Academic literature on the topic 'K 46.5 UL 2012 C293'

Abstract Introduction. In the past years there were many attempts to replace or improve the IPI score for overall survival evaluation (OS) in diffuse large B cell lymphoma (DLBCL). We focused our attention on prognostic factors, studied in the past or in recent years, that could be used as surrogates of the disease status. We considered the serum albumin (SA) level as surrogate of age, comorbidity and disease severity; LDH as surrogate of cell activity and disease stage; absolute monocyte count (AMC) as surrogate of inflammatory status and absolute lymphocyte count (ALC) as surrogate of immune status of patients. Patients and method We collected data of 322 patients comprehensive of IPI factor, SA, AMC and ALC recorded in the "Gruppo Itliano Studio Linfomi" (GISL) database from 2003 to 2012. The score was obtained summing the factors SA <3.7 g/dL, LDH >UNL, AMC>630 /uL and ALC <840 /uL, any with weight one. The factors were not the results of statistical procedure but were chosen on the basis of clinical and pathophysiological considerations, about the role played by these factors in the DLBCL. The OS was estimated using the Kaplan-Meier method; the discriminate ability of the score was checked by means of log-rank test and using the ROC curve, sensibility and specificity at 3-years of follow-up. Results All the 322 patients included in the study were treated with R-CHOP and R-CHOP like regimens. The median age at diagnosis was 67 years (range 22-86) and 54% were males; SA <3.7 was identified in 44% of the patients, LDH>UNL in 51%, AMC >630 in 33% and ALC <840 in 23%. The sum of those four factors defined a score with three levels of risk: low (0-1, n=69, 21%), intermediate (2, n=94, 29%) and high (3-4, n=159, 49%). The OS at 5-yrs was 96%, 76% and 46% for score 0-1, 2 and 3-4, respectively The log-rank between score 0-1 and 2 was 11.2 (p=0.0008) and 16.9 between score 2 and 3-4 (p<0.0001). The ROC curve at 5-yrs was 72.1%, with 75.8% of sensitivity and 68.5% of specificity. The score showed a moderate accordance with IPI coded 0-1, 2 and 3/5 (k-statistic 0.37). Conclusion This approach showed that it is possible to define a simple prognostic score taking into account simple factors, easily available in every hospital, and related to the disease status. This selection was based on the clinical and pathophysiological knowledge accumulated over the years and, also, avoiding complicated statistical procedures for the selections of the prognostic factors. As it appears in the graph (Fig.1) , patients can be clearly stratified in three groups with deeply different survival outcome, based only on biochemical factors. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background Hematologic toxicity is a common treatment complication of chronic hepatitis C virus (HCV) infection, especially when interferon (IFN) and ribavirin are used. The side effects of treatment are often augmented in cancer patients due to baseline cytopenias. These adverse events often lead to dose reduction or discontinuation of antivirals. Hematopoietic growth factors (GF) and blood transfusions are used to counteract toxicities allowing patients to complete treatment. We aimed to evaluate the incidence and management of hematological toxicity associated with different types of HCV treatment in cancer patients. Methods Medical records of cancer patients treated for HCV infection at MD Anderson Cancer Center between 2009 and 2014 were reviewed. Those seen from 8/2009 to 10/2012 were analyzed retrospectively, whereas those seen from 11/2012 to 7/2014 were prospectively studied. Patients who received combination treatment with peg-IFN and ribavirin (PR), telaprevir or boceprevir plus PR (TBPR), sofosbuvir plus PR (SPR), sofosbuvir with simeprevir (SS) and sofosbuvir with ribavirin (SR) were included in the study. Data regarding treatment interventions (dose reductions and/or discontinuation of antivirals), use of GFs or blood transfusions in the management hematological side effects were analyzed. Categorical variables were analyzed using the χ2 or Fischer's exact test. Results Sixty-five patients were identified (Table). The need for treatment interventions, GFs or blood transfusions was comparable between patients with hematologic malignancies and solid tumors. Seventeen (81%) of the PR group, 13 (93%) of the TBPR group, 6 (67%) of the SPR group, 9 (64%) of the SR group and 0 of the SS group required treatment interventions (p <0.001) (Figure). Twelve (57%) of the PR group, 9 (64%) of the TBPR group, 3 (33%) of the SPR group, 2 (14%) of the SR group and 0 of SS group required the use of GFs (p <0.01). Six (29%) patients of the PR group, 9 (64%) from the TBPR group, 1 (11%) from the SPR group, 1 (7%) from the SR group and 0 from the SS group received blood transfusions (p <0.01). From patients who received GFs (N=26), 2 received epoetin alfa, 11 darbepoetin alfa, 2 filgrastim, 17 pegfilgrastim, 4 eltrombopag and 1 romiplostim. Ten of them (39%) required multiple GFs, with darbepoetin alfa and pegfilgrastim being the most common combination. Combined use of GFs was only needed in those receiving TBPR (56%), PR (33%) or SPR (33%). Overall, 82% of the patients who received treatment interventions, 77% of those who received GFs and 47% of those who received blood transfusions were able to complete HCV treatment. Thirteen patients (62%) from the PR group, 12 (86%) from the TBPR group, 3 (33%) from the SPR group, 2 (14%) from the SR group and 0 from the SS group developed grade 3 or 4 hematologic toxicities (p <0.001). One (25%) of 4 patients receiving eltrombopag developed portal vein thrombosis. No other patients developed side effects attributed to GF support. Conclusions Hematologic toxicity during HCV treatment in cancer patients is common. The use of GFs helps manage such toxicity, allowing completion of antiviral therapy. The newer HCV direct-acting antiviral agents are associated with less hematological toxicity, requiring fewer interventions, GFs and blood transfusions. No hematologic side effects were seen with the IFN-free, ribavirin-free combination of SS. Abstract 4126. Table Characteristics of HCV-infected cancer patients treated with different antiviral regimens PR (N=21)% TBPR (N=14)% SPR (N=9)% SR (N=14)% SS (N=7)% Age, median (range) 54.3 (45-68) 59.7 (49-69) 54.7 (35-75) 62.7 (33-82) 60.9 (46-64) Male gender 13 (62) 6 (43) 4 (44) 8 (57) 4 (57) Type of cancer Solid Hematologic 16 (76)5 (24) 10 (71)4 (29) 4 (44)5 (56) 6 (43)8 (57) 4 (57)3 (43) Cirrhosis 5 (24) 7 (50) 2 (22) 3 (21) 6 (86) Baseline labs, median (range) Hemoglobin (g/dL) Platelets (x1,000 K/uL) Absolute Neutrophil count (K/uL) 12.8 (10-15.9)165 (83-408)1385 (940-6120) 13.5 (9.6-16.3)112 (52-397)2360 (800-4900) 13.8 (8.8-14.2)183 (121-268)2680 (1650-5810) 13.1 (9.8-15.5)179 (57-390)2490 (1040-4040) 13.8 (12.3-16.1)141 (59-239)3000 (1390-5030) FDA-recommended duration of antiviral treatment, weeks 24-48 24-48 12 12-24 12 Duration of antiviral treatment, median (range) 24 (2-48) 19 (3-52) 12 (1-12)* 12 (3-24)* 6 (3-12)* *Patients may still be on treatment. Figure Management of hematologic toxicity during HCV treatment of cancer patients Figure. Management of hematologic toxicity during HCV treatment of cancer patients Disclosures Torres: Genentech,: Consultancy; Vertex Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc. : Consultancy, Research Funding; Gilead Sciences: Consultancy.

Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin <11.5 g/dl (68%), platelet count <100 K/uL (12%), albumin <3.5 g/dl (39%), b2-microglobulin ≥3 mg/l (70%), serum IgM level ≥7,000 mg/dl (6%), bone marrow involvement ≥60% (54%), previously untreated for WM (33%), time to ibrutinib <3 years (46%). MYD88 L265P and CXCR4 mutations were detected in 98% and 38% of patients, respectively. At 6 months, 71% of patients obtained PR, and 17% VGPR. Multivariate logistic regression analyses showed higher odds of PR at 6 months for hemoglobin <11.5 g/dl (78% vs. 56%; OR 2.8, 95% CI 1.1-6.9; p=0.03) and serum albumin <3.5 g/dl (90% vs. 66%; OR 3.2, 95% CI 1.0-10; p=0.045), while CXCR4 mutations associated with lower odds (44% vs. 82%; OR 0.15, 95% CI 0.06-0.37; p<0.001). Multivariate logistic regression analyses showed higher odds of VGPR at 6 months for b2-microglobulin ≥3 mg/l (21% vs. 3%; OR 3.3, 95% CI 1.1-10; p=0.04) and lower odds for serum IgM level ≥4,000 mg/dl (9% vs. 23%; OR 0.3, 95% CI 0.1-0.8; p=0.02). The median follow-up was 30 months, and the median PFS has not yet been reached. The 5-year PFS rate was 60% (95% CI 48-69%). In the multivariate Cox regression analysis, worse outcomes were seen with CXCR4 mutations (5-year PFS: 45% vs. 71%; HR 2.8, 95% CI 1.4-5.8; p=0.004) and serum albumin <3.5 g/dl (5-year PFS: 36% vs. 68%; HR 2.7, 95% CI 1.3-5.5; p=0.007). A novel PFS risk score was designed using CXCR4 mutational status and serum albumin (Figure), which divided patients into 3 distinct groups: low risk (no risk factors: 43%; 5-year PFS 81%), intermediate risk (1 risk factor: 46%; 5-year PFS 51%) and high risk (2 risk factors: 11%; median PFS 25 months). The PFS difference between groups was statistically significant (p<0.001). The PFS risk score showed consistent results when evaluating previously treated and untreated patients, as well as patients on and off clinical trials. Conclusion: Serum albumin and CXCR4 mutations emerge as important factors predictive of PR at 6 months and also prognostic of PFS in WM patients treated with ibrutinib. A novel PFS stratification tool that separates patients into 3 risk groups was established and would need further validation. Figure Disclosures Castillo: Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Hunter:Janssen: Consultancy. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

Abstract Background Nucleoside analogues such as cladribine can increase the efficacy of ara-C by modulating deoxycytidine kinase. The addition of cladribine to standard 7+3 chemotherapy has been shown to improve survival in pts with AML (Holowiecki JCO 2012). High dose ara-C (HiDAC) during induction improves outcomes for younger pts (Burnett JCO 2013, Willemze JCO 2013). We conducted a phase-2 clinical trial to study the efficacy of cladribine combined with HiDAC and idarubicin as induction regimen in younger pts with AML. Methods The 3-drug treatment protocol consisted of the combination of cladribine, idarubicin, and ara-C (CLIA) in pts with AML aged ≤ 65. Three cohorts were enrolled: de novo AML, secondary AML (s-AML), and relapsed/refractory (salvage). S-AML was defined as pts with AML arising from MDS, MPN, or AA and treated for that disorder prior to enrolling. Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5, followed by ara-C 1000 mg/m2 IV on days 1-5, and idarubicin 10 mg/m2 IV days 1-3. Consolidation consisted of up to 5 more cycles of CLIA. Pts with FLT3-ITD could receive sorafenib 400mg PO BID added to CLIA. Pts with FLT3+ disease, presenting WBC count > 100 K/uL, or LDH > 700 IU/dL received prophylactic intrathecal ara-C at count nadir during cycle 1. Mutation profiling was performed using next generation sequencing prior to starting therapy. Results A total of 101 pts were enrolled, with a median age of 55 years (range, 19-65), including 47 pts (47%) in the frontline cohort, 8 (8%) pts in the s-AML cohort, and 46 (46%) in the salvage cohort. Pt characteristics by cohort are outlined in Table 1. In the frontline cohort, 47 pts, who received a median of 3 (1-6) cycles, were evaluable for response. 36 pts achieved CR (77%) after a median of 1 (1-4) cycle and 4 pts CRp, giving an ORR of 81%. The 4- and 8-week mortality rates were 0% and 4%, respectively. In s-AML cohort, 8 pts were evaluable for response, receiving a median of 2 courses (1-3). The rates of CR, CRp, and CRi were 0% (0/8), 25% (2/8), and 0% (0/8) for an ORR of 25%. The 4- and 8-wk mortality rates were 13% and 13%. In the salvage cohort, 46 pts received a median of 1 (1-4) cycle, and were evaluable for response. Ten pts achieved CR (22%), 4 CRp (9%), and 4 CRi (9%), achieving an overall response rate (ORR) of 39%. A median of 1 (1-3) cycle was required for response. The 4- and 8-wk mortality rates were 7% and 15%, respectively. At the time of CR, 21 (55%), 0 (0%), and 8 (44%) of pts achieved MRD negativity by multiparameter flow cytometry in the frontline, s-AML, and salvage cohorts respectively. Pts in the salvage cohort were previously treated with a median of 2 (1-5) prior therapies. ORR by subgroup is summarized in Table 2. After a median follow-up of 12 months (0.9 - 24.1), the 6-month OS estimates were 89%, 26% and 58% and 6 month remission durations were 95%, 100%, and 55% for the frontline, s-AML, and salvage cohorts, respectively (Figure 1A-B). Among MRD negative pts, 1 frontline pt relapsed at 6.7 months and 4 salvage pts relapsed at month 3.4, 3.9, 5.1 and 5.2 (median 4.5). In frontline pts, pretreatment serum ferritin level of < 1000 was associated with improved OS compared to those who had ferritin ≥ 1000 (1-year OS 81% vs. 47%, P=0.04). The regimen was well tolerated. The most common ≥ grade 3 non-hematologic adverse events were fever/infection (17), tumor lysis syndrome (1), cardiac arrhythmia (1), Rash (1), elevated bilirubin (1) and creatinine (1). Conclusion The 3-drug combination, CLIA, is safe and effective in younger pts with AML. Outcomes in pts with s-AML were poor, highlighting a subgroup of AML that should be handled separately. Response rates for pts in the newly-diagnosed AML, FLT3-ITD+, and early salvage settings are promising and should be explored further in larger studies and compared to current standard regimens. Disclosures Jabbour: Bristol-Myers Squibb: Consultancy. Daver:Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding. Jain:Genentech: Research Funding; Servier: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Research Funding; BMS: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of hypomethylating agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a hypomethylating agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active agents are needed to improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Thrombotic microangiopathy (TMA) is seen in up to 30% of patients receiving solid organ transplantation and almost always occurs in the setting of calcineurin inhibitor (CNI) therapy. The underlying pathophysiology of calcineurin induced TMA is poorly understood. Long term follow up in non renal transplant patients with TMA suggests that in spite of plasma exchange therapy the 1 year mortality following TMA is up to 70%. Between November 2010 and August 2012, 7 patients at our institution who underwent organ transplants ( 5 small bowel, 2 orthotopic liver) developed clinical and laboratory evidence of TMA while receiving CNI therapy. TMA was diagnosed from 3 to 13(median 11) months post transplant and none of the patients responded symptomatically or by laboratory parameters to a reduction in dose of CNI. Other unsuccessful therapies included substitution of other immunosuppressive agents (N=1) and 11 daily plasma exchanges (N=1). At the time of TMA diagnosis notable laboratory values included platelets 22-73 (median 46) K/UL, hemoglobin 4.5 to 8.1(median 6.9) GM/DL, serum creatinine 1.16-5.4 (median 2.66)MG/DL, LDH 262-2903(median 435) Units/L, and ADAMSTS13 37-137%. All patients had a negative DAT, schistocytes on peripheral smear and all but one had undetectable haptoglobin. ( Table 1 ) Clinical symptoms at diagnosis included nausea, vomiting, abdominal pain, fever, hypertension, cerebral vascular accident (N=1), acute coronary syndrome (N=1). None of the patients had evidence of graft rejection on biopsy of the transplanted organ at the time of TMA diagnosis however 2 patients with small bowel transplants had pathologic evidence of ischemic changes and vascular thrombi on biopsy of the small bowel graft.Table 1Comparison of Medians of TMA Laboratory ParametersMedian ValuesPreTransplantTMA Diagnosis4 weeks post eculizumabPlatelet count K/UL12046202Hemoglobin GM/DL11.06.99.0Serum Creatinine MG/DL0.832.661.7LDH Units/L174435322HaptoglobinNT<3190 Eculizumab is a monoclonal antibody which binds with high affinity to C5 and is highly effective in disorders associated with abnormalities in the regulation of complement such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS) another TMA disease. Due to the clinical and laboratory similarities of post transplant CNI associated TMA and aHUS all patients in our series were treated with the standard induction dose of eculizumab 1200mg weekly for 4 weeks and 900mg every 2 weeks thereafter. Treatment duration ranges from 4 weeks to 107 weeks. All patients were successfully maintained on adequate immunosuppression with calcineurin inhibitor (tacrolimus in all cases) to inhibit graft rejection. All patients demonstrated a rapid and complete resolution of laboratory and clinical manifestations of TMA. After the fourth dose of eculizumab platelet counts ranged from 104-291(median 202), hemoglobin 8.1-10.9(median 9.0), serum creatinine 0.70-4.08(median 1.7), LDH 157-475(median 322) and haptoglobin 23-204(median 90). Only 1 of the 4 patients requiring dialysis at TMA diagnosis remained on dialysis at 4 weeks of therapy.( Table 1) No patients show evidence of recurrent TMA or increase in infectious complications on continued eculizumab plus calcineurin inhibitor therapy at greater than 2 years of eculizumab therapy. The excellent clinical and laboratory response of our patients to eculizumab strongly suggests a central role for complement dysregulation in the pathophysiology of calcineurin induced TMA. There are multiple theories regarding the mechanism by which CNIs induce complement dysregulation including: (1) an underlying genetic predisposition to complement dysregulation worsened or exacerbated by CNI therapy, (2) CNI therapy may induce widespread and significant endothelial damage which serves as a stimulus for chronic complement activation, or (3) chronic over stimulation of complement production secondary to CNI inhibition of T-cell function .While the mechanism remains to be elucidated the clinical implications seem clear: CNI induced TMA is mediated by complement and is treated very effectively with eculizumab allowing patients to continue on graft function preserving CNI therapy. Disclosures: Broome: Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Off Label Use: Eculizumab for the treatment of calcineurin induced TMA.

Abstract Background: The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Discontinuation of ibrutinib has been associated with an adverse prognosis in patients with chronic lymphocytic leukemia and mantle cell lymphoma. However, reasons for discontinuing ibrutinib therapy and the outcomes following discontinuation in patients with WM has not been previously evaluated. Methods: We identified patients seen at our institution between May 2012 and April 2017 who met clinicopathological criteria for WM and received ibrutinib therapy. An IgM rebound was defined as a 25% increase in the serum IgM level (with an absolute increase of 500 mg/dl) following the discontinuation of ibrutinib. Time to events was estimated using the Kaplan-Meier method. Univariate and multivariate logistic regression models were fitted to evaluate the association between clinical variables and the occurrence of ibrutinib discontinuation and an IgM rebound. The Cox-proportional hazard regression model was used to fit univariate and multivariate models for overall survival (OS). P-values &lt;0.05 were considered statistically significant. Results: A total of 189 patients with WM who received treatment with ibrutinib were identified, of whom 51 (27%) have discontinued ibrutinib therapy. The overall cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months was 22%, 25%, 35%, and 43%, respectively. Ibrutinib was discontinued due to progressive disease (PD) in 27 patients (53%). The median time to PD discontinuation was 12 months (95% CI 7-25), and the 12-, 24-, 36-, and 48-month cumulative incidence was 2%, 4%, 7%, and 11%, respectively. Non-PD events caused ibrutinib discontinuation in 24 patients (47%) attributable to toxicity (n=15; 63%), non-response (n=5; 21%), and miscellaneous (n=4; 17%). The median time to non-PD discontinuation was 5 months (95% CI 3-7), and the 12-, 24-, 36-, and 48-month cumulative incidence was 6%, 7%, 10%, and 12%, respectively. A baseline platelet count &lt;100 K/uL (OR 3.85, 95% CI 1.20-12.3; p=0.02) and CXCR4 mutation (OR 3.89, 95% CI 1.74-8.69; p=0.001) were associated with higher odds of ibrutinib discontinuation, whereas a serum IgM level &gt;4,000 mg/dl was associated with lower odds (OR 0.38, 95% CI 0.17-0.86; p=0.02). An IgM rebound was observed in 37 patients (73%) following ibrutinib discontinuation. The cumulative incidence of an IgM rebound at 4 and 8 weeks following discontinuation was 48% and 79%, respectively. An increased risk of an IgM rebound at 4 weeks (72% versus 29%) and 8 weeks (95% versus 66%) was observed for patients with PD versus non-PD discontinuation. Six patients (16%) developed symptomatic hyperviscosity requiring emergent plasmapheresis. Male sex was associated with lower odds of an IgM rebound following ibrutinib discontinuation (OR 0.18, 95% CI 0.03-0.90; p=0.04). Thirty-eight patients (76%) received salvage therapy following ibrutinib discontinuation. The median time to salvage therapy was 5 weeks (95% CI 3.6-8.1). Twenty-seven patients (73%) responded to salvage therapy with the following regimens: combination therapy with an anti-CD20 monoclonal antibody and alkylator (16/22; 73%), proteasome inhibitor (4/5; 80%), or nucleoside analogue (2/2; 100%), BCL2 inhibitor (3/5; 60%), and other (2/5; 40%). Patients without an IgM rebound were more likely to respond to salvage therapy versus those with an IgM rebound (100% versus 62%; p=0.04). Thirteen patients (24%) have not received salvage therapy. Reasons for not receiving salvage therapy include: treatment not required (n=6; 46%), patient choice (n=4; 31%), death (n=2; 15%), and acute myeloid leukemia (n=1; 8%). The median OS was 32 months (95% CI 19-NR) following discontinuation with an estimated 1-, 2-, and 3-year OS of 72%, 56%, and 45%, respectively. Response to salvage therapy was associated with a decreased risk of death following ibrutinib discontinuation (HR 0.18, 95% CI 0.04-0.72; p=0.02) Conclusion: Ibrutinib discontinuation is associated with CXCR4 mutations in WM patients. Rapid increases in serum IgM level often occur following discontinuation, which can result in hyperviscosity syndrome. Patients who must discontinue ibrutinib require close monitoring, and continuation of ibrutinib until initiation of the next therapy should be considered. Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding.