Factors Affecting Survival Outcomes in Patients with Blast Phase CML (CML-BP) in the Tyrosine Kinase Inhibitor (TKI) Era: A Cohort Study of 498 Patients

Abstract Introduction: TKIs have changed the natural history of CML with a markedly reduced risk of transformation to CML-BP. However, some patients (pts) become resistant to therapy and progress and a few pts present with CML-BP at diagnosis. In this study, we have identified the clinical characteristics, prognostic factors and outcome of pts with CML-BP from a single center cohort of pts treated with a TKI at some point during the course of their disease. Methods: We analyzed all CML pts diagnosed with CML-BP (defined as ≥30% blasts or extramedullary disease) from 07/1997 to 07/2015. Among a total of 498 pts included with CML-BP, 302 presented to MDACC already in BP (of whom 72 had BP at the time of initial diagnosis, in many instances prior to referral to MDACC); 84 presented in accelerated phase (AP) and later progressed, and 112 presented in chronic phase (CP) and progressed to BP. All pts were enrolled in clinical trials with different TKI/non-TKI based therapies. Clinical characteristics were collected at the time of initial presentation to MDACC in BP. Failure free survival (FFS) and overall survival (OS) were defined from the time of initial presentation to MDACC to treatment failure/death, respectively. Results: Median age for all 498 pts was 52 years (range, 2 to 84); 63% were male and 64% were Caucasian. Median time from initial diagnosis to BP was 36 months (0.4 to 298 months) for all pts excluding the 72 pts who were already in BP at diagnosis; median time from AP to BP (n=160) was 14 months (0.3-161). Immunophenotype was myeloid in 67%, lymphoid in 29%, mixed lineage in 3%, biphenotypic in 1% and megakaryocytic in 0.2%. Sixty-one percent of pts had additional chromosomal abnormalities besides the Ph chromosome, including double Philadelphia (17%), iso17q (7%), trisomy 8 (16%), chromosome 3 aberration (11%), del7q (8%), and trisomy 19 or 21 (4% each). Six percent of pts had a variant Ph. BCR-ABL mutation screening was performed in 174 pts at the time of BP, with mutations identified in 68 (39%), most commonly T315I (n=24) and E255K (n=13). Extramedullary (EMD) BP was detected in 26% pts, the most common being CNS involvement in 39% pts with EMD. Eighty-four percent had received one or more TKI by the time of transformation. The median OS was 12 months (10 months for myeloid and 17 months for lymphoid) and median FFS was 5 months. In univariate analysis, factors significantly associated with inferior OS were older age, high bone marrow blast %, female gender, lower hemoglobin, higher LDH, presence of trisomy 19 or chromosome 3 aberrations, prior TKI treatments, myeloid phenotype and prior AP (Figure-1 A-C). Recursive partitioning analysis revealed that age ≥56 years and LDH ≥888 were associated with increased risk of death. In multivariate analysis (MVA), adjusting for the above variables, age ≥ 56 yrs (HR=1.73, p<0.001), prior TKI (HR=1.53, p=0.02), LDH ≥888 (HR 1.56, p=0.002) and myeloid phenotype (HR=1.67, p<0.001) were significantly associated with inferior OS. We then analysed FFS in pts with information available on their initial therapy for BP (n=319). As for OS, myeloid phenotype and prior TKI therapy were predictive of inferior FFS by MVA. In a subset analysis, with only pts with EMD, presence of CNS involvement (vs other EMD) and advanced age were associated with inferior OS while high LDH and prior TKI therapy predicted for inferior FFS. Conclusions: Despite progress in therapy for CML, those who transform to CML-BP have a dismal outcome, particularly if previously treated with TKI. Patients with age ≥ 56, LDH ≥ 888 and those pts with myeloid phenotype had the worst outcomes. Better treatment options are needed for this small but poor prognosis subset of patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Wierda:Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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Clinical Characteristics of Philadelphia Positive T-Cell Lymphoid Leukemias - (de novo and blast phase CML)

Blood ◽

10.1182/blood.v128.22.5436.5436 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5436-5436

Author(s):

Preetesh Jain ◽

Hagop M. Kantarjian ◽

Elias J. Jabbour ◽

Rashmi Kanagal-Shamanna ◽

Keyur P. Patel ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Clinical Characteristics ◽

De Novo ◽

Initial Diagnosis ◽

The Other ◽

Initial Presentation ◽

Molecular Response ◽

Cns Involvement ◽

Blast Phase

Abstract Introduction: The Philadelphia chromosome (Ph+) is a hallmark of CML and is also present in a subset of patients with acute lymphoblastic leukemia (ALL). Lymphoid blast phase (CML-BP) and Ph+ ALL almost always affect B cell lineage. In this report, we present the clinical characteristics of the rare subset of patients with Ph+ ALL or CML-BP with T-cell lymphoid phenotype. Methods: We reviewed the institutional database for all patients with blast phase CML (n=498) and de novo T-ALL (n=150) diagnosed since 07/1997. All clinical characteristics at the time of the diagnosis of BP or Ph+ ALL were collected. Seven patients with Ph+ T-cell lymphoid leukemia were identified. Results: Among the total of 498 CML-BP patients, 5 patients had T-cell lymphoid CML-BP (0.01%); in addition 2 patients with de novo Ph+ T-ALL were identified among 150 patients with T-ALL seen during the same time period (1.3%). Median age of the seven patients was 57 years (range 31-72 years); 71% were male. Among patients with CML-BP, all were in BP at the time they were referred to MDACC (one had progressed from an initial diagnosis in CP, 1 from accelerated phase, and 3 were in BP at initial diagnosis). Only 2 patients with CML-BP received prior TKI therapy; the 2 patients with T-ALL were previously untreated at the time of referral. Immunophenotype included 2 cortical, 3 early T-cell and 2 early T-cell precursor; 2 patients were negative and one was dim positive for TdT (summarized in Table-1). Extramedullary disease at initial presentation was seen in all patients [2 with lymphadenopathy alone, 2 with mediastinal involvement (one also with lymphadenopathy and the other with splenomegaly and lymphadenopathy), 2 with pleural effusion (1 with lymphadenopathy and another with splenomegaly) and 1 patient with splenomegaly alone]. None had CNS involvement at initial presentation, but one patient developed CNS involvement at first relapse. One patient had variant Ph+ and 2 had complex karyotype. Three patients had lymphoblastic lymphoma and 4 patients had T-ALL. Five patients died (3 from disease progression, one from complications of SCT, and one from intestinal obstruction and sepsis) and 2 are alive (25 and 49 months from BP diagnosis). The median survival for all patients was 13 months (range 1-49 months). Five patients received hyper-CVAD based therapy as an induction regimen: 3 of them received hyper-CVAD alone - one achieved CR then underwent a SCT but died due to complications of SCT, another achieved PR and was given imatinib followed by dasatinib which he did not tolerate; he was subsequently lost to follow up; and one patient had no response. The other 2 patients received hyper-CVAD with dasatinib - one achieved PR, then underwent allo-SCT and achieved CR but later had a CNS relapse and progressed; the other patient developed nodal progression 9 months after achieving CR with HCVAD-dasatinib which was later found to represent metastatic prostate cancer in the lymph nodes with no T-ALL recurrence and is currently on dasatinib with major molecular response. Two patients never received any TKI therapy and progressed on chemotherapy alone. Two patients received nelarabine as first salvage - one as a single agent (no response) and another with dasatinib (with PR). Conclusions: Ph+ T-cell lymphoid leukemias are very rare and have clinical features similar to those of de novo T-ALL. Induction with a combination of HCVAD and TKIs may achieve prolonged remission in some patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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Factors Influencing Time from Initial Presentation to Start of Plasma Exchange (PEX) in Patients with Acute Thrombotic Thrombocytopenic Purpura (TTP)

Blood ◽

10.1182/blood-2020-133371 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Rory McCulloch ◽

Tom Bull ◽

Phillip LR Nicolson ◽

Rebecca J Shaw ◽

Zara Sayar ◽

...

Keyword(s):

Plasma Exchange ◽

Median Time ◽

Research Funding ◽

Advisory Board ◽

Initial Presentation ◽

Red Cell ◽

Cns Involvement ◽

Thrombocytopenic Purpura ◽

Time To Initiation ◽

Cell Fragments

Background: Acute Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening medical emergency and plasma exchange (PEX) is the only treatment shown to significantly impact acute mortality (Rock et al, N Engl J Med 1991). Diagnosis can be challenging and therein arrangements for PEX must be made, with most centers in the United Kingdom (UK) having to co-ordinate transfer to a tertiary site. To understand issues affecting practice the trainee research network HaemSTAR conducted a retrospective nationwide review of patients presenting to UK hospitals with TTP against British Society of Haematology clinical guidelines (Scully et al, B J Haem 2012). Analysis was conducted on the time from hospital presentation to initiation of treatment and impact on patient outcomes. Method: Adults ≥18 years presenting to hospital between 1st June 2014 and 1st June 2019 with first episode acute TTP and ADAMTS13 level <10% were identified by local clinicians. Anonymized data of baseline characteristics and treatment times was submitted via an online secure server. Time to PEX was defined as time from receipt of the first full blood count sample in the laboratory to time of plasma release for PEX from blood bank. Where patients were transferred between sites data was linked retrospectively. Results: Data on 148 patients treated at 80 UK hospitals was used for analysis (demographics table 1). 142 patients (96%) received PEX, 67 (47%) at site of presentation and 75 (53%) after hospital transfer. 6 patients died before receiving PEX. 37 patients (25%) received PEX within 8 hrs of hospital presentation, 91 patients (61%) within 24 hrs. 33 patients (22%) commenced PEX more than 48 hrs from presentation. The overall median time to PEX from initial presentation was 15 hours (95% CI 11.3-18.7). Availability of on-site PEX was associated with earlier treatment initiation with median time to PEX for those treated on site 10 hrs (95% CI 7.7-12.3) vs. 21 hrs (95% CI 16.8-25.2) for patients transferred. A blood film comment of red cell fragments significantly impacted time to treatment: in 24 cases with no fragments documented median time to PEX was 110 hrs (95% CI 39-181) vs. 10 hrs (95% CI 8.5-11.5) in cases where fragments were reported (fig 1). On univariate and multivariate analysis age <60 years, hemoglobin (Hb) <100 g/L, presence of fragments, PEX available on-site and admissions occurring after May 2017 were significant predictors for PEX initiation within 8 hrs. PEX within 24 hrs was associated with age <60 years, platelet count <30 x 109/L, Hb <100 g/L and presence of fragments only. The presence of cardiac and/or central nervous system (CNS) involvement was not predictive of time to initiation of PEX (table 1). 96 patients (62%) received steroids within 24 hrs of presentation, 98 of 128 patients with cardiac/CNS involvement (77%) received rituximab within 48 hrs and 12 patients (8%) received platelet transfusion in the absence of major bleeding. 19 patients (12%) died within 30 days of presentation (median time to death 10 days, range 0-23). In 7 of these cases (37%) a delay >24 hrs from presentation to diagnosis was reported despite presence of fragments in 4 cases. Mortality did not correlate with availability of on-site PEX. Discussion: This is the first multi-center record of time to treatment from initial presentation of acute TTP. Results comply with guidance for rapid initiation of PEX with 61% patients commencing within 24 hrs of presentation and, from June 2017, 34% of patients initiating PEX within 8 hrs. The recent increase in early PEX initiation correlates with initiatives to improve treatment pathway efficiency following diagnosis of TTP. Early use of steroids and rituximab correlated with earlier use of PEX indicating where timely diagnosis was made there was good compliance with guidelines. Inappropriate use of platelets appeared attributable to misdiagnosis. Older patients, those with higher platelet counts and Hb and absence of red cell fragments on film report were more likely to experience prolonged time to initiation of PEX. This does not appear related to PEX access, but most likely the difficulty of making TTP diagnosis in this cohort. That 22% of patients initiated PEX over 48 hrs from admission indicates the issue is relatively common and with several deaths occurring in this group we suggest initiatives to increase early diagnosis should be prioritised. Full contributor list: http://haemstar.org/flash-mob-audit-2019/ Disclosures McCulloch: Sanofi: Research Funding. Nicolson:Principia Biopharma: Research Funding; Novartis: Research Funding; Rigel pharmaceuticals: Research Funding; Bayer: Honoraria. Shaw:Octapharma: Research Funding. Scully:Alexion: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau.

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A Retrospective Cross Sectional Study of Clinical Characteristics and Prognostic Factors of Covid 19 Patients Admitted to a Gambian Teaching Hospital

10.21203/rs.3.rs-603762/v1 ◽

2021 ◽

Author(s):

Sheikh Omar Bittaye ◽

Abubacarr Jagne ◽

Abdoulie Badjan ◽

Babakunta Fofana ◽

Ebrima Barrow ◽

...

Keyword(s):

Diabetes Mellitus ◽

Prognostic Factors ◽

Oxygen Saturation ◽

Respiratory Rate ◽

Health Facility ◽

Teaching Hospital ◽

Clinical Characteristics ◽

Risk Of Death ◽

Increased Risk ◽

Lower Level Health Facility

Abstract Background: The first case of Novel coronavirus disease (COVID 19) was diagnosed in The Gambia on the 17th March 2020. We therefore investigate the clinical characteristics and prognostic factors of COVID 19 patients admitted at a Gambian teaching Hospital. Method: Out of 407 suspected COVID 19 patients, 137 (33.7%) tested positive for COVID 19 and were recruited. Clinical features, treatment and outcomes were recorded. Univariate and multivariate logistic regression analyses were used to assess prognostic factors of survival in our patients. Results: The median age of our patients was 60 years (19-100) and 86 (62.8%) were men. Eighty nine (64.9%) patients had co-morbidities, mostly Hypertension 51 (37.2%) and Diabetes Mellitus 47 (34.3%). The most common symptoms were cough 71 (51.8%) and dyspnea 53 (38.7%) and majority of patients presented with SPO ≤ 93% 75 (54.7%). Patients with SPO2 ≤ 93% were older 63.2 vs. 53.1 years (p=0.001), more likely to present with dyspnea (p=0.002), Cough (0.035), higher respiratory rate (p<0.001) and co-morbidities (p=0.009) compared to patients with SPO2>93%. Non survivors were older 63.2 vs 53.1 years (p=0.001), more likely to present with higher respiratory rate (p=0.014), lower oxygen saturation (p=<0.001), to be referred from lower level health facility (p=0.012) and to have Diabetes mellitus (p=0.007) as compared to survivors. Our cumulative mortality is 49 (35.8%) and mortality rate of patients referred from lower level heath facilities was 46 % as compared to 25 % for self referred patients. Multivariate analysis showed increasing odds of mortality independently associated with Age≥ 60 years (odd ratio, 2.87: 95% CI, 1.21 to 6.83, p=0.012), Diabetes mellitus (odd ratio, 3.47: 95% CI, 1.44 to 8.36, p=0.006), oxygen saturation ≤ 93% (odd ratio, 3.18: 95% CI, 1.27 to 7.99, p=0.014) and referral from lower level health facility (odd ratio, 2.87: 95% CI, 1.11 to 6.82, p=0.017).Conclusion: Older patients, patients with Diabetes Mellitus, hypoxemia or patients referred from lower level health facilities are at increased risk of death. In resource limited countries where critical care/emergency medicine resources are limited, our results may help guide the clinical management of patients with severe COVID-19.

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A Multicentre, Double-Blind, Randomized, Phase 2 Trial Comparing Pegfilgrastim with Filgrastim as an Adjunct to Chemotherapy for Acute Myeloid Leukaemia (AML).

Blood ◽

10.1182/blood.v104.11.866.866 ◽

2004 ◽

Vol 104 (11) ◽

pp. 866-866 ◽

Cited By ~ 4

Author(s):

Alberto Bosi ◽

Jeffrey Szer ◽

Jeannine Kassis ◽

Jorge Sierra ◽

Claire Desborough ◽

...

Keyword(s):

Median Time ◽

Induction Chemotherapy ◽

De Novo ◽

Severe Neutropenia ◽

Single Administration ◽

Serious Adverse Events ◽

Treatment Groups ◽

Risk Of Death ◽

Increased Risk ◽

Significant Difference

Abstract BACKGROUND: Heil et al (Blood ‘97) demonstrated that the duration of neutropenia and its clinical consequences following induction chemotherapy for AML were significantly reduced by the addition of filgrastim, with no increased risk of death, second malignancy or relapse (ASH ‘99). A single injection of pegfilgrastim has been shown to be comparable to daily injections of filgrastim in the management of chemotherapy-induced neutropenia. The primary aim of this trial was to estimate the difference in time to recovery from severe neutropenia (SN, ANC < 0.5 x109/L) in the first induction chemotherapy cycle (Induction 1) in AML subjects treated with pegfilgrastim or filgrastim. METHODS: Subjects with de novo AML received 1 or 2 courses of induction chemotherapy (idarubicin 12mg/m2 IV days 1–3, cytarabine 100mg/m2 IV 12 hourly days 1–7 [IA 3+7]) then, if in remission, consolidation chemotherapy (cytarabine 2 [subjects < 55 years] or 3g/m2 [subjects ≥ 55 years] IV 12 hourly days 1, 3, 5). Subjects received either single administration 6μg pegfilgrastim or daily 5μg/kg filgrastim starting 24 hours after completion of chemotherapy until neutrophil recovery. Time to recovery from SN was defined as the number of days from the first day of chemotherapy until the first of two ANC consecutive values after the nadir that were ≥ 0.5 x 109/L whereas duration of SN was defined as the total number of days during the cycle with an ANC < 0.5 x 109/L. RESULTS: Of 84 subjects randomised into the study, 83 received study drug (42 pegfilgrastim, 41 filgrastim). The treatment groups were generally well balanced for demographics and baseline characteristics. The median time to recovery from SN (ANC < 0.5 x109/L) in Induction 1 was 22 days in both treatment groups (95% CI for treatment difference: −1.9, 1.9). There was also no statistically significant difference in the median duration of SN between the 2 groups (21 days pegfilgrastim, 20 days filgrastim). Subjects in the filgrastim group required a median of 16 daily injections compared to a single administration of pegfilgrastim in the second group. Median serum concentration of pegfilgrastim in Induction 1 remained above clinically relevant concentrations until 21 days after the start of chemotherapy, results that are consistent with the neutrophil-mediated clearance of pegfilgrastim. The incidence of serious adverse events was comparable between the 2 groups except for infectious complications, which were higher in the filgrastim group (5 subjects [12%] pegfilgrastim versus 9 subjects [22%] filgrastim). CONCLUSION: In the setting of the first cycle of IA 3+7 induction chemotherapy in AML patients, once per cycle administration of 6 mg pegfilgrastim or daily administration of 5mg/kg filgrastim result in similar median time to recovery to ANC ≥ 0.5 x109/L. Pegfilgrastim is safe and well tolerated in this subject population.

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Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma: Analysis of Incidence and Prognostic Factors

Blood ◽

10.1182/blood.v124.21.1666.1666 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1666-1666

Author(s):

Masahiro Uni ◽

Yuki Kagoya ◽

Yasuhito Nannya ◽

Fumihiko Nakamura ◽

Mineo Kurokawa

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Initial Diagnosis ◽

High Dose ◽

Cns Involvement ◽

Large B Cell Lymphoma ◽

Cns Relapse ◽

Large B Cell

Abstract The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone) has significantly improved the outcome of diffuse large B-cell lymphoma (DLBCL). However, its secondary involvement in the central nervous system (CNS) is still a fatal event, and optimal therapeutic strategies have remained to be established. Combined immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine is currently in use for patients with CNS relapse, though treatment outcome has not been evaluated enough. In the present study, we aimed to analyze the incidence and prognosis of CNS relapse of aggressive B-cell lymphoma in comparison with those of systemic relapse in the era of rituximab-containing regimens. We also estimated the risk factors and prognostic factors for CNS relapse. We retrospectively analyzed 278 consecutive adult patients (≥16 years old) who were diagnosed as DLBCL or primary mediastinal large B-cell lymphoma (PMLBL) at The University of Tokyo Hospital, Tokyo, Japan, from August 2003 through August 2013. We excluded patients who had CNS or intraocular involvement at diagnosis since those patients had received high-dose methotrexate-based therapy instead of R-CHOP. Four to six courses of intrathecal administration of methotrexate were performed in patients with adrenal gland, testis or breast involvement as prophylaxis for CNS relapse. The median follow-up period was 42 months, and the median age was 66 years (range, 23-91). Overall, 67 patients (24.1%) had relapse at any site, of which 24 patients (35.8%) had CNS involvement. The median interval between initial diagnosis and the occurrence of secondary CNS involvement was 212 days, and 15 of the 24 patients (62.5%) had CNS relapse within 1 year from the initial diagnosis. Multivariate analysis revealed that multiple or diffuse extranodal involvement at initial diagnosis (hazard ratio [HR] 3.74, 95% confidence interval [CI] 1.28-10.91; P<0.01) was associated with the development of CNS relapse against non-CNS relapse. Chromosomal abnormality was investigated in 112 patients, of which 38 had abnormal karyotypes as identified by G-banding analysis for lymph nodes. Patients with CNS relapse more frequently harbored chromosomal abnormalities compared with those without relapse in univariate analysis (P=0.01). We also analyzed the survival of patients with primary CNS lymphoma (PCNSL) as a control. Only two (7%) of 27 patients with PCNSL died during the follow-up period. Five-year OS from initial diagnosis was 92.3% (95% CI: 82.5-100.0%), and was significantly better than that for patients with CNS relapse (33.9%, 95% CI: 17.3-66.3%, P<0.01). Among 24 patients with CNS relapse, eight (33%) had systemic lesions other than CNS when diagnosed as CNS relapse, and four (17%) patients newly developed systemic lesions while treated for CNS relapse. Patients without concurrent systemic lesions attained a rather good prognosis by chemo-radiotherapy, while those harboring concurrent systemic lesions had dismal outcome (one-year OS after the diagnosis of relapse: 74.0% versus 12.4%, P<0.01, Figure 1, systemic relapse was treated as a time-dependent covariate). These results indicate that controlling systemic lesions as well as CNS ones is essential for treating patients with secondary CNS involvement of DLBCL. CNS lesions would be well controlled with R-MPV implementation as salvage therapy, nevertheless we should be careful for concurrent systemic lesions which might require different therapeutic strategies. Disclosures Nannya: Chugai Pharmaceutical　CO., LTD: Speakers Bureau; Pfizer: Research Funding. Kurokawa:Chugai Pharmaceutical　CO., LTD: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding.

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Prognostic Impact of Transfusions Intensity on Survival and Development of Thrombocytopenia in Newly Diagnosed Lower-Risk MDS Patients Participating in the European Leukemianet EU-MDS Registry

Blood ◽

10.1182/blood.v126.23.1677.1677 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1677-1677

Author(s):

Louise De Swart ◽

Tom Johnston ◽

Alexandra Smith ◽

Pierre Fenaux ◽

Argiris Symeonidis ◽

...

Keyword(s):

Lower Risk ◽

Research Funding ◽

Control Group ◽

Rapid Decline ◽

Prognostic Impact ◽

Platelet Counts ◽

Risk Of Death ◽

Increased Risk ◽

The Impact

Abstract Background The outcome of lower-risk MDS patients with red blood cell transfusions (RBCT) dependency is inferior to that of RBCT independent patients, but whether the intensity of RBCT is important for prognosis is unknown. The EUMDS Registry is a non-interventional, observational longitudinal study enrolling patients with lower-risk MDS from 142 sites in 17 countries as described elsewhere (1). The EUMDS registry has accrued 1,902 patients as of July 21, 2015. We hypothesized that RBCT intensity is an independent prognostic factor for survival. Methods We first assessed the impact of RBCT intensity in the first year post-diagnosis (1yrPD) on progression-free survival among the 1034 patients who survived at least 1yrPD and had potential for a further year of follow-up. Secondly, we developed a longitudinal model of platelet counts throughout follow-up for 1660 patients in the registry with potential for at least one year follow-up. Results Among the 1034 patients, 323 patients had died: 67 after progression to higher-risk MDS/AML and 256 without progression. A further 41 surviving patients had progressed to AML. The overall 5-year survival was 52%. In a proportional hazards regression model (Table), the risk of death or progression increased in a non-linear fashion with age at diagnosis (p<0.001). The risk of death was increased in the intermediate IPSS-R risk group compared to low risk. Patients with RARS and 5q- syndrome had a better outcome compared to RCMD. Increased RBCT intensity in 1yrPD (Table, Figure) was strongly associated with an increased risk of death (p<0.001). In the 1660 patients no significant decline in platelet counts was observed (0.16x109 platelets/l average monthly decline, p=0.16) among patients who were not RBC transfused at any time during follow-up. However platelet counts of patients receiving RBCT declined more quickly (p<0.0001) at an average rate of 1.14x109 platelets/l/month. Among the 920 RBCT dependent patients, lower platelet counts were associated with receiving more RBCT units in the preceding six months. 185 Patients had at least 2 observations both before and after becoming RBCT dependent, defined as 1st RBCT. 50% of these patients had a decreasing trend of platelets prior to their 1st RBCT and 67% had a decreasing slope of platelets after their 1st RBCT. In the control group of RBC untransfused patients, decreasing slopes of platelets occurred in around 50% of the patients throughout the whole observation period of 4 visits. Logistic regression of the risk of having a post-1st RBCT decreasing trend in platelets showed that transfused patients were at a greater risk (OR=1.7, 95% CI: 1.1-2.7) of having a post-1st RBCT decreasing trend in platelets than untransfused patients. Conclusion These multivariate regression models including age, sex, country, IPSS and WHO classification showed that more intensive RBCT treatment is associated with poor prognosis and a more rapid decline of platelets. This indicates that the intensity of RBCT should be incorporated in the regular prognostic scoring systems and the choice of therapeutic interventions. (1): De Swart L et al. Br J Haematol 2015; 170: 372-83. Disclosures Fenaux: NOVARTIS: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Research Funding. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Mittelman:Roche: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Research Funding. Almeida:Bristol Meyer Squibb: Speakers Bureau; Shire: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Park:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Itzykson:Oncoethix: Research Funding. de Witte:Novartis: Research Funding.

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The Prognostic Calculator Easix Predicts Acute Gvhd, Non-Relapse Mortality and Overall Survival in Adult Patients Undergoing Reduced Intensity Conditioning Allogeneic HCT

Blood ◽

10.1182/blood-2018-99-111036 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2069-2069

Author(s):

Miriam Sanchez-Escamilla ◽

Patrick Hilden ◽

Molly Maloy ◽

Samira A Fatmi ◽

Doris Ponce ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Acute Gvhd ◽

Endothelial Damage ◽

Adult Patients ◽

Stress Index ◽

Unrelated Donor ◽

Risk Of Death ◽

Increased Risk ◽

Reduced Intensity

Abstract Keywords Allogeneic transplantation; endothelial damage; biomarkers. Background Endothelial damage is associated with severe complications and increased risk of death after allogeneic hematopoietic cell transplantation (AlloHCT). The recently developed Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses clinical lab values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at onset of acute graft versus host disease (aGVHD) in reduced intensity (RIC) alloHCT (Luft, Lancet Haematol 2017). We hypothesized that EASIX may be valuable for more broadly predicting aGVHD, NRM and OS after AlloHCT, beyond time of onset of aGVHD. Design We evaluated 152 adult patients who received an unmodified RIC AlloHCT from a related or unrelated donor with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose MTX for treatment of lymphoid malignancies, between April 2008 and May 2017. The EASIX formula (LDH*Creatinine/platelet counts) was calculated at multiple timepoints (pre-HCT, day 30, day 100, onset TMA and aGVHD). For all EASIX assessments post-HCT, a landmark analysis was conducted at the given timepoint A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Kaplan-Meier, cumulative incidence, and cox modeling (cause specific for NRM and aGVHD) were used to evaluate EASIX as it relates to outcomes of interest. Relapse and death or relapse were considered competing risks for NRM and aGVHD respectively. Results The median age at transplant was 54 years (range 23-78), 70% were males, a majority had non-Hodgkin lymphoma (68%), and most had sensitive disease at time of HCT (CR=56%; PR=33%). All patients, except two, received peripheral blood stem cells. Sixty-three patients had an HLA-identical related donor, while the remaining 89 had an unrelated donor transplant (HLA-matched in 75 patients, and HLA-mismatched in 14 patients). HCT-CI was 0 in 49 patients, 1-2 in 41 and ≥ 3 in 62 patients. With a median follow-up in surviving patients of 5.4 years (range, 0.8-10), the 1 and 3 years OS rate was 84.2% (95% CI, 77.3-89.1) and 67.9% (95% CI, 59.6-74.8), respectively. The NRM rate at 1 and 3 years was 7.9% (95% CI, 4.3-12.9) and 16.4% (95% CI, 10.9-22.8), respectively. The 1-year cumulative incidences of grades 1-4, 2-4 and 3-4 aGVHD were 56.6% (95% CI, 48.3-64.1), 42.1% (95% CI, 34.2-49.8) and 7.9% (95% CI, 4.3-12.9), respectively. Post-HCT thrombotic microangiopathy was only observed in 13 patients, representing too few events for EASIX analysis. As expected, HCT-CI was significantly associated with both OS and NRM. Pre-HCT EASIX was significantly associated with increased NRM (HR=1.60 [95% CI, 1.15-2.23], p=0.005) and aGVHD grade 1-4 and 2-4 (HR=1.33 [95% CI, 1.08-1.64], p=0.006 and HR=1.39 [95% CI, 1.10-1.75], p=0.005; respectively), but not OS or grade 3-4 aGVHD (Table 1). EASIX at day 30 and day 100 was significantly associated with both OS and NRM (Figures 1-4). Furthermore, confirming the results of Luft, EASIX calculated at onset of any grade aGVHD was significantly associated with OS (HR=1.34 [1.10-1.63], p=0.004) and NRM (HR=1.47 1.11-1.94], p=0.007). Finally, there was no correlation between HCT-CI and EASIX score. Conclusions We conclude that the EASIX formula, calculated at various timepoints pre and post AlloHCT, is significantly associated with NRM and OS. Pre-HCT EASIX also predicts risk of aGVHD, confirming prior results, EASIX at onset of acute GVHD is a predictor of NRM and OS in adult recipients RIC AlloHCT. EASIX provides an independent and easily accessible tool to predict important AlloHCT outcomes that can be used in addition to HCT-CI to better risk stratify patients. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees.

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Thrombosis and Risk of Mortality in Newly Diagnosed High-Risk Polycythemia Vera: An Analysis of the Medicare Claims Database in the United States

Blood ◽

10.1182/blood-2020-141370 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Naveen Pemmaraju ◽

Aaron T. Gerds ◽

Shreekant Parasuraman ◽

Jingbo Yu ◽

Anne Shah ◽

...

Keyword(s):

High Risk ◽

Median Time ◽

Research Funding ◽

Index Date ◽

Newly Diagnosed ◽

Publicly Traded ◽

Risk Of Mortality ◽

Increased Risk ◽

History Of

Background Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with an increased risk of thrombotic events (TEs), a major cause of morbidity and mortality. Patients aged ≥60 years and/or with a history of thrombosis are considered to have high-risk PV. There is limited contemporary, real-world evidence exploring the effect of TEs on mortality in patients with PV. The aim of this analysis was to compare the risk of mortality in patients newly diagnosed with high-risk PV who experienced a TE vs those who did not experience a TE. Study Design and Methods All data from the Medicare Fee-for-Service (FFS) claims database (Parts A/B/D) from January 2010-December 2017 were used to identify patients with a PV diagnosis (all high risk based on cohort being ≥65 years of age) with ≥1 inpatient or ≥2 outpatient claims. The index date was the date of the first qualifying PV claim. Patients with a PV diagnosis or use of cytoreductive therapy within 12 months before the index date (pre-index period) were excluded; ≥12-months continuous medical and pharmacy enrollment pre-index dates was required. The study sample was categorized into TE and non-TE groups based on the occurrence of any of the following events during follow-up: deep vein thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, transient ischemic attack, peripheral arterial thrombosis, or superficial thrombophlebitis. TEs were evaluated from the index date to the end of follow-up. Cox regression analyses with time-varying effects were used to assess mortality risk among patients with PV, with post-index TE as a time-dependent variable, stratified by pre-index TE, and adjusting for patient demographic characteristics and comorbid conditions. Results A total of 56,176 Medicare FFS beneficiaries with PV diagnoses met inclusion criteria. The median age was 73 years, 51.9% were men, and 90.7% were white; 10,110 patients (18.0%) had a history of TE before diagnosis (ie, pre-index). In the follow-up period, 20,105 patients (35.8%) had a TE and 36,071 patients (64.2%) did not have a TE. In the comparison between the TE vs non-TE groups, the median (range) age (75.0 [65-104] vs 73.0 [65-106] years, respectively), mean (SD) Charlson comorbidity index score (3.1 [2.6] vs 2.2 [2.3]), and percentage of patients with a history of cardiovascular events (34.1% vs 23.8%), bleeding (13.3% vs 10.4%), or anemia (28.6% vs 23.4%) were higher (Table 1). Among all patients with PV, the median time from diagnosis to first post-index TE was 7.5 months. Among those with pre-index TE (n=10,093), median time from index to first post-index TE was 0.6 months, whereas patients without pre-index TE (n=46,083) had a median time to first post-index TE of 14.2 months. Among all patients with TE during follow-up, the most common TEs were ischemic stroke (47.5%), transient ischemic attack (30.9%), and acute myocardial infarction (30.5%). The risk of mortality was increased for patients who experienced a TE compared with those who did not (hazard ratio [HR; 95% CI], 9.3 [8.4-10.2]; P<0.0001). For patients who experienced a pre-index TE, the risk of mortality was increased for patients who experienced a subsequent TE during follow-up compared with patients who did not (HR [95% CI], 6.7 [5.8-7.8]; P<0.0001). Likewise, for patients who did not experience a pre-index TE, the risk of mortality was increased for patients who experienced a TE during follow-up compared with patients who did not (HR [95% CI], 13.1 [11.4-15.0]; P<0.0001). Conclusions In this real-world study, approximately one-third of patients with newly diagnosed high-risk PV experienced a TE during follow-up and had a 9-fold increased risk of mortality vs those who did not experience a TE. TE risk mitigation remains an important management goal in patients with PV, particularly in those with prior TE. Disclosures Pemmaraju: Samus Therapeutics: Research Funding; Celgene: Honoraria; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Incyte Corporation: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding; DAVA Oncology: Honoraria. Gerds:Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Pfizer: Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding. Parasuraman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yu:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Shah:Avalere Health: Current Employment. Xi:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Kumar:Avalere Health: Current Employment; Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding.

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Clinical characteristics and outcomes of adult patients admitted with COVID-19 in East London: a retrospective cohort analysis

10.1101/2020.10.08.20193623 ◽

2020 ◽

Author(s):

Daryl Oswald Cheng ◽

Claire Jacqueline Calderwood ◽

Erik Wilhelm Skyllberg ◽

Adam Denis Jeremy Ainley

Keyword(s):

Clinical Characteristics ◽

Clinical Course ◽

Cohort Analysis ◽

Short Term ◽

Asian Ethnicity ◽

Persistent Symptoms ◽

Risk Of Death ◽

Increased Risk ◽

Male Sex

AbstractBackgroundDescriptions of clinical characteristics of patients hospitalised with coronavirus disease 2019 (COVID-19), their clinical course and short-term in- and outpatient outcomes in deprived urban populations in the United Kingdom are still relatively sparse. We describe the epidemiology, clinical course, experience of non-invasive ventilation and intensive care, mortality and short-term sequalae of patients admitted to two large District General Hospitals across a large East London NHS Trust during the first wave of the pandemic.MethodsA retrospective analysis was carried out on a cohort of 1,946 patients with a clinical or laboratory diagnosis of COVID-19, including descriptive statistics and survival analysis. A more detailed analysis was undertaken of a subset of patients admitted across three Respiratory Units in the trust.ResultsIncreasing age, male sex and Asian ethnicity were associated with worse outcomes. Increasing severity of chest X-ray abnormalities trended with mortality. Radiological changes persisted in over 50% of cases at early follow up (6 weeks). Ongoing symptoms including hair loss, memory impairment, breathlessness, cough and fatigue were reported in 67% of survivors, with 42% of patients unable to return to work due to ongoing symptoms.ConclusionsUnderstanding the acute clinical features, course of illness and outcomes of COVID-19 will be vital in preparing for further peaks of the pandemic. Our initial follow up data suggest there are ongoing sequalae of COVID-19 including persistent symptoms and radiological abnormalities. Further data, including longer term follow up data, are necessary to improve our understanding of this novel pathogen and associated disease.Section 1: What is already known on this topicPrevious studies have reported that increasing age, male sex, Black and Asian ethnicity increased risk of death for patients admitted to hospital with coronavirus disease 2019 (COVID-19). There is little published literature regarding the follow up of patients with COVID-19.Section 2: What this study addsOur study is one of the first with follow up data for patients admitted to hospital with COVID-19. We show that radiological abnormality persisted at 6 weeks in over 50% of patients, as well as significantly increased breathlessness in patients without baseline dyspnoea. Our study confirms that increasing age, male sex and Asian ethnicity increased risk of death for patients, but also in an ethnically and socioeconomically diverse population in East London.

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Risk factors for death among children aged 5–14 years hospitalised with pneumonia: a retrospective cohort study in Kenya

BMJ Global Health ◽

10.1136/bmjgh-2019-001715 ◽

2019 ◽

Vol 4 (5) ◽

pp. e001715 ◽

Cited By ~ 1

Author(s):

Liana Macpherson ◽

Morris Ogero ◽

Samuel Akech ◽

Jalemba Aluvaala ◽

David Gathara ◽

...

Keyword(s):

Risk Factors ◽

Cohort Study ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Clinical Characteristics ◽

Univariate Analysis ◽

Older Age ◽

Who Criteria ◽

Risk Of Death ◽

Increased Risk

IntroductionThere were almost 1 million deaths in children aged between 5 and 14 years in 2017, and pneumonia accounted for 11%. However, there are no validated guidelines for pneumonia management in older children and data to support their development are limited. We sought to understand risk factors for mortality among children aged 5–14 years hospitalised with pneumonia in district-level health facilities in Kenya.MethodsWe did a retrospective cohort study using data collected from an established clinical information network of 13 hospitals. We reviewed records for children aged 5–14 years admitted with pneumonia between 1 March 2014 and 28 February 2018. Individual clinical signs were examined for association with inpatient mortality using logistic regression. We used existing WHO criteria (intended for under 5s) to define levels of severity and examined their performance in identifying those at increased risk of death.Results1832 children were diagnosed with pneumonia and 145 (7.9%) died. Severe pallor was strongly associated with mortality (adjusted OR (aOR) 8.06, 95% CI 4.72 to 13.75) as were reduced consciousness, mild/moderate pallor, central cyanosis and older age (>9 years) (aOR >2). Comorbidities HIV and severe acute malnutrition were also associated with death (aOR 2.31, 95% CI 1.39 to 3.84 and aOR 1.89, 95% CI 1.12 to 3.21, respectively). The presence of clinical characteristics used by WHO to define severe pneumonia was associated with death in univariate analysis (OR 2.69). However, this combination of clinical characteristics was poor in discriminating those at risk of death (sensitivity: 0.56, specificity: 0.68, and area under the curve: 0.62).ConclusionChildren >5 years have high inpatient pneumonia mortality. These findings also suggest that the WHO criteria for classification of severity for children under 5 years do not appear to be a valid tool for risk assessment in this older age group, indicating the urgent need for evidence-based clinical guidelines for this neglected population.

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