Saar Gill

Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma

Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.

Natural Killer Cells in Allogeneic Transplantation: Effect on Engraftment, Graft- versus-Tumor, and Graft-versus-Host Responses

Natural killer (NK) cells are effectors of the innate immune system and recognize cells transformed by viruses or neoplasia. Their response to missing self signals was described 3 decades ago, but the recent discovery of a panoply of activating receptors has made it clear that NK cell reactivity arises from a combination of inhibitory and activating signals. Successful clinical exploitation of NK cell reactivity was demonstrated in allogeneic transplantation for acute myelogenous leukemia from HLA-haploidentical donors when matched donors were not available. Multiple clinical studies have since attempted to use NK reactivity in the setting of both HLA-matched and -mismatched transplantation, with varying results. This review summarizes the heterogeneous clinical results and explains them based on a succinct description of NK cell biology.

[18F]Fluorodeoxyglucose Positron Emission Tomography Scanning for Staging, Response Assessment, and Disease Surveillance in Patients with Mantle Cell Lymphoma

BACKGROUNDnPositron emission tomography (PET) is an important imaging modality in the staging and response assessment of patients with lymphoma, but data on its specific use in mantle cell lymphoma (MCL) are lacking.nnnPATIENTS AND METHODSnThe records of 28 patients with MCL who had a total of 123 [18F]fluorodeoxyglucose (FDG) PET scans between March 1999 and November 2005 were reviewed. Nine patients had staging scans. The other scans were performed for response assessment or relapse surveillance.nnnRESULTSnFDG-PET sensitivity was 100% for nodal disease in the 9 patients studied at baseline. Positron emission tomography scans performed for response assessment were concordant with conventional imaging in 47% and discordant in 53% of cases. Positron emission tomography scanning led to earlier diagnosis of relapse in 1 of 17 patients but produced a high rate of false-negative findings in the evaluation of gastrointestinal involvement.nnnCONCLUSIONnFDG-PET appears to be a sensitive modality for staging and for response assessment in MCL but was not found to be useful in relapse surveillance or in the evaluation of gastrointestinal disease.

Mantle cell lymphoma with central nervous system involvement: frequency and clinical features

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4–26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12u2003months (range 1–58) from diagnosis, with a crude incidence of 6·5% and 5‐year actuarial incidence of 5u2003±u20033%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2–9u2003months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (Pu2003=u20030·0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno‐chemotherapy regimens containing CNS‐penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first‐line treatment.

Therapeutic options in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive lymphoma requiring intensive chemotherapy ± autologous stem cell transplantation (SCT) to achieve optimal rates of progression-free survival. Here we review the treatment options for patients with newly-diagnosed or relapsed MCL and discuss recent advances in management, including the role of autologous and allogeneic SCT.

The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy

BACKGROUNDnFludarabine-based chemoimmunotherapy has well-recognised efficacy and short-term toxicity in the treatment of lymphoid malignancies. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly quantified.nnnMETHODSnSixty-one patients receiving initial therapy with fludarabine-based regimens were categorised according to the presence of post-treatment cytopenias (haemoglobin <110-130 g/l depending on sex and age, neutrophils <2.0 x 10(9)/l, or platelets <140 x 10(9)/l) lasting >3 months.nnnRESULTSnPersistent cytopenias unrelated to persistent disease were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (P = 0.03) and predicted for worse overall survival (61% versus 96% at 60 months, P = 0.05). Increasing age predicted for persistent cytopenias (P = 0.02), but the presence of pretreatment cytopenias and delivered dose intensity were not predictive. The median times to resolution of anaemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively.nnnCONCLUSIONSnCytopenias often persist >3 months after first-line fludarabine combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting treatment response status in chronic lymphocytic leukaemia.

Prolonged haematological toxicity from the hyper-CVAD regimen: manifestations, frequency, and natural history in a cohort of 125 consecutive patients

The hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) regimen has impressive efficacy in several haematological malignancies but is associated with considerable short-term haematological toxicity. Secondary myelodysplasia (MDS) or acute myeloid leukaemia (AML) also occurs. In this retrospective study, we also describe other prolonged haematological sequelae of this regimen. One hundred and twenty-five patients were treated with a median of six hyper-CVAD cycles and followed for a median of 28xa0months. Follow-up for cytopenias was censored at the next cytotoxic therapy. At 3xa0months post-therapy, 77 patients were evaluable. Cytopenias persisted in 59% of patients. Requirement for dose attenuation was the only factor significantly associated with persisting cytopenias (pu2009<u20090.05). The median time to normalisation of counts for those with post-treatment cytopenias in the respective lineages was 9xa0months (range, 6–12) for anaemia, 6xa0months (range, 6–30) for neutropenia and 9xa0months (range, 6–30) for thrombocytopenia. MDS/AML was diagnosed in four patients at 4, 21, 24 and 37xa0months after therapy with a cumulative incidence rate of 4.43% at 4xa0years. These results indicate a considerable rate of prolonged haematological toxicity after hyper-CVAD and a modest rate of MDS at this limited follow-up. These findings likely reflect cumulative damage to haematopoietic stem cells.

What is the real risk of central nervous system involvement in mantle cell lymphoma

It is well recognised that histologically highlyaggressive forms of non-Hodgkin lymphoma (NHL) such as lymphoblastic and Burkitt lymphoma have a very high risk of central nervous system (CNS) dissemination and CNS-directed prophylaxis is essential and highly beneficial [1]. Conversely, clinically indolent lymphomas, such as follicular or marginal zone, have a vanishingly low rate of CNS dissemination (as distinct from the rare cases of primary CNS marginal zone NHL) [2], and CNSdirected prophylaxis is not required. Between these extremes, in large series of unselected HIV-negative patients with systemic diffuse large B-cell lymphoma, the risk of CNS-dissemination is reported to be *5% [3], too low to justify universal routine CNS-directed prophylaxis. However, clinical, histologic and anatomic features have been established as identifying specific patient sub-groups with a 10–30% risk of CNS dissemination, justifying selective ‘‘riskadapted’’ CNS-directed prophylaxis in these specific sub-groups [3–5]. So where does mantle-cell lymphoma (MCL) fit within this spectrum of CNS risk, is cerebro-spinal fluid (CSF) cytology required at initial staging in all patients, and which (if any) patients with MCL warrant CNS-directed prophylactic therapy? MCL comprises approximately 6% of NHL [6] and patients typically present with advanced stage disease and a propensity for leukemic and gastrointestinal involvement. The subtype of blastoid MCL is thought to carry a poorer prognosis [7]. Involvement of the CNS in MCL has previously been reported to range from 4 to 26% [8–11] in series of 64–108 patients (Table I). Between 20% and 50% of cases had blastoid histology at diagnosis or blastoid transformation at relapse, and the majority of cases occur in the context of systemic relapse. The risk in the context of blastoid histology is difficult to accurately quantify, but our interpretation of the available data is that approximately 20– 25% of patients with blastoid histology will have CNS involvement [10,11]. The patients are almost uniformly symptomatic at the time of diagnosis of CNS disease (that is, few are diagnosed incidentally on routine CSF sampling, which may reflect the infrequent use of this modality in staging of MCL patients). This also reinforces the appropriateness of the current policy of not routinely performing CSF sampling as a part of initial staging, unless patients have specific CNS signs or symptoms which warrant investigation. The variable incidence of CNS involvement, as reported by the above quoted studies, may be explained by several factors. In the absence of uniform guidelines on CNS prophylaxis, incidental CNS disease at presentation would only be diagnosed by lumbar puncture for staging, a diagnostic modality not currently routinely performed by most units. The use of high-doses of systemic CNSpenetrating agents such as cytarabine or methotrexate, or specific CNS prophylaxis, which among the popular first-line regimens for MCL is utilised only in the hyper-CVAD program, may influence the incidence of clinically manifest CNS dissemination. However, the fact that in most reports, CNS involvement occurs late and in the setting of systemic

What is the role of 18F-fluorodeoxyglucose positron emission tomography in mantle cell lymphoma?

Recent trends in the management of patients with mantle cell lymphoma (MCL), including the use of intensive chemo-immunotherapy regimens, have led to high overall and complete response rates [1], and prolongation of progression-free survival (PFS) when first response is consolidated with high-dose therapy and autologous stem cell transplantation [2,3]. Although these strategies have led to event-free survival rates as high as 80–90% at 3 years [3,4], most reported overall survival curves still generally show a pattern of ongoing continuous relapse [5]. In the context of these currently attainable results, it is clear that further research into new therapeutic approaches and more sophisticated prognostic stratification are required to identify subgroups who might benefit from more aggressive treatment strategies, or in whom the prognosis is already sufficiently good to obviate morbid treatment approaches. In diffuse large B-cell lymphoma and Hodgkin lymphoma, accurate initial staging is of clear prognostic utility and response assessment with Ffluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to predict therapeutic outcome with greater accuracy than conventional staging techniques alone [6–8]. Hence in these lymphomas, FDG-PET scanning is recommended in pre-treatment evaluation and required for response assessment as part of routine practice [9,10]. Current data on the use of FDG-PET in MCL are scant and, with few exceptions [11,12], patients with MCL constitute a small subgroup of those described in series with heterogeneous histologies [13]. The study by Brepoels and colleagues in this edition of the journal provides a useful addition to the published literature, although some of their conclusions warrant careful consideration [14].