Outcome of Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis (RARS-T) In a Large Cohort of Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4113-4113 ◽  
Author(s):  
Francois Girodon ◽  
Julien Broseus ◽  
Lourdes Florensa ◽  
Esther Zipperer ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Platelet Count ◽  
Myeloproliferative Neoplasms ◽  
Hemoglobin Concentration ◽  
Large Cohort ◽  
Refractory Anemia ◽  
White Blood Count ◽  
Employment Equity ◽  
Disease Evolution ◽  
Ringed Sideroblasts ◽  
Equity Ownership

Abstract Abstract 4113 Introduction: Most of the data related to RARS-T, a rare disorder, involve small cohorts of patients. We aimed to analyze more patients also considering a variety of myelodysplastic or myeloproliferative disorders. Objective: To compare a large cohort of patients with RARS-T to refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and multilineage dysplasia (RARS-MD) or essential thrombocythemia (ET) at the time of diagnosis and during disease evolution, in terms of survival and complications. Materials: Data of a European multi-center study was used including 199 cases of RARS-T 173 cases of RARS, 102 cases of RARS-MD and 431 cases of ET. Results: At baseline, compared to RARS and RARS-MD patients, RARS-T patients had similar hemoglobin concentration, but a higher white blood count. The JAK2V617F mutation was observed in 43%, 12% and 5% in RARS-T, RARS and RARS-MD patients, respectively. When separated in 2 groups (450,000<platelet count <600,000 and platelet count >600,000 × 109/l), RARS-T patients were comparable for sex, age, hemoglobin level and survival. However, patients with platelet count > 600,000 × 109/l had higher WBC (11 ×109/l versus 7.5 ×109/l, p<0.001). Similarly, no difference was noted in the survival in the JAK2 positive and negative RARS-T patients. The age and sex standardised overall survival of RARS-T patients was similar to RARS and RARS-MD patients, but lower than ET patients (p<0.001). This was despite a higher risk of transformation in acute leukemia, relative to RARS-T afflicted individuals, of 2.4 and 3.5 in RARS-MD and RARS patients, respectively. Conclusion: According to our results, the outcome in RARS-T more closely mimics myelodysplastic syndromes rather than myeloproliferative neoplasms. Our results agree with the WHO 2008 classification that considers RARS-T as a separate disorder. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Gattermann:Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Next-Generation Deep-Sequencing Enables a Quantitative Monitoring of RUNX1 Mutations in 534 Patients with Myelodysplastic/Myeloproliferative Neoplasms and Myelodysplastic Syndromes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2792-2792
Author(s):  
Alexander Kohlmann ◽  
Vera Grossmann ◽  
Stefan Harbich ◽  
Frank Dicker ◽  
Niroshan Nadarajah ◽  
...  
Keyword(s):  
Disease Progression ◽  
Deep Sequencing ◽  
Myelodysplastic Syndromes ◽  
Myeloproliferative Neoplasms ◽  
Refractory Anemia ◽  
Patient Specific ◽  
Next Generation ◽  
Employment Equity ◽  
Clone Size ◽  
Equity Ownership

Abstract Abstract 2792 Introduction: Somatic mutations of key candidate genes have gained interest as biomarkers predicting poor survival in myelodysplastic/myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). RUNX1 (runt-related transcription factor 1) deregulations constitute such a disease-defining molecular aberration and are usually tested applying a combination of denaturing high-performance liquid chromatography and direct Sanger sequencing. Patient-specific RUNX1 mutations were proposed to represent clinically useful molecular alterations to follow disease progression from MDS to s-AML. Study design: Using genomic DNA obtained from mononuclear cells a next-generation amplicon deep-sequencing (NGS) assay targeting the complete coding region of RUNX1 was developed on a longitudinal series of 116 retrospective samples obtained from 25 patients collected between 11/2005 and 6/2010 (454 Life Sciences, Branford, CT). Subsequently, this assay was applied to characterize an unselected prospectively collected MPN/MDS patient cohort during their course of disease. Results: Here, we present analyses on a cohort of 534 patients (females: 200; males 334). The median age was 72.0 years (25.2–95.7 years). The cohort included 149 chronic myelomonocytic leukemias (CMML), 11 cases with 5q- syndrome, 10 cases with refractory cytopenia with unilineage dysplasia (RCUD), 15 cases with refractory anemia with ring sideroblasts (RARS), 105 cases with refractory cytopenia with multilineage dysplasia (RCMD), 135 cases with refractory anemia with excess blasts-1 (RAEB-1), 87 cases with refractory anemia with excess blasts-2 (RAEB-2), and 22 cases with t-MDS, respectively. In total, 130 RUNX1 mutations were observed in 17.8% (95/534) of these patients. The mutational clone size ranged from 1.7% to 94% and amounted to a median of 31%. In comparison to our data from an AML cohort, i.e. 460 patients at diagnosis with 112 (24.3%) cases mutated, the median clone size was about 10% lower in MPN/MDS. In detail, 74.7% (71/95) of patients harbored one mutation, whereas 25.3% (24/95) of cases harbored two (17.9%; 17/95) or >=3 (7.4%; 7/95) mutations. The 130 RUNX1 mutations were characterized as follows: 29% frame-shift mutations, 42% missense, 14% nonsense, 13% exon-skipping, and 2% in-frame insertion/deletion alterations, respectively. The following codons were recurrently mutated: Arg174 (8/95 patients; 9.4%), Arg177 (6/95 patients; 7.0%), and Arg135 (5/95 patients; 5.3%). The mutations were predominantly located in the RHD domain (55%) and TAD domain (13%) and in cases with 2 or more alterations only 15% (4/24) harbored mutations outside of these regions. In all cases with 3 concomitant mutations both domains were affected (4/4 patients). Further, cases with >1 RUNX1 mutation were more frequently observed in CMML (33.3%; 8/24 mutated), RAEB-1 (17.2%; 5/29 mutated) and RAEB-2 (34.5%, 10/29 mutated) as compared to other disease groups, respectively. In subsequent serial analyses including 56 samples from 22 cases the amplicons carrying the respective known alteration were analyzed with increased coverage for disease status monitoring (in median 833 reads/amplicon were sequenced; leading to a sensitivity of ∼1:800). With a median time span of 2.5 months between the molecular analyses a total of 2 to 4 samples per patient were analyzed. In 5/22 patients, this assay then allowed to monitor the treatment success of allogeneic stem cell transplantation: in 3 cases the mutations known before transplantation became undetectable; in 2 cases the same mutated clones still remained detectable at a level of 0.2% and 23%, respectively. Further, in 17 patients quantitative assessment of mutated RUNX1 read counts was used to monitor stable disease (n=12) or allowed to follow an increasing clone size in 3 patients that progressed into s-AML (39% -> 53% increase; 31% -> 42% increase; 7% -> 37% increase). Summary: Unbiased techniques such as deep-sequencing provide the required diagnostic specificity and sensitivity to enable classification and individualized monitoring of disease progression. We here demonstrate that amplicon-based NGS is a suitable method to accurately detect and quantify the broad spectrum of molecular RUNX1 aberrations with high sensitivity. It is therefore suitable for therapy guidance. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment; Roche Diagnostics: Honoraria. Grossmann:MLL Munich Leukemia Laboratory: Employment. Harbich:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Differential Association of Calreticulin Type 1 and Type 2 Mutations with Myelofibrosis and Essential Thrombocytemia: Relevance for Disease Evolution

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1823-1823 ◽  
Author(s):  
Xenia Cabagnols ◽  
Jean-Philippe Defour ◽  
Valérie Ugo ◽  
Jean Christophe Ianotto ◽  
Pascal Mossuz ◽  
...  
Keyword(s):  
Platelet Count ◽  
Triple Negative ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Hemoglobin Concentration ◽  
Disease Evolution ◽  
Calr Mutations ◽  
Calr Mutation

Abstract Recent advances in myeloproliferative neoplasms (MPN) have highlighted the prevalence of mutations in the calreticulin gene (CALR), bringing a major new actor in these disorders. CALR mutations were reported in 25% of ET and in 35% of MF patients, which were non-mutated for JAK2 and MPL. CALR mutations lead to a frame-shift generating a common 36 amino acids C-terminal end and loss of the KDEL motif. Two variants account for 85% of the CALR mutations in ET and PMF: type 1, a 52-bp deletion and type2, a 5-bp insertion. 572 MPN patients negative for JAK2 and MPL mutations were collected from several French and Belgian hospitals. In our series, 396 patients were diagnosed as ET, 108 as MF and 68 as mixed MDS/MPN. We identified mutations of CALR in 368 patients (63.3%). The remaining 204 patients were designated as triple negative. In MF there was an over representation of type 1 mutation (70%) and an under representation of type 2 mutation (13%) as compared to patients with ET. This bias was associated with a higher allelic burden of CALR mutation in MF. MF patients represent a quite homogeneous group, mostly composed of men diagnosed at a median age of 62.5 with a low hemoglobin concentration (10.1 g/dl) and a low platelet count (median at 237 x 109/l). In ET patients the clinical presentation was more heterogeneous. They were mostly women (more than 61%) at a median age of diagnosis of 57 with a median platelet count of 724 x 109/l. In CALR mutated patients there were no sex prevalence and a more important thrombocytosis (785 x 109/l). The type of CALR mutation impacted also age and platelet count. We report the caracterisation of triple negative patients. In ETs they were mostly women (76.9%), particularly for ET patients under 50 years old that were almost exclusively women (27/28). In MF, triple negative patients presented a low hemoglobin concentration (8.85 g/dl) and a low leukocyte count (1.995 x 109/l). A striking characteristic is their platelet count, which was significantly lower than their group mates either in ET or in MF. This lower platelet count may suggest that in the general population, putative asymptomatic triple negative ET male patients could be retrieved, which would only be diagnosed at more advanced age with a symptomatic MF. Taken together, our results underline the differences between the two most frequent types of CALR mutation and show that CALR mutated patients should not be considered as a single entity. Disclosures No relevant conflicts of interest to declare.

Platelet Count Is an IPSS-Independent Risk Factor Predicting Survival in Refractory Anemia with Ringed Sideroblasts.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2455-2455
Author(s):  
Shanique R. Palmer ◽  
Ayalew Tefferi ◽  
David P. Steensma
Keyword(s):  
Platelet Count ◽  
Mayo Clinic ◽  
Proportional Hazards ◽  
Pearson Correlation ◽  
Univariate Analysis ◽  
Hazard Ratio ◽  
Refractory Anemia ◽  
Type I ◽  
Ringed Sideroblasts ◽  
Platelet Mass

Abstract Background: We sought to validate the International Prognostic Scoring System (IPSS) for myelodysplastic syndromes (MDS) in a well-characterized group of patients with refractory anemia with ringed sideroblasts (RARS), as well as to assess the validity of novel and easily obtained prognostic factors such as complete blood count (CBC) parameters. For instance, Bowles and colleagues (Br J Haematol2006; 135: 198) recently reported that a low platelet mass (i.e., mean platelet volume (MPV) x platelet count &lt;0.60 mL/L) is a marker for poor survival (median, 5 months) in patients with MDS, and also asserted the MPV and platelet count do not correlate so the MPV provides independent prognostic information. Because platelet parameters have been of particular interest in RARS, especially with respect to the provisional entity RARS with thrombocytosis (RARS-T), we assessed the prognostic relevance of MPV and platelet count/mass in this MDS subtype. Methods: We analyzed all pts diagnosed with RARS by FAB criteria at Mayo Clinic between 1994 and 2002, a period chosen because it was the interval when the MPV was routinely reported along with CBCs at our center. We excluded pts who were evaluated at Mayo Clinic &gt;6 months after initial diagnosis or were being treated for other malignancies (e.g., lymphoma or myeloma). Medical records, blood parameters, bone marrow findings, and cytogenetic results were reviewed. We performed time-to-event analysis using Kaplan-Meier estimates and Cox proportional hazards modelling, with Chi-Square statistics to assess significance (i.e., type I error rate &lt;0.05). Results: A total of 127 pts (79 males; median age 73 years, range 51-90) were identified, with 78 verified events during the follow-up period. The median survival was 3.9 years. The correlation between MPV and platelet count was poor (Pearson correlation coefficient, -0.18). Platelet count was low in 26 pts, within the normal range in 93 pts, and elevated in 8 pts (but &gt;600 ×109/L in only 2). In univariate analysis, lower Hb, lower MCV (but not MPV), higher total white count, lower platelet count, abnormal cytogenetics, and higher IPSS score each predicted poorer survival. In multivariate analysis using a proportional hazards model, only the platelet count (hazard ratio 0.93 for each increase in count by 25, 95% confidence interval (CI) 0.88-0.98, p=0.0055) and IPSS score (hazard ratio 7.7 for each increase in IPSS score by 1, 95% CI 4.1-14.4, p&lt;0.0001) remained independently predictive of survival. Relatively few patients with RARS have either low platelet mass (&lt;0.60 mL/L, 8%) or intermediate platelet mass (0.60-1.20 ml/L, 12%) as defined by Bowles et al. While the platelet mass was indeed predictive of survival (p&lt;0.0001), this was due entirely to the platelet count, and there was no additional information from the MPV. Conclusion: The IPSS is an excellent predictor of survival in pts with RARS, and the quantitative platelet count adds independent information. The MPV has no additional effect on survival in patients with RARS.

Mutations of TET2 and JAK2 but Not CBL Are Detectable in a High Portion of Patients with Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1766-1766
Author(s):  
Johanna Flach ◽  
Sonja Schindela ◽  
Frank Dicker ◽  
Susanne Schnittger ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Stop Codon ◽  
Myeloproliferative Neoplasms ◽  
Premature Stop Codon ◽  
Jak2v617f Mutation ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Myeloid Malignancies ◽  
Ring Sideroblasts ◽  
Equity Ownership

Abstract Abstract 1766 Poster Board I-792 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) forms a provisional entity within the category of MDS/MPN-U in the 2008 WHO classification. Although the identification of the JAK2V617F mutation was an important first step in distinguishing this entity from other hematological diseases, further genetic characterization is necessary. We performed comprehensive cytogenetic and molecular genetic investigations including targeted analysis of JAK2V617F, TET2, MPLW515 and CBL, markers known to be altered in MPN, as well as genome-wide single nucleotide polymorphism microarray analysis (SNP-A) in 23 RARS-T patients who fulfilled WHO 2008 diagnostic criteria. The JAK2V617F mutation was detectable in 15 out of 19 analyzed patients (78.9%), four of which were homozygous. However, our patients neither carried a MPLW515 mutation nor mutations in exons 8 or 9 of CBL genes. These genes were recently described to be mainly mutated in myeloproliferative neoplasms. In addition, conventional cytogenetic analysis did not reveal any recurrent cytogenetic abnormalities in RARS-T patients. We also performed SNP microarray analysis in a subset of 10 RARS-T patients. Although we did neither observe recurrent chromosomal gains or losses nor recurring regions of UPD, one patient showed a deletion spanning a 1.3 Mb region on the long arm of chromosome 4 (start: 105,497,200 bp from pter; end: 106,825,780 bp from pter). The deleted region contained TET2, a gene recently found to be altered in many subtypes of myeloid malignancies. To further clarify the 4q24 deletion detected by SNP-A analysis we performed fluorescence in situ hybridization (FISH). 20 out of 100 analyzed interphase nuclei and three metaphases showed only one signal for the probe spanning the TET2 gene in this patient. Interphase FISH with the TET2 probe was performed in nine additional cases not analyzed by SNP arrays due to a lack of material, but no additional case showing a deletion was detected. In addition to FISH, we performed TET2 sequencing in 19/23 RARS-T patients. TET2 mutations were detected in 5/19 patients (26%), of which 3/5 also presented the JAK2V617F mutation, whereas the remaining 2/5 did neither show JAK2V617F nor MPL nor CBL mutations. The five patients showed 6 individually different TET2 mutations. Three were nonsense and two missense mutations. One patient displayed a frameshift mutation leading to a premature stop codon. In summary, RARS-T patients demonstrated a high frequency of both JAK2 and TET2 mutations. Together with the less common MPL mutations described by others RARS-T presents a variety of mutations that overlap with the spectrum of mutations seen in MPN and other myeloid malignancies. Thus, a combination of molecular markers including JAK2 and TET2 should be investigated to more precisely describe RARS-T as an independent disease entity. Disclosures Flach: MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

In BCR-ABL1 Negative Myeloproliferative Neoplasms the Detection of JAK2exon12, MPLW515, CBL, KITD816V, FIP1L1-PDGFRA Mutations Are Closely Linked to Specific Entities, Whereas the JAK2V617F, TET2, or EZH2 Mutations Demonstrate a Broader Diversity: Patterns From Diagnostic Reports of 18,547 Patients Analyzed

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 458-458
Author(s):  
Susanne Schnittger, ◽  
Christiane Eder ◽  
Frank Dicker ◽  
Vera Grossmann ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Hematologic Malignancy ◽  
Rare Event ◽  
Jak2v617f Mutation ◽  
Patient Specific ◽  
Second Step ◽  
Double Positive ◽  
Employment Equity ◽  
Equity Ownership ◽  
Diagnostic Work

Abstract Abstract 458 The first mutation detected in BCR-ABL1 negative myeloproliferative neoplasms (MPN) was JAK2V617F that revolutionized diagnostics of MPN during the last five years. However, although this genetic marker is useful to discriminate MPN from reactive disorders, it is not specific for one entity. In addition, approximately 5% of all polycythemia vera (PV) and 50% of essential thrombocytosis (ET) and primary myelofibrosis (PMF) are not JAK2V617F mutated. In these entities other activating mutations, e.g. MPLW515 mutations or JAK2exon12 mutations, cover additional small proportions of patients without JAK2V617F mutation. To further improve the molecular genetic characterization of MPN research focuses on the identification of novel mutations and, recently, CBL, TET2, and EZH2 genes were identified to be mutated in MPN. We here report on our single centre experience in applying these markers in a daily diagnostic work flow comprizing a total cohort of 18,547 cases with suspected MPN that were investigated between 8/2005 und 8/2010 with individual patient specific combinations of these markers as soon as published. Thus, the most frequently tested marker was JAK2V617F that was applied in 17,027 pts. In 6,622/17,027 (38.9%) a definite diagnosis of MPN could be made or confirmed on the basis of the detection of JAK2V617F mutation. More detailed, the percentage of JAK2V617F positive cases varied depending on the suspected diagnoses: In patients with cytomorphologically confirmed or suspected ET 581/891 (65.2%) were JAK2V617F positive, in PMF: 168/290 (57.9%), in PV: 800/942 (84.9%), in MPN-U: 51/212 (24.0%), in CMML: 38/383 (9.9%), in “MPN” not further specified by the referring physician: 4741/11249 (42.1%), and in those with unexplained leukocytosis/thrombocytosis/splenomegaly or suspected hematologic malignancy: 139/2492 (5.6%). Many of the before mentioned cases were suspected MPN and therefore analyzed for both JAK2V617F and BCR-ABL1. Thus, in 9,924 pts BCR-ABL1 and JAK2V617F testing were performed in parallel. As such, in 541/9,924 (5.5%) analyses BCR-ABL1 positive CML was identified and 3,558 cases were JAK2V617F mutated (35.9%). Only 8 pts were BCR-ABL1/JAK2V617F double positive (0.08%), thus this is a very rare event. In cases with JAK2V617F negative PV in a second step JAK2exon12 mutation was analyzed and 27/147 (18.3%) were tested positive. JAK2V617F negative ET or PMF were analyzed in a second step for MPLW515 mutations. In ET 24/258 (9.3%) and in PMF 14/164 (8.5%) cases were tested positive. JAK2exon12 or MPLW515 were never concomitantly detected with JAK2V617 in our cohort (parallel assessments: n=3,769). PCR for detection of FIP1L1-PDGFRA was performed in 1,086 cases with suspected HES/CEL or unclear eosinophilia but only 26 (2.4%) were tested positive and a CEL could be diagnosed. However, in 36/130 (27.7%) FIP1L1-PDGFRA negative cases a KITD816V mutation was detected and thus a diagnosis of mastocytosis could be established. In addition, confirmation of mastocytosis was achieved in further 326/731 (44.6%) pts with suspected mastocytosis, three of these pts had a JAK2V617F mutation in addition. Further analyses were recently done on selected well characterized cohorts of MPN: CBL mutations were analyzed in 623 cases and tested positive in 54 (8.7%): 26/199 CMML (13.0%), 1/25 PMF, 27/293 MPN-U (9.2%), but never were detected in ET (n=61) or PV (n=45). TET2 sequencing detected mutations in 56/191 (29.3%) of pts analyzed: ET: 6/28 (21.4%), PMF: 4/12 (33.3%), PV: 10/31 (32.3%), CMML: 17/22 (77.3%) cases, MPN-U: 17/86: (19.8%), HES: 1/9 cases, Mastocytosis: 1/3 cases. Thus, TET2 mutations are widely spread in different entities and were frequently associated with other mutations: JAK2V617F: n=16, JAK2exon12: n=1, MPLW515: n=2, CBL: n=5, FIP1L1-PDGFRA: n=1, KITD816V: n=1, and EZH2: n=2. Finally, EZH2 sequence analysis detected mutations in 4/68 (5.9%) cases (1/16 PV, 2/11 PMF, 1/17 MPN-U, 0/20 ET, 0/4 CEL). In conclusion, these data show that the analysis of molecular mutations greatly improved the diagnostic work up of MPN in the last 5 years. The detection of some mutations (JAK2exon12, MPLW515, CBL) are useful to further subclassify MPNs. Others (JAK2V617F, TET2, EZH2) are widely distributed and are helpful for classification and also to discriminate MPN from reactive disorders. The individual power of each marker for prognostication in MPN remains to be defined in future studies. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Eder:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Final Results of Open-Label Treatment with Eltrombopag During ENABLE 1: A Study of Eltrombopag As An Adjunct for Antiviral Treatment of Hepatitis C Virus Associated with Thrombocytopenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2232-2232 ◽  
Author(s):  
Geoffrey Dusheiko ◽  
Nezam H Afdhal ◽  
Edoardo Giannini ◽  
Pei-Jer Chen ◽  
Kwang-Hyub Han ◽  
...  
Keyword(s):  
Platelet Count ◽  
Hepatitis C ◽  
Research Funding ◽  
Antiviral Treatment ◽  
Treatment Phase ◽  
Open Label ◽  
Employment Equity ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 2232 Introduction: Thrombocytopenia (TCP) is a common complication of cirrhosis in patients with hepatitis C virus (HCV) infections (Louie et al 2011); the presence of TCP impairs the ability to initiate peginterferon alpha (PEG) therapy and necessitates PEG dose reduction or discontinuation, thus reducing the potential for sustained virologic response (SVR). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic immune thrombocytopenia, increases platelet counts in patients with TCP due to HCV-related cirrhosis (McHutchison et al 2007). ENABLE 1 was a phase 3, multicenter, two-part study of eltrombopag for the treatment of HCV-associated TCP. Part 1 involved open-label, pre-antiviral treatment with eltrombopag. Patients achieving platelet counts ≥90,000/μL were randomized in Part 2 to receive eltrombopag or placebo in combination with antiviral therapy (PEG-2a plus ribavirin). Aim: To assess the safety and efficacy of eltrombopag during the open-label, pre-antiviral treatment phase (Part 1) of ENABLE 1 in patients with cirrhosis. Methods: Patients with chronic HCV and a baseline platelet count <75,000/μL were enrolled. In Part 1, all patients received open-label oral eltrombopag (25 mg daily with dose escalations every 2 weeks to a maximum dose of 100 mg) for up to 9 weeks or until platelet counts reached ≥90,000/μL. Patients who failed to achieve platelet counts ≥90,000/μL following 3 weeks of eltrombopag 100 mg daily did not enter Part 2 and attended scheduled follow-up visits. Patients achieving these counts were randomized 2:1 to eltrombopag or placebo (Part 2) at the final dose received in Part 1, in combination with antiviral therapy for up to 48 weeks. Results: A total of 716 patients were enrolled; 1 patient withdrew due to a protocol deviation, and 715 entered the open-label pre-antiviral phase. At study entry, most patients were male (62%) and Caucasian (72%); 17% were of Japanese/East Asian heritage. The median age was 52 years (range, 19–76). 488 patients (68%) had cirrhosis (FibroSURE™ score equivalent to METAVIR F4). The median duration of treatment during Part 1 was 20 days and the median of the mean daily dose was 25 mg (range, 0.8–75 mg). Median baseline platelets were 59,000/μL; these increased to 89,000/μL by week 2 and remained consistently elevated throughout open-label treatment (Figure). Following a median of 2 weeks of treatment (range, 0.1–9.6 weeks), 691 patients (97%) achieved platelet counts ≥90,000/μL. Treatment was discontinued during Part 1 for 33 patients (5%): platelets <90,000/μL (11); adverse events (AEs, 9); investigator discretion (7); patient decision (3); loss of follow-up (2); or a protocol deviation (1). During Part 2, 682 patients (95%) were randomized, 2 patients withdrew consent following randomization, and 680 patients (95%) initiated antiviral treatment. Of the patients who initiated treatment, 451 (66%) did so within 2 weeks and 627 (92%) did so within 4 weeks. The most common AEs observed during the open-label treatment phase were headache (7%), fatigue (4%), nausea (3%), and diarrhea (3%). Ninety-five patients (13%) experienced platelet counts >200,000/μL. No thromboembolic events were observed during open-label treatment. Conclusions: Eltrombopag was generally well-tolerated and resulted in sustained increase in platelet counts during the open-label, pre-antiviral treatment phase. Platelet count increases were seen as early as 2 weeks following initiation of treatment. The vast majority of patients (97%) achieved platelet count increases to ≥90,000/μL, the threshold for initiating PEG-2a plus ribavirin therapy, and most did so within 4 weeks of initiating eltrombopag treatment. Disclosures: Dusheiko: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Off Label Use: Eltrombopag, inteferon and Ribavirin; eltrombopag is a thrombopoetin receptor agonist. Its efficacy and safety in raising platelet counts in hepatitis C positive patients (most with cirrhosis) and thrombocyotopaenia was studied in this protocol. Afdhal:Merck: Consultancy, Honoraria, Research Funding; Vertex: Consultancy, Honoraria, Research Funding; Idenix: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Springbank: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmasett: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding. Giannini:GlaxoSmithKline: Consultancy, Speakers Bureau; Hoffman-LaRoche: Consultancy, Speakers Bureau. Chen:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Geib:GlaxoSmithKline: Employment. Vasey:GlaxoSmithKline: Employment. Patwardhan:GlaxoSmithKline: Employment, company shares. Campbell:GlaxoSmithKline: Employment, Equity Ownership. Theodore:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

In Myelodysplastic/Myeloproliferative Neoplasms Aberrant Antigen Expression As Assessed by Multiparameter Flow Cytometry Is Related to Molecular Genetic Mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5152-5152
Author(s):  
Wolfgang Kern ◽  
Susanne Schnittger ◽  
Tamara Alpermann ◽  
Claudia Haferlach ◽  
Torsten Haferlach
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Molecular Genetic ◽  
Antigen Expression ◽  
Multiparameter Flow Cytometry ◽  
Employment Equity ◽  
Aberrant Expression ◽  
Equity Ownership ◽  
Diagnostic Work ◽  
Work Up ◽  
Diagnostic Work Up

Abstract Abstract 5152 Background: Immunophenotyping by multiparameter flow cytometry (MFC) is increasingly used in the diagnostic work-up of patients with cytopenias and suspected myelodysplastic syndromes (MDS). Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise a group of diseases with some features of MDS and is separately classified in the current WHO system. While the immunophenotype of chronic myelomonocytic leukemia has been described in detail, data is scarce on the use of MFC in myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPNu) as well as on refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), which is a provisional entity in the current WHO classification. Aim: To assess patients with MDS/MPNu and RARS-T for MDS-related aberrant immunophenotypes in the context of a comprehensive diagnostic work-up including cytomorphology, cytogenetics, and molecular genetics. Patients and Methods: A total of 91 patients were analyzed in parallel by cytomorphology, cytogenetics, and MFC applying an antibody panel designed to diagnose MDS. MFC was used to detect expression of mature antigens in myeloid progenitors; abnormal CD13-CD16- and CD11b-CD16-expression patterns, aberrant expression of myeloid markers and reduced side scatter signal in granulocytes; reduced expression of myelomonocytic markers in monocytes; aberrant expression of CD71 in erythroid cells; as well as expression of lymphoid markers in all myeloid cell lines. In 77/91 patients molecular genetic markers were investigated. The median age of the patients was 75.1 years (range, 35.3–87.4). The male/female ratio was 60/31. Six patients had RARS-T and 85 had MDS/MPNu. Results: In 54/91 (59.3%) patients MFC identified an MDS-immunophenotype. This was true in 4/6 (66.7%) RARS-T and in 50/85 (58.8%) MDS/MPNu (n.s.). Cases with MDS-immunophenotype displayed aberrancies significantly more frequently than those without as follows: in myeloid progenitor cells (number of aberrantly expressed antigens, mean±SD: 0.5±0.6 vs. 0.2±0.4, p=0.002), granulocytes (2.7±1.3 vs. 1.2±1.1, p<0.001), and monocytes (1.7±1.2 vs. 0.5±0.7, p<0.001). Accordingly, there was a significant difference in the total number of aberrantly expressed antigens (4.9±2.4 vs. 2.0±1.4, p<0.001). The presence of an aberrant karyotype was not related to an MDS-immunophenotype which was observed in 11/18 (61.1%) cases with aberrant karyotype and in 43/73 (58.9%) with normal karyotype (n.s.). Mutations in RUNX1 and TET2 as well as FLT3-ITD were predominantly present in cases with an MDS-immunophenotype (10/33, 30.3%) and occurred less frequently in cases without (1/7, 9.1%, n.s.). In detail, RUNX1 mutations were present in 4/26 (10.3%) vs. 0/2, TET2 mutations were present in 4/6 (66.7%) vs. 1/2 (50%), and FLT3-ITD was present in 3/29 (10.3%) vs. 0/5. Accordingly, in cases with RUNX1 or TET2 mutations or with FLT3-ITD a significantly higher number of aberrantly expressed antigens was observed as compared to cases with none of these mutations (mean±SD, 6.4±2.0 vs. 4.4±2.5, p=0.024). In contrast, JAK2V617F mutations occurred at identical frequencies in patients with and without MDS-immunophenotype (11/38, 28.9% vs. 9/31, 29.0%). Regarding prognosis, the presence of an MDS-immunophenotype had no impact on overall survival. Conclusions: These data demonstrates that MDS-related aberrant antigen expression is present in the majority of patients with RARS-T and MDS/MPNu. While there is no association between the presence of an MDS-immunophenotype and the detection of JAK2 mutations cases with an MDS-immunophenotype tended to more frequently carry mutations in RUNX1 and TET2 as well as FLT3-ITDs. These data therefore suggests that MDS/MPNu may be subdivided based on molecular genetics and on the immunophenotype into cases with MDS-related features and those without. Further analyses are needed to validate these findings and their potential significance in RARS-T. Disclosures: Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Undertreatment of Patients (Pts) with Myelodysplastic Syndromes (MDS): Analysis of a Large Electronic Medical Records (EMR) Database Cohort of US Pts with MDS

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4768-4768 ◽  
Author(s):  
David P. Steensma ◽  
Bart L Scott ◽  
Xiaomei Ma ◽  
Albert Fliss ◽  
Pavel Kiselev ◽  
...  
Keyword(s):  
Platelet Count ◽  
Iron Chelation ◽  
International Classification Of Diseases ◽  
Initial Therapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Care Patterns ◽  
The Usa ◽  
Equity Ownership

Abstract Introduction: Little is known about current care patterns for pts with MDS across the US with respect to the use of available therapeutic agents. Using a cohort of 5,162 MDS pts we previously identified from the GE Centricity EMR database (GE Healthcare IT, Princeton, NJ) (Ma X, et al. Blood. 2015;126:abstract 3319), we examined associations between pt characteristics and treatment patterns, including sequence of therapies for pts with MDS. Methods: Pts with data in the EMR from Jan 2006 to end of Feb 2014 were included in this analysis. Pts were grouped by treatment received (erythropoiesis-stimulating agents [ESA], lenalidomide [LEN], hypomethylating agents [HMA; azacitidine or decitabine], and iron chelation therapy [ICT]), either alone, in combination, or as part of a sequence with other therapies. Transfusions were not included in this analysis, as transfusion data were often unrecorded due to transfusions occurring in facilities outside the EMR system. Pt characteristics were evaluated for each treatment group. Results: Of 5,162 pts evaluated, 1,843 (35.7%) received only 1 therapy, 2,079 (40.3%) received ≥ 1 therapy, with only 236 (4.6%) receiving ≥ 2 therapies. Pts who received ≥ 1 treatment of interest are shown in the Figure. Baseline characteristics for treatment groups are shown in the Table. A total of 85 pts were recorded as having deletion 5q by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding; of these, 66 were recorded as receiving ≥ 1 treatment. Pts were in the EMR system for a median of 29 days (date of first entry to date of last entry), with 36%, 26%, and 15% of pts present in the system for > 6 months, 1 year, and 2 years, respectively. The most common initial therapy was ESA (n = 1,508; 72.5% of treated pts). Pts treated with ESA first had a median age of 78.0 years; 1,330 (88%) received ESA exclusively. ESA-only pts were the oldest among the treatment groups (median age 79.0 years), had the highest proportion with comorbidities at baseline (69%), and most commonly had isolated anemia. Only a small proportion of pts treated with ESA first subsequently received LEN (n = 79; 5.2%) or HMA (n = 68; 4.5%) as second therapy; median ages of these patients were 76.0 and 73.5 years, respectively. 682 pts (32.7% of treated pts) received a therapy approved specifically for MDS, i.e. HMA and/or LEN, during their treatment. Pts who received LEN as first treatment (n = 258; 12.4% of treated pts) had a median age of 74.0 years. These pts had a lower median hemoglobin (Hb), lower median absolute neutrophil count (ANC), and similar median platelet count vs pts receiving ESA as first treatment. Most pts who received LEN as their first therapy received it exclusively (244; 94.6% of treated pts); a small number (n = 14) were subsequently treated with HMAs. Pts who received LEN second (n = 99) or third (n = 13) in a sequence of therapies were similar in age (median 76.0 and 74.0 years, respectively) and had similar Hb levels, higher ANCs, and higher platelet counts at baseline than pts who received LEN as first therapy. Most pts (n = 79; 80%) who received LEN as second therapy previously received ESA. Of 252 pts (12.1% of treated pts) who received HMA as first therapy, 228 (90.4%) received HMA only; median age of patients who received HMAs as first therapy was 75.0 years, and median Hb level, median ANC, and median platelet count were lower than in pts who received ESA as first therapy. Another 100 pts and 28 pts received HMA as second and third therapies, respectively; median age was 73.0 years in each group. Pts receiving HMA third had higher median Hb level, ANC, and platelet count than pts who received HMA as first therapy. Only 61 pts (2.9% of treated pts) received ICT as first therapy. Conclusions: Pts diagnosed with MDS in the USA are likely to be undertreated. Consistent with findings from physician surveys (e.g. Sekeres M., et al. J Natl Cancer Inst. 2008;100:1542-51), ESAs are the most commonly used therapies despite the lack of a labeled indication for MDS. ESAs are usually the first therapy chosen by physicians and often the only therapy pts with MDS receive. Use of LEN and HMA, which have been approved for the treatment of MDS for ~10 years, appears low in this EMR. Disclosures Steensma: Genoptix: Consultancy; Celgene: Consultancy; Millenium/Takeda: Consultancy; Ariad: Equity Ownership; Amgen: Consultancy; Janssen: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ma:Celgene Corporation: Consultancy. Fliss:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Sugrue:Celgene Corporation: Employment, Equity Ownership.

scholarly journals Population Pharmacokinetic (PK)/Pharmacodynamic (PD) Modeling of Myelosuppression in Patients with Hematologic Malignancies for CPX-351 and Standard-of-Care 7+3 Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4037-4037
Author(s):  
Qi Wang ◽  
Sarah F. Cook ◽  
Scott A. Van Wart ◽  
Donald E. Mager ◽  
Stefan Faderl
Keyword(s):  
Platelet Count ◽  
Median Time ◽  
Median Duration ◽  
Model Development ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Compartment Models ◽  
Platelet Counts ◽  
Population Pk ◽  
Equity Ownership

Abstract CPX-351 (Vyxeos®), a liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, has demonstrated a significant survival benefit vs standard 7+3 in patients (pts) with high-risk/secondary AML. A population PK/PD analysis assessed the correlation between cytarabine and daunorubicin plasma concentrations and myelosuppressive effects (neutropenia, thrombocytopenia) of CPX-351 and 7+3. The PK/PD population for model development included pts with advanced hematologic malignancies from 3 clinical studies. For CPX-351 and 7+3, respectively, 129 and 79 pts were included in the final neutropenia PK/PD analysis and 137 and 86 pts were included in the final thrombocytopenia PK/PD analysis. For the neutropenia model, median age and body weight were 67 y (range: 23-81) and 78.7 kg (39.5-156.5) for CPX-351 and 68 y (60-75) and 83.0 kg (53.9-136.0) for 7+3. PK/PD analyses were conducted using nonlinear mixed-effects modeling in NONMEM. Pt-specific PK profiles were simulated using previously developed population PK models for CPX-351 and 7+3. Blood cell dynamics were described by transit-compartment models with proliferating, maturating, and circulating neutrophils or platelets. The effects of CPX-351 or 7+3 were applied to the proliferation phases of the compartment models by a molar composite PK driver (plasma cytarabine + daunorubicin). Inhibition of proliferation of blood cells by CPX-351 and 7+3 is assumed to be similar, via a sigmoidal Imax function. Co-medication of granulocyte colony stimulating factor (GCSF) or platelet infusion was accounted for during model development. Covariates (eg, demographics, clinical laboratory measures, disease status) were evaluated. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and graphical representations of goodness-of-fit. In the final neutrophil PK/PD models, baseline circulating neutrophil counts were similar for CPX-351 (3.55 × 109/L) and 7+3 (3.76 × 109/L). Mean transit times (MTT) between maturation compartments were estimated at values of 113 h for CPX-351 and 88 h for 7+3. Effects of GCSF on neutrophil production were assumed to be similar for CPX-351 and 7+3. Both treatments had similar maximum inhibition on neutrophil proliferation, with Imax values around 1. However, estimated IC50 values were very different: 24.9 µM for CPX-351 and 0.0286 µM for 7+3. In the final platelet PK/PD models, baseline circulating platelet counts were the same (98.1 × 109/L) for both CPX-351 and 7+3. The MTTs between each compartment of the maturation processes were 91.2 h for CPX-351 and 120 h for 7+3. Drug-specific parameters for CPX-351 and 7+3, respectively, were as follows: Imax, 0.316 and 1; IC50, 0.324 and 0.0982 µM. To better understand the behavior of the models and parameter estimates, simulations were conducted to evaluate the temporal events of myelosuppression. Model simulations were conducted for 200 pts with characteristics similar to the PK/PD model population. During simulations, no platelet transfusion or GCSF was administered. Pts received CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) as a 90-min IV infusion on Days 1, 3 and 5 or 7+3 (cytarabine 100 mg/m2/day IV for 7 days continuously + daunorubicin 60 mg/m2 IV on Days 1-3). Median time to initially observe a blood neutrophil count <0.5 × 109/L was longer following CPX-351 (8.3 d) vs 7+3 (7.4 d) treatment. The median duration with neutrophil counts <0.5 × 109/L was longer with CPX-351 (23 d) vs 7+3 (14 d). The median lowest neutrophil counts were well below 0.2 × 109/L for both CPX-351 (0.007 × 109/L) and 7+3 (0.026 × 109/L). Median time to initially observe a platelet count <50 × 109/L was 6.4 d after CPX-351 and 5.8 d after 7+3, while the median time to an observed platelet count <20 × 109/L was 10.8 d and 8.9 d, respectively. The median duration with platelet counts <20 × 109/L was longer with CPX-351 (18 d) vs 7+3 (8 d), and the median duration of platelet counts <50 × 109/L was 22 d and 15 d, respectively. The median lowest platelet counts were 11.3 × 109/L with CPX-351 and 4.7 × 109/L with 7+3. In summary, the median duration of myelosuppressive effects was longer with CPX-351 than 7+3, and the median time for initial detection of myelosuppression with CPX-351 was 1 to 2 days later than with 7+3, which might affect the clinical monitoring scheme. Disclosures Wang: Jazz Pharmaceuticals: Employment, Equity Ownership. Cook:Jazz Pharmaceuticals: Consultancy. Van Wart:Jazz Pharmaceuticals: Consultancy. Mager:Jazz Pharmaceuticals: Consultancy. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership.

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