Publications by authors named "Samar Issa"

25 Publications

  • Page 1 of 1

Extent of radiological response does not reflect survival in primary central nervous system lymphoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab007. Epub 2021 Feb 15.

Department of Neuro-Oncology, Erasmus MC Cancer Institute, Brain Tumor Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: In primary central nervous system lymphoma (PCNSL), small enhancing lesions can persist after treatment. It is unknown whether a difference in response category (complete response [CR], complete response unconfirmed [CRu], or partial response [PR]) reflects survival. We aimed to determine the value of a central radiology review on response assessment and whether the extent of response influenced progression-free and/or overall survival.

Methods: All patients in the HOVON 105/ALLG NHL 24 study with at least a baseline MRI and one MRI made for response evaluation available for central review were included. Tumor measurements were done by 2 independent central reviewers, disagreements were adjudicated by a third reviewer. Crude agreement and interobserver agreement (Cohen's kappa) were calculated. Differences in progression-free and overall survival between different categories of response at the end-of-protocol-treatment were assessed by the log-rank test in a landmark survival-analysis.

Results: Agreement between the central reviewers was 61.7% and between local and central response assessment was 63.0%. Cohen's kappa's, which corrects for expected agreement, were 0.44 and 0.46 (moderate), respectively. Progression agreement or not was 93.3% (kappa 0.87) between local and central response assessment. There were no significant differences in progression-free and overall survival between patients with CR, CRu, or PR at the end-of-protocol-treatment, according to both local and central response assessment.

Conclusions: Reliability of response assessment (CR/CRu/PR) is moderate even by central radiology review and these response categories do not reliably predict survival. Therefore, primary outcome in PCNSL studies should be survival rather than CR or CR/CRu-rate.
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http://dx.doi.org/10.1093/noajnl/vdab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883767PMC
February 2021

MMSE is an independent prognostic factor for survival in primary central nervous system lymphoma.

J Neurooncol 2021 Apr 21;152(2):357-362. Epub 2021 Feb 21.

Department of Neuro-Oncology, Erasmus MC Cancer Institute, Brain Tumor Center, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, Netherlands.

Introduction: To assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients.

Methods: In the HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable.

Results: In univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01-1.08; OS 1.06 (95% CI 1.02-1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02-2.35); OS 1.68 (1.05-2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value.

Conclusion: Neurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old.
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http://dx.doi.org/10.1007/s11060-021-03708-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997829PMC
April 2021

Neurocognitive functioning and radiologic changes in primary CNS lymphoma patients: results from the HOVON 105/ ALLG NHL 24 randomised controlled trial.

Neuro Oncol 2021 Feb 9. Epub 2021 Feb 9.

Erasmus MC Cancer Institute, Brain Tumor Center, University Medical Center Rotterdam, Department of Neuro-Oncology, the Netherlands.

Background: To analyze the effect of treatment on neurocognitive functioning and the association of neurocognition with radiological abnormalities in primary central nervous system lymphoma (PCNSL).

Methods: 199 patients from a phase III trial (HOVON 105/ALLG NHL 24), randomized to standard chemotherapy with or without rituximab, followed in patients ≤60 years-old by 30Gy WBRT, were asked to participate in a neuropsychological evaluation before and during treatment, and up to 2 years post-treatment. Scores were transformed into a standardized z-score; clinically relevant changes were defined as a change in z-score of ≥1 standard deviation. The effect of WBRT was analyzed in irradiated patients. All MRIs were centrally assessed for white matter abnormalities and cerebral atrophy, and their relation with neurocognitive scores over time in each domain was calculated.

Results: 125/199 patients consented to neurocognitive evaluation. Statistically significant improvements in neurocognition were seen in all domains. A clinically relevant improvement was seen only in the motor speed domain, without differences between the arms. In the follow-up of irradiated patients (n=43), no change was observed in any domain score, compared to after WBRT. Small but significant inverse correlations were found between neurocognitive scores over time and changes in white matter abnormalities (regression coefficients: -0.048 to -0.347) and cerebral atrophy (-0.212 to -1.774).

Conclusions: Addition of rituximab to standard treatment in PCNSL patients did not impact neurocognitive functioning up to two years post-treatment, nor did treatment with 30Gy WBRT in patients ≤60 years-old. Increased white matter abnormalities and brain atrophy showed weak associations with neurocognition.
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http://dx.doi.org/10.1093/neuonc/noab021DOI Listing
February 2021

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Br J Haematol 2021 Mar 16;192(6):1049-1053. Epub 2020 Jul 16.

Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
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http://dx.doi.org/10.1111/bjh.16946DOI Listing
March 2021

Bing-Neel syndrome presenting as isolated CNS lymphoplasmacytic lymphoma: A case report and review of the literature.

J Clin Neurosci 2020 Jan 18;71:277-280. Epub 2019 Dec 18.

Department of Haematology, Middlemore Hospital, 100 Hospital Road, Otahuhu, Auckland, New Zealand.

Bing-Neel syndrome (BNS) is characterised by infiltration of the central nervous system by lymphoplasmacytic lymphoma (LPL) cells and is traditionally regarded as a complication of pre-existing systemic Waldenström's macroglobulinaemia (WM). We describe the case of a 49 year old woman with leptomeningeal LPL who did not fulfil diagnostic criteria for concomitant systemic WM at presentation, and who failed to respond to conventional chemotherapy treatment (including high dose methotrexate) but did respond to the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib. This highlights an important variation in the typical natural history of this rare disease and also further supplements emerging evidence regarding efficacy of ibrutinib in its treatment.
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http://dx.doi.org/10.1016/j.jocn.2019.11.013DOI Listing
January 2020

Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis.

Hematol Oncol 2019 Dec 9;37(5):548-557. Epub 2019 Oct 9.

Department of Medical Oncology, University Hospital Basel and University of Basel, Basel, Switzerland.

The CD-20 antibody rituximab is a standard component of treatment of non-Hodgkin B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial-level random-effects meta-analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression-free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment-related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52-1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression-free survival (HR 0.65; 95% CI, 0.45-0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment-related mortality (RR 0.53; 95% CI, 0.20-1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate-based chemotherapy may improve progression-free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.
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http://dx.doi.org/10.1002/hon.2666DOI Listing
December 2019

Carbazole scaffolds in cancer therapy: a review from 2012 to 2018.

J Enzyme Inhib Med Chem 2019 Dec;34(1):1321-1346

b Faculté de Pharmacie - ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, Université de Lyon, Université Claude Bernard Lyon 1 , Lyon , France.

For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.
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http://dx.doi.org/10.1080/14756366.2019.1640692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691762PMC
December 2019

First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study.

J Clin Oncol 2019 04 27;37(12):984-991. Epub 2019 Feb 27.

14 US Oncology Research, The Woodlands, TX.

Purpose: The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) for treatment-naive patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma. This publication provides long-term follow-up data.

Patients And Methods: Patients were monitored for a minimum of 5 years after completion of study treatment for the time-to-event end points of progression-free survival (PFS), event-free survival, duration of response, and overall survival per investigator assessment. Data on the number of patients who received second-line anticancer treatment and the occurrence of other malignancies were also collected.

Results: The medians were not reached for any of the time-to event end points for either the BR or R-CHOP/R-CVP study treatment groups by study completion. PFS rates at 5 years were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with a hazard ratio of 0.61 (95% CI, 0.45 to 0.85; = .0025). The hazard ratio for event-free survival and duration of response ( = .0020 and .0134, respectively) also favored the BR regimen over R-CHOP/R-CVP. However, no significant difference in overall survival was observed. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected; no new safety data were collected during long-term follow-up. A higher number of secondary malignancies was noted in the BR treatment group.

Conclusion: Overall, BR demonstrated better long-term disease control than R-CHOP/R-CVP and should be considered as a first-line treatment option for patients with indolent and mantle-cell lymphoma.
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http://dx.doi.org/10.1200/JCO.18.00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494265PMC
April 2019

Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study.

Lancet Oncol 2019 02 7;20(2):216-228. Epub 2019 Jan 7.

Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.

Background: The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma.

Methods: This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18-70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group-WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m on days 1 and 15, intravenous carmustine 100 mg per m on day 4, intravenous teniposide 100 mg per m on days 2 and 3, and oral prednisone 60 mg per m on days 1-5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing.

Findings: Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55-67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9-51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39-58) in the MBVP group (no rituximab) and 52% (42-61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70-1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes.

Interpretation: We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma.

Funding: Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren.
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http://dx.doi.org/10.1016/S1470-2045(18)30747-2DOI Listing
February 2019

Ibrutinib for the treatment of Bing-Neel syndrome: a multicenter study.

Blood 2019 01 6;133(4):299-305. Epub 2018 Dec 6.

Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.
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http://dx.doi.org/10.1182/blood-2018-10-879593DOI Listing
January 2019

Primary idiopathic CNS non-amyloidogenic light chain deposition disease complicated by treatment-resistant focal seizure disorder.

J Clin Neurosci 2019 Jan 10;59:313-315. Epub 2018 Nov 10.

Department of Neurology, Auckland City Hospital, Auckland, New Zealand.

Light chain deposition disease (LCDD) is a systemic disorder characterised by the pathologic deposition of immunoglobulin light chains, which is histologically distinguished from amyloidosis by failure to stain with Congo red. Central nervous system (CNS)-restricted LCDD is among the rarest manifestations. We describe a unique case complicated by focal onset epilepsy with impaired awareness for which control with anticonvulsant therapy proved difficult.
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http://dx.doi.org/10.1016/j.jocn.2018.10.123DOI Listing
January 2019

Obese non-Hodgkin lymphoma patients tolerate full uncapped doses of chemotherapy with no increase in toxicity, and a similar survival to that seen in nonobese patients.

Leuk Lymphoma 2016 11 4;57(11):2584-92. Epub 2016 Mar 4.

a Department of Haematology , Middlemore Hospital , Auckland , New Zealand ;

The aim of this study is to compare the risk of treatment-related toxicities and long-term survival between obese and nonobese patients with non-Hodgkin lymphoma when treated with full uncapped doses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. A total of 133 patients and 733 cycles of chemotherapy were analyzed. Obese patients did not experience an increased risk of acute treatment-related toxicities (adjusted odds ratio 0.825, p = 0.197), or delayed toxicities (adjusted odds ratio 0.819, p = 0.779). In the subgroup of diffuse large B-cell lymphoma patients (n = 109), treatment response rate was similar between the two body mass index (BMI) groups, and obese patients tended to have superior overall and progression-free survivals, albeit not statistically significant. Full uncapped doses of R-CHOP chemotherapy administered to obese patients with non-Hodgkin lymphoma (NHL) are safe, well tolerated, and do not lead to inferior treatment response or long-term outcomes.
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http://dx.doi.org/10.3109/10428194.2016.1151508DOI Listing
November 2016

Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2016 Apr 15;16(4):182-190.e1. Epub 2016 Jan 15.

Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN.

Background: We previously reported results of the phase III, randomized, noninferiority trial comparing bendamustine-rituximab (BR) with standard R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone)/R-CVP (rituximab/cyclophosphamide/vincristine/prednisone) in previously untreated advanced indolent non-Hodgkin and mantle cell lymphomas. Here we report health-related quality of life (HRQOL) results from the trial.

Methods: HRQOL, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), was a secondary end point. Differences between group means in global health status (GHS), 5-item functioning, and 9 symptoms/single-item measures at week 1 of cycle 1 and end-of- cycles 3 and 6 were examined using the screening (baseline) score as a covariate in analysis of covariance.

Results: Overall EORTC QLQ-C30 compliance was 75.2%, 89.5%, and 89.9% at week 1 of cycle 1 and end-of-cycles 3 and 6, respectively. Patients treated with BR reported improvements in Cognitive Functioning, Physical Functioning, Social Functioning, Emotional Functioning, and GHS as well as reduction in dyspnea, constipation, and fatigue at some, but not all, time points. Patients treated with standard therapy reported less nausea/vomiting at one time point.

Conclusion: Compared with patients treated with standard therapy, patients treated with BR reported better quality of life in several areas.
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http://dx.doi.org/10.1016/j.clml.2016.01.001DOI Listing
April 2016

TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets.

Blood 2015 Feb 17;125(6):915-23. Epub 2014 Dec 17.

Department of Haematology, and Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide, Australia; Australasian Leukemia and Lymphoma Group, Melbourne, Australia; Cancer Theme, South Australia Health and Medical Research Institute, Adelaide, Australia;

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10%, ≤1%, and ≤0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 ≤0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404.
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http://dx.doi.org/10.1182/blood-2014-07-590315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161008PMC
February 2015

Biologically active carbazole derivatives: focus on oxazinocarbazoles and related compounds.

J Enzyme Inhib Med Chem 2015 Apr 3;30(2):180-8. Epub 2014 Apr 3.

EA 4446 Biomolécules Cancer et Chimiorésistances, Faculté de Pharmacie - ISPB, Université Lyon 1 , Lyon , France .

Four series of carbazole derivatives, including N-substituted-hydroxycarbazoles, oxazinocarbazoles, isoxazolocarbazolequinones, and pyridocarbazolequinones, were studied using diverse biological test methods such as a CE-based assay for CK2 activity measurement, a cytotoxicity assay with IPC-81 cell line, determination of MIC of carbazole derivatives as antibacterial agents, a Plasmodium falciparum susceptibility assay, and an ABCG2-mediated mitoxantrone assay. Two oxazinocarbazoles Ib and Ig showed CK2 inhibition with IC50 = 8.7 and 14.0 µM, respectively. Further chemical syntheses were realized and the 7-isopropyl oxazinocarbazole derivative 2 displayed a stronger activity against CK2 (IC50 = 1.40 µM). Oxazinocarbazoles Ib, Ig, and 2 were then tested against IPC-81 leukemia cells and showed the ability to induce leukemia cell death with IC50 values between 57 and 62 μM. Further investigations were also reported on antibacterial and antiplasmodial activities. No significant inhibitory activity on ABCG2 efflux pump was detected.
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http://dx.doi.org/10.3109/14756366.2014.899594DOI Listing
April 2015

Acute transient global ventricular dysfunction as the presenting symptom of anaplastic large-cell lymphoma.

J Clin Oncol 2015 May 24;33(15):e71-3. Epub 2014 Mar 24.

Middlemore Hospital, Auckland, New Zealand

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http://dx.doi.org/10.1200/JCO.2012.48.0996DOI Listing
May 2015

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study.

Blood 2014 May 3;123(19):2944-52. Epub 2014 Mar 3.

Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN;

This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
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http://dx.doi.org/10.1182/blood-2013-11-531327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975PMC
May 2014

Regulation of microRNAs in cancer metastasis.

Biochim Biophys Acta 2014 Apr 22;1845(2):255-65. Epub 2014 Feb 22.

Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, 450 Brookline Avenue, HIM 246, Boston, MA 02215, USA. Electronic address:

Metastasis is a phenomenon of crucial importance in defining prognosis in patients with cancer and is often responsible for cancer-related mortality. It is known that several steps are necessary for clonal cells to disseminate from their primary tumor site and colonize distant tissues, thus originating metastatic lesions. Therefore, investigating the molecular actors regulating this process may provide helpful insights in the development of efficient therapeutic responses. Recent evidences have indicated the role of microRNAs (miRNAs) in modulating the metastatic process in solid tumors. miRNAs are small regulatory non-coding RNAs that bind to specific target mRNAs, leading to translational repression. miRNAs are known to act as negative regulators of gene expression and are involved in the regulation of biological processes, including cell growth, differentiation and apoptosis, both in physiological conditions and during diseases, such as tumors. In the specific field of tumorigenesis, miRNAs play an important role in mediating oncogenesis and favoring tumor progression, as a result of their ability to modulate epithelial-to-mesenchymal transition (EMT) and other series of events facilitating the formation of metastasis. The role of miRNAs in cancer development has been widely studied and has helped elucidate events such as the change in expression of oncogenes, tumor-suppressors and cancer-related proteins. This review focuses on the mechanisms underlying the role of miRNAs as part of the metastatic process.
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http://dx.doi.org/10.1016/j.bbcan.2014.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170185PMC
April 2014

Is rheumatoid arthritis a B-cell haematological disease with a predilection for the joints? Following the B cell thread to its logical conclusion.

Med Hypotheses 2014 Mar 21;82(3):266-70. Epub 2013 Dec 21.

Department of Molecular Medicine and Pathology, FMHS, University of Auckland, Auckland, New Zealand; Department of Haematology, Middlemore Hospital, Counties Manakau District Health Board, Auckland, New Zealand.

B-cell depleting therapy (BCDT) is effective in suppressing synovitis and erosions in rheumatoid arthritis suggesting that a cell of the B-lymphocyte lineage is critical in the pathogenesis of this disease. Non-Hodgkins lymphoma (NHL) also responds to BCDT but multiple myeloma (MM), does not as cells have differentiated beyond the CD20-bearing stage. However, there are similarities between B-NHL, MM and RA that suggest all 3 conditions could be initiated and perpetuated by the same cellular players. Numerous plasma cells and B cells are present within rheumatoid synovial membrane, and subarticular bone where they contribute to osteitis. On MRI scans this appears as bone oedema, which has been demonstrated to precede the development of bone erosions. Plasma cell clonality has been detected within RA synovial membrane and bone marrow. It is proposed that RA could represent a "forme fruste" of a B cell neoplastic condition, with production of autoantibodies that target a self-antigen within the joint. The activation of rheumatoid bone osteoclasts by anticitrullinated protein antibodies supports this theory. The erosions of RA would have parallels with the lytic lesions of MM but autoantigen targeting dictates that erosions occur at joint margins. This theory is discussed from rheumatologic and haematologic perspectives.
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http://dx.doi.org/10.1016/j.mehy.2013.12.007DOI Listing
March 2014

A case of refractory anemia with ring sideroblasts and associated thrombocytosis.

Blood 2013 May;121(21):4256

Middlemore Hospital, New Zealand.

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http://dx.doi.org/10.1182/blood-2012-11-469189DOI Listing
May 2013

Central nervous system recurrence of systemic lymphoma in the era of stem cell transplantation--an International Primary Central Nervous System Lymphoma Study Group project.

Haematologica 2013 May 9;98(5):808-13. Epub 2012 Nov 9.

Dept of Neuro-Oncology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Autologous stem cell transplantation has greatly improved the prognosis of systemic recurrent non-Hodgkin's lymphoma. However, no prospective data are available concerning the feasibility and efficacy of this strategy for systemic lymphoma relapsing in the central nervous system. We, therefore, we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centers in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World Health Organization performance status of 2, of whom 76% had diffuse large B-cell histology. The majority (79%) of these patients were treated with systemic chemotherapy with or without intravenous rituximab. Twenty-seven patients (29%) were transplanted; age and insufficient response to induction chemotherapy were the main reasons for not being transplanted in the remaining 65 patients. The median overall survival was 7 months (95% confidence interval 2.6-11.4), being 8 months (95% confidence interval 3.8-5.2) for patients ≤ 65 years old. The 1-year survival rate was 34.8%; of the 27 transplanted patients 62% survived more than 1 year. The Memorial Sloan Kettering Prognostic Index for primary central nervous system lymphoma was prognostic for both undergoing transplantation and survival. In conclusion, despite the availability of autologous stem cell transplantation for patients with central nervous system progression or relapse of systemic lymphoma, prognosis is still poor. Long-term survival is, however, possible and more likely in patients able to undergo stem cell transplantation.
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http://dx.doi.org/10.3324/haematol.2012.070839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640129PMC
May 2013

Primary prophylaxis with granulocyte colony-stimulating factor (GCSF) reduces the incidence of febrile neutropenia in patients with non-Hodgkin lymphoma (NHL) receiving CHOP chemotherapy treatment without adversely affecting their quality of life: cost-benefit and quality of life analysis.

Support Care Cancer 2013 Mar 13;21(3):841-6. Epub 2012 Sep 13.

Haematology Department, Middlemore Hospital, Auckland, New Zealand.

Purpose: Treatment of non-Hodgkin lymphoma (NHL) with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) is known to be associated with a significant risk of febrile neutropenia (FN) of up to 50% [Osby et al. 2003 Blood 101(10): 3840-3848; Lyman and Delgado 2003 Cancer 98(11): 2402-2409]. This study sought to examine the impact of primary granulocyte colony-stimulating factor (GCSF) prophylaxis on the incidence of FN, quality of life and overall cost.

Methods: In this retrospective cohort study, a group of 65 consecutive patients who received CHOP chemotherapy for NHL between December 2006 and October 2009 was studied. Patients either received filgrastim (300 mcg, average of seven doses), pegylated filgrastim (6 mg, single dose), or no GCSF prophylaxis. In addition, 19 patients were asked to complete Functional Assessment of Cancer Therapy: General quality-of-life questionnaires.

Results: Overall, patients who received primary GCSF prophylaxis had significantly fewer FN compared to those who did not (5 vs. 60%, p < 0.0001; numbers needed to treat of 1.8; 95% confidence interval, 1.6-2.9). Cost-benefit analysis showed that the GCSF prophylaxis was associated with only a small increase in direct financial cost ($238 NZD [US$189] more to give primary GCSF prophylaxis per patient vs. no prophylaxis). The quality of life assessment showed that the patients' quality of life scores were similar to the published data from the validation study population (466 patients with mixed cancers) for Functional Assessment of Cancer Therapy.

Conclusions: Our study shows that primary GCSF prophylaxis is effective in preventing FN in patients receiving CHOP chemotherapy for NHL without adversely affecting their quality of life, and is cost effective.
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http://dx.doi.org/10.1007/s00520-012-1589-2DOI Listing
March 2013

Immunochemotherapy with intensive consolidation for primary CNS lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI.

Clin Cancer Res 2012 Feb 6;18(4):1146-55. Epub 2012 Jan 6.

Division of Hematology/Oncology, University of California San Francisco, Box 1270, 505 Parnassus Avenue, San Francisco, CA 94143, USA.

Purpose: We evaluated a novel therapy for primary central nervous system lymphoma (PCNSL) with induction immunochemotherapy with high-dose methotrexate, temozolomide, and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADC(min)) derived from diffusion-weighted MRI (DW-MRI) in patients treated with this regimen.

Experimental Design: Thirty-one patients (median age, 61 years; median Karnofsky performance score, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable central nervous system (CNS) disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADC(min) of contrast-enhancing lesions.

Results: The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADC(min) less than 384 × 10(-6) mm(2)/s was significantly associated with shorter progression-free and overall survival.

Conclusions: MT-R induction was effective and well tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens with chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADC(min) derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288204PMC
February 2012

Synthesis and antiproliferative activity of oxazinocarbazole and N,N-bis(carbazolylmethyl)amine derivatives.

Eur J Med Chem 2010 Jun 24;45(6):2567-77. Epub 2010 Feb 24.

Université de Lyon, Université Lyon 1, ISPBL, EA 4443, Lyon F-69003, France.

The synthesis, structure elucidation and antitumoral activity of novel heterocyclic compounds containing a carbazole nucleus are reported. Oxazinocarbazoles were synthesized by application of the Mannich reaction to the corresponding hydroxylated derivatives leading to 41 new molecules. Their cytotoxic activity was evaluated against various human tumor cell lines including three leukemic cell lines: CEM and Jurkat (type T), Raji (type B); breast cancer cell line (MCF-7); colorectal cancer cell line (Caco-2). A primary screening at 100 microM allowed the selection of the 10 most active compounds, which showed an antiproliferative activity on all the cell lines. A dose-effect study between 12.5 and 100 microM sorted two compounds with a significant activity: 5t and 7e against leukemic cell lines CEM, Jurkat and Raji with IC50 values around 12 microM.
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http://dx.doi.org/10.1016/j.ejmech.2010.02.045DOI Listing
June 2010

Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma.

J Clin Oncol 2007 Apr 20;25(11):1350-6. Epub 2007 Feb 20.

Division of Hematology/Oncology, and the Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.

Purpose: We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL).

Patients And Methods: The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients.

Results: The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy.

Conclusion: These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.
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http://dx.doi.org/10.1200/JCO.2006.09.7311DOI Listing
April 2007