Aaron Polliack

A Prognostic Score for Advanced Hodgkin's Disease

BACKGROUND Two thirds of patients with advanced Hodgkins disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail. METHODS Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkins disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation. RESULTS The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. CONCLUSIONS The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkins disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

BACKGROUND Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern.

Using homology searches, we identified a novel human inhibitor of apoptosis (IAP) gene. This gene has two splicing variants that contain open reading frames of 298 and 280 amino acids and both contained a single copy of baculovirus IAP repeat (BIR) and RING domain. We refer here to the longer and shorter variants as Livin α and β, respectively. Semiquantitative reverse transcriptase‐polymerase chain reaction demonstrated a tissue‐specific and non‐correlated expression pattern in both adult and fetal tissues. Both mRNA variants were detected in various transformed cell lines. Despite their very close similarity, the two isoforms have different antiapoptotic properties. Both isoforms have a significant antiapoptotic activity in the Jurkat T cell line after triggering apoptosis via tumor necrosis factor and CD95 receptors. The Livin α but not β protects cells from apoptosis induced by staurosporine, but in contrast, apoptosis initiated by etoposide was blocked only by the β isoform. This difference in biological activities may indicate the presence of critical amino acids outside the BIR and RING domains. These functional and tissue distribution differences of Livin α and β suggest that Livin may play a complex role in the regulation of apoptosis.

Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients

Abstract: Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non‐Hodgkins lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986–95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy‐proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL.

Suppressive Effect of Ferritin on in Vitro Lymphocyte Function

Summary. This study describes the effect of ferritin on lymphocyte function in vitro. Peripheral blood lymphocytes isolated from normal donors were incubated with purified human splenic ferritin, and the mitogenic effect of phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and mixed lymphocyte reaction (MLR) were assessed by the uptake of 3H‐thymidine (3H‐TdR). Ferritin (0·25–5·0 μg/ml culture) caused a marked suppression of PHA and Con A blastogenesis but had no suppressive effect on PWM‐induced transformation. Maximal suppression was obtained at a ferritin concentration of 1 μg/ml and this was not enhanced by increasing ferritin concentrations. Ferritin also reduced the Con A capping phenomenon in normal lymphocytes from 22% to 6%, suppressed the MLR reaction but had no effect on the ability of normal lymphocytes to form E, EA and EAC rosettes or on in vitro lymphocyte cytoxicity against the K‐562 cell line. Visual proof of the suppressive effect of ferritin on mitogen induced blastogenesis was provided by scanning electron microscopy, and direct evidence for the ability of lymphocytes to bind ferritin was obtained from studies with radioiodine labelled ferritin. The above findings indicate that ferritin suppresses certain parameters of T‐lymphocyte function in vitro. The relation of the present findings to recognized abnormalities of T‐cell function encountered in certain neoplastic disorders associated with high serum ferritin levels is at present unknown.

Image-guided core-needle biopsy in malignant lymphoma: experience with 100 patients that suggests the technique is reliable.

PURPOSE In an initial evaluation of 1,500 computed tomography (CT)-guided core-needle biopsies performed at our institute during the period from 1989 to 1994, we encountered 100 patients with the diagnosis of lymphoma. Here, we review the clinical impact of 109 image-guided needle biopsies in these 100 patients with non-Hodgkins lymphoma (NHL) and Hodgkins disease (HD). PATIENTS AND METHODS NHL was diagnosed in 71 patients, and 29 had HD. Among the NHL patients, 17 (24%) had proven lymphoma diagnosed before the biopsy was performed; in 54 (76%) core-needle biopsy was performed as the first diagnostic procedure. Of 29 HD patients, nine (31%) were already established cases of HD, and in 20 (69%) core-needle biopsy was the first diagnostic procedure attempted. Most of the biopsies were performed under CT control using a 20- or 18-gauge Turner biopsy needle. RESULTS Eighty-six patients received therapy based on the results of the needle biopsy alone. Fourteen patients received therapy after undergoing surgical biopsy for a suspected diagnosis of lymphoma, which could not be established with certainty on the basis of an earlier core-needle biopsy alone. In 78% of the patients, the needle biopsy saved a further surgical procedure that may have been difficult to perform because of the primary location of the tumor. CONCLUSION From our experience in this study, image-guided core-needle biopsies provide sufficient information for the diagnosis of and subsequent therapeutic decision to treat most cases of lymphoma.

Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8–9 April 2010

One hundred and fifty hemato-oncologists and nuclear medicine specialists from more than 20 countries joined in April 2010 the 2-day Second International Workshop on interim PET in lymphoma. During the nuclear medicine session the advantages of the five-point scale Deauville criteria for interim PET reporting over the other sets of visual criteria were presented. The specific problems of PET reporting in escalation/de-escalation trials in Hodgkin lymphoma (HL) were addressed as well as the limitations of visual analysis for early PET evaluation in non-Hodgkin lymphoma (NHL). The applicability, efficacy, and reproducibility of quantitative criteria (ΔSUVmax analysis and tumor/liver SUV ratio) for interim PET in NHL were reported. In retrospective and prospective series. Some of the interim PET-based clinical trials ongoing worldwide in HL and NHL were reported. In early-stage HL, three trials aimed at determining the feasibility of omitting radiotherapy in interim PET negative patients, and in advanced-stage HL two PET-based ABVD escalation or BEACOPP de-escalation trials, in NHL two studies reported preliminary results of interim PET in follicular lymphoma, in DLBCL a round-table discussion pointed out the lack of definite criteria for interim PET, and a few observational studies in DLBCL reported the comparison of the various techniques of interim PET reporting (visual versus quantitative). The preliminary results of two international validation studies of the five-point scale criteria in HL and NHL launched in 2009 were reported. The presentations of the meeting are available on http://eitti.free.fr

Report on the Third International Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, 26–27 September 2011 and Menton 2011 consensus

Abstract One hundred and ninety-three hemato-oncologists and nuclear medicine specialists from 23 countries joined the 2-day Third International Workshop on Interim Positon Emission Tomography in Lymphoma held in September 2011. Forty scientific posters were presented or discussed in the plenary session. Final results of international validation studies of Deauville criteria and change in maximum standardized uptake value (ΔSUVMAX) analysis in Hodgkin lymphoma (HL) as well as non-Hodgkin lymphoma (NHL) were reported. These studies were confirmatory of the prognostic value of interim positron emission tomography (PET) in 261 patients with advanced HL after two cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) when reported with the 5-point scale and in 120 patients with diffuse large B-cell lymphoma (DLBCL) after two cycles of a rituximab-containing immunochemotherapy regimen when using ΔSUV analysis. A preliminary consensus on interim PET was established among experts on the assessment of marrow response, refinement of scores 4 and 5 of the 5-point scale, the need to focus on interim PET results for NHL other than DLBCL, methods to compute ΔSUV and factors affecting ΔSUV measurements. Recommendations were given on how to use ΔSUV analysis in NHL taking into account the levels of initial SUVMAX and interim SUVMAX. For the next meeting (October 2012), the majority of the audience strongly favored extending the topics, including in the workshop all aspects of PET in lymphoma, rather than just limiting it to interim PET.

Pulmonary involvement in lymphoma

Intrathoracic involvement is common in both Hodgkins disease (HD) and non-Hodgkins lymphoma (NHL). The most common manifestation is mediastinal lymphadenopathy. In HD, nodal involvement is by contiguity and usually involves the superior mediastinum, while the findings in NHL are more variable. Pulmonary parenchymal disease occurs in 38% of HD and 24% of NHL. In untreated HD, parenchymal involvement is invariably associated with mediastinal lymphadenopathy and often with widespread disease. Three distinct radiological patterns of pulmonary lymphoma are recognised: nodular, bronchovascular-lymphangitic and pneumonic-alveolar. Rarely lymphoma may be endobronchial. Pleural effusion occurs in 16% of lymphoma patients and is usually associated with disease elsewhere. It is frequently caused by lymphatic obstruction but may be due to direct pleural involvement by tumour. Chylothorax may occur in NHL but is unusual in HD. Diagnosis of intrathoracic lymphoma is by transbronchial or transthoracic biopsy or by needle aspiration of tissue or pleural fluid. The addition of immunostaining improves the diagnostic yield in equivocal cases. Treatment and prognosis vary depending on cell-type, location and extent of disease.

The late adverse events of rituximab therapy--rare but there!

Rituximab, an anti CD20 monoclonal antibody, has now become a cornerstone in the treatment of many CD20 positive hematological malignancies and a variety of autoimmune disorders. In contrast to the acute allergic and cytokine associated reactions, late adverse events of rituximab are indeed uncommon but at the same time probably under-reported. In this review, we detail late adverse events reported since its use in hemato-oncological neoplasias and other disorders. These adverse events include the development of late-onset neutropenia, defects of immune reconstitution with associated immune compromise, infections, progressive multifocal leukoencephalopathy, reactivation of hepatitis, intestinal perforation and interstitial pneumonitis. Possible mechanisms involved in rituximab-associated complications and the pathogenesis of these adverse effects are reviewed and discussed. Evidence based graded recommendations for the management of these adverse effects are proposed.