Esa Jantunen

Up-Front Autologous Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: NLG-T-01

PURPOSE Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study. PATIENTS AND METHODS Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT. RESULTS Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL. CONCLUSION Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

Prediction of mobilisation failure in patients with non-Hodgkin's lymphoma

Summary:Factors affecting progenitor cell mobilisation in patients with non-Hodgkins lymphoma (NHL) are incompletely understood. We have analysed factors predicting mobilisation failure in 97 consecutive patients with NHL (59 males, 38 females; median age 49 years) who received mobilisation with intermediate-dose CY (4 g/m2) followed by G-CSF. The histology included large cell B (N=50), mantle cell (N=16), follicular (N=16) and other NHL (N=15). The disease status was 1CR/PR/primary refractory in 66 patients and >1 CR/PR in 31 patients. The minimum criterion for successful mobilisation was the collection of ⩾1.5 × 106/kg CD34+ cells. In all, 18 patients (19%) failed to reach this threshold. In univariate analysis, premobilisation factors associated with mobilisation failure included BM involvement at the time of diagnosis (P=0.001) or prior to mobilisation (P=0.001) and low platelet count just prior to mobilisation (P=0.001). In multivariate analysis, only BM involvement at diagnosis (P=0.004) and platelet count just prior to mobilisation (P=0.01) were associated with mobilisation failure. A mathematical model based on these two factors and presented in the form of a receiver operating characteristics curve showed a sensitivity of 0.71 and a specificity of 0.77 in the prediction of mobilisation failure. Patients at a high risk of mobilisation failure may benefit from novel approaches.

Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin's lymphoma

Abstract:  Thirty adult patients with non‐Hodgkins lymphoma who were planned to receive up to 8–10 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) to a cumulative doxorubicin dose of 400–500 mg/m2 were studied to evaluate the value of serial plasma atrial natriuretic peptide (ANP), N‐terminal pro‐ANP (NT‐proANP) and brain natriuretic peptide (BNP) measurements in the early detection of doxorubicin‐induced left ventricular dysfunction. Plasma levels of natriuretic peptides were measured before every treatment course and 4 wk after the last one. Cardiac function was monitored with serial radionuclide ventriculography. Twenty‐eight patients were evaluable for cardiotoxicity. Clinical heart failure developed in 2 patients (7%). Left ventricular ejection fraction (LVEF) decreased from 58.0 ± 1.3% to 49.6 ± 1.7% (p<0.001). Plasma levels of ANP increased from 16.4 ± 1.3 pmol/l to 22.7 ± 2.4 pmol/l (p = 0.002), NT‐proANP from 288 ± 22 to 380 ± 42 pmol/l (p = 0.019) and BNP from 3.3 ±0.4 to 8.5 ± 2.0 pmol/l (p =0.020). There was a significant correlation between the increase in plasma ANP and the decrease in LVEF (r = ‐0.447, p = 0.029), and a trend towards significance between the increase in NT‐proANP and the decrease in LVEF (r=‐0.390, p = 0.059). The decrease in LVEF started very early and could already be seen after the cumulative doxorubicin dose of 200 mg/m2, whereas the increase in plasma natriuretic peptides was not evident until the cumulative doxorubicin dose of 400 mg/m2. Our results show that neuroendocrine activation — increased concentrations of plasma natriuretic peptides — occurs when left ventricular function has reduced substantially and its compensatory capacity has been exceeded resulting in atrial and ventricular overload. Thus, serial natriuretic peptide measurements cannot be used in predicting the impairment of left ventricular function. On the other hand, our study suggests that natriuretic peptides are useful in the detection of subclinical left ventricular dysfunction in patients receiving doxorubicin therapy.

Acute lymphoblastic leukemia in adolescents and young adults in Finland

Recent reports indicate that adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric rather than adult therapeutic protocols. This Finnish study did not show any major difference between patients treated with pediatric protocols and those treated with adult protocols, but confirmed that adolescents and young adults with acute lymphoblastic leukemia still have a poorer outcome than children below 10 years of age. See related perspective article on page 1124. Background Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland. Design and Methods This population-based study included 225 consecutive patients aged 10–25 years diagnosed with acute lymphoblastic leukemia during 1990–2004. One hundred and twenty-eight patients (10–16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17–25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients. Results For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%.The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white bood cell count ≥ 100×109/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification. Conclusions Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols. Key words: acute lymphoblastic leukemia, adolescents, survival, treatment outcome, young adults.

High-dose melphalan (200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (≥65 years) myeloma patients : comparison with younger patients treated on the same protocol

Limited information is available on the feasibility and efficacy of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients >65 years of age. In 1995–2005, 22 myeloma patients ⩾65 years (median 68, eight ⩾70) and 79 patients <65 years (median 57) were included in an identical treatment protocol. The first progenitor cell mobilization with cyclophosphamide plus granulocyte-colony stimulating factor (G-CSF) was successful in 95 and 96% of the patients, respectively. To date, 92 patients have received MEL (melphalan) 200 mg/m2 supported by ASCT. No early treatment-related deaths were observed among 22 elderly patients, whereas one younger patient died early. Engraftment and the need for supportive care were comparable between groups. The elderly patients tended to have more WHO grade 3–4 oral or gastrointestinal toxicity when compared to the younger patients (45 vs 23%, P=0.06). After ASCT, a complete response was observed in 44% of the elderly patients and 36% of the younger patients, respectively. No difference was observed between these age groups in progression-free survival (23 vs 21 months) or overall survival (57 vs 66 months) after ASCT. We conclude that MEL200 is a safe and efficacious treatment in selected elderly myeloma patients.

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.

Low-dose or intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor for progenitor cell mobilisation in patients with multiple myeloma.

Summary:Cyclophosphamide (CY) combined with granulocyte colony-stimulating factor (G-CSF) is commonly used to mobilise blood progenitor cells to support high-dose therapy in patients with multiple myeloma (MM). The optimal dose of CY in this setting is unknown. We have retrospectively analysed mobilisation efficiency and need for supportive care in 57 patients with newly diagnosed myeloma previously treated with VAD±local radiotherapy. The patients were mobilised either with low-dose CY (LD-CY, 1.2–2 g/m2) (n=25) or intermediate-dose CY (ID-CY, 4 g/m2) (n=32) plus G-CSF. Both regimens proved to be effective in the progenitor cell mobilisation. At least 2×106/kg CD34+ cells were collected from 88% and 84% of the patients with a single apheresis, respectively. Only one patient in the LD-CY group (4%) failed to mobilise vs none in the ID-CY group. Patients mobilised with LD-CY plus G-CSF had less toxicity: fewer hospital days during the mobilisation and apheresis procedures (5 vs 9 days, P<0.001), lower frequency of fever (20 vs 73%, P<0.001) and less need for supportive care including platelet transfusions (0 vs 24%, P=0.004) and days on parenteral antibiotics (0 vs 4 days, P<0.001). While these regimens seem to be equally effective in terms of progenitor cell mobilisation in newly diagnosed patients with MM, LD-CY+G-CSF is preferential because of more optimal resource utilisation and more favourable toxicity profile.

Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: Causes and consequences

The objective of this study was to evaluate etiology and consequences of neutropenic fever in AML patients. Two hundred and ninety neutropenic periods following chemotherapy in 84 AML patients were retrospectively evaluated. Neutropenic fever was found in 280 periods (97%). Severe sepsis developed in 35 occasions (13%) and 9 patients (11%) died due to severe sepsis. In 165 episodes with neutropenic fever (59%), the potential causative organism was found in blood cultures. Gram-negative bacteria were more commonly found in patients who developed severe sepsis (40% vs. 23%, p = 0.03). CRP after 2 – 3 days from start with fever was higher in patients with severe sepsis (190 mg/L vs. 96 mg/L, p < 0.001) but the rise in CRP rather coincided than preceded with the development of severe sepsis. Severe sepsis is associated with significant mortality in AML patients. Earlier methods than CRP are needed to predict development of severe sepsis.

Hospital water supply as a source of disseminated Mycobacterium fortuitum infection in a leukemia patient.

Nosocomial acquisition of Mycobacterium fortuitum led to a disseminated infection in a leukemia patient. A linkage to showerhead water was supported by molecular typing of clinical and environmental isolates. Contamination of the hospital water system with microbes that are relatively resistant to common sanitation processes poses an increased risk of infection to neutropenic patients.

Inherited giant platelet disorders

Giant platelet disorders (GPD) refer to rare, usually inherited states characterized by abnormally large platelets, thrombocytopenia and bleeding tendency of variable severity. This review summarizes major clinical and laboratory features of three GPDs (Bernard‐Soulier syndrome, May‐Hegglin anomaly and gray platelet syndrome). Differential diagnosis between immunological thrombocytopenia and GPDs is important. Although rare, giant platelet disorders should be borne in mind, since bleeding tendency in some individuals may be severe and knowledge of bleeding diathesis is of importance before delivery or surgical procedures also in less symptomatic individuals.