10 results on '"Crawley, Charles"'
Search Results
2. Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.
- Author
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Othman J, Tiong IS, O'Nions J, Dennis M, Mokretar K, Ivey A, Austin M, Latif AL, Amer M, Chan WY, Crawley C, Crolla F, Cross J, Dang R, Elliot J, Fong CY, Galli S, Gallipoli P, Hogan F, Kalkur P, Khan A, Krishnamurthy P, Laurie J, Loo S, Marshall S, Mehta P, Murthy V, Nagumantry S, Pillai S, Potter N, Sellar R, Taylor T, Zhao R, Russell NH, Wei AH, and Dillon R
- Subjects
- Humans, Prognosis, Mutation, Cytarabine, Neoplasm, Residual genetics, Nucleophosmin, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic
- Abstract
Abstract: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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3. NICE guidance on nivolumab plus ipilimumab for untreated, unresectable malignant pleural mesothelioma.
- Author
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Adler AI, Slayen S, Stegenga H, Guo Y, Diaz R, Welton NJ, Westwood N, Doull I, and Crawley C
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Ipilimumab therapeutic use, Nivolumab therapeutic use, Mesothelioma drug therapy, Mesothelioma pathology, Mesothelioma, Malignant drug therapy, Pleural Neoplasms drug therapy, Pleural Neoplasms pathology
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- 2022
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4. RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature.
- Author
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Chapman MA, Sive J, Ambrose J, Roddie C, Counsell N, Lach A, Abbasian M, Popat R, Cavenagh JD, Oakervee H, Streetly MJ, Schey S, Koh M, Willis F, Virchis AE, Crowe J, Quinn MF, Cook G, Crawley CR, Pratt G, Cook M, Braganza N, Adedayo T, Smith P, Clifton-Hadley L, Owen RG, Sonneveld P, Keats JJ, Herrero J, and Yong K
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dexamethasone therapeutic use, Doxorubicin therapeutic use, Humans, Kaplan-Meier Estimate, Machine Learning, Mutation, Proportional Hazards Models, Sequence Analysis, RNA, Transcriptome, Treatment Outcome, United States, Antineoplastic Agents therapeutic use, Bortezomib therapeutic use, Lenalidomide therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma genetics
- Abstract
Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma., (© 2018 by The American Society of Hematology.)
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- 2018
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5. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).
- Author
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Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, Nunnick J, Khanum R, Raghavan M, Cook M, Snowden JA, Griffiths M, Russell N, Yin J, Crawley C, Cook G, Vyas P, Moss P, Malladi R, and Craddock CF
- Subjects
- Adult, Aged, Antigens, Neoplasm immunology, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Azacitidine administration & dosage, Azacitidine adverse effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cytokines metabolism, Epitopes immunology, Female, Humans, Leukemia, Myeloid, Acute therapy, Lymphocyte Count, Lysosomal-Associated Membrane Protein 1 metabolism, Male, Middle Aged, T-Lymphocytes, Regulatory drug effects, Transplantation, Homologous, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.
- Published
- 2012
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6. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution.
- Author
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Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P, Milligan D, Collin M, Crawley C, Johnson P, Clark A, Parker A, Bloor A, Pettengell R, Snowden J, Pettitt A, Clark R, Hale G, Peggs K, Thomson K, Morris E, and Mackinnon S
- Subjects
- Adult, Alemtuzumab, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm immunology, Antigens, CD immunology, Antigens, Neoplasm immunology, Antineoplastic Agents administration & dosage, Antineoplastic Agents immunology, Antineoplastic Agents pharmacokinetics, CD52 Antigen, Female, Glycoproteins immunology, Graft vs Host Disease immunology, Graft vs Host Disease pathology, Humans, Male, Melphalan administration & dosage, Melphalan therapeutic use, Middle Aged, Siblings, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antineoplastic Agents therapeutic use, Graft vs Host Disease prevention & control, HLA Antigens immunology, Stem Cell Transplantation methods, Transplantation Conditioning
- Abstract
In vivo alemtuzumab reduces the risk of graft-versus-host disease (GVHD) and nonrelapse mortality after reduced intensity allogeneic transplantation. However, it also delays immune reconstitution, leading to frequent infections and potential loss of graft-versus-tumor responses. Here, we tested the feasibility of alemtuzumab dose deescalation in the context of fludarabine-melphalan conditioning and human leukocyte antigen (HLA)-identical sibling transplantation. Alemtuzumab was given 1-2 days before graft infusion, and dose reduced from 60 mg to 20 mg in 4 sequential cohorts (total n = 106). Pharmacokinetic studies were fitted to a linear, 2-compartment model in which dose reduction led to incomplete saturation of CD52 binding sites and greater antibody clearance. Increased elimination was particularly evident in the 20-mg group in patients who had CD52-expressing tumors at time of transplantation. The 20-mg dose was also associated with greater risk of severe GVHD (acute grade III-IV or chronic extensive) compared with > 20 mg (hazard ratio, 6.7; 95% CI, 2.5-18.3). In contrast, dose reduction to 30 mg on day -1 was associated with equivalent clinical outcomes to higher doses but better lymphocyte recovery at 12 months. In conclusion, alemtuzumab dose reduction to 30 mg is safe in the context of reduced intensity conditioning and HLA-identical sibling transplantation. This trial was registered at http://www.ncrn.org.uk as UKCRN study 1415.
- Published
- 2010
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7. Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia.
- Author
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Heaney NB, Copland M, Stewart K, Godden J, Parker AN, McQuaker IG, Smith GM, Crawley C, Shepherd P, and Holyoake TL
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- Adult, Benzamides, Graft Survival, Graft vs Host Disease, Humans, Imatinib Mesylate, Length of Stay, Middle Aged, Piperazines therapeutic use, Pyrimidines therapeutic use, Treatment Outcome, Virus Activation, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Lymphocyte Transfusion methods
- Abstract
Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.
- Published
- 2008
- Full Text
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8. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning.
- Author
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Crawley C, Iacobelli S, Björkstrand B, Apperley JF, Niederwieser D, and Gahrton G
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- Adult, Aged, Disease-Free Survival, Female, Humans, Male, Middle Aged, Recurrence, Retrospective Studies, Risk Factors, Survival Rate, Transplantation, Homologous, Lymphocyte Depletion, Multiple Myeloma mortality, Multiple Myeloma therapy, Peripheral Blood Stem Cell Transplantation, Transplantation Conditioning
- Abstract
Despite the widespread adoption of reduced-intensity conditioning (RIC) for myeloma, there are few data comparing outcomes with RIC with myeloablative conditioning (MAC). We report the outcomes of patients undergoing allogeneic transplantations for myeloma and reported to the EBMT. A minimum data set was available on 320 RIC and 196 MAC allografts performed between 1998 and 2002. The RIC patients were older (51 vs 45 years) with more progressive disease (28% vs 21%) and more had received a prior transplant (76% vs 11%). In addition, there was a longer time to transplantation and an increased use of peripheral blood and T-cell depletion. For RIC and MAC, respectively, the nonrelapse mortality (NRM) at 2 years was 24% and 37% (P = .002); overall survival, 38.1% and 50.8% (not significant [ns]); and progression-free survival (PFS), 18.9% and 34.5% (P = .001). On multivariate analysis, RIC was associated with a reduction in NRM (HR, 0.5), but this was offset by an increase in relapse risk (HR, 2.0), and the conditioning intensity did not impact on overall survival or retain significance for PFS. These data suggest that there is a continuing need to investigate dose intensity in the conditioning for myeloma allografts.
- Published
- 2007
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9. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT.
- Author
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Crawley C, Szydlo R, Lalancette M, Bacigalupo A, Lange A, Brune M, Juliusson G, Nagler A, Gratwohl A, Passweg J, Komarnicki M, Vitek A, Mayer J, Zander A, Sierra J, Rambaldi A, Ringden O, Niederwieser D, and Apperley JF
- Subjects
- Adolescent, Adult, Aged, Benzamides, Disease Progression, Europe, Female, Graft vs Host Disease, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Male, Middle Aged, Piperazines therapeutic use, Prognosis, Pyrimidines therapeutic use, Risk Factors, Societies, Scientific, Survival Rate, Transplantation Conditioning, Treatment Outcome, Bone Marrow Transplantation, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive surgery
- Abstract
This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.
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- 2005
- Full Text
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10. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT.
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Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, Juliusson G, Ahlberg L, Nagler A, Shimoni A, Sureda A, Boiron JM, Einsele H, Chopra R, Carella A, Cavenagh J, Gratwohl A, Garban F, Zander A, Björkstrand B, Niederwieser D, Gahrton G, and Apperley JF
- Subjects
- Adult, Aged, Female, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Humans, Lymphocyte Depletion, Male, Middle Aged, Multiple Myeloma complications, Multiple Myeloma mortality, Risk Factors, Survival Analysis, Transplantation Conditioning methods, Transplantation, Homologous, Treatment Outcome, Vidarabine therapeutic use, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma therapy, Vidarabine analogs & derivatives
- Abstract
We report the outcome of 229 patients who received an allograft for myeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the European Group for Blood and Marrow Transplantation (EBMT). The median age was 52 years and 64% were male. Conditioning regimens were heterogeneous, but most were fludarabine based and T cell depleted with antithymocyte globulin or alemtuzumab. Transplantation-related mortality (TRM) at 1 year was 22%. The 3-year overall survival (OS) and progression-free survival (PFS) were 41% and 21%, respectively. Adverse OS was associated with chemoresistant disease (relative risk [RR], 2.9), more than 1 prior transplantation (RR, 2.0), and male patients with female donors (RR, 1.45). Adverse PFS was associated with chemoresistance (RR, 2.4) and alemtuzumab (RR, 1.8). TRM was increased with female-to-male donation (RR, 2.5) and transplantation more than 1 year from diagnosis (RR, 2.3). Grades II to IV acute graft-versus-host disease (aGvHD) occurred in 31%. Chronic GvHD was associated with better OS and PFS and were 84% and 46% for limited, 58% and 30% for extensive, and 29% and 12% in its absence suggesting that a graft-versus-myeloma effect is important. While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit.
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- 2005
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