Successful Management of Neutropenic Sepsis Is Key to Better Survival of Patients With Blood Cancer in Sri Lanka: Real-World Data From the Resource-Limited Setting.

PURPOSE: Sepsis is the main cause of nonrelapse mortality, and there are no published data on applicability of supportive care protocols from high-income countries such as Sri Lanka. The aim of the study was to investigate management and mortality of neutropenic episodes among Hemato-Oncology patients. MATERIALS AND METHODS: Retrospective analysis of clinical characteristics, management, morbidity, and mortality of neutropenic Hemato-Oncology patients presented to the Lanka Hospital Blood Cancer Centre from January 1, 2019 to December 31, 2019 was performed. RESULTS: A total of 169 neutropenic episodes were identified; 115 (68%) of such episodes were related to chemotherapy. Acute leukemia, lymphoproliferative disorders, and plasma cell disorders accounted for 23%, 69%, and 8% of patients, respectively. The median age of patients who had sepsis was 56 years, whereas that of those who had no sepsis was 53 years (P = .49). The median time to neutropenia was 9 days for those in the sepsis group compared with 8 days in the group that had no sepsis (0.64). The median neutrophil count in the group that had sepsis was 0.06, whereas it was 0.69 in the group that had no sepsis (P ≤ .05). The median time to commencement of antibiotics was 20 minutes. CONCLUSION: To our knowledge, this is the only documented study related to outcome and successful applicability of western supportive care protocols to Sri Lankan patients with neutropenia. In this study, we have shown that neutropenic sepsis can be successfully managed in the setting of limited resources with service development, following guidelines and staff training.

Response and Survival Estimates of Patients With Plasma Cell Myeloma in a Resource-Constrained Setting Using Protocols From High-Income Countries: A Single-Center Experience From Sri Lanka.

PURPOSE: There is a significant disparity in global cancer care and outcome between countries. Progress in the treatment of symptomatic plasma cell myeloma (PCM) in high-income countries is not seen in low- and middle-income countries. MATERIALS AND METHODS: This is was a retrospective cohort study of all patients diagnosed with PCM between May 1, 2013, and September 30, 2021, at the first hemato-oncology center in Sri Lanka. We aimed to provide data on clinicopathologic characteristics, response, and survival estimates. RESULTS: A total of 79 patients with PCM received first-line therapy during the study period. The median age was 64 years, and approximately one third (33%) of patients were older than 70 years. There were 42 (53%) males and 37 females. Hypercalcemia, renal impairment, anemia, and bone disease were detected in 36.7%, 38%, 72.1%, and 81%, respectively. Thirty-nine, 34, and six patients received a combination of cyclophosphamide, thalidomide, and dexamethasone; bortezomib, thalidomide, and dexamethasone; and other treatments, respectively. The overall response rate (≥ partial response) was approximately 97% for both cyclophosphamide, thalidomide, and dexamethasone and bortezomib, thalidomide, and dexamethasone. Twenty-three (29%) of these patients died during the study period, but only 14 (18%) died due to PCM or associated sepsis. After a median follow-up of 40.6 months (range, 35.2-59.07 months), the median overall survival was 84.2 months (95% CI, 60.87 to not available). The 5-year estimated overall survival was 65%. CONCLUSION: To our knowledge, this is the only well-characterized study on long-term survival of patients with PCM in Sri Lanka. We have shown that it is possible to successfully apply Western treatment and supportive care protocols to the local population. These published data will help to benchmark and improve the treatment and develop blood cancer care in the local setting.

Blood cancer care in a resource limited setting during the Covid-19 outbreak; a single center experience from Sri Lanka.

BACKGROUND: The Covid-19 pandemic has caused significant morbidity and mortality among patients with cancer. Most countries employed measures to prevent spread of Covid-19 infection which include shielding, quarantine, lockdown, travel restrictions, physical distancing and the use of personal protective equipment. This study was carried out to assess the change in patient attendance and the efficacy of newly implemented strategies to mitigate the impact of Covid-19 on services at the Lanka Hospital Blood Cancer Centre (LHBCC) in Colombo, Sri Lanka. METHODOLOGY: Telephone consultation, infection control, personal protective measures and emergency admission policy were implemented with the aim of having a Covid-19 free ward and to prevent cross-infections. This descriptive cross-sectional study was conducted with 1399 patient episodes (in-patient care or day-case review). We analysed patients treated as in-patient as well as day-case basis between 01st April 2020 and 31st December 2020. RESULTS: There were 977 day-case based episodes and 422 in-patient based episodes. There was a 14% drop in episode numbers compared to same period in 2019. There was no cross infection and no patients with Covid-19 related symptoms or positive test results entered the LHBCC during the study period. CONCLUSION: Services in blood cancer care were maintained to prevent late stage presentation and adverse outcome. Measures implemented to prevent Covid-19 were effective to allow continuation of treatment. This study highlights the importance of implementing strict protocols, clinical screening, use of appropriate personal protective equipment in delivering blood cancer care during the Covid-19 pandemic. This is the only documented study relating to outcome and successful applicability of measures to prevent spread of Covid-19 infection and maintaining services among blood cancer patients in Sri Lanka.

Applicability of protocols from high-income countries in a resource limited setting; real world data of histopathology, clinical features and long-term outcome of Hodgkin Lymphoma in Sri Lanka.

Background:: There is a significant disparity in global cancer care and out-come between countries. We aimed to provide data on characteristics, average cost of treatment and survival estimates in patients with Hodgkin Lymphoma in Sri Lanka. Methods: All patients diagnosed with Hodgkin Lymphoma between 01.05.2013 and 01.10.2020 were included in the analysis. Findings: Classical Hodgkin Lymphoma(cHL) diagnosed in 85%; 68% presented with B symptoms and 61% had advanced stage of disease. Treatment was discontinued by 23% either before or just after starting treatment of whom 72% percent were females. The complete response (CR) rate of patients who continued treatment was 86% while the estimated five-year survival rate is 92%. Seventeen percent of these patients died but only two percent due to Hodgkin Lymphoma or associated treatment in the group which continued treatment compared to 45% in the group who defaulted treatment (p-value 0.0002). Five-year survival rate of patients who defaulted treatment was 50% while patients who continued treatment have an estimated five-year survival rate of 90%. Average cost of first line treatment was between US$ 2280 and US$ 7642. First treatment failure may incur substantially higher health care costs. Interpretation: This is the only well characterized study on long-term survival of patients with Hodgkin Lymphoma in Sri Lanka. We have shown that it is possible to successfully apply western treatment and supportive care protocols to the local population. This published data will help to bench mark and improve the treatment and develop blood cancer care in the local setting.

Applicability of Western protocols in resource-limited setting: Real-world data of long-term outcome of intensive treatment of adult acute myeloid leukaemia in Sri Lanka.

There are no published data on long-term survival and applicability of treatment protocols from developed countries in acute myeloid leukaemia (AML) in Sri Lanka. Eighty-seven AML patients were reviewed; there were 56 newly diagnosed patients between 18 and 65 years. Thirty-one out of 33 who started treatment achieved complete remission after first cycle of treatment. The induction mortality was one of 33. Twelve out of 20 patients who completed treatment are alive at the time of analysis. The estimated 5-year overall survival rate is 0.629. Strict infection control and treatment and superior clinical experience may have contributed towards better outcome.

Defining the prognosis of early stage chronic lymphocytic leukaemia patients.

Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow-up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.

Alemtuzumab therapy in T-cell prolymphocytic leukemia: comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route.

Intravenous alemtuzumab is an effective and well-tolerated treatment for T-cell prolymphocytic leukemia (T-PLL). Alemtuzumab given intravenously as first-line treatment in 32 patients resulted in an overall response rate of 91% with 81% complete responses. Studies in B-cell chronic lymphocytic leukemia have shown subcutaneous alemtuzumab to be equally as effective as intravenous alemtuzumab. The UKCLL05 pilot study examined the efficacy and toxicity of this more convenient method of administration in 9 previously untreated patients with T-PLL. Only 3 of 9 patients (33%) responded to treatment. Furthermore, 2 of 9 patients (22%) died while on treatment. Recruitment was terminated because of these poor results. After rescue therapy with intravenous alemtuzumab and/or pentostatin, median progression-free survival and overall survival were similar to the intravenous group. Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL.

CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL.

The world of chronic lymphocytic leukemia (CLL) research is awash with prognostic markers. However, very few of the current group play a clearly defined role in the pathology of this disease and even fewer represent a tractable therapeutic target. One such marker that fulfils both of these criteria is the integrin CD49d. This molecule been implicated in the capacity of CLL cells to migrate into lymphoid tissues and there is a CD49d blocking antibody, Natalizumab, currently in clinical trials. Here we carried out the largest multi-centre evaluation of CD49d as a prognostic marker in 652 primary CLL samples. We confirm that CD49d is predictive for time to first treatment (P<0.0001) and overall survival (P<0.0001) and increases the prognostic power of CD38, ZAP-70 and IGHV gene mutation status in concordant cases. Furthermore, CD49d retained independent prognostic significance in multivariate analysis. In contrast to previous studies, we showed no correlation between CD49d expression and in vitro resistance to fludarabine in liquid cultures (P=0.28) but CD49d(hi) cells were significantly more resistant than CD49d(lo) cells when assays were carried out on fibronectin-coated plates (P=0.03). Furthermore, we showed for the first time that the expression of CD49d is strongly associated with expression of the chemokine receptor CXCR4 suggesting a co-ordinated role for these molecules in the trafficking of CLL cells to the lymphoid tissues. Taken together, our data support the introduction of CD49d into routine immunophenotyping panels for CLL and indicate that the therapeutic targeting of this molecule may prove useful in this disease.

Treatment options for high-risk chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western world. The natural history of CLL is extremely variable with a survival time from initial diagnosis that ranges from 2 to more than 20 years. Understanding the clinical diversity and allowing the subclassification of CLL into various prognostic groups not only assists in predicting future outcome for patients, but also helps to direct treatment decisions. Chlorambucil and fludarabine were the standard therapy for CLL for decades. Randomized studies have reported superior overall response and progression-free survival (PFS) for fludarabine compared with alkylator-based therapy and for the fludarabine-cyclophospamide (FC) combination over fludarabine alone. More recently the addition of rituximab to the FC regimen (R-FC) has shown significant improvement in overall response, PFS and overall survival compared with FC alone. However, there are patients for whom this regimen still provides less satisfactory results. Within the above studies CLL patients who have some of the poorer prognostic markers, such as unmutated IgVH genes and/or high beta-2 microglobulin (B2M), and those who fail to achieve a minimal residual disease (MRD) negative remission are likely to have a shorter PFS compared with those without these features. Various strategies have been explored to improve the outcome for such patients. These include the addition of agents to a frontline R-FC regimen, use of consolidation and consideration of maintenance. The only group that can be clearly identified pretreatment for whom conventional fludarabine-based therapies produce significantly inferior response rates, PFS and overall survival are the patients who harbour a genetic fault; deletion or mutation or a combination of deletion and mutation of tumour protein p53 (TP53). TP53 inactivation is a less common finding at first treatment but becomes much more common in fludarabine-refractory patients. Alemtuzumab and high-dose corticosteroids have been shown to be effective in this group of CLL patients. Trials combining these two agents have shown improved responses, particularly for those patients with bulky nodal disease for whom alemtuzumab alone may be insufficient. Since the duration of responses remains relatively short, suitable patients should be considered for allogeneic stem cell transplantation according to the European Group for Blood and Marrow Transplantation (EBMT) guidelines. Furthermore, there are a number of other new treatments on the horizon, including humanized antibodies directed against novel targets and small-molecule inhibitors.

Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia.

Aminopeptidase enzyme inhibition is thought to deplete the free intracellular amino acids needed by malignant cells for growth and development, resulting in profound anti-proliferative and apoptotic effects. In this study, we investigated the effects of the metalloenzyme-inhibitor CHR-2797 (tosedostat), in primary acute myeloid leukemia (AML) cells. CHR-2797 demonstrated marked in vitro cytotoxicity in AML samples and strong synergy with Cytarabine (Ara-C), but significantly less cytotoxicity to normal marrow progenitors. Furthermore mechanistic investigations revealed that CHR-2797 inhibited the intrinsic nuclear, cytoplasmic and cell surface aminopeptidase function of AML blasts in a dose-dependent manner, demonstrating a promising novel approach for AML therapy.

Interaction with vascular endothelium enhances survival in primary chronic lymphocytic leukemia cells via NF-kappaB activation and de novo gene transcription.

Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro, suggesting that the in vivo microenvironment provides crucial antiapoptotic signals. Overexpression of the antiapoptotic proteins Bcl-2 and Mcl-1 is a hallmark of CLL, and their expression is further enhanced in the lymphoid tissues. However, the high levels of Mcl-1 found in peripheral blood samples, coupled with its short half-life, led us to hypothesize that it must be actively maintained in the peripheral circulation. Coculture of CLL cells with human vascular endothelial cells significantly enhanced tumor cell survival, an effect that was not observed with normal B cells. This was associated with elevated levels of the antiapoptotic proteins Bcl-2, Mcl-1, and Bcl-X(L) and marked increased expression of CD38 and CD49d, both of which are associated with clinically aggressive disease. Because CD38, CD49d, and some Bcl-2 family genes are transcriptional targets for NF-κB, we assessed NF-κB activation following coculture with endothelial cells. DNA binding of the NF-κB subunit Rel A was significantly increased and strongly correlated with changes in transcription of CD38, CD49d, BCL2, MCL1, and BCLXL, effects that were reversed by a peptide inhibitor of Rel A. These effects were not observed following coculture with nonendothelial cell lines. Therefore, CLL cells receive specific survival signals following interaction with endothelial cells mediated through the activation of NF-κB and the induction of downstream target genes. This type of interaction in the peripheral vasculature may explain the constitutive NF-κB activation and the overexpression of Bcl-2 family proteins commonly seen in this disease.

Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis.

We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue, reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction, and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples, indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from persons with the shortest telomeres revealed limited numbers of repeats at the breakpoint, subtelomeric deletion, and microhomology. Array-comparative genome hybridization analysis of persons displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. The telomere dynamics observed in CLL B cells were indistinguishable from that observed in cells undergoing crisis in culture after abrogation of the p53 pathway. Taken together, our data support the concept that telomere erosion and subsequent telomere fusion are critical in the progression of CLL and that this paradigm may extend to other malignancies.

The NF-kappaB inhibitor LC-1 has single agent activity in multiple myeloma cells and synergizes with bortezomib.

Multiple myeloma remains incurable with conventional therapeutics. Thus, new treatments for this condition are clearly required. In this study we evaluated the novel NF-kappaB inhibitor LC-1 in multiple myeloma cell lines and plasma cells derived from multiple myeloma patients. LC-1 was cytotoxic to multiple myeloma cell lines H929, U266, and JJN3, and induced apoptosis in a dose-dependent manner with an overall LD(50) of 3.6 micromol/L (+/-1.8) after 48 hours in culture. Primary multiple myeloma cells, identified by CD38 and CD138 positivity, had a mean LD(50) for LC-1 of 4.9 micromol/L (+/-1.6); normal bone marrow cells were significantly less sensitive to the cytotoxic effects of LC-1 (P = 0.0002). Treatment of multiple myeloma cell lines with LC-1 resulted in decreased nuclear localization of the NF-kappaB subunit Rel A and the inhibition of NF-kappaB target genes. In addition, LC-1 showed synergy with melphalan, bortezomib, and doxorubicin (combination indices of 0.72, 0.61, and 0.78, respectively), and was more effective when cells were cultured on fibronectin. These data show that LC-1 has activity in multiple myeloma cell lines and primary multiple myeloma cells, and its ability to inhibit NF-kappaB seems important for its cytotoxic effects. Furthermore, LC-1-induced transcriptional suppression of survivin and MCL1 provides a potential explanation for its synergy with conventional agents.

Genetic modification of primary chronic lymphocytic leukemia cells with a lentivirus expressing CD38.

Studies of the role of individual genes in chronic lymphocytic leukemia (CLL) have been hampered by the inability to consistently transfect primary tumor cells. Here, we describe a highly efficient method of genetically modifying primary CLL cells using a VSVG pseudotyped lentiviral vector. We transduced CD38 negative CLL cells with a lentiviral vector encoding CD38 which caused increased surface CD38 expression in all the samples tested (n=17) with no evidence of plasmacytoid differentiation. The mean percentage of positive cells expressing CD38 was 87%+/-8.5% and the mean cell viability 74%+/-17%. This high level of transduction of all the CLL cell samples tested demonstrates the utility of this technique which should prove applicable for the introduction and analysis of other genes in these non-dividing cells.

NF-kappaB as a prognostic marker and therapeutic target in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is the most common adult leukemia and is currently incurable with conventional chemotherapeutic agents. Over the last few years, significant discoveries have been made regarding the biology that underpins this disease. These new insights have allowed us to develop more rational prognostic tools and identify promising novel therapeutic targets. In this review, we highlight the importance of both constitutive and inducible DNA binding of the transcription factor NF-kappaB in chronic lymphocytic leukemia. We describe the current knowledge regarding the activity and function of specific NF-kappaB subunits in this disease, and discuss the complex mechanisms that regulate NF-kappaB activation in vivo. In addition, we provide compelling evidence for the utility of the NF-kappaB subunit, Rel A, as a prognostic marker and as a therapeutic target in this disease, and we also describe how this protein may contribute to the drug resistance commonly encountered with this condition.

Acute renal failure as the presenting feature of leukaemic infiltration in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a neoplastic condition of B cells which commonly affects the lymph nodes, liver, spleen and bone marrow. Leukaemic involvement of the kidney is also relatively common in CLL, but characteristically is not associated with renal impairment. Our report describes a patient who developed acute renal failure as the initial presenting feature of CLL. The renal failure was subsequently found to be due to direct leukaemic infiltration. Treatment with chlorambucil and prednisolone resulted in stabilisation of the renal function for approximately 1 year prior to the need for long-term haemodialysis. Leukaemic infiltration of kidney should always be considered when a patient with CLL presents with renal impairment, regardless of the clinical stage, as the renal failure often responds well to chemotherapy.

Rel a is an independent biomarker of clinical outcome in chronic lymphocytic leukemia.

PURPOSE: We recently demonstrated the biologic importance of the nuclear factor kappa B (NF-kappaB) subunit Rel A in chronic lymphocytic leukemia (CLL) and hypothesized that Rel A DNA binding would have prognostic significance in this disease. PATIENTS AND METHODS: Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA-binding enzyme-linked immunosorbent assay-based method. We then investigated the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers. RESULTS: Rel A DNA binding was strongly associated with advanced Binet stage (P < .0001) but did not correlate with immunoglobulin V(H) (IgV(H)) mutation status (P = .25), CD38 expression (P = .87), or zeta-chain-associated protein kinase 70 (ZAP-70) expression (P = .55). It was predictive of time to first treatment (P = .02) and time to subsequent treatment (P = .0001). In addition, Rel A was the most predictive marker of survival both from date of diagnosis (hazard ratio [HR], 9.1; P = .01) and date of entry into the study (HR, 3.9; P = .05) and retained prognostic significance in multivariate analysis for both time to first treatment and overall survival in the presence of Binet stage, IgV(H) mutation status, CD38, and ZAP-70. CONCLUSION: Rel A is an independent prognostic marker of survival in CLL and seems to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target are now warranted.

Quantitative nuclear proteomics reveals new phenotypes altered in lymphoblastoid cells.

B-lymphocytes are essential for the production of antibodies to fight pathogens and are the cells of origin in 95% of human lymphomas. During their activation, and immortalisation by Epstein-Barr virus (EBV) which contributes to human cancers, B-lymphocytes undergo dramatic changes in cell size and protein content. This study was initiated to compare the proteome of two B-cell lines, from the same individual, that reflect different patterns of activation, one is EBV negative and the other is EBV positive. Using isobaric tags, LC-MALDI TOF-TOF and subcellular fractionation, we quantified 499 proteins from B-cells. From a detergent lysed protein extract, we identified 34 proteins that were differentially expressed in EBV-immortalised B-cells. By analysing a nuclear extract, we identified a further 29 differentially expressed proteins with only four proteins shared between the two extracts, illustrating the benefit of subcellular fractionation. This analysis has identified proteins involved in the cytoskeletal phenotype of activated B-cells and the increased antigen recognition in EBV-immortalised cells. Importantly, we have also identified new regulators of transcription and changes in ribonuclear proteins that may contribute to the increased cell size and immortalisation of lymphoblastoid cells.

The novel nuclear factor-kappaB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine.

PURPOSE: We have recently shown that the novel nuclear factor-kappaB (NF-kappaB) inhibitor LC-1 is effective in primary chronic lymphocytic leukemia (CLL) cells. Here we elucidated the mechanism of action of LC-1, evaluated its relative cytotoxicity in prognostic subsets, and investigated its potential synergistic interaction with fludarabine. EXPERIMENTAL DESIGN: Ninety-six fully characterized CLL cases were assessed for in vitro sensitivity to LC-1 and fludarabine. In selected cases, caspase activation, inhibition of Rel A DNA binding, and the transcription of CFLAR, BIRC5, and BCL2 were measured before and after exposure to LC-1. In addition, the efficacy of LC-1 was assessed in the presence of the survival factors CD154 and interleukin-4, and the potential synergistic interaction between LC-1 and fludarabine was evaluated. RESULTS: Cell death was associated with caspase-3 activation mediated via activation of both caspase-8 and caspase-9. Apoptosis was preceded by a reduction of nuclear Rel A DNA binding and inhibition of CFLAR, BIRC5, and BCL2 transcription. Importantly, LC-1 overcame the cytoprotective effects by interleukin-4 and CD40 ligand and was equipotent in CLL cells derived from good and bad prognostic subsets. LC-1 exhibited strong synergy with fludarabine, and the combination produced a highly significant mean dose reduction index for fludarabine of > 1,000. CONCLUSIONS: In view of imminent first-in-man study of LC-1 in Cardiff, these data show an important mechanistic rationale for the use of LC-1 in this disease. Furthermore, it validates the concept of targeting nuclear factor-kappaB in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance.