Criteria For Initiation Of Therapy Research Articles

Systemic Medical and Procedural Therapies for Mucosal Lichen Planus: Update and Review of Challenges and Successes

Context: Mucosal lichen planus is a chronic inflammatory debilitating condition that commonly affects the oral mucosa, but other sites such as the genital and ocular mucosae, esophagus and ear canal may also be involved, with risk of scarring and functional compromise. Spontaneous remission is rare and the condition tends to be recalcitrant to therapy, which makes management challenging. Topical therapies are often ineffective in severe cases and official treatment guidelines including systemic agents and procedural interventions are currently not available. Methods: We performed a literature review on current systemic therapies for mucosal lichen planus using PubMed, MEDLINE and Cochrane databases, with 74 publications identified including retrospective and prospective studies, case reports, and clinical trials. Therapies reviewed included biologics, immunosuppressive therapies, immunomodulating and anti-inflammatory drugs, vitamin A derivatives, devices and interventional therapies, and non-prescription drugs. Results: Reported treatments were classified into the following categories: biologics, anti-metabolic immunosuppressives, direct anti-T cell agents, other immunodulatory agents, antibiotics, retinoids, and procedure based interventions. Most studies on mucosal lichen planus are descriptive in nature and demonstrate low levels of evidence. Randomized controlled trials are lacking, which makes it difficult to directly compare different grading scales and outcome. Conclusions: The authors suggest clinical criteria for initiation of therapy in mucosal lichen planus, such as severe disease, lack of response to topical therapy, mucous membranes involvement and involvement of organs at risk of non-function. The authors also propose a stepwise treatment algorithm based on data from this review and their personal experience in an academic tertiary referral center.

Prognostic Value of TTM with TTM Distribution and Ball Score in Relapsed/Refractory Ibrutinib Treated B-CLL - in the Real-World Setting

There is a high number of clinical and biological parameters with impact on prognosis in B-CLL and number of successful prognostic models were developed (clinical stages, CLL IPI, MDACC score, etc.). However, rapidly changing therapeutic landscape with more successful targeted terapines with different modes of action, render most of these models developed in era of chemo and chemoimmunotherapy less useful. Recently simple prognostic score (BALL score) based on 4 parameters (LDH>UNL, B2microglobulin>5mcg/l, Hemoglobin<120 g/l in males and 110g/l in females, and time from start of last therapy- 0-1 parameters - low risk, 2-3 - intermediate risk and 4 high risk) was developed and validated in number of cohorts (Soumerai et al, Lancet Hematol). High cost of novel drugs in less affluent countries led to a higher criterion for reimbursement. Until recently in Croatia ibrutinib was reimbursed only for early relapse (less than 24 months from last therapy) or refractory disease with additional criteria for high risk disease including Rai stages III and IV or high tumor burden demonstrated by TTM score >15. TTM score (www.b-cll.org) is old, simple and continuous parameter useful for prognosis and response assessment (Jaksic B et al BJH 1980) and because it cover tumor mass in all major lymphoid compartments and allow tumor distribution assessment (Jaksic O et al, Haematologica 2001) it can be very useful for response assessment to novel agents were redistribution of lymphocytes can be significant (Jaksic O BJH 2014). In other to evaluate usefulness of novel BALL score and old TTM score in real life setting where the novel drug is available only to patients with higher risk defined by respective scores, we have evaluated series of 42 RR CLL patients treated with ibrutinib at our institution since March 2015. There were 15 females and 27 males, median age 70 years (range 53 to 82), 9 patients had 17p deletion, median TTM was 14 (range 1.2-28), 20 patients had Rai stage III/IV. Median follow up was 24 months, and maximal 64 months. Since all patients were in early relapse or refractory, we have actually used simplified BALL score based on only 3 parameters. There was no significant relationship between BALL and TTM in our patient population. In our patient cohort low risk BALL score had only 3 patients, 28 patients had intermediate risk and 11 high risk and it showed only marginal discriminative power (p=0.054) While TTM>15 did not show discriminative power (p=0.14). When we added TTM>18 as an additional parameter (point) to BALL score, this modified score (0-3 low/intermediate - 23 patients and 3-4 high risk - 19 patients) showed significant discriminative power (p=0.002) (Figure 1). Observed results indicate that: 1) performance of prognostic models may be significantly dependent on discriminative power of its components and if these components are criteria for initiation of therapy with novel agent(i.e. only high risk group defined by these parameters) it significantly lower its prognostic power, and vice versa 2) such criteria for therapy selection/initiation until these criteria are met may actually mean that we treat patients with novel agents when these are less effective. We have shown that addition of TTM significantly improves BALL score. Refinement of prognostic scores with parameters that may have predictive power for novel drugs, as well as adaptation criteria for reimbursement in future studies (including pharmacoeconomics) may further improve quality of care of B-CLL patients. Disclosures Jaksic: Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Pejsa:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pliva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alvogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oktal Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenström macroglobulinaemia.

Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8g/l (range 31-124g/l). Forty-four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3months, whereas the median time for patients with serum IgM level of 50·01-60g/l was approximately 3years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival (P=0·12). The findings support the use of serum IgM level >60g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

Épuration extrarénale et insuffisance rénale aiguë en soins intensifs

Renal replacement therapy for acute kidney injury has been used for more than 60 years. Except when life-threatening metabolic complications such as severe hyperkalaemia are present, renal replacement therapy initiation criteria are the subject of intense debate. Significant progress has been made with the publication of the AKIKI multicenter trial, which showed that a delayed renal replacement therapy initiation strategy (in the absence of life-threatening metabolic complications) was not associated with a difference in mortality compared to an early renal replacement therapy initiation strategy. In addition, this delayed strategy obviated the need for renal replacement therapy in almost 50% of cases was associated with a more rapid renal function recovery and with a lower incidence of catheter-bloodstream related infections. Research on renal replacement therapy modalities (continuous vs. intermittent renal replacement therapy, citrate vs. heparin anticoagulation, jugular vs. femoral catheterization) did not show any obvious superiority of one modality over another. Thus, the choice depends mainly on local considerations (patient recruitment, availability of modalities, staff experience). The criteria for renal replacement therapy discontinuation are still unclear due to difficulties in assessing renal function recovery. Urine output remains the main criteria in the decision to wean from renal replacement therapy. Pending the confirmation of AKIKI trial by similar studies in progress, it seems reasonable to choose a delayed renal replacement therapy initiation strategy under watchful surveillance in case of severe acute kidney injury in the absence of life-threatening metabolic complications.

Indications of initiation renal replacement therapy among patients with chronic renal disease

Introduction: Chronic renal failure (CRF) is a major cause of morbidity and mortality and renal replacement dialysis is necessary for the preservation of life, despite the fact that it is characterized by multiple restrictions and complications.Aim: The purpose of the present systematic review was the investigation of the absolute and relevant renal replacement therapy initiation criteria among patients with end-stage renal disease (ESRD).Material and Method: There was an extensive research at Pubmed, IATROTEK and Cinahl during the period 2000-2015. The key words that were used for data search included “CRF”, “renal replacement therapy”, “initiation criteria”, “glomerular filtration rate”, and “guidelines”. In the present review, 20 studies were included. Results: Renal replacement therapy initiation constitutes a challenge for both nephrologists and patients since there is no consensus regarding the initiation criteria. GFR should not be the only marker for the initiation of renal replacement therapy since it is influenced by multiple factors. Renal replacement therapy should start at the presence of uremic signs and symptoms or complications, and co morbidity and individualized characteristics of patients should be taken into account. The doctors’-nephrologists’ characteristics seemed to influence the time of initiation of renal replacement therapy.Conclusions: CRF patients should be monitored by an interdisciplinary team and for the decision for the renal replacement therapy initiation, a relationship of cooperation between the doctor and the patient should be encouraged.

Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children Ages 1-5 Years: A Causal Modeling Analysis.

There is limited evidence regarding the optimal timing of initiating antiretroviral therapy (ART) in children. We conducted a causal modeling analysis in children ages 1-5 years from the International Epidemiologic Databases to Evaluate AIDS West/Southern-Africa collaboration to determine growth and mortality differences related to different CD4-based treatment initiation criteria, age groups, and regions. ART-naïve children of ages 12-59 months at enrollment with at least one visit before ART initiation and one follow-up visit were included. We estimated 3-year growth and cumulative mortality from the start of follow-up for different CD4 criteria using g-computation. About one quarter of the 5,826 included children was from West Africa (24.6%).The median (first; third quartile) CD4% at the first visit was 16% (11%; 23%), the median weight-for-age z-scores and height-for-age z-scores were -1.5 (-2.7; -0.6) and -2.5 (-3.5; -1.5), respectively. Estimated cumulative mortality was higher overall, and growth was slower, when initiating ART at lower CD4 thresholds. After 3 years of follow-up, the estimated mortality difference between starting ART routinely irrespective of CD4 count and starting ART if either CD4 count <750 cells/mm³ or CD4% <25% was 0.2% (95% CI = -0.2%; 0.3%), and the difference in the mean height-for-age z-scores of those who survived was -0.02 (95% CI = -0.04; 0.01). Younger children ages 1-2 and children in West Africa had worse outcomes. Our results demonstrate that earlier treatment initiation yields overall better growth and mortality outcomes, although we could not show any differences in outcomes between immediate ART and delaying until CD4 count/% falls below 750/25%.

REVIEW OF ANTI-TNF MONOCLONAL ANTIBODY USE

Background Anti-tumour necrosis monoclonal antibodies are being used increasingly in both gastroenterology and rheumatology services at Southampton Children9s Hospital. Concern has been raised that initiation may be outside the boundaries of the relevant National Institute for Health and Clinical Excellence (NICE) technology assessments or licensed indications. In addition, patients should be investigated for latent or active tuberculosis prior to starting treatment, usually with a Quantiferon Gold test and, if this is positive, then a chest x-ray should be requested. Aim To review the use of infliximab and adalimumab at Southampton Children9s Hospital. Objectives Determine whether infliximab and adalimumab are being used according to NICE guidelines for IBD. Determine whether adalimumab is being used within its licensed indications for juvenile idiopathic arthritis (JIA). Establish whether all patients have a Quantiferon Gold test and/or a chest x-ray prior to starting treatment. Method A retrospective review of electronic records for all patients administered infliximab and adalimumab between April 1st 2013 and March 31st 2014. A modified NICE audit tool was used to collect the data. Electronic records accessed included clinic letters, microbiology and radiology reports and pharmacy dispensing records. Results Sixty two children met the criteria for inclusion in the audit. Fifty four received infliximab, 16 received adalimumab and 12 children received both. Forty-five children had a diagnosis of Crohn9s disease, 12 had Juvenile Idiopathic Arthritis (JIA) and five had another diagnosis. Fifty seven children had not responded to conventional immunosuppression, six were intolerant of first-line therapy and seven had another rationale for treatment e.g. severity of disease at diagnosis. All the patients prescribed infliximab or adalimumab for an inflammatory bowel disease met the relevant NICE criteria for initiation of therapy. Use for JIA was within the licence. Prior to starting treatment 15 (24%) patients had a Quantiferon Gold test, two of which were positive, 49 (79%) of patients had a chest x-ray and 15 (24%) patients had neither. Conclusion Whilst, there are no NICE technology assessments for JIA, adalimumab is licensed for this indication, whereas infliximab is not. Six of the children who received infliximab for JIA had not responded to or had had an adverse reaction to adalimumab. It is of significant concern that 15 children received either infliximab or adalimumab without apparently being assessed for tuberculosis (TB). There is confusion about the most appropriate test to perform to investigate a patient9s TB status, with some having a chest x-ray and others a Quantiferon Gold. We are instigating a “No negative test – No Dispensing” rule, where clinical pharmacists will confirm a negative test result prior to ordering therapy. The gastroenterologists, rheumatologists and infectious diseases clinicians are writing a guideline to improve the safe use of these treatments and clarify the most appropriate testing procedure prior to starting therapy.

Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children aged 1-5 Years: A Causal Modelling Analysis

Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children aged 1-5 Years: A Causal Modelling Analysis

Poor quality of life among untreated Thai and Cambodian children without severe HIV symptoms

There are limited data on quality of life (QOL)1in untreated HIV-infected children who do not have severe HIV symptoms. Moreover, such data do not exist for Asian children. Poor QOL could be a factor in deciding if antiretroviral therapy (ART) should be initiated. Thai and Cambodian children (n=294), aged 1–11 years, naïve to ART, with mild to moderate HIV symptoms and CD4 15–24% were enrolled. Their caregivers completed the Pediatric AIDS Clinical Trials Group QOL questionnaire prior to ART commencement. Six QOL domains were assessed using transformed scores that ranged from 0 to 100. Higher QOL scores indicated better health. Mean age was 6.1 (SD 2.8) years, mean CD4 was 723 (SD 369) cells/mm3, 57% was female, and%CDC N:A:B was 2:63:35%. One-third knew their HIV diagnosis. Mean (SD) scores were 69.9 (17.6) for health perception, 64.5 (16.2) for physical resilience, 84.2 (15.6) for physical functioning, 77.9 (16.3) for psychosocial well-being, 74.7 (28.7) for social and role functioning, 90.0 (12.1) for health care utilization, and 87.4 (11.3) for symptoms domains. Children with CD4 counts above the 2008 World Health Organization (WHO) ART-initiation criteria (n=53) had higher scores in health perception and health care utilization than those with lower CD4 values. Younger children had poorer QOL than older children despite having similar mean CD4%. In conclusion, untreated Asian children without severe HIV symptoms had relatively low QOL scores compared to published reports in Western countries. Therapy initiation criteria by the WHO identified children with lower QOL scores to start ART; however, children who did not fit ART-initiation criteria and those who were younger also displayed poor QOL. QOL assessment should be considered in untreated children to inform decisions about when to initiate ART.

New Guidelines

In late 2009, new guidelines for the management of human immunodeficiency virus infection were published by the European AIDS Clinical Society and the United States Department of Health and Human Services. A comparison of the European AIDS Clinical Society guidelines (presented in November at the European AIDS Conference) and the Department of Health and Human Services guidelines (published online in December at http://www.aidsinfo.nih.gov) is presented in this brief communication. Significant differences include criteria for initiation of therapy and preferred regimens for naive patients.

Experience with Fludarabine, Cyclophosphamide, Rituximab (FCR) Plus GM-CSF in Frontline Therapy for Chronic Lymphocytic Leukemia (CLL)

Combination chemoimmunotherapies with purine analogues are frequently used as initial therapy of patients with CLL. We investigated the efficacy and tolerability of the combination of FCR plus GM-CSF (sargramostim, Leukine) as initial therapy of patients with CLL based on the following rationale:high response rates of FCR in frontline CLL as previously reported;ability of GM-CSF to stimulate granulocyte and macrophage natural cytotoxicity and therefore to potentiate antibody-dependent cellular cytotoxicity (Voso MT, Haematol. 2002);ability of GM-CSF to increase surface CD20 expression on CLL cells making them a better target for rituximab (Venugopal P, Leuk. Res. 2000); andthe potential to reduce the myelosuppressive effect of the FCR combination.Patients with untreated CLL, who met NCI-WG criteria for initiation of therapy, were eligible for this trial. We limited accrual to patients with standard risk disease as determined by beta-2-microglobulin ≤ to 4 mg/dL. Patients received fludarabine 25 mg/m2 i.v. days 2–4, cyclosphosphamide 250 mg/m2 i.v. days 2–4, rituximab 375 mg/m2 i.v. day 1. GMCSF was given sc at 250 mcg/m2 on day -1 and days 5–11. For courses 2–6, FCR started day 1 together with rituximab 500 mg/m2, and GM-CSF was given sc at 250 mcg/m2 on day -1 and days 5–11 or until neutrophil recovery. Courses were repeated every 4–6 weeks. Patients were trained to self-administer GM-CSF during course 1 and therefore required to receive course 1 at our center. Local oncologists administered courses 2–6. All patients received standard anti-viral and PCP prophylaxis throughout the duration of therapy. Sixty patients were enrolled of whom 46 are evaluable for response and toxicity. The median age was 55 years (range 35–77). Twelve patients (20%) had Rai stage III–IV. Median beta-2-microglobulin was 2.8 mg/L (1.7–4.2). Seventeen patients (28%) had 11q deletion and 2 patients (3%) had 17p deletion by FISH. Unmutated IgVH occurred in 57% of the patients and ZAP-70 immunohistochemistry was positive in 53%. Thirty-three patients (72%) achieved CR, 5 patients (11%) nPR, and 8 patients (17%) PR, with an OR rate of 100%. Twenty-four patients (52%) had < 1% CD5/CD19+ cells in the marrow at the end of therapy. Twenty-four patients were evaluated for minimal residual disease (MRD) by PCR and 15 patients (63%) achieved MRD negativity at the end of therapy. Grade >/= 3 neutropenia occurred in 35 (76%) of the patients, thrombocytopenia in 8 (17%). Infectious episodes were seen in 5 patients (11%) including one patient who died after 4 cycles because of pneumonia. Nine patients (20%) discontinued GM-CSF after 1 (2 patients), 3 (3 patients) and 4 (4 patients) courses, because of pain/erythema at the injection site (7 patients), fever (1 patient) and syncope (1 patient). Thirty-nine patients (85%) completed all 6 planned courses and only 2 patients (4%) received less than 4 courses. In conclusion, FCR plus GM-CSF has a high CR rate in symptomatic frontline patients with CLL. This regimen has a favorable toxicity profile and was easily administered in the community setting. This study has completed accrual and time-to-event parameters and a comparison with FCR will be presented.

Management of antiretroviral therapy (ART) in Albania

of results There are 45 male and 28 female HIV patients under therapy. Resistance testing, HLA B 5701 screening testing and Pap smear screening testing are not available as part of the initial assessment of the patient. Criteria for initiation of therapy include symptomatic patient and CD4 <200. Most used first-line combinations are: ZDV/3TC + EFV in 40 adult patients and d4T + 3TC + EFV in 14 adult patients. The preferred back-bone nucleotide combination is AZT + 3TC. NNRTI-based initial regimen is preferred, with EFV as the most preferred drug. The only PI drug available in Albania is LPV/r which is used in six patients for the second-line therapy in combination with TNF and ddI.

The International Prognostic Scoring System for Waldestrom's Macroglobulinemia (ISSWM) Is Applicable in Patients Treated with Rituximab-Based Regimens.

Introduction: An ISSWM was recently proposed (Morel et al, ASH 2006), which was based on a large number of patients treated primarily with alkylating agents and /or nucleoside analogues. The ISSWM based on 5 adverse covariates wich defined 3 risk groups: low, intermediate and high risk with 5-years survival rates of 87%, 68% and 36% respectively. In our current analysis, we assessed the impact of this system in patients with WM who received primary treatment with rituximab-based regimens.Patients and methods: Ninety-three previously untreated, symptomatic patients who received treatment either with single agent rituximab (21 patients) or with the combination of dexamethasone, rituximab, and cyclophosphamide (72 patients) were classified according to the ISSWM, which is based on 5 adverse covariates: age> 65 years, hemoglobin ≤11.5 g/dl, platelet count ≤ 100 x 109/L, β2- microglobulin <3mg/L, serum monoclonal protein concentration >70g/L. Low risk is defined by the presence of ≤ 1 adverse characteristics except age, high risk by the presence of >2 adverse characteristics and intermediate risk by the presence of 2 adverse characteristics or age >65 years.Results: The disease features of the 93 patients were typical of symptomatic WM: age > 65 years in 63%, males 65%, B-symptoms in 22%, splenomegaly in 29%, lymphadenopathy in 34%. 15% of patients were rated as low risk, 65% as intermediate risk and 20% as high risk. Criteria for initiation of therapy included cytopenia, hyperviscosity, constitutional symptoms, organomegaly or IgM-related disorders. Overall, 62% of patients were alive at 6 years. Median survival was not reached for low and intermediate risk and was 38 months for high risk patients (p=0.006). There was a clear separation of the survival curves in the three groups. At the time of last follow-up the percentage of patients alive was 100%, 82% and 58% for patients classified as low, intermediate and high-risk group respectively.Conclusions: The recently proposed ISSWM is applicable in patients with WM who receive primary treatment with rituximab-based regimens and may serve as a basis to compare outcomes in different studies.

Hepatitis B Virus and HIV Coinfection: Results of a Survey on Treatment Practices and Recommendations for Therapy

The management of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is challenged by the selection of patients for therapy, options for antiviral medications, and inconsistency in published treatment guidelines. A survey was sent to 161 sites in a multicenter HIV clinical trials group to assess HBV screening, criteria for initiation of therapy, and treatment choices for patients coinfected with HBV and HIV. Of 161 sites, 78 completed the survey (response rate, 48.4%). Of these sites, 98.7% screened for HBV infection, 86% vaccinated HIV-infected patients who were not immune to HBV infection, and 79% made treatment decisions without referral to a hepatologist or gastroenterologist. Treatment recommendations varied; 42% of the sites initiated therapy when patients' levels of alanine aminotransferase and aspartate aminotransferase were elevated and HBV DNA level was >10(5) copies/mL, whereas 49% of the sites initiated therapy in the presence of any detectable HBV DNA level. Antiviral treatment choices for patients who were not concurrently receiving antiretroviral therapy were lamivudine plus tenofovir, adefovir, or interferon. Patients concurrently receiving antiretroviral therapy received lamivudine plus tenofovir preferentially, followed by tenofovir plus emtricitabine, adefovir, or interferon. Ninety-one percent of the sites screened for hepatocellular carcinoma. The majority of HIV-infected patients were screened and vaccinated for HBV infection and underwent surveillance for hepatocellular carcinoma. Decisions regarding the performance of liver biopsy, threshold to initiate therapy, and criteria to discontinue therapy varied, reflecting inconsistencies in available treatment guidelines. Treatment decisions reflected concerns regarding future drug resistance in patients who are naive to antiretroviral therapy and the emergence of drug resistance in patients receiving antiretroviral therapy.

International Prognostic Scoring System (IPSS) for Waldenström's Macroglobulinemia (WM).

The outcome of patients (pts) with WM, a rare B-cell malignancy, varies widely. The international community has convened a panel to develop a prognostically meaningful staging system for survival after treatment initiation. Toward establishing IPSS, we performed multivariate analyses with bootstrap validation in a series of 587 pts (median age 67, range: 28 to 95, M/F ratio: 1.7) diagnosed between September 1979 and December 2001. Diagnostic and treatment criteria fulfilled recommendations of the 2nd international WM workshop. Front-line treatment was initiated at diagnosis in 69% and 4 mo to 164 mo later in the remaining pts. Criteria for initiation of therapy included cytopenia, constitutional symptoms, organomegaly, hyperviscosity, IgM-related disorders, which pertained to 51%, 44%, 35%, 31% and 13%, respectively. Treatment regimens comprised alkylating agents, fludarabine and rituximab in 369, 195 and 23 subjects, respectively. Baseline parameters included age>65 yr in 57%, Hb≤11.5 g/dL in 65%, platelet count ≤100 x109/L in 9%, granulocyte count ≤1.5 x109/L in 9%, B2M >3 mg/L in 56%, albumin ≤3.5 g/dL in 36% and monoclonal protein >7.0 g/dL in 7%. With a median follow-up of 64 mo (range, 6 mo–182 mo), the median survival after treatment initiation was 87 mo (95%CI 79–103) regardless of the type of therapy applied (p=0.3). Using results of univariate survival analyses, recursive partitioning and martingale residuals analyses, 7 adverse characteristics for inclusion in multivariate analyses were identified during an expert meeting: age >65 yr, platelet count ≤ 100x109/L, B2M >3 mg/L, M-protein >7.0 g/dL, granulocytes ≤1.5 x109/L, Hb ≤11.5 g/dL and albumin ≤3.5 g/dL. The Cox proportional hazard model with stepwise selection selected the first 6 covariates. Bootstrap resampling (500 replicates) validated the selection of the first 4 covariates in at least 80% of the replicates. Selection of at least one of the last 2 covariates in more than 80% of the replicates indicated a correlation between these 2 covariates, and validated the inclusion of Hb only. Using the combination of age, Hb, platelet count, B2M and M-protein, low risk was defined by the presence of ≤1 adverse characteristic except age, high risk by the presence of >2 adverse characteristics; the remaining patients with 2 adverse characteristics or age >65yr had intermediate risk, comprising 27%, 38% and 35% of patients with 5-yr survival rates of 87%, 68% and 36% (p<0.0001), independent of treatment and age. IPSS split each subgroup identified by previous scoring systems (Morel, Merlini, Dhodapkar). Conversely, log-rank test was significant only when the latter prognostic system was assessed in low IPSS-risk pts. Thus the combination of age, B2M, M-protein and blood counts provides simple prognostic model for survival in WM, hopefully serving as an objective basis for initiation of therapy and comparison of treatment results.

Amyloidosis and Waldenström’s Macroglobulinemia

Primary systemic amyloidosis is an immunoglobulin light chain disorder that is 1/5th as common as multiple myeloma. Amyloidosis is regularly seen in the practice of a hematologist and has recently undergone major advances in terms of the ability to evaluate responses as well as new therapeutic options that were not available when this topic was covered as an education session at the American Society of Hematology meeting 5 years ago. Waldenström macroglobulinemia (WM) is rarer than amyloidosis (1500 per year WM versus 3000 per year amyloid in the US), and recent consensus panels have established the definition of the disease, the diagnostic criteria, criteria for initiation of therapy and a new classification scheme. In this session, new developments in amyloid and macroglobulinemia, from suspicion of the diagnosis to treatment, are covered. In Section I, Dr. Morie Gertz answers four specific questions: (1) When should amyloidosis be suspected? (2) How does one heighten ones index of suspicion for amyloid? (3) How is the diagnosis confirmed and the type classified as primary? (4) What is the prognosis and how is it accurately assessed? Recent findings on cardiac biomarkers, presenting features and use of the free light chain assay are reviewed. Staging for amyloid and recently proposed criteria of response and progression are covered. In Section II, Dr. Giampaolo Merlini comprehensively reviews therapy of amyloidosis from the use of standard melphalan/prednisone to the recently described standard dose therapies including dexamethasone, thalidomide/dexamethasone, melphalan/dexamethasone and IV melphalan/dexamethasone. An extensive discussion of the role of high-dose therapy with stem cell reconstitution follows and includes patient selection, predictors of immediate morbidity and mortality, and survival expectation. Finally, a therapeutic strategy is proposed. In Section III, Drs. Steven Treon and Giampaolo Merlini review the most current information on WM. The consensus panel results and recommendations of the clinical pathologic definition of WM, the prognostic markers and the indications to initiate therapy in WM, the uniform response criteria in WM and available treatments for the disease are reviewed. Drs. Treon and Merlini cover recently published treatment protocols that use rituximab, purine nucleoside analogs, and alkylating agents. The current data on thalidomide, alpha interferon, and high-dose therapy are also covered.

A phase II trial of oral UFT plus cisplatin (CDDP) in patients with non-small cell lung cancer (NSCLC)

Based on the results of our previous pilot study, we conducted a multi-institutional phase II study of combination chemotherapy consisting of oral UFT (Taiho Pharmaceutical Co. Ltd, Tokyo) plus cisplatin (CDDP) in patients with advanced non-small cell lung cancer (NSCLC). UFT capsule containing 100 mg tegafur and 224 mg uracil was orally administered in two divided doses on days 1 through 21 making the total tegafur dose 400 mg/m2/day (maximum 600 mg/body). CDDP was administered by drip infusion at a dose of 20 mg/m2 on a 5-day schedule from day 8 to 12. Treatment was repeated every 4 weeks as long as the criteria for initiation of therapy were still met. Between April 1995 and March 1997, 51 patients were entered into the study. The mean age of all 50 eligible patients was 64 years(range: 40–78). There were 21 patients with clinical stage IIIB disease and 29 patients with IV disease. Thirty-two patients had adenocarcinoma, 14 had epidermoid carcinoma, and four had large cell carcinoma. Of the 47 assessable patients, 18 achieved a partial response with an overall response rate of 38.3% (95% confidence interval: 24.4–52.2%). The median response duration was 113 days. The median survival time of the eligible patients was 12.8 months, and the 1-year suvival rate was 54%. Among the 51 patients enrolled, grade 3 or 4 leukopenia developed in one patient (2%), neutropenia in six patients (11. 8%), thrombocytopenia in six patients (11. 8%), and anemia in three patients (5. 9%). Non-hematological grade 3 or 4 toxicities included anorexia in 10 patients (19.6%), nausea in ten (19.6%), vomiting in two (3.9%), and diarrhea in two (3. 9%). Grade 3 abnormal laboratory data included bilirubinemia in four (7. 8%), GPT elevation in one (2.0%), and hematuria in one (2.0%). In conclusion, combination of CDDP plus oral UFT is efficacious, with low toxicity, in the treatment of advanced NSCLC. In particular, the low hematological toxicity may warrant application of this regimen to the treatment of elderly patients and in trials of concurrent chemoradiotherapy in patients with locally advanced NSCLC.

Treatment of invasive aspergillosis

Invasive aspergillosis is generally a life-threatening invasive opportunistic mycosis affecting principally the upper and lower respiratory tract. Therapeutic response rates vary considerably from one host group to another with particularly high mortality rates in bone marrow transplant, liver transplant and patients with aplastic anaemia or AIDS. Only two drugs are useful for therapy, amphotericin and itraconazole. Recent advances in the formulation of amphoterin B (AmBisome and Amphocil) have resulted in intravenous preparations with lower toxicity, particularly nephrotoxicity, but it has yet to be shown that they have an increased therapeutic index for the treatment of invasive aspergillosis. Itraconazole can only be used orally and in some particularly high-risk or critically ill patients adequate serum concentrations cannot be achieved. The addition of flucytosine or rifampicin to amphotericin B therapy has, at best, only a marginal benefit. Surgery is essential for some manifestations of invasive aspergillosis. This article reviews therapeutic strategies including criteria for initiation of therapy, combination and sequential therapy, duration of therapy and secondary prophylaxis and indications for surgery in invasive aspergillosis.

Prediction of CD4 count from CD4 percentage experience from three laboratories

CD4 counts have been used to monitor progression of disease in HIV infection as criteria for initiation of therapy, and to stratify and follow patients in clinical trials. Recently, the Centers for Disease Control and Prevention (CDC) has made CD4 counts part of the classification of HIV disease. Because a CD4 percentage may be the only laboratory information available, this study was initiated to determine whether the correlation between CD4 percentages and CD4 counts is sufficiently high to enable these measures to be substituted for each other. One thousand consecutive CD4 measurements from the University of Washington (UW) were used to create a model that was tested using datasets of 1000 CD4 measurements each from Maryland Medical Laboratories (MML) and Rush-Presbyterian-St Luke's Medical Center (Rush). The patients were not selected for age, sex, risk group or treatment. All patients from MML and Rush were known to be HIV-positive, while the HIV status of all UW patients was unknown. The model predicted that a patient with a CD4 percentage > or = 14% would have a CD4 count > or = 200 x 10(6)/l(if CD4 percentage of 14% was used, 9% of patients would have a CD4 count > or = 200 x 10(6)/l), and a patient with a CD4 percentage > or = 27% would have a CD4 count > or = 500 x 10(6)/l(if CD4 percentage of 27% was used, 17% of patients would have a CD4 count > or = 500 x 10(6)/l). These CD4 percentage correlations may be useful when a white blood cell and lymphocyte count are not available to calculate the CD4 count.

B-chronic lymphocytic leukemia. Prognostic implication of bone marrow histology in 120 patients experience from a single hematology unit.

The available staging systems for B-chronic lymphocytic leukemia (B-CLL) do not always predict the clinical course and the prognosis of the disease. In these systems, the pattern of bone marrow histology is not incorporated. In the current report we investigate the prognostic value of the diffuse or nondiffuse pattern of bone marrow involvement in 120 B-CLL patients in relation to their actuarial survival, and we compare these results with the actuarial survival based on the International Workshop system. In addition, we analyze the influence of the diffuse or nondiffuse pattern on the actuarial survival, in relation to the individual clinical stages (A, B, C). All patients were diagnosed and followed-up in the same Unit. Our patients were divided into Stage A (64), Stage B (22), and Stage C (34). They were also subdivided into those with a diffuse (46) and those with a nondiffuse (74) pattern of bone marrow histology. The difference in the actuarial survival in relation to their clinical stage (A, B, C) was statistically significant (P less than 0.025). A greater statistical difference (P less than 0.005) was found when the actuarial survival was analyzed in relation to the diffuse or nondiffuse pattern of bone marrow histology. No statistically significant differences could be found (P greater than 0.1), when the actuarial survival was calculated in every stage (A, B, C), on the basis of the diffuse or nondiffuse pattern of bone marrow histology. When our Stage A and B patients were analyzed for disease progression, in relation to the diffuse or nondiffuse bone marrow histology, it was found that 66.6% of the diffuse Stage A patients and 88% of the diffuse Stage B patients had disease progression as compared to only 8.6% for the nondiffuse Stage A patients and 33% for the nondiffuse Stage B patients. Our findings indicate that: the pattern of bone marrow histology in B-CLL patients is the single most important prognostic parameter in this disease; a clinicopathologic staging system for B-CLL may be justified; and the diffuse pattern of bone marrow histology could be considered as the best criterion for initiation of therapy in these patients.