Fernández-Rañada Jm

Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination

B cell neoplasms present heterogeneous patterns of lymphoid organ involvement, which may be a result of the differential expression of chemokine receptors. We found that chemokine receptor (CCR)7, CXC chemokine receptor (CXCR)4, or CXCR5, the main chemokine receptors that mediate B cell entry into secondary lymphoid tissues and their homing to T cell and B cell zones therein, were highly expressed in B malignancies with widespread involvement of lymph nodes. Conversely, those pathologies with little or no nodular dissemination showed no expression to very low levels of CCR7 and CXCR5 and low to moderate levels of CXCR4. These findings provide evidence for the role of CCR7, CXCR4, and CXCR5 in determining the pattern of lymphoid organ involvement of B tumors. Functional studies were performed on B malignancies expressing different levels of CCR7, CXCR5, and CXCR4. Multiple myeloma (MM) cells did not express CCR7 nor CXCR5 and did not migrate in response to their ligands; a moderate expression of CXCR4 on MM cells was accompanied by a migratory response to its ligand, CXCL12. By contrast, cells from B cell chronic lymphocytic leukemia (B‐CLL) expressed the highest levels of these chemokine receptors and efficiently migrated in response to all ligands of CCR7, CXCR4, and CXCR5. In addition, the migration index of B‐CLL cells in response to both of the CCR7 ligands correlated with the presence of clinical lymphadenopathy, thus indicating that the high expression of functional chemokine receptors justifies the widespread character of B‐CLL, representing a clinical target for the control of tumor cell dissemination.

Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma : high-dose cyclophosphamide plus GM-CSF vs G-CSF alone

The best method for peripheral blood progenitor cell (PBPC) mobilization in patients with multiple myeloma (MM) remains controversial. We report the results of two different methods of PBPC collection for autologous transplantation in 40 patients with stage II or III MM. In group I (n = 18), HD-CY, 4 g/m2 i.v., was administered followed by GM-CSF, 8 μ g/kg/day s.c., until the end of collection, starting the leukaphereses after hematological recovery (>1 × 109/l WBC). In group II (n = 22), G-CSF, 10 μ g/kg/day s.c., was used alone until the last day of collection, starting consecutive aphereses on the 5th day. A minimum of two aphereses were performed to collect at least 2 × 106/kg CD34+ cells. Both patient groups were comparable for age, sex and clinical prognostic features as well as previous therapies. In group I, the median yields per pheresis were: MNC 1.47 (1.38–2.32) × 108/kg, CFU-GM 0.82 (0.18–13.2) × 104/kg and CD34+ cells 1.98 (0.96–6.96) × 106/kg. In group II these results were: MNC 2.44 (2.06–3.6 × 108/kg) (P = 0.03), CFU-GM 0.75 (0.16–7.8) × 104/kg and CD34+ 1.05 (0.32–3.4) × 106/kg (P = 0.02). The median number of aphereses performed in each group was 5 (4–12) with a median of 5.24 ± 2.51 in group I and 3 (2–6) with a median of 3.1 (±0.91) in group II (P = NS). Hospitalization for PBPC mobilization was required in all patients in group I and the treatment-related toxicity was greater in this group: 12 patients (66%) developed fever requiring antibiotics during the neutropenic period after HD-CY and six (33%) patients required transfusion support. After receiving busulfan 12 mg/kg p.o. and melphalan 140 mg/m2 i.v., as the conditioning regimen, the median periods to reach granulocytes (>0.5 × 109/l) and platelet (>20 × 109/l) engraftment were 12 and 11 days respectively (ranges 8–20 and 10–16) in group I (HD-CY plus GM-CSF group), and 11 and 13 days respectively (ranges 7–42 and 10–38) in group II (G-CSF group) (P = NS). In conclusion, these data suggest that although HD-CY plus GM-CSF is superior to G-CSF alone based on mean CD34+ cell yield per pheresis, adequate CD34+ cell collections can be achieved with G-CSF alone in most MM patients with less toxicity and with simplification of the procedure.

Busulfan and melphalan as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma.

Summary. Twenty‐four patients with multiple myeloma (MM), three (12‐5%) in complete remission (CR) and 21 (87‐5%) in partial remission (PR) were treated with high‐dose chemotherapy (HDCT) (busulfan 12 mg/kg‐l‐melphalan 140mg/m2) as preparative regimen for autologous peripheral blood stem cell (PBSC) transplantation. These cells were previously collected by leukapheresis after mobilization by high‐dose cyclophosphamide (HD Cy) + rhGM‐CSF (18 patients) or rhG‐CSF alone (six patients). Considering 23 evaluable patients following HDCT, the CR rate was 58% (14 patients) and the PR rate was 38% (nine patients). One transplant‐related death occurred following this regimen (4%). With a median follow‐up of 20 months (range 4‐34) after transplantation, 21 patients are alive (87%). Disease progression after transplantation was observed in four patients. Overall and relapse‐free actuarial survival at 24 months was 91% and 74%, respectively. 12 patients (50%) remain in CR 15 months (4‐34) post transplant. The major toxicity was mucositis. Busulfan + melphalan is a safe and feasible conditioning regimen for APBSCT in MM with acceptable toxicity and a high objective response rate, which may result in prolonged survival.

Progressive multifocal leukoencephalopathy after stem cell transplantation, unsuccessfully treated with cidofovir

We report a patient with progressive multifocal leukoencephalopathy (PML) after autologous stem cell transplantation (SCT) for non-Hodgkins lymphoma (NHL). This is an unusual association, and to date only seven cases have been reported. This is the first case of PML after SCT treated with cidofovir, and the fifth case treated with this drug in a patient without human immunodeficiency virus (HIV) infection. In the previous four patients treated with cidofovir the outcome was discouraging, as was the case in this patient.

Interferon alpha for chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation.

Interferon alpha (IFN alpha) induces cytogenetic responses in patients with chronic myeloid leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT). The purpose of this study was to analyze the therapeutic role of IFN alpha in this setting. The experience of a single institution and the published results on this topic were evaluated. We have included patients who received IFN alpha as a single agent, excluding those patients who received previous or simultaneous donor leukocyte infusions. The outcomes of 11 patients treated in our center and those of 108 previously reported patients have been analyzed. Five out of 11 patients treated in our institution obtained a complete cytogenetic response (CGR). Two patients continue in complete cytogenetic response 3.5 and 8.2 years later, and the qualitative RT-PCR is negative for bcr-abl RNA. The CGR has been transient in one patient, and follow-up is short in the other two. Secondary effects have been acceptable, with myelosuppression as the main toxic effect. Graft-versus-host disease did not occur. The literature review identified 108 patients treated with IFN alpha as sole therapy for relapsed CML. Cytogenetic response and CGR seem to be better in patients with cytogenetic relapse, as compared to patients with hematologic relapse (61% vs 45% and 45% vs 28%, respectively). Several patients remained in CGR for more than 5 years. This overview also suggests that CGR is more frequent when IFN alpha is used in patients relapsing after non T-depleted BMT. IFN alpha induces complete cytogenetic response in nearly half of the patients with CML who relapse after allogeneic BMT, with acceptable toxicity. We believe that these results using IFN alpha as a front-line therapy for CML relapsing after BMT warrant a randomized comparison with donor lymphocyte infusions.

The prevalence of hepatitis C virus infection in patients with non-Hodgkin's lymphoma

Aim Lymphomagenesis is a multifactorial process in which genetic, environmental and infectious factors can be involved. The aim of the present study was to assess the prevalence of hepatitis C virus (HCV) infection among patients with non-Hodgkins lymphoma (NHL), and to compare it with that of a control group of voluntary blood donors. Methods All consecutive patients with a histological diagnosis of NHL from January 1996 to December 2001 were included in this prospective study. As control group for HCV infection, voluntary blood donors recruited over the same time period from the same geographical area were considered. The presence of anti-HCV antibodies was investigated by ELISA-II and RIBA-II, and viraemia (HCV RNA) was tested by using a polymerase chain reaction (PCR). HCV genotyping was also performed. Results Ninety-nine patients (mean age 48 years) with NHL were diagnosed during the study period. Histological classification of NHL was high–intermediate grade (63 patients), and low grade (36 patients). Immunophenotype distribution was type B (86 patients) and type T (13 patients). Seven of the 99 NHL patients (7%) were infected with HCV (both using serology and PCR), five of them with immunophenotype B and two with immunophenotype T. The prevalence of HCV infection according to NHL phenotype was 5.8% in B-cell NHL and 15.4% in T-cell NHL. The HCV genotype was 1b in six cases, and 3a in one. In voluntary blood donors (mean age 45 years), HCV infection was detected in 517/55 587 (0.93%). Therefore, HCV infection was more frequent in NHL patients than in controls (odds ratio = 8.1; 95% CI = 3.7–17.6). The odds ratio for the association of HCV and B-cell NHL was 6.2 (95% CI = 2.5–15.3), and for T-cell NHL 16.4 (95% CI = 3.7–72.8). Conclusion The prevalence of HCV infection in patients with NHL (both B- and T-type) is higher than that observed in controls, suggesting a role of HCV in lymphoma aetiopathogenesis.

Absence of influence of prior treatment with interferon on the outcome of allogeneic bone marrow transplantation for chronic myeloid leukemia.

Timing of transplantation in the chronic phase of chronic myeloid leukemia (CML) and previous treatment with interferon remains controversial. We have tried to discover what influence pretreatment with interferon alpha (IFN-A) has on the results of allogeneic bone marrow transplantation for CML patients treated in a single institution. Fifty-one consecutive patients with chronic phase Ph-positive CML who received an allogeneic bone marrow transplantation from a HLA-identical familial donor were evaluated. Thirty had been treated with IFN-A (IFN+ group) prior to BMT and twenty-one had not (IFN− group). Both groups were homogeneous for clinical characteristics such as age, sex, previous chemotherapy, disease status, and time from diagnosis to transplant. No difference was found in neutrophil and platelet count recovery between the IFN+ and IFN− group. The incidence of acute and chronic GVHD, VOD and severe mucositis was not significantly different. Relapse and both overall survival and DFS were similar for both groups. No adverse effects of prior IFN exposure on the outcome of HLA-identical sibling donor BMT for chronic phase CML patients were found in this study.

Results of a pilot study of 40 patients using high-dose therapy with hematopoietic rescue after standard-dose adjuvant therapy for high-risk breast cancer

The study was designed to determine the toxicity, feasibility, and effectiveness of high-dose cyclophosphamide (6 g/m2), thiotepa (500 mg/m2) and carboplatin (800 mg/m2) (CTCb) with hematopoietic rescue as consolidation after standard-dose adjuvant chemotherapy treatment of primary high-risk breast cancer. From October 1991 to September 1994, 40 patients with stage II or III breast cancer involving 10 or more nodes were treated with CTCb after six cycles of adjuvant therapy with an anthracycline-containing regimen. Bone marrow (BM) was used as the source hematopoietic stem cell in the first 23 patients and G-CSF-mobilized peripheral blood progenitor cells (PBPC) in the other 17. No therapy-related deaths occurred, but three life-threatening complications were recorded which resolved: bilateral pulmonary hemorrhage, veno-occlusive disease of the liver and pulmonary thromboembolism. PBPC result in faster hemopoietic reconstitution with significantly lower transfusion requirements. With a median follow-up of 35 months (23–59) actuarial event-free survival for the study patients at 3 years is 72% (CI 95%: 66–81%). Even in patients over 50–60 years, CTCb is a relatively well tolerated regimen which appears, after a median follow-up of nearly 3 years, to decrease relapse frequency as compared with historical series, although a definite role of HDT in the treatment of high-risk primary breast cancer needs confirmation in prospective randomized trials.

Autologous stem cell transplantation (ASCT) for poor prognostic Hodgkin's disease (HD) : Comparative results with two CBV regimens and importance of disease status at transplant

Clinical outcome of 47 consecutive patients with advanced HD who underwent ASCT in our Department was analyzed retrospectively. Median age was 28 years (28 males and 19 females). At transplant, 15 (32%) patients were in CR (five in first CR after two chemotherapy regimens and 10 in second CR), eight (17%) in PR (seven without a prior CR), 22 (51%) had relapsing disease (19 with sensitive relapse) and two had primary refractory disease. The CVB regimen with two different schedules was used: 22 (47%) patients received standard CBV (CY 6 g/m2, BCNU 300 mg/m2 and etoposide 600 mg/m2) and 25 (53%) received an increased CBV dose (CY 7.2 g/m2, BCNU 440 mg/m2 and etoposide 2 g/m2). Antitumor response for 28 evaluable patients was similar for both CBV regimens: 87 and 75% (P = 0.39). At 7.2 years, actuarial overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) for the whole series were 51.7±8%, 34±9% and 28±8%, with a median follow-up for the surviving patients of 3 years (0.7–7.6). No differences in these survival functions according to the CBV regimen used were observed (P = 0.57). A history of a prior CR (P = 0.003), duration of first CR >1 year (P = 0.04), absence of bulky nodal disease at transplant (P = 0.054), absence of extranodal disease at transplant (P = 0.01), and a CR status at transplant (P = 0.0006) were associated with a better PFS on univariant analysis. On multivariate analysis, only CR status at transplant remained significant (P = 0.05). When patients in second CR at transplant and those in first sensitive relapse were analyzed separately, no differences in clinical characteristics or in treatment received pretransplant were observed; however, PFS was significantly different (P = 0.01). In conclusion, CR status at transplant is useful in identifying ‘good risk’ patients and is necessary to obtain the greatest benefit from ASCT independent of the CBV regimen used.

Dose‐escalated CHOP and tailored intensification with IFE according to early response and followed by BEAM/autologous stem‐cell transplantation in poor‐risk aggressive B‐cell lymphoma: a prospective study from the GEL–TAMO Study Group

Objectives:  The role of high‐dose therapy and autologous stem‐cell transplantation (HDT/ASCT) in the up‐front treatment of poor‐risk aggressive lymphoma is still unknown. We conducted a prospective multi‐centre trial with dose‐escalated CHOP (MegaCHOP) and tailored intensification prior to HDT/ASCT according to early response assessed by CT and gallium scan (Ga67S).