Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis

BackgroundFew data on patterns of care and outcomes are available for elderly patients with diffuse large B-cell lymphoma (DLBCL) outside of clinical trials.MethodsWe identified patients with DLBCL older than 60 years from a regional cancer registry between 2000 and 2010. Based on registry data and chart review, 128 patients from the oncology network of Eastern Switzerland were analysed for patient characteristics, treatment and outcomes of DLBCL. Three age groups were compared: 60–69, 70–79 and over 80 years old.ResultsMedian age was 73 years (range: 60 to 95 years). 52/121 treated patients received 6 cycles of R-CHOP/CHOP, of those 30 (58%), 18 (35%) and 4 (7%) patients were 60–69 years, 70–79 years or older than 80 years respectively, with a significant difference by age group, p = 0.001. Median OS of patients 60–69, 70–79, and 80 years and older receiving 6 cycles of R-CHOP/CHOP were: 54 months, 31 months and 24 months respectively. In comparison, patients receiving other than 6 cycles of R-CHOP/CHOP treatment regimens had a median OS of 22 months, 17 months and 6 months, respectively. In the multivariable analysis other than 6 cycles of R-CHOP/CHOP were significantly associated with poor survival. The risk of dying increased by a mean of 6% for each year of age from age 60 years onwards.ConclusionIn conclusion, treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival in our oncology network. The possibility of using R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL.     

Outcomes following watchful waiting for stage II–IV follicular lymphoma patients in the modern era

To examine the effectiveness of an initial management strategy of watchful waiting for follicular lymphoma (FL) in clinical practice, we compared outcomes for patients diagnosed 2004–2007 in the United States initially managed with watchful waiting with outcomes following initial rituximab monotherapy and chemoimmunotherapy. In total, 1754 stage II–IV patients in the National LymphoCare Study underwent watchful waiting (n = 386), rituximab monotherapy (n = 296) or rituximab plus chemotherapy (n = 1072) as initial management strategy. Female patients and those who received treatment in the Northeast or in an academic setting more commonly underwent watchful waiting versus initial chemoimmunotherapy; whereas patients with grade 3 histology, anaemia, elevated lactate dehydrogenase, extranodal involvement, B symptoms or performance status ≥1 more commonly received chemoimmunotherapy. Although time to new treatment and progression‐free survival following first‐ and second‐line therapy were improved with chemoimmunotherapy, and time to chemotherapy was improved with rituximab monotherapy, there were no differences in overall survival between watchful waiting and chemoimmunotherapy or rituximab monotherapy. With 8‐year overall survival estimates of 74%, initial management with watchful waiting in the context of sequential therapy remains a viable option for FL patients in the modern era. This trial was registered at www.clinicaltrials.gov (NCT00097565).     

Clinical analysis of eight patients with primary follicular lymphoma in the duodenum

We performed a clinical analysis on 8 patients with primary follicular lymphoma in the duodenum taken from among 26 cases of primary gastrointestinal malignant lymphoma treated in our division. The median age was 60 years (range 48 to 82 yr). The ratio of males to females was 4:4. The chief complaints were no symptoms in 4 cases, heartburn in 2 cases, lower abdominal pain in 1 case, and back pain in 1 case. All patients were in clinical stage I EA. Gastroendoscopic findings showed multiple whitish granules around the ampulla of Vater in all patients. Involvement of the site in 6 cases was only located at the second portion; lesions in the other 2 cases were located at the second portion, and at the third portion or fourth portion, respectively. A histological study showed follicular lymphoma grade 1, and an immunohistological study demonstrated that the lymphoma cells were positive for CD79a, CD10, CD20, and bcl-2. Five patients were positive for the FISH analysis fusion signal of IgH/bcl-2 genes. Rituximab with CHOP therapy was performed for 7 patients. Seven patients are currently alive, and one died of uterine cancer. At the medium-term 39 month-follow-up, 7 patients were in complete remission, and 1 patient was in partial remission. Rituximab with CHOP (CVP) therapy is a possible treatment for primary follicular lymphoma in the duodenum. Further consideration of appropriate therapy for this disease might be necessary.     

Determinants of the optimal first‐line therapy for follicular lymphoma: A decision analysis

Combination immunochemotherapy is the most common approach for initial therapy of patients with advanced‐stage follicular lymphoma, but no consensus exists as to the optimal selection or sequence of available regimens. We undertook this decision analysis to systematically evaluate the parameters affecting the choice of early therapy in patients with this disease. We designed a Markov model incorporating the three most commonly utilized regimens (RCVP, RCHOP, and RFlu) in combinations of first‐ and second‐line therapies, with the endpoint of number of quality‐adjusted life years (QALYs) until disease progression. Data sources included Phase II and Phase III trials and literature estimates of long‐term toxicities and health state utilities. Meta‐analytic methods were used to derive the values and ranges of regimen‐related parameters. Based on our model, the strategy associated with the greatest number of expected quality‐adjusted life years was treatment with RCHOP in first‐line therapy followed by treatment with RFlu in second‐line therapy (9.00 QALYs). Strategies containing RCVP either in first‐ or second‐line therapy resulted in the lowest number of QALYs (range 6.24–7.71). Sensitivity analysis used to determine the relative contribution of each model parameter identified PFS after first‐line therapy and not short‐term QOL as the most important factor in prolonging overall quality‐adjusted life years. Our results suggest that regimens associated with a longer PFS provide a greater number of total QALYs, despite their short‐term toxicities. For patients without contraindications to any of these regimens, use of a more active regimen may maximize overall quality of life. Am. J. Hematol. 2010. © 2010 Wiley‐Liss, Inc.     

Incidence and clinical impact of chemotherapy induced myelotoxicity in cancer patients: An observational retrospective survey

Purpose

To evaluate the frequency of chemotherapy-induced myelotoxicity in cancer patients, the related treatment (G-CSF, rHuEPO), and the occurrence of chemotherapy dose reductions, delays or discontinuations.

Patients and methods

We retrospectively collected data from 1175 patients who completed at least four chemotherapy courses at 64 Italian Centres.Myelotoxicity was defined as anemia (Hb < 10 g/dL) and neutropenia (ANC < 1500/mm³). The study population was divided by age, in 664 adult patients aged ≤65 years and 511 elderly patients, aged >65 years. The association between events during chemotherapy and myelotoxicity indices were assessed by logistic regression.

Results

The median age of the patients was 64 years. Myelotoxicity was observed in 633 patients (53.9%), anemia (<10 g/dL) in 263 (22.4%) and neutropenia in 530 (45.1%); 686 patients (58.5%) showed mild anemia (Hb < 12 g/dL). Dose reductions were observed in 199 patients (16.9%), dose delays in 338 (28.7%), and discontinuations in 157 (13.4%), with no significant difference between age groups.Myelotoxicity accounted for 20% of treatment withdrawals with no differences between age groups. G-CSF was administered to 53.4% of the neutropenic patients, and rHuEPO to 53.1% of the anemic patients.Logistic regression analyses showed a significant (P < 0.001) association between chemotherapy dose delays, dose reductions and myelotoxicity. Considering age strata, the association between dose reduction and myelotoxicity was significant. The risk of neutropenia in the adults was higher than in elderly (50.0% vs 38.7%).

Conclusion

Our results show that anemia and neutropenia occur in a substantial proportion of cancer patients receiving chemotherapy, and have an impact on chemotherapy dose delivery. G-CSF and rHuEPO are treatments widely used in about one half of neutropenic and anemic patients.Particular attention should be given to elderly patients, who are at high risk of myelotoxicity and should be carefully evaluated for the prophylactic use of G-CSF and monitored for the appropriate use of rHuEPO.     

Follicular lymphoma-like B cells of uncertain significance (in situ follicular lymphoma) may infrequently progress,but precedes follicular lymphoma,is associated with other overt lymphomas and mimics follicular lymphoma in flow cytometric studies

In situ follicular lymphoma, more recently known as follicular lymphoma-like B cells of uncertain/undetermined significance is well accepted. However, the morphological criteria have evolved since it was first described and data are limited and conflicting regarding its clinical implications and whether the extent of involvement predicts an association with overt lymphoma. It is also unknown how often it will be identified by flow cytometric studies and how often it precedes overt follicular lymphomas. A multiparameter study of 31 biopsies with follicular lymphoma-like B cells of uncertain significance and 4 ‘benign’ lymph node biopsies that preceded an overt follicular lymphoma was, therefore, performed. Fifty-two percent of biopsies with follicular lymphoma-like B cells were associated with a prior or concurrent lymphoma but only 6% subsequently developed lymphoma (median follow up 26 months). Neither the number, proportion or density of BCL2⁺ germinal centers were associated with overt follicular lymphoma/diffuse large B-cell lymphoma. Flow cytometric studies identified follicular lymphoma-like B cells in 8 of 15 evaluable cases. The proportion but not the absolute number of BCL2⁺ germinal centers was associated with the likelihood of positive flow cytometric studies (P<0.01). All 4 ‘benign’ biopsies that preceded an overt follicular lymphoma demonstrated follicular lymphoma-like B cells. Thus, although few patients with follicular lymphoma-like B cells of uncertain significance progress within the follow-up period, it at least precedes many follicular lymphomas. The extent of involvement does not predict the occurrence of prior or concurrent lymphomas. Flow cytometric studies demonstrating follicular lymphoma-like B cells must not be over-interpreted as they may only reflect follicular lymphoma-like B cells.     

Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi

Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma were studied with the aim of developing a prognostic model specifically devised for this type of lymphoma. We collected information on age, sex, Ann Arbor stage, number of extranodal disease sites, bone marrow (BM) involvement, bulky disease, B symptom criteria (fever, night sweats, and weight loss), performance status (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin level, and erythrocyte sedimentation rate (ESR). In the training sample of 429 patients with complete data, multivariate analysis showed that age, sex, number of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive for overall survival. Using these 6 variables, a prognostic model was devised to identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62; P <. 0001). The model was also predictive (P =.0001) in the validation sample of 265 patients with complete data only for the 6 variables used in the development of the model and even in the group of 210 patients from the validation sample uniformly treated with doxorubicin-containing regimens (P =.0001). The prognostic model appears to be very useful in identifying patients with follicular lymphoma at low, intermediate, or high risk.     

Polymerase chain reaction detection of cells carrying t(14;18) in bone marrow of patients with follicular and diffuse large B-cell lymphoma: the importance of analysis at diagnosis and significance of long-term follow-up

The t(14;18) is the most frequent chromosomal aberration observed in follicular lymphoma (FL), and is less frequent in diffuse large cell lymphoma (DLCL). The bcl-2/IgH rearrangement constitutes good target for polymerase chain reaction (PCR) detection that allows to find out one tumor cell in 100,000 normal cells. The PCR assay was used to detect bcl-2-rearranged cells in blood and bone marrow (BM) in 63 previously untreated patients with DLCL and in 53 patients with FL. Twenty five FL patients (47%) and 9 DLCL patients (14%) had PCR-detectable lymphoma cells in BM and peripheral blood. Minimal residual disease (MRD) was evaluated in 17 FL and 5 DLCL patients undergoing first-line chemotherapy. Three DLCL patients (60%) but only 1 FL (6%) patient achieved molecular response (PCR-negative status in BM). Two PCR bcl-2/IgH positive patients with FL were treated with rituximab (anti-CD20 antibody) and had no PCR-detectable lymphoma cells in BM after the therapy. Peripheral blood stem cells (PBSC) were harvested in 5 FL (1 PCR-negative) and in 2 DLCL (1 PCR-negative) patients. PCR-positive lymphoma cells contamined PBSC in all patients with BM PCR-positivity before harvesting. Five FL patients underwent autologous transplantation (AT). No bcl-2/IgH positive cells were detected in 4 patients (80%) at any point after AT. One patient achieved molecular response after rituximab treatment. All the patients are in CR 6, 22, 30, 31 and 42 months respectively, after AT. On the other hand, 4 FL patients in clinical complete remission, but with persistent PCR positivity in BM relapsed with median of 21 months (interval, 14-28 months) from the end of a first-line chemotherapy. Thus, the results show that PCR detection of the bcl-2/IgH rearrangement is a very useful method in evaluating the BM infiltration by lymphoma cells especially in the situation of MRD. Conventional chemotherapy did not eradicate bcl-2 positive cells in BM in most of lymphoma patients, but autologous transplantation or rituximab immunotherapy can induce molecular response in a significant proportion of them. Our results support the previous observations of the molecular response importance in view of better disease free and probably also overall survival.     

Frequency of t(14;18) in follicular lymphoma patients: geographical or technical variation

The t(14;18) translocation is the most distinguishing molecular finding in follicular lymphoma (FL). However, the reported frequencies of t(14;18) in FL show significant variation, which is often attributed to geographical and/or methodological factors. The methods used to detect t(14;18) include Southern blotting, conventional cytogenetics, fluorescent in situ hybridization, and polymerized chain reaction (PCR). Because of its practicality and superior sensitivity, PCR is becoming the more commonly used method in clinical laboratories. The identification of the main breakpoint regions on chromosome 18, including the major breakpoint region (MBR), the minor cluster region (mcr), and the newly defined intermediate cluster region (icr), increased the detection frequency of PCR. In our study, using a highly sensitive nested PCR strategy with primers for MBR, mcr and icr regions, we were able to detect t(14;18) in 95% of FL patients, which is one of the highest reported frequencies using PCR. We screened 58 FL patient samples collected retrospectively from different hospitals in Jordan. DNA was extracted from archival paraffin-embedded samples, some of which were >10 years old. The respective breakpoint distributions were, 47 for MBR (81%), two for mcr (3.5%) and six for icr (10.3%). In this report, we analyze this high frequency of t(14;18) detection in a general review of the recent literature, in an attempt to assess the geographical vs. methodological influences on the reported frequencies.     

A retrospective analysis of bleeding complications in 438 patients with acute leukaemia during the years 1972–1991

Abstract: The incidence and mortality of bleeding complications have been investigated in 438 patients with acute leukaemia consolidated either by chemotherapy (n = 241) or by bone marrow transplantation (n = 197). Bleeding signs on admission were found in 38% of the chemotherapy-treated group. Haemorrhagic deaths during the 1st month were seen in 10%. The majority of the major bleedings were localized intracranial, but gastrointestinal haemorrhages were also common. The platelet count was significantly lower (40 × 10⁹/1 versus 69 × 10⁹/1, p < 0.001) and the leukocyte count significantly higher (31.2 × 10⁹/1 versus 11.6 × 10⁹/1, p<0.001)in the group with bleeding complications than in those without. The haemorrhagic mortality in patients consolidated with chemotherapy compared with transplant patients was similar, 23% and 19%. The majority of the lethal haemorrhages in the latter group were observed in patients undergoing allogenic bone marrow transplantation after engraftment. Septicaemia, graft-versus-host and venous occlusive disease were contributing factors.     

SMABcare study: subcutaneous monoclonal antibody in cancer care: cost-consequence analysis of subcutaneous rituximab in patients with follicular lymphoma

Rituximab is used as a standard of care for follicular lymphoma and is usually administered intravenously. A novel subcutaneous formulation recently showed non-inferior efficacy with similar pharmacokinetic and safety profiles compared to intravenous rituximab in patients with follicular lymphoma. This new approach is promising in terms of comfort for patients and time-saving for hospital staff. To evaluate the real-life economic impact of subcutaneous rituximab as maintenance therapy in patients with follicular lymphoma in real life, we conducted a cost-consequence analysis from the hospital’s point of view in three French teaching hospitals. Health-related quality of life (EQ-5D-3L) was investigated as well as patients’ and nurses’ perception. Compared to intravenous rituximab, subcutaneous administration showed an estimated cost-saving of €109.20 per patient per cycle (p < 0.001), 78.6% of which could be attributed to the rituximab cost. Health-related quality of life showed no significant difference between the two groups despite tendencies for greater pain in the subcutaneous group and greater anxiety in the intravenous group. Thus, subcutaneous rituximab had a favorable pharmacoeconomic profile, with clinical efficacy similar to that of intravenous rituximab. The subcutaneous form was preferred by almost all patients, but further consideration should be given to improve the patients’ experience: a dedicated day unit with trained medical, nursing, and pharmaceutical staff could be helpful.     

Second line chemotherapy in patients with enteropathy-associated T cell lymphoma: a retrospective single center analysis

Enteropathy-associated T cell lymphoma (EATL) is a rare disease with a dismal prognosis. Due to the low efficacy of chemotherapy and the poor performance status of patients failing first line, no data on second line therapy exist. A retrospective analysis of 19 patients with EATL at our institution identified six patients (31%) undergoing second line chemotherapy after CHOP-like regimens. Three patients had progressive disease (PD) during first line therapy, while the other three patients showed relapse after an initial complete remission (CR). The time from the last cycle of first line chemotherapy to second line therapy was 1–62 months. Two patients received ifosfamide, carboplatin and etoposide (ICE), two were given fludarabine and cyclophosphamide (FC) and one each had dexamethasone, cisplatin and cytarabine (DHAP) and cladribine chemotherapy. One patient progressed after one course of cladribine, while two patients developed intestinal perforation and died after one course of ICE and DHAP, respectively. Three patients achieved a CR lasting 4, +7 and +64 months, with two being alive without evidence of disease. Our data again confirm the poor prognosis of patients with EATL. A small subset of patients, however, apparently benefits from initiation of second line chemotherapy.