Yiu-Lam Kwan

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

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-Hodgkins 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.

Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn’s disease

Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohns disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohns disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease.

Isolation of Human CD138(+) Microparticles from the Plasma of Patients with Multiple Myeloma.

The confinement of multiple myeloma (MM) to the bone marrow microenvironment requires an invasive bone marrow biopsy to monitor the malignant compartment. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity mainly because they indirectly measure tumor burden inside the bone marrow and fail to capture the patchy, multisite tumor infiltrates associated with MM. Microparticles (MPs) are 0.1- to 1.0-μm membrane vesicles, which contain the cellular content of their originating cell. MPs are functional mediators and convey prothrombotic, promalignant, proresistance, and proinflammatory messages, establishing intercellular cross talk and bypassing the need for direct cell-cell contact in many pathologies. In this study, we analyzed plasma cell–derived MPs (CD138+) from deidentified MM patients (n = 64) and normal subjects (n = 18) using flow cytometry. The morphology and size of the MPs were further analyzed using scanning electron microscopy. Our study shows the proof of a systemic signature of MPs in MM patients. We observed that the levels of MPs were significantly elevated in MM corresponding to the tumor burden. We provide the first evidence for the presence of MPs in the peripheral blood of MM patients with potential applications in personalized MM clinical monitoring.

Consensus guidelines for 'rainy day' autologous stem cell harvests in New South Wales.

Autologous stem cell transplantation (ASCT) has a well‐established role in the treatment of haematological malignancies. Stem cells are commonly collected following salvage chemotherapy although there may be advantages in collecting earlier in the disease course. A ’rainy day’ harvest (RDH) refers to the collection of autologous haemopoietic stem cells for long‐term storage. Although there are few data to support RDH, there is increasing evidence that such harvests are being carried out, creating storage pressures in stem cell laboratories across New South Wales. The Bone Marrow Transplant Network New South Wales conducted a three‐staged exercise to develop consensus‐based RDH guidelines. Using available evidence, guidelines were developed supporting RDH for specific patients with acute and chronic myeloid leukaemias, follicular and other lymphomas, and multiple myeloma. Physician agreement with these disease‐specific guidelines ranged between 58 and 100%. These consensus guidelines will improve equity of access to appropriate RDH and assist the planning of future storage requirements in New South Wales.

Abstract B52: A novel personalized therapeutic management in multiple myeloma

Introduction: Multiple Myeloma (MM) is an incurable hematological malignancy affecting plasma cells marked by highly heterogeneous survival rate. Relapse is a significant impediment to the successful treatment of MM clinically. One of the main causes for relapse is drug resistance to cancer chemotherapy. Currently risk stratification to MM sub -groups and categorization of complete response to therapy are assessed based on molecular, cytogenetic markers using bone marrow biopsy as available systemic markers are incompetent in this regard. We are exploring the clinical significance of our recent in vitro and in vivo findings of a novel non-genetic basis to MDR whereby tiny vesicles called microparticles (MPs) shed from cancer cell9s surface transfer MDR phenotype intercellularly. MP isolated from the blood of patients who suffer from Multiple Myeloma will be phenotyped for resistance, adhesion and dissemination markers and assessed whether these characteristics are predictive of treatment outcome. Materials and Methods: We have analysed 44 de-identified Multiple Myeloma patients. The platelet free plasma was ultracentrifuged, MM- derived microparticles were identified and quantified with flow cytometry using Annexin V450, CD138 APC, P-glycoprotein -FITC in BD TruCount tubes. Also platelet derived MPs were identified and excluded using CD41a PE and compared to age-matched healthy volunteers. Western blot analysis was conducted on microparticle lysate probing for the presence of Lung-resistance related protein (LRP). Results: Plasma cell derived MPs were identified based on the CD138 expression from the peripheral blood plasma of MM patients. The number of systemic microparticles was found to be significantly higher in MM patients compared to the healthy volunteers. Also the systemic microparticles carried the drug resistance markers. Conclusions: There are elevated numbers of microparticles in MM that potentially correlate with tumour aggressiveness and they carried MDR phenotypes systemically. Phenotyping MM –derived microparticles holds the potential for a non-invasive personalised systemic biomarker to predict therapeutic response. Citation Format: Rajeev S. Krishnan, Frederick Luk, R. D. Brown, Y. L. Kwan, Mary Bebawy. A novel personalized therapeutic management in multiple myeloma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B52.

Abstract 5306: Microparticles as novel prognostic markers in multiple myeloma

Introduction: Multiple Myeloma (MM) is an incurable hematological malignancy affecting plasma cells marked by highly heterogeneous survival rates and confinement of the disease to bone marrow (BM). Relapse is a significant impediment in the clinical setting and the development of multidrug resistance (MDR) to therapy is the main cause of relapse. Currently, risk stratification to MM sub-groups and categorization of complete response to therapy are established on molecular and cytogenetic markers using bone marrow biopsies. We are exploring the clinical significance of plasma cell derived microparticles as a novel prognostic indicator in MM. Materials and Methods: We have analysed 79 de-identified MM patients and 24 normal subjects. Platelet free plasma was centrifuged and plasma cell derived MPs were identified and quantified by flow cytometry using Annexin V450, CD138 APC, anti-P-glycoprotein (P-gp)-FITC (17F9) in BD TruCount tubes. Platelet derived MPs were excluded from the analysis using CD41a-PE. All patient samples were compared to age-matched healthy volunteers. Western blot analysis was conducted on MP lysates probing for the presence of Lung-Resistance related Protein (LRP) and P-glycoprotein (P-gp). Morphology and the size of MP fraction from MM patients were investigated using scanning electron micrographs Results: The number of systemic MPs and CD138+MPs were found to be significantly higher in MM patient samples compared to the healthy volunteers. MDR markers (LRP & P-gp) were expressed on systemic MPs from relapsing MM patients. MPs from patients were spherical in shape and had smooth surface consistent with those isolated from the MM cell line OPM2. Conclusions: There are elevated numbers of systemic MPs in all the 79 MM subjects (across all disease stages) compared to the healthy volunteers. The expressions of CD138 on MPs in the MM patients offer a sensitive assessment of disease progression and therapeutic outcome. Systemic MPs from MM patients carry a ‘snapshot’ of the less accessible bone marrow compartment and may provide a novel systemic ‘biosignature’ of MM progression and therapeutic outcome in the clinical setting. The MDR markers on systemic MPs may support dosage regimen and therapeutic decisions in MM clinical setting. Acknowledgements: This project has ethical approval from Sydney Local Health District Human Research Ethics Committee (CRGH)- EC00118 # HREC/11/CRGH/223 (CH62/6/2011/150). We would like to thank all the volunteers whom have contributed to this study. Citation Format: Sabna Rajeev Krishnan, Mary Bebawy, Ross Duncan Brown, Frederick Luk, Yiulam Kwan. Microparticles as novel prognostic markers in multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5306. doi:10.1158/1538-7445.AM2015-5306