Publications by authors named "Peter Ganly"

25 Publications

  • Page 1 of 1

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma.

J Clin Oncol 2021 Aug 11;39(22):2430-2442. Epub 2021 Jun 11.

University Hospital Hôtel Dieu, Nantes, France.

Purpose: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS).

Patients And Methods: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 2 or 3), previous proteasome inhibitor (PI) exposure (yes no), and International Staging System disease stage (I or II III). OS (intent-to-treat population) was a key secondary end point.

Results: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns.

Conclusion: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
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http://dx.doi.org/10.1200/JCO.21.00972DOI Listing
August 2021

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion.

Haematologica 2020 10 13;106(9):2354-2363. Epub 2020 Oct 13.

Dana-Farber Cancer Institute, Boston, MA.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.
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http://dx.doi.org/10.3324/haematol.2020.259432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409041PMC
October 2020

c-MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide-dexamethasone in myeloma.

Eur J Haematol 2020 Jul 15;105(1):35-46. Epub 2020 Apr 15.

Department of Hematology, University Hospital Hôtel Dieu, University of Nantes, Nantes, France.

Objectives: In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).

Methods: RNA sequencing data were used to investigate the basis of these differences.

Results: The PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.

Conclusions: PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.
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http://dx.doi.org/10.1111/ejh.13405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317705PMC
July 2020

Impact of increased access to novel agents on the survival of multiple myeloma patients treated at a single New Zealand centre.

Intern Med J 2019 05;49(5):598-606

Haematology Research Group, Christchurch Hospital and Department of Pathology and Biomedical Science, Christchurch, New Zealand.

Background: The impact of changes in novel agent (NA) usage on the survival of multiple myeloma (MM) patients in real-world hospital settings is unclear. In New Zealand (NZ) in 2011, frontline bortezomib became available and thalidomide availability was expanded.

Aim: This retrospective study analyses the impact these change had on the survival of MM patients treated at a NZ hospital.

Methods: Clinical and overall survival (OS) data were collected on MM patients who were treated at Christchurch Hospital during 2000-2009 (pre-cohort, n = 337) and 2011-2017 (post-cohort, n = 343). Outcomes were compared using pre-cohort data truncated at 2011.

Results: Patients in the post-cohort had significant increases (P < 0.001) in not only NA usage (85 vs 55%) and OS (median = 56 vs 44 months) but also the proportion (74 vs 49%) of young patients (age < 70) who received an autologous stem cell transplant (ASCT). Separate analysis of older patients demonstrated that those in the post-cohort had significantly longer OS (median OS 28 vs 17, P < 0.001) although 5-year relative survival remained less than 50%. Separate analysis of young patients demonstrated that those in the post-cohort had significantly increased initial OS with the survival curves converging at 5 years. Although ASCT-treated patients had similar OS in each cohort, their progression-free survival (PFS) was significantly increased in the post-cohort (median 40 vs 20 months, P < 0.0001).

Conclusion: In the setting of a NZ hospital the increased availability of NA was associated with a significant improvement in both the OS of older patients and the PFS of ASCT patients.
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http://dx.doi.org/10.1111/imj.14155DOI Listing
May 2019

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients.

Blood 2017 12 20;130(24):2610-2618. Epub 2017 Oct 20.

Dana-Farber Cancer Institute, Boston, MA.

Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.
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http://dx.doi.org/10.1182/blood-2017-06-791228DOI Listing
December 2017

Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.

Lancet Haematol 2017 May 20;4(5):e225-e236. Epub 2017 Mar 20.

Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias.

Methods: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187.

Findings: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study.

Interpretation: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited.

Funding: CTI BioPharma Corp.
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http://dx.doi.org/10.1016/S2352-3026(17)30027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209752PMC
May 2017

Precision oncology for acute myeloid leukemia using a knowledge bank approach.

Nat Genet 2017 Mar 16;49(3):332-340. Epub 2017 Jan 16.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.

Underpinning the vision of precision medicine is the concept that causative mutations in a patient's cancer drive its biology and, by extension, its clinical features and treatment response. However, considerable between-patient heterogeneity in driver mutations complicates evidence-based personalization of cancer care. Here, by reanalyzing data from 1,540 patients with acute myeloid leukemia (AML), we explore how large knowledge banks of matched genomic-clinical data can support clinical decision-making. Inclusive, multistage statistical models accurately predicted likelihoods of remission, relapse and mortality, which were validated using data from independent patients in The Cancer Genome Atlas. Comparison of long-term survival probabilities under different treatments enables therapeutic decision support, which is available in exploratory form online. Personally tailored management decisions could reduce the number of hematopoietic cell transplants in patients with AML by 20-25% while maintaining overall survival rates. Power calculations show that databases require information from thousands of patients for accurate decision support. Knowledge banks facilitate personally tailored therapeutic decisions but require sustainable updating, inclusive cohorts and large sample sizes.
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http://dx.doi.org/10.1038/ng.3756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764082PMC
March 2017

Genomic Classification and Prognosis in Acute Myeloid Leukemia.

N Engl J Med 2016 Jun;374(23):2209-2221

Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Cancer, Institute of Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); and the Department of Pathology, University of Otago, Christchurch, New Zealand (P.G., P.J.C.).

Background: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice.

Methods: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes.

Results: We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials.

Conclusions: The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.).
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http://dx.doi.org/10.1056/NEJMoa1516192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979995PMC
June 2016

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

N Engl J Med 2016 Apr;374(17):1621-34

From University Hospital Hôtel Dieu, Nantes (P.M., C.T.), the Department of Hematology, Institut Paoli-Calmettes, Marseille (A.-M.S.), and the Department of Hematology and Cell Therapy, Hospital Saint Antoine, Paris (L.G.) - all in France; the Department of Haematology and Stem Cell Transplantation, St. István and St. László Hospital, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary (T.M.); the Department of Haemato-oncology and Bone Marrow Transplantation, Medical University of Lublin, and St. John's Cancer Center, Lublin, Poland (N.G.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary (N.J.B.), and the Division of Hematology, Department of Medicine, University of Alberta, Edmonton (I.S.) - both in Canada; the Department of Hematology, Skåne University Hospital, Lund University, Lund, Sweden (M.H.); Hematology and Oncology, University Hospital Brno, Brno, Czech Republic (L.P.); the Department of Haematology, Christchurch Hospital, Christchurch (P. Ganly), the Department of Haematology, Palmerston North Hospital, Palmerston North, Manawatu (B.W.B.), the Department of Haematology, Middlemore Hospital, Auckland (S.R.J.), and the Department of Haematology, North Shore Hospital, Auckland (D.R.S.) - all in New Zealand; the Department of Hematology, University Hospital Rigshospitalet, Copenhagen (P. Gimsing); Myeloma Unit, Division of Hematology, University of Turin, Turin (A.P.), and Seràgnoli Institute of Haematology, Bologna University School of Medicine, St. Orsola-Malpighi University Hospital, Bologna (M.C.) - both in Italy; the Division of Hematology, Mayo Clinic, Rochester, MN (S.K., F.K.B.); and Dana-Farber Cancer Institute, Boston (J.P.L., P.G.R.), and Millennium Pharmaceuticals, Cambridge (D.T.B., J.L., A.D.B., A.-M.H., H.V.) - both in Massachusetts.

Background: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival.

Results: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups.

Conclusions: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).
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http://dx.doi.org/10.1056/NEJMoa1516282DOI Listing
April 2016

Allogeneic hematopoietic cell transplant for multiple myeloma using reduced intensity conditioning therapy, 1998-2006: factors associated with improved survival outcome.

Leuk Lymphoma 2011 Sep;52(9):1727-35

Australasian Bone Marrow Transplant Recipient Registry, Darlinghurst, NSW, Australia.

This study reports on the outcome of 95 allogeneic hematopoietic cell transplants (HCTs) using reduced intensity conditioning (RIC) performed for patients with multiple myeloma (MM) in Australia and New Zealand between 1998 and 2006. The median age at HCT was 52 years. Of the 32 patients for whom the allograft was performed as a first transplant, 15 (47%) had their allograft less than 1 year from diagnosis, while for the 63 patients who had an allograft following an autograft, nine (14%) were allografted within 1 year post-diagnosis (p < 0.001). The cumulative incidence of transplant-related mortality (TRM) was 19% at 1 year post-transplant. At 5 years post-transplant the overall survival (OS) was 40% and progression-free survival (PFS) was 23%, with no apparent survival plateau. Three factors were independently favorable predictors of OS in a Cox regression model: immunoglobulin G (IgG) myeloma (hazard ratio [HR] = 0.42, 95% confidence interval [CI] 0.24-0.75, p = 0.004), a human leukocyte antigen (HLA)-identical sibling donor (HR = 0.37, 95% CI 0.18-0.74, p = 0.005), and less than 1 year between MM diagnosis and RIC HCT (HR = 0.27, 95% CI 0.12-0.59, p = 0.001). Patterns of outcome indicate that RIC HCT may offer the potential for cure for only a small group of patients with MM.
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http://dx.doi.org/10.3109/10428194.2011.582201DOI Listing
September 2011

Chronic myeloid leukemia in the Asia-Pacific region: current practice, challenges and opportunities in the targeted therapy era.

Leuk Res 2010 Nov;34(11):1459-71

Division of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.

Chronic myeloid leukemia (CML) management varies across Asia due to disparities in affluence and healthcare provision. We surveyed CML management practice at 33 hospitals in 14 countries/regions to identify treatment challenges and opportunities for harmonization. Patients were generally treated according to international guidelines; however, tyrosine kinase inhibitors (TKIs) and molecular monitoring are inaccessible to many patients not covered by national insurance or eligible for subsidized treatment. Late diagnosis and suboptimal monitoring, often due to cost and accessibility issues, are challenges. Priorities for Asia include: extending accessibility to TKIs; specialist laboratory monitoring; and enriching data to support regional CML management guidelines.
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http://dx.doi.org/10.1016/j.leukres.2010.03.033DOI Listing
November 2010

Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia.

J Clin Oncol 2010 Apr 1;28(10):1756-65. Epub 2010 Mar 1.

Department of Hematology, Medical University of Lodz, Ciolkowskiego 2, Lodz, Poland 93-510.

Purpose: Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL.

Patients And Methods: This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276).

Results: After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life.

Conclusion: R-FC significantly improved the outcome of patients with previously treated CLL.
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http://dx.doi.org/10.1200/JCO.2009.26.4556DOI Listing
April 2010

Randomized, double-blind, placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia.

Curr Med Res Opin 2009 Sep;25(9):2109-20

Temple University Hospital, Philadelphia, PA, USA.

Objective: Darbepoetin alfa is effective in treating chemotherapy-induced anemia (CIA). Administration of subcutaneous darbepoetin alfa every 3 weeks (Q3W) could simplify treatment through synchronization with common Q3W chemotherapy regimens. We report results from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of fixed-dose Q3W darbepoetin alfa in patients with a wide variety of tumor types who experienced CIA.

Research Design And Methods: Patients aged > or = 18 years with anemia (hemoglobin <11 g/dL) being treated for nonmyeloid malignancy were randomized 1:1 to receive darbepoetin alfa 300 microg (n = 193) or placebo (n = 193) subcutaneously Q3W from weeks 1 to 13 in this 16-week study. Doses could be adjusted per prespecified rules.

Main Outcome Measures: The primary endpoint was the proportion of patients who received > or =1 red blood cell (RBC) transfusion between week 5 and the end of the treatment period (EOTP). The study also analyzed the proportions of patients achieving a hemoglobin concentration > or =11 g/dL and subsequently maintaining hemoglobin levels above 11 g/dL, and the change in hemoglobin concentration over time.

Results: The proportion of patients requiring RBC transfusions between week 5 and EOTP was significantly lower in the darbepoetin alfa-treated group than in the placebo-treated group (24 vs. 41% of patients, a 16.3% difference, p < 0.001). There were no differences between the two treatment arms in quality-of-life measures. Cardiovascular/thromboembolic adverse events were uncommon and were not associated with increases in hemoglobin levels. Study limitations suggest caution in the interpretation of these results: transfusions, the primary endpoint, were recommended but not required if hemoglobin concentrations were < or =8.0 g/dL, and protocol deviations (primarily dosing errors) occurred in approximately one-half of the patients in both treatment groups.

Conclusions: In this study, fixed-dose Q3W darbepoetin alfa appeared to be well-tolerated and effective for the treatment of CIA.

Trial Registration: Study 20030232; ClinicalTrials.Gov Identifier: NCT00110955.
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http://dx.doi.org/10.1185/03007990903084164DOI Listing
September 2009

Successful treatment of transplant-associated microangiopathy with rituximab.

N Z Med J 2009 Apr 3;122(1292):72-4. Epub 2009 Apr 3.

The microangiopathic anaemia with thrombocytopenia--which can occur after haematopoietic stem cell transplant--resembles thrombotic thrombocytopenic purpura but has different pathophysiology and does not respond to plasma exchange. We describe a patient with severe manifestations of this disorder who recovered promptly following treatment with rituximab, an anti-CD20 antibody.
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April 2009

Not walking or communicating--is all well?

Lancet 2008 Dec;372(9655):2086

Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand.

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http://dx.doi.org/10.1016/S0140-6736(08)61870-XDOI Listing
December 2008

A prospective double-blind randomized trial comparing intraluminal ethanol with heparinized saline for the prevention of catheter-associated bloodstream infection in immunosuppressed haematology patients.

J Antimicrob Chemother 2008 Oct 11;62(4):809-15. Epub 2008 Jul 11.

Department of Pathology, Christchurch School of Medicine and Health Sciences, Otago University, Christchurch, New Zealand.

Objectives: The aim of this study was to prospectively evaluate the use of intraluminal ethanol for the prevention of catheter-associated bloodstream infection (CABSI) in immunosuppressed haematology patients.

Patients And Methods: Patients receiving chemotherapy for haematological malignancy or haematopoietic cell transplantation were randomized in a double-blinded manner to receive either intraluminal 70% ethanol/water or heparinized saline locks on a daily basis throughout a prophylactic treatment period. The primary endpoint was an episode of CABSI (defined as 'bacteraemia in a febrile patient with a central venous catheter that was in use within the preceding 48 h and with no other identified focus of infection'). The trial was registered with the Australian Clinical Trials Register: number ACTRN012605000383662.

Results: There were 34 and 30 prophylactic treatment periods in the ethanol and control groups, respectively. CABSI occurred in 3 (9%, 0.60/100 catheter-days) and 11 (37%, 3.11/100 catheter-days) prophylactic treatment periods in the ethanol and control groups, respectively (OR = 0.18, 95% CI 0.05-0.65, P = 0.008). Eleven (32%) and 5 (17%) patients in the ethanol and control groups, respectively, remained afebrile throughout the prophylactic treatment (P = 0.18).

Conclusions: The daily administration of ethanol locks into lumens of central venous catheters effectively reduces the incidence of CABSI.
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http://dx.doi.org/10.1093/jac/dkn284DOI Listing
October 2008

Written advice can provide a safe and acceptable alternative to new patient assessment for selected referrals to haematologists.

Med J Aust 2008 Jan;188(1):9-12

Department of Haematology, Canterbury Health Laboratories and Christchurch Hospital, Christchurch, New Zealand.

Objective: To measure the safety and acceptability of providing written advice (WA) for selected patients referred to a haematology service, as an alternative to inpatient or outpatient assessment.

Design, Setting And Participants: Review of the initial management and subsequent course of patients newly referred to a tertiary referral hospital in Christchurch, New Zealand, between 16 October 2003 and 8 June 2006. Structured questionnaires were sent to all referring doctors and patients recently managed with WA.

Main Outcome Measures: Numbers and diagnoses of patients managed with WA, early assessment or delayed assessment; re-referral and treatment details; characteristics of WA letters; and opinions of referring doctors and their patients on the WA process.

Results: 26% of new referrals (714/2785) were managed with prompt WA, while 16% (455/2785) received the alternative of delayed assessment. After a median follow-up of 23 months (range, 8-40 months), 13% of those managed with WA (91/714) were re-referred back to the same haematologists; 7% (52/714) were assessed in hospital and 2% (15/714) eventually required treatment. There were no deaths due to haematological causes. Over 90% of responding referring doctors said the WA process was rapid and effective, and 77% of recently managed patients were pleased to be treated by their own doctors.

Conclusions: Using WA to manage a substantial minority of patients referred to haematologists can be rapid and safe. It is widely accepted by referring doctors.
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http://dx.doi.org/10.5694/j.1326-5377.2008.tb01495.xDOI Listing
January 2008

Treatment with intravenous immunoglobulin is not a panacea but should be limited to those who can benefit.

N Z Med J 2006 Dec 1;119(1246):U2335. Epub 2006 Dec 1.

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December 2006

Identification of JAK2V617F in patients with polycythemia is highly correlated with conventional criteria for diagnosis of polycythemia vera.

Am J Hematol 2007 Jan;82(1):80-2

Cancer Genetics Research Group, Christchurch School of Medicine and Health Science, Christchurch, New Zealand.

One hundred and forty four patients with a clinical indication of suspected polycythemia vera (PV), essential thrombocythemia, or idiopathic myelofibrosis were screened for JAK2(V617F) and the mutation frequency was 47, 51, and 50%, respectively. Previous investigations enabled 42 of 66 patients with suspected PV to be definitively diagnosed either as PV according to WHO criteria or to have this diagnosis excluded. Ninety-six percent of those with PV were JAK2(V617F), whereas all patients without PV did not have the mutation. Early screening of suspected PV patients for JAK2(V617F) rapidly identifies nearly all those with PV without invasive or less specific conventional investigations.
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http://dx.doi.org/10.1002/ajh.20721DOI Listing
January 2007

Translocation (5;10)(q22;q24) in a case of acute lymphoblastic leukemia.

Cancer Genet Cytogenet 2006 Feb;165(1):36-40

Cancer Genetics Research Group, Department of Pathology, Christchurch School of Medicine & Health Sciences, PO Box 4345, University of Otago, Christchurch, New Zealand.

The activation of genes important to acute lymphoblastic leukemia (ALL) may be evidenced by somatically acquired chromosomal translocations found recurrently in different patient subgroups. It is for this reason that research efforts have focused on the molecular dissection of recurring chromosomal rearrangements. However, even though a large number of leukemia-causing genes have been identified, the genetic basis of many ALL cases remains unknown. We and others have reasoned that novel translocations found in the leukemic cells of ALL patients may mark the location of more frequent gene rearrangements that are otherwise hidden submicroscopically within normal or complex karyotypes. Towards this end, we here describe the first reported association of a t(5;10)(q22;q24) with adult ALL. Fluorescence in situ hybridization (FISH) and Southern blot hybridization studies have eliminated likely involvement of the candidate genes APC and MCC on chromosome 5, and PAX2, TLX1, and NFKB2 on chromosome 10. Results further suggest that the breakpoint on chromosome 5 lies centromeric of APC and the chromosome 10 breakpoint is centromeric of PAX2. The genomic regions disrupted by this t(5;10)(q22;q24) have not previously been associated with leukemia.
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http://dx.doi.org/10.1016/j.cancergencyto.2005.08.008DOI Listing
February 2006

Familial mutations of the transcription factor RUNX1 (AML1, CBFA2) predispose to acute myeloid leukemia.

Leuk Lymphoma 2004 Jan;45(1):1-10

Cancer Genetics Research Group, Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand.

RUNX1 (AML1, CBFA2) is mutated in affected members of families with autosomal dominant thrombocytopenia and platelet dense granule storage pool deficiency. Many of those affected, usually by point mutations in one allele, are predisposed to the development of acute myeloid leukemia (AML) in adult life. The RUNX1 protein complexes with core binding factor beta (CBFB) to form a heterodimeric core binding transcription factor (CBF) that regulates many genes important in hematopoiesis. RUNX1 was first identified as the gene on chromosome 21 that is rearranged by the translocation t(8;21)(q22;q22.12) recurrently found in the leukemic cells of patients with AML. In addition to the t(8;21), RUNX1 is rearranged with one of several partner genes on other chromosomes by somatically acquired translocations associated with hematological malignancies. Point mutations of RUNX1 are also found in sporadic leukemias to reinforce the important position of this gene on the multi-step path to leukemia. In animal models, at least one functional copy of RUNX1 is required to effect definitive embryonic hematopoiesis. Cells expressing dominant-negative mutants of RUNX1 are readily immortalized and transformed, and those RUNX1 mutants which retain CBFB binding ability may possess dominant-negative function. However, in some families there is transmitted one mutated allele of RUNX1 with no dominant-negative function, demonstrating that simple haploinsufficiency of RUNX1 predisposes to AML and also causes a generalized hematopoietic stem cell disorder most recognizable as thrombocytopenia.
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http://dx.doi.org/10.1080/1042819031000139611DOI Listing
January 2004

Constitutional t(5;7)(q11;p15) rearranged to acquire monosomy 7q and trisomy 1q in a patient with myelodysplastic syndrome transforming to acute myelocytic leukemia.

Cancer Genet Cytogenet 2004 Mar;149(2):125-30

Cancer Genetics Research Group, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand.

We report the case of a 61-year-old woman who presented with a myelodysplastic syndrome (MDS) and a t(5;7)(q11.2;p15) in her bone marrow cells. Subsequent analysis of phytohemagglutinin-stimulated peripheral blood lymphocytes and cultured skin fibroblasts showed that the translocation was constitutional. Disruption of chromosome bands 5q11.2 and 7p15 has been described recurrently in MDS and acute myelocytic leukemia (AML) and, although the age of onset was not earlier than usual, it is nonetheless possible that genes interrupted by this translocation may been a predisposing factor for her condition. With progression to AML, a further rearrangement of the constitutional der(7)t(5;7) occurred, involving chromosome arm 1q. Fluorescence in situ hybridization (FISH) with whole-chromosome paints showed that the result of the second rearrangement, a t(1;7)(q32.1;q32), was observed, leading to trisomy of the segment 1q32.1 approximately qter and monosomy of the segment 7q32.1 approximately qter. The acquired imbalances, particularly loss of 7q, are commonly associated with MDS/AML and a poor prognosis; however, this patient remained in remission after treatment for more than two years before AML relapse, perhaps because the affected regions fall outside of the critical regions of imbalance.
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http://dx.doi.org/10.1016/j.cancergencyto.2003.07.006DOI Listing
March 2004

A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloid leukaemia.

Br J Haematol 2002 Jun;117(4):878-81

Cancer Genetics Research Group, Christchurch School of Medicine, Christchurch, New Zealand.

The RUNX1 (AML1, CBFA2) gene is a member of the runt transcription factor family, responsible for DNA binding and heterodimerization of other non-DNA binding transcription factors. RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and lymphoblastic leukaemia. Germline mutations of RUNX1 have also recently been described and are dominantly associated with inherited leukaemic conditions. We have identified a unique point mutation of the RUNX1 gene (A107P) in members of a family with autosomal dominant inheritance of thrombocytopenia. One member has developed acute myeloid leukaemia (AML).
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http://dx.doi.org/10.1046/j.1365-2141.2002.03512.xDOI Listing
June 2002

Fibrinogen Hillsborough: a novel gammaGly309Asp dysfibrinogen with impaired clotting.

Blood 2002 May;99(10):3597-601

Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand.

We present a novel gamma-chain dysfibrinogen that was discovered in a 32-year-old asymptomatic man admitted to the hospital after a car accident. He presented with a low fibrinogen concentration, 0.5 mg/mL, and a prolonged thrombin clotting time, 58 seconds. Analysis of purified fibrinogen by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a gamma-chain variant with an apparently higher molecular weight. Isoelectric focusing (IEF) demonstrated an anodal shift in the banding pattern of the chains and electrospray ionization mass spectrometry (ESIMS) showed a 27-Da increase in the average mass of the unresolved variant and normal gamma chains. DNA sequence analysis showed a heterozygous mutation of GGC (Gly)-->GAC (Asp) at codon 309 of the gamma chain gene. This Gly--> Asp substitution was consistent with the charge change shown by IEF as well as the mass change identified by ESIMS. Functional analysis revealed that thrombin-catalyzed polymerization occurred with a longer lag time, lower rate of lateral aggregation, and similar final turbidity compared to normal and that factor XIII cross-linking was normal. The polymerization results suggest that residue gamma309 is necessary for proper alignment of fibrinogen molecules, specifically in protofibril formation and D:D interactions. gammaGly309 is highly conserved and x-ray structures support the conclusion that the lack of a side chain at this position helps facilitate the close contact between abutting gammaD domains of condensing fibrin monomers during polymerization.
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http://dx.doi.org/10.1182/blood.v99.10.3597DOI Listing
May 2002
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