Untreated Aggressive non-Hodgkin's Lymphoma Research Articles

Are the high serum interleukin-6 and vascular endothelial growth factor levels useful prognostic markers in aggressive non-hodgkin lymphoma patients?

Objective:Pro-inflammatory and pro-angiogenic cytokines play an important role in the pathogenesis of lymphoma, and recent studies have shown that cytokines can be used as prognostic markers. Non-Hodgkin lymphoma (NHL) patients with high levels of serum interleukin-6 (s-IL6) and serum vascular endothelial growth factor (s-VEGF) have poor prognosis and shorter survival time. We aimed to determine pre-treatment levels of s-IL6 and s-VEGF and their relation with known prognostic markers, especially International Prognostic Index (IPI) scores, and to examine their effects on overall survival in newly diagnosed, untreated aggressive NHL patients. Materials and Methods:The study included 51 newly diagnosed NHL patients and 17 healthy controls. Blood samples were obtained to study s-IL6 and s-VEGF cytokine levels. Results:Patients with aggressive NHL diagnosis had higher s-VEGF and s-IL6 levels than the healthy population. If the s-IL6 levels of patients were above the cut-off levels, the overall survival time was shorter. There was no relation between s-VEGF and overall survival time. Conclusion:s-IL6 is an independent prognostic factor that may be included in IPI risk classification. In addition to the s-IL6 level, age, erythrocyte sedimentation rate, beta-2 microglobulin, WHO performance status, and IPI score are independent prognostic factors that are effective, especially for overall survival, in the clinical follow-up of NHL patients.

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Phase II Study of Vincristine Sulfate Liposome Injection (Marqibo) and Rituximab for Patients With Relapsed and Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma in Need of Palliative Therapy

VSLI (Marqibo) is active in advanced non-Hodgkin lymphoma (NHL) and untreated aggressive NHL. Because of its favorable hematologic toxicity profile, VSLI might be useful in patients unable to tolerate myelosuppressive therapies. Twenty-two patients with heavily pretreated, advanced CD20(+) DLBCL or MCL were treated with VSLI 2.0 mg/m(2), without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m(2). ORR, complete response (CR), or partial response (PR), was the primary end point. Secondary end points included response duration, time to progression (TTP), and OS. Safety variables included adverse events and neurologic assessments. The ORR was 13 of 22 (59%); 6 patients achieved a CR (27%), and 7 patients achieved a PR (32%). Median response duration, TTP, and OS were 147 days, 121 days, and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. Grade 3 peripheral neuropathy, febrile neutropenia, and constipation were reported in 4, 2, and 1 patients, respectively. VSLI plus rituximab resulted in durable responses in patients with heavily pretreated advanced stage DLBCL and MCL. The toxicity profile was predictable and manageable with limited hematologic toxicity. Despite near-universal previous VCR exposure (96%) and doses of VSLI unachievable with standard VCR treatment, peripheral neuropathy and constipation were modest. This study supports further evaluation of VSLI as a component of DLBCL management.

Gem-(R)CHOP versus (R)CHOP: a randomized phase II study of gemcitabine combined with (R)CHOP in untreated aggressive non-Hodgkin’s lymphoma - EORTC lymphoma group protocol 20021 (EudraCT number 2004-004635-54)

Despite recent improvements, many patients with aggressive non-Hodgkin's lymphoma (NHL) ultimately succumb to their disease. Therefore, improvements in front-line chemotherapy of aggressive NHL are needed. Gemcitabine is active in lymphoma. We performed a randomized phase II trial of the addition of gemcitabine to standard CHOP chemotherapy with or without rituximab [(R)CHOP]. The trial was also designed to determine the maximal tolerated dose (MTD) of gemcitabine in this combination. Patients with previously untreated aggressive NHL were randomized to receive either eight cycles of (R)CHOP given every 3 wk or (R)CHOP combined with gemcitabine [Gem-(R)CHOP]. Twenty-five patients were enrolled in the trial before early closure. Twelve were randomized to Gem-(R)CHOP and 13 to (R)CHOP. MTD of gemcitabine was 800 mg/m(2) given on days 1 and 8; dose-limiting toxicity was hematologic. Five patients (42%) treated with Gem-(R)CHOP achieved complete response in comparison with 10 (77%) treated with (R)CHOP. Median time to treatment failure was 1.5 yr for Gem-(R)CHOP and 3.1 yr for (R)CHOP. Three patients receiving Gem-(R)CHOP had serious pulmonary toxicity, when compared to none receiving (R)CHOP. One patient died of pneumonitis. In this group of patients, addition of gemcitabine did not seem to improve outcomes. Gem-(R)CHOP in previously untreated patients with aggressive NHL occasionally results in severe, potentially fatal, pulmonary toxicity.

Phase I-II Study of Dose Dense PEG-Filgrastim and GM-CSF as Support for Dose Dense CHOP-R Front Line Therapy for Aggressive Non-Hodgkin's Lymphoma (NHL).

AbstractAbstract 2789 Background:Standard front line therapy for large B cell lymphoma is R-CHOP every 21 days. However, a randomized study by Pfreundschuh comparing CHOP every 21 vs. CHOP every 14 days showed an advantage in favor of CHOP-14 (Pfreundschuh et al. Blood 104:626–33, 2004). Growth factor support is necessary in CHOP-14. Preclinical studies have shown that low dose GM-CSF augments the effect of Rituximab by enhancing various effector functions such as ADCC and upregulation of CD 20 antigen expression. We proposed to investigate in a phase I-II study, the standard combination of CHOP-Rituximab plus PEG-Filgrastim (PEG-F, Neulasta..), and a short course of GM-CSF (Leukine..). Rituximab 375 mg/m2 was given on day 1, CHOP on day 2. The phase I portion had shown that PEG-F at 4 mg SC on day 3 combined with a short course (4 doses) of GM-CSF 250 mcg given on days 6, 8, 10 and 13 was capable of supporting recovery from myelosuppression so as to allow repetition of chemotherapy cycles every 14 days (Cabanillas et al. JCO. 25: abstr 18501, 2007). We now report the results of the antitumor activity of this combination, which was designed to generate preliminary pilot data as to the effectiveness in regards to complete response (CR) rate and event free survival (EFS). Methods:We had proposed in the protocol a CR rate of >50%, using the modified IWC criteria which includes FDG-PET scan, as interesting enough to justify a larger study to be planned for the future. As an additional endpoint, EFS at 2 years was also included. Between January 2006 and June 2010, a total of 59 pts of a planned accrual of 60 pts, with previously untreated aggressive NHL have been enrolled. Eligibility criteria included age>18 (no top age limit), stages I-IV NHL, HIV negative. A total of 6 courses of CHOP-R-Peg-F-GM-CSF every 14 days were planned. Results:54 patients (pts) are currently evaluable and 5 too early. Among these patients, histologies were: DLCL-B= 83%, Follicular grade 3= 8%, others 9%. Risk factors were distributed as follows: median age 56 (25-87); 40% were > 60 years, IPI ≥ 3 =30%, Stage III-IV= 54%. Metabolic CR rate (by PET criteria) was 88%. Pts < 60 years of age (y/o) had a CR rate= 91% vs. 82% for ≥ 60 y/o. At a median follow up of 27 months, 3 yr progression free survival (PFS) was 77%, EFS was 74% and 3 yr overall survival (OS) 76%. No pts have relapsed beyond 18 months. Pts < 60 y/o had 3 yr EFS of 77%, while those older than 60 y/o had EFS of 71%, p=0.42. Pts > 60 y/o had an OS at 3 yrs= 65%, while pts < 60 y/o had a OS= 85%, p=0.18. Pts with IPI > 3 had 3 yr PFS= 61% and EFS of 58% as compared with low IPI who had a PFS= 83%, EFS of 81%, p=0.11. Febrile neutropenia occurred in 7 pts and toxic death in 1 pt. Grade 3/4 leukopenias at any cycle were present in 44 pts (grade 3=19, and grade 4=25) and grade 3 anemia in 8 pts. Conclusions:R-CHOP-14-GMCSF-Peg-F achieved a CR of 88% which surpassed the planned primary endpoint which had been set at 50%. In an unplanned subset analysis, for the first time we have noticed the same outcome in pts ≥ 60 and <60 y/o (Fig. 1). This could mean that treatment has erased age as an adverse prognostic factor, possibly suggesting a favorable impact of GM-CSF on pts ≥60 y/o. A randomized trial in this particular age group is justified to test this hypothesis. [Display omitted] Disclosures:Cabanillas:Bayer Pharmaceuticals: Research Funding; Genentech: Research Funding. Off Label Use: Leukine,neutrophil recovery for NHL, and possible augmentation of rituximab effect. Rivera:Genentech: Stocks.

Long-term results of pirarubicin versus doxorubicin in combination chemotherapy for aggressive non-Hodgkin’s lymphoma: single center, 15-year experience

Pirarubicin is an analog of doxorubicin. Few studies have compared the long-term outcomes of patients receiving pirarubicin-based THP-COP and doxorubicin-based CHOP in the treatment of non-Hodgkin's lymphoma (NHL). We retrospectively compared the efficacy and safety of these two regimens in 459 previously untreated aggressive NHL patients admitted to Sun Yat-Sen University Cancer Center from 1987 to 2003. For initial treatment, 205 patients received the THP-COP regimen, and 254 patients received the CHOP regimen. The patients' characteristics were well balanced. The groups did not differ in the complete remission rate (THP-COP, 57.1% vs. CHOP, 57.0%; P = 0.998) or response rate (THP-COP, 82.9% vs. CHOP, 81.5%; P = 0.691). At a median follow-up of 95.7 months, the 8-year survival rates were also similar (overall survival: THP-COP, 55.8% vs. CHOP, 56.7%; progression-free survival: THP-COP, 47.3% vs. CHOP, 43.5%; lymphoma-specific survival: THP-COP, 51.2% vs. CHOP, 48.5%). The THP-COP group had fewer cases of alopecia (P < 0.001) and gastrointestinal toxicities (P = 0.015). A tendency toward decreased arrhythmia (P = 0.075), especially in elderly patients (P = 0.030), was found. In combination chemotherapy for aggressive NHL, pirarubicin has comparable efficacy to doxorubicin and has a lower incidence of alopecia, gastrointestinal toxicities, and arrhythmia. Further studies are warranted to confirm these results.

Cyclophosphamide, Vincristine, Myocet and Prednisone ± Rituximab (COMP±R) Regimen Is Safe and Effective as First Line or Salvage Therapy in Elderly Non Hodgkin Lymphoma (NHL): Preliminary Data of Single Centre Experience.

Abstract 3747Poster Board III-683 Backgrounddespite the prognosis of aggressive non-Hodgkin Lymphoma has considerably improved over the past decades, the treatment of elderly patients with NHL is still a difficult challenge for the clinician.A retrospective EORTC study conducted in patients with aggressive NHL and age above 70 years showed that about half of patients received an aggressive treatment and that only 15% of investigators employed full-dose regimens from the first cycle.We here present the preliminary data of CHOP-like regimen delivered as first-line or salvage therapy to elderly or young patients with NHL and not eligible for more aggressive therapy. Patients and methodsfrom July 2006 to January 2009, 27 pts (M/F:11/16) with a median age of 71 years (range: 53-84) were included in the study.Twenty-four pts (88%) were more than 65 yo, 18 (66%) had high-grade and 9 (34%) an indolent lymphoma. Stage III-IV disease according to Ann Arbor staging occurred in 18 pts (66%) whereas aaIPI, evaluated only for pts with aggressive NHL, was 3 2 in 9 pts (18%). ENS involvement ≥ 1 was present in 11 (41%) and BM involvement in 13 pts (48%). Most of pts (60%) had ECOG PS ≥ 1. Twenty out of 27 pts (74%) received COMP±R as first-line treatment and 7 (26%) as salvage therapy; all but one of pre-treated pts had received more than 1 line of chemotherapy (range 2-4). Twenty-five (92%) pts had co-morbidity with more than 1 disease in 44% of cases. Median LVEF was 59% (range: 35-80%). COMP±R regimen consisted of cyclophosphamide 750 mg/m2 IV d1, vincristine 1.4 mg/m2 IV d1 (capped at 2mg), liposome-encapsulated doxorubicin (MyocetÒ) at the dose of 50 mg/m2 IV d1 and Prednisone 100 mg/die PO d 1-5 with or without Rituximab at dose of 375 mg/m2 d8 at first course and at d1 of subsequent courses according to B or T-cell lymphoma phenotype respectively. To pts with early stage disease were planned 4 courses of COMP±R±IF-RT while those with advanced stage of disease received six courses of chemotherapy delivered every 3 weeks. Median number of cycles delivered was 5.6 (range: 4-8). All patients completed the planned treatment and most of them (92%) received G-CSF at dose of 300 mg/die as primary (67%) or secondary (25%) prophylaxis. ESA support was need in 8 pts (30%). Resultscomplete response (CR) was achieved in 21 (78%) and partial response (PR) in 3 (11%) of pts with an ORR of 89%; three pts had stable (n=2) or progressive disease (n=1). The regimen was safe and well tolerated with dose reduction occurring in 9 pts (34%). None of pts developed cardiac toxicity. The mainly adverse events recorded was neutropenia occurring in 15% of pts and febrile neutropenia in 6 pts (23%). Extra-haematological toxicity was mild (WHO grade 1-2) and recorded in 18% of pts. There was no treatment-related fatal toxicity. With a median follow-up of 15 months (range 6-33) the OS and EFS was 93% and 89% respectively. ConclusionCOMP±R regimen shows to be safe and effective in a group of elderly patients both as first line or salvage therapy. However more patients and longer follow-up is required to assess definitively the role of this regimen in elderly patients with untreated aggressive NHL. A prospective phase II trial is ongoing at our Institution.Tab. 1Response According to HistologyDLBCL (n=12)MZL (n=6)MCL (n=3)PTCL (n=3)FL (n=2)B-CLL (n=1)CR (%)11 (90)4 (66)2 (66)2 (66)2 (100)0PR (%)01 (16)1 (34)1 (34)00ORR %90%821001001000Tab. 2Response According to Status at TreatmentFirst line (n=20)Relapsed (n=7)CR (%)16 (80)5 (71)PR (%)3 (15)0ORR %9571 Disclosures:No relevant conflicts of interest to declare.

High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation (auto-SCT) Versus CHOP Regimen in Patients with Untreated Aggressive Non-Hodgkin's Lymphoma: An Update of the GOELAMS 072 Trial with a Median Follow-up of 9.8 Years

The interest of autologous stem cell transplantation upfront in aggressive non-Hodgkin's lymphomas (NHL) remains controversial. The GOELAMS 072 was a multicenter randomized prospective trial that enrolled untreated aggressive NHL patients. It was designed to compare the interest of high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) to the standard CHOP regimen (8 courses every 21 days). From november 1994 to december 1999, 197 patients were enrolled and randomly assigned to receive either auto-SCT (n= 98) or CHOP regimen (n=99). Because the trial has been initiated in 1994, Rituximab was not included in the therapeutic strategy. According to the aa-IPI index, 80 patients presented at diagnosis with a low intermediate and 105 with a high intermediate risk of death. The final results demonstrated that highdose chemotherapy followed by auto-SCT was superior to CHOP: the 5-year event-free survival estimates (EFS) were 55% versus 37% and the 5-year overall survival (OS) estimates for high intermediate IPI patients were 74% versus 44%, respectively.The results of the GOELAMS 072 trial was published in the NEJM in 2004 (Milpied et al., NEJM). Second line treatment was left at the discretion of the investigators. This study reports an update of the GOELAMS 072 trial with an extended follow-up (FU) period.All of the GOELAMS 072 pts were considered elligible for the purpose of this analysis. The primary endpoints were EFS (defined as progression, relapse or death) and OS). To date, 151 among the 197 patients have been evaluated: 77 patients were initially randomized in CHOP Arm and 74 in auto-SCT Arm. Patients characteristics at diagnosis were similar in both arms. The median FU (calculated from time of diagnosis) was 9.8 years. Fifty six events (72.2 % of the patients) have been reported in CHOP arm compared to 41 (55.4%) in the auto-SCT arm. Three patients experienced a secondary malignancy after auto-SCT compared to 4 patients after CHOP. The 9.8 year EFS and OS estimates for patients assigned to receive CHOP versus those assigned to receive auto-SCT were 45.7% vs 27% (p=0.1) and 55% vs 33% (p=0.068); respectively. Among patients with a high intermediate risk of death, the 9.8 year EFS and OS estimates were 47% vs 22% (p=0.049) and 57 vs 28% (p=0.015), respectively (see figure 1).In conclusion, this long-term analysis (with a median FU of 9.8 years) of the GOELAMS 072 trial confirms that auto-SCT remains superior to CHOP in term of EFS and OS. In note, the advantage of an intensive strategy including auto-SCT is particulary observed for untreated aggressive NHL patients presenting with a high intermediate IPI score. Interstingly, the occurrence of a EFS plateau suggests that a subgroup of patients might be cure by auto-SCT. Because Rituximab has been shown to prolonge OS in aggressive NHL, the interest of high-dose chemotherapy plus Rituximab followed by auto-SCT compared to R-CHOP is still pending. The ongoing GOELAMS 075 prospective trial is addressing this issue. [Display omitted]

A phase II study of liposomal daunorubicin, in combination with cyclophosphamide, vincristine and prednisolone, in elderly patients with previously untreated aggressive non-Hodgkin lymphoma

Liposomal daunorubicin (DaunoXome) was substituted for doxorubicin in the CHOP regimen, aiming to reduce toxicity and maintain or improve efficacy in elderly patients. Eligibility criteria included: age ≥60 years; previously untreated aggressive non-Hodgkin Lymphoma (NHL) and performance status (PS) 0–2. Treatment was cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (maximum 2 mg), and DaunoXome 100 mg/m2 iv on day 1, prednisolone 100 mg po on days 1–5 and G-CSF 5 µg/kg/day sc, for 6–8 cycles. For the 51 patients, median age was 70 years (range 60–88), 94% had diffuse large B-cell lymphoma (DLBCL) and 55% were high-intermediate or high-risk according to the age-adjusted international prognostic index. A mean of 6 cycles was delivered, with dose reductions of DaunoXome in 8.3% of cycles. The combined CR and CRu rate was 65.2%, survival was 566 days and 5-year survival 35%. Three deaths occurred during treatment and may have been related to COP-X. Only 4 (7.8%) of the remaining patients had ≥10% reduction in LVEF. However, 35% of patients were hospitalised during treatment, mostly for febrile neutropenia. The response rate to COP-X was similar to that expected with CHOP, with low cardiac toxicity. The high rate of infectious complications suggests that the DaunoXome dose used may be too high for this patient group. These results support further investigation of this regimen in patients with aggressive NHL.

Pegfilgrastim to support CHOP-14 in elderly patients with non-Hodgkin's lymphoma

This study investigated whether pegfilgrastim support would enable on-schedule delivery of dose-dense cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-14) to elderly patients with non-Hodgkin's lymphoma (NHL). Thirty patients 60 years of age and older with aggressive NHL were evaluated after receiving up to six cycles of CHOP-14 supported with pegfilgrastim. The median age was 68 years (range 61 – 74). Forty-seven per cent of patients received full dose chemotherapy on schedule for all cycles (range 65 – 93). Chemotherapy was delayed in 10 patients and dose reduced in 15 patients. Hematological toxicity was the most common reason for delays and dose reduction. Six of nine patients (67%) achieved a peripheral blood CD34+ count of at least 20 cells×106 L−1 on day 12 of cycle one. The delivery on schedule of dose-dense CHOP-14 to elderly patients with previously untreated aggressive NHL is safe and efficacious with once per cycle pegfilgrastim support.

Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma

The present study aimed to determine the long-term safety and efficacy of chimeric anti-CD 20 antibody rituxan (rituximab, Biogen IDEC, San Diego, CA, USA; Genentech, South San Francisco, CA, USA) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated aggressive B-cell NHL received six infusions of rituximab (375 mg/m2 per dose) on day 1 of each cycle of CHOP chemotherapy, given on day 3 of each cycle of therapy. Currently, the patients now have a median follow-up of 63 months (range 34 – 82 months). The overall response (OR) rate was 94% and the complete response (CR) rate was 61% at the end of therapy. Of the 33 patients, 2 patients experienced disease progression and subsequently died of their disease, 2 patients experienced disease progression but were alive at last follow-up following additional therapy, and 2 patients died without experiencing disease progression: one due to a cerebral vascular accident at 9 months after therapy and a second patient due to small cell lung carcinoma at 55 months. The 5-year survival rate was 88% (95% confidence interval (CI) 72 – 97) and the 5-year progression-free survival was 82% (95% CI 64 – 93). There were no long-term adverse events noted directly related to the rituximab. The long-term follow-up of patients in this phase II trial of rituximab with CHOP chemotherapy for previously untreated aggressive NHL demonstrates a high response rate, which remains very durable with high 5-year overall and progression-free survivals.

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.

Serum-soluble interleukin-2 receptor (sIL-2R) level determines clinical outcome in patients with aggressive non-Hodgkin?s lymphoma: in combination with the International Prognostic Index

The aim of the present study was to assess the prognostic significance of serum soluble interleukin-2 receptor (sIL-2R) in aggressive non-Hodgkin's lymphoma (NHL). One hundred and thirteen consecutive patients with previously untreated aggressive NHL (diffuse large B-cell lymphoma, 96; peripheral T-cell lymphoma, 17) prospectively participated in this study between 1995 and 2001. The patients were treated with 6-8 cycles of a CHOP or THP (pirarubicin)-COP regimen. A high serum sIL-2R level (2,000 U/ml and over) at onset was associated with a low complete remission rate. Patients with high sIL-2R had significantly lower survival rates (5-year, 24%) than those with low sIL-2R (under 2,000 U/ml) (74%) (P<0.01). Multivariate analysis employing sIL-2R levels and conventional prognostic factors demonstrated that high sIL-2R, presence of B-symptoms, and advanced age (60 years and older) were significantly unfavorable variables for overall survival. In addition, we attempted to use sIL-2R in combination with the International Prognostic Index (IPI). The patients in the high (H) risk group and those with high sIL-2R in the low-intermediate (LI)/high-intermediate (HI) risk group had significantly lower survival rates than the patients in the low (L) risk group and those with low sIL-2R in the LI/HI risk group (P<0.001). The results suggest that a high serum sIL-2R level predicts a poor prognosis in aggressive NHL and may be a useful biomarker for selecting appropriate treatment when used in combination with the IPI.

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

Long-term results of a multicentre randomised, comparative phase III trial of CHOP versus CNOP regimens in patients with intermediate-and high-grade non-Hodgkin's lymphomas

59 previously untreated patients with intermediate- or high-grade, stage II–IV non-Hodgkin's lymphoma (NHL) were entered into an open-label, randomised, multicentre study to compare the efficacy and safety of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) with that of CNOP (cyclophosphamide, mitoxantrone, vincristine and prednisolone). 10 patients refused treatment following randomisation. The remaining 349 patients received either the CHOP or CNOP regimen every 3 weeks for a maximum of six to eight cycles. The randomisation procedure was violated for 34 patients treated at two study centres. Data from these 34 patients were analysed separately for efficacy and survival. Data from the remaining 325 patients, 164 assigned to CHOP and 161 to CNOP, were used in the major efficacy and survival analyses. Of these 325 patients, 263 (81%) met the eligibility criteria of the protocol. Supplementary analyses of data from these 263 patients, 132 assigned to CHOP and 131 to CNOP, were conducted for efficacy and survival. Data from all 349 treated patients were analysed for safety. In the 325 randomised patients, the overall objective response rate was not significantly different between the two groups (χ 2 test, P = 0.35). The CHOP regimen had a 51% ( 83 164 ) complete remission (CR) rate compared with 40% ( 64 161 ) for the CNOP regimen ( P = 0.05). Among those with CR, the median time to response was 104 days with the CHOP regimen and 77 days with the CNOP regimen, and the median duration of CR was 667 and 1833 days, respectively. The median time to progression was 449 days for CHOP patients and 564 days for CNOP patients. The median survival time was 932 days for CHOP patients and 1801 days for CNOP patients, with a risk of death on CNOP relative to CHOP of 0.93 (95% confidence interval 0.68–1.27). After 5 years, 50% of patients in the CNOP arm and 40% of patients in the CHOP arm were still alive; these differences between treatment groups were not statistically significant. The median time to treatment failure (TTF) was 285 days for patients on the CHOP arm and 282 days for patients on the CNOP arm. Separate analyses of 263 eligible randomised patients, and 34 patients in whom the randomisation procedure was not followed, yielded similar results for remission rate, TTF, duration of CR and estimated overall survival. The incidence of non-haematological events, such as severe nausea and vomiting ( P < 0.01), mucositis ( P < 0.05) and alopecia ( P < 0.001), were significantly lower in patients treated with CNOP as compared with those who received the CHOP regimen. The incidence of cardiovascular toxicity of any severity was similar in the two groups. While severe and potentially life-threatening neutropenia occurred more frequently in patients treated with CNOP compared with CHOP (0.05 > P > 0.10), the incidence of infection of any severity was similar in both arms. We conclude that CHOP and CNOP regimens were both efficacious in patients with previously untreated aggressive NHL.