Outcome of Multiple Myeloma Patients Treated with Carrd-PACE Chemomobilization: A Single-Center Experience

Abstract Background: Bortezomib was originally incorporated into DT-PACE (thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) as an intensive induction regimen (VTD-PACE) prior to high-dose melphalan and autologous transplant for multiple myeloma (MM). This regimen is effective in the induction setting, and also for patients with relapsed disease (Barlogie British Journal of Haematology 2007, Singh ASCO 2013). At our center, we examined the outcomes of MM patients undergoing chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (CarRD-PACE). Methods: Twenty MM patients with measureable disease received CarRD-PACE for chemomobilization. We excluded in this report patients with plasma cell leukemia, renal insufficiency, heart failure, or those patients who were refractory to carfilzomib. Results: The median age was 61.5 years (range, 35- 69). Nine of these patients were women (45%). The median left ventricular ejection fraction pre-treatment was 62% (range, 50 - 77%). Of patients with initial staging information, 8 were ISS stage I (47%), 5 patients ISS II (29%), and 4 were ISS III (24%). High risk cytogenetics, defined as presence of deletion 17p, t(4;14), t(14;16), were present in 5 patients at time of chemomobilization (25%). Fourteen patients (82%) had bulky disease (defined as having > 3 lesions, or having a single lesion > 3 cm on PET-CT or MRI) prior to treatment, assessed by MRI (n=12) or PET-CT (n= 2). The median time from diagnosis to mobilization was 9.5 months (range, 4- 44). Patients had previously received a median of 2 regimens of therapy (range, 1- 5). Fifteen patients received 1 cycle of CarRD-PACE, and 5 patients received 2 cycles. Eighteen patients response evaluable; in these patients, the overall CR/PR response rate after completion of treatment was 25% (4 PR, 1 CR), with fifteen patients (75%) having SD. A total of 18 patients (90%) collected stem cells after mobilization, requiring a median of 1 day of collection (range, 1-2), and collected a median of 18.3 x 10^6 CD34+ cells/kg (range, 4.8 - 69.88). Grade 3-4 toxicities occurred in 6 patients (30%), most common was neutropenic fever (n=4) (20%). No patients experienced a cardiac toxicity. Hospital readmission following treatment occurred in 4 patients (20%) for a median of 6.5 days (range, 3 - 15). Eighteen patients (90%) underwent a single autologous transplant, and 2 (10%) received tandem autologous-allogeneic transplant. Following autologous transplant, the median time to neutrophil engraftment was 18 days (range, 14 - 29 days), and the median time to platelet engraftment was 13 days (range, 7 - 19 days). The PFS at 6 months was 63% (95% CI, 0.382 - 1), and the OS at 6 months was 91% (95% CI, 0.754 - 1) (Figure). Discussion: CarRD-PACE is a well-tolerated and effective therapy in heavily treated multiple myeloma patients with substantial disease burden at the time of autologous transplant, and can successfully mobilize autologous PBSC. Despite the theoretical concern regarding the combination of 2 agents with cardiac toxicity (carfilzomib and doxorubicin), we did not observe any cardiac toxicities of any grade during treatment. This approach may be particularly useful in individuals with bortezomib associated neuropathy and or those with bortezomib refractory disease. Figure Kaplan-meier plots for progression free and overall survival. Figure. Kaplan-meier plots for progression free and overall survival. Disclosures Becker: GlycoMimetics: Research Funding. Shadman:Pharmacyclics: Honoraria, Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Emergent: Research Funding. Gopal:Seattle Genetics: Research Funding.

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Impact of PET staging in limited-stage SCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7098 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7098-7098

Author(s):

Eric Xanthopoulos ◽

Surbhi Grover ◽

Michael Nino Corradetti ◽

Annemarie Therese Fernandes ◽

Miranda Kim ◽

...

Keyword(s):

Overall Survival ◽

Median Time ◽

Patient Characteristics ◽

Concurrent Chemoradiation ◽

University Of Pennsylvania ◽

Limited Stage ◽

Distant Failure ◽

Kaplan Meier ◽

Pet Ct ◽

Cox Analysis

7098 Background: Although PET/CT has been established for the initial staging of NSCLC, it is still unproven for SCLC. This study examines clinical outcome in patients with limited-stage SCLC staged with and without PET/CT. Methods: An institutional database was reviewed to identify all patients that presented with limited-stage SCLC and treated definitively with concurrent chemoradiation. Overall survival and associations were assessed by the Kaplan-Meier approach, log-rank tests and Cox modeling. Results: From 01/04 – 08/10, 54 consecutive limited-stage SCLC patients were treated with concurrent chemoradiation at the University of Pennsylvania. 40 patients underwent PET staging; 14 underwent CT staging only; all had MR of the brain. Patient characteristics were well distributed, including age (p = 0.35), race (p = 0.21), sex (p = 0.93), dose (45 Gy, p = 0.89), and fractions per day (p = 0.89). PET-staged patients had median survival of 32 vs 15 months in patients without PET (p = 0.03). Survival rate was 57% vs 29% at 24 months. Median time to distant failure of 29 vs 11 months (p = 0.05). Median time to local failure was 41 vs 12 months (p = 0.03). Median followup was 38 months in the 19 surviving PET-staged patients and 40 in the 2 surviving non-PET patients (p = 0.59). Lack of PET-staging (OR = 0.92, p = 0.04) and race (OR = 1.02, p = 0.03) associated with increased distant failure on multivariate Cox analysis. Only PET-staging (OR = 0.93, p = 0.04) associated with increased overall survival on univariable Cox modeling. Conclusions: Median and overall survival of PET-staged SCLC patients compared favorably with those who were not. These findings are presumably due primarily to identification of CT-occult distant disease by PET. This study underscores the value of PET in staging patients with SCLC.

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The Transcriptome of Immunomodulator-Resistant Multiple Myeloma

Blood ◽

10.1182/blood-2019-123407 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1772-1772

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Martha Q. Lacy ◽

Jessica L. Haug ◽

Angela Dispenzieri ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Overall Survival ◽

Differentially Expressed Genes ◽

Research Funding ◽

Differentially Expressed ◽

Resistant Disease ◽

Kaplan Meier ◽

Gene Coding ◽

Cellular Pathways

Introduction: While the molecular target of immunomodulators such as pomalidomide (POM) and lenalidomide (LEN) has been identified, the mechanisms underlying therapeutic resistance remain incompletely understood. The uniformly emerging resistance to therapy over time in the absence of identifiable cereblon pathway mutations in the majority of patients raises questions about alternative mechanisms including aberrant gene expression. Methods: We performed gene expression profiling using an Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray on CD138+ bone marrow cells from patients with relapsed / refractory (RRMM) and newly diagnosed (NDMM) multiple myeloma prior to initiating treatment. Patients were treated on two phase II clinical trial protocols (MC0789: POM ± dexamethasone in RRMM; MC0884: LEN ± dexamethasone in NDMM) between 2007 and 2012. We categorized patients based on their IMWG response as non-responders (SD) and responders (VGPR+). We selected 15 responders and 15 non-responders from MC0789 (n = 30) and compared overall survival, gene expression patterns, and involved cellular pathways between the two groups. We selected 5 responders and 5 non-responders from MC0884 (n = 10) for targeted validation of differentially expressed candidate genes. After data quality control and normalization of gene expression values, differential gene expression was estimated using limma. Statistical significance was adjusted for multiple testing in the discovery set using a false discovery rate-based approach for genome-wide experiments (q-value). We used Gene Ontology and PANTHER pathway analysis for functional annotation of differentially expressed genes. Overall survival estimates were calculated using the Kaplan-Meier method. Computation and visualization were performed in R. Results: Median age at treatment initiation on MC0789 was 65 years (40 - 82), 65% of the patients were male. Pomalidomide resistance was associated with an increase in mortality (median overall survival 1.6 versus 6.4 years, p = 0.009, Kaplan-Meier plot). There were 1076 differentially regulated genes between responders and non-responders (521 up- and 555 down-regulated, q < 0.050 for all genes, volcano plot). Expression of CRBN was 1.5-fold down-regulated in non-responders (q = 0.005). Supervised hierarchical clustering of the top 500 differentially expressed genes demonstrated distinct patterns in pomalidomide-resistant disease (heatmap). Gene ontology analysis revealed protein synthesis as one of the most enriched biological processes (bar graph). Pathway analysis showed a 6-fold enrichment (FDR = 0.007) of the ubiquitin proteasome pathway in pomalidomide-resistant disease. Differentially expressed genes involved key protein degradation pathways, epigenetic modifiers, and transcription factors. Targeted validation in MC0884 revealed 13 common genes with at least 1.5-fold differential expression (5 up- and 8 down-regulated), 12 of which have previously been implicated in the regulation of apoptosis, tumor glucose metabolism, Rho and Wnt signaling, miRNA-driven resistance to chemotherapy, and ubiquitin-dependent protein degradation (Table and Sankey diagram). The most up-regulated gene in non-responders was MYRIP, a gene coding for a vesicle trafficking protein associated with platinum resistance and suppression of pro-apoptotic BCL-2 family members in solid malignancies. The most down-regulated gene was FRZB, a gene coding for a negative regulator of Wnt signaling, previously implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. Conclusions: Overall survival of patients with pomalidomide-resistant RRMM remains poor. Pomalidomide resistance was associated with differential gene expression in several potentially targetable cellular pathways beyond the known drug target cereblon. Targeted validation of candidate genes revealed common cellular pathways in immunomodulator-resistant disease. Elucidating the exact molecular mechanisms underlying immunomodulator resistance is of considerable interest for biomarker development and the identification of novel therapeutic targets and warrants further exploration. Figure Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Alnylam: Research Funding; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Akcea: Consultancy; Takeda: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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Five-Year Follow-up of Randomized, Phase II Trial of Idiotype-Pulsed Dendritic Cell Vaccine with Adjuvant Cytokines In Plateau Phase and Post-Transplant Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.1958.1958 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1958-1958

Author(s):

Yi Lin ◽

Morie Gertz ◽

Sumithra Mandrekar ◽

Kristina Laumann ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Dendritic Cell Vaccine ◽

Cell Vaccine ◽

Plateau Phase ◽

Time To Progression ◽

Kaplan Meier

Abstract Abstract 1958 Vaccines may offer additional benefit as consolidation therapy after plateau phase or autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously the results of another phase II trial showing that using APC8020 (Mylovenge™) after ASCT improved the overall survival (OS 5.3 yrs, 95% CI 4.0 yrs – NA) compared to ASCT alone (3.4 yrs, 95% CI 2.7 – 4.6 yrs; p = 0.02; Lacy, AJH (84): 799). We now report the results from a randomized, phase II trial using the same vaccine plus adjuvant cytokines in MM patients in plateau phase after either chemotherapy or ASCT. Twenty patients were enrolled between 2001 and 2003 and were randomized to receive APC8020 and adjuvant cytokine of either interferon-g (IFNg, arm A, n = 10) or interleukin-2 (IL2, arm B, n = 10). Each cycle of treatment included five days of daily subcutaneous injections of either IFNg (106 IU, arm A) or IL2 (200 mg, arm B) followed by APC8020 injection. Each patient received a cycle of treatment every 2 weeks for 4 cycles. One patient in each arm was in plateau phase post-chemotherapy. Time from diagnosis to treatment was 11.9 mos for the patient in arm A and 16.2 mos for arm B. Time to progression (TTP) was 3.7 and 68 months respectively the patient in arm A and B. Both patients were alive at five years. For the 9 post-ASCT patients in each arm, no statistically significant differences were seen in the baseline characteristics between the 2 arms. The median time from diagnosis to treatment was 15.4 months. No grade 4 or 5 adverse events (AEs) were reported. Two patients in each arm had grade 3 AE, including lymphopenia, thrombocytopenia, hemorrhage, infection, and fatigue. One patient in arm B had grade 3 autoimmune disorder that was deemed possibly related to study treatment. The most common AEs were grade 1 fatigue (n = 7) and anemia (n = 5) in arm A and grade 1 anemia (n = 7) and injection site reaction (n = 5) in arm B. The median TTP was 9.3 months (95% CI: 3.9 – 19.3 months) for arm A and 6.6 months for arm B (95% CI: 6.3 – 29.6 months) with no statistically significant difference between the two arms (p = 0.89). The median OS had not been reached for either arm; the 5-year OS rate was 67% and 56% for arms A and B respectively (p = 1.0). Interestingly, similar to our previous study where TTP was not different while OS was improved with vaccine, when we compared the clinical outcome for all patients in this vaccine trial to that of 78 matched control patients who only received ASCT during the same time frame, we did not see significant improvement in TTP (Figure 1). However, the 5-year overall survival for all patients in this trial is significantly improved at 71% (95%CI: 51–96%) compared to ASCT control patients (41%, 95% CI: 31 – 54%; p = 0.03; Figure 1). This trial suggests improved OS with vaccine plus cytokine. It is possible that modulation of patients’ immunity may help them live longer with multiple myeloma. Further investigation is needed to compare the approach in this trial with dendritic cell vaccine alone to better understand optimal strategy for vaccine therapy in MM. Figure 1. Kaplan-Meier curves for time to progression and overall survival Figure 1. Kaplan-Meier curves for time to progression and overall survival Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Lacy:Celgene: Research Funding.

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Pretransplant PET Positivity Predicts Early Relapse with Poor Outcome in Patients of Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v124.21.3997.3997 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3997-3997 ◽

Cited By ~ 1

Author(s):

Bhausaheb Bagal ◽

Hasmukh Jain ◽

Uma Dangi ◽

Manju Sengar ◽

Sadhana Kannan ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Progression Free Survival ◽

Response Evaluation ◽

Post Transplant ◽

Group 4 ◽

Kaplan Meier ◽

Pet Ct ◽

Group 1

Abstract Background: Multiple Myeloma is a heterogeneous disease with few patients enjoying overall survival up to a decade while others dying within few years from diagnosis. Multiple staging systems and risk stratification models based on clinical features, laboratory parameters and cytogenetics have been used to predict the response to therapy and outcomes. Positron emission tomography integrated with computerised tomography (PET-CT) offers several advantages as compared to conventional bone imaging modalities in terms of ability to assess extramedulary disease, detection of bone marrow involvement and extent of active disease. Especially important is ability of PET-CT to assess treatment response in terms of FDG activity as bone changes like lytic lesions may persist long on conventional imaging even when disease is in remission. There is scarce data on potential role of PET-CT in response evaluation and prognostication in patients with multiple myeloma. We prospectively analysed the prognostic relevance of PET-CT done prior to autologous stem cell transplant (ASCT). Method: Consecutive patients of multiple myeloma who underwent ASCT between March 2011 and June 2014 were included in this study. All patients received standard novel agent based induction regimen, bortezomib based in 38 patients and lenalidomide based in 5 patients. Patients were evaluated for response by using international myeloma working group (IMWG) criteria after 4-6 cycles of induction regimen. Subsequently patient's stem cells were harvested from peripheral blood by chemomobilization with cyclophosphamide along with G-CSF. All patients underwent PET-CT immediately pretransplant along with response evaluation by IMWG criteria. PET-CT was considered to be negative if there were no FDG avid lytic lesion and no FDG avid extramedulary disease/soft tissue component was seen. Conditioning regimen used for ASCT were melphalan- 200mg/m2 in 37 patients, reduced doses of melphalan (100-140 mg/m2) in 2 patients or bortezomib- melphalan in 4 patients. Post transplant response evaluation was done at 3 months from transplant and at 3 monthly interval thereafter by SIEP, immunofixation, 24 hours urine BJP, and serum free light chain assay. Probabilities of overall survival and progression free survival were estimated using the Kaplan–Meier method and were compared by log rank test. Results: Forty three patients of multiple myeloma underwent ASCT during the study period. The median age of patients at diagnosis was 49 years and 31 (72 %) were male. As per International Staging System, 15 were stage I, 9 were stage II and 14 were stage III disease at time of diagnosis. After induction therapy, 17 patients achieved CR, 13 patients achieved VGPR, 10 patients had PR while 3 patients had progressive disease (PD) pretransplant. Simultaneously done PET-CT was positive in 15 (34%) patients while it was negative in remaining. At a median follow up of 2.6 years from diagnosis 8 patients had progression of disease and 3 patients have died because of disease progression. So as to evaluate the prognostic utility of PET-CT, patients were grouped into four groups as follows- group 1 - CR/VGPR and PET-CT- negative, group 2 - CR/VGPR and PET-CT- positive, group 3 - PR/PD and PET-CT- negative, group 4 - PR/PD and PET-CT- positive as shown in table 1. Table 1: Pretransplant response according to IMWG criteria and PET-CT. PET negative pretransplant PET positive pretransplant Pre transplant CR/VGPR 25 5 Pretransplant PR/PD. 3 10 At a median follow up of 1.68 years post transplant, 4 patients from group 1 and 4 patients from group 4 have progressed. The estimated probability of overall survival and progression free survival from transplant by Kaplan–Meier method at 3 year is 92 % and 62 % respectively. The time to progression after transplant was significantly short in group 4 as compared to group 1 (median time to progression of 6 months versus 26 months; p=0.001). Out of 8 patients who have relapsed post transplant, 3 patients who were PET-CT positive pretransplant have died while all the 4 patients who were PET negative pretransplant are alive. Conclusion: Pretransplant PET-CT positivity predicts early relapse after ASCT. Survival of such patients is poor after relapse post ASCT. These findings needs validation in larger cohort of patients with longer follow up. Disclosures No relevant conflicts of interest to declare.

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Prognostic Implications of Multiple Cytogenetic High-Risk Abnormalities in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5615.5615 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5615-5615

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Rhett P. Ketterling ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cumulative Effect ◽

Newly Diagnosed ◽

Advisory Committees ◽

Kaplan Meier ◽

Prognostic Implications

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. The presence of specific cytogenetic abnormalities is known to confer a poor prognosis, less is known about the cumulative effect of multiple cytogenetic high-risk abnormalities. We aimed to evaluate the prognostic implications of the presence of multiple cytogenetic high-risk abnormalities at the time of diagnosis. Methods: We studied 226 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and presented with cytogenetic high-risk abnormalities. High-risk cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in patients with single and multiple cytogenetic high-risk abnormalities. A multivariable-adjusted Cox regression model was used to assess the effect of multiple cytogenetic high-risk abnormalities on overall survival adjusting for age, sex, and Revised International Staging System (R-ISS) stage. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (32 - 90), 129 (57%) of the patients were male. The median overall survival was 3.5 years (3.1 - 4.9) for the entire cohort (n = 226), 4.0 years (3.3 - 5.1) for those with one cytogenetic high-risk abnormality (n = 182, 80%), and 2.6 years (1.7 - 3.1) for those with two cytogenetic high-risk abnormalities (n = 44, 20%). There were no patients with more than two cytogenetic high-risk abnormalities. Ninety-eight patients (45%) had a high-risk translocation, 77 (35%) had del(17p), 39 (18%) had a high-risk translocation plus del(17p), and 5 (2%) had gain(1q) plus either a high-risk translocation or del(17p). Figure 1 shows the Kaplan-Meier overall survival estimates stratified by the number of cytogenetic high-risk abnormalities (n = 226). The presence of two cytogenetic high-risk abnormalities (compared to one) was of prognostic significance after adjusting for age, sex, and R-ISS stage (HR 2.01, 95% CI 1.27 - 3.19, p = 0.003, n = 205). Conclusions: Approximately one in five patients with newly diagnosed high-risk multiple myeloma presented with two high-risk abnormalities at the time of diagnosis. These patients experienced inferior overall survival suggesting a cumulative effect of multiple cytogenetic high-risk abnormalities. The relatively low number of observed gain(1q) was likely related to the fact that not all patients were evaluated for that abnormality. Therefore the presented hazard ratio represents a conservative effect estimate and may underestimate the true effect. Figure 1 Figure 1. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; 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; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Kumar:Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

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Characterization and Prognosis of Temozolomide-Induced Aplastic Anemia

Blood ◽

10.1182/blood-2021-146376 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2193-2193

Author(s):

Albert K. Park ◽

Anem Waheed ◽

Deborah A. Forst ◽

Hanny Al-Samkari

Keyword(s):

Overall Survival ◽

Aplastic Anemia ◽

Median Time ◽

Research Funding ◽

Refractory Disease ◽

Hematopoietic Growth Factors ◽

Entire Cohort ◽

Kaplan Meier ◽

Thrombopoietin Receptor ◽

Cns Malignancies

Abstract Introduction: Temozolomide-induced aplastic anemia (TIAA) is a very rare and highly challenging complication of temozolomide (TMZ) chemotherapy. TMZ is a mainstay of therapy in patients with central nervous system (CNS) malignancies. Single-patient case reports and small case series have described variable morbidity and mortality associated with TIAA. However, quantitative evidence describing prognosis, clinical characteristics, and treatment of this entity is absent or very limited. Methods: We performed a 5-center, 22-year observational cohort study of patients with CNS malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. We compared patients who achieved meaningful hematologic recovery [partial hematologic recovery (PHR) or complete hematologic recovery (CHR)] to those who did not recover [refractory disease (RD)]. We used descriptive statistics, T-tests, and chi-square tests to evaluate patient characteristics, outcomes, and laboratory values. Overall time to hematologic recovery and overall survival of patients with PHR, CHR, and RD were estimated using the Kaplan-Meier method and compared using the log-rank test, and a multivariable logistic model evaluated potential predictors of achieving CHR. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery (TABLE 1). Results: Study Population and TIAA Prevalence. Of 3,821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA (FIGURE 1). Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle (TABLE 2). Complications and Outcomes of Hematologic Recovery. 23 patients (67.6%) ultimately achieved a hematologic recovery and the remaining 11 patients (32.4%) had refractory disease. Figure 2A illustrates the time from TIAA diagnosis to PHR and CHR for the cohort. In Kaplan-Meier survival analysis, the median time from TIAA diagnosis to PHR was 84 days and the median time to CHR was 134 days. Patients without recovery were more likely to develop serious complications (TABLE 3), including febrile neutropenia (72.7% vs. 30.4%, P=0.03), major infection (45.5% vs. 8.7%, P=0.02), hospitalization (81.8% vs. 43.5%, P=0.04), and death (100.0% vs. 60.9%, P=0.02). This increased risk of complications in patients not achieving hematologic recovery was observed despite a similar median time from TMZ initiation to TIAA diagnosis in the two groups (45 days vs. 40 days). Figure 2B illustrates the overall survival in the entire cohort and by each hematologic recovery subgroup. In Kaplan-Meier survival analysis, median overall survival from the time of TIAA diagnosis was as follows: entire cohort, 355 days; achieved PHR, 752 days; achieved CHR, 1414 days; refractory disease, 28 days (P<0.0001 for comparison of PHR, CHR, and refractory disease). In a multivariable logistic model, none of the evaluated covariates (age, sex, TMZ dose, body surface area, and use of hematopoietic growth factors) were significantly associated with achieving CHR. Treatment of TIAA and Outcomes of Therapy. 29 patients (85.3%) received hematopoietic growth factors (TABLE 3); no patients were treated with immunosuppression or hematopoietic stem cell transplant. Hematologic recovery rates were numerically higher in patients receiving thrombopoietin receptor agonists vs. those who did not (81.8% vs. 54.2%, P=0.15), but were not higher in patients receiving granulocyte colony stimulating factors vs. those who did not (68.0% vs. 66.7%, P=0.99). Conclusions: TIAA occurs in less than 1% of patients receiving temozolomide for CNS malignancies, occurring rapidly after TMZ initiation, but is highly morbid and often fatal when it occurs, precluding further use of cytotoxic therapy in the vast majority of patients. In the one-third who do not recover, risks of febrile neutropenia, infection, and hospitalization are increased, and overall survival greatly diminished. Hematologic recovery is potentially aided by the use of thrombopoietin receptor agonists, as has been demonstrated in classical autoimmune aplastic anemia. Further study of TIAA treatment is needed for this serious complication of TMZ therapy. Figure 1 Figure 1. Disclosures Forst: Eli Lilly: Current holder of individual stocks in a privately-held company. Al-Samkari: Rigel: Consultancy; Argenx: Consultancy; Moderna: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

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Sex differences in pharmacotherapy and long-term outcomes in patients with ischaemic heart disease and left ventricular dysfunction

European Heart Journal ◽

10.1093/ehjci/ehaa946.1059 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Dagan ◽

D Dinh ◽

J Stehli ◽

C Tan ◽

A Brennan ◽

...

Keyword(s):

Heart Disease ◽

Ischaemic Heart Disease ◽

Medical Therapy ◽

Left Ventricular Dysfunction ◽

Ventricular Dysfunction ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Kaplan Meier ◽

Long Term Mortality

Abstract Background Left ventricular dysfunction and ischaemic heart disease are common amongst women, however, women tend to present later and are less likely to receive guideline-directed medical therapy compared to their male counterparts. Purpose To investigate if a sex discrepancy exists for optimal medical therapy (OMT) and long-term mortality in a cohort of patients with known ischaemic heart disease (IHD) and left ventricular dysfunction. Methods We analysed prospectively collected data from a multicentre registry database collected between 2005–2018 on pharmacotherapy 30-days post percutaneous coronary intervention (PCI) in 13,015 patients with left ventricular ejection fraction (LVEF) <50%. OMT at 30-days was defined as beta-blocker (BB), angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) ± mineralocorticoid receptor antagonist (MRA). Long-term mortality was determined by linkage with the National Death Index, with median follow up of 4.7 (IQR 2.0–8.6) years. Results Mean age was 65±12 years; women represented 20.2% (2,634) of the cohort. Women were on average 5 years older, had higher average BMI, higher rates of hypertension, diabetes, renal dysfunction, prior stroke and rheumatoid arthritis. Men were more likely to have sleep apnoea, be current/ex-smokers and to have had prior myocardial infarction, PCI and bypass surgery. Overall, 72.3% (9,411) of patients were on OMT, which was similar between sexes (72.7% in women vs. 72.2% in men, p=0.58). Rates of BB therapy were similar between sexes (85.2% vs. 84.5%, p=0.38), while women were less likely to be on an ACEi/ARB (80.4% vs. 82.4%, p=0.02) and more likely to be on a MRA (12.1% vs. 10.0%, p=0.003). Amongst those with LVEF ≤35% (n=1,652), BB (88.7% vs. 87.3%, p=0.46), ACEi/ARB (83.3% vs. 82.1%, p=0.59) and MRA use (32.5% vs. 33.3%, p=0.78) was comparable. Aspirin use was similar between sexes (95.3% vs. 95.9%, p=0.12), while women were less likely to be on statin therapy (93.5% vs. 95.3%, p<0.001) and a second antiplatelet agent (94.4% vs. 95.6%, p=0.007). On unadjusted analysis women had significantly higher long-term mortality of 25.4% compared to 19.0% for men (p<0.001). Kaplan-Meier analysis out to 14 years demonstrated that men on OMT have the best long-term survival overall and women on sub-OMT have significantly poorer outcomes compared to men on sub-OMT. However, after adjusting for OMT and other comorbidities there was no difference in long-term mortality between sexes (HR 0.99, 95% CI 0.87–1.14, p=0.94). Conclusion From this large multicentre registry, we found similar rates of guideline-directed pharmacotherapy for left ventricular dysfunction between sexes, however women were less likely to be on appropriate IHD secondary prevention. The increased unadjusted long-term mortality amongst women is likely due to differing baseline risk, given that adjusted mortality was similar between sexes. Kaplan-Meier Survival Analysis Funding Acknowledgement Type of funding source: None

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18F-FDG PET/CT and Urothelial Carcinoma: Impact on Management and Prognosis—A Multicenter Retrospective Study

Cancers ◽

10.3390/cancers11050700 ◽

2019 ◽

Vol 11 (5) ◽

pp. 700 ◽

Cited By ~ 5

Author(s):

Fabio Zattoni ◽

Elena Incerti ◽

Fabrizio Dal Moro ◽

Marco Moschini ◽

Paolo Castellucci ◽

...

Keyword(s):

Overall Survival ◽

Urothelial Carcinoma ◽

Fdg Pet ◽

Patient Management ◽

Survival Prediction ◽

Primary Tumor Site ◽

Kaplan Meier ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

Objectives: To evaluate the ability of 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to predict survivorship of patients with bladder cancer (BC) and/or upper urinary tract carcinoma (UUTC). Materials: Data from patients who underwent FDG PET/CT for suspicion of recurrent urothelial carcinoma (UC) between 2007 and 2015 were retrospectively collected in a multicenter study. Disease management after the introduction of FDG PET/CT in the diagnostic algorithm was assessed in all patients. Kaplan-Meier and log-rank analysis were computed for survival assessment. A Cox regression analysis was used to identify predictors of recurrence and death, for BC, UUTC, and concomitant BC and UUTC. Results: Data from 286 patients were collected. Of these, 212 had a history of BC, 38 of UUTC and 36 of concomitant BC and UUTC. Patient management was changed in 114/286 (40%) UC patients with the inclusion of FDG PET/CT, particularly in those with BC, reaching 74% (n = 90/122). After a mean follow-up period of 21 months (Interquartile range: 4–28 mo.), 136 patients (47.4%) had recurrence/progression of disease. Moreover, 131 subjects (45.6%) died. At Kaplan-Meier analyses, patients with BC and positive PET/CT had a worse overall survival than those with a negative scan (log-rank < 0.001). Furthermore, a negative PET/CT scan was associated with a lower recurrence rate than a positive examination, independently from the primary tumor site. At multivariate analysis, in patients with BC and UUTC, a positive FDG PET/CT resulted an independent predictor of disease-free and overall survival (p < 0,01). Conclusions: FDG PET/CT has the potential to change patient management, particularly for patients with BC. Furthermore, it can be considered a valid survival prediction tool after primary treatment in patients with recurrent UC. However, a firm recommendation cannot be made yet. Further prospective studies are necessary to confirm our findings.

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Prolonged overall survival with second on-demand autologous transplant in multiple myeloma

American Journal of Hematology ◽

10.1002/ajh.20641 ◽

2006 ◽

Vol 81 (6) ◽

pp. 426-431 ◽

Cited By ~ 43

Author(s):

Francesca Elice ◽

Roberto Raimondi ◽

Alberto Tosetto ◽

Anna D'Emilio ◽

Eros Di Bona ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Autologous Transplant ◽

On Demand

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Efficacy of Subsequent Therapies in Multiple Myeloma Patients after Progression on a BCMA Targeting Therapy: A Single-Center Experience

Blood ◽

10.1182/blood-2020-141637 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-13

Author(s):

Barry Paul ◽

Myra Robinson ◽

Kristen Cassetta ◽

Daniel Slaughter ◽

Jordan Robinson ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Overall Survival ◽

Research Funding ◽

Subsequent Treatment ◽

Single Center ◽

Targeting Therapy ◽

Single Center Experience ◽

Best Response ◽

Car T

Background: Targeting B-cell maturation antigen (BCMA) with antibody-drug conjugates (ADCs), bispecific antibodies, or chimeric antigen receptor t-cells (CAR-Ts) has proven safe and effective in recent clinical trials, but relapses remain common. As most patients treated with BCMA targeting therapies are refractory to conventional anti-myeloma therapies, management of these patients poses unique challenges once they progress, with no data available to guide subsequent therapies. Methods: We performed a retrospective chart review of all relapsed refractory multiple myeloma (RRMM) patients at our institution who progressed while on or after a BCMA targeting therapy and were treated with subsequent therapies. We evaluated the best response achieved and overall survival (OS) measured from progression on BCMA targeting therapies. Kaplan Meier methods were used to estimate OS curves and landmarks between classes of BCMA targeting therapy received (ADC, bispecific antibody or CAR-T), and by type of subsequent therapy. Results: At a median follow up of 6 months, a total of 47 patients were treated with a BMCA targeting therapy. Of those, a total of 21 (44.7%) patients have progressed, with 18 (38.3%) receiving another therapy. Twelve-month overall survival of the patients who received a subsequent treatment was 51.1% (figure 1a), but varied considerably based on the class of BCMA therapy they received (figure 1b). Patients who progressed after a BCMA CAR-T had the best OS (N =2, 6 mo OS: 100%, 12 mo OS: Of the 18 patients who progressed and were treated with subsequent therapies, 7 (38.9%) received 2 lines of therapy, 5 (27.8%) received 3 lines of therapy, and 1 patient (5.6%) received 5 lines of therapy. In the first relapse, 4 (22.2%) patients received infusional chemotherapy with CAR-D PACE or CAR-DCEP, 4 (22.2%) received the combination of elotuzumab, pomalidomide, and dexamethasone (Elo-Pd; one of which was first treated with CAR-DCEP), 3 (16.7%) received selinexor based regimens. The best response seen after first-line post BCMA treatment was a partial response (PR) in 5 (27.8% of patients), whereas 8 (61.5%) patients who received second-line treatment post-BCMA therapy had a PR or better, including 3 (23.1%) who had a very good partial response (VGPR). In the third line post-BCMA, 1 (16.7%) had a VGPR, while 1 (16.7%) had stable disease as their best response. The use of Elo or Dara after anti-BCMA progression seemed to correlate with improved OS (see figure 1c below). While all these patients were Elo naïve, the majority (94.4%) were previously Dara exposed. Conclusions: Our data demonstrate that many RRMM patients who progress on BCMA targeting therapies still derive benefit from subsequent treatment. Early evidence from our experience suggests a survival advantage with monoclonal antibody-based therapies even in patients who had previously been exposed to these agents-suggesting a possible resensitization with BCMA directed therapy. Although our dataset is a single-center experience, to our knowledge it represents the first report of post-BCMA exposed management of RRMM and provides valuable insight into the treatment of this challenging and ever-expanding population. Disclosures Paul: Bristol-Myers Squibb: Other: Stock Ownership (prior employee); Amgen: Consultancy, Speakers Bureau; Regeneron: Membership on an entity's Board of Directors or advisory committees. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Prothena: Other: Clinical Trial Funding to Institute; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute. Voorhees:Adaptive Biotechnologies: Other: Personal fees; Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Novartis: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Usmani:Celgene: Other; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Atrash:BMS, Jansen oncology, Sanofi: Speakers Bureau; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; Amgen, GSK, Karyopharm.: Research Funding.

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