Search

Leukemia and lymphoma cell lines have been pivotal in the cytogenetic and molecular analysis of recurring chromosomal translocations, elucidating the pathogenesis of several hematological malignanc...

ASXL1 mutations are recurrent in acute myeloid leukemia (AML), but it is unclear whether ASXL1 genotype might influence patient management. We analyzed frequency and impact in younger (15-59 years) and older (≥ 60 years) patients with primary or secondary disease. Overall, 9% had truncating mutations. Incidence was significantly lower in younger patients with primary than with secondary disease (4%, 12%; p = 0.03). In older patients it did not differ significantly (11%, 15%; p = 0.5). In univariate analysis, ASXL1-mutated patients had a worse outcome (5-year relapse 83% vs. 56%, p = 0.01; overall survival [OS] 6% vs. 22%, p = 0.02). However in multivariate analysis, ASXL1 mutations had no prognostic significance (for OS, p = 0.3), because age was a major confounding factor. The low incidence of mutations in younger patients with primary disease and the lack of significance in multivariate analysis indicate that there is a limited role for screening at diagnosis for ASXL1 mutations for the purpose of prognostic stratification.

The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.

Lymphoplasmacytic lymphoma (LL) is incurable by standard therapy (median survival: 60 months). UK transplant registry data 1984-2003 identified 18 cases of histologically verified LL (median age: 50 years, range: 38-58 years). Nine patients received high dose chemotherapy [plus total body irradiation (TBI) in 1/9] and autologous peripheral blood stem cells (PBSC). Disease status at transplant was complete remission (2), partial remission (5), primary refractory (1) or relapse (1). Transplant related mortality (TRM) at 12 months was 0%. Median follow-up is 44 months with 4 year disease free survival 43% and overall survival 73%. Karnofsky performance status (KPS) is 80-100%. The nine allografted patients (median age: 49 years, range: 39-56 years) were conditioned with standard TBI (2), BEAM (2) or FLU-MEL (5) and received PBSC from HLA-matched sibling (8) or unrelated (1) donors. Disease status at transplant was partial remission (7) or primary refractory (2). TRM at 12 months was 44%. Complications included graft failure (2), grades I-II acute graft versus host disease (aGVHD) (2), grades III-IV aGVHD (3) and chronic GVHD (4). Median follow-up is 32 months with 4 year disease free survival 44% and overall survival 56%. KPS is 70-100%.

Treatment options for patients who relapse following autologous transplantation for Hodgkin's lymphoma are limited. There are anecdotal reports of lengthy remissions following second autologous procedures, although treatment-related toxicity can be significant. We report a single centre experience of second autologous transplant performed in seven highly selected patients, who relapsed following initial high-dose therapy. They were all young and had slow tempo disease, which was still sensitive to conventional dose chemotherapy. All received BEAM conditioning for the first transplant, and six of the seven received BEAM for the second. All six of these patients regenerated successfully and with no delay, the final patient dying during the procedure following alternative conditioning. Only one case of presumed carmustine-related pneumonitis was seen, which responded rapidly to corticosteroid therapy. Four patients have subsequently relapsed, of whom three have died at 29, 33, and 38 months postprocedure. One is alive with active disease at 68 months, and the final two are alive and in continuing complete remission at 104 and 68 months.

Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Autosomal dominant and sporadic forms of the disease have subsequently been recognized. All forms of the disease are manifest by persistent severe neutropenia and recurrent bacterial infection. Cyclical neutropenia (CyN) is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, heterozygous mutations in the ELA2 gene encoding neutrophil elastase (NE) have been described in the majority of cases of CyN and sporadic and autosomal dominant SCN. A case of paternal mosaicism has provided genetic "proof" of the pathogenicity of such mutations, but the exact pathogenic mechanism remains elusive. This review will focus on the mosaic proof and examine possible pathogenic mechanisms. The lack of obvious associations and indeed overlap between the mutations that cause the two diseases will also be discussed. Clinically to date, the discovery of an elastase mutation has been of limited value to individual patients. However, it is hoped that further genotype/phenotype studies may improve assessment of patient prognosis.

Several studies have shown that mutations in the FLT3 gene are common events in AML, with approximately one third of adult patients harbouring either an internal tandem duplication in the juxtramembrane domain or a D835 mutation in the kinase domain. The majority of studies in pediatric and adult AML have shown that FLT3 mutations are powerful prognostic factors predicting for increased relapse risk and adverse overall survival. Some reports have suggested that loss of the wild type allele might be associated with an even worse prognosis. Changes in the pattern of FLT3 mutations between disease presentation and relapse restrict their value as a marker of minimal residual disease, and have significant implications for therapy. The optimum treatment for patients with FLT3 mutations remains unknown and large prospective studies are warranted to evaluate the efficacy of various treatment modalities such as bone marrow transplantation and targeted therapy with tyrosine kinase inhibitors.

The outcome of conventional therapy in adult acute lymphoblastic leukaemia (ALL) is disappointing. Allogeneic bone-marrow transplantation may give improved results but has only limited applicability because of the lack of a suitable donor in most patients. We have therefore investigated intensive chemotherapy and chemo/radiotherapy protocols with autologous bone-marrow rescue. 31 patients have been treated, 14 beyond first remission and 17 in first remission. The result of this therapy in both groups is poor with only 2 longterm survivors in each group. There is no reason to believe from this study that ablative therapy with autologous bone-marrow rescue will yield superior results to conventional therapy in adult ALL but further experience with TBI containing regimes is required.