ALBERT

Description: Background: The discovery that gut microbial dysbiosis correlated with prognosis, immune reconstitution and development of graft-versus-host disease (GVHD) in patients undergoing allogeneic stem cell transplantation (allo-SCT) highlights the clinical relevance of the gut microbiome in shaping anti-tumor immune responses. Treatment of allo-SCT patients with antibiotics has recently been associated with increased GVHD mortality (Routy et al. 2017). Based on these studies and the association of distinct gut bacteria with increased efficacy to PD-1 blockade in patients with solid tumors (Derosa et al. 2018), we performed a retrospective analysis to determine if infection treated with antibiotics affected the outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: A list of all MM patients treated at our institution between January 2012 through December 2015 was obtained and 1095 patients were identified. A comprehensive review of the electronic medical record (EMR) of the first 142 who received ASCT was performed. Information was collected from diagnosis to the date of last contact. Baseline characteristics, treatment history, transplant course, antibiotic treatment, and infection severity using common terminology criteria for adverse event (CTCAE) version 4 were reviewed. Prophylactic antibiotics were excluded. Response was measured and defined using the International Myeloma Working Group Criteria. Progression free survival (PFS) and overall survival (OS) were estimated using log rank tests. Cox hazard stepwise regression model examined for multiple factors affecting PFS and OS using the Akaike information criterion. Results: Of the 142 patients, 93 (65%) were Durie Salmon (DS) III, 20 (14%) were Revised International Staging System (R-ISS) III, 44 (31%) had high-risk cytogenetics, and 76 (54%) were male. The median age at diagnosis was 60. Although there was a similar frequency of DS III (67% vs 61%) and high-risk cytogenetics (35% vs 25%) among patients in the antibiotic and non-antibiotic treated groups, there was an over-representation of R-ISS 3 (19% v 4%) patients in the antibiotic-treated group. Treatment with antibiotics was associated with decreased median PFS (2.38 vs 6.58 years (yrs), p =0.00003) (Figure 1a) and decreased median OS (7.43 vs 17.39 yrs, p =

Description: Abstract 4517 Oral mucositis is a common toxicity associated with many cancer therapies and has been correlated with risk for infection, mortality, and extended hospital stay. Prophylactic use of a supersaturated calcium phosphate mouth rinse (SSCPR, Caphosol..) was found in a phase III study to reduce the frequency, intensity, and duration of oral mucositis in patients (pts) undergoing allogeneic or autologous hematopoietic stem cell transplantation (Papas, et al. Bone Marrow Transpl 2003;31:705). That study also found a faster time to recovery of an absolute neutrophil count (ANC) ≥0.2×109/l, but not for other engraftment endpoints, possibly a result of the mixed pt population studied. We performed a single-center retrospective review of a uniform population of pts

Description: Background: The BCR-ABL tyrosine kinase inhibitor nilotinib elicits faster and deeper molecular responses (MRs) vs imatinib in patients with CML-CP. Achievement of sustained deep MR is associated with improved long-term outcomes and is a key criterion for entry into treatment-free remission (TFR) studies. Given the importance of accurately measuring deep MR in patients with CML, increasingly sensitive techniques are needed for monitoring minimal residual disease. In ENESTnext, MR to nilotinib was assessed using conventional methodology (real-time quantitative reverse transcriptase polymerase chain reaction [RQ-PCR]) and a novel microfluidic digital PCR assay that is 〉 1 log more sensitive than standard RQ-PCR. Methods: In this single-arm, open-label, multicenter study (NCT01227577), adults with CML-CP diagnosed within 6 months of enrollment were treated with nilotinib 300 mg twice daily (BID) for up to 2 years. Dose escalation to nilotinib 400 mg BID for patients with suboptimal response or treatment failure (per modified European LeukemiaNet 2009 recommendations) was permitted per physician discretion. RQ-PCR evaluation of peripheral blood samples was performed by a central laboratory (monthly for the first 3 months and every 3 months thereafter) according to the International Scale (IS). The primary endpoint is the rate of confirmed (≥ 2 samples taken 3 months apart) MR4.5 (≥ 4.5-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.0032%) with 2 years of nilotinib therapy; complete cytogenetic response (CCyR) and major MR (MMR; 3-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.1%) were evaluated as secondary endpoints. Per protocol, assessment of cytogenetic response was not required at specified time points for all patients on study. In an exploratory analysis, samples from patients with confirmed MR4.5by conventional RQ-PCR were also evaluated using the more sensitive Fluidigm digital PCR platform. The data cutoff date for this analysis was April 30, 2014. Results: A total of 128 patients were enrolled (median age, 56.5 years [range, 21.0-89.0 years]); 64 patients (50.0%) were male and 103 (80.5%) were Caucasian. As of the data cutoff, 45 patients (35.2%) had completed the study, 49 (38.3%) remained on treatment, and 34 (26.6%) had discontinued early. With a median treatment duration of 12.7 months, 88 (68.8%), 94 (73.4%), and 32 (25.0%) patients achieved CCyR, MMR, and MR4.5, respectively, at any time (Table). Of 32 patients who achieved MR4.5, 14 achieved MR4.5 by 6 months. A total of 169 samples from 32 patients with confirmed MR4.5 by conventional RQ-PCR were analyzed by digital PCR. Using the digital PCR platform, 6 of these patients initially had detectable BCR-ABL transcripts that subsequently became undetectable with continued nilotinib therapy. Of the remaining 26 patients, 12 had BCR-ABL transcripts that were initially undetectable and remained undetectable by digital PCR, 12 had detectable BCR-ABL transcripts that remained detectable, and 2 had undetectable BCR-ABL transcripts that became detectable. The most common (≥ 4 patients) grade 3/4 adverse events (AEs) regardless of relationship to study drug were increased lipase (n = 14), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), anemia (n = 4), and nausea (n = 4). Reasons for study discontinuation were AEs (n = 15), unsatisfactory therapeutic effect (n = 5), withdrawn consent (n = 4), death (n = 3; causes of death were other malignancy, pneumonia, and not specified/no AE [n = 1 each]), protocol deviation (n = 3), abnormal laboratory values (n = 2), loss to follow-up (n = 1), and administrative problems (n = 1). Conclusions: Frontline treatment with nilotinib 300 mg BID in patients with newly diagnosed CML-CP led to rapid achievement of MR4.5 as assessed with conventional RQ-PCR. As 〉 40% of samples with at least MR4.5according to standard RQ-PCR were positive using the digital PCR assay, this tool may have potential in evaluating MR to determine eligibility for TFR studies. Table Response CCyRa MMR MR4.5 Patients with response, n (%) 88 (68.8) 94 (73.4) 32 (25.0) Time to response, n (%) 〈 3 mo 26 (20.3) 21 (16.4) 2 (1.6) 3 to 〈 6 mo 42 (32.8) 41 (32.0) 12 (9.4) 6 to 〈 12 mo 16 (12.5) 22 (17.2) 11 (8.6) 12 to 〈 18 mo 4 (3.1) 9 (7.0) 7 (5.5) ≥ 18 mo 0 1 (0.8) 0 a Cytogenetic response was not assessed in all patients at all time points. Disclosures Mauro: Novartis Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Rizzieri:Sanofi: Consultancy; Celgene: Consultancy, Speakers Bureau. Keir:Novartis: Employment, Equity Ownership. Yi:Novartis Pharmaceuticals: Employment. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; MolecularMD: Consultancy, Equity Ownership. Goldberg:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Research Funding. Kuriakose:Teva: Speakers Bureau; Alexion: Speakers Bureau. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy.

Description: Introduction The CureCloud™ is being created by the Multiple Myeloma Research Foundation (MMRF) as a follow-up project to the CoMMpass Trial. The CureCloud direct-to-patient (CC-DTP) registry's goal is to accumulate over 5,000 well-characterized myeloma patients with linked data from EHR, myeloma-specific 77-gene NGS panels, exome genomic panels, and patient reported data. COTA, Inc. and MMRF have formed a partnership to populate the CC-DTP with real-world data (RWD). COTA manages the record retrieval and abstraction of data from various contributing provider institutions. Methods After obtaining IRB approval, electronically-signed consent forms were obtained from patients during the online registration process for the CC-DTP registry. During an initial 24 patient pilot, COTA presented the consent forms to 54 provider organizations to obtain medical records for abstraction. A request package containing the signed consent, IRB certificate of action, and overview of the CC-DTP registry was prepared and submitted to each of the institutions using fax or direct mail. Metrics tracked during the record retrieval process included time to delivery and fees for record release. Additionally, all returned data was screened for the presence of structured, coded medical information prior to a manual abstraction process into the CC-DTP data dictionary format. Results Of the 54 institutions contacted in the pilot, 80% of record returns were in under 30 days, but 20% took over 40 days, and half of those (or a total of 10%) took over 60 days. The median retrieval time across all sites was 25 days (range of 5 to 87). In two instances, a processing fee request in excess of $300 was initially tied to the release of the medical record, and human intervention was required to have the fees waived. MMRF and COTA recorded that six of the 54 (11%) institutions that received a medical record request rejected the use of electronically-signed patient consent forms and five of the six institutions required their own authorization to be used in place of the IRB-approved patient consent. At 10 of the 54 institutions, the information requests were rejected in favor of hand-signed documents before patient records were provided. Additionally, for all retrieved records, the only coded information included were ICD-10 codes for the primary diagnosis. All other ICD10, LOINC, RxNORM, SNOMED or any other coded vocabulary were absent from the records. In no cases were any adverse events coded with MedDRA. Discussion Despite a significant investment in electronic health solutions in the United States, many of the institutions approached as part of the CC-DTP pilot were unable to provide all of the needed data in a timely, cost-free, and coded manner. The four major challenge areas were: 1) extensive administrative delays (slow processing times), 2) rejection of electronic patient signatures on consent forms, 3) unexpected high fees to obtain EHR record abstracts, and 4) virtually all structured, coded medical information was stripped from provided abstracted EHR records. These challenges not only delayed the gathering of clinical data but forced a series of complex and costly work-arounds. The goal of building a fully linked registry complete with coded EHR data remains challenging. Future studies to explore obstacles of record retrieval and limited codified data should be conducted. A comprehensive, research-focused data abstraction process for coded data exchange is being put into place and will be needed to support future RWD projects of this nature. Disclosures Goldberg: Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Keogh:COTA: Employment, Other: Equity. Belli:COTA: Employment, Other: Equity. Norden:COTA: Employment, Other: Equity.

Description: Abstract 2291 Background: Nilotinib is a potent and the most selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy vs imatinib with higher and faster molecular responses and a significantly lower rate of progression on treatment to accelerated or blast phases of CML. Nilotinib has been previously shown to prolong the QT interval. The cardiac safety profile of nilotinib was previously described in pts with imatinib-resistant and -intolerant CML-CP enrolled in phase 2 clinical trials. Here, we report cardiac safety data on nilotinib 300 and 400 mg twice daily (bid), and imatinib, in pts with newly diagnosed CML-CP from the ENESTnd trial. Methods: A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. Pts were excluded from study participation if they had known uncontrolled or medically significant cardiac disease, left ventricular ejection fraction (LVEF) 〈 45%, or QTcF interval 〉 450 msec. Prospective cardiac monitoring was conducted throughout the study for QT prolongation (via electrocardiogram) and LVEF (via echocardiogram) at regular intervals. Results: QTcF increases of 〉 30 msec from baseline occurred in 26% of pts in each nilotinib arm and in 18% of pts in the imatinib arm. QTcF increases of 〉 60 msec from baseline were uncommon, occurring in 〈 1% of pts in all three arms (Table). The highest mean changes from baseline in QTcF interval were 10.4, 12.4, and 7.9 msec in nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively, which occurred between months 3–6 of therapy in all arms. Furthermore, there was a modest linear correlation between nilotinib serum concentration and QTcF change from baseline that was similar to previously reported results. No pt in any treatment arm demonstrated an absolute QTcF interval 〉 500 msec. Analysis was conducted to identify any potential case of clinically symptomatic QT prolongation. Only events of syncope were identified (1 pt in each arm with drug-related events) by this analysis and none of these could be attributed to QT prolongation; there were no episodes of torsades de pointes in any treatment arm. Additionally, there was no decrease from baseline in mean LVEF observed anytime on treatment in any arm (Table). No patient in any treatment arm had a LVEF of 〈 45% on treatment or an absolute reduction from baseline in LVEF of 〉 15%. Importantly, no pt discontinued therapy due to QT prolongation or LVEF change. An analysis of grouped adverse event terms was performed to identify cases consistent with ischemic heart disease (IHD) or left ventricular dysfunction. A total of 11 pts in all treatment arms experienced IHD events after median treatment duration of 18 months: 3 (1%) on nilotinib 300 mg bid, 6 (2%) on nilotinib 400 mg bid, and 2 (〈 1%) on imatinib. Of these 11 pts, 10 had preexisting cardiac disease or risk factors and only 1 pt discontinued treatment due to an IHD event. Nine pts reported angina pectoris. Two pts experienced myocardial infarction (MI) and 1 of these pts died during coronary artery bypass surgery (perisurgical MI). A total of 7 pts in all treatment arms with events consistent with left ventricular dysfunction were identified: 1 (〈 1%) on nilotinib 300 mg bid, 4 (1%) on nilotinib 400 mg bid, and 2 (〈 1%) on imatinib. Of these 7 pts, 4 pts experienced reduction in LVEF (3 were asymptomatic grade 1/2) and 3 pts experienced cardiac failure/congestive failure; 5 of these 7 pts had prior history of cardiovascular disease and/or preexisting cardiovascular risk factors. None of these 7 pts discontinued treatment due to events with left ventricular dysfunction. There were no sudden deaths reported on study. Conclusions: Overall, QT prolongation, changes in LVEF, and clinical cardiac events were uncommon in all arms and seldom led to discontinuation. There was no cumulative effect of nilotinib exposure on cardiac safety with a median of 18 months follow-up. Nilotinib at both doses had a favorable cardiac safety profile that was similar to imatinib in pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Lopez: Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gallagher: Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp: Novartis: Employment. Ortmann: Novartis: Employment. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Kantarjian: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Description: Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status 〉 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (〈 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged 〈 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged 〈 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged 〈 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of 〉 60 msec from baseline in older pts and 3 in nilotinib-treated pts 〈 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of 〉 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of 〉 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts 〈 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 3453 Individuals undergoing allogeneic transplantation receive multiple red blood cell transfusions both as part of the transplant procedure and as part of the pre-transplant care of the underlying disease. Therefore these patients may be at risk for complications of transfusional iron overload. Several studies have noted that individuals entering the transplant with baseline elevated serum ferritin values have decreased overall survival and higher rates of disease relapse. Whether the iron is a direct contributor to inferior outcomes or is a marker of more advanced disease (thereby requiring greater transfusions) is unclear. Little is known about the incidence and consequences of iron overload among long-term survivors of allogeneic transplantation. Methods: Using Kaplan-Meier and Cox regression analyses, we performed a single center, retrospective cohort study of consecutive allogeneic transplants performed at Hackensack University Medical Center from January 2002 through June 30, 2009 to determine the association between serum ferritin (measured approximately 1 yr post allogeneic transplant) and overall survival. Results: During the study time frame, 637 allogeneic transplants (Donor Lymphocyte Infusion procedures excluded) were performed at our center and 342 (54%) survived ≥ one year. Among 1-year survivors 240 (70%) had post-transplant serum ferritin values available for review, including 132 (55%) allogeneic sibling, 68 (28%) matched unrelated, and 40 (17%) mismatched unrelated donor transplants. The median post-transplant ferritin value among 1-year survivors of allogeneic transplant was 628 ng/ml (95% CI 17, 5010), with 93 (39%) above 1000 ng/ml and 40 (17%) above 2500 ng/ml. The median post-transplant ferritin levels varied by underlying hematologic disease (aplastic anemia = 1147, acute leukemia = 1067, MDS = 944, CLL = 297, CML = 219, lymphoma = 123, multiple myeloma = 90). The Kaplan-Meier projected 5-year survival rate was 76% for the cohort that had survived one year and had available ferritin values. Fifty late deaths have occurred; causes of late death were disease relapse (n=37, 74%), GVHD (n=7, 14%), infection (n=4, 8%), cardiac (n=1, 2%) and second malignancy (n=1, 2%). The 1-year post-transplant serum ferritin value was a significant predictor of long term survival. Using a cut-off ferritin value of 1000 ng/ml, the 5-year projected survivals were 85% (95 CI 75%-91%) and 64% (95% CI 52–73%) for the low and high ferritin cohorts respectively (Figure, log-rank p

Description: Abstract 4569 Background: Oral mucositis is a common toxicity associated with cancer therapies and increases risk for infection, mortality, and extended hospital stay. Prophylactic use of a supersaturated calcium phosphate mouth rinse (SSCPR, Caphosol®) was found in a phase III study to reduce the frequency, intensity, and duration of oral mucositis in patients (pts) undergoing allogeneic or autologous hematopoietic stem cell transplantation (Papas, et al. Bone Marrow Transpl 2003;31:705). That study also found a faster time to recovery of an absolute neutrophil count (ANC) ≥0.2×109/l, but not for other engraftment endpoints, likely a result of the mixed pt population studied. Objective: A single-center retrospective review of two uniform populations undergoing autologous peripheral blood stem cell transplantation (PBSCT) to determine if an effective regimen of mucositis prophylaxis results in faster engraftment and shorter hospital stays. Methods: Two different uniform population of pts ≤70 years of age with Hodgkin or non-Hodgkin lymphoma (HL/NHL) and multiple myeloma (MM) undergoing PBSCT between 1/1/07 and 12/31/09 (Table 1). MM pts were conditioned with single dose melphalan (N= 16 with 140 mg/m2; N= 203 with 200 mg/m2). HL/NHL pts were conditioned with BEAM. Oral ice chips were given during the melphalan infusion for all pts. Filgrastim, 5 ug/kg, was given on days +3, +5, +7, +9 and then daily until granulocyte engraftment. A regimen of oral hygiene using sodium bicarbonate (NaHCO3) tooth cleaning after each meal with as needed rinsing was encouraged. SSCPR was added to this regimen in May 2008 with pts instructed to rinse 4-times daily after teeth cleaning and as needed. Granulocyte engraftment was defined as the first day with a rising ANC ≥0.5×109/l, and platelet engraftment was defined as the first day of a rising platelet count ≥20×109/l. Prospective scoring of mucositis was not performed and the use of intravenous fluconazole, ciprofloxacin, and/or acyclovir prophylaxis was recorded as a surrogate indicator of severe mucositis. Engraftment times and time to hospital discharge were estimated using the method of Kaplan and Meier, and the groups were compared using the log-rank test. The Mann-Whitney U test was used to assess differences in median values of age and CD34 cells infused, and Fisher's Exact test was used to assess the significance of differences categorical parameters. Results: No differences were found between the control and study populations for age, gender, diagnosis, or CD34+ cell content of the graft (Table 1). For the HL/NHL control group one pt failed to engraft and was censored at the time of infusion of backup PBSC. In the MM groups no pts failed to engraft. No pts for either diagnosis were censored for death or relapse before hospital discharge. For both populations, pts using SSCPR achieved the primary endpoints of engraftment and were discharged home a median of 1 day faster than the respective control group pts (Table 2). 18 pts in the HL/NHL control group and 20 pts in the SSCPR group experienced febrile neutropenia (p=1.0) and 4 pts in each group were given intravenous medications (p=1.0). 73 pts in the MM control group and 53 pts in the SSCPR group experienced febrile neutropenia (p=0.22). 11 pts in the control group and 10 pts in the SSCPR group were given intravenous medications (p=1.0). These retrospective data of sequentially treated cohorts suggest that an effective regimen of mucositis prophylaxis may result in faster engraftment and shorter hospital stays with fewer days of antibiotics and cytokines. This retrospective study lacks detail regarding the incidence of mild/moderate mucositis and a mechanism of this action cannot be discerned from these data. Disclosures: Rowley: EUSA Pharmaceautical: Speakers Bureau.

Description: Background: Panobinostat (LBH589) is a novel, high potent pan-deacetylase inhibitor, which acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. It induces degradation of wild-type, as well as BCR-ABL with the T315i and E255K mutations in BaF3 cells. Based on this encouraging data, we initiated a Phase II trial to investigate the efficacy and safety of oral panobinostat in patients (pts) with chronic phase (CP) CML who had received at least 2 prior BCR-ABL tyrosine kinase inhibitors (TKI). Methods: This was a single arm, 3-stage, open-label, multicenter, Phase II study. The primary objective was to estimate the proportion of pts attaining major cytogenetic response (MCyR). Complete hematologic response (CHR) was one secondary objective. All patients received panobinostat orally 20 mg/day on a thrice weekly, consecutive weekly schedule. If ≥3 confirmed MCyRs were observed among 25 pts in Stage 1, Stage 2 was planned to be opened with a total of 32 pts. Dose reduction to 10 and 5 mg/day for toxicity and re-escalation to 20 mg/day was allowed. Dose escalation beyond 20 mg/day for poor response was not foreseen. Results: 29 pts were enrolled in Stage 1 between February and November 2007. Median age was 56 years (yrs) (range 31–75). Time since diagnosis of CML was ≥5 yrs in 69% and 500 ms (Gr 3) in another pt required study drug discontinuation. 5 serious AEs were reported as possibly related to study drug: pulmonary embolism and the QTcF prolongation (see above) in 1 pt, and sepsis, followed by multiple organ failure with fatal outcome in a second pt. SAEs considered as non-related to study drug included: 1 case each of DVT, lung infection, pericardial effusion, pleural effusion, and cardiac failure. To date, 452 post baseline ECGs were assessed: minimal QTcF prolongations (30–60 ms) were seen in 4 and 〉60 ms in 1 pt. Gr 3/4 hematologic lab abnormalities were: anemia and neutropenia in 4 pts each and thrombocytopenia in 3 pts. Nonhematologic lab abnormalities were: Gr 4 hypokalemia (1), Gr 3 hyponatremia (1), hyperkalemia (1), and hypermagnesemia (2). Conclusions: No MCyR but 1 CHR with eradication of the T315i mutation were observed in 29 TKI-resistant CP CML pts, treated orally with 20 mg/day panobinostat, thrice weekly. Since the number of MCyRs required by the protocol was not seen, Stage 2 of the study was not opened. Safety/tolerability were comparable to what was reported for the same dose/schedule in other panobinostat studies, and no new safety findings were identified. The explanation that no more CRs were seen might be 2-fold: a dosing issue considering encouraging responses reported with oral, thrice weekly ≥40 mg/day single-agent panobinostat in pts with refractory Hodgkin’s disease and AML1 and quite early hematologic progression in many pts, not allowing for longer exposure to panobinostat in this more resistant population.