Management of Chronic Lymphocytic Leukemia in Less-Resourced Countries.

ABSTRACT: Despite the practice-changing advances achieved in the prognostic stratification and treatment of chronic lymphocytic leukemia (CLL), a large fraction of the world population resides in countries where access to many of these advances remains unavailable or subject to severe constraints. Although some of these countries display incidence rates of CLL that are lower than those of developed Western countries, a large number of patients are expected to be diagnosed with CLL in these regions every year. In this article, we review issues regarding management of CLL in some less-resourced countries, with a focus on the evidence basis for epidemiological and clinical information on this disease, the availability of diagnostic and therapeutic resources, and participation in clinical trials. Going forward, challenges that still need to be addressed include the development of unified countrywide registries, guidelines for management applicable to each country, wider availability of prognostic tools, access to new drugs, and policies that ensure these drugs are affordable to all patients worldwide.

Ethnic and geographic diversity of chronic lymphocytic leukaemia.

East Asians, Asian Indians and Amerindians have a five to ten-fold lower age-adjusted incidence rate (AAIR) of chronic lymphocytic leukaemia (CLL) compared with persons of predominately European descent. The data we review suggest a genetic rather than environmental basis for this discordance. All these populations arose from a common African Black ancestor but different clades have different admixture with archaic hominins including Neanderthals, Denisovans and Homo erectus, which may explain different CLL incidences. There are also some differences in clinical laboratory and molecular co-variates of CLL between these populations. Because the true age-adjusted incidence rate in African Blacks is unknown it is not possible to determine whether modern Europeans acquired susceptibility to CLL or the other populations lost susceptibility and/or developed resistance to developing CLL. We also found other B-cell lymphomas and T- and NK-cell cancers had different incidences in the populations we studied. These data provide clues to determining the cause(s) of CLL.

Cardiac Involvement in Vasculotoxic and Neurotoxic Snakebite - A not so Uncommon Complication.

BACKGROUND: Cardiac toxicity following snakebite envenomation has been previously observed, but not studied in detail, especially the involvement in neurotoxic bites. This prospective observational case study evaluates the incidence of cardiac toxicity along with the difference between vasculotoxic and neurotoxic bites and analysing the predictors for development of cardiotoxicity. METHOD: 96 patients who had snake bite envenomation were evaluated for features of cardiotoxicity with clinical features, ECG, echocardiogram and troponin-I levels. RESULTS: Cardiac toxicity was observed in 42.7% of patients, the majority were either ECG changes, noted in 34.3% and rise in troponin-I, noted in 21.9% of patients. Other changes included echocardiographic changes in 4.2%, and Takotsubo cardiomyopathy in 1%. There was no significant difference in the incidence of cardiotoxicity between the neurotoxic (41.7%) and vasculotoxic (42.9%) (p value =1) snake bites, even though the predominant changes seen in neurotoxic snake bites were ECG changes. There were no deaths in the current study. None of the demographic or clinical parameters studied could predict the development of cardiac events. CONCLUSION: Cardiac toxicity is a well defined complication of poisonous snake bite and incidence is more frequent than previously thought. Both vasculotoxic and neurotoxic snake bites are associated with cardiac toxicity and is not associated with increase in mortality.

Capillary leak syndrome in Daboia russelii bite-a complication associated with poor outcome.

Background: Capillary leak syndrome (CLS) has been previously observed as a complication of Daboia russelii bite but not clearly defined or studied in length. This observational case-control study evaluates the mortality along with associated clinical and laboratory features. Methods: Twenty-five patients who developed CLS were compared with 25 patients without CLS following Daboia russelii (Russell's viper) bite. Results: Development of CLS is associated with a significantly high risk of mortality; 11 (44%) patients with CLS died compared with 1 (4%) control (odds ratio 18.8 [95% confidence interval 2.2 to 161.99], p=0.002). Disease-defining manifestations included myalgia (22 [88%]), thirst (20 [80%]), parotid swelling (15 [60%]), conjunctival chemosis (19 [76%]) and hypotension (22 [88%]), which were unobserved in controls. Although several clinical and laboratory parameters were found to be predictive for development of CLS in univariate analysis, none of them had independent predictive value in multivariate analysis. Similarly, development of parotid swelling was the only factor with independent predictive value for mortality in multivariate analysis. Even though the number of vials of snake antivenom used is more in CLS, it seems unlikely to improve the mortality in CLS. Conclusions: This study proves that CLS is a well-defined complication of Russell's viper bite with high mortality but with clear predictors for the development of CLS and mortality.

Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation.

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease (MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival (PFS) and overall survival (OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [PFS: 78% vs. 39% (P = 0·010), OS: 89% vs. 64% (P = 0·029)].

A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia.

Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front-line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two-stage, Phase II trial of FCM and FCM-R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty-two patients were entered, 26 in each arm. The overall response rates to FCM and FCM-R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4-35%) for FCM and 42% (95%CI:23-63%) for FCM-R, with eight patients achieving MRD negativity (3 FCM; 5 FCM-R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.

Eradicating minimal residual disease in chronic lymphocytic leukemia: should this be the goal of treatment?

Even though chronic lymphocytic leukemia (CLL) is the most prevalent leukemia of the Western world, the development of treatment approaches for CLL has lagged behind the development of approaches to various other hematologic malignancies for a variety of reasons. In recent years, the treatment approach to patients with CLL has evolved rapidly, with the addition of several new prognostic markers, highly effective immunochemotherapy combinations, and attainment of remission up to the point of the eradication of minimal residual disease (MRD). Highly sensitive methods now available to detect MRD can detect a single CLL cell in 10(4) leukocytes using either allele-specific oligonucleotide polymerase chain reaction or four-color or six-color flow cytometry. Over the past decade, several studies have examined the possible advantage of MRD eradication in CLL. This article reviews our current understanding of MRD eradication and analyzes whether it is a desirable goal in the routine clinical treatment of CLL, which will optimize the management of individual patients.

Assessment of bone marrow response in Waldenström's macroglobulinemia.

In this study we used bone marrow flow cytometry and immunohistochemistry to evaluate response to fludarabine therapy in patients with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma. Responses in serum M protein were typically delayed with a median time to maximum response of 6 months following the completion of therapy (range, 0-18 months). In contrast, bone marrow responses occurred promptly in responding patients such that there were no detectable clonal B cells at the end of therapy in 55% of patients assessed. Persistent monoclonal plasma cells were, however, readily identified by CD138 immunohistochemistry, explaining the persistence of serum M protein in these patients. This simple observation has significant implications for the assessment of responses in WM as well as the design of future therapeutic strategies.