Jain, Tania

Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract Background: Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET), polycythemia vera (PV), and early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in myeloproliferative (MPN) patients treated outside the constraints of a clinical trial. Methods: Charts were analyzed for demographic and clinical data. Toxicity to therapy was assessed per CTCAE 3.0 criteria. Therapeutic responses for ET and PV were calculated by the revised ELN/IWG-MRT criteria including complete remission (CR), partial resmission (PR), no response (NR), or progressive disease (PD). Responses in MF were calculated by EUNMET: complete response (CR), major response (MR), moderate response (MoR), minor response (MiR) and NRand the revised IWG-MRT/ELN criteria: CR, PR, clinical improvement (CI), stable disease (SD) or PD. Results: Patients: 75 patients were identified overall. There were 36 PV patients (48%), 20 ET patients (26.7%), and 19 MF patients (25.6%). Thirteen MF patients were post-PV/ET MF. The median age at diagnosis was 51.5 yrs (range 28.8-75.1). JAK2 V617 mutation was present in 53 patients (70.7%). Median baseline hemoglobin (g/dL), leukocyte (x10 9), and platelet count (x109) for PV was 13.6, 8.6, 369, for ET was 12.5, 6.8, 517, and for MF was 11.4, 8.0, and 420, respectively. DIPSS risk category for the 19 MF patients: Low in 6 (31.5%) patients, Intermediate-1 in 3 (15.7%), Intermediate-2 in 8 (42%), and High in 2 (10.5%) patients. The majority of patients (82.2%) had received at least one prior cytoreductive therapy for their disease. Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range 45-90). The median peak dose was 90 micrograms/week (range 45-270). The median tolerated dose was 60 micrograms/week (range 5.6-180). The median duration of treatment was 24 months (range 3.6-85). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity included: leukopenia at grade 1 in 13 patients (17.3%), grade 2 in 5 patients (6.7%), and grade 3 in 1 patient (1.3%), anemia at grade 1 in 10 patients (13.3%) and grade 2 in 1 patient (1.3%), thrombocytopenia at grade 1 in 13 patients (17.3%) and grade 2 in 1 patient (1.3%). The most common non-hematologic toxicity included: fatigue at grade 1 in 14 patients (18.7%) and grade 2 in 4 patients (5.3%), transaminitis at grade 1 in 6 patients (8%) and grade 2 in 3 patients (4%), myalgias at grade 1 in 4 patients (5.3%). Response: See Table #1 PV/ET: 56 patients were evaluated by ELN/IWG-MRT criteria overall: A complete remission (CR) was seen in 8 patients (14.3%), a partial remission (PR) in 18 patients (32.1%), either a CR or PR in 18 patients (32.1%) when histologic remissions were unable to be documented due to lack of restaging bone marrow examination, no response in 11 patients (19.6%), and progressive disease in 1 patient (1.8%). Of the 12 patients receiving at least1 phlebotomy per month, 10 patients (83.3%) became phlebotomy independent with therapy. Of the 20 ET patients, 12 patients (60%) had platelet normalization (<400 x 109). MF: 19 patients were evaluated by IWG-ELN criteria: a PR was seen in 2 patients (10.5%), CI in 4 patients (21.1%), SD in 12 patients (63.2%), and PD in 1 patient (5.3%). Utilizing EUNMET critieria: 1 patient (5.3%) with a CR, 5 patients (26.3%) with a MR, 3 patients (15.8%) with MoR, 5 patients (26.3%) with MiR, and 5 patients (26.3%) with NR. Table 1. Peg INF2a Patient Responses RESPONSE Disease IWG-ELN response criteria: (Patient #, %) (Barosi, Blood 2013, Tefferi, Blood 2013) EUMET response criteria: (Patient #, %) (Barosi, Blood 2005) PV: N=36 CR: 3 pts (8.3%) PR: 14 pts (38.8%) CR/PR: 14 pts (38.8%) NR: 5 pts (13.8%) PD: 0 NA ET: N=20 CR: 5 pts (25%) PR: 4 pts (20%) CR/PR: 4 pts (20%) NR: 6 pts (30%) PD: 1 (5%) NA MF: N=19 IWG-ELN: PR: 2 pts (10.5%) CI: 4 pts (21.1%) SD: 12 pts (63.2%) PD: 1 pt (5.3%) EUNMET: CR: 1 pt (5.3%) MR: 5 pts (26.3%) MoR: 3 pts (15.8%) MiR: 5 pts (26.3%) NR: 5 pts (26.3%) NA: Not applicable Conclusions: Peg INF2a is active and well-tolerated when administered outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Disclosures Mesa: Pfizer: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding.

Abstract Among mechanisms underlying cytotoxic drug resistance is activation of diverse DNA damage response (DDR) pathways. Poly(ADP-ribose) polymerases (PARP)-1/2 facilitate both single- and double-strand break (DSB) repair and play a key role in the base excision repair (BER) of chemotherapy-damaged DNA. The PARP inhibitor veliparib (V) potentiates the cytotoxicity of different chemotherapeutics, including temozolomide (TEM). TEM induces distinct alkylating events in neoplastic cells whose ultimate outcome depends on the interaction of BER, mismatch repair (MMR), O(6)-methylguanine-DNA methyltransferase (MGMT), and DSB repair. While clinical activity of TEM has been mainly observed in MGMT-deficient AML, V potentiated cytotoxicity of TEM in leukemia cells in vitro in the setting of MGMT overexpression or deficient MMR pathway (Mol Cancer Ther, 2009). Methods: We conducted a Phase I study to determine maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of V+TEM, using a 3+3 dose escalation. Patients (pts) ≥60 years (yrs) with newly diagnosed poor cytogenetic-risk AML/ALL who were not candidates for intensive therapy, or ≥18 yrs with relapsed/refractory AML/ALL, secondary AML (therapy-related or arising from MDS or MPN), and CMMoL-2 were eligible. Any number of prior regimens, including allogeneic transplant (alloSCT), were allowed. V was given orally day (d)1 once, then twice a day on d4-12 at one of 6 dose levels (DL) (DL1A-B 20mg; DL2-DL3-DL4-DL5-DL6: 40-80-120-150-200 mg). TEM was given orally once a day on d3-9 (DL1A 150 mg/m2/d; DL1B-DL6 200 mg/m2/d). 28-day cycles (cy) were repeated depending on response/tolerability (4-6 weeks delay allowed) with V on d1-8 and TEM d1-5. TEM was taken on empty stomach with antiemetics and V was taken irrespective of meals. Results: Forty-nine pts with median age 69 yrs (range, 22-88; 47% ≥70) were treated. Of 47 AML pts, 29 (62%) had secondary AML and 27 (57%) adverse karyotype. Median number of prior treatments for AML was 1 (range, 0-6): 18 (38%) had median 1 prior therapy (range, 1-3) for MDS; 30 (64%), 9 (18%), 34 (69%) received hypomethylating agents, alloSCT and intensive chemotherapy, respectively. Overall 42 (85%) pts were refractory to their last treatment. Pts received a median of 1 (range, 1-7) cy of therapy. Two did not complete cy 1, pt withdrawal d5 and progressive fungal pneumonia d9 with death d15 of progressive disease (PD). The MTD/RP2D was defined at V 150 mg and TEM 200 mg/m2; 2 of 4 pts treated at V 200 mg and TEM 200 mg/m2 developed dose-limiting toxicity of grade (gr) 3 oral mucositis/esophagitis. The most frequent drug-related toxicities (NCI CTC v4) were gr 1/2 nausea/vomiting (39%), fatigue (26%), oropharyngeal mucositis (26%), constipation (12%), and diarrhea (10%). Other common toxicities were infectious, including febrile neutropenia (29%), pneumonia (20%), bacteremia (18%). One (2%) pt died ≤d30 and 12 (24%) ≤d60 mainly of PD (1 pt fungal pneumonia before count recovery d31). Overall response rate was 33% (complete remission (CR), hematologic improvement (HI)/stable disease) with 8 (16%) pts achieving CR (1 CRi). Median overall survival was 5.03 months, for all responders 11.58 months, and for CR pts 19.89 months (Fig 1). Responses occurred at all DLs. Three CR pts underwent alloSCT; 2 remain in CR at ~3 yrs. Pharmacokinetics (PK): V or TEM PKs were not altered with co-administration. There was a correlation between the DLT of mucositis and V single (Cmax P=0.005; AUC P=0.009) and multiple dose exposure (Cmax P = 0.02; AUC P=0.03). Pharmacodynamics and pharmacoepigenetics: Four of 39 pts examined had MGMT methylation (3 CR; 75%) and 2 had BRCA-1 methylation (1 HI) in peripheral blood (PB) or bone marrow (BM) mononuclear cells (MC). Defective FancD2 pathway was observed in the BMMC of 19/19 pts using FancD2 ubiquitylation assays but did not correlate with response. V reduced PAR levels by >75% in PBMC of most pts and in the presence of TEM. Induction of γ-H2AX in CD34+ cells was seen upon V/V+TEM treatment. Conclusion: V plus TEM demonstrated safety and activity in this resistant and elderly leukemia population. Response rate was higher in MGMT methylated pts, but responses were also seen in pts who had no MGMT methylation, had failed multiple therapies, had secondary AML and/or adverse karyotype. Future clinical study should aim to identify pts with defective DDR pathways who are most likely to respond to this therapeutic approach. Figure 1. Figure 1. Disclosures Off Label Use: Temozolomide is not approved for AML. Beumer:Millenium: Other: Research support. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract Introduction: Hematologic response (HR) particularly complete response (CR) is critical in patients (pts) with AL since it improves overall survival (OS) because of organ response (OrgR). Bor based therapies especially in combination with cyclophosphamide and dexamethasone (CyBorD) have shown to be an active regimen in AL. So far, there have been no comparative studies studying the effect of treatment with B-based regimens prior to SCT (Bor-SCT) versus SCT upfront or SCT preceded by non-Bor therapies (non-Bor-SCT). We present a retrospective analysis of data with an aim to compare the OS, OrgR and HR in the two cohorts. Methods: Charts were reviewed for the pts who underwent SCT for AL since 2004 until 2015 at Mayo Clinic in Arizona. HR and OrgR were determined using the consensus criteria from International Society of Amyloidosis.1 HR were noted at 3, 6 and 12 months from SCT. Results: Patients and disease characteristics: 63 pts were identified who underwent SCT for AL, of which 34 were in Bor-SCT and 29 were in the non-Bor-SCT cohort. Median age at diagnosis was 59.5 (range, 39 - 72) and 63 (range, 38 - 76) years and at SCT was 60 (range, 40 - 72) and 63 (range, 39 - 76) years for Bor-SCT and non-Bor-SCT, respectively. There were 13 (38%) females in Bor-SCT and 9 (31%) in non-Bor-SCT. Mean bone marrow involvement of plasma cells at diagnosis was 18% (SD±16.5) in Bor-SCT and 6.8% (SD±7.8) in non-Bor-SCT (p = 0.004). All pts had an ECOG performance score of better than 3 at the time of SCT. Fifteen (44%) pts had single organ involvement at diagnosis and 9 (26.5%) had 2-organ involvement in Bor-SCT. In non-Bor-SCT, 21 (72%) pts had single and 6 (21%) had 2-organ involvement (p = 0.04). More than 2 organs were involved in 10 (29%) pts in Bor-SCT and 2 (7%) in non-Bor-SCT. Heart was involved in 18 (53%) pts in Bor-SCT and 8 (28%) in non-Bor-SCT (p = 0.04) while kidney involvement was seen in 27 (79%) in Bor-SCT and 23 (79%) in non-Bor-SCT (p = 0.99). Median creatinine was not significantly different in the 2 groups at diagnosis or at the time of SCT. In Bor-SCT, no pts were on hemodialysis at the time of diagnosis or SCT. In non-Bor-SCT, 1 pt at diagnosis and 3 pts at SCT progressed to need hemodialysis. Lambda light chain was involved in 27 (82%) and 22 (76%) (p = 0.56) with a mean level of involved light chains being 59(SD±88.7) g/dL and 43.3 (SD±64.6) g/dL (p=0.4539) in Bor-SCT and non-Bor-SCT, respectively. Treatment: Thirty-one (91%) out of 34 pts in Bor-SCT group got treatment with CyBorD while 2 (6%) got Bor with dexamethasone and 1 (3%) got Bor with pegylated liposomal doxorubicin. In the non-Bor-SCT group, 20 (69%) out of 29 got no treatment, 4 (14%) got melphalan prednisone, 2 (7%) got dexamethasone alone, 1 (3%) got vincristine dexamethasone and 2 (7%) got lenalidomide dexamethasone prior to SCT. Transplant factors: Median time from diagnosis to SCT was 226.5 (range, 65 - 1108) days in Bor-SCT and 150.5 (48 - 1139) days in non-Bor-SCT (p=0.32). Full dose of melphalan (200 mg/m2) was used in 21 (62%) pts in Bor-SCT and 13 (34%) pts in non-Bor-SCT (p <0.001). Mean dose of cells used for SCT was 4.6 (SD±0.9) and 4.8 (SD±2.2) x 106/kg in Bor-SCT and non-Bor-SCT, respectively. Median time to neutrophil and platelet engraftment was 13 (range, 10 - 27) and 16 (range, 8 - 28) days in Bor-SCT while 11 (range, 7 - 16) and 13 (range, 10 - 25) days in non-Bor-SCT. Responses: HR at 3, 6 and 12 months from SCT and OrgR by the time of last follow up is described in table 1. Survival: Median OS was not reached in Bor-SCT as compared to 53.4 months in non-Bor-SCT (p =0.001), Figure 1. Conclusions: Our study suggests a benefit in HR, OrgR as well as OS by reduction of disease burden by Bor-based therapy prior to SCT. This benefit was observed despite a higher percentage of pts with cardiac involvement, more than 2 organ involvement and mean bone marrow plasma cells at diagnosis in Bor-SCT. Currently, it is not standard practice to use Bor-based therapy prior to SCT. A prospective study with larger number of pts would be required to confirm these findings. References: 1. Gertz MA et al. Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): A Consensus Opinion From the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematol. 2005;79(4):319-328. Disclosures Dueck: Bayer: Honoraria. Mikhael:Abbvie, Celgene, Onyx, Sanofi: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Reeder:Novartis, Millennium, BMS and Celgene: Research Funding. Stewart:celgene: Consultancy. Fonseca:AMGEN: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; BMS: Consultancy; Celgene: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy.

Abstract Background: Donor cell chimerisms are tested at frequent intervals after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the predictive value of this testing in patients with myelofibrosis (MF) is not well-defined. In this study, our primary objective is to evaluate the correlation of day 30 and day 100 donor cell chimerism and overall survival (OS) in patients (pts) who undergo alloHSCT for MF. Methods: Charts were reviewed for pts who underwent alloHSCT for MF at Mayo Clinic in Arizona, Minnesota and Florida between January 2005 and December 2015. Patients who died within 30 days of alloHSCT were excluded. Chimerism studies were evaluated in the peripheral blood for CD3 and CD33 fractions at day +30 (D30) and day +100 (D100). Cut-off value of 100% and less than 100% was used because of limited variability below 100%. Standard statistical methods were used to compare continuous and categorical variables. The Kaplan-Meier method was used to provide survival curves. Results: Baseline characteristics: Sixty three consecutive patients who underwent alloHSCT for MF since January 2005 until December 2015, and had D30 and/or D100 chimerism studies available were included in the study. Of these, 24 (38%) were female. Median age at diagnosis was 56 years (range, 19 - 73 years) and median age at AHSCT was 58 years (range, 19 - 73 years). Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus) risk category at the time of alloHSCT was high in 31 (49%), intermediate-2 in 30 (48%) and intermediate-1 in 2 (3%) pts. JAK2 V617F mutation status was available in 61 pts and was positive in 35 (57%) pts. Nineteen (30%) pts had been treated with a JAK2 inhibitor prior to alloHSCT. Fifty-two (83%) pts had at least grade-2 fibrosis in bone marrow at the time of HCT. Transplantation: Median time from diagnosis to AHSCT was 12.9 months (range, 2.3 - 248.2 months). Fifty-five (87%) received a reduced intensity conditioning (RIC) regimen while 8 (13%) received myeloablative conditioning regimen. Of these 55 pts, RIC regimens used were busulfan fludarabine based regimen in 15 (27%), fludarabine melphalan based regimen in 18 (33%) and fludarabine melphalan carmustine in 22 (40%) pts. Donor source was matched related in 30 (48 %), matched unrelated in 28 (44%), single-antigen mismatched related in 4 (6%) and mismatched unrelated in 1 (2%). Peripheral blood stem cells were used in all AHSCTs. Outcomes: Median follow-up was 24.4 months (range, 1.5 - 83.6 months). Amongst pts who had <100% donor chimerism at D30 in CD33 fraction, 2 had 90%, 1 had 80% and 2 had zero% donor chimerism. At D100, 1 pt had 95%, 1 had 90%, 1 had 60%, 2 had 5% and 1 had zero% donor chimerism. Eighteen out of 57 (32%) pts who had 100% donor chimerism in CD33 fraction at D30 had died at the time of analysis compared to 4 out of 5 (80%) patients with less than 100% (p=0.03). Eight out of 38 pts (21%) who had 100% donor chimerism in CD33 fraction at D100 died versus 3 out of 6 (50%) with less than 100% (p=0.12). There was no significant survival effect of CD3 chimerism (p values=0.68, 0.59). Of the 23 deaths that had occurred at the time of analysis, cause of death was disease progression or relapse in 8 (35%), graft versus host disease in 6 (26%), transplant related (sepsis / engraftment failure) in 5 (22%) and unrelated causes in 4 (17%). Survival analysis: As depicted in the Kaplan Meier curve (figure 1), median overall survival (OS) for pts with 100% donor chimerism in CD33 fraction at day 30 was not reached while for <100% donor chimerism was 16 months (p=0.04). Survival at 3 years for patients with 100% CD33 donor chimerism at D30 was 65% while it was 40% for pts with less than 100%. Also, survival at 3 years for patients with 100% CD33 donor chimerism at day 100 was 75% compared to 50% for patients with less than 100%. Conclusions: In our study, 100% donor chimerism in CD33 fraction is associated with improved survival after alloHSCT for MF compared to pts with less than 100%. Further understanding regarding the reason for this relationship is critical. Larger studies to replicate these results would be imperative to validate these findings. Disclosures Mesa: Incyte: Research Funding; Ariad: Consultancy; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy.

Abstract Background: Proteasome inhibition with carfilzomib (CFZ) has shown to be effective therapy in relapsed refractory multiple myeloma (MM).1 Cardiac toxicity induced by CFZ has been reported in a small subset of patients treated in phase 3 clinical trials, including congestive heart failure (CHF) in approximately 2-5% of patients. The natural history or reversibility of cardiac dysfunction with CFZ has not been fully reported. The myocardium constantly contracts in adults and thus, adequate protein metabolism may be essential; and hence, effective proteasome degradation may pose a risk for contractility. Methods and results: We identified 12 patients, who received CFZ at Mayo Clinic in Arizona, and had a drop in ejection fraction (EF) attributable to the use of CFZ. Medical records were reviewed for baseline cardiovascular (CV) risk factors, CV disease reversibility and mortality resulting from CFZ induced cardiac dysfunction. Patients who had a drop in EF attributed to other causes, were not included in this count. The median age at the time of initiation of therapy with CFZ was 62.5 years (range, 55-70 years), median body mass index was 27.65 (range, 21 - 40), with 4 (33%) patients being obese and 6 (50%) in the overweight range. Two (17%) patients had history of coronary artery disease while 9 (75%) had hypertension, and were on medical treatment prior to CFZ initiation. Six (46%) patients had a previous history of CHF. Two of these had symptomatic systolic dysfunction, however at the time of CFZ initiation, EF had improved. The other 4 with prior CHF had sub-normal EFs noted on echocardiograms done prior to initiation of CFZ (median EF of these 4 was 49%). Overall, baseline EF was available for 10 out of these 12 patients and median EF at baseline was 55% (range, 45 - 67%). Other risk factors predisposing to cardiac dysfunction were smoking in 1 patient and history of radiation to the chest in 2 (17%) patients. No patient had received cardiotoxic dose of anthracyclines prior to starting CFZ. Myeloma therapies: All patients had received multiple lines of therapy for MM (median 4, range, 2-7). Ten (83%) patients had previous received bortezomib and 10 (83%) had received autologous stem cell transplant. Cardiac events and CFZ use: Median duration of CFZ therapy received prior to documented systolic dysfunction was 4 months (range, 0.5 - 20 months), with 3 episodes happening with less than one month of total CFZ therapy. Five out of the 12 (42%) patients had previously discontinued CFZ for other reasons when the systolic dysfunction was noted. However they were included since CHF occurred shortly after treatment (median of 2 months, range, 0.5 - 3). The median drop in EF was 22% (range, 9 - 45%). Recovery/ outcomes: Follow-up echocardiograms were available in 8 patients and all of these showed some improvement in EF (table 1). Median improvement in EF noted by the time of last follow up was 16% (range, 7-30%). Median best EF noted after the initial drop was 48% (range, 35 - 67%). Two patients never discontinued CFZ and EF improved spontaneously, to 67% and 64% respectively, after an initial drop. Another patient was rechallenged with CFZ due to progression of MM, 8 months after initial discontinuation, and did not have recurrence of systolic dysfunction. No patients succumbed to CHF. Six (50%) out of these 12 patients had died by the time of last follow-up. Cause of death was progressive MM in 4 (67%) and sepsis secondary to immunosuppression resulting from chemotherapy in 2 (33%). Conclusions: Our data, although with limited number of patients, suggests using caution when treating patients who have underlying cardiac risk factors with CFZ. Nevertheless, the cardiotoxicity was mostly reversible, with the minimal EF after recovery of 35%. In the setting of a life threatening malignancy, the impact and reversibility of cardiotoxicity needs to be understood so as not to prevent the utilization of otherwise effective therapy such as CFZ. Larger studies are needed to confirm these findings. References: 1. Stewart et al. Carfilzomib, Lenalidomide and Dexamethasone for relapsed multiple myeloma. NEJM 2015;372:142-52. Disclosures Mikhael: Celgene: Research Funding; Abbvie: Research Funding; Sanofi: Research Funding; Onyx: Research Funding. Reeder:Novartis, Millennium, BMS and Celgene: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Fonseca:Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Millennium, a Takeda Company: Consultancy; Novartis: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Celgene: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy.

Abstract Background: The current standard of care for eligible newly diagnosed multiple myeloma (MM) patients is induction therapy with novel agents followed by high dose chemotherapy and autologous stem cell transplant (ASCT). The International Myeloma Working Group proposed the Revised International Staging System (R-ISS) based on the presence of adverse chromosomal abnormalities (CA) detected by FISH (t(4;14), t(14;16) or del17p), in combination with ISS and LDH at diagnosis. However, there are a limited number of studies that have validated this risk model in the transplant and novel agents setting. Aims: To determine whether R-ISS is an appropriate risk-model for estimating overall survival (OS) and progression free survival (PFS) for transplant-eligible MM patients. Patients and Methods: We retrospectively studied a cohort of 519 MM patients who received novel drugs in the induction and subsequently underwent ASCT at Mayo Clinic Arizona from 2005 to 2014. In all, 95 patients met the inclusion criteria: comprising complete data at diagnosis (ISS, serum LDH level, and CA by FISH). The primary endpoint was OS from SCT and the secondary end point was PFS from ASCT. R-ISS groups were defined as described by Palumbo et al. J Clin Oncol. 2015; 33(26):2863-2869. Results: There were 50 (52.6%) men and 45 (47.4%) women who underwent ASCT in this period, with a median age at the time of transplant of 66-years-old (range, 36-78). There were 27 patients (28.4%) with high-risk CA: 12 patients (12.6%) with del17p; 11 patients (11.6%) with t(4;14); and 6 (6%) with t(14;16). In addition, 8 patients (8.5%) had high LDH levels and 9 patients (9.5%) presented with renal impairment at diagnosis. The patients were staged at diagnosis according to the three R-ISS groups: 44 patients (46.3%) had stage I, 26 (27.4%) had stage II, and 25 (26.3%) had stage III. CyBorD was the preferred induction regimen which was received by 42 patients (44%). There were 14 patients (15%) who received at least 2 lines of induction. All patients were in at least partial response (PR) at the moment of transplant: 32 in complete response (CR), 32 in very good partial response (VGPR) and the remaining 31 in PR. The response achieved at day +100 after ASCT improved, with 54 patients (57%) in CR, and only 18 patients (19%) in PR. After a median follow-up of 61 months (range, 14-135), median OS from SCT was 108 months (95% CI: 85 - 132 months) and the median PFS was 45.4 months (95% CI: 31.1 - 53.8 months) in the whole series.MM patients with R-ISS III had a significantly shorter median OS compared to patients with R-ISS II or R-ISS I (32.1 months vs. 94.7 months vs. not reached, respectively, P<0.0001) (Figure). No statistically significant differences in baseline characteristics were identified among these groups to explain the differences in OS observed. PFS among these groups was not statistically significant, only showing a trend towards shorter PFS in R-ISS III compared with either R-ISS I or II: median 22.1 months vs. 35.7 months, respectively, (P=0.2). Renal impairment at diagnosis, IgA subtype, ≥ 2 lines of induction treatment, and less than CR achieved at day +100 after ASCT were also associated with significantly inferior OS. Multivariate analysis selected R-ISS as an independent predictor for OS (HR: 2.3, 95% CI: 1.1-4.8; P=0.03), as well as ≥ 2 lines before ASCT. CR at day +100 after ASCT was the most important independent factor for predicting PFS (HR: 0.4; 95% CI: 0.2-0.6; P<0.001). Conclusion: R-ISS assessed at diagnosis was an independent predictor for OS after ASCT in our series, with median OS for the different R-ISS groups comparable to those reported by Palumbo et al. in their subgroup of younger patients. Thus, this study lends further support for the R-ISS as a reliable prognostic tool for estimating OS in transplant-eligible MM patients. In addition, new treatment approaches are needed for the high-risk patients (R-ISS III) with a median OS of 2.5 years. Figure Figure. Disclosures Reeder: Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Mikhael:Abbvie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Stewart:celgene: Consultancy. Fonseca:Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Bayer: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Novartis: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms.

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, is a DNA oncovirus known for its role in the development of Kaposi’s sarcoma (KS) and several lymphoproliferative disorders (LPDs). HHV-8 promotes lymphoproliferation via the activation of the interleukin-6 receptor signaling pathway, as well as a host of other regulatory mechanisms. The spectrum of HHV-8-associated LPDs is increasing. The World Health Organization has recently updated the classification of HHV-8-associated LPDs by introducing HHV-8-positive germinotropic LPD (GLPD) in addition to the previously recognized entities of HHV-8-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), primary effusion lymphoma (PEL), and HHV-8-positive multicentric Castleman’s disease (MCD). We present here a case of an HIV-positive woman with a history of KS, who later developed three HHV-8-associated LPDs, including HHV-8-positive MCD, PEL, and GLPD. To the best of our knowledge, this is the first reported case of a patient with this combination of individually rare HHV-8-associated LPDs. This case illustrates the spectrum and the sequential development of the different clinical manifestations of HHV-8-associated diseases. Detection of HHV-8 can have clinical significance in the diagnosis and management of certain HHV-8-associated conditions. Recently discovered variants of HHV-8-associated LPDs indicate that this group represents a diverse spectrum of disorders, whose classification may require further refinement beyond the currently recognized entities.

Abstract Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure. Blinatumomab, a monoclonal antibody targeting CD19, is associated with cytokine release syndrome (CRS) and neurotoxicity, both of which require prompt recognition and management primarily with corticosteroids. CRS and neurotoxicity are more common and more severe with chimeric antigen receptor T-cell therapy (CAR-T). The fact that CAR-T cannot be discontinued on demand adds a layer of complexity to the management of related toxicities of this therapy. Tocilizumab, an interleukin-6 receptor blocker, is used to treat severe CRS from CAR-T, whereas corticosteroids remain the mainstay for neurotoxicity management. Although effective, these drugs carry a high price tag, and we review the available data on cost-effectiveness of these agents, keeping in mind that median follow-up on most of these studies is limited and that long-term data on durability of response remain to be seen.