Maija Itälä

Allogeneic Hematopoietic Stem-Cell Transplantation for Chronic Lymphocytic Leukemia With 17p Deletion: A Retrospective European Group for Blood and Marrow Transplantation Analysis

PURPOSE Patients with chronic lymphocytic leukemia (CLL) and 17p deletion (17p-) have a poor prognosis. Although allogeneic hematopoietic stem-cell transplantation (HCT) has the potential to cure patients with advanced CLL, it is not known whether this holds true for patients with 17p-CLL. PATIENTS AND METHODS Baseline data from patients, for whom information on the presence of 17p-CLL was available, were downloaded from the European Group for Blood and Marrow Transplantation database. Additional information on the course of CLL and follow-up was collected with a questionnaire. RESULTS A total of 44 patients with 17p-CLL received allogeneic HCT between March 1995 and July 2006 from a matched sibling (n = 24) or an alternative donor (n = 20). 17p-CLL had been diagnosed by fluorescent in situ hybridization in 82% of patients and by conventional banding in 18% of patients. The median age was 54 years. Before HCT, a median of three lines of chemotherapy had been administered. At HCT, 53% of patients were in remission. Reduced-intensity conditioning was applied in 89% of patients. Acute, grade 2 to 4 graft-versus-host disease (GVHD) occurred in 43% of patients, and extensive chronic GVHD occurred in 53% of patients. At last follow-up, 19 patients were alive, with a median observation time of 39 months (range, 18 to 101 months). Three-year overall survival and progression-free survival rates were 44% and 37%, respectively. The cumulative incidence of progressive disease at 4 years was 34%. No late relapse occurred in nine patients with a follow-up longer than 4 years. CONCLUSION Allogeneic HCT has the potential to induce long-term disease-free survival in patients with 17p-CLL.

Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study

Abstract: Objectives: This prospective multicentre study was conducted to assess the efficacy of the monoclonal anti‐CD20 antibody rituximab in patients with chronic lymphocytic leukaemia (CLL). Secondary objectives were defined as the tolerability and feasibility of rituximab in patients with CLL. Methods: Twenty‐four heavily pretreated patients with CLL were treated with a standard dose of 375 mg m−2 of rituximab given once weekly for four doses. Results: The overall response rate was 35% and all the responses were partial as defined by the revised NCI criteria. In 17 (85%) of 20 patients with initially measurable peripheral lymph nodes the size of lymph nodes decreased by at least 50%, while an improvement of the bone marrow infiltration was observed only in two (11%) of 18 evaluable patients. The median duration of the overall response was 12.5 wk. Rituximab was relatively well tolerated. Although side‐effects were common (75%) they were usually mild or moderate. There was only one grade 3 adverse event and no grade 4 events. Conclusions: Standard‐dose rituximab has activity in heavily pretreated patients with CLL, although the response is mainly limited to the lymph nodes and of short duration. Since rituximab has in vitro synergism with chemotherapeutic agents and is well tolerated by CLL patients, it is reasonable to investigate rituximab in combination with other treatments.

Infections and serum IgG levels in patients with chronic lymphocytic leukemia.

Abstract: To review our policy of prophylactic treatment with intravenous immunoglobulin (i.v.IG) in chronic lymphocytic leukemia (CLL), we analyzed the infection history, serum IgG levels (S‐IgG) and disease stage of 146 patients who were treated and followed at our institution in 1980–1989. S‐IgG was available for 98 patients: 55% were hypogammaglobulinemic and 56% had had at least one severe infection. There were significant associations between S‐IgG and the occurrence of infections (p<0.01) and disease stage (p < 0.02). There was also a significant association between disease stage and occurrence of infections (p< 0.001). Severe infections tended to accumulate in patients with subnormal S‐IgG and advanced disease stage. Totally, 292 infections were recorded, and the incidence of moderate to severe infections was 0.47 per patient year. Infection mortality was high: 42 patients died of a severe infection (46% of all causes of death). Patients with a low S‐IgG and advanced disease stage are the most susceptible to death from infection and would be most likely to benefit most from i.v.IG prophylaxis; however, the cost of this therapy is so high that strict individual consideration still remains crucial for treatment decisions.

Invasive fungal infections in autologous stem cell transplant recipients: a nation-wide study of 1188 transplanted patients

Abstract:  Based on small single‐centre series, the risk of invasive fungal infections (IFI) has been considered small in autologous stem cell transplant (ASCT) recipients. Purpose: To analyse epidemiological and clinical features of (IFI) among ASCT recipients in Finland 1990–2001. Patients: During the study period, 1188 adult patients received high‐dose therapy supported by ASCT in six centres. Altogether, 1112 patients (94%) received blood progenitor cells. The graft was CD34+ selected in 261 patients (22%). The major diagnostic groups were non‐Hodgkins lymphoma (n = 417), multiple myeloma (n = 395), breast cancer (n = 132) and Hodgkins lymphoma (n = 53). Results: Eighteen patients (1.5%) with IFI were identified. The incidence of proven or probable invasive aspergillosis was 0.8%, followed by candidaemia with an incidence of 0.3%. The median time to the diagnosis of IFI was 35 d (6–162) from the progenitor cell infusion. In fourteen patients (78%) IFI was diagnosed during lifetime and they were treated with antifungal therapy for a median of 50 d. Nine patients (64%) were cured. Conclusions: IFI appears to be a rare event after ASCT and Aspergillus infections seem to be predominant. These epidemiological features have an impact in planning prophylactic and empirical antifungal strategies in ASCT recipients.

Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients.

Abstract:  Objectives: To evaluate early (<100 d) treatment‐related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. Patients: Altogether 1482 adult patients received ASCT in six Finnish centres 1990–2003. The most common diagnoses were non‐Hodgkins lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkins lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Results: Forty‐two patients (2.8%) died from treatment‐related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0–99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). Conclusions: This nation‐wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.

Late non‐relapse mortality among adult autologous stem cell transplant recipients: a nation‐wide analysis of 1482 patients transplanted in 1990–2003

Introduction:  Data on the incidence and causes of late (>100 d) non‐relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited.

Long-term outcome of intensive chemotherapy for adults with de novo acute myeloid leukaemia (AML): the nationwide AML-92 study by the Finnish Leukaemia Group.

Objective:  To investigate the long‐term outcome of idarubicin‐ and cytarabine‐based intensive chemotherapy in adult acute myeloid leukaemia (AML).

Autologous Stem Cell Transplantation in Patients with Mantle Cell Lymphoma

High-dose therapy followed by autologous stem cell transplantation (ASCT) has been considered a potential treatment approach in order to improve the poor prognosis in mantle cell lymphoma (MCL), but its role has not yet been clearly established. We analyzed retrospectively the outcome and prognostic factors in 48 consecutive patients with MCL scheduled for ASCT in five transplant centers. In 14 patients (29%), a sufficient amount of stem cells could not be collected. Mobilization failure was associated with female sex, blastoid cytology, and low hemoglobin level. Altogether 35 patients underwent ASCT, 24 patients as part of the first-line treatment and 11 patients later. After transplantation 28 patients (80%) remained in or achieved remission. Two patients died of transplant-related complications. During the median follow-up time of 38 months, nine patients have relapsed. The median event-free survival (EFS) was 39 months. Age over 60 years and elevated C-reactive protein level at diagnosis were associated with poorer outcome after transelantation. ASCT is an effective treatment in MCL with a high response rate and a longer survival than seen in conventionally treated patients. However, no plateau was seen in the EFS curve after ASCT. Whether cure Can be achieved in a proportion of patients with ASCT is currently unknown and should be studied in larger patient series with a longer follow-up.

Effect of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) on Chemotherapy-Induced Myelosuppression in Patients with Chronic Lymphocytic Leukemia: A Crossover Study

Patients with advanced, refractory chronic lymphocytic leukemia (CLL) have an high morbidity and mortality from infections following chemotherapy-induced myelosuppression. A crossover study on the prophylactic effect of GM-CSF therapy on neutropenia was carried out in 12 patients with advanced CLL. The patients received GM-CSF in association with every second cycle of COP (cyclophosphamide, vincristine, prednisone) chemotherapy. A total of 40 COP cycles were analyzed. Blood neutrophil levels were significantly higher two to three weeks after the first COP cycle followed by GM-CSF (medians 2.24 and 5.47 x 10(9)/l) when compared to the first cycle without GM-CSF support (0.59 and 0.75 x 10(9)/l; p < 0.0195 and <0.002, respectively). In the next two cycles the same tendency persisted, although the difference was not statistically significant. There were no significant differences in the number of febrile days, days on intravenous antibiotics, hospitalization days, or the number of red blood cell transfusions. Mortality during COP treatment was 8%. In conclusion, GM-CSF efficiently ameliorates chemotherapy-induced neutropenia in CLL patients with a poor bone marrow reserve due to advanced disease.

Stem cell transplantation in poor‐risk chronic lymphocytic leukemia: assessment of post‐transplant minimal residual disease using four‐ and six‐color flow cytometry and allele‐specific RQ‐PCR

A total of 178 bone marrow samples were taken for minimal residual disease (MRD) analysis after 34 stem cell transplantations for poor‐risk chronic lymphocytic leukemia, and 86 of them were analyzed in parallel by flow cytometry and allele‐specific oligonucleotide‐PCR (ASO‐PCR). ASO primer was successfully designed for all patients whose frozen diagnosis samples were available. Flow cytometry and ASO‐PCR were concordant, i.e. both either positive or both negative, in 78% of the analyses. Flow cytometry did not detect MRD in any of the samples that were PCR‐negative cases. In contrast, ASO‐PCR detected MRD in samples that were negative for MRD by flow cytometry in 22% of the analyses. In one patient, the immunophenotype but not the IgVH gene sequence had changed during a course of the disease, and MRD could not be followed by flow cytometry. In the remaining cases, the discrepancy was due to a higher sensitivity of ASO‐PCR. Autologous stem cell transplantation resulted in clinical complete response in 87% (20/23) of the patients. By flow cytometry, 35% (8/23) of autotransplanted patients became MRD‐negative, but only 12.5% (2/16) PCR‐negative (sensitivity of ASO‐PCR <0.001 and <0.01, respectively). All allotransplanted patients achieved or maintained hematological CR, and five out of nine patients (56%) became PCR‐negative (sensitivity of PCR between <0.001 and <0.003), two of them having non‐myeloablative conditioning. None of the patients who became PCR‐negative after allogeneic transplantation have relapsed.