Daniele Laszlo

Clinical Activity of Rituximab in Gastric Marginal Zone Non-Hodgkin's Lymphoma Resistant to or Not Eligible for Anti–Helicobacter Pylori Therapy

PURPOSE Preliminary results using rituximab in extranodal marginal zone (MALT) non-Hodgkins lymphoma (NHL) patients seem to indicate a relevant clinical activity. Aim of the present study is to investigate the efficacy of conventional weekly treatment using rituximab in gastric MALT NHL patients resistant/refractory or not suitable for eradication treatment, and to evaluate the relevance of the t(11; 18)(q21; q21) translocation and its possible role as a predictive criteria of response. PATIENTS AND METHODS Twenty-seven patients presenting with gastric MALT NHL at any stage, relapsed/refractory to initial treatment or not suitable for eradication were treated with rituximab in a weekly conventional schedule and evaluated for response and relapse. Flourescence in situ hybridization (FISH) analysis for the presence of 18q21 translocation was performed in 21 patients and was evaluated with clinical outcome. RESULTS Among the 26 evaluated patients, 20 (77%) achieved an objective response. Twelve patients (46%) had a pathological and clinical complete remission, and eight (31%) had a partial response. With a median follow-up of 33 months, only two patients relapsed at 26 and 14 months, respectively. No correlation was founded between FISH analysis and response or relapse. CONCLUSION Our experience seems to confirm the clinical activity of rituximab in gastric MALT NHL patients resistant/refractory to antibiotics treatment or not presenting with clinical evidence of Helicobacter pylori infection. The t(11; 18)(q21; q21) translocation seems not to be a predictive marker to response or to subsequent relapse.

Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study

PURPOSE Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy. PATIENTS AND METHODS Patients not responding to or not suitable for local therapy were eligible. In arm A, chlorambucil was given daily 6 mg/m(2) orally (PO) for 6 weeks. Responding patients and those with stable disease continued to be given daily chlorambucil 6 mg/m(2) PO for 14 consecutive days every 28 days for four cycles. In arm B, intravenous rituximab 375 mg/m(2) per day was added on days 1, 8, 15, 22, 56, 84, 112, and 140. After completion of the planned accrual, the protocol was amended to introduce a third arm with rituximab alone. We report the planned final analysis of the first two arms (113 patients in arm A and 114 in arm B). RESULTS At a median follow-up of 62 months, the 5-year event-free survival (EFS) was significantly better for the patients treated in arm B (68% v 50%; P = .002) who, despite similar overall response rates (90% v 87%), achieved a higher complete remission rate (78% v 65%; P = .025). Progression-free survival was also improved but it did not reach statistical significance (P = .057). Five-year overall survival (OS) was 89% in both arms. Both treatments were well tolerated without unexpected toxicities. CONCLUSION Both treatments were active; the better response rate and EFS obtained with the addition of rituximab did not translate into improved OS.

Second Allogeneic Bone Marrow Transplantation in Acute Leukemia: Results of a Survey by the European Cooperative Group for Blood and Marrow Transplantation

PURPOSE Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. PATIENTS AND METHODS One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. RESULTS Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade > or = 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. CONCLUSION Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.

The transactivating isoforms of p63 are overexpressed in high-grade follicular lymphomas independent of the occurrence of p63 gene amplification

p63 is a p53‐related gene mapping to 3q28 that codes for multiple mRNA transcripts with (TA‐p63) or without (ΔN‐p63) transactivating effects on genes that promote cell differentiation and apoptosis. We analysed p63 alterations by immunohistochemistry, quantitative real‐time RT‐PCR and FISH in a series of 45 follicular lymphomas (FL). None of the tumours showed immunoreactivity for the p40 antibody, which recognizes only the truncated isoforms of p63, or ΔN‐p63 mRNA expression. Immunoreactivity for the 4A4 antibody, which recognizes both the transactivating and the truncated p63 isoforms, was found in 5 ± 5.5%, 6.85 ± 4.88% and 33.2 ± 22.31% of grade I, II and III FL cells, respectively (p < 0.0001). Quantitative RT‐PCR analysis showed that all cases but one had TA‐p63 mRNA levels higher than non‐neoplastic lymphocytes, and that TA‐p63 mRNA expression correlated significantly (r = 0.9194, p < 0.0001) with the prevalence of p63 immunoreactivity. FISH extra signals for the p63 gene were found in seven (23.3%) of the 30 cases analysed (0/6 grade I, 2/15 grade II and 5/9 grade III; p = 0.01937). Further hybridizations showed a pattern highly suggestive of chromosome 3 polysomy in six cases. One of these cases also bore extra copies of the p63 and bcl‐6 genes. Co‐localization of p63 and IgH signals was found in one case. No association between the prevalence of p63 immunoreactivity and extra p63 gene signals was detectable when the cases were dichotomized according to a p63 immunoreactivity threshold of 10%. Our data suggest that TA‐p63 is overexpressed in high‐grade FL, possibly independent of the occurrence of gene abnormalities, and that it may be involved in the highly complex mechanism of regulation of apoptosis of FL cells. Copyright

Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma

Although the efficacy of plerixafor in peripheral blood stem cell (PBSC) mobilization has been explored in several studies, factors associated with successful plerixafor mobilization after administration of granulocyte–colony‐stimulating factor (G‐CSF), with or without chemotherapy, have not been investigated. We analyzed data on PBSC mobilization from a large Italian database of lymphoma and myeloma plerixafor‐treated patients.

Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non‐Hodgkin's lymphoma

Summary. We investigated the toxicity and efficacy of the chimaeric anti‐CD20 antibody rituximab in combination with standard‐dose chlorambucil in newly diagnosed and relapsed/refractory indolent B‐cell lymphoma patients. A total of 29 patients (15 newly diagnosed and 14 relapsed/refractory) with low‐grade or follicular B‐cell non‐Hodgkins lymphoma (NHL) were included in this phase II study. Therapy consisted of chlorambucil 6 mg/m2/d for 6 consecutive weeks in combination with a standard 4‐weekly rituximab administration schedule in the induction phase. Patients responding to the induction therapy received four additional cycles with chlorambucil (6 mg/m2/d for 2 weeks/month) plus rituximab (once a month). Twenty‐six patients (89%) completed the treatment; only one patient discontinued treatment because of haematological toxicity. At the end of the study, the dose of chlorambucil had to be reduced in seven patients (27%) and six patients (23%) required a delay in further treatment, as a result of toxicity during consolidation therapy. Only one patient was withdrawn from the study because of progressive disease; the 27 patients evaluable for response at the end of consolidation achieved a clinical response (63% complete response and 26% partial response). A significant CD4+ and CD56+ depletion was observed after induction and during consolidation therapy; two herpes zoster virus infections and one perianal abscess represented major infectious morbidities registered during the study. Based on our preliminary data, the combination of chlorambucil with rituximab seemed to be well tolerated and active. Its definitive role in the treatment of low‐grade NHL should be further evaluated in randomized trials.

Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03

PURPOSE Rituximab maintenance therapy has been shown to improve progression-free survival in patients with follicular lymphoma; however, the optimal duration of maintenance treatment remains unknown. PATIENTS AND METHODS Two hundred seventy patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma were treated with four doses of rituximab monotherapy in weekly intervals (375 mg/m(2)). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of 5 years or until disease progression or unacceptable toxicity). The primary end point was event-free survival (EFS). Progression-free survival, overall survival (OS), and toxicity were secondary end points. Comparisons between the two arms were performed using the log-rank test for survival end points. RESULTS One hundred sixty-five patients were randomly assigned to the short-term (n = 82) or long-term (n = 83) maintenance arms. Because of the low event rate, the final analysis was performed after 95 events had occurred, which was before the targeted event number of 99 had been reached. At a median follow-up period of 6.4 years, the median EFS was 3.4 years (95% CI, 2.1 to 5.3) in the short-term arm and 5.3 years (95% CI, 3.5 to not available) in the long-term arm (P = .14). Patients in the long-term arm experienced more adverse effects than did those in the short-term arm, with 76% v 50% of patients with at least one adverse event (P < .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups. CONCLUSION Long-term rituximab maintenance therapy does not improve EFS, which was the primary end point of this trial, or OS, and was associated with increased toxicity.

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

An abnormal expression of cyclin D3, a key regulator of the cell cycle, has been documented in a variety of human malignancies, and the cyclin D3 gene, mapping to 6p21, may be deregulated in plasma cell myeloma and non‐Hodgkins lymphoma as a result of the t(6;14)(p21.1;q32.3) translocation and/or gene amplification. In the current study, we for the first time investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) the prevalence of cyclin D3 abnormalities in follicular lymphomas (FLs), comparing the results with traditional clinicopathologic characteristics, p27 and skp2 immunoreactivity (IR) and Ki‐67 labeling index (LI). Cyclin D3, skp2 and Ki‐67 IR significantly increased from grade I to grade III FL (p = 0.0003, p = 0.0001 and p < 0.0001, respectively), while p27 IR was significantly (p < 0.0001) more prevalent in low‐grade tumors. Cyclin D3 IR was directly correlated with the Ki‐67 LI (p < 0.0001) and inversely correlated with p27 IR (p = 0.050). None of the 13 cases analyzed by FISH showed the t(6;14) translocation, but in 2 (15.3%) grade I FLs 3 cyclin D3 signals were detected. Cohybridization with probes specific for the centromeric region and the long arm of the chromosome 6 indicated trisomy in one case and a pattern highly suggestive for the presence of an isochromosome 6p in the other case. Our data suggest that the t(6;14) translocation may be extremely uncommon in FL and that a deregulated expression of cyclin D3, possibly due to epigenetic mechanisms, may be involved in the pathogenesis of high‐grade tumors.

Plerixafor and Filgrastim XM02 (Tevagastrim®) as a first line peripheral blood stem cell mobilisation strategy in patients with multiple myeloma and lymphoma candidated to autologous bone marrow transplantation

Plerixafor, a CXCR4 antagonist, has shown to be effective in increasing the number of circulating stem cells, even in patients failing a previous mobilisation attempt. Recently a number of non‐glycosylated recombinant human granulocyte‐colony stimulating factor (G‐CSF) has been clinically approved for the same indications as the originator G‐CSF for comparable safety and efficacy and their reduced cost. In an attempt to provide a less toxic strategy, 14 patients affected by haematological malignancies (non‐Hodgkin’s lymphoma = 4, Hodgkin’s disease = 2 and multiple myeloma = 8), received the combination of biosimilar filgrastim and plerixafor as a first line mobilising strategy. The median number of circulating CD34+ cells on day 4 was 16 (3–42); Plerixafor was administered to all, but one patient who had already 42 CD34+ cells per μL on day 4. On day 5, after plerixafor administration, the median number of circulating CD34+ cells had raised to 60 per μL (14–138). All the patients underwent leukapheresis and were able to collect a number of CD34+ cells ≥2.0 × 106/kg in a median number of procedures of one. Although preliminary, these data show the combination of biosimilar filgrastim and plerixafor is effective and provides a non‐toxic approach to mobilise stem cells.

Rituximab and Subcutaneous 2-Chloro-2′-Deoxyadenosine as Therapy in Untreated and Relapsed Waldenström's Macroglobulinemia

With the aim to assess the efficacy of subcutaneous cladribine in combination with rituximab, 29 newly diagnosed/pretreated WM patients were enrolled in a multicenter phase II trial. Intended therapy consisted of rituximab on day 1 followed by s.c. cladribine 0.1 mg/kg for 5 consecutive days, administered monthly for 4 cycles. The expression of genes involved in cladribine metabolism was evaluated. With a median follow-up of 50 months the ORR rate observed was 89.6% without any difference between newly or pretreated patients (P=.522). The therapy was well tolerated; no major infections were observed, no patients developed transformation to high-grade NHL nor myelodysplasia. Low expression levels of hCNT1 correlated with the failure to achieve a CR (P=.024). The combination of rituximab/cladribine is safe and effective in WM patients requiring treatment. The pharmacogenomic analysis suggests that hCNT1 might be beneficial in predicting clinical response to such a combination treatment.