Hilde Demuynck

Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis

In a 10-year consecutive series of 263 allogeneic bone marrow transplant recipients, we identified five cases (1.9%) of invasive mucormycosis. Only one infection occurred within the first 100 days after transplantation, while the remainder complicated the late post-transplant course (median day of diagnosis: 343). Sites of infection were considered ‘non-classical’ and included pulmonary, cutaneous and gastric involvement. No case of fungal dissemination was observed. Mucormycosis was the primary cause of death in three of the five patients. Corticosteroid-treated graft-versus-host disease, either acute or chronic, or severe neutropenia were present in all cases. However, compared with a matched control population, the most striking finding was the demonstration of severe iron overload in each of the mucormycosis patients. The mean level of serum ferritin, transferrin saturation and number of transfused units of red cells (2029u2009μg/l, 92% and 52 units, respectively) in the study group is significantly higher compared with the control group (P < 0.05). the difference with other risk groups for mucormycosis, including deferoxamine-treated dialysis patients and acidotic diabetics, was analyzed in view of the possible pathogenic role of iron. although these infections are often fatal, limited disease may have a better prognosis if diagnosed early and treated aggressively.

Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib

Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40

Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.

Treatment and prognostic factors in myelodysplastic syndromes.

While MDS remains an enigmatic disease, substantial progress has been made in the elucidation of its origin and the better understanding of its natural course. The advent of newer molecular and cytogenetic techniques has tremendously improved the older morphological and histopathological prognostic criteria. More refined scoring systems may ultimately allow for individualized treatment programmes which will better preserve quality of life, while at the same time offer improved chances for survival and cure. Much can be expected from newer cytokines, such as thrombopoietin, stem cell factor, interleukin-11 or of the combination of different cytokines and growth factors, to alleviate MDS-symptoms and to possibly alter the course of the disease. After the initial disappointment with differentiation inducers, the availability of newer agents and/of combinations may offer better perspectives for the future. Much interest will also be generated on the use of mdr-reversal agents in the attempts to improve on chemotherapeutic efficacy. Finally, while allogeneic transplantation still remains the only option for definite cure of the disease, the spectacular advances made in the use and manipulation of autologous peripheral blood haemopoietic stem cells probably constitute the best hope for brightening the grim outlook most MDS patients still have.

Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON

Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON

BMI1, The polycomb‐group gene, is recurrently targeted by genomic rearrangements in progressive B‐cell leukemia/lymphoma

BMI1, a Polycomb‐group gene located at 10p12.2, is implicated in the pathogenesis of a variety of tumors. However, the genetic molecular mechanisms underlying its aberrant expression in cancer cells remain largely unknown. In this study, we show that BMI1 is recurrently targeted by chromosomal aberrations in B‐cell leukemia/lymphoma. We identified a novel t(10;14)(p12;q32)/IGH‐BMI1 rearrangement and its IGL variant in six cases of chronic lymphocytic leukemia (CLL) and found that these aberrations were consistently acquired at time of disease progression and high grade transformation of leukemia (Richter syndrome). The IG‐BMI1 translocations were not associated with any particular molecular subtype of CLL and the leukemias were negative for common mutations of NOTCH1 and TP53, known to increase a risk of progression and transformation in CLL. In addition, using FISH and SNP array analysis, we identified a wide range of BMI1‐involving 10p12 lesions in 17 cases of mantle cell lymphoma (MCL). These aberrations included various balanced and unbalanced structural abnormalities and very frequently but not exclusively, were associated with gain of the BMI1 locus and loss of the 10p terminal sequences. These findings point to genomic instability at the 10p region in MCL which likely promotes rearrangements and deregulation of BMI1. Our findings are in line with previously published observations correlating overexpression of BMI1 with tumor progression and chemoresistance. In summary, our study provides new insights into genetic molecular mechanisms underlying aberrant expression of BMI1 in lymphoma and documents its contribution in the pathogenesis of Richter syndrome and MCL.

Consensus on the clinical use of myeloid growth factors.

Myeloid growth factors have significantly improved the quality of life and reduced the morbidity of patients experiencing chemotherapy‐induced neutropenia or undergoing bone marrow transplantation. However, in only a few instances have they directly contributed to improved response rates, better disease‐free survival, or decreased mortality. With their increased use, concern has risen about their cost‐effectiveness and appropriateness. To justify the use of myeloid growth factors and maximize patient benefit while minimizing the cost to health care systems and society, the development of guidelines for the clinical use of these expensive drugs is of great importance. In recent years both a European and an American expert panel have tried to establish consensus guidelines based on published evidence. A remarkable agreement can be found between results of both working parties. Clear recommendations for an optimal and more rational use of myeloid growth factors in clinical practice on both sides of the ocean have been delineated.

The t(14;20)(q32;q12): a rare cytogenetic change in multiple myeloma associated with poor outcome

and concurrent sepsis causing diagnostic delay and significant morbidity. We believe that these predisposing events are common to all patients receiving high-dose chemotherapy for CNS lymphomas and that this complication is under-recognized. Evidence shows that cancer and its treatment is the leading case of WE in the paediatric population and that the diagnosis is commonly missed (Vasconcelos et al, 1999). We propose that prophylactic, parenteral thiamine should be administered to all patients receiving second-line anti-emetic therapy during high-dose chemotherapy for CNS malignancy.

Diagnosis and follow-up of monoclonal gammopathies of undetermined significance; information for referring physicians

Abstract The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.

A single course of remission reinduction chemotherapy for acute myelogenous leukemia relapsing after allogeneic bone marrow transplantation is complicated by graft-versus-host disease and followed by sustained complete remission.

Graft-versus-host disease (GVHD) remains a major immunological complication after allogeneic bone marrow transplantation (allo-BMT), but also favors development of the beneficial graft-versus-leukemia (GVL) effect. A patient with AML-M4 (inv (16)) is described, who was given non-myeloablative remission reinduction therapy for leukemic relapse (inv (16), trisomy 8) diagnosed on day 184 after HLA-compatible sibling BMT. On day 236, ie about 6 weeks after completion of this course, a clinical syndrome suggestive of acute GVHD grade 3 had developed. Skin biopsy confirmed the clinical diagnosis of GVHD, with a compatible liver biopsy. Transfusion-associated GVHD was ruled out by analysis of short tandem repeat (STR) alleles in the skin biopsy, revealing alleles from donor and recipient but not from third party origin. Cyclosporin A (CsA) therapy, which had been tapered between days 150 and 175, was resumed, resulting in a favorable response and gradual transition to limited chronic GVHD. The patient has since remained in complete remission with an excellent performance status for more than 40 months, without further chemotherapy. Thus this biopsy proven case of GVHD was induced by marrow donor lymphocytes more than 200 days after transplantation and apparently triggered by remission reinduction chemotherapy. The case indicates that intensive non-myeloablative chemotherapy can cure AML relapsing after allo-BMT. The therapeutic effect in this case probably involved a direct pharmacological suppression of the leukemic clone followed by a GVL effect initiated by donor-derived alloreactive T lymphocytes.