scholarly journals Conventional Chemotherapy Treatment Induces Unique Patterns of Clonal Evolution in a North American Adult T Cell Leukemia/Lymphoma Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1551-1551
Author(s):  
R. Alejandro Sica ◽  
Nishi Shah ◽  
Ana Acuna-Villaorduna ◽  
Nivetha Vishnuvardan ◽  
Urvi A Shah ◽  
...  
Keyword(s):  
Research Funding ◽  
Clonal Evolution ◽  
The Other ◽  
Refractory Disease ◽  
Adult T Cell Leukemia ◽  
Equity Ownership ◽  
Group 2 ◽  
Education Resource ◽  
Clonal Replacement ◽  
Group 1

Adult T cell leukemia / lymphoma is a rare neoplasm with dismal cure rates and poor response to chemotherapy. The genetic basis of refractoriness against conventional agents is not known. We follow one of the largest cohorts of ATLL in the US and recently showed that North American ATLL (NA-ATLL) has a distinct mutational profile from Japanese ATLL (J-ATLL) with a higher incidence of epigenetic mutations (Shah et al, Blood, 2018; 132(14):1507-1518). Here, we analyze the mutational landscape of ATLL clones at diagnosis and at relapse in a pilot study of 7 NA-ATLL patients using deep targeted sequencing of 236 recurrently mutated genes. Our goal was to examine clonal evolution patterns that may result as a consequence of the selective pressure of chemotherapy by determining changes in mutational profiles as well as clonal abundance on patients with aggressive ATLL [acute and lymphomatous] (Table 1). All patients were treated with EPOCH (Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin) chemotherapy after initial diagnosis except one patient who received interferon therapy. Distinct patterns of clonal evolution were observed in patients with primary refractory disease when compared to those who relapsed after an initial remission. Group 1 has 3 cases (Pts 1 to 3), all of which experienced early relapse and showed mutation patterns suggestive of clonal replacement by a new emerging clone at relapse. Group 2 has 3 patients (Pts 4-6) that are characterized by worsening of primary refractory disease. Mutation patterns in the before-and-after sample pairs suggest linear progression from a previously existing clone during therapy. The clonal evolution status was not resolved in our third group (Pt#7) indicating that mutations outside the 236 genes evaluated might have been present. Frequent epigenetic mutations were found in both diagnostic and refractory/relapsed samples. Surprisingly, 4 epigenetic mutations (KMT2D, EP300, SPEN, SETBP1) identified in 4 cases were confirmed or suspected of germline origin. This suggests that ancestral genomic differences between the Caribbean and Japanese populations could contribute to the mutational and clinical disparities between NA- and J-ATLL. Multiple mutations with similar variant allele frequencies (VAF) at the time of relapse were identified, suggesting simultaneous acquisition of several mutations during clonal evolution. Clonal replacement by an emerging clone (Group 1) such as GATA3 (Pt#3) or KMT2D (Pt#1) (either germline or founding mutation) was observed in patients who achieved an initial response. On the other hand, in primary refractory disease (Group 2), relapse was driven by dominant TBL1XR1 mutations in 2 out of the 3 cases either alone (Pt#6) or in combination with mutated SMARCB1 (Pt#5). The protein encoded by TBL1XR1 is a negative regulator of the nuclear receptor corepressor (NCoR) /histone deacetylase 3 (HDAC3) complex. Therefore, TBL1XR1 inactivation is expected to result in hyper-activity of NCoR/HDAC3, an epigenetic abnormality targetable by HDAC inhibitors. SMARCB1 is also an epigenetic regulator associated with several malignancies and has been targeted with alisertib. A subclonal expansion of EP300 (a histone acetyltransferase) appears to drive relapse in the other case of this group (Pt#4). Therefore, our primary refractory cases show that epigenetic mutations seem to be of utmost importance not only at diagnosis as we have previously shown, but as the driving force behind chemotherapy refractoriness and subsequent relapse. Conclusion: To our knowledge, this is the first mutation-based clonal evolution study aimed to examine dynamic changes induced by chemotherapy among NA-ATLL patients. Early relapse appears to be driven by the emergence of new mutant clones. On the other hand, primary refractory disease appears to have epigenetic drivers that convey chemotherapy refractoriness and evolve from linear progression of a previously existing clone. Serial mutational testing can provide critical information on clonal architecture and identify actionable molecular vulnerabilities in a cohort without effective therapeutic options and a dismal prognosis. Disclosures Sica: Physician's Education Resource (PER): Honoraria. Shah:Physicians' Education Resource: Honoraria. Steidl:Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2771-2771 ◽  
Author(s):  
Sikander Ailawadhi ◽  
Carole B. Miller ◽  
Anand P. Jillella ◽  
Nebu Koshy ◽  
Brian Tudor ◽  
...  
Keyword(s):  
Research Funding ◽  
Molecular Response ◽  
Employment Equity ◽  
Transcript Levels ◽  
Log Reduction ◽  
End Point ◽  
Day Range ◽  
Equity Ownership ◽  
Group 2 ◽  
Group 1

Abstract Abstract 2771 Background: NIL is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult pts with Philadelphia-chromosome positive (Ph+) CML-CP and in Ph+ CML-CP and accelerated-phase pts who are resistant or intolerant to IM. Achieving complete cytogenetic response (CCyR) and major molecular response (MMR, 3-log reduction of Bcr-Abl transcript level from the baseline mean) are favorable prognostic factors for CML. This multicenter, open-label study (ENABL) was designed to explore nilotinib Bcr-Abl effects in pts with CCyR but who have suboptimal molecular response to IM. Methods: This study evaluates change in Bcr-Abl trends in 2 groups of CML-CP pts (total n = 18) who achieved CCyR but have suboptimal molecular response to IM defined as: (Group 1) treated ≥ 1 year with IM, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1-log increase in Bcr-Abl transcript levels from best response regardless of IM treatment duration. Pts are treated with NIL 300 mg twice daily for ≥ 1 year. RQ-PCR analysis is performed by a central lab at screening, then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR monthly for the first 3 mos, then every 3 mos. The 1° end point is change in Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR at 12 mos. The data cutoff date for this analysis was June 30, 2011. Results: Eighteen pts (Group 1, n = 17; Group 2, n = 1) have been treated with NIL for a median of 17 mos on study (range 3–34 mos). Thirteen pts have been treated for ≥ 6 mos and 10 for ≥ 12 mos. One pt was deemed ineligible due to lack of evidence of CCyR at baseline but is included in the analysis because there was at least 1 post-baseline evaluation performed. The remaining 17 pts had CCyR at baseline. Before enrollment, pts were treated with at least 400 mg once-daily IM; the mean dose of prior IM treatment was 487 mg/day (range 342–786 mg/day). Median duration of prior IM treatment was 3.4 yrs (range 1.3–10.2 yrs). Three pts had prior interferon treatment. All 18 pts were treated for ≥ 3 mos and had ≥ 1 post-baseline RQ-PCR result. Overall, 15 of 18 evaluable pts (83%) achieved MMR during treatment; 10 pts by 3 mos, 1 pt by 4.5 mos (measured at end of study), 1 pt by 6 mos, 2 pts by 9 mos, and 1 pt by 30 mos (Figure 1). The 3 pts who did not reach MMR at any point were only followed for up to 3 mos before discontinuing from the trial but showed a decreasing Bcr-Abl trend. Overall, pts achieved a median log reduction of PCR transcript levels of 3.1 (0.08% IS) at 3 mos; median 3.3-log reduction (0.05% IS) at 6 mos, and median 3.5-log reduction (0.035% IS) at 9 mos. Four pts had > 4-log (≤ 0.01% IS) reduction in Bcr-Abl; of these, 2 pts reached > 4.5-log (≤ 0.0032% IS) reduction in Bcr-Abl at least once during the study. Median Bcr-Abl transcript log reduction at 12 mos was 3.6 (0.025% IS, 1° end point) for 10 evaluable pts. All these pts reached MMR during NIL treatment; 9 pts by 12 mos, 1 pt after 30 mos. NIL was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Seven of 18 pts were dose reduced for NIL-related AEs and re-escalated if the patient recovered from the AEs. Patients were permitted to dose escalate to 400 mg b.i.d. per physician's discretion if MMR was not achieved after 6 mos (n = 1). The Grade 3 AEs reported include 2 cases of rash and 1 case each of pneumonia, squamous cell carcinoma, bladder prolapse, uterine prolapse, bradycardia, hypertension, hyperbilirubinemia and hypophosphatemia. The rashes and bradycardia were suspected to be related to NIL. No Grade 4 AEs were reported. The median dose intensity was 600 mg/day (range 300–683 mg/day). Five pts were discontinued from the study (3 due to abnormal laboratory values, 1 due to an AE, and 1 due to protocol violation). No pts who experienced QTcF changes had differences > 33 msec from baseline. No QTcF prolongation > 500 msec was observed. Conclusions: NIL treatment results in high molecular response rates in CML-CP pts with suboptimal molecular responses to IM. Overall 83% of pts who switched to NIL achieved MMR, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.6 (0.025% IS). The IRIS study has shown that MMR rates increase with time in pts treated with IM (Hughes Blood 2010); however, this study appears to demonstrate that MMR is achieved relatively quickly in suboptimal molecular IM-treated pts when switched to NIL. Disclosures: Ailawadhi: Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lin:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. DeAngelo:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

Minimal Residual Disease (MRD) Re-Growth Kinetics Are An Independent Predictor for Progression Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) and Are Related to Biologically Defined CLL-Subgroups– Results From the CLL8 Trial of the German CLL Study Group (GCLLSG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1777-1777 ◽  
Author(s):  
Sebastian Boettcher ◽  
Matthias Ritgen ◽  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Raymonde Busch ◽  
...  
Keyword(s):  
Thymidine Kinase ◽  
Growth Kinetics ◽  
Research Funding ◽  
Prognostic Significance ◽  
Mutational Status ◽  
Group 3 ◽  
Equity Ownership ◽  
Group 2 ◽  
Single Time Point ◽  
Group 1

Abstract Abstract 1777 MRD single time point assessments during therapy and at the end of treatment have been identified as independent predictors of PFS and overall survival in CLL patients (pts) by our group and others. However, it is currently unknown whether MRD kinetics during follow-up (FU) also have prognostic significance and whether kinetics show associations with CLL risk features. We therefore investigated MRD during treatment-free FU within the CLL8 trial of the GCLLSG (phase III, front-line RFC vs FC, Hallek et al., Lancet 2010) MRD kinetics were analyzed in 256 pts who had not progressed 1 year after completion of therapy and for whom at least 2 peripheral blood MRD assessments during the subsequent year were available. The slope of the common logarithm of MRD / time was calculated for 193 patients with at least 2 positive MRD measurements. Median MRD increase was 6.3fold during the observation period for the whole group (i.e. 0.80 log MRD unit increase / year). We compared groups of pts who (1) were always MRD negative (25% of all 256 pts), (2) had measurable disease with a slope below median (slow re-growth, 37% of pts), and (3) had measurable disease with a slope above median (fast re-growth, 39 %). The medians of the first measurable MRD levels during observation did not differ significantly between groups 2 (4.3 × 10−3) and 3 (1.7 × 10−3, p=.16). Pts with faster MRD re-growth kinetics (group 3) experienced a shorter median PFS (40 months) than pts with slower re-growth (group 2, 66 months), whereas median PFS has not been reached in pts who were always MRD negative (group 1, log-rank p= 3 × 10−14). Compared to group 1, group 2 and 3 pts carried increasingly higher risks of progression (HR 3.1 and 7.7, resp.). Pts showing a slow re-growth pattern (group 2) had a 2.5fold lower risk of clinical progression than pts with a greater MRD slope (group 3, p=5 × 10−6). The prognostic significance of MRD kinetics for PFS was also tested in Cox regression analysis together with clinical response, deletion 17p, IGHV mutational status, number of treatment cycles, treatment arm, thymidine kinase, beta2-microglobulin, pre-therapeutic WBC and MRD levels 1 year after completion of therapy. MRD kinetics (p=4×10−9), MRD levels (7×10−14), cycle number (8×10−5) and IGHV mutational status (1×10−3) remained independently significant for PFS in this multivariate analysis. We next correlated MRD slopes during the second year of FU and prognostic features in 204 pts (groups 2 and 3 plus 11 pts with early clinical relapse but measurable MRD slope during second FU year). Pts who required treatment within 2 years from diagnosis experienced a faster re-growth after therapy (.92/a) than pts with a longer treatment-free interval (.68, p=.04). The slope was significantly lower in pts with Binet A disease prior to therapy (.43/a) than in Binet B (.77/a, p =.03) and Binet C (.88/a, p=.02) pts. Pts carrying a chromosomal deletion (del) 13q as single abnormality had a significantly slower MRD re-growth pattern (.58/a) than those with del(11q) (1.0/a, p=.0004) or without cytogenetic abnormalities (1.1/a, p=.001), while the difference to pts with 12q+ (.71/a) was not significant. Pts with a mutated IGHV gene progressed slower (.54/a) than those with unmutated IGHV (.96/a, p=.0002). A thymidine kinase of at least 10 U/L was associated with a steeper MRD slope (.82/a) than lower levels (.61/a, p=.03). MRD slopes were not significantly associated with gender, WBC prior to therapy, beta2-microglobuline levels, presence of B-symptoms, or treatment arm. We demonstrate for the first time the independent prognostic significance of MRD kinetics during FU in CLL. MRD kinetics improve the prediction of PFS even when single time point MRD assessments during FU and other major risk features in CLL are additionally considered. MRD kinetics classify known CLL risk factors into two groups. IGHV, cytogenetics, thymidine kinase, stage, and time to treatment distinguish CLL subgroups with different re-growth kinetics, likely characterizing the relationship of proliferation to spontaneous apoptosis of the CLL clone itself. Other risk features did not show an association with kinetics in spite of proven significance in the CLL8 trial. Those features likely identify differences in responsiveness to therapy. We hypothesize that maintenance strategies will chance the course of the disease most effectively in patients who are responsive to therapy but relapse early due to fast CLL re-growth. Disclosures: Boettcher: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants. Ritgen:Hoffmann La Roche: Research Funding. Fischer:Hoffmann La Roche: Travel grants. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fingerle-Rowson:Hoffmann-La Roche: Employment. Fink:F. Hoffmann La Roche: Travel grants. Wenger:Hoffmann La Roche: Employment, Equity Ownership. Mendila:Hoffmann La Roche: Employment, Equity Ownership. Wendtner:Hoffmann-La Roche: Honoraria, Research Funding. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants. Hallek:Hoffmann-La Roche: Honoraria, Research Funding. Kneba:Hoffmann La Roche: Honoraria, Research Funding.

scholarly journals Treatment Practices and Outcomes in Older Adults with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated in the Veterans Health Administration

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4205-4205 ◽  
Author(s):  
Ahmad S Halwani ◽  
Kelli M Rasmussen ◽  
Vikas Patil ◽  
Catherine Li ◽  
Christina Young ◽  
...  
Keyword(s):  
Older Patients ◽  
Research Funding ◽  
High Dose ◽  
High Dose Therapy ◽  
Employment Equity ◽  
Treatment Practices ◽  
Dose Therapy ◽  
Equity Ownership ◽  
Group 2 ◽  
Group 1

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive Non-Hodgkin lymphoma, with approximately one third of patients not responding (or relapsing) after receiving first-line (1L) therapy, typically a multi-agent chemoimmunotherapy regimen containing rituximab and doxorubicin. These patients may be treated with a second-line (2L) chemotherapy (CT) or chemoimmunotherapy (CIT) regimen, with the intention to proceed to a high-dose therapy followed by an autologous stem cell transplant (SCT). Unfortunately, a significant proportion of older patients are unable to tolerate such treatment. There is little data on treatment practices and outcomes in older DLBCL patients receiving 2L CT or CIT after failure of 1L therapy. Using electronic healthcare record data from the largest integrated health system in the United States, the Veterans Health Administration (VHA), we examined real-world outcomes of DLBCL patients ≥ 65 years of age receiving 2L CT or CIT following 1L therapy with rituximab and doxorubicin containing regimens. Methods: DLBCL patients diagnosed from 2001-2015 and treated at the VHA were identified by linking information from the VA Clinical Registry System (VACRS) in the VHA Corporate Data Warehouse (CDW) to administrative, laboratory and pharmacy data, and clinical notes in the CDW. Patients were included in the analysis if they: had no evidence of a prior malignancy, were diagnosed with DLBCL, received 1L therapy containing rituximab and doxorubicin for ≥ 21 days, then subsequently received a 2L CT or CIT, and were ≥ 65 years of age at time of 2L treatment. Patient age, gender, race/ethnicity; stage at diagnosis, lactate dehydrogenase (LDH), and Charlson Comorbidity Index (CCI) were extracted from VACRS and/or CDW. Patients were censored at end of study observation period (Dec 31, 2016) or if a second cancer diagnosis occurred following their DLBCL diagnosis. Patients were divided into 2 groups: Group 1 included patients receiving a 2L regimen that, per the National Comprehensive Cancer Network (NCCN) guidelines, is typically used with intention to proceed to high-dose therapy; Group 2 included patients receiving a regimen that, per NCCN, is used in non-candidates for high-dose therapy. Receipt of SCT was identified using ICD codes and/or clinical notes. Results: 230 DLBCL patients met our inclusion criteria. Of these, 223 (97%) were male and 171 (74%) were of non-Hispanic, white ethnicity. Baseline characteristics (at time of 1L) were as follows: 156 (68%) had stage III-IV disease, 154 (67%) had LDH > ULN, and median CCI was 4 (IQR:2-5). The majority of patients (217, 94%) received RCHOP as 1L, with the remaining receiving RCHOP + etoposide (13, 6%). Two thirds of patients, (151, 66%) started 2L within 1 year of starting 1L with a median of 10.6 months between start of 1L and start of 2L. Patients were almost equally divided between the two groups, with Group 1 (109, 47%) and Group 2 (121, 53%). Of the 109 Group 1 patients, 68 (62%) received ifosfamide, carboplatin, etoposide (ICE) +/- rituximab (R), and 22 (20%) received etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) +/- R. Of the 109 Group 1 patients, 14 (13%) proceeded to SCT within VHA (SCT outside VHA was not extracted for this study). The remaining 121 Group 2 patients received 2L therapy with the following: bendamustine (B) +/- R (28, 23%), gemcitabine, oxaliplatin (Gem-Ox) +/- R (21, 17%), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) +/- R (17, 14%), cyclophosphamide, etoposide, vincristine, prednisone (CEOP) +/- R (14, 12%), cyclophosphamide, etoposide, prednisone, procarbazine (CEPP) +/- R (12, 10%); CHOP + etoposide +/- R (6%), lenalidomide +/- R (6%). Fewer than 10 of these patients proceeded to SCT. The median OS of all patients was 8 months. Conclusions: This is the first study that details treatment practices and outcomes in a nationwide cohort of older adult patients (≥ 65 years old) with relapsed/refractory DLBCL. Approximately half of these older patients did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant. OS for the entire cohort was less than a year. Despite significant advances in available treatments for DLBCL, there remains an unmet need in treatment of relapsed/refractory DLBCL, especially in older patients who have difficulty tolerating high-dose regimens. Disclosures Halwani: Takeda: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Miragen: Research Funding; Kyowa Hakko Kirin: Research Funding; Immune Design: Research Funding; Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Schulz:Genentech: Employment, Equity Ownership; Roche: Equity Ownership. Li:Roche: Equity Ownership; Genentech: Employment. Masaquel:Genentech: Employment, Equity Ownership; Roche: Equity Ownership. Halloran:Genentech, Inc.: Employment, Equity Ownership; Janssen Pharmaceuticals, Inc: Employment, Equity Ownership. Delong-Sieg:Roche: Equity Ownership; Genentech, Inc.: Employment. Sauer:Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; COHRDATA: Research Funding; Amgen: Research Funding.

scholarly journals Emerging Real-World Midostaurin Treatment Patterns and Outcomes in FLT3-Mutated Acute Myeloid Leukemia at a Comprehensive Cancer Center

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4745-4745
Author(s):  
Connor Willis ◽  
Jyothi Menon ◽  
Sudhir Unni ◽  
Trang Au ◽  
Briana Ndife ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Treatment Patterns ◽  
Consolidation Therapy ◽  
Advisory Committees ◽  
Group 3 ◽  
Equity Ownership ◽  
Group 2 ◽  
Relapse Rates ◽  
Group 1

Abstract Introduction: Fms-like tyrosine kinase 3 (FLT3) gene mutation occurs in approximately 25-30% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. Decreased overall survival is reported in FLT3-mutated vs. FLT3-wildtype. Midostaurin, a pan-targeted kinase inhibitor that inhibits activated FLT3 received FDA approval in April 2017 for adult patients with newly diagnosed FLT3-mutated AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. We report descriptive US clinical treatment patterns and outcomes in FLT3-mutated early midostaurin-users, historical FLT3-mutated patients prior to midostaurin approval, and historical FLT3-wildtype AML patients all treated with 7+3 induction therapy at an academic cancer specialty hospital to support the development of a larger database across several comprehensive cancer centers. Methods: This retrospective, observational study utilized ICD codes, tumor registry data, and pharmacy records from the Huntsman Cancer Institute (HCI) to identify AML patients treated with 7+3 induction chemotherapy from 2007 to July 2018. FLT3-mutated midostaurin-users treated with 7+3 induction including midostaurin from May 2017 to July 2018 comprise Group 1. Historical FLT3-mutated patients prior to midostaurin approval (non-users) and FLT3-wildtype patients comprise Groups 2 and 3, respectively. Complete response (CR), relapse rates, overall survival and treatment patterns were described. Results: A total of 105 patients met eligibility for inclusion in the study. Groups 1, 2, and 3 included five, 39 and 61 patients, respectively. Off-label midostaurin use in Group 1 after induction therapy was observed in one patient with post-consolidation monotherapy and salvage therapy in combination with ATRA (tretinoin) and CLAG (cladribine, cytarabine, and filgrastim). Following midostaurin approval, two FLT3-mutated patients received induction therapy without midostaurin due to enrollment in clinical trials that excluded midostaurin use for induction and consolidation therapy. These two patients were excluded from the study. Descriptive results of the comparative groups are summarized in Table 1. CR rate from induction therapy was 100% for Group 1, 90% for Group 2, and 77% for Group 3. The proportion of patients who received consolidation therapy was 60%, 74%, and 67%, and patients who maintained CR during consolidation therapy was 100%, 83%, and 49% for Groups 1, 2, and 3, respectively. Sixty-six percent of eligible Group 1 patients, 74% of Group 2 patients, and 54% of Group 3 patients received transplant. Median time from diagnosis to transplant was 81, 99, and 145 days for Groups 1, 2, and 3, respectively. The proportion of patients who received salvage therapy in Groups 1, 2, and 3 was 20%, 38%, and 56% respectively. Median follow-up was 6 months for Group 1, 14 months for Group 2, and 24 months for Group 3. After CR, 20% of Group 1, 49% of Group 2, and 59% of Group 3 relapsed. All Group 1 patients were alive at time of analysis while four Group 2, and eight Group 3 patients died during the study period. Discussion: Similar CR and relapse rates were observed between the comparative groups, although early use observations indicate improved response rates of induction therapy and consolidation therapy in a limited Group 1 sample. Patients in Group 1 and Group 2 underwent transplant earlier and more frequently than patients in Group 3, which may explain the higher relapse rate in Group 3. As this data resource is expanded across similar institutions, statistical comparisons of FLT3-mutated AML patients treated with and without midostaurin can be made. Sponsorship: Funding for this study was provided by Novartis Pharmaceuticals. Disclosures Unni: Novartis: Research Funding. Ndife:Novartis: Employment. Joseph:Novartis Pharmaceuticals Corporation: Employment; Amgen: Equity Ownership; Pfizer: Equity Ownership; Express Scripts: Equity Ownership. Bonifacio:Novartis: Employment. Stein:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Brixner:BD: Consultancy; Abbott: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Millcreek Outcomes Group: Equity Ownership; University of Utah: Research Funding. Stenehjem:Novartis: Research Funding.

Myeloid neoplasms in the setting of chronic lymphocytic leukaemia/chronic lymphocytic leukaemia-like disease: a clinicopathological study of 66 cases comparing cases with prior history of treatment to those without

2021 ◽  
pp. jclinpath-2020-207334
Author(s):  
Catherine Luedke ◽  
Yue Zhao ◽  
Jenna McCracken ◽  
Jake Maule ◽  
Lian-He Yang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
The Other ◽  
Prior History ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
History Of ◽  
Cytogenetic Profile ◽  
Group 2 ◽  
Group 1

AimsMyeloid neoplasms occur in the setting of chronic lymphocytic leukaemia (CLL)/CLL-like disease. The underlying pathogenesis has not been elucidated.MethodsRetrospectively analysed 66 cases of myeloid neoplasms in patients with CLL/CLL-like disease.ResultsOf these, 33 patients (group 1) had received treatment for CLL/CLL-like disease, while the other 33 patients (group 2) had either concurrent diagnoses or untreated CLL/CLL-like disease before identifying myeloid neoplasms. The two categories had distinct features in clinical presentation, spectrum of myeloid neoplasm, morphology, cytogenetic profile and clinical outcome. Compared with group 2, group 1 demonstrated a younger age at the diagnosis of myeloid neoplasm (median, 65 vs 71 years), a higher fraction of myelodysplastic syndrome (64% vs 36%; OR: 3.1; p<0.05), a higher rate of adverse unbalanced cytogenetic abnormalities, including complex changes, −5/5q- and/or −7/7q- (83% vs 28%; OR: 13.1; p<0.001) and a shorter overall survival (median, 12 vs 44 months; p<0.05).ConclusionsMyeloid neoplasm in the setting of CLL/CLL-like disease can be divided into two categories, one with prior treatment for CLL/CLL-like disease and the other without. CLL-type treatment may accelerate myeloid leukaemogenesis. The risk is estimated to be 13-fold higher in patients with treatment than those without. The causative agent could be attributed to fludarabine in combination with alkylators, based on the latency of myeloid leukaemogenesis and the cytogenetic profile.

scholarly journals Comparison of peribulbar anesthesia and topical anesthesia on outcome of phacoemulsification

2017 ◽  
Vol 5 (6) ◽  
pp. 2608 ◽  
Author(s):  
Rishi Mehta ◽  
Sharda Punjabi ◽  
Nutan Bedi ◽  
Chandra Kant Nagar
Keyword(s):  
Intraoperative Complications ◽  
Visual Outcome ◽  
Topical Anesthesia ◽  
Satisfaction Score ◽  
The Other ◽  
Patients Satisfaction ◽  
Peribulbar Anesthesia ◽  
Group 2 ◽  
A Prospective Study ◽  
Group 1

Background: Due to advancement in phacoemulsification techniques, there has been growing shift from peribulbar anesthesia (PA) to topical anesthesia (TA). But dilemma exists regarding the supremacy of one over the other as both types have certain advantages and disadvantages.Methods: A prospective study was conducted. Patients were divided into two groups. Group-1 underwent PA while group-2 underwent TA. Satisfaction score of patients and surgeons and incidence of complications were noted. The data was analyzed.Results: Lowest patients’ satisfaction score among group-1 vs. group-2 was 160 (87.9%) vs.82 (45.81%). Highest surgeons satisfaction score among group-1 and group-2 was 74(40.65%) vs. 2(1.1%). Intraoperative complications among the group-1 and group-2 were 35 (19.2%) vs. 86(48.0%).Conclusions: While TA provides initial painless phase of surgical procedure, PA results in lesser intraoperative complications resulting in better visual outcome.

scholarly journals Efficacy of Chemotherapy or Chemo-Anti-PD-1 Combination after Unsatisfactory Response of Anti-PD-1 Therapy for Relapsed and Refractory Hodgkin Lymphoma: A Retrospective Series from Lysa Centers

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 652-652
Author(s):  
Cédric Rossi ◽  
Julia Gilhodes ◽  
Marie Maerevoet ◽  
Charles Herbaux ◽  
Pauline Brice ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Complete Response ◽  
High Rate ◽  
High Dose ◽  
Group 2 ◽  
Group 1

Abstract Introduction: Hodgkin lymphoma (HL) pts who relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV) therapy have a poor outcome. For these relapsed and refractory (R/R) HL pts, anti-PD-1 therapy gives a high rate of objective responses. However, the rate of complete response (CR) remains modest and in the updated results of anti-PD-1 therapy clinical trials, about 50% of pts are still without progressive disease after one year of treatment. As anti-PD-1 therapy modifies the anticancer immune response, we hypothesize that anti-PD-1 therapy may increase sensitivity to chemotherapy (CT) given after anti-PD-1 therapy (sequential strategy) or in combination with anti-PD-1 therapy after an unsatisfactory response to immunotherapy (concomitant strategy). We retrospectively analyzed these two clinical situations in 30 R/R HL pts from LYSA centers treated with anti-PD-1 therapy. Methods: We included R/R HL pts from 14 LYSA centers who received anti-PD-1 therapy in the context of clinical trials (N=4) or an authorization for temporary use (ATU) from the French medical drug agency (N=26). Before the anti-PD-1 therapy, pts had received a median of six (range, 2-14) lines of therapy, 69% had HDT+ASCT, 14% had allograft and 93% had been treated with BV. We considered two groups of pts: i. 19 pts (63%) in whom the anti-PD-1 therapy was stopped at the introduction of CT (Group 1); ii. 11 pts (37%) with an unsatisfactory response to anti-PD-1 therapy in whom a combination of CT with immunotherapy was initiated to optimize the response (Group 2). The quality of the response after the introduction of CT was evaluated retrospectively by each treating physicians according to Cheson 2007 or 2014 criteria. We also determined whether new CT treatments after and in combination with anti-PD-1 therapy led to unexpected toxicities and whether new treatment schedules made pts eligible for allograft. Results: At the start of anti-PD-1, the median age of pts was 37 years old (range, 20-75), 24% had Ann Arbor III/IV stages, 34% had B symptoms and 21% had a performance status (PS) of 2-3. Patients received a median of 10 infusions (range, 2-52) of anti-PD-1 therapy with nivolumab (N=26, 87%) or pembrolizumab (N=4, 13%). The best responses achieved during anti-PD-1 therapy were a complete response (CR) for 5 patients, a partial response (PR) for 17 pts, stable disease (SD) for 2 pts and progression for 6 pts. In group 1, 17 pts were in progression, one pt in PR, and another pt in SD at the end of anti-PD-1 therapy alone. In group 1, after anti-PD-1 therapy, the pts were treated with vinblastine (N=3), gemcitabine (N=2) or bendamustine alone (N=3) or in combination with BV (N=4), GVD (N=1), ICE (N=1), DHAP (N=1), escalated BEACOPP (N=1), vinorelbine (N=1), vepeside (N=1) and caelyx (N=1). In group 2, before the combination, the response status was progression for 7 pts and PR for 4 pts. In group 2, to optimize the response to anti-PD-1, pts received vinblastine (N=7), gemcitabine (N=2) and BV (N=2). In the 28 evaluable pts, 11/18 (61%) in group 1 and 9/10 (90%) in group 2 showed an improved response after chemotherapy alone or combination with anti-PD-1 therapy respectively. In group 1, there were 6 CR (32%), 5 PR (26%), 1 SD (5%) and 6 PD (32%) (Figure 1B). In group 2, there were 5 CR (45%), 5 PR (45%) and 1 SD (10%) (Figure 1A). Of note, among the ten pts treated with vinblastine, 4 were in CR, 3 in RP, 1 in SD and 2 in progression. No unexpected toxicity was observed during the CT. Four pts had an allograft after the sequential CT (N=3) and concomitant CT strategy (N=1). Three pts were in CR 274, 279 and 480 days after the allograft and the fourth has not yet been evaluated. Allografts are now scheduled for 6 pts. With a median follow-up of 9.1 months (95%CI, 6.1-14) following the initiation of chemotherapy (alone or combined) the median PFS and OS were 8.4 and 14.6 months, respectively. Conclusions: Our retrospective study showed that pts with an unsatisfactory response or PD with anti-PD-1 therapy had a new objective response with CT alone (61%) or CT in combination with anti-PD-1 therapy (90%). This response could make some pts eligible for allograft. Prospective clinical trials are needed to confirm the synergistic effect of CT with anti-PD-1 therapy and to determine which CT provides the best results in combination with these checkpoint inhibitors. Figure 1 Figure 1. Disclosures Ysebaert: Janssen: Consultancy, Research Funding, Speakers Bureau. Ghesquières: Celgene and Mundipharma: Consultancy, Honoraria; Roche: Research Funding.

Detection Of Potentially Embolic Intracardiac Thrombus In Patients With Cerebral Ischaemia

1981 ◽  
Author(s):  
R M Donaldson ◽  
C Humphrey ◽  
R W Emanuel ◽  
C Earl
Keyword(s):  
Cerebral Ischaemia ◽  
Clinical Evidence ◽  
The Other ◽  
Intracardiac Thrombus ◽  
Cardiac Assessment ◽  
Patients At Risk ◽  
Group 2 ◽  
Histological Confirmation ◽  
A Prospective Study ◽  
Group 1

In a prospective study, 5 8 consecutive patients presenting clinically with transient or permanent focal cerebral ischaemia underwent cardiac assessment which included twodimensional echocardiography (2DE). All had been referred after neurological investigations failed to establish the underlying cause of the neurological event. 5 0 of these patients had no evidence of heart disease (Group 1); the other 28 patients had clinical evidence of an underlying cardiac abnormality or arrhythmia (Group 2). One of the patients in Group 1 had echocardiographic evidence of mitral valve prolapse; no cardiac pathology was visualised in the other 29 patients in this group. In 5 of the 28 patients from Group 2, intracardiac thrombus presumed responsible for the neurological manifestations was demonstrated by 2DE and histological confirmation obtained following surgery or at necropsy in 4 of these cases. No abnormality was found on 2DE in the other 23 patients. All acoustically dense thrombi were larger than 1.5 cm and had some degree of organisation. Two were recent, histologically showing red blood cells and mplatelet-fibrin columnation. The accoustical similarity of small thrombi to the surrounding blood or endocardium may hinder the sensitivity of the method.The technique may help to define patients at risk from embolisation. As intracardiac thrombi are a common and potentially an easily prevented cause of stroke,a 2DE screen should be undertaken in patients with arrhythmias or clinical evidence of cardiac disease who have experienced one or more episodes of cerebral ischaemia.

Hyaluronan affects extravascular water in lungs of unanesthetized rabbits

1989 ◽  
Vol 66 (6) ◽  
pp. 2595-2599 ◽  
Author(s):  
J. Bhattacharya ◽  
T. Cruz ◽  
S. Bhattacharya ◽  
B. A. Bray
Keyword(s):  
Body Weight ◽  
Water Content ◽  
Extravascular Lung Water ◽  
Volume Expansion ◽  
The Other ◽  
Lung Water ◽  
Intravenous Saline ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

We have determined whether changes in lung hyaluronan content affect extravascular water in lungs of unanesthetized rabbits. Three groups of experiments were performed. In group 1 (n = 12), no infusions were given; in group 2, nine pairs of rabbits received either intravenous hyaluronidase (750 U.kg-1.min-1) or an equivalent volume of saline; in group 3, nine pairs of rabbits received either hyaluronidase or saline, followed by intravenous saline infusion amounting to 24% of body weight. At the end of each experiment, one lung was analyzed for extravascular lung water by the wet-dry method. Except for group 3, in all animals the other lung was analyzed for hyaluronan content by a method that involved hydrolyzing lung hyaluronan with fungal hyaluronidase to release reducing N-acetyl glucosamine groups, which were quantified. In group 1, lung hyaluronan, which varied from 50 to 159 micrograms/g dry wt (mean 106 +/- 35 micrograms/g dry wt), significantly correlated with variation in extravascular lung water (mean 4.2 +/- 0.3 g/g dry wt). In group 2 rabbits given hyaluronidase, lung hyaluronan was 40% lower and extravascular lung water was 14.6% lower than in paired controls (P less than 0.01). In group 3, volume expansion did not affect lung water, except after hyaluronidase when lung water was 47% higher than paired controls. We conclude that in the lung the content of hyaluronan is one of the determinants of extravascular water content.

scholarly journals Evaluation of the concentration of malondialdehyde and nitrite in patients with sickle cell anemia treated or not with hydroxyurea

2010 ◽  
Vol 8 (4) ◽  
pp. 414-418 ◽  
Author(s):  
Darcielle Bruna Dias Elias ◽  
Rivelilson Mendes de Freitas ◽  
Romélia Pinheiro Gonçalves ◽  
Hemerson Yuri Ferreira Magalhães ◽  
Jacqueline Holanda de Sousa ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Serum Levels ◽  
The Other ◽  
Control Group ◽  
Clinical Variables ◽  
Short Period ◽  
Significant Difference ◽  
Group 2 ◽  
Group 1

ABSTRACT Objective: To determine the serum levels of malondialdehyde and nitrite in patients with sickle cell anemia treated or not with hydroxyurea in outpatient's setting. Methods: Of the 65 patients with sickle cell anemia selected for the study, 51 were not treated with hydroxyurea (Group 1), 14 made chronic use of hydroxyurea (Group 2) and 20 individuals had no hemoglobinopathies (Control Group). Results: The Control Group had a lower and more homogeneous concentration of malondialdehyde levels as compared to the other groups. The results of Groups 1 and 2 showed increased values of malondialdehyde levels when compared to the Control Group. Considering the values of Groups 1 and 2, there were no significant changes in the malondialdehyde levels. There was no significant difference in the serum levels of nitrite between the groups. Group 2 presented a statistically significant correlation between serum malondialdehyde levels and the clinical variables investigated. In turn, Group 1 showed correlation only with occurrence of three or more vaso-occlusive crises. There was no correlation between nitrite levels and the clinical variables. Conclusion: The results revealed that during the pathogenesis of sickle cell anemia, an increase in lipid peroxidation was observed. On the other hand, no changes in oxidative parameters were detected during treatment with hydroxyurea, probably due to the short period of treatment of the patients studied.

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