For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than ...standard treatment.
We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life.
For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04).
For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.
To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing ...chemotherapy alone.
This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation.
One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio HR, 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT.
Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.
This retrospective study was undertaken to evaluate the outcome of patients with stage I or II (limited stage), grade I-II follicular non-Hodgkin's lymphoma (FL) treated with radiation therapy (RT) ...alone as initial management.
Patients with stage I or II and pathologically confirmed WHO grade I or II FL treated initially with RT alone between 1982 and 2008 were identified from a population based cancer registry.
Forty patients with a mean age 61.3 years at diagnosis were identified. The median follow up was 6.9 years from the end of radiation therapy. Stage was I (n = 26) and II (n = 14). None had B symptoms. The Follicular Lymphoma International Prognostic Index (FLIPI) was low risk in 26 patients and intermediate risk in 5. Doses ranged from 15 Gy to 48 Gy, with a median dose of 35 Gy. All patients achieved a complete clinical response (CR). 5 and 10 year overall survival (OS) was 86% and 59%, progression free survival (PFS) 67% and 54%. Age ≥60 at diagnosis was associated with reduced OS, p = 0.029, but did not affect PFS. No other clinical features including grade or FLIPI were significant for outcomes. Local failure was uncommon occurring in 8% (3/40) although this was 21% (3/14) of all recurrences.
OS and PFS outcomes for radiation alone in limited stage low grade FL patients from this single institution study are consistent with previously published data. No predictors were prognostic for PFS. A dose of ≤35 Gy may be appropriate. In this highly selected homogeneous group the FLIPI loses discriminating ability. Local control is excellent, and a majority of patients are free of disease after 5 years.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bortezomib has demonstrated promising activity in patients with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of bortezomib added to rituximab, ...cyclophosphamide, vincristine, and prednisone (R-CVP) in previously untreated advanced-stage FL.
This is a phase II multicenter trial adding bortezomib (1.3 mg/m(2) days 1 and 8) to standard-dose R-CVP (BR-CVP) for up to eight cycles in patients with newly diagnosed stage III/IV FL requiring therapy. Two co-primary end points, complete response rate (complete response CR/CR unconfirmed CRu) and incidence of grade 3 or 4 neurotoxicity, were assessed.
Between December 2006 and March 2009, 94 patients were treated with BR-CVP. Median patient age was 57 years (range, 29 to 84 years), and the majority had a high (47%) or intermediate (43%) Follicular Lymphoma International Prognostic Index score. BR-CVP was extremely well tolerated, with 90% of patients completing the intended eight cycles. No patients developed grade 4 neurotoxicity, and only five of 94 patients (5%; 95% CI, 0.8% to 9.9%) developed grade 3 neurotoxicity, which was largely reversible. On the basis of an intention-to-treat analysis, 46 of 94 patients (49%; 95% CI, 38.8% to 59.0%) achieved a CR/CRu, and 32 of 94 patients (34%) achieved a partial response, for an overall response rate of 83% (95% CI, 75.4% to 90.6%).
The addition of bortezomib to standard-dose R-CVP for advanced-stage FL is feasible and well tolerated with minimal additional toxicity. The complete response rate in this high-risk population compares favorably to historical results of patients receiving R-CVP. Given these results, a phase III trial comparing BR-CVP with R-CVP is planned.
The optimal preparative regimen for non-Hodgkin's lymphoma patients undergoing autologous peripheral blood stem cell transplantation (PBSCT) is unknown. We compared a total body irradiation ...(TBI)-based regimen with a chemotherapy-alone regimen.
A retrospective cohort study was performed at a Canadian cancer center. The TBI regimen consisted of cyclophosphamide, etoposide, and TBI 12 Gy in six fractions (CY/E/TBI). The chemotherapy-alone regimen consisted of carmustine, etoposide, cytarabine, and melphalan (BEAM). We compared the acute and long-term toxicities, disease relapse-free survival, and overall survival (OS).
Of 73 patients, 26 received CY/E/TBI and 47 received BEAM. The median follow-up for the CY/E/TBI group was 12.0 years and for the BEAM group was 7.3 years. After PBSCT, no differences in acute toxicity were seen between the two groups. The 5-year disease relapse-free survival rate was 50.0% and 50.7% in the CY/E/TBI and BEAM groups, respectively (p = .808). The 5-year OS rate was 53.9% and 63.8% for the CY/E/TBI and BEAM groups, respectivey (p = .492). The univariate analysis results indicated that patients with Stage IV, with chemotherapy-resistant disease, and who had received PBSCT before 2000 had inferior OS. A three-way categorical analysis revealed that transplantation before 2000, rather than the conditioning regimen, was a more important predictive factor of long-term outcome (p = .034).
A 12-Gy TBI-based conditioning regimen for PBSCT for non-Hodgkin's lymphoma resulted in disease relapse-free survival and OS similar to that after BEAM. PBSCT before 2000, and not the conditioning regimen, was an important predictor of long-term outcomes. TBI was not associated with more acute toxicity or pneumonitis. We found no indication that the TBI regimen was inferior or superior to BEAM.
To compare in a phase III study the safety and efficacy of fludarabine to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous ...response to systemic treatment.
Patients were randomized to fludarabine (25 mg/m(2) intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m(2) and vincristine 1.2 mg/m(2) both intravenously on day 1 and prednisone 40 mg/m(2) orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument.
Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response CR, 9%) for fludarabine versus 52% (CR, 7%) for CVP (P =.72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P =.03) and TFS (15 months v 11 months; P =.02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P =.95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P =.008); no other differences in QoL were detected.
In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS.
We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with ...melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival, progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.
•Thalidomide and prednisone maintenance after transplantation improves progression-free but not overall survival.
Abstract 4944
DLBCL is the most common form of aggressive non-Hodgkin lymphoma (NHL). Despite its aggressive nature, the majority of patients are diagnosed and managed in an out-patient setting and ...only minority of patients require hospital admission, for symptom control or management of associated co-morbid conditions. The outcomes of patients admitted to hospital with newly diagnosed DLBCL, though presumed to be inferior to patients managed in an outpatient setting, due to advanced disease or poorer performance status is presently unknown. The aims of this study were to identify predictors of treatment location (in-patient vs. out-patient), and assess the survival of patients according to treatment location (in-hospital or out-patient).
Retrospective chart review over 5 years (January 2005 to December 2009) of newly diagnosed patients with DLBCL in Winnipeg, Canada. These patients were treated either in a teaching hospital, at Health Sciences Center, or in the out-patient setting, at CancerCare Manitoba. Clinical predictors of treatment setting were analyzed using multivariable logistic regression. Survival at one and three years was assessed with Kaplan-Meier statistics.
We included140 patients (46 in-patients and 96 outpatients). The mean age of the in-patient population was 68.3 (SD 14.2); while for the out-patient group it was 65.2 (SD 15.3). The in-patient group was comprised of 47.8% female, with the outpatient having 52.1%. Fifty percent of the in-patient group came from a rural residence, while only 28.1% of the out-patient group was from a rural residence. Of the in-patient group 21.7% had a favorable IPI (0-2), compared with 70.8% of the out-patient population.
Of the 46 in-patients, 28 (60.9%) received R-CHOP, compared with 69 (71.9%) from the out-patient group. Four (8.7%) in-patients received an alternate form of chemotherapy (e.g. R-CVP), compared with 18 (18.8%) outpatients. Fourteen (30.4%) in-patients received no chemotherapy, compared with 9 (9.4%) in the out-patient group. Patients with an IPI of 3 or higher at diagnosis were significantly more likely to require hospital admission for initial treatment Odds ratio (OR) = 8.43; (95% CI 2.55–19.30), p-value <0.01. Patients living in rural setting were more likely to be hospitalized compared to those who resided in Winnipeg OR = 2.34; (95% CI 0.86–6.46), p-value = 0.04. Overall survival at one and three year was 50.0% and 38.8% for the in-patient group, compared with 85.3% and 69.3 for the out-patient group (p<0.01). In a subgroup of patients who received R-CHOP, survival for in-patients compared with out-patients was 71.4%% vs. 89.7%% at one year, and 57.7% vs. 76.8% (p=0.03) at three years respectively. Survival of in-patients with a low IPI (0-2) that completed R-CHOP (six cycles) therapy was 100% at one year, compared with 97.7% in the out-patient group (p=0.10). Survival of in-patients with high IPI (≥3) that completed R-CHOP was 68.2% at one year, compared to 66.7% in the out-patient group (p=0.51).
The overall survival of patients with DLBCL that require hospital admission to receive their first cycle of chemotherapy is inferior to patients who can be treated in the out-patient setting. Observed differences in survival may relate to the decreased administration of chemotherapy among in-patients, which may further relate to patient co-morbidity and functional status. Among patients who receive a full course of chemotherapy, the location of treatment initiation does not appear to impact survival. Factors found to be associated with in-patient treatment initiation include high IPI and rural status. Initial in-patient treatment is not a necessarily associated with poor prognosis if a complete course of chemotherapy can be delivered and to better inform prognosis, further studies are needed to predict which patients will ultimately not be able to tolerate a full course of chemotherapy and thus be at high risk for death.
Rubinger:Roche Canada: Consultancy.
Abstract 2899
Multiple myeloma (MM) is recognized as the second most common cancer of the blood. It is a malignant disorder of plasma cells and commonly affects adults past the age of 50. Although ...risk factors have been established, it is currently not possible to assess the individual risk to cancer progression. Moreover, the causes of disease progression from its precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to full-blown MM and its progression to relapsed MM remain elusive. We have performed previous studies on the three-dimensional (3D) nuclear organization of telomeres and found that normal and tumor cells display significant differences in their nuclear organization. These differences were objectively quantified with two software programs, TeloView and TeloScan developed by our group.
We now report on a new double blinded preliminary study with 36 patients, including 20 MM, 12 MGUS and 4 relapsed MM. Using blood- and bone marrow-derived plasma cells from the respective patient groups, we have examined 3D nuclear telomeric profiles of the above patients. Plasma cells from MM, MGUS and relapsed MM exhibit specific 3D telomeric signatures. MM have the highest telomere numbers, followed by MGUS, while relapsed MM presents with the lowest numbers of telomeres and the shortest telomeres. Additional telomere parameters, such as cell cycle distribution profiles (a/c ratio), telomere aggregate numbers, distances from nuclear centre and also exhibited significance (p< 0.001).
Within the MGUS and MM patient groups we studied are patients whose 3D telomeric profiles indicate the beginning of a new signature that resembles signatures of MM and relapsed MM respectively. Blood and bone marrow gave us comparable results opening the future opportunity to base diagnostics and monitoring on blood samples, sparing the patient form invasive bone marrow sampling with potentially adverse effects. Based on our current preliminary data, we propose the following 3D telomeric criteria that define individual signatures of MGUS and MM and progression within each of the groups: telomere numbers, telomere sizes, presence of telomeric aggregates, telomeres per nuclear volume, and a/c ratios. The clinical significance of these findings is the early identification of individuals with high risk of progression. This opens the possibility for better monitoring and early intervention with newer treatments with an acceptable efficacy and low toxicity ratio.
No relevant conflicts of interest to declare.
Acute promyelocytic leukemia (APL) is often curable in adults. However, in 10-20% of patients with initial remission, leukemic relapse occurs. For these patients extended disease free survival is ...possible following stem cell infusion during second complete remission (CR2). The choice between allogeneic and autologous transplantion is dependent on the availability of suitable donors, the presence of minimal residual disease (MRD) and comorbid illnesses. The risks of treatment related mortality (TRM) associated with allografts must be balanced against a possible higher recurrence rate when autografts are used. To compare the utility of allogeneic and autologous transplantation in the arsenic era, we reviewed 294 patients with APL undergoing HCT in CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2006. Outcomes included overall survival (OS), disease free survival (DFS), relapse incidence, and TRM following either allogeneic or autologous HCT. The influence of pre-HCT molecular MRD status on outcome was examined in 114/232 allogeneic grafts and 41/62 autologous grafts. As summarized in Table 1, OS significantly favored autologous transplant, largely related to differences in TRM. Multivariate analysis confirmed that treatment failure was increased with age >40 years (HR=2.30, 95% CI 1.44-3.67, p= 0.0005), and after allogeneic HCT (HR=1.88, 95% CI=1.16-3.06, p=0.011). OS was significantly worse with allogeneic vs. autologous HCT (HR= 2.66, 95%CI 1.52-4.65, p=0.0006; age >40 (HR=3.29, 95% CI 1.95-5.54, p<0.001) and short CR1 (HR=1.56 95% CI 1.07-2.26, p=0.021). Relapse rates (RR) at 5 years were similar after autologous 30% (95% CI 19-42%) vs. allogeneic HCT (18% (95% CI 14-24%); adjusted HR=0.71, 95%CI 0.4-1.28, p=0.26). As expected, TRM in allogeneic was significantly higher at 31% (25-37) compared to autologous 7 % (2-17) with a HR of 7.07(2.56-19.57) P=0.0002. These results are summarized in Table 1. In patients with pre-HCT positive molecular or cytogenetic MRD, the allogeneic group (n=17) had a 5 year relapse rate of 27%, DFS 60%, and OS 65%. Notably, in MRD+ autologous group (n=6), only 1 relapsed at 6 months and died; 5 remain alive and disease-free at 47, 60, 61, 72, and 129 months after HCT. Surprisingly, pre-HCT molecular status did not influence relapse, treatment failure or OS in either group. Although the mechanism is not clear, this observation suggests effective eradication of residual disease in vivo. In this diverse cohort of patients, this retrospective study identifies that autologous transplantation offers superior overall survival when compared to allogeneic transplantation. The finding of long term survival in autologous transplanted patients with MRD+ grafting remains an important subject for further study.
Table 1Outcome of Patients with APL Undergoing HCT in C2OutcomeAutoAlloP-valueOS54%(48-61)75%(68-85)0.02TRM31%(25-37)7%(2-17)<0.0001DFS50%(44-57)63%(49-75)0.10RR18%(14-24)30%(19-42)0.40
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No relevant conflicts of interest to declare.
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