Anas Younes

Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

BACKGROUND Hodgkins lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35). METHODS In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kilogram of body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily Hodgkins lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation. RESULTS The maximum tolerated dose was 1.8 mg per kilogram, administered every 3 weeks. Objective responses, including 11 complete remissions, were observed in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. CONCLUSIONS Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase 1 study. Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects. (Funded by Seattle Genetics; ClinicalTrials.gov number, NCT00430846.).

Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma

PURPOSE Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. PATIENTS AND METHODS In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkins lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. RESULTS The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. CONCLUSION The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

PURPOSE Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkins lymphoma. PATIENTS AND METHODS Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstroms macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.

High Rate of Durable Remissions After Treatment of Newly Diagnosed Aggressive Mantle-Cell Lymphoma With Rituximab Plus Hyper-CVAD Alternating With Rituximab Plus High-Dose Methotrexate and Cytarabine

PURPOSE To determine the response, failure-free survival (FFS), and overall survival rates and toxicity of rituximab plus an intense chemotherapy regimen in patients with previously untreated aggressive mantle-cell lymphoma (MCL). PATIENTS AND METHODS This was a prospective phase II trial of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD; considered one cycle) alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine (considered one cycle) for a total of six to eight cycles. RESULTS Of 97 assessable patients, 97% responded, and 87% achieved a complete response (CR) or unconfirmed CR. With a median follow-up time of 40 months, the 3-year FFS and overall survival rates were 64% and 82%, respectively, without a plateau in the curves. For the subgroup of patients < or = 65 years of age, the 3-year FFS rate was 73%. The principal toxicity was hematologic. Five patients died from acute toxicity. Four patients developed treatment-related myelodysplasia/acute myelogenous leukemia, and three patients died while in remission from MCL. A total of eight treatment-related deaths (8%) occurred. CONCLUSION Rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine is effective in untreated aggressive MCL. Toxicity is significant but expected. Because of the shorter FFS concurrent with significant toxicity in patients more than 65 years of age, this regimen is not recommended as standard therapy for this age subgroup. Larger prospective randomized studies are needed to define the role of this regimen in the treatment of MCL patients compared with existing and new treatment modalities.

Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence-Based Review

PURPOSE Tumor lysis syndrome (TLS) has recently been subclassified into either laboratory TLS or clinical TLS, and a grading system has been established. Standardized guidelines, however, are needed to aid in the stratification of patients according to risk and to establish prophylaxis and treatment recommendations for patients at risk or with established TLS. METHODS A panel of experts in pediatric and adult hematologic malignancies and TLS was assembled to develop recommendations and guidelines for TLS based on clinical evidence and standards of care. A review of relevant literature was also used. RESULTS New guidelines are presented regarding the prevention and management of patients at risk of developing TLS. The best management of TLS is prevention. Prevention strategies include hydration and prophylactic rasburicase in high-risk patients, hydration plus allopurinol or rasburicase for intermediate-risk patients, and close monitoring for low-risk patients. Primary management of established TLS involves similar recommendations, with the addition of aggressive hydration and diuresis, plus allopurinol or rasburicase for hyperuricemia. Alkalinization is not recommended. Although guidelines for rasburicase use in adults are provided, this agent is currently only approved for use in pediatric patients in the United States. CONCLUSION The potential severity of complications resulting from TLS requires measures for prevention in high-risk patients and prompts treatment in the event that symptoms arise. Recognition of risk factors, monitoring of at-risk patients, and appropriate interventions are the key to preventing or managing TLS. These guidelines should assist in the prevention of TLS and improve the management of patients with established TLS.

Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma.

PURPOSE Although most patients with indolent lymphomas respond to initial therapy, virtually all experience relapse. Secondary therapy is often beneficial, but responses are rarely, if ever, durable. We conducted this phase II trail to evaluate the therapeutic efficacy and toxicity of fludarabine, mitoxantrone, and dexamethasone (FND) in patients with relapsed indolent lymphoma. PATIENTS AND METHODS Fifty-one patients with recurrent or refractory indolent lymphoma were treated with a regimen of fludarabine 25 mg/m2/d intravenously (IV) on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1, and dexamethasone 20 mg/d IV or orally on days 1 to 5. Treatment was repeated at 4-week intervals for a maximum of eight courses. Late in the course of this trial, trimethoprim-sulfamethoxazole (TMP-SMX) was incorporated for Pneumocystis carinii (PCP) prophylaxis. RESULTS Responses were complete (CR) in 24 patients (47%) and partial (PR) in 24 (47%). The median failure-free survival time was 21 months for CR patients and 9 months for PR patients. Notable activity of FND was seen even in the elderly, in those with high serum lactate dehydrogenase (LDH) or beta2-microglobulin levels, and in those with multiple prior treatment regimens. The predominant toxic effects were myelosuppression and infections; other toxic effects were modest. Infections occurred in 12% of courses. Almost half of the infections were proven or suspected opportunistic infections, including six cases of dermatomal herpes zoster and two cases of proven PCP pneumonia. CONCLUSION The FND combination is highly active in patients with recurrent or relapsed indolent lymphoma and results in a high percentage of CRs. Because of the risk of opportunistic infections, we currently recommend prophylaxis with TMP-SMX and advise deletion of corticosteroids for patients who develop opportunistic infections.

Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial

Background Malignant cells of classical Hodgkin lymphoma (cHL) are characterised by genetic alterations at the 9p24·1 locus. This leads to overexpression of the programmed death 1 (PD-1) ligands and enables tumour cells to evade immune surveillance. A phase 1b study showed that nivolumab, a PD-1-blocking antibody, produced a high response rate in patients with relapsed and refractory cHL, with an acceptable safety profile. This phase 2 study assessed the clinical benefit of nivolumab monotherapy in patients with cHL after autologous stem-cell transplantation and brentuximab vedotin failure. Methods This ongoing phase 2 study (NCT02181738) assessed the efficacy and safety of nivolumab, administered intravenously over 60 minutes at 3 mg/kg every 2 weeks, in adult patients with cHL who had failed both autologous stem-cell transplantation and brentuximab vedotin. The primary endpoint was objective response rate by independent radiologic review committee (IRRC) assessment. Secondary and other endpoints included duration of response, safety, and assessment of PD-L1 and PD-L2 loci and PD-L1 and PD-L2 protein expression. Findings Among 80 treated patients, the median number of prior therapies was four (range 3–15). With a mean (SD) follow-up of 8·6 months (2·02), objective response rate per IRRC was 66·3% (53/80). The most common drug-related adverse events (≥15%) included fatigue, infusion-related reaction, and rash. The most common drug-related grade 3–4 adverse events were neutropenia and increased lipase levels (both n=4). The most common serious adverse event (any grade) was pyrexia (n=3). Interpretation Nivolumab demonstrated a high response rate and an acceptable safety profile in patients with cHL who progressed following autologous stem-cell transplantation and brentuximab vedotin. Nivolumab may therefore provide a novel treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. Funding Bristol-Myers Squibb.BACKGROUND Malignant cells of classical Hodgkins lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkins lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkins lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. METHODS In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkins lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738. FINDINGS Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8·9 months (IQR 7·8-9·9), 53 (66·3%, 95% CI 54·8-76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related. INTERPRETATION Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkins lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. FUNDING Bristol-Myers Squibb.

Antibiotic Treatment of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue: An Uncontrolled Trial

Gastric low-grade B-cell lymphoma is related to Helicobacter pylori infection according to histopathologic, epidemiologic, and clinical characteristics. Although normal gastric mucosa does not contain organized lymphoid tissue, lymphoid follicles develop with H. pylori infection (1) and with autoimmune diseases, such as the Sjgren syndrome (2). Low-grade B-cell lymphoma has been postulated to arise within this mucosa-associated lymphoid tissue (MALT) and is often called low-grade MALT lymphoma (3, 4). The incidence of gastric low- and high-grade MALT lymphoma is increased in populations with a high prevalence of H. pylori infection, and H. pylori infection has been reported in up to 90% of patients with low-grade MALT lymphoma (4-6). In addition, investigators have shown that growth of this tumor may depend on antigenic stimulation by H. pylori: They demonstrated that the proliferation of lymphoma B cells in cell culture can be stimulated by H. pylori-specific T cells and related cytokines in the presence of H. pylori (7). On the basis of these findings, trials of antibiotic treatment of gastric low-grade MALT lymphoma have been initiated, and the regression of lymphoma after cure of H. pylori infection has been reported in a high proportion of patients with low tumor burden (8-13). Data on patients with significant tumor infiltration are still forthcoming (13, 14). Because MALT lymphoma has only recently been approached as a distinct clinicopathologic entity (15, 16), its natural history and clinical course are not fully defined. Current data suggest that it is often an indolent tumor with long periods of mild activity and confinement to the stomach. Patients often present with nonspecific upper intestinal discomfort, ulcer-associated symptoms, or gastric bleeding. The endoscopic appearance may suggest benign gastritis, and extensive biopsies may be required for diagnosis. Progression to significant tumor mass, dissemination, or transformation to high-grade, aggressive lymphoma occur in an undefined subset of patients, who may present with early satiety or weight loss. Spontaneous remissions are rare (17-20). Because low-grade MALT lymphoma is an uncommon, often indolent form of cancer with few clinical findings and because the risk for progression to high-grade MALT lymphoma is still unknown (15, 16), definitive data on cure require long-term follow-up of large cohorts from standardized clinical trials. This report presents an interim analysis of an ongoing trial designed to determine the long-term response of low-grade gastric MALT lymphoma to antibiotic treatment and to define criteria for treatment and follow-up. Methods Patients Patients with gastric MALT lymphoma restricted to the stomach and perigastric lymph nodes (modified Ann Arbor stage I and II N1) were eligible for the study. The University of Texas, M.D. Anderson Cancer Center (MDACC), Internal Review Board approved the study, and all patients provided written informed consent. The National Cancer Institute and the institutional review boards of participating institutions approved the multi-institutional protocol. To enable a follow-up period of at least 18 months, only patients treated before May 1997 were included in this analysis. Study Design and Treatment The interim data are derived from an ongoing, prospective, uncontrolled treatment trial with third-party patient registry. Patients were studied at four participating centers. Pathologic diagnosis and resolution of MALT lymphoma were confirmed at MDACC, and all but one patient were examined endoscopically at MDACC. Study design included 1) tumor staging with bilateral bone marrow biopsies and aspirates and computed tomography of the abdomen and pelvis done at baseline and yearly; 2) endoscopy at baseline, at weeks 6 to 8, at 3- to 4-month intervals thereafter until resolution of MALT lymphoma was seen on two consecutive endoscopies, at 6-month intervals thereafter for 2 years, and then yearly thereafter; and 3) endoscopic ultrasonography at baseline and at each endoscopy until resolution of masses or infiltration of the muscularis propria, if present (defined as thickness>2 mm or obliteration of wall architecture), and then at 6- to 12-month intervals. The treatment protocol consisted of two of the following three oral antibiotic regimens1] amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2) tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times dailyadministered sequentially for 21 days at baseline and at 8 weeks along with a proton-pump inhibitor (lansoprazole, 30 mg twice daily [n=29], or omeprazole, 20 mg twice daily [n=5]), and bismuth subsalicylate, two tablets four times daily. Patients who were allergic to penicillin received the tetracycline-based regimens. Tumor Staging Tumors were staged endoscopically to separate superficial gastritis from significant ulcers and infiltration and from mass lesions. A modified Ann Arbor staging system that incorporated changes proposed by Blackledge, Musshoff, and Rohatiner and their coworkers was used initially (21-23). The TNM (tumor, node, metastasis) classification of the American Joint Committee on Cancer and Union Internationale Contre le Cancer (24, 25), which corresponds to the modified Ann Arbor staging, was subsequently adapted and applied (Table 1). The extent of tumor (T) infiltration through the stomach wall and to adjacent organs corresponds to T staging of gastric cancer. Modified Ann Arbor stage I corresponds to stage I T1-4 N0 M0. Modified Ann Arbor stage II1 (22) (involvement of perigastric lymph nodes) corresponds to stage II T1-4 N1 M0. Modified Ann Arbor stage II2 (22) (involvement of distant lymph nodes caudal to the diaphragm, including para-aortic and retroperitoneal lymph nodes) corresponds to stage II T1-4 N2 M0. Ann Arbor stage III (lymph node involvement on both sides of the diaphragm) is designated by stage III T1-4 N3 M0. Ann Arbor stage IV (organ metastasis or involvement of a second extranodal site) is designated by stage IV T1-4 N0-3 M1. Table 1. Staging of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Criteria for Response Response to treatment was evaluated at 3- to 4-month intervals beginning with the fifth month after treatment. Treatment was considered to have failed if patients did not meet criteria for improvement; these patients were removed from the study. In stage I T2, I T3, and II N1 tumors, improvement was defined as regression to a lower stage, 30% reduction in abnormal wall thickness, or 30% reduction in the size of the tumor mass (product of the greatest diameters). These patients remained in the study if sequential improvement was evident at each 3-month interval. Patients with persistent mucosal disease (stage I T1) documented by histopathology were formally reviewed at 12-month intervals; a consensus on withdrawal from or continuation in the study was based on clinical considerations, current knowledge, and patient preference. Initially, patients with persistent stage I T1 disease were withdrawn from the study at 12 months (n=2). Subsequently, patients with persistent stage I T1 disease were observed for more than 36 months if improvement was documented at 12-month intervals. Criteria for improvement in stage I T1 disease included reduction in the number of affected gastric sites or affected biopsy specimens or improved histologic score (8), endoscopic appearance of progressive atrophy and scarring, or resolution of abnormal wall thickness on endoscopic ultrasonography. Complete remission was defined as the absence of histopathologic evidence of lymphoma and an endoscopic appearance of gastritis or better. Partial remission was defined as a reduction in endoscopic stage in stage I T2 disease or at least 50% reduction in the size of the mass lesions in stage I T3 or II T3 N1 disease. In stage I T1 disease, partial remission was defined as at least 75% reduction in the number of gastric sites or biopsy specimens showing lymphoma. Treatment was considered to have failed in patients who met criteria for failure or who were withdrawn from the study before complete remission occurred. Endoscopy and Biopsies The gastric mapping protocol included 2 or more maximum-capacity biopsies from each of 7 to 12 areas of the gastric map (26) and at least 6 biopsies from 2 or more of the most abnormal areas. The more extensive mapping was done at baseline and at clinically relevant time points. Studies, done at defined intervals, included routine histopathology, H. pylori testing by Genta stain, rapid urease test (CLO-test, Delta West, Bentley, Australia) or serology, Southern blot or polymerase chain reaction (PCR) for immunoglobulin gene rearrangement analysis, and immunoglobulin light-chain immunocytochemistry. Diagnostic Criteria Low-grade B-cell MALT lymphoma was diagnosed by established histologic criteria [15, 27], including 1) a dense diffuse infiltrate of marginal-zone centrocyte-like B cells with round to slightly irregular nuclear contours, often with abundant pale cytoplasm; 2) presence of lymphoepithelial lesions, characterized by infiltration and disruption of gastric glands or crypts by groups of neoplastic lymphoid cells; and 3) absence of any areas where large cells predominate. Minor criteria supporting but not essential for diagnosis included presence of immunoglobulin light-chain restriction; presence of residual secondary follicle centers with or without intact mantles; and presence of follicular colonization, defined as replacement of follicle centers by neoplastic lymphoid cells. Immunophenotypic expression of pan-B-cell antigens, such as CD20, and lack of expression of CD5 or CD10 supported the diagnosis. Patients with foci of large-cell transformation were excluded from the study. Southern Blot and Polymerase Chain Reaction High-molec

Brentuximab Vedotin (SGN-35)

Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization monomethylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n = 102) and 87% in patients with anaplastic large cell lymphoma (n = 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed–Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration. Clin Cancer Res; 17(20); 6428–36. ©2011 AACR.

Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus

Tumour lysis syndrome (TLS) is a life‐threatening oncological emergency characterized by metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. These metabolic complications predispose the cancer patient to clinical toxicities including renal insufficiency, cardiac arrhythmias, seizures, neurological complications and potentially sudden death. With the increased availability of newer therapeutic targeted agents, such as rasburicase (recombinant urate oxidase), there are no published guidelines on the risk classification of TLS for individual patients at risk of developing this syndrome. We convened an international TLS expert consensus panel to develop guidelines for a medical decision tree to assign low, intermediate and high risk to patients with cancer at risk for TLS. Risk factors included biological evidence of laboratory TLS (LTLS), proliferation, bulk and stage of malignant tumour and renal impairment and/or involvement at the time of TLS diagnosis. An international TLS consensus expert panel of paediatric and adult oncologists, experts in TLS pathophysiology and experts in TLS prophylaxis and management, developed a final model of low, intermediate and high risk TLS classification and associated TLS prophylaxis recommendations.