Relapsed Aggressive non-Hodgkin Lymphoma Research Articles

Haploidentical Hematopoietic Stem Cell Transplantation Compared with HLA-Matched Stem Cell Transplantation for Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma

Background: Non-Hodgkin's lymphoma (NHL) is a malignant hematological tumor that accounts for approximately 90% of lymphoma in China. About 2/3 of NHL patients can be treated or even cure, but still about one-third will die from refractory or relapsed disease, especially high-risk patients. In these cases, continued conventional chemotherapy will not benefit, and may even lead to significant chemo-related toxicity and reduce the quality of life. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is an effective treatment for whom with chemoresistent, recurrence after autologous transplantation or without autologous transplantation indication. However, less than 30% of patients can find HLA-matched relative donors. hematopoietic stem cell transplantation (haplo-HSCT) enables more than 90% of patients to find suitable donors in the shortest time, bringing good news to patients without HLA-matched donors.Therefore, we compare the efficacy of haploidentical stem-cell transplantation (haplo-SCT) for patients with refractory relapsed(R/R) aggressive non-Hodgkin lymphoma (NHL) with those who contemporaneously receiving HLA-matched SCT in myeloablative conditioning settings. Methods: One hundred and fifty-one patients who had undergone haplo-SCT (n=81) or HLA-matched SCT (n=70, sibling or unrelated) in our center between January 2006 and December2018 were enrolled. A median age at alloSCT was 30(5-59) years old. All patients received a myeloablative conditioning (MAC) consisting of total body irradiation (12 Gy) combined cyclophosphamide or busulphan plus cyclophosphamide,and followed by infusion of granulocyte-colony stimulating factor-primed bone marrow (G-BM) and/or peripheral blood stem cells without in vitro T cell depletion. In the case of haplo-SCT and HLA-matched unrelated donor for SCT, the GVHD prophylaxis consisted of antithymocyte globulin, cyclosporine A, mycophenolate mofetil and a short course of methotrexate. The clinical effect, hematopoietic reconstitution, and transplant-related complications were retrospective analyzed. Results: One hundred and forty-five (96%) patients engrafted with a median time to neutrophil and platelet recovery of 12 and 15 days, respectively. At a median follow-up of 20 months, 66 of 151 patients were alive (43.7%) and 67 (44.4%) were dead (39 disease recurrence, 27 transplantation-related mortality (TRM)). Between the haplo-SCT and HLA-matched SCT group, the corresponding progress free survival (PFS) rate was 60.5% and 54.3% (P = .938), respectively; and overall survival (OS) rate were 67.9% and 55.7% (P = .460), respectively. The cumulative incidences of relapse (RI) were 36.6% and 37.7% (P = .836), and those of NRM were 20.0 % and 24.7% (P = .530), respectively. And cumulative incidences of chronic GVHD were 33.3% and 30.0%(P=.407), respectively. These data showed no difference in every major HSCT endpoint between two groups. Multivariate analysis suggested that occurrence of grade Ⅲ-Ⅳ aGVHD had a significant worse outcome, primary chemorefractory was the strongest factors for relapse. Conclusion: The haplo-SCT group obtained the OS and PFS similar to HLA-matched SCT. And there is no higher incidence of GVHD observed in haplo group. Our results indicate that the outcomes of haplo-SCT are equivalent to HLA-matched SCT, and that MAC followed by haplo-SCT can be an acceptable and feasible alternative for patients with R/R NHL who having no access to a HLA-matched donor. Figure Disclosures No relevant conflicts of interest to declare.

Clinical Outcomes of Fludarabine and Melphalan With an 800 cGy Total Body Irradiation Conditioning Regimen in Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionAllogeneic hematopoietic stem cell transplant with reduced-intensity conditioning is an effective therapeutic option for patients with refractory or relapsed aggressive non-Hodgkin lymphoma (NHL). Patients and MethodsWe retrospectively evaluated survival outcomes and the efficacy of our fludarabine/melphalan/total body irradiation (TBI) (FMT) regimen. A total of 89 patients had received the FMT regimen from 2007 to 2017. ResultsThe majority of patients (n = 81; 91%) belonged to the histologic subtype of aggressive NHL. The estimated 3-year overall survival and disease-free survival for the entire cohort during a median follow-up of 31 months were 47.1% (95% confidence interval, 36%-57%) and 45.4% (95% confidence interval, 35%-56%), respectively. The cumulative incidence rates of relapse and non-relapse mortality at 3 years were 33.1% and 13.8%, respectively. In analyses of risk factors affecting survival outcomes, chemosensitive disease status at transplant (hazard ratio [HR], 2.45; P = .010), delayed relapse after first-line chemotherapy (HR, 2.101; P = .009), no grade III to IV acute graft-versus-host disease (HR, 11.212; P < .001), and mild chronic graft-versus-host disease (HR, 0.448; P = .016) were independent significant predictors of favorable overall survival. Also, similar parameters were related to favorable disease-free survival. All non-hematologic toxicities occurred within 50 days after allogeneic hematopoietic stem cell transplant, and most of the adverse events were tolerable and manageable with a < 30% incidence. ConclusionOur FMT regimen shows favorable transplant outcomes with relatively low-risk toxicities, so it may be a promising strategy for patients with relapsed or refractory aggressive NHL.

Haploidentical Stem Cell Transplantation after Myeloabaltive Conditioning Is a Valid and Safe Option for Young Patients with Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma: A Study Compared with HLA-Matched Transplant

Purpose: The role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) therapy for refractory or relapsed (R/R) aggressive non-Hodgkin lymphoma (NHL) patients was still unknown. In this study, we aimed to explore the clinical outcome of R/R aggressive NHL patients received haplo-HSCT treatment.Patients and Methods: 23 R/R aggressive NHL patients who had undergone haplo-HSCT in our center between February 2006 and October 2015 were retrospectively analyzed, and 25 R/R aggressive NHL patients who received HLA-matched HSCT at the same period were also involved in this study. All patients received myeloablative conditioning (MAC) regimen, and antithymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. 12 patients had experienced autologous HSCT prior to allo-HSCT.Results: The median age of the total 48 patients was 33 (16-58) years old, and there were 33 males and 15 females in the total cohorts. The diagonosis were as following: 16 (33%) diffuse large B cell lymphoma and 22 (46%) peripheral T cell lymphoma. There were no difference in sex, age at transplantation, histologic diagnosis, aaIPI score, previous ASCT and conditioning regime between HLA-matched HSCT and Haplo-hsct groups. 44 patients had achieved engrafment, and the median times to neutrophil and platelet recovery were 12 and 15 days, respectively. Incidences of grade 3-4 acute GVHD were 18.3% in haplo-HSCT group and 16.7% in HLA-matched HSCT groups(p=0.87), while 2 years cumulative incidences of chronic GVHD in these two groups were 43.5% and 36.7% (P=0.68). For 16 patients who had chemoresistant disease at transplantation in haplo-HSCT group, four patients achieved complete remission, and ten patients achieved partial remission, while the other two patients experienced disease progression at 21 days and 37 days, respectively. With a median follow-up of 25 months, 12 patients experienced disease recurrence or progression in haplo-HSCT. And four patients died of transplantation related mortality: infection (n=2); acute GVHD (n=1) and multi-organ failure (n=1). There were no differences in overall survival (OS) rate at 2 years (52.8% vs 57.0%, P=0.85) and 2 years progress free survival (PFS) rate (52.7% vs 56.9%, p=0.73) between the haplo-SCT and HLA-matched SCT groups. Multivariate analyses suggested that old age (>45 years)(p=0.02), primarychemorefractory (p=0.04)and occurrence of grade3-4 aGVHD (p=0.01) may contribute to poor prognosis.Conclusion: Haploidentical hematopoietic stem cell transplantation withmyeloablative conditioning regimenachieved satisfactory outcome with acceptable side-effects. This approachcan be a feasible and acceptabletherapy for young patients withR/R NHLwho have no access to a HLA-matched donor. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comorbidity at Relapse Is An Independent Predictor for Eligibility and Outcome of Autologous Stem Cell Transplantation in Aggressive Non-Hodgkin Lymphoma.

Abstract 2313Poster Board II-290 BACKGROUND:The ability to receive an autologous stem cell transplant (ASCT) is the main factor determining outcome in patients with refractory or relapsed aggressive non-Hodgkin lymphoma (NHL). Final eligibility for ASCT is mainly dependent on response to salvage therapy. The secondary age-adjusted international prognostic index (saa-IPI) at relapse can predict for response to salvage therapy and outcome after transplantation. In allogeneic settings, comorbidity according to the stem cell transplant comorbidity index (HCT-CI) has shown to be an independent predictor for survival in hematologic malignancies. The aim of the current analysis is to assess the additional prognostic value of comorbidity at time of relapse (R-HCT-CI) for ASCT eligibility and outcome after autologous transplant. PATIENTS AND METHODS:We retrospectively analyzed 156 consecutive patients with refractory or relapsed NHL, referred to our center for salvage chemo-immunotherapy between 1999 and 2007. Patients responding to salvage treatment and able to receive further treatment were considered eligible for subsequent high-dose chemotherapy and ASCT. Comorbidity according to the hematopoietic stem cell transplant comorbidity index (Sorror et al; Blood 2005) was scored twice: i at relapse (R-HCT-CI), before start of salvage re-induction and ii. at start of high-dose chemotherapy (BEAM) before ASCT (HCT-CI). Primary endpoints were receipt of actual transplantation and overall survival (OS). RESULTS:R-HCT-CI scores of 0, 1-2 and ≥3 were found among 64 (41%), 62 (40%) and 30 (19%) patients, respectively at relapse. Comorbidity at transplantation (HCT-CI) did not substantially differ from scores at time of relapse. 108/156 patients achieved at least PR after salvage chemo-immunotherapy. All responsive patients were considered eligible to receive ASCT. Of these responsive patients, 13 did not receive ASCT mainly because of progressive lymphoma just before starting BEAM. Ultimately 95 patients received ASCT. Higher R-HCT-CI scores were associated with significant less chance on receiving ASCT with odds ratios of 2.9 and 4.3 for R-HCT-CI scores of 1-2 and ≥3 respectively (p< .01). However, in multivariate analysis together with saa-IPI scores, comorbidity did not retain significance (p= .08). Comorbidity at relapse could predict for overall survival independent from saa-IPI scores: hazard ratios of 2.5 and 1.7 for R-HCT-CI scores of 1-2 and ≥3 respectively (p= .02). Overall survival rates at 5 years for transplanted patients were 62%, 30% and 17% for R-HCT-CI scores of 0, 1-2 and ≥3 respectively (Figure). CONCLUSION:In patients with relapsed aggressive NHL, comorbidity at relapse can predict for ASCT eligibility and, after transplantation, for subsequent survival independently from saa-IPI. Both indices can therefore contribute to a more accurate selection of patients who may benefit most from intensive salvage treatment and subsequent ASCT. [Display omitted] Overall survival according to Comorbidity score at relapse for patients receiving ASCT. Disclosures:No relevant conflicts of interest to declare.

Equitoxicity of bolus and infusional etoposide: results of a multicenter randomised trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) in elderly patients with refractory or relapsing aggressive non-Hodgkin lymphoma using the CEMP regimen (cisplatinum, etoposide, mitoxantrone and prednisone)

To compare toxicity of etoposide bolus with continuous infusion and to assess the efficacy of the CEMP (cisplatinum, etoposide, mitoxantrone, prednisone) regimen, 47 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma older than 60 years (n=43) or not qualifying for high-dose chemotherapy (n=4) received five four-weekly CEMP cycles. Patients were randomised to start with bolus or continuous-infusion etoposide and then received bolus and infusional etoposide in an alternating fashion. The primary objective was the comparison of differences in the course of leukocytopenia and thrombocytopenia between the two application schedules. CEMP was well tolerated with little organ and moderate haematotoxicity. There was no difference in toxicity between bolus and continuous-infusion etoposide. Complete remission rate was 44% in patients relapsing >or=1 year, 27% in patients relapsing within the first year after achieving complete remission and 5% in primary refractory patients. Median event-free and overall survivals for all patients were 3 and 10 months, respectively. The observed equitoxicity and the more challenging logistics of a 60-h infusion make bolus injection the preferred application of etoposide. As the CEMP regimen is well tolerated and efficacious in elderly patients with relapsed or refractory aggressive non-Hodgkin's lymphoma for whom more aggressive therapies are not feasible, a three-weekly modification of CEMP should be tested in combination with rituximab.

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study

Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

HLA-Matched Related (MRD) or Unrelated Donor (URD) Non-Myeloablative Hematopoietic Cell Transplantation (HCT) for Patients (pts) with Refractory and Relapsed Aggressive Non Hodgkin Lymphoma (NHL).

There are few treatment options for pts with relapsed aggressive T and B cell NHL after failure of auto HCT and subsequent high dose allo HCT has resulted in high rates of non-relapse mortality (NRM). We evaluated utility of allo HCT after non-myeloablative conditioning for these pts to reduce NRM risks while exploiting graft versus tumor (GVT) effects. Between 12/1999 and 2/2004, 42 pts, median age 50 (range, 17–66) years, with refractory or relapsed aggressive NHL [diffuse large B cell (DLBCL) (n=32), T-cell anaplastic large cell (ALCL) (n=4), T-cell lymphoblastic (n=3), T- cell immunoblastic (n=2) and Burkitt's (n=1)] were studied. Median time from dx to allo HCT and number of prior regimens were 40 (range, 7–222) months and 4 (range, 1–6), respectively. Twenty-seven pts (62%) had previous auto HCT: 24 had relapsed while 3 had planned auto HCT for cytoreduction before allo HCT. Median time from auto to allo HCT was 15 (range, 2–29) months. Allo conditioning consisted of 2 Gy TBI alone (n = 3 MRD) or with added fludarabine (90 mg/m2) (n = 39; 26 MRD, 13 URD) followed by mycophenolate mofetil and cyclosporin. PBSC (n = 41) or marrow (n = 1) were infused from MRD (n = 29) or URD (n = 13). At HCT, 18 pts were in complete remission (CR) and 24 had measurable disease [10 partial remission (PR) 14 untreated relapse and refractory]. All pts engrafted (see table). The overall incidences of grades II, III and IV acute GVHD were 33%, 15% and 4%, respectively. 2-year probability of chronic GVHD was 57%. Early death from aspergillosis occurred in 2 pts. Of the 18 pts given HCT in CR, 13 (72%) remained in CR after HCT, while 64% of pts (7/11) who were in PR and 23% of pts (3/13) who had relapsed/refractory disease at HCT, achieved CR. The overall response rate was 46%. Of the 24 pts who had relapsed after auto HCT, 2 died early, 11 (46%) achieved CR and 11 progressed after allo HCT. With a median follow up of 19 (range, 6–50) months, 20 of 42 pts (48%) (12 MRD, 8 URD) were alive: 18 in CR (43%) (10 MRD, 8 URD) and 2 with progressive disease. Twenty two pts died a median of 5 (range, 3–26) months after HCT: 14 from relapse and 8 from non-relapse causes (7/8 from infections + GVHD). Day 100, and 1-year NRM* were 10% and 15%, respectively. One year overall* (OS) and progression free survivals* (PFS), and relapse rates* were 63% (MRD: 62%; URD: 85%), 49% (MRD: 45%; URD: 62%) and 36% (MRD: 34%; URD: 38%), respectively. Allo HCT after non-myeloablative conditioning offers a therapeutic option for pts with relapsed aggressive NHL including those in relapse after auto HCT, especially when the disease can be cytoreduced before HCT.All pts (n=42)MRD (n=29)URD (n=13)Disease status at HCT18 CR, 10 PR, 10 Rel, 4 Ref12 CR, 8 PR, 6 Rel, 3 Ref6 CR, 2 PR, 4 Rel, 1 RefOverall response rate11/24 (46%);(10 CR, 1 PR)8/17 (47%);(7 CR, 1 PR)3/7 (43%); (3 CR)CR at HCT, sustained CR13/18 (72%)8/12 (67%)5/6 (83%)PR at HCT, sustained CR7/11 (64%)5/9 (56%)2/2 (100%)Rel or Ref at HCT, sustained CR3/13 (23%)2/8 (25%)1/5 (20%)Living pts status18 CR, 2 PD10 CR, 2 PD8 CRDay 100 NRM*10%14%0%1 year NRM*15%21%0%1 year OS*63%62%63%1 year PFS*49%45%62%1 year Rel rate*36%34%38%Rel : Relapse; Ref : Refractory;*Cumulative probability

Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin's Lymphoma (NHL): Follow-Up Results of a Phase II Study Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin's Lymphoma (NHL): Follow-Up Results of a Phase II Study.

Sphingosomal vincristine (SV) is a novel formulation of vincristine encapsulated in sphingomyelin liposomes or ‘sphingosomes'. SV was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst. 412, 1999). The addition of rituximab to CHOP improves response in aggressive B-cell lymphomas in the elderly (Coiffier et al., NEJM 2002: 346; 235–42). Based on these data, a phase II study of RCHOP, substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL (excluding rituximab if T-cell lymphoma).Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH Abst. 338, 2002).Results: Of 73 patients enrolled in the study, 68 were evaluable for response. Median age was 63 (range 22–80). IPI score was 0–2 in 44 pts and ≥ 3 in 24 pts. Patients received a median of 6 study treatments (range 1–8). ORR was 93% (63/68 pts) with 62 pts achieving CR and Cru (91%), and 1 PR (2%). 3 pts had PD (4%) and 2 were not assessed for response (3%). The median PFS and OS have not been reached at a median follow up of 29.5 months. Responses according to IPI score were as follows:ResultsIPI 0–2 (n=44)IPI ≥3 (n=24)Total (n=68)ORR93% (41)92% (22)93% (63)−CR77% (34)88% (21)81% (55)−Cru14% (6)4% (1)10 (7)−PR2% (1)0% (0)2% (1)PD5% (2)4% (1)4% (3)Not Assessed2% (1)4% (1)3% (2)The probability of being progression free at 25 months was 86% (5 relapses and 1 death, reason unknown) for pts with IPI 0–2 and 77% (6 relapses) for pts with IPI ≥3. Overall survival probability was 94% at 28 months (1 death in the group with IPI 0–2 and 2 deaths in the group with IPI ≥3). Neuropathy was generally mild (Gr.1–2). Hematological toxicities were as follows: 64% Gr.3–4 neutropenia, 6% Gr.3 anemia, and 14% Gr.3–4 thrombocytopenia.Conclusions: CHOP plus rituximab regimen with sphingosomal vincristine substituted for free vincristine demonstrated promising activity with durable responses similar in both groups of patients with IPI score 0–2 and IPI ≥ 3. The treatment was well tolerated with only mild neurotoxicity.

Ifosfamide, Epirubicin and Etoposide (IEV) Regimen as Salvage and Mobilization Therapy for Refractory or Early Relapsing Patients with Aggressive Non-Hodgkin's Lymphoma

The prognosis of early relapsing or refractory aggressive non-Hodgkin's lymphoma (NHL) is still poor. Effective salvage therapy should be able to induce high response rate as well as to mobilize hematopoietic precursors. A combination of ifosfamide, epirubicin and etoposide (IEV) was given to 28 patients with refractory or relapsing high grade NHL (4 lymphoblastic lymphoma and 24 large cell lymphoma). All patients were evaluated for response. After 2 courses of IEV, the overall and complete response rate were 64% and 39%, respectively. All patients were controlled for mobilization of peripheral blood stem cells, which was successful in 26 out of 28 (93%). Overall, 25 out of 26 patients proceeded to autologous stem cell transplantation (ASCT). Toxicity was mild, with no occurrence of severe persisting extra-hematologic side-effects. Following the entire therapeutic program, including IEV and ASCT, median progression free survival has not yet been reached and 21 patients are alive (18 in continuous complete remission) after a median follow-up of 18 months. Our results demonstrate that treatment with IEV regimen is effective in refractory or relapsing aggressive NHL, resulting in a high percentage of successful stem cell mobilization and feasibility of ASCT.

Sphingosomal vincristine in CHOP is a promising new treatment for elderly, as well as poor prognosis patients with aggressive non-Hodgkin's lymphoma (NHL): Follow-up results of a phase II study

8080 Background: Individuals older than 60 years have a worse prognosis than younger patients with aggressive NHL. Vincristine is active in malignant lymphomas. Sphingosomal vincristine (SV) was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst. 412, 1999). Based on these data, a phase II study of CHOP with or without rituximab, and substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL. Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH abst. 338, 2002). Results: Of 73 patients enrolled on study, 68 were evaluable for response. Median age was 63 (range 22–80), 37 pts (54%) were > 60. Overall, 24 pts (23 elderly) had an IPI score ≥ 3. Patients received a median of 6 study treatments (range 1–8). ORR was 92.6% (63/68 pts) with 55 pts achieving CR (80.1%), 7 CRu (10.3%), and 1 PR (1.5%). 3 pts had PD (4.4%) and 2 wer...

Sphingosomal vincristine in CHOP is a promising new treatment for elderly, as well as poor prognosis patients with aggressive non-Hodgkin's lymphoma (NHL): Follow-up results of a phase II study

8080 Background: Individuals older than 60 years have a worse prognosis than younger patients with aggressive NHL. Vincristine is active in malignant lymphomas. Sphingosomal vincristine (SV) was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst. 412, 1999). Based on these data, a phase II study of CHOP with or without rituximab, and substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL. Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH abst. 338, 2002). Results: Of 73 patients enrolled on study, 68 were evaluable for response. Median age was 63 (range 22–80), 37 pts (54%) were > 60. Overall, 24 pts (23 elderly) had an IPI score ≥ 3. Patients received a median of 6 study treatments (range 1–8). ORR was 92.6% (63/68 pts) with 55 pts achieving CR (80.1%), 7 CRu (10.3%), and 1 PR (1.5%). 3 pts had PD (4.4%) and 2 were not assessed for response (2.9%). ORR was similar in both elderly (>60) and younger pts (≤ 60): 91.9% and 93.5% respectively. The median PFS and OS have not been reached at a median follow up of 22 months. The probability of being progression free at 17 mos was 0.88 (5 relapses) for elderly pts and 0.86 (4 relapses) for pts ≤ 60. Overall survival probability was 0.98 (1 death) at 22 mos. Neuropathy was generally mild (Gr.1-2). Hematological toxicities were as follows: 56% Gr.3-4 neutropenia, 6% Gr.3 anemia, and 13% Gr.3-4 thrombocytopenia. Toxicites were comparable in both elderly and younger patients. Conclusions: CHOP plus rituximab regimen with sphingosomal vincristine substituted for free vincristine is a well tolerated therapy with only mild neurotoxicity. Remarkably, the activity in the elderly is comparable to that in younger patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration INEX

A Literature Review of Single Agent Treatment of Multiply Relapsed Aggressive Non-Hodgkin's Lymphoma

To analyze the available literature describing the treatment of relapsed aggressive non-Hodgkin's lymphoma (NHL) with single-agent chemotherapies, several comprehensive electronic and manual inspections of the literature were performed for the period from 1966 to the present. Each paper was examined to capture the following data: study type; patient demographics and characteristics; study endpoints, including responses, and method used to evaluate response; toxicities, and the power of the study. A wide variety of single-agent protocols continue to be studied, indicating no currently accepted standard therapy in this patient population. Reported response rates varied between 0 and 67%. The majority of trials were small, uncontrolled studies that used widely varying inclusion/exclusion criteria and had limited reporting of histology, response, prior treatments, and other key parameters. We were able to find only four agents, etoposide, vincristine, vinorelbine and possibly rituximab, with sufficient reproducible evidence to suggest greater than 30% activity (CR+PR rate) when given to patients with second or greater relapse of aggressive NHL. Consequently, the usefulness of the agents in these reports remains to be established in larger trials with more detailed reporting. The advantages that would be brought by an active non-myelosuppressive agent for patients having this condition emerge clearly from this review.

Paclitaxel plus topotecan treatment for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma

Used as single agents, paclitaxel and topotecan have demonstrated promising activity in treating patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase II clinical trial to investigate the activity and tolerability of the combination of both drugs. Patients with refractory or relapsed aggressive NHL who had previously been treated with a maximum of two prior chemotherapeutic regimens were given intravenous infusions of paclitaxel 200 mg/m2 over three hours on day one and topotecan 1 mg/m2 over 30 minutes daily from days one to five. All patients received daily subcutaneous injections of filgrastim (granulocyte colony-stimulating factor) 5 microg/kg starting 24 hours after the last dose of chemotherapy until neutrophil recovery. Treatments were repeated every three weeks for a maximum of six courses. Patients who achieved partial remission or complete remission (CR) after at least two courses were offered stem cell transplantation, if eligible. Of the 71 patients eligible for this trial, 66 (93%) were evaluable for treatment response. The median age was 53 years (range 23 to 74 years). Thirty-six percent of the patients had previously been treated with ara-C/platinum-based regimens, and 48% failed to achieve CR after primary induction therapy. Sixty-seven percent of the patients had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall response rate was 48% (95% confidence interval (95% CI): 36%-61%). Patients who had primary refractory disease had a response rate of 31%, compared with 65% for patients who did not. Similarly, the response rate of patients who failed to achieve CR after their most recent previous therapy was 37%, compared with a 65% response rate in patients who relapsed from a first or second CR. The median duration of response was six months. A total of 199 courses were given, with a median of three courses per patient. Neutropenia at levels < or = 500 leukocytes per microliter was observed after 32% of the courses, and thrombocytopenia at levels < or = 20,000 platelets per microliter was observed after 17% of the courses. Grade 3-4 neutropenic fever occurred after 6% of the courses. Non-hematologic toxic effects were predominantly grade 1-2. The combination of paclitaxel and topotecan is an effective first or second line salvage therapy for patients with relapsed or refractory aggressive NHL who had prior anthracycline- or platinum-based chemotherapy.

Dexa-BEAM is not Effective in Patients with Relapsed or Resistant Aggressive High-Grade Non-Hodgkin's Lymphoma

The aim of the present study was to evaluate the feasibility and response of the Dexa-BEAM regimen as a salvage therapy followed by high-dose chemotherapy (HDCT) with peripheral blood stem cell transplantation (PBCST) in responding patients with high-grade relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL). Sixteen pretreated patients (mean age 44, range 26–59) with relapsed (8) or resistant (8) NHL were treated with 1–4 cycles of Dexa-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) in order to attain maximal response. Patients achieving complete response (CR) or partial response (PR) received HDCT with PBSCT. The conditioning regimen used was BEAM. Three patients achieved CR and one patient PR, resulting in an overall response rate of 25%. Three of four responding patients underwent high-dose chemotherapy and were successfully transplanted with autologous blood stem cells. Progressive disease developed in one patient after transplantation.Myelosuppression (WHO III°-IV°), the major side effect, was observed in all courses of Dexa-BEAM. Myelosuppression-related infection WHO IV° occurred in four patients. The protocol was not well tolerated in this heavily pretreated group of patients with four severe myelosuppression-related infections WHO IV° and one treatment-related death. The overall response rate in this study is not comparable to other salvage regimens published and led to the discontinuation of the trial. In conclusion Dexa-BEAM was only effective in a minority of patients with refractory or relapsed aggressive NHL and was not useful as a cytoreductive regimen prior to HDCT.

Combined Results of Two Phase Il Studies of Taxol (Paclitaxel) in Patients with Relapsed or Refractory Lymphomas

This study was performed to determine the clinical activity and safety of paclitaxel in the treatment of patients with refractory or relapsing aggressive Non-Hodgkin's lymphoma (NHL). Between May 3, 1994 and February 16, 1996, 39 patients with refractory or relapsing NHL consented to be enrolled in two, multicenter, open-labelled studies to evaluate the efficacy, safety, time to progression and overall survival of paclitaxel given at a dose of 175mg/m2 by a 3-hour IV infusion every three weeks without G-CSF use. Data from the two studies is combined. One patient, although registered, did not receive treatment. Of the remaining 38 patients, 17 men and 21 women aged 26–82 years (median 60) were given 104 courses of paclitaxel [median 2 (range 1–6)]. Seventeen patients had stage IV, 7 stage III, 8 stage II, 5 stage 1 and 1 unknown stage of disease. Histologic grades included 1 low, 33 intermediate, and 4 high. Three patients had bone marrow involvement. Median time from diagnosis to study entry was 19 months (1–160). The median number of previous chemotherapy regimens was 2 (range 1–6). Three of the 35 (8.6%) patients evaluable for response had partial remission (PR) of their disease for 1–7 months (median 2) and 11/35 (31.4%) stable disease (SD) for 1 to 19 months (median 3). All three responders and 3 of the 11 SD patients had received paclitaxel after relapsing from a CR. At analysis, nine of the 38 patients were alive. Median duration of follow up at analysis was 6 months (3 days - 29 months). The estimated survival rates for all patients at 1 and 2 years are 34% and 27%, respectively (Kaplan-Meier) from the start of paclitaxel treatment. The median survival time was 5.4 months (3 days to 28+ months). Febrile neutropenia occurred in two patients. Seven (18%) patients developed a neutrophil nadir of <0.5 × 109/L and 2 (5%) patients developed a platelet nadir of <50 × 109/L. Six patients received blood transfusions. Non-hematologic toxicity was generally mild to moderate with all patients experiencing some toxicity. Twenty-seven patients experienced grade III toxicity including: alopecia (n=19), pain (n=9), fatigue (n=5), nausedvomiting (n=3), diarrhoea (n=2), pulmonary/shortness of breath (n=2), anorexia (n=l) and fluctuating levels of consciousness and somnolence (n=1). Two patients experienced grade IV toxicity (infection, peripheral neuropathy, pain). No patient discontinued paclitaxel for a severe hyper-sensitivity reaction. In summary, administered as a 3-hour infusion, paclitaxel 175 mg/m2 results in mild myelotoxicity but minimal antitumor activity in patients with refractory NHL.

Peripheral blood stem cell transplantation for relapsed or refractory aggressive lymphoma in patients over 60 years of age

Intensive chemotherapy with autologous bone marrow transplantation is now considered the treatment of choice for young patients with sensitive relapse of non-Hodgkin's lymphoma (NHL) but results of this procedure in older patients remain unknown. We evaluated the feasibility of two cycles of salvage therapy followed by an autologous peripheral blood stem cell (PBSC) transplantation in 13 patients aged more than 60 years (median age: 62; range 61-72) suffering from relapsed (n = 10) or refractory (n = 3) aggressive NHL. All patients had previously received first-line treatment containing doxorubicin. An association of ifosfamide, VP16, cytosine-arabinoside with or without high-dose methotrexate was used as salvage and priming therapy prior to collection of PBSC. All patients received G-CSF following salvage therapy. PBSC collection could be performed in 10 patients and yielded a median number of CFU-GM: 98.4 x 10(4)/kg (range 68-369). Nine patients underwent a transplantation using BEAM conditioning regimen. The median time to granulocyte and platelet recovery was 13 days (range respectively: 9-25 and 9-16). One patient died from sepsis after transplantation. The main adverse experience occurring after transplantation was a prolonged decline of performance status. Seven patients achieved a complete remission and one failed to respond. Three patients are still alive in CR. We conclude that PBSC collection was possible in selected patients over 60 years of age with refractory or relapsed aggressive NHL and myeloablative therapy could be used with tolerable toxicity. Hematologic recovery and organ toxicity appears to be similar to those observed in younger patients. Deterioration of performance status after transplantation is the most important factor that could limit this procedure. Further investigations are necessary to determine which patients will be able to benefit by this procedure in terms of survival and quality of life.