cytogenetics and above-normal levels of BRD4 had inferior survival compared with those with normal levels of BRD4 (22.4 vs 38.9 weeks; P = .0043; Figure 3C). BRD4 expression was found to be strongly correlated (R > 0.2 and P < 0.0001 or 0.00001) either positively (n = 48) or negatively (n = 14) with proteins known to be important in AML. BRD4 expression was positively correlated with various cell proliferation-related proteins (Hsp90, pSTAT5, nucleolin and mTOR), anti-apoptotic protein (Bcl-2), oncoproteins (FLI1, CREB and ELK1), proteins important for stem cell functions (Ash2L and LSD1), hematopoietic transcription factors (ERG and PU.1/Spi1), and Smad proteins, signal transducers for the members of the transforming growth factor-β (TGF-β) superfamily. The stability, activity and function of several mutated, chimeric, and overexpressed signaling proteins crucial for oncogenesis are often maintained by Hsp90. Our study also demonstrates that BRD4 stability is dependent upon Hsp90 activity and pharmacologic inhibition of Hsp90 promoted ubiquitination followed by proteasome-dependent degradation of BRD4 protein.Conclusions: These findings suggest BRD4 as a prognostic biomarker for unfavorable outcomes and supports the clinical rational for using BRD4 inhibitors in AML. Future studies could identify mechanistic insights into BRD4-associated proteins as biomarkers for response to BET inhibition. DisclosuresKarnad:ADC Therapeutics: Research Funding. Weitman:Tolero Pharmaceuticals, Inc.: Employment. Iyer:Takeda: Research Funding; Genentech: Research Funding.

Mutation Patterns Identify Adult Patients with De Novo Acute Myeloid Leukemia (AML) Aged 60 Years or Older Who Respond Favorably to Standard Chemotherapy: an Analysis of Alliance Studies

Abstract Background: Despite changes in treatment regimens, the patient's age (and the corresponding treatment intensity) remains one of the most important prognostic factors in AML. Thus far, only 5-15% of AML patients aged ≥60 years (y) are cured with chemotherapy. Identification of patients who are more (or less) likely to respond to standard cytarabine/daunorubicin-based chemotherapy might help to enable early risk stratification toward alternative treatment regimens. Aims: To provide a comprehensive molecular profile of a large cohort of adults with de novo acute myeloid leukemia (AML) aged ≥60 y, and to determine if specific molecular and/or cytogenetic features could identify patients who are more likely to respond to standard chemotherapy. Methods: We used a next-generation sequencing panel of 80 cancer- and/or leukemia-associated genes to profile molecularly 423 patients aged ≥60 y with de novo AML and available cytogenetic data similarly treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology. Results: Overall, we detected 1377 mutations, with a median of 3 mutations per patient (range: 0-8). The outcome of the whole patient cohort was poor, with complete remission (CR) rate of 55% and disease-free (DFS) and overall survival (OS) 3y-rates of 14%. In multivariable analyses (MVA), mutated NPM1 was the only factor positively associated with achieving CR (P Summary: We identified combinations of mutations whose presence is associated with favorable outcome in older AML patients treated with standard chemotherapy. Patients with intermediate and adverse molecular features should be considered for alternative treatment regimens. Download : Download high-res image (186KB) Download : Download full-size image Figure 1 . Disclosures Stone: Otsuka: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Ono: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenix: Other: DSMB; Arog: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Fujifilm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle genetics: Membership on an entity's Board of Directors or advisory committees; Sumitomo: Membership on an entity's Board of Directors or advisory committees. Kolitz: Gilead, Magellan, Novartis, Pharmacyclics, and Seattle Genetics: Consultancy; Gilead, Magellan, and Novartis: Honoraria; Celgene, Jazz: Equity Ownership; Boehringer Ingelheim, Cantex, Erytech, and Millennium: Research Funding; Gilead, Novartis, and Seattle Genetics: Other: Travel Support. Powell: Rafael Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrd: Janssen: Research Funding; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S.

Differential Impact of Prognostically Significant Gene Mutations in Acute Myeloid Leukemia (AML) Patients (Pts) Older Than 70 Years (y) Treated with Cytarabine-Based Induction Therapy

Differential Impact of Prognostically Significant Gene Mutations in Acute Myeloid Leukemia (AML) Patients (Pts) Older Than 70 Years (y) Treated with Cytarabine-Based Induction Therapy

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax

AbstractHighly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.

Outcomes in Adolescent and Young Adult (AYA) Acute Lymphoblastic Leukemia (ALL): A Report from the Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC)

Introduction Acute lymphoblastic leukemia (ALL) diagnosed in adolescent and young adults (AYA) poses unique challenges. Despite using more intensive "pediatric-type" protocols, outcomes are generally inferior to those seen in children. The reasons are wide ranging, but when compared to pediatric ALL, AYA ALL has higher-risk biology, poorer tolerance to intensive treatments, and worse compliance with treatment regimens. India has one of the largest AYA populations in the world and AYA-ALL form a significant proportion of leukemias. The Indian acute leukemia research database [INwARD] was established in 2018 and had reported outcomes of ALLs from various centers of all age groups (Korula A, et al. Blood 2018 132:1374). Here, we present data focused on AYA-ALL from this database. Methods Retrospective data of AYA (15-29 years) patients with ALL (diagnosed between January 2012 to December 2017) from 9 centers were entered into an independent centralized online data capture system and analyzed for presenting characteristics, treatment and survival outcomes. Protocol choice was based on individual-center preference. For the purpose of this analysis, patients with WBC ≥30000 (B cell) and ≥100,000 (T-cell and other subtypes) were considered as high risk. Intensive protocols (MCP-841, BFM-95, COG), predominantly meant for children were labeled as "pediatric-type" and less intense protocols (GMALL, Hyper CVAD, UKALL) were considered as "adult-type". Results In the 6-year period, 1454 patients were registered [Males: 1114(76%), Median age: 20 years (15-29), Fig. 1.B; Subtype: B -ALL: 916(63%), T-ALL: 396 (27%); Fig. 1.C; High risk disease: 406 (28%)]. Of these,1100 (75%) underwent treatment. Poor financial support was the major reason for not taking treatment (Fig. 1.A). "Pediatric-type" protocols were used in 881 (81%) patients. After induction, 72% achieved complete remission (CR), 11% were refractory, 4% died during induction and 14% were not evaluable. Minimal residual disease was assessed in 581 and was present in 356 (61%). Attainment of CR, induction mortality, or MRD achievement was not affected by the type of regimen. Among these 1100 patients, 138 (12%) were lost to follow up and did not complete treatment. BCR ABL was tested in 636 and was positive in 112 (17%) [19% among patients with B-ALL (107/557)]and 106 of these were treated with additional tyrosine kinase inhibitors [imatinib (N=83) and dasatinib (N=23)]. Survival analysis: After a median follow up of 21 months, 270 patients relapsed [median time to relapse: 24 months (73% medullary, 17% CNS or testis, and 10% had a combined relapse) and 259 had died. The estimated 2-year event-free (EFS), relapse-free (RFS) and overall survival (OS) were 64%, 75% and 75% respectively. On univariate analysis the factors associated with inferior survival were as follows: EFS: WBC count ≥30,000/cmm, and ECOG PS 2-4; RFS: WBC count ≥30,000/cmm and ECOG PS 2-4; OS: use of "adult-type" protocols, ECOG PS 2-4, and BCR-ABL positive disease. On multivariate cox regression analysis, the only factors associated with inferior OS were: use of "adult" protocols (HR: 1.6), and BCR -ABL positive status (HR1.56) (Fig. 1.D). High WBC count at presentation predicted for inferior RFS while no factor could predict EFS on multivariate analysis. Conclusions In a multicenter analysis of AYA-ALL from different parts of India, we found that a quarter of newly diagnosed patients do not start treatment and another 12% are lost from follow up before treatment completion. Majority (80%) of the centers used "pediatric-type" protocols to treat AYA-ALL. Though superior survival was achieved with "pediatric-type" protocols, results must be interpreted with caution as these regimens were likely to be used more often in in younger patients. Variations in treatment protocols used between centers and the retrospective nature of the data are other caveats. Despite these limitations, this is one of the largest reports of AYA ALL from any part of the world and serves as a benchmark for planning prospective studies. Disclosures No relevant conflicts of interest to declare.

2121. Isavuconazole (ISAV) as Primary Anti-Fungal Prophylaxis (PAP) in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): An Open-Label, Prospective Study

BackgroundMold-active antifungal prophylaxis (ppx) is recommended in neutropenic patients with newly diagnosed AML or MDS. ISAV is an extended spectrum triazole with superior tolerability, reliability of absorption, fewer drug–drug interactions, lack of QTc prolongation or need for therapeutic drug monitoring, approved for the treatment of invasive aspergillosis (IA) and mucormycosis. NCT03019939 is an investigator-initiated, phase 2 trial of PAP with ISAV in patients with AML/MDS.MethodsTreatment-naïve adult patients with AML or MDS initiating remission-induction chemotherapy (RIC) received ISAV per the dosing recommendations in the United States label until recovery from neutropenia (neutrophils (ANC) ≥ 0.5 × 109/L) and attainment of complete remission (CR), occurrence of proven or probable invasive fungal infection (IFI, EORTC/MSG criteria), or for a maximum of 12 weeks. The primary endpoint was incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV).Results67 patients were enrolled (April 28, 2017 to February 14, 2019) and 60 patients were eligible for assessment (median age 67 years, 57 patients with AML, median ANC on enrollment was 660). Reasons for study completion were achievement of CR with ANC recovery (n = 35), completion of 12 weeks of PAP (n = 9), possible IFI (n = 7), investigator decision (n = 3), death (n = 2, 1 disease progression, 1 cardiac arrest), proven/probable IFI (n = 3), and mild transaminitis, possibly ISAV-related (n = 2). The median durations of neutropenia and ISAV ppx were 33 (7–86) and 31 (7–86) days, respectively. One microbiologically-proven (gluteal abscess due to Candida glabrata) and 2 cases of probable breakthrough IFIs (probable IA with positive galactomannan) occurred (IFI incidence 5%). ISAV trough serum concentrations were available in 31 patients on both day 8 (median 3.74 µg/mL, 2.03–7.65) and day 15 (median 4.10 µg/mL, 2.17–9.25), and were not significantly different.ConclusionISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC, with a breakthrough (proven/probable) IFI rate of 5%. ISAV serum levels were adequate in patients with AML/MDS undergoing RIC. Pharmacological features make ISAV attractive for PAP in the era of recently approved or emerging small-molecule AML therapies.Disclosures All authors: No reported disclosures.

Serum Flt3 ligand is a biomarker of progenitor cell mass and prognosis in acute myeloid leukemia

AbstractFms-like tyrosine kinase 3 (Flt3) is expressed on progenitor cells and acute myeloid leukemia (AML) blasts. Fms-like tyrosine kinase 3 ligand (Flt3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Conversely, Flt3+ AML is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering complete remission (CR) but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the bone marrow. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 140 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib or placebo. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney UP < .0001). Day 26 Flt3L was also associated with survival; Flt3L ≤291 pg/mL was associated with inferior event-free survival (EFS), and Flt3L >1185 pg/mL was associated with higher overall survival (OS; P = .0119). The separation of EFS and OS curves increased when minimal residual disease (MRD) status was combined with Flt3L measurement, and Flt3L retained a near-significant association with survival after adjusting for MRD in a proportional hazards model. Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML illustrates the potential value of monitoring Flt3L to identify relapse. Measurement of Flt3L is a noninvasive test with the potential to inform clinical decisions in patients with AML.

Short-Term Steroid Regimen for Adult Steroid-Sensitive Minimal Change Disease

Background: In pediatric patients with steroid-sensitive nephrotic syndrome, recent trials have revealed that a 2-month, short-term steroid regimen is not inferior to an extended steroid course. However, the optimal duration of initial steroid therapy for adult steroid-sensitive minimal change disease (MCD) remains unclear. Objectives: The aim of present study was to evaluate the effectiveness of a 2-month, short-term steroid regimen in the treatment of adult steroid-sensitive MCD patients. Method: This was a prospective observational study. Adult patients with steroid-sensitive MCD (n = 35) who were initiated on a short-term steroid regimen between January 2015 and June 2016 were included. The details of the regimen are as follows: (1) prednisolone was administered at an initial dose of 0.8–1.0 mg/kg/day and continued for 4–6 weeks and (2) dosage was reduced to 0.5–0.6 mg/kg/alternate day and continued for 4 weeks. Control patients (n = 140), who were treated using conventional steroid administration, were selected from our previous adult MCD cohort. All patients fulfilled the following criteria: biopsy-proven MCD, age ≥20 years, first episode of nephrotic syndrome, and attainment of complete remission within 4 weeks. The following parameters of patients who received short-term treatment regimen and control patients were compared: any relapse and frequent relapse, adverse events caused by steroid treatment and cumulative steroid dose. Results: Throughout the observation period (median: 17.3 months), 24 (68.6%) patients in the short-term group developed at least one relapse. The short-term regimen showed earlier occurrence of any relapse than the conventional regimen (adjusted hazard ratio [aHR] 2.45; 95% CI 1.51–3.97; p < 0.001), but there was no difference in frequent relapse (aHR 1.31; 95% CI 0.43–3.99; p = 0.63). None of the patients showed any symptoms of adrenal insufficiency after discontinuation of corticosteroids. The cumulative steroid dose during the observational period was significantly lower in the short-term group than in the conventional group. Conclusions: The short-term steroid regimen may represent an effective treatment option that ensures lower steroid exposure when treating adult steroid-sensitive MCD patients.

Isavuconazole (ISAV) As Primary Anti-Fungal Prophylaxis in Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-Label, Prospective Study

Isavuconazole (ISAV) As Primary Anti-Fungal Prophylaxis in Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-Label, Prospective Study

ABCG2 and CD200 define patients at high risk of relapse in ELN favorable subgroup of AML.

Overexpression of ABCG2 and CD200 has been independently associated with poor outcome in acute myeloid leukemia (AML). However, no data are available on the role of these two factors in patients with core-binding factor (CBF)-positive or FLT3-negative/NPM1-mutated cytogenetically normal (CN) AML. We analyzed 65 adult AML patients with CBF+ (n=16) or FLT3-/NPM1+ CN (n=49), evaluating clinical and biological factors associated with complete remission attainment, leukemia-free survival (LFS) and overall survival (OS). ABCG2 was expressed in 36 (55%) cases, and CD200 was positive in 33 (51%) cases, six at high levels. Both ABCG2 and CD200 positivity have a negative impact on relapse risk: 3-year LFS was 51% vs 82% in ABCG2+ cases (RR 3.3), 49% vs 82% in CD200+ patients (RR=4.4), and 25% in CD200- high cases (RR=17.1). ABCG2 and CD200 affected also OS with 3-year OS of 39% in ABCG2+ (compared to 71% in ABCG2-; RR=2.6) and CD200+ (compared to 68% in CD200-; RR=2.5) patients. Our data confirm a negative impact of ABCG2 and CD200 overexpression also in AML patients considered at favorable risk according to ELN cytogenetic/molecular classification.

Attainment of Complete Remission Is Significantly Associated with Longer Survival Outcomes in Relapsed/Refractory (R/R) CLL: A Meta-Analysis

Introduction: Chronic lymphocytic leukemia (CLL) is an incurable, indolent neoplasm of B lymphocytes, associated with a heterogeneous clinical course. Complete response (CR) with or without minimal residual disease in first-line chemoimmunotherapy has been associated with more favorable progression-free survival (PFS) and overall survival (OS). However, patients with R/R CLL and/or those with TP53 abnormalities (ie, 17p deletion and/or TP53 mutation) are less likely to achieve deep responses and experience poorer outcomes. Therefore, less is known about the relationship between complete response and survival outcomes in R/R CLL patients. To quantify this association, we generated meta-analytic estimates of PFS and OS reported in clinical trials using the proportion of study patients with CR as a predictor variable.Methods: We performed a systematic literature review of PubMed and EMBASE up to November 2014 and congress abstracts between 2012 and 2014. Randomized controlled trials and observational studies evaluating any treatment in R/R CLL patients were eligible for inclusion. Data were extracted from publications as median survival, the proportions of patients surviving at specific follow-up times, or individual event or censoring times from reported Kaplan-Meier (KM) curves, along with the proportion of patients with CR. Data were synthesized to estimate overall OS and PFS including population-level CR as a covariate using a Weibull proportional hazards model within a Bayesian meta-analysis framework.Results: 74 published studies of treatment outcomes in R/R CLL patients were identified from the peer-reviewed literature and congress abstracts. 56 of these studies reported the proportion of CRs together with either OS or PFS outcomes and were included in the analysis. Individual patient data were extracted from KM curves of 29 studies generating 5176 individual patient OS and PFS data points in addition to 54 study-level data points including 3638 patients. There were no clinically meaningful differences in study or patient characteristics among the included studies that were not also associated with CR, our variable of interest. The hazard ratio (HR; and 95% credible interval, the Bayesian analog to confidence intervals) of survival for each 10% increase in CR among a study population was estimated to be 0.64 (0.60, 0.68). Estimated median OS for hypothetical populations with 0% CR, 25% CR, or 50% CR were 20.4 mo, 44.7 mo, and 61.9 mo. Corresponding median PFS estimates were 10.0 mo, 21.9 mo, and 30.3 mo. (Figure)Conclusions: We have demonstrated that the attainment of CR is significantly associated with longer OS and PFS outcomes in R/R CLL at the study level. Moreover this can be expressed linearly, with each 10% increase in CR rate corresponding to a 36% reduction in the risk of progression or death. To our knowledge, this is the first meta-analysis to quantify the relationship between CR and survival outcomes in R/R CLL patients. It must be noted that these results reflect the study (population) level CR versus survival association and therefore do not necessarily represent the expected survival gain associated with an individual achieving CR. Further, CR is less likely to be achieved in patients with TP53 abnormalities, a factor not explicitly considered in our analysis. These results synthesize data from 56 clinical trials and strongly support the importance of achieving CR to improve long-term outcomes in R/R CLL patients. In particular, given the negative association between CR and TP53 abnormalities, treatments focused on improving the likelihood of CR in these hard-to-treat patients are likely to confer the greatest impact on survival outcomes. [Display omitted] DisclosuresEktare:Pharmerit International, paid consultants to AbbVie: Employment. Fox:AbbVie: Consultancy; Gilead: Honoraria, Other: travel funding; Takeda: Honoraria, Other: travel funding; Janssen: Honoraria, Other: travel funding; Adienne: Honoraria, Research Funding. Taylor:AbbVie: Consultancy. Timothy:Pharmerit International, paid consultants to AbbVie: Employment. Pena:AbbVie: Employment, Equity Ownership. Maher:AbbVie: Employment, Equity Ownership. Snedecor:Pharmerit International, paid consultants to AbbVie: Employment.

Prognostic significance of day+14 plasma cell count after initial induction therapy in Acute Myeloid Leukemia.

e18056 Background: Induction therapy regimens for acute myeloid leukemia (AML) target attainment of complete remission. Bone marrow biopsy is done usually after two to three weeks after the start o...

Prognostic effect of peripheral blood cell counts in advanced diffuse large B-cell lymphoma treated with R-CHOP-like chemotherapy: A single institution analysis.

The primary objective of the present study was to correlate blood cell counts (lymphocyte, monocyte and platelet counts) with early disease relapse following the attainment of complete remission (CR) by the rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)-like regimen in patients with advanced diffuse large B-cell lymphoma (DLBCL). In total, 30 patients were evaluated, with a median follow-up period of 43 months. All the participating patients attained CR. In total, eight patients experienced relapse within two years of the diagnosis, and the three-year overall survival rate was recorded as 77%. The peripheral counts for lymphocytes, monocytes and platelets, and the lymphocyte-monocyte ratio, all of which have been reported to be prognostic in DLBCL, were assessed. None of these parameters were correlated with the incidence of early relapse or with the prognosis. The lymphocyte count was higher in the patients with durable remission than in those who relapsed, however, no significant differences were identified. Thus, the present study concluded that early disease relapse was not predicted by peripheral blood cell counts in advanced DLBCL that reached CR using the R-CHOP-like regimen.

CD68 tumor-associated macrophage marker is not prognostic of clinical outcome in classical Hodgkin lymphoma

A novel biomarker, CD68, which marks tumor-associated macrophages (TAMs) in the microenvironment, has recently been reported to affect the prognosis of Hodgkin lymphoma (HL). We aimed to evaluate its role in our patient cohort (n = 100) by utilizing a routine immunohistochemistry method on whole tissue sections and a semiquantitative method for CD68 scoring. Clinical data were taken from medical records. Correlation with baseline characteristics, attainment of complete remission (CR), progression-free survival (PFS) and disease-specific survival (DSS) was done by categorical analysis using different cut-offs of CD68 score and also by taking absolute CD68 score as a continuous variable. There was no significant association between levels of CD68 expression and baseline characteristics or CR after primary therapy. CD68 score (neither categorical nor absolute continuous values) also did not predict for any difference in PFS or DSS. We conclude that CD68 TAM marker does not have prognostic value in HL.

Clinical features and outcome of T-cell acute lymphoblastic leukemia in patients older than 9 years: A single center experience of 110 patients from AIIMS, New Delhi, India.

7081 Background: It is known that T cell acute lymphoblastic leukemias (ALL) have poorer outcomes than their B cell counterparts. Data on T-ALL in the age group of &gt;9 years from India is minimal. Methods: This is a single institutional analysis of patients of above 9 years who were treated from January 2000 to December 2010. All patients who completed at least 4 weeks of induction therapy were analysed for various outcomes. Results: T-ALL formed 30% of all ALL in this age group. Of the 110 newly registered patients of T-ALL, the median age was 17 years (Range 10-50 years) with an M:F ratio of 5.9:1. Of this 62%, 30% and 18% patients belonged to 10-18, 19-30 and &gt; 31 years age group respectively. Eighteen (19%) and 2 (2%) and 33 (30%) had CSF, testicular and other extramedullary sites involvement respectively. Twenty eight per cent had a total leucocyte count (TLC) of above 100x109/L. Patients available for survival analysis were 104(94.5%). Complete remission (CR)rate was 68.2% and induction mortality was 14.4%. At a median follow up of 56.4 months 5 year leukemia free survival was 52.3% (median not attained). Twenty seven (38%) patients relapsed (median relapse time of 15.2 months, range 0.7 to 47.3 months), 55% during maintenance phase. The 5 year overall survival (OS) was 46.9% (median OS of 35.4 months). The 5 year OS of 10-18, 19-30 and &gt; 31 years age groups were 42.8%, 71% and 16.6% respectively (p value not significant). Not attaining CR in 1st induction, spontaneous tumor lysis syndrome and peripheral blood blast count of &gt; 80% were significant poor prognostic factors for survival. Conclusions: This is one of the largest study of T-ALL outcomes in patients above 9 years from a single center from India. Attainment of CR in 1st induction was the most important risk factor for survival. 5 year OS was 47%.

Adverse Prognostic Impact of GAS6 Expression in De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) (CALGB 8461, 9665, 20202; Alliance)

AbstractAbstract 1293Receptor tyrosine kinases (RTKs) constitutively activated by gene mutation, overexpression and/or autocrine activation via ligand expression have been shown to negatively impact on outcomes of AML patients (pts). AXL, a member of the TAM (TYRO3, AXL, MERTK) RTK gene family was reported to be overexpressed and associated with poor survival in AML (Rochlitz, et al, Leukemia, 1999: 13:1352–8). No AXL mutations have been described, suggesting its activation may occur via aberrant expression in leukemic blasts of a TAM RTK ligand, GAS6. GAS6 was shown to be overexpressed in AML (Dirks, et al Leuk. Res. 23:643–51); yet its prognostic relevance is unknown. We report clinical and molecular associations and prognostic impact of aberrant GAS6 expression, in the context of TAM RTKs and known prognostic markers in de novo CN-AML pts (n=270; aged 18–83 y) treated with cytarabine/anthracycline-based therapies. Sixty-nine (26%) pts expressed GAS6 (>background signal; derived from microarray gene expression profiles of AML samples). TYRO3 expression status [positive (+) vs negative (–)] was similar in GAS6+ and GAS6– pts (P=.74), while AXL+ (P<.001) and low expression MERTK (P=.02) were more frequent in GAS6+ pts. Compared to GAS6– pts, GAS6+ pts were older (P=.02), had more platelets (P=.03), lower % blood blasts (P=.01) and increased frequency of hepatomegaly (P=.006); were more often NPM1 (P<.001) and CEBPA (P=.02) wild-type, and RUNX1 (P<.001) and ASXL1 (P=.002) mutated and expressed higher MN1 levels (P=.05). In univariable analyses, none of the TAM RTKs associated with complete remission (CR) and only TYRO3+ associated with reduced disease-free (DFS; P=.005), overall (OS; P=.005) and event-free survival (EFS; P=.008). GAS6+ vs GAS6– pts had lower CR rates (P<.001), shorter DFS (P=.03), OS (P=.004) and EFS (P<.001). While no TAM RTK entered the CR multivariable (MVA) model, GAS6+ expression status remained an independent marker for lower CR rate after adjusting for NPM1 status, white blood count (WBC) and age group (Table). In the DFS, OS and EFS models (Table), there was an interaction between GAS6 and the combined dual receptor (TYRO3/AXL) variable. GAS6 independently associated with shorter survival in TYRO3–/AXL– pts but not TYRO3+/AXL+ pts after adjusting for other variables. We show for the 1st time that GAS6 expression is an independent prognostic marker in CN-AML; negatively impacting on CR attainment, independent of TAM RTKs and on survival endpoints in pts lacking TYRO3 and AXL expression, regardless of MERTK expression. Our results suggest that GAS6 expressed by AML blasts plays a role in chemotherapy resistance. As GAS6 is expressed but not its RTKs in a subgroup of pts with poor outcome, this may lead to the hypothesis that the prognostic impact of GAS6 in those patients is mediated by the encoded ligand acting on cells other than AML blasts including, for example, natural killer cells, where activation of AXL RTK is reported to suppress innate immunity.TableMVA modelsVariableCRDFSOSEFSPOR (95% CI)PHR (95% CI)PHR (95% CI)PHR (95% CI)GAS6 expression, + v –.020.46 (0.24, 0.88).03*1.78 (1.07, 2.96).05*1.59 (1.00, 2.52).03*1.59 (1.06, 2.41)NPM1, mut v wt.0012.97 (1.53, 5.77)––––.0060.64 (0.46, 0.88)FLT3-ITD, present v absent––.0031.66 (1.19, 2.33)––.0051.55 (1.14, 2.11)WT1, mut v wt––––<.0013.42 (1.97, 5.96).031.84 (1.06, 3.18)RUNX1, mut v wt––––.0022.00 (1.29, 3.10)––ASXL1, mut v wt––––––.0031.66 (1.05, 2.60)DNMT3A R882 mut v wt Non-R882 v wt.006 .211.65 (1.15, 2.36) 1.33 (0.85, 2.08)WBC, continuous, 50 unit increase<.0010.56 (0.41, 0.76)––––<.0011.25 (1.12, 1.39)Age group, ≥ 60 y v < 60 y.010.40 (0.19, 0.83)<.0012.09 (1.44, 3.03)<.0012.64 (1.80, 3.87)<.0012.16 (1.54, 3.02)OR, odds ratio; HR, hazard ratio; CI, confidence interval; mutated, mut; wild-type, wt.ORs > (<) 1.0 mean higher (lower) CR rate, and HRs > (<) 1.0 mean higher (lower) risk for relapse or death (DFS, EFS), respectively, for the higher values of the continuous variables and the first category listed for the categorical variables. Variables significant at α =.20 in univariable models were considered, although all considered variables are not shown.*There are interactions between GAS6 and TYRO3/AXL dual receptor status for DFS (P=.16), OS (P=.06) and EFS (P=.12). The P-values, HRs and CIs are for comparisons of GAS6+ v GAS6– pts within the TYRO3–/AXL– subset. Disclosures:No relevant conflicts of interest to declare.