Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma: a multicentre phase II study.

There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non-Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty-two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40-86); 38% bulky disease; 19% malignant effusions; 91% advanced-stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0-2 vs. 3-5 was 60% vs. 26% respectively (P = 0·02), with corresponding OS rates of 92% and 81% respectively (P = 0·16). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL.

High incidence of gastrointestinal tract disorders and autoimmunity in primary cutaneous marginal zone B-cell lymphomas.

IMPORTANCE: To our knowledge, this is the first comprehensive study addressing comorbidities associated with primary cutaneous marginal zone B-cell lymphomas (PCMZLs). OBJECTIVE: To determine if patients with PCMZL were at risk for other medical conditions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study at a cutaneous lymphoma clinic and a dermatopathologic consultation service at a single academic institution using an extensive questionnaire of illnesses, symptoms, and environmental exposures for 80 sequential patients with PCMZL and 80 matched controls. MAIN OUTCOMES AND MEASURES: The frequency of several morbidities was obtained in both groups from data gathered from the questionnaire and corroborated by reviewing medical records when available. RESULTS: We found a high incidence of past or present gastrointestinal tract problems in 49 patients (61.2%) with PCMZL compared with 30 participants (37.5%) in the control group (CG) (P = .003). Gastroesophageal reflux was reported in 50.0% (40 vs 27 in the CG, P = .04) and gastric ulcers in 10.0% (8 vs 3 in the CG, P = .13); 20.0% of the cohort had positive Helicobacter pylori serology (16 vs 2 in the CG, P = .003). Colon disorders, including irritable bowel syndrome and inflammatory bowel disease, were more common in the PCMZL cohort (20 vs 7 in the CG, P = .01). Autoimmunity was reported in 20.0% of participants (16 vs 6 in the CG, P = .03). Eight patients had a history of Hashimoto thyroiditis. Three patients had a positive antinuclear antibody. Two had a diagnosis of lupus erythematosus and 1 had Sjögren syndrome. Sicca syndrome was noted in 12.5% (10 vs 3 in the CG, P = .052). A history of noncutaneous malignant neoplasms was observed in 21.3% of the patients (17 vs 8 in the CG, P = .050). Other notable morbidities did not reach statistical significance. CONCLUSIONS AND RELEVANCE: Our results indicate a high incidence of systemic conditions in patients with PCMZL, especially involving the gastrointestinal tract, but also autoimmunity and cancer.

Novel Phenotypic Fluorescent Three-Dimensional Co-Culture Platforms for Recapitulating Tumor in vivo Progression and for Personalized Therapy.

Because three-dimensional (3D) in vitro models are more accurate than 2D cell culture models and faster and cheaper than animal models, they have become a prospective trend in the biomedical and pharmaceutical fields, especially for personalized and targeted therapies. Because appropriate 3D models can be customized to mimic the in vivo microenvironment wherein various cell populations grow within an intricate but well organized extracellular matrix (ECM), they can accurately recapitulate physiological and pathophysiological progressions. The majority of cancers are carcinomas, which originate from epithelial cells, and dynamically interact with non-malignant cells including stromal cells (fibroblasts), vascular cells (endothelial cells and pericytes), immune cells (macrophages and mast cells), and the ECM. Employing a tumor monoclonal colony, tumor xenograft or patient cancer biopsy into an in vivo-like microenvironment, the native signaling pathways, cell-cell and cell-matrix interactions, and cell phenotypes are preserved and our fluorescent phenotypic 3D co-culture platforms can then accurately recapitulate the tumor in vivo scenario including tumor induced angiogenesis, tumor growth, and metastasis. In this paper, we describe a robust and standardized method to co-culture a tumor colony or biopsy with different cell populations, e.g., endothelial cells, immune cells, pericytes, etc. The procedures for recovering cells from the co-culture for molecular analyses, imaging, and analyzing are also described. We selected ECM solubilized extract derived from Engelbreth-Holm-Swam sarcoma cells. Because the 3D co-culture platforms can provide drug chemosensitivity data within 9 days that is equivalent to the results generated from mouse tumor xenograft models in 50 days, the 3D co-culture platforms are more accurate, efficient, and cost-effective and may replace animal models in the near future to predict drug efficacy, personalize therapies, prevent drug resistance, and improve the quality of life.

Acute kidney injury and bisphosphonate use in cancer: a report from the research on adverse drug events and reports (RADAR) project.

PURPOSE: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration's Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. METHODS: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were "renal problems" and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. RESULTS: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 ± 10 years. Multiple myeloma (n = 220, 46%), breast cancer (n = 98, 20%), and prostate cancer (n = 24, 5%) were identified. Agents included ZOL (n = 411, 87.5%), pamidronate (n = 8, 17%), and alendronate (n = 36, 2%). Outcomes included hospitalization (n = 304, 63.3%) and death (n = 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. CONCLUSION: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS.

Cutaneous γδ T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas.

We reviewed our multicenter experience with gamma-delta (γδ) T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54% (25/46) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (3/42 cases) and bone marrow involvement (5/28 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55% (22/39) of the patients. Abnormal positron emission tomography and/or computed tomography scans in 20/37 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3+/CD4⁻/CD5⁻/CD8⁻/BF1⁻/γ-M1+/TIA-1+/granzyme-B+/CD45RA-/CD7-, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous γδ T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.

Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.

Evidences showing wide presence of small genomic aberrations in chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western population. Although genetic factors are considered to contribute to CLL etiology, at present genomic aberrations identified in CLL are limited compared with those identified in other types of leukemia, which raises the question of the degree of genetic influence on CLL. We performed a high-resolution genome scanning study to address this issue. FINDINGS: Using the restriction paired-end-based Ditag Genome Scanning technique, we analyzed three primary CLL samples at a kilobase resolution, and further validated the results in eight primary CLL samples including the two used for ditag collection. From 51,632 paired-end tags commonly detected in the three CLL samples representing 5% of the HindIII restriction fragments in the genomes, we identified 230 paired-end tags that were present in all three CLL genomes but not in multiple normal human genome reference sequences. Mapping the full-length sequences of the fragments detected by these unmapped tags in seven additional CLL samples confirmed that these are the genomic aberrations caused by small insertions and deletions, and base changes spreading across coding and non-coding regions. CONCLUSIONS: Our study identified hundreds of loci with insertion, deletion, base change, and restriction site polymorphism present in both coding and non-coding regions in CLL genomes, indicating the wide presence of small genomic aberrations in chronic lymphocytic leukemia. Our study supports the use of a whole genome sequencing approach for comprehensively decoding the CLL genome for better understanding of the genetic defects in CLL.

Accuracy and efficacy of intrathecal administration of morphine sulfate for treatment of intractable pain using the Prometra(®) Programmable Pump.

OBJECTIVES: Intrathecal infusion pumps are increasingly used to deliver analgesics for chronic intractable pain. This trial evaluated the accuracy and efficacy of the new Prometra® Programmable Pump System for intrathecal administration of morphine sulfate to treat chronic intractable pain. METHODS: One hundred and ten patients were given continuous intrathecal morphine sulfate and assessed monthly for up to six months. Accuracy was determined as the ratio of delivered to programmed drug volume (DP ratio). Efficacy was assessed using the visual analog and numeric rating scales and the Oswestry Disability Index. RESULTS: The mean accuracy of the Prometra pump was 97.1%, with a 90% confidence interval of 96.2-98.0%. Decreases in pain and disability were reported at 68.4% of patient visits. No unanticipated adverse events or device complications were reported. CONCLUSIONS: The Prometra pump provides an accurate, effective, and safe system for intrathecal administration of morphine sulfate for treatment of chronic intractable pain.

Mantle cell lymphoma: biological insights and treatment advances.

Mantle cell lymphoma (MCL) exhibits considerable molecular heterogeneity and complexity, and is regarded as one of the most challenging lymphomas to treat. With increased understanding of the pathobiology of MCL, it is proposed that MCL is the result of 3 major converging factors, namely, deregulated cell cycle pathways, defects in DNA damage responses, and dysregulation of cell survival pathways. In the present era of targeted therapies, these biologic insights have resulted in the identification of several novel rational targets for therapeutic intervention in MCL that are undergoing active clinical testing. To date, there is no standard of care in MCL. Several approaches including conventional anthracycline-based therapies and intensive high-dose strategies with and without stem cell transplantation have failed to produce durable remissions for most patients. Moreover, considering the heterogeneity of MCL, it is increasingly being recognized that risk-adapted therapy might be a relevant therapeutic approach in this disease. At the first and second Global Workshops on Mantle Cell Lymphoma, questions addressing advances in the pathobiology of MCL, optimization of existing therapies, assessment of current data with novel therapeutic strategies, and the identification of molecular or phenotypic risk factors for utilization in risk-adapted therapies were discussed and will be summarized herein.

Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma.

OBJECTIVES: To study the clinical features, therapeutic responses, and outcomes in patients with folliculotropic mycosis fungoides (FMF) and to compare our single-center experience of 43 patients with the findings from the Dutch Cutaneous Lymphoma Group. SETTING: A single-center experience from the Northwestern University Multidisciplinary Cutaneous Lymphoma Group. PATIENTS: Forty-three patients with FMF were included in the study and compared with 43 age- and stage-matched patients with classic epidermotropic mycosis fungoides (MF) with similar follow-up time. RESULTS: Folliculotropic mycosis fungoides showed distinct clinical features, with 37 patients having facial involvement (86%) and only 6 having lesions limited to the torso (14%). The morphologic spectrum of lesions is broad and includes erythematous papules and plaques with follicular prominence with or without alopecia; comedonal, acneiform, and cystic lesions; alopecic patches with or without scarring; and nodular and prurigolike lesions. Sixty-five percent of patients had alopecia, which in 71% of cases involved the face. Severe pruritus was seen in 68% of patients. In general, patients responded poorly to skin-directed therapy and in almost all cases required systemic agents to induce even a partial remission, including patients with early-stage disease. Overall survival was poor. Patients with early-stage disease (< or =IIA) had a 10-year survival of 82%, which took a steep drop off to 41% by 15 years. Patients with late-stage disease (> or =IIB) had an outcome similar to those patients in the control group with conventional epidermotropic MF of a similar stage. CONCLUSIONS: The morphologic spectrum of clinical presentation for FMF is broad and distinct from those in conventional MF. This is at least partially attributed to the ability of FMF to simulate a variety of inflammatory conditions afflicting the follicular unit. The disease course is aggressive, and many patients, including those with early disease, show a poor outcome particularly between 10 and 15 years after the initial onset of disease. Response to skin-directed therapy is poor even in early-stage disease, and our best results were seen with psoralen plus UV-A (PUVA) therapy with oral bexarotene or PUVA with interferon alfa. These findings corroborate those of the Dutch Cutaneous Lymphoma Group and further validate the classification of FMF as a distinct entity.

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma.

BACKGROUND: Primary cutaneous marginal zone lymphoma is recognized as a unique subset of low-grade cutaneous B-cell lymphoma with indolent course in the current World Health Organization-European Organization on Research and Treatment of Cancer classification system. However, few large series on this entity have been reported, including the new TNM (tumor, (lymph) node, metastasis) classification for non-mycosis fungoides cutaneous lymphomas. OBJECTIVE: We aimed to characterize the clinical features including new TNM classification for non-mycosis fungoides cutaneous lymphomas, as well as outcomes and responses to therapy in 30 patients with primary cutaneous marginal zone lymphoma. RESULTS: Primary cutaneous marginal zone lymphoma typically presents with deep-seated nodular or papular lesions on the upper extremities or trunk (25/30). Disease course is indolent and none of 30 patients died of disease. Sustainable complete remissions were obtained only in patients with T1a (n = 3) and T2a (n = 1) disease. Most patients have persistent stable disease independent of treatment. Two patients developed systemic disease and 5 developed large cell transformation. LIMITATIONS: The average follow-up time was 63 months (range, 3-204 months). Longer follow-up time is needed to determine whether patients with untreated persistent stable disease are at greater risk relative to patients treated aggressively early in the disease course. CONCLUSIONS: Primary cutaneous marginal zone lymphoma is a distinct subtype of marginal zone lymphoma with an indolent disease course. Patients with T1a or T2a disease (ie, single lesions or a localized cluster of lesions) may achieve sustained complete remission, whereas patients with multiple nonlocalized lesions are unlikely to maintain complete remission independent of treatment modality. Systemic involvement is typically preceded by large cell transformation and may be an indication for more systemic therapy. Death from disease is rare.

Long-term remission after allogeneic hematopoietic stem cell transplantation for refractory cutaneous T-cell lymphoma.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation has proved to be an effective therapeutic option in various hematologic neoplastic disorders. Because patients with advanced cutaneous T-cell lymphoma have a poor prognosis, with minimal possibilities of sustained remission, we studied the therapeutic potential of hematopoietic stem cell transplantation. OBSERVATIONS: Three young patients with refractory tumor stage mycosis fungoides underwent allogeneic HLA-matched sibling transplantation with combined marrow and CD34-enriched peripheral blood stem cell transplantation after cytoreductive chemotherapy and total-body irradiation. Complete and sustained clinical and histologic remission was achieved in 2 patients, and both remain disease free 4(1/2) years and 15 months later. One patient was in complete remission for 9 months, followed by limited cutaneous recurrence. Mild graft-vs-host disease and graft-vs-tumor effect have contained the recurring disease as a low-grade process. CONCLUSIONS: Allogeneic hematopoietic stem cell transplantation has the potential for sustained remission and the possibility of cure for young patients with advanced and recalcitrant cutaneous T-cell lymphoma. Even in the absence of complete remission, an allogeneic graft-vs-tumor effect may provide an immune mechanism to control the malignant T-cell process and alter the natural history of disease.