Caroline L. Alvares

The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide-vincristine-doxorubicin-methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis

A retrospective case-matched study was conducted to compare the oral regimen CTD (cyclophosphamide – thalidomide – dexamethasone) and infusional CVAMP (cyclophosphamide – vincristine – doxorubicin – methylprednisolone) as induction therapy followed by autologous peripheral blood stem-cell transplantation (PBSCT) for newly diagnosed multiple myeloma patients. The response rate after three cycles of treatment was statistically higher with CTD (n = 27) compared to CVAMP (n = 27) (89% vs. 56%, P = 0.016). Toxicity studies showed more neutropenia (grade 3/4) (4% vs. 60%, P = 0.0002) with CVAMP and more thrombotic episodes with CTD (11% vs. 4%). CTD may emerge as the superior induction regimen prior to PBSCT, in terms of high efficacy and better tolerability.

Long-term outcomes of previously untreated myeloma patients: responses to induction chemotherapy and high-dose melphalan incorporated within a risk stratification model can help to direct the use of novel treatments

Induction chemotherapy followed by high‐dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention‐to‐treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long‐term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7·47 years for responders (CR and PR) versus 4·89 years for non‐responders; P = 0·035]. The attainment of CR at 3 months post‐HDM correlated with a prolonged progression‐free survival (PFS) (median PFS, 7·4 years in CR group versus 5·3 years in non‐CR group; P = 0·023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk‐adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

Isolated Bone Marrow Involvement in Diffuse Large B Cell Lymphoma: A Report of Three Cases with Review of Morphological, Immunophenotypic and Cytogenetic Findings

Diffuse large B cell lymphoma (DLBL) comprises a heterogenous entity characterized by the presence of large cells, exhibiting a mature B cell phenotype. The high proliferation rate and aggressive disease remain a therapeutic challenge, but the apparent biological diversity permits a risk-stratification model for prognostic grouping through the International Prognostic Index (IPI). Empirical to this approach is the consideration of cytogenetic data, offering an insight into the pathogenetic events which may underlie neoplastic clonal evolution and disease progression. We describe three cases of DLBL presenting with isolated marrow disease, a rare primary finding in this lymphoma. All three cases showed involvement of blood and bone marrow without evidence of splenic or lymph node involvement on imaging studies. Histological and immunophenotypic findings were similar in all three cases, outlining the phenotypic maturity of this disease. Cytogenetic analysis revealed complex karyotypes in the two cases examined. M-FISH (multicolour fluorescent in situ hybridization) performed on bone marrow from case 1 showed several cryptic translocations not evident on G-banding, including a novel translocation between 2p and 9p, and an unbalanced translocation between 14q and 11q. Cytogenetic analysis in case 2 showed abnormalities involving 7q, 9p at the site of the INK4a gene, and the bcl-2 locus, findings confirmed by M-FISH. These cases serve to highlight the biological and cytogenetic heterogenity of DLBL and emphasize the need for complementary investigations in the characterization of this entity.

Tyrosine kinase inhibitor insensitivity of non‐cycling CD34+ human acute myeloid leukaemia cells with FMS‐like tyrosine kinase 3 mutations

The efficacy of tyrosine kinase (TK) inhibitors on non‐cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non‐cycling cells from a small series of human FMS‐like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non‐cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non‐cycling cells, indicating their leukaemic origin. Significantly, the FLT3‐internal tandem duplication (ITD) mutation was found in the non‐cycling fraction of four out of five cases. Exposure to the FLT3‐directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short‐term cultures and colony‐forming unit assays. Crucially, non‐cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer‐term cultures, TKI258‐treated non‐cycling cells showed no growth impairment compared to treatment‐naive non‐cycling cells. These findings suggest that non‐cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted.