Person:

Castillo, Jorge

HIV-associated PBL is an AIDS-defining cancer, classified by WHO as a distinct entity of aggressive DLBCL. To date less than 250 cases have been published, of them 17 are pediatric. The pathogenesis of this rare disease is related to immunodeficiency, chronic immune stimulation and EBV. Clinically is a rapid growing destructive disease mainly involving the oral cavity even if extraoral and extranodal sites are not infrequent. The diagnosis requires tissue mass or lymph node biopsy and core needle or fine needle biopsy is acceptable only for difficult access sites. Classically immunophenotype is CD45, CD20, CD79a negative and CD38, CD138, MUM1 positive, EBER and KI67 is >80%. Regarding the therapy, standard treatment is, usually, CHOP or CHOP-like regimens while more intensive regimens as CODOX-M/IVAC or DA-EPOCH are possible options. Use of cART is recommended during chemotherapy, keeping in mind the possible overlapping toxicities. Rituximab is not useful for this CD20 negative disease and CNS prophylaxis is mandatory. Intensification with ABMT in CR1 may be considered for fit patients. For refractory/relapsed patients, therapy is, usually, considered palliative, however, in chemo-sensitive disease, intensification + ABMT or new drugs as Bortezomib may be considered. Factors affecting outcome are achieving complete remission, PS, clinical stage, MYC, IPI score. Reported median PFS ranges between 6–7 months and median OS ranges between 11–13 months. Long term survivors are reported but mostly in pediatric patients. Finally, due to the scarcity of data on this subtype of NHL we suggest that the diagnosis and the management of HIV-positive PBL patients should be performed in specialized centers.

The diagnosis of Waldenström macroglobulinemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations taken place to address these issues. We provide recommendations for history taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations such as anemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.

CXCR4WHIM somatic mutations are distinctive to Waldenstrom Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4WHIM mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction(AS-PCR) assays for detecting the most common CXCR4WHIM mutations (CXCR4S338X C>A and C>G) in WM. The AS-PCR assays detected CXCR4S338X mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%)untreated WM, previously treated WM, IgM MGUS and marginal zonelymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cellfraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution(median 35·1%, range 1·2–97·5%). Combined AS-PCR and Sangersequencing revealed multiple CXCR4WHIM mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show thatCXCR4WHIM mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88L265P in WM oncogenesis. The presence of multiple CXCR4WHIM mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma (LPL) cells colonize the central nervous system (CNS). In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 x 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.

Follicular lymphoma (FL) is a prevalent type of non-Hodgkin lymphoma in the United States and Europe. Although, FL typically presents with nodal involvement, extranodal sites are less common, and leukemic phase at diagnosis is rare. There is mounting evidence that leukemic presentation portends a worse prognosis in patients with FL. We describe 7 patients with a pathological diagnosis of FL who presented with a leukemic phase. We compared our cases with 24 additional cases reported in the literature. Based on our results, patients who present with leukemic FL tend to have higher risk disease. Leukemic FL also seems to be associated with a worse prognosis; however, larger studies are needed to confirm our findings. A discrepancy with previously reported cases of FL in leukemic phase raises the possibility of differences attributable to geographic regions.

Introduction Previous studies have suggested a relationship between smoking and Hodgkin's lymphoma (HL). The main objective of this study was to evaluate this potential association with a meta-analysis of observational studies.

Patients and Methods A literature search was undertaken through December 2010 looking for observational studies evaluating the association between smoking and HL. From 714 articles, 17 were included in this study. Outcome was calculated and reported as odds ratio (OR). Heterogeneity was assessed by using the I2 index. Publication bias was evaluated by trim-and-fill analysis. Quality assessment was performed with the Newcastle-Ottawa scale.

Results Our analysis showed an OR of developing HL of 1.35 (95% CI, 1.17 to 1.56; P < .001) in current smokers. Former smokers did not have an increased risk of HL. In subset analyses of current smokers, men and older individuals had ORs of HL of 1.78 (95% CI, 1.46 to 2.17; P < .001) and 1.77 (95% CI, 1.23 to 2.54; P = .002), respectively. In addition, the OR of HL was increased in individuals who smoke more than 20 cigarettes per day, have smoked more than 20 years, or have smoked more than 15 pack-years at 1.51 (95% CI, 1.16 to 1.98; P = .002), 1.84 (95% CI, 1.47 to 2.32; P < .001), and 1.97 (1.53 to 2.54; P < .001), respectively. Meta-regression analyses showed a relative OR of HL of 1.007 (95% CI, 1.001 to 1.013; P = .025) per cigarette per day and of 1.013 (95% CI, 1.006 to 1.019; P < .001) per year of smoking.

Conclusion Smoking seems to increase the odds of developing HL in current smokers. The risk of HL is higher in men and older individuals and increases with higher intensity and longer duration of smoking.

Chronic lymphocytic leukemia (CLL) is an indolent but incurable disease. Despite the improvement of the available therapies, the management of heavily-treated CLL patients represents a challenge for modern practitioners. Ofatumumab is a second-generation, fully human anti-CD20 monoclonal antibody that has shown activity in CLL patients who have failed very effective therapies such as fludarabine, alemtuzumab and rituximab. Potential benefits of ofatumumab include powerful complement-dependent cytotoxicity, less immunogenicity, faster infusions and activity in resistant CLL patients. Recently, the FDA has approved ofatumumab for the treatment of CLL patients who have failed fludarabine and alemtuzumab-based regimens. The aim of this review is to summarize the current knowledge regarding pharmacology, mechanism of action, pre-clinical and clinical development, and the role of ofatumumab for the treatment of CLL patients who have failed previous therapies. Further research is necessary to further define the role of ofatumumab in the treatment of CLL.

Plasmablastic lymphoma (PBL) is a very aggressive variant of diffuse large B-cell lymphoma initially described in the oral cavity of HIV-infected individuals. PBL represents a diagnostic challenge given its characteristic morphology and lack of CD20 expression, and also a therapeutic challenge, with early responses to therapy, but with high relapse rates and poor prognosis. In recent years, our understanding and clinical experience with PBL has increased in both HIV-positive and -negative settings. However, given its rarity, most of the data available rely on case reports and case series. The main goal of this article is to systematically review the most recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and prognosis in patients with PBL. Specific covered topics include new pathological markers for diagnosis, its association with Epstein-Barr virus, and the need of more intensive therapies.

Acute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance.

Background: MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.

Methods: We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects.

Results: After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).

Conclusions: Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug.