ALBERT

Description: Introduction: Acute myeloid leukemia (AML) developing in chronic lymphocytic leukemia (CLL) patients is very uncommon and is usually treatment-related. Acute promyelocytic leukemia (APL) occurring concurrently with CLL is extremely rare and there is only one published case of treatment-related APL. No case of concomitant APL and CLL in patients without history of malignancy has been found in the literature. We report such a case of coexisting CLL and APL. Case report: A 52-years-old Caucasian male with past medical history of hypertension, diabetes mellitus, and coronary artery disease, presented to an outside facility with chest pain and dyspnea for two day duration. He had lymphocytosis (WBC 31,500 /µL and 66 % lymphocytes) one year prior, however, was lost to follow up and no further workup was pursued. On examination, he was pale with no petechiae or ecchymosis. There was no lymphadenopathy or hepatosplenomegaly. Labs showed WBC 17,000/µL with 97% lymphocytes and 2% blasts, Hemoglobin 6.0 g/dL, and platelet 16,000/µL. Serum troponin was 0.30 ng/mL. EKG revealed ST-depression in lateral leads concerning for non-ST elevation MI (NSTEMI). Patient was admitted and received packed red blood cells and platelet transfusion with resolution of chest pain. Upon transfer to our hospital, he was afebrile and hemodynamically stable. Lab work showed WBC of 72,000/µL and platelet count of 9,000/µL. Slides from outside facility were reviewed and immunohistochemistry from bone marrow specimen revealed dense staining of myeloperoxidase (MPO) on sheets of myeloid blasts and strong CD79a staining on clumps of lymphocytes. Peripheral blood, bone marrow aspiration and biopsy showed two distinct morphological abnormalities including immature myeloid blasts with prominent cytoplasmic granules as well as increased number of small lymphocytes. Flow cytometry demonstrated a clonal B-cell population consistent with chronic lymphocytic leukemia. Further evaluation with fluorescent in-situ hybridization (FISH) revealed presence of a t(15;17) (q22;q12), PML-RARA translocation consistent with acute promyelocytic leukemia. Co-existence of CLL and APL was confirmed. Treatment with All-trans-retinoic acid (ATRA) and hydroxyurea was started immediately along with dexamethasone for prevention of differentiation syndrome. Shortly after initiation of ATRA, patient developed acute hypoxic respiratory failure with extensive patchy opacities in bilateral lungs on chest radiography. WBC further increased to 130,000/µL. Respiratory failure worsened despite bi-level positive airway pressure (BiPAP) and diuretics, and he was subsequently transferred to intensive care unit (ICU). Patient's clinical condition deteriorated rapidly, developed disseminated intravascular coagulation (DIC), and eventually died from cardiopulmonary arrest. Discussion: CLL is the most common hematologic malignancy in adults in western countries and the treatment of CLL is associated with increased incidence of secondary malignancies. However, transformation of CLL into AML is uncommon and most reported cases were therapy-related (t-AML). In patients with t-AML, exposure to topoisomerase II inhibitors (mainly Etoposide), alkylating agents and ionizing radiation are among the main causative factors. AML after treatment with DNA-topoisomerase II inhibitors has a short latency period, presents without a prior myelodysplastic syndrome, and is associated with 11q23 translocation. There was only one reported case of APL which developed 2 years after radiotherapy for prostate cancer in a patient with chronic lymphocytic leukemia. Although no treatment was given for CLL, radiotherapy for prostate cancer in that patient might have contributed to the development of APL, which is considered therapy-related. High dose of radiation has also been considered to increase the risk of t-AML. To date, no report in literature has been found on simultaneous occurrence of CLL and APL in patients without any previous treatment, either for CLL or for other co-existing conditions. We report here the first case of CLL co-existing with APL, diagnosed as two separate disease entities based on evidence from molecular testing and immunohistochemistry staining. APL is a hematological emergency. Management of APL, regardless of it being de novo or therapy-related, is the same. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 2675 Background: Initial treatment of diffuse large B-cell lymphoma (DLBCL) involves 6–8 cycles of chemo-immunotherapy and may be curative in 60–65% of patients. However, in the remaining patients, subsequent therapies appear inadequate for long lasting remission. A strategy to improve patient outcomes could involve early identification of patients who do not respond to treatment as expected and then employing different/aggressive treatment modalities in these patients. PET scan done during mid-treatment (interim PET, i-PET) may help identify these patients early. However, the value of i-PET in DLBCL is not established as there is controversy about its prognostic value and studies are ongoing to evaluate its benefit. Aims: To determine predictive value of i-PET on progression-free survival (PFS), overall survival (OS) in DLBCL patients. Methods: We performed retrospective analysis of DLBCL patients treated at LSU Health Shreveport, LA, between Jan 2002 – July 2012. All patients were treated with R-CHOP chemotherapy. PET-CT was performed at baseline at time of diagnosis, after 2 to 4 courses (i-PET) and at the end of therapy (final PET, f-PET). Results: Forty-four patients were evaluable for analysis. The median age was 55 years (range 21–84), 32 (73%) were males. Ann-arbor staging showed 5 patients each in stage I and II, 11 patients in stage III, 23 in stage IV, and the median IPI score was 3. Median time to i-PET was after 3 cycles of chemotherapy, and median days to i-PET after chemotherapy were 16. The median follow-up duration from start of chemotherapy was 23 months (range 4 – 89). The PET results were as follows: i-PET negative 30 (68%), i-PET positive 14 (32%) patients. Final PET results were: f-PET negative 33 (75%), f-PET positive 11 (25%) patients. The 3-year PFS was 96.3% and 35.7% for i-PET negative versus positive patients respectively (p

Description: Abstract 1432 Previously we demonstrated that inhibition of anti-apoptotic BCL-2 family members sensitize leukemic cells to 5-Azacytidine (5-Aza), using siRNA and pharmacological inhibition with the BH3-mimetic ABT-737, both in vitro and ex vivo (Bogenberger, JM., et. al. ASH Annual Abstracts 2011;118:Abstract 3513). Crucially, several anti-apoptotic BCL-2 members (e.g. BCL-2 and BCL-XL) required concurrent inhibition for potent and universal sensitization to 5-Aza. Anti-apoptotic BCL-2 proteins block the execution of programmed cell death (apoptosis) by binding to and counteracting two types of pro-apoptotic BCL-2 family proteins: the “BH3-only” proteins, including both activators (BIM and BID) and sensitizers (e.g. NOXA, PUMA, HRK), and the multi-domain effector proteins (BAX and BAK). Cells dependent on anti-apoptotic BCL-2 family members for survival have been defined as “primed for death” (Certo, M., et. al. Cancer Cell 2006 May;9(5):351-65). Importantly, the priming status reflects a dependence on anti-apoptotic BCL-2 family proteins and can be characterized with the BH3 profiling functional assay. This assay measures induction of mitochondrial outer membrane permeabilization (MOMP) in response to treatment with peptides derived from BH3-only proteins (Ni Chonghaile, T., et. al. Science 2011 Nov 25;334(6059);1129-33). Thus, the unique BH3 profile associated with a specific malignant cell population, is a function of the anti-apoptotic BCL-2 family member/s contextual expression in that cell population. Based on our observations of potent 5-Aza sensitization in combination with anti-apoptotic BCL-2 protein family inhibition, we hypothesized that BH3-profiling would predict response to 5-Aza. To address the potential utility of BH3 profiling in predicting response to 5-Aza in myeloid malignancies, we assayed a broad panel of AML-derived cell lines (N=13) by BH3 profiling and correlated BH3 metrics with 5-Aza response. Identical cell line passages were assayed by BH3 profiling and in 5-Aza drug dose response assays. The cell panel comprised lines derived from AML FAB subtypes M7, M6, M5, M4, M2 and M0, as well as diverse cytogenetics such as t(11;21), t(9;11), t(4;11), t(6;11), del 5q, del 7, and a broad spectrum of mutations such as FLT3, N-RAS, CDKN2A, NPM1 and DNMT3A. The panel included a normal karyotype AML cell line (CG-SH) (Munker, R., et. al. Leuk Res 2009 Oct:33(10):1405-8) and a blastic cell line derived from a patient with MDS (MDS-L) (Tohyama, K., et. al. Br J Haematol 1994 Jun;87(2):235-42). Partition modeling using several BH3 metrics discriminates 5-Aza response with statistical significance (N=13, Mann-Whitney p

Description: Background: The prognosis of multiple myeloma (MM) has improved significantly over the last 20 years due to the introduction of autologous stem cell transplantation and novel drugs. The standard regimen for conditioning in MM is melphalan 200 mg/m2, since a study published in 2002 (Moreau et al.) showed a survival advantage of melphalan (MEL) only over melphalan- total body irradiation (MEL-TBI) conditioning. Ionizing radiation is an independent treatment modality and has activity in MM. We decided to reevaluate the outcome of MEL-TBI conditioning in the age of novel drugs. Patients and Methods: In a retrospective chart review, we identified 50 patients with MM who underwent autologous hematopoietic cell transplantation at Tulane University Medical Center and were conditioned with MEL-TBI between December 1995 and March 2012. Stem cells were collected following a stimulation by 10 µg/ kg filgrastim for 4 days. In case of insufficient collection, plerixafor was administered. Between 1995 and 2003 cyclophosphamide priming was used in most cases. Patients received melphalan 140 mg/m2 as a single dose given intravenously on day -5. TBI was administered in fractionated doses of 150 cGy between days -4 and -1 (total dose 12 Gy). Peripherally harvested stem cells were infused on day 0. Standard supportive measures were followed. Log-rank test and Kaplan-Meier curves were used to calculate overall survival (OS) and progression-free survival. Significance levels were standard (p

Description: Tyrosine kinase inhibitors (TKIs) have been successfully introduced for the treatment of cancer. Imatinib, dasatinib and nilotinib target bcr/abl and were found to induce molecular remissions in chronic myeloid leukemia. Imatinib has also been found to be active in other malignancies like gastrointestinal stromal tumors. Sunitinib and sorafenib are multi-targeted tyrosine kinase inhibitors and so far, have shown activity against renal cell carcinoma and other cancers. Gefitinib targets the tyrosine kinase of epidermal growth factor receptor and has been found to be active against some cases of non-small cell lung cancer. There is circumstantial evidence that tyrosine kinases and their receptors (e.g. VEGF, IGF-1 and FGFR3) are active in multiple myeloma. In order to develop new treatments for multiple myeloma (MM), we tested several currently available TKIs for their activity against MM cell lines. Materials and methods: The a cell lines MC/CAR, ARH77, RPMI 8226, ARP1, JJN3, MM1S, and INA-6 were treated with various concentrations of TKIs and analyzed for cell growth in liquid culture, proliferation, apoptosis, and gene expression pattern screening 14,500 genes using U133A_2 arrays. Results: Imatinib, nilotinib, dasatinib, gefitinib induced cytotoxicity in most cases at high concentrations (50% inhibitory concentration ≥ 100 μMol), whereas sunitinib and sorafenib were active at lower concentrations (50% IC 1– 5 μMol). The cytoxicity was observed early (within 4 to 24 hours of exposure) and involves apoptosis. Interleukin-6 did not offer protection against the cytotoxicity of sorafenib or sunitinib, however the inhibition of proliferation was more pronounced in low fetal calf serum (2.5 versus 10%). A short-term exposure of the myeloma cell line MM1S to 10 μMol sorafenib resulted in more than 2 fold changes in 283 genes or sequences (175 up, 108 down). If only 10 fold changes are considered, 21 genes or sequences were upregulated (mainly enzymes, regulators and ligands) and 11 downregulated (mainly regulatory proteins, among them IL6 signal transducer). Conclusion: We found that the multitargeted TKIs sorafenib and sunitinib are active in vitro against multiple myeloma. We plan to investigate patient samples, and to elucidate the targets and the mechanisms of action. Our data will support clinical trials both as single agent and in combination with other drugs like bortezomib, thalidomide, alkylators and ionizing radiation.

Description: Background: The treatment of acute myeloid leukemia (AML) has made major progress in the last 30 years. Well-known risk factors are age, cytogenetics and treatment intensity. Many other factors including access to healthcare modify treatment outcomes. According to smaller studies, the type of insurance (payer status) may or may not influence treatment outcomes. In the wake of the Affordable Care Act and its impact on insurance coverage, evaluating the effect of insurance status on health outcomes is urgently necessary. This study characterizes the relationship between payer status and overall survival for AML patients by analyzing data from the large National Cancer Data Base (NCDB). Methods: Data was analyzed from 67,443 men and women (≥ 18 years of age) registered in the NCDB who were diagnosed with AML between 1998 and 2011 and had follow-ups to end of 2012. The primary predictor variable was payer status and the outcome variable was overall survival. Additional variables addressed and adjusted for included sex, age, race, Charleson Comorbidity index, level of education, income, distance traveled, facility type, diagnosing/treating facility, treatment delay, and chemotherapy. Results: Among these 67,433 patients, the mean age at diagnosis was 61 years (median, 64 years) with a median survival of 7.98 months. The mean ages at diagnosis were 46.8, 51.8, 44.6, 73.6, and 57.9 years old for uninsured, private, Medicaid, Medicare and unknown payer status, respectively. In multivariate analysis, after adjusting for secondary predictor variables, payer status was a statistically significant predictor of overall survival from AML. Relative to privately insured patients, patients with Medicaid had a 17% increased risk, no insurance had a 21% increased risk, Medicare had a 19% increased risk, and unknown insurance had a 22% increased risk of mortality from AML. The percentage of patients surviving from AML after 24 months was 37.6%, 31.4%, 32.3%, 31.8%, and 33.1% for private, unknown, Medicare, uninsured, and Medicaid payer status, respectively. All factors investigated were found to be significant predictors of AML survival except distance travelled. Patients aged 65-74 were 2.9 times more likely to die compared to those aged 19-49. Patients who received chemotherapy were 22% less likely to die compared to those who did not. In the more recent time period (2005-2011 versus 1998- 2004, the prognosis of AML has improved, however the imbalance as per payer status did not change significantly. Conclusion: We observed that payer status has a statistically significant relationship with overall survival from AML. This remained true after adjusting for other predictive factors. Medicaid and uninsured patients had the highest mortality while privately insured patients had the lowest mortality. Further research is necessary how the disparities associated with different types of insurance result in inferior treatment outcomes and how they can be addressed. Multivariate Cox regression, hazard ratio of death by factorsTable 1.FactorLevelHR*LowerUpperAge18-491.0050-641.961.902.0265-742.862.752.9875+4.143.964.32InsurancePrivate1.00Uninsured1.211.141.28Medicaid1.161.111.21Medicare1.191.161.23Unknown1.231.151.31Year of diagnosis98-04105-110.850.820.87RaceWhite1.00Black1.081.041.12Asian0.920.860.98Charleson Comorbidity index01.0011.221.181.2621.491.421.56Unknown1.3521.3211.384ChemotherapyNo Chemo1Single Agent0.780.740.83Multiple Agent0.620.580.65*Adjusted for sex, income, education, distance traveled, facility type, diagnosing/treating facility, and treatment delay. Disclosures No relevant conflicts of interest to declare.

Description: Immune checkpoint inhibitors (CPI) are widely used in modern oncology and have improved the prognosis of lung cancer, bladder cancer, malignant melanoma and other malignancies. Unlike cytotoxic chemotherapy, drugs like nivolumab, pembrolizumab and ipilimumab are associated with a high frequency of immune-related adverse effects. We recently observed a patient with lung cancer who developed a fulminant warm-antibody autoimmune hemolytic anemia (AIHA) and reviewed the literature and public databases of the Food and Drug Administration (FDA) to help understand the association between CPI use and AIHA. A total of 68 cases of AIHA were identified in the FDA database during the time period 2012-2018; 43 associated with nivolumab, 13 with pembrolizumab, 7 with ipilimumab and 5 with atezolizumab administration (see Table 1). All episodes of AIHA were listed as serious. If the total number of adverse effect cases reported to the FDA is taken as a reference, AIHA is rare, but occurred more frequently with PD-1 or PDL1 targeting agents (0.15 to 0.25%) than with CTLA4-inhibitors (0.06%). The underlying cancer diagnoses corresponded mostly to the approved indications for CPI (32 cases of malignant melanoma, 24 cases of lung cancer). In about a quarter of cases with AIHA other immune related side effects were reported. In addition to our case, the literature review identified 10 similar cases. AIHA can occur earlier and later after the administration of CPI (median of 10 weeks, range 2- 78). Most cases of AIHA responded to steroids, but 2/11 were fatal. In conclusion, we describe AIHA as a rare and serious immune-related side effect of checkpoint inhibitors. Because of its seriousness and the underlying comorbidities, early aggressive management is necessary. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Acute undifferentiated leukemia (AUL) is rare and by definition has neither lymphoid nor myeloid lineage specific markers. Given its rarity, little is known about its incidence, survival, and optimal management. We queried the SEER (Surveillance, Epidemiology, and End Results) registry database to obtain information about the incidence and survival of AUL in comparison to acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Methods We identified patients with microscopically confirmed AUL from the SEER database between 2000 and 2016. Incidence rates of AUL were calculated and age-adjusted according to the 2000 US Standard Population. Annual percentage change was estimated using the weighted least square method to measure trends of AUL over this time period. Survival analysis compared AUL vs AML vs ALL patients who were diagnosed in the same period (patients with a preceding malignancy were excluded). Age, sex, race, ethnicity, year of diagnosis, and use of chemotherapy were compared across the three groups. Overall survival (OS) was estimated using the Kaplan-Meier method and comparisons were made using the log-rank test. All factors with p-values

Description: Background: Historically, Kentucky has had one of the highest rates of cancer mortality in USA. In non-hematologic malignancy, the Appalachian region of the eastern United States is also associated with poor outcomes, however, the relationship with hematologic malignancy is poorly understood. We aim to study the disparities of Plasma Cell Neoplasms (PCN) in this region utilizing the Surveillance, Epidemiology, and End Results Program (SEER) database. Methods: We identified patients with PCN (multiple myeloma [MM], solitary plasmacytomas [PC], and plasma cell leukemia [PCL]) from the SEER database between 2000-2015. Data obtained included demographics, state, residence in an Appalachian region, rural/urban continuum code, median annual household income, and overall survival (OS) outcomes. Kentucky and Georgia are the only states that report to SEER which have populations from Appalachia. Therefore, patients were classified into 5 groups: Appalachia/Kentucky, non-Appalachia/Kentucky, Appalachia/Georgia, non-Appalachia/Georgia, and other (non-Appalachian) states. We used Kaplan-Meier & Cox regression to analyze survival outcomes. Income was analyzed as a continuous variable. Variables with a p value 〈 0.1 in univariate analysis were included in a stepwise multivariate Cox proportional hazard ratio (HR) model. Results A total of 68,627 patients were identified and included in the study (5.5% [n=3806] in Kentucky and 94.5% in other states). 3028 were identified as Appalachian (1969 in Georgia and 1059 in Kentucky). Baseline characteristics were comparable between Kentucky and other states except for income and rural/urban code. Percentages of patients with an income of