Ingrid Vášová

Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study

BACKGROUND The definition and role of bulky disease in young patients (ie, aged 18-60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. METHODS Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. FINDINGS Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1.090 [95% CI 1.051-1.130], p < 0.0001) and OS (1.119 [1.057-1.184], p = 0.0001), and after CHOP-like treatment and rituximab for OS (1.089 [1.003-1.183], p = 0.043), but not for EFS (1.044 [0.991-1.099], p=0.103). For CHOP-like treatment alone, 3-year EFS ranged from 78.2% (MTD < 5.0 cm, 95% CI 68.3-85.4) to 41.3% (MTD > or = 10.0 cm, 31.8-50.4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83.2% (MTD < 5.0 cm, 72.8-89.9) to 72.7% (MTD > or = 10.0 cm, 63.8-79.7). With CHOP-like treatment alone, 3-year OS decreased from 92.9% (MTD < 5.0 cm, 84.9-96.8) to 73.5% (MTD > or = 10.0 cm, 63.9-81.0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98.0% (MTD < 5.0 cm, 92.2-99.5) to 85.2% (MTD > or = 10.0 cm, 77.0-90.6). For CHOP-like treatment, any cut-off point between 5.0 cm and 10.0 cm separated two populations with a significant EFS difference (p < 0.0001 for all log-rank tests) and OS difference (p < or = 0.003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10.0 cm separated two populations with a significant EFS difference (log-rank p = 0.047), but any cut-off point of 6.0 cm or more separated two populations with a significant OS difference (log-rank p values 0.0009-0.037). INTERPRETATION Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5.0 cm and 10.0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10.0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease.

Cardiopulmonary exercise testing in the evaluation of functional capacity after treatment of lymphomas in adults

The present study assessed several parameters of cardiopulmonary function in patients, after treatment for aggressive non-Hodgkins lymphoma and Hodgkins disease, to determine the influence of these parameters on patients performance status. One hundred and six patients (66 male and 40 female) aged 40 ± 15 years were examined 1–2 years (median 14 months) after anticancer treatment. The patients were examined by means of rest and dynamic stress echocardiography and cardiopulmonary exercise. The rest and post-exercise ejection fraction (EF), Doppler parameters of left ventricular diastolic function and peak oxygen consumption (pVO2) were used as parameters of cardiopulmonary performance. The cumulative dose (CD) of doxorubicin (DOX) given was 240 ± 70 (240 mg/m2). Thirty-seven percent of patients received mediastinal irradiation in accordance with the used treatment protocol. Sixty-four patients (60%) experienced fatigue after the treatment. Three patients (3%) demonstrated an decreased EF <50%, 34 (32%) demonstrated impaired diastolic function, 14 (13%) demonstrated decreased pVO2<20 ml/kg/min and 15 (14%) demonstrated a value of pVO2 below the reference value, respectively. None of the patients exhibited clinical signs of heart failure. Apart from three patients with a rest EF<50%, all the other patients responded to stress echocardiography with an increment of EF > 5%. The parameter pVO2 significantly correlated with stress EF (0.58, P < 0.0002). A significant relationship was found with all parameters of diastolic function: to index E/A of diastolic filling (r = 0.67, P < 0.0001), isovolumic relaxation time (r = −0.56, P < 0.0009) and to deceleration time (r = −0.54, P < 0.009), respectively. A negative relationship was found with age (r = −0.74, P < 0.0001), CD of DOX (r = −0.53, P < 0.003) and radiotherapy-involving mediastinum (r = − 0.44, P < 0.04), respectively. Using multivariate analysis, a significant relationship was found between pVO2 and parameters of diastolic filling, age, female sex and CD of DOX, respectively (r = 0.58, P < 0.0001). Diastolic dysfunction was correlated with age, CD of DOX and radiotherapy-involving mediastinum, respectively (r = 0.51, P < 0.01). The results show that diastolic dysfunction was the most affected parameter of cardiopulmonary function in cancer survivors. This parameter negatively influenced cardiopulmonary performance and was significantly correlated with the cumulative dose of doxorubicin given and radiotherapy on mediastinum. Despite a high number of patients experiencing fatigue, the study demonstrates that only a relatively small number of patients show a depressed pVO2 on a cardiopulmonary stress test and other cardiac abnormalities. The results of the tests support the introduction of regular aerobic exercise for cancer survivors to increase their cardiopulmonary performance and well-being. Hypothetically, aerobic training may also positively influence diastolic function. However, this assumption warrants a prospective follow-up.

Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma

We treated 40 patients with poor prognosis lymphomas. Patients with non-Hodgkin’s lymphoma (NHL, n = 14) received MINE chemotherapy (mesna, ifosfamide 1330 mg/m2 and etoposide 65 mg/m2 by i.v. infusions on days 1–3, mitoxantrone 8 mg/m2 i.v. on day 1), and those with Hodgkin’s disease (HD, n = 26) received VIM chemotherapy (mesna, ifosfamide 1200 mg/m2 by i.v. infusion on days 1–5, etoposide 90 mg/m2 by i.v. infusion on days 1, 3 and 5, and methotrexate 30 mg/m2 i.v. on days 1 and 5). Chemotherapy was followed by G-CSF (10 or 16 μg/kg in two divided doses daily) to mobilize PBSC. We performed 134 aphereses (median three leukaphereses per patient) starting on either day 13 (median; VIM) or day 12 (median; MINE). The median yield was 9.9 × 106 CD34+ cells/kg and 53.2 × 104 CFU-GM/kg for VIM, and 13.5 × 106 CD34+ cells/kg and 53.4 × 104 CFU-GM/kg for MINE. Except for predictable myelosuppression, no serious toxicity was seen. Response rate using MINE was 63% (18% CR, 45% PR) and using VIM 50% (17% CR, 33% PR). We conclude that VIM and MINE are effective and well-tolerated salvage regimens in patients with lymphomas and, followed by G-CSF, they also exhibit good capacity to mobilize stem cells in a predictable time interval.

Gene expression profiling in follicular lymphoma and its implication for clinical practice

Follicular lymphoma (FL) is characterized by an indolent and relapsing course. Recently, the clinical outcome of FL has been distinguished by immune microenvironment-associated gene signatures. In our study, gene expression profiling (GEP) was performed in 31 non-selected patients with follicular lymphoma (FL), 12 of whom were in relapse and the remaining 19 newly diagnosed. A custom oligonucleotide microarray (Agilent 8 × 15K) was used which contained probes for about 3500 genes, including those that had been previously published as demonstrating significant prognostic value. An unsupervised approach was not able to recognize clinically different FLs. As the previously published prognostically relevant gene signatures could not be properly verified, probably due to microarray platform differences, template matching was therefore used in order to define two gene sets with differential gene expression among our samples. These gene sets shared an overrepresentation of genes with similar biological functions and were termed ‘T-CELL’ and ‘PROLIFERATION’ profiles. The ‘poor profile’ was then defined by a high PROLIFERATION score (upper tertile) and/or low T-CELL score (lower tertile). The ‘poor profile’ cohort contained a significantly higher proportion of relapsed cases (p < 0.05, Fishers exact test). Additionally, a comparison of samples from initial diagnosis and from relapse showed significant differences mainly in the T-CELL profile (p = 0.036; χ2). This supports the hypothesis that the number of T-cells and their expression pattern play a major role in FL development.

The persistence of t(14;18)-bearing cells in lymph nodes of patients with follicular lymphoma in complete remission: the evidence for ‘a lymphoma stem cell’

Monitoring of t(14;18) in blood or bone marrow in follicular lymphoma (FL) remains controversial. We attempted to monitor t(14;18) in lymph nodes by ultrasound-guided fine needle aspirations (UG-FNA). First, we confirmed t(14;18) in 27/31 UG-FNAs of lymph nodes with fluorescent in situ hybridisation (FISH) and/or polymerase chain reaction (PCR) in patients with advanced disease. In complete (CR) and molecular remission, there were repeated 18 UG-FNAs in 17 patients. Five of 18 UG-FNA were technically unsuccessful and 6/18 samples contained fibrosis. Despite that, these patients had a better prognosis. In 7/7 aspirations in six patients, t(14;18) was detected. Three patients are still in CR, even one of them remains in long lasting remission despite two consecutive evidences of t(14;18) in UG-FNA. Another three of these patients relapsed a few months after UG-FNA. This study is proof of the principle of the detection of residual t(14;18) bearing cells in previously involved lymph nodes despite patients being in remission.

Efficacious but insidious: A retrospective analysis of fludarabine-induced myelotoxicity using long-term culture–initiating cells in 100 follicular lymphoma patients

OBJECTIVE Fludarabine has been recognized as effective treatment in patients with follicular lymphoma (FL), but can induce myelotoxicity of unknown mechanism. MATERIALS AND METHODS Myelotoxicity was assessed by cultivation of two types of hematopoietic progenitor cells: colony-forming units granulocyte-macrophage (CFU-GM) and long-term culture-initiating cells (LTC-IC). Pretreatment amounts of CFU-GM and LTC-IC were correlated to age, gender, stage of disease, bone marrow involvement, and previous therapy. Posttreatment comparison of CFU-GM and LTC-IC was performed after different regimens of chemotherapy: fludarabine-based (FND +/- R), procarbazine-based (COPP +/- R), and CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone) +/- R(Rituximab). RESULTS One-hundred patients (median age 55 years; 21 patients relapsed) treated for FL were analyzed. The total number of progenitor hematopoietic cells in both types of cultures varied in wide ranges; for LTC-IC between 0 and 874 cells/mL with a median of 77.71 cells/mL and for CFU-GM between 0 and 531 x 10(2) cells/mL with a median of 30.58 x 10(2) cells/mL. Bone marrow involvement, gender, stage of disease, or previous therapy had no influence on LTC-IC and CFU-GM counts. We identified an increase in LTC-IC, but not CFU-GM, associated with age (p = 0.01). Median figures for CFU-GM and LTC-IC were found to be significantly lower after FND +/- R and COPP +/- R than after CHOP +/- R therapy, compared to baseline values (p < 0.01). CONCLUSIONS Fludarabine and procarbazine have a dramatic influence, especially on the most immature hematopoietic cells, mirrored in reduced numbers of LTC-IC. This finding is consistent with clinical observations (poor mobilization after fludarabine) and offers an insight into the mechanism of fludarabine-induced myelotoxicity.

Treatment of high-risk aggressive B-cell non-Hodgkin lymphomas with rituximab, intensive induction and high-dose consolidation: long-term analysis of the R-MegaCHOP-ESHAP-BEAM Trial

Abstract We have studied the feasibility and efficacy of intensified R-MegaCHOP-ESHAP-BEAM therapy in high-risk aggressive B-cell lymphomas. Altogether 105 patients (19–64 years) with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL) or follicular lymphoma grade 3 (FL3) with an age-adjusted International Prognostic Index of 2–3 were recruited. Treatment consisted of three cycles of high-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), followed by three cycles of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) and high-dose consolidation with BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem cell transplant. The 5-year progression-free survival (PFS) was 72% (DLBCL 60%, PMBL 89%) and overall survival (OS) was 74% (DLBCL 61%, PMBL 89%) after a median follow-up of 85 months. However, an independent prognostic factor was age only, with patients ≤ 45 years having 5-year PFS 90% and patients > 45 years having PFS 54%. PMBL had better prognosis than DLBCL/FL3 in patients > 45 years (PFS, 88% vs. 48%), but not in younger patients (PFS, 91% vs. 94%).