Christian Buske

Molecular characterization of acute lymphoblastic leukemia (ALL) has greatly improved the ability to categorize and prognostify patients with this disease. In this study, we show that the proto-oncogene CDX2 is aberrantly expressed in the majority of cases with B-lineage ALL and T-ALL. High expression of CDX2 correlated significantly with the ALL subtype pro-B ALL, cALL, Ph⁺ ALL and early T-ALL. Furthermore, high expression of CDX2 was associated with inferior overall survival and showed up as a novel and strong risk factor for ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in adult patients with ALL.

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene-expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes), which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P = .002), event-free survival (HR = 1.73; P = .001), and relapse-free survival (HR = 1.76; P = .025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD, and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR = 4.11; P < .001), event-free survival (HR = 2.90; P < .001), and relapse-free survival (HR = 3.14, P < .001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene-expression signature that offers additional prognostic information for patients with CN-AML.

Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.

Many effective treatments are currently available for patients with follicular lymphoma (FL). However, given the heterogeneity of this disease, identifying the most beneficial treatment for an individual patient remains a challenge, although clinical, genetic and biological features can all potentially be used to refine therapies in individual cases. The Follicular Lymphoma international prognostic index (FLIPI) algorithm is a valuable prognostic tool for risk categorisation. Despite its current limitations, further investigation will help to develop the role of FLIPI in treatment decision-making, and will increase its value in identifying the optimal therapy for individuals. Biological factors such as bulky disease, over-expression of Bcl-2, or histological grade can help to identify patients at high risk of relapse, and distinguish between the benefits of early intervention vs. a watch-and-wait policy in early-stage FL. The tumor microenvironment plays an important role in the development of FL, and identification of biological and genetic markers could help clinicians determine the prognosis of individual patients. Although much work remains to be done, a greater understanding of the biology of FL will lead to the development of novel therapeutic targets and therapies, bringing individualised treatment a step closer.

Die Behandlungsmöglichkeiten von Patienten mit follikulären Lymphomen haben sich in den letzten Jahren durch die Etablierung neuer, insbesondere antikörpergestützter Therapieansätze deutlich verbessert. So ist heute der Anti-CD20-Antikörper Rituximab fester Bestandteil der Therapie des fortgeschrittenen follikulären Lymphoms und wird in Kombination mit Chemotherapie oder auch als Einzeltherapie zur Remissionsinduktion und als Erhaltungstherapie nach erfolgreicher Induktionstherapie eingesetzt. Ermutigende Ergebnisse liegen ebenfalls für monoklonale Anti-CD20-Antikörper vor, die an Radionuklide gekoppelt sind und die hohe Strahlensensibilität der Lymphome ausnutzen: Beispiel hierfür ist der an ⁹⁰Yttrium gekoppelte Anti-CD20-Antikörper Ibritumomab Tiuxetan, der eine vergleichbare Aktivität wie Rituximab beim fortgeschrittenen Lymphom aufweist. Aktuelle klinische Studien überprüfen, ob z. B. der sequenzielle Einsatz von unterschiedlichen Therapiebausteinen wie einer Rituximabchemotherapieinduktion und einer konsolidierenden myeloablativen Therapie gefolgt von autologer Stammzelltransplantation und abschließender Rituximaberhaltung die Therapieergebnisse weiter verbessert und bei einem Teil der Patienten sogar kuratives Potential besitzt. The treatment options for patients with follicular lymphoma have substantially improved in the last years, in particular with the development of innovative, antibody-based therapeutic strategies. Thus, the anti-CD20 antibody rituximab is one of the cornerstones in the therapy of follicular lymphoma today. It is used in combination with chemotherapy or as a single agent therapy for remission induction and as maintenance therapy. Encouraging results were also reported from monoclonal anti-CD20 antibodies, which are conjugated to radionuclides and exploit the high radiosensitivity of lymphomas. An example for this is the anti-CD20 antibody ibritumomab tiuxetan, which is coupled to ⁹⁰Yttrium and shows comparable activity to rituximab. Current trials are underway testing whether, for example, the sequential application of a rituximab/chemotherapy induction, myeloablative consolidation therapy followed by autologous stem cell transplantation and rituximab maintenance further improves the therapeutic outcome in follicular lymphoma, or even has curative potential in a subgroup of patients with this disease.

Recent retrospective analyses indicate prolonged survival for patients with follicular lymphoma over the past 25 years, attributed most likely to improved supportive care and sequential application of effective therapies. Encouraging results were obtained from several randomized trials evaluating myeloablative therapy followed by autologous stem cell transplantation (ASCT) as consolidation therapy applied to patients with advanced-stage follicular lymphoma either in first remission or as salvage therapy. However, because of the successful introduction of rituximab to the standard therapeutic repertoire, with its long-term beneficial clinical impact, ASCT must be reevaluated in prospective clinical trials, especially taking into account the potential short- and long-term toxicity associated with high-dose therapy. The concept of in vivo purging before or after ASCT and the introduction of radioimmunotherapy as part of the myeloablative regimen may further improve treatment results, reduce toxicity, and increase applicability. Combination of these novel strategies into a multimodal approach justifies hope that the treatment outcome of patients suffering from follicular lymphoma will be further improved.

The Follicular Lymphoma International Prognostic Index (FLIPI) was developed to predict prognosis of patients with follicular lymphoma (FL). However, it was based on different protocols, none of which included rituximab. The current analysis aimed at evaluating the predictive value of the FLIPI for treatment outcome in 362 patients with advanced-stage FL treated front-line with rituximab/CHOP in a prospective trial of the German Low Grade Lymphoma Study Group. According to the FLIPI, 14% of the patients were classified as low-risk, 41% as intermediate-risk, and 45% as high-risk patients. With a 2-year time to treatment failure (TTF) of 67%, high-risk patients had a significantly shorter TTF as compared with low- or intermediate-risk patients (2-year TTF of 92% and 90%, respectively; P < .001). Our data demonstrate that the FLIPI is able to identify high-risk patients with advanced-stage FL after first-line treatment with rituximab/chemotherapy.