Baseline International Prognostic Index Research Articles

Ibrutinib as part of risk-stratified treatment for posttransplant lymphoproliferative disorder: the phase 2 TIDaL trial

AbstractPosttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as # ISRCTN32667607.

Risk Stratification for Diffuse Large B-Cell Lymphoma by Integrating Interim Evaluation and International Prognostic Index: A Multicenter Retrospective Study.

The baseline International Prognostic Index (IPI) is not sufficient for the initial risk stratification of patients with diffuse large B-cell lymphoma (DLBCL) treated with R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The aims of this study were to evaluate the prognostic relevance of early risk stratification in DLBCL and develop a new stratification system that combines an interim evaluation and IPI. This multicenter retrospective study enrolled 314 newly diagnosed DLBCL patients with baseline and interim evaluations. All patients were treated with R-CHOP or R-CHOP-like regimens as the first-line therapy. Survival differences were evaluated for different risk stratification systems including the IPI, interim evaluation, and the combined system. When stratified by IPI, the high-intermediate and high-risk groups presented overlapping survival curves with no significant differences, and the high-risk group still had >50% of 3-year overall survival (OS). The interim evaluation can also stratify patients into three groups, as 3-year OS and progression-free survival (PFS) rates in patients with stable disease (SD) and progressive disease (PD) were not significantly different. The SD and PD patients had significantly lower 3-year OS and PFS rates than complete remission and partial response patients, but the percentage of these patients was only ~10%. The IPI and interim evaluation combined risk stratification system separated the patients into low-, intermediate-, high-, and very high-risk groups. The 3-year OS rates were 96.4%, 86.7%, 46.4%, and 40%, while the 3-year PFS rates were 87.1%, 71.5%, 42.5%, and 7.2%. The OS comparison between the high-risk group and very high-risk group was marginally significant, and OS and PFS comparisons between any other two groups were significantly different. This combined risk stratification system could be a useful tool for the prognostic prediction of DLBCL patients.

Early risk stratification for diffuse large B-cell lymphoma integrating interim Deauville score and International Prognostic Index.

The aim of this study was to evaluate the prognostic relevance of early risk stratification in diffuse large B-cell lymphoma (DLBCL) using interim Deauville score on positron emission tomography-computed tomography (PET-CT) scan and baseline International Prognostic Index (IPI). This retrospective study included 220 patients (median age, 64 years; men, 60%) diagnosed with DLBCL between 2007 and 2016 at our institution, treated with rituximab-based chemotherapy. Interim PET-CT was performed after three cycles of immuno-chemotherapy. Interim Deauville score was assessed as 4 or 5 in 49 patients (22.3%), and 94 patients (42.7%) had high-intermediate or high-risk IPI scores. In multivariate analysis, interim Deauville score (1-3 and 4-5) and baseline IPI (low/low-intermediate and high-intermediate/high) were independently associated with progression-free survival (for Deauville score, hazard ratio [HR], 1.00 vs. 2.96 [95% confidence interval (CI), 1.83-4.78], P < 0.001; for IPI, HR, 1.00 vs. 4.84 [95% CI, 2.84-8.24], P < 0.001). We stratified patients into three groups: low-risk (interim Deauville scores 1-3 and low/low-intermediate IPI), intermediate-risk (Deauville scores 1-3 with high-intermediate/high IPI or Deauville scores 4-5 with low/low-intermediate IPI), and high-risk (Deauville scores 4-5 and high-intermediate/high IPI). This early risk stratification showed a strong association with progression-free survival (HR, 1.00 vs. 3.98 [95% CI 2.10-7.54] vs. 13.97 [95% CI 7.02-27.83], P < 0.001). Early risk stratification using interim Deauville score and baseline IPI predicts the risk of disease progression or death in patients with DLBCL. Our results provide guidance with interim PET-driven treatment intensification strategies.

PF296 UPDATE OF THE SINGLE‐ARM PHASE II L‐MIND STUDY OF MOR208 PLUS LENALIDOMIDE IN RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA: HIGH OVERALL RESPONSE RATES IN PATIENT SUBGROUPS WITH POOR PROGNOSIS

Please indicate where the abstract has been published before: 2018 ASH abstract was published in Blood 2018 132:227; doi: https://doi.org/10.1182/blood‐2018–99–113399Background:The CD19 antigen is broadly and homogeneously expressed across different B‐cell malignancies, including relapsed/refractory diffuse large B‐cell lymphoma (R‐R DLBCL). MOR208, an Fc‐enhanced, humanized, anti‐CD19 monoclonal antibody has shown single agent activity in patients (pts) with R‐R DLBCL and encouraging activity when combined with lenalidomide (LEN) in the single‐arm phase II L‐MIND study. Here we report updated data for the primary endpoint and patient subgroup analyses (data cutoff of June 5, 2018).Aims:To assess the efficacy and safety of MOR208 combined with LEN in pts with R‐R DLBCL.Methods:Key inclusion criteria were adequate organ function, ≤3 prior lines of therapy, including ≥1 anti‐CD20 therapy, and ineligibility for stem cell transplantation. Treatment comprised up to 12, 28‐day (d) cycles (C) of MOR208, 12 mg/kg IV, weekly C1–3 (loading dose on d4 of C1), and every two weeks C4–12 plus LEN 25 mg PO d1–21, C1–12. Pts progression‐free after 12 C received MOR208 every two weeks until progression. The primary endpoint was independent review committee (IRC)‐assessed overall response rate (ORR) as per Cheson 2007 criteria. Secondary endpoints included investigator (INV)‐assessed ORR, duration of response, progression‐free survival (PFS) and overall survival (OS), safety, and analysis of outcomes according to cell of origin.Results:Recruitment is complete with 81 pts enrolled and analyzed for safety and efficacy. Median age was 72 years (range 41–87), 41 (51%) pts had received ≥2 prior lines of therapy (median 2, range 1–4), 19 (23%) pts had early relapse (≤12 months from initial diagnosis), 32 (40%) pts were rituximab refractory (no response to or progression during or within 6 months of a prior rituximab therapy), 34 (42%) pts were refractory to their last therapy, 21 (26%) pts had non‐germinal center B cell‐like (GCB)‐DLBCL and 40 (49%) had GCB‐DLBCL, and 42 (52%) pts had an International Prognostic Index (IPI) of 3–5. MOR208 plus LEN therapy was well tolerated, and 58 (72%) of pts stayed on a LEN dose of ≥20 mg/day. Treatment‐related serious adverse events consisted of infections (10%) and neutropenic fever (5%). No infusion‐related reactions were reported. Investigator (INV)‐assessed complete response (CR) and partial response rates were 33% and 25%, respectively, giving an ORR of 58%. IRC‐assessed ORR and CR rates were 54% and 32%, respectively. INV‐assessed ORR was 70% in pts with 1 prior therapy, 46% in pts with ≥2 prior therapies, 59% in rituximab‐refractory pts, 56% in last treatment‐refractory pts, 58% in early relapse pts, 57% in pts with a baseline IPI of 3–5, and 71% in pts with non‐GCB‐DLBCL and 53% in pts with GCB‐DLBCL, respectively. At a median follow‐up of 12 months, the INV‐assessed median PFS and OS (intention‐to‐treat analysis) were 16.2 months (95% CI: 6.3 months–NR) and not reached (95% CI: 18.6 months–NR), respectively.Summary/Conclusion:The combination of MOR208 and LEN has shown encouraging activity including a durable PFS in elderly pts with R‐R DLBCL. High activity and long lasting responses were also reported in patient subgroups with poor prognosis, who urgently need effective therapies.

Update of the single-arm phase II L-MIND study of MOR208 + lenalidomide (LEN) in relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL): Response rates in patient subgroups with poor prognosis.

7521 Background: MOR208, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody has shown single agent activity in patients (pts) with R-R DLBCL and encouraging activity when combined with LEN in the phase II L-MIND study. Here we report an update with primary endpoint and subgroup analyses (cut off June 5, 2018). Methods: Key inclusion criteria were adequate organ function, ≤3 prior lines of therapy, including ≥1 anti-CD20 therapy, and ineligibility for stem cell transplantation. Treatment comprised up to 12, 28-day (d) cycles (C) of MOR208, 12 mg/kg IV, q1w C1–3 (loading dose on d4 of C1), and q2w C4–12 + LEN 25 mg PO d1–21, C1–12. Pts progression-free after 12 C received MOR208 q2w until progression. The primary endpoint was independent review committee (IRC)-assessed ORR as per Cheson 2007 criteria. Results: Recruitment is complete (N = 81): median age 72 years (range 41–87), median of 2 prior therapies, 19 (23%) of pts had early relapse (≤12 months [mo] from diagnosis), 32 (40%) were rituximab (RTX) refractory (no response to or progression during or within 6 mo of a prior RTX therapy), 34 (42%) were refractory to their last therapy, 21/40 (26%/49%) pts had non-germinal center B cell-like (GCB)- / GCB-DLBCL, and 42 (52%) had an International Prognostic Index (IPI) of 3–5. MOR208 + LEN therapy was well tolerated; 72% of pts stayed on a LEN dose of ≥20 mg/day. Treatment-related serious adverse events, mainly infections (10%) or neutropenic fever (5%), occurred in 17% of pts. Investigator (INV)-assessed complete response (CR) and partial response rates were 33% and 25%, respectively, giving an ORR of 58%, comparable to the IRC assessment (ORR 54%; CR 32%). ORR was 46% in pts with ≥2 prior therapies, 59%/56% in rituximab- / last treatment-refractory pts, 58% in early relapse pts, 57% in pts with a baseline IPI of 3–5, and 71% in pts with non-GCB- vs 53% with GCB-DLBCL. INV-assessed median PFS and OS (ITT analysis) were 16.2 mo (95% CI: 6.3–NR) and not reached (95% CI: 18.6–NR), respectively. Conclusions: MOR208 + LEN shows encouraging activity including a durable PFS in R-R DLBCL, and in pt subgroups with poor prognosis. Clinical trial information: NCT02399085.

Risk Stratification Integrating Deauville Score on Interim PET-CT Scan and Baseline International Prognostic Index in Diffuse Large B-Cell Lymphoma Patients

BackgroundInterim 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan may predict outcomes in patients with diffuse large B-cell lymphoma (DLBCL). However, overall accuracy in predicting treatment outcomes on adopting 5-point Deauville score (DS) was considerably low in DLBCL because of mainly low positive predictive value of interim PET-CT scans. This suggested that additional tool might be needed to more accurately predict treatment outcomes. International prognostic index (IPI) was greatly associated with outcomes for DLBCL and considered to reflect biologic aggressiveness of DLBCL. Thus, we hypothesized that combined assessments using DS on interim PET-CT scan and baseline IPI might improve the prediction of treatment outcomes in DLBCL patients. In this study, we aimed to establish the risk predicting model integrating DS on interim PET-CT as an estimate of early metabolic response and baseline IPI as a predictor of biologic aggressiveness in patients with newly diagnosed DLBCL.MethodsIn this retrospective cohort study, we consecutively enrolled patients with newly diagnosed DLBCL. Patients were eligible if they were histologically confirmed with DLBCL from Jan 2007 to June 2016, received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), and had PET-CT scan data at baseline and at interim after 3 cycles of R-CHOP. Primary CNS or transformed DLBCLs were excluded. Interim PET-CT was assessed using 5-point DS and four point or higher was regarded as positive. All PET-CT scans were assessed by 2 experienced nuclear medicine physicians, who were masked to treatment outcomes of the patients. Discrepant interpretations between 2 nuclear medicine physicians were resolved by consensus through mutual discussion.ResultsA total of 316 patients were screened for eligibility. Ninety-six patients were excluded from the analysis due to following reasons: unavailable baseline (n=9) or interim PET-CT scans (n=48), early death before interim PET-CT (n=16), Primary CNS or transformed DLBCLs (n=15), and insufficient medical records (n=8). Thus, 220 patients were analyzed. Median age was 64 years (range, 19-87) and 132 (60%) were male. Based on the IPI risk, patients were classified as the low or low-intermediate (LI; N=126, 57%), and high-intermediate (HI) or high (N=94, 43%) groups. Interim DS was determined as 1 (n=67, 30.5%), 2 (n=65, 29.5%), 3 (n=39, 17.7%), 4 (n=36, 16.4%), and 5 (n=13, 5.9%).With a median follow-up of 56.6 months (IQR 36.0-71.8), 5-year progression-free survival (PFS) rate was 65.2% (95% CI, 58.1-72.3) and overall survival (OS) rate was 69.9% (95% CI, 63.2-76.6). Interim DS (1-3 vs 4-5) and the IPI (low-LI vs HI-high) were independently associated with PFS (for interim DS of 4-5, hazard ratio [HR], 2.96 [95% CI, 1.83-4.78], P < 0.001; for HI-high IPI, HR, 4.84 [2.84-8.24], P < 0.001) and OS (for interim DS of 4-5, HR, 2.98 [1.79-4.98], P < 0.001; for HI-high IPI, HR, 5.75 [3.14-10.51], P < 0.001) in the multivariate analysis. We stratified patients into 3 groups based on the risk of progression: Low (low-LI IPI and interim DS 1-3), Intermediate (low-LI IPI with interim DS 4-5, or HI-high IPI with interim DS 1-3), and High (HI-high IPI and interim DS 4-5) risk groups. The risk stratification model showed a significant association with PFS (for low risk vs intermediate risk, HR 3.98 [95% CI, 2.10-7.54], P<0.001; for low risk vs high risk, HR 13.97 [7.02-27.83], P<0.001; Fig 1A) and OS (for low risk vs intermediate risk, HR 4.14 [2.01-8.54], P<0.001; for low risk vs high risk, HR 16.05 [7.59-33.94], P<0.001; Fig 1B).ConclusionCombining interim DS with baseline IPI can improve risk stratification in patients with newly diagnosed DLBCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Interim PET Evaluation By Deauville Criteria Is an Effective Risk Stratification Tool in PTCL

Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive non-Hodgkin lymphomas. The most commonly used initial treatment is CHOP-based chemotherapy often followed by consolidation with an autologous transplant. 18-fluorodeoxyglucose positron emission tomography (PET) imaging is often used to evaluate response to therapy. While the international prognostic index (IPI) and Prognostic Index for T-cell Lymphoma (PIT) can help risk stratify patients, little data exists regarding the use of interim PET using the 5-point Deauville criteria in PTCL.Methods: We retrospectively identified patients with PTCL-not otherwise specified (PTCL-NOS),angioimmunoblastic T-cell lymphoma (AITL), andAlk-negative anaplastic large cell lymphoma (ALK- ALCL) in the Memorial Sloan Kettering Cancer Center (MSKCC) database who were initially treated with CHOP based therapy and had PET imaging between 2001 and 2015 and had at least 6 months follow up, or an event of progression or death. Baseline, interim and end of treatment PET scans werere-read for this study using the Deauville score. Data regarding disease characteristics, relapse and survival status were collected. Event free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier method, and compared by the log rank test.Results: 112 patients were identified with PTCL-NOS (n=40), AITL (n=49),ALK- ALCL (n=23) in the MSKCC database. Of these, 99 patients had interim PET images for review and 90 had PET images following cycle 6. The median estimated OS and EFS for the series was 93 months and 35 months respectively with a median follow up of 45 months. When evaluated by the Deauville criteria, patients with an interim PET with a score of 1-3 (n=83) had a median OS and EFS of 104 months and 64 months compared to those with a score of 4-5 (n=16) who had a median OS and EFS of 19 and 11 months (p<0.001).In this cohort, patients with baseline PIT score²1 (n=61) had a median EFS of 64 months compared to those with a score of >1 (n=51) who had a median EFS 24 months (p=0.019). Interim Deauville score more accurately identified patients at risk for poor outcome compared to baseline PIT score alone (p<0.001). (Figure 1A and 1B)In this cohort, patients with baseline IPI score²3 (n=90) had a median OS and EFS of 104 and 38 months compared to those with a score of >3 (n=22) who had a median OS and EFS of 51 and 13 months (p<0.05). Furthermore, interim Deauville further risk stratified patients compared to baseline IPI (p<0.001).Conclusion: Interim PET when evaluated by the 5-point Deauville criteria carries prognostic value in PTCL. In this cohort, interim PET more accurately identified patients at risk of poor outcome compared to baseline IPI and PIT. [Display omitted] [Display omitted] DisclosuresMoskowitz:BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Huya: Consultancy; ADCT Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy; Infinity: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding.

Limited role for surveillance PET–CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy

Background:The usefulness of positron emission tomography with computed tomography (PET–CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied.Methods:We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET–CT after achieving complete metabolic response (CMR) following primary therapy.Results:Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8–133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI⩾3. Including indeterminate scans, PET–CT retained high sensitivity 95% and specificity 97% for relapse.Conclusion:Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ⩾3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

CHOP-R + Bortezomib as Initial Therapy for Mantle Cell Lymphoma (MCL).

Abstract 2682Poster Board II-658 BACKGROUND:Bortezomib is a proteasome inhibitor with single agent activity in mantle cell lymphoma. Preclinical studies have demonstrated that addition of bortezomib to chemoimmunotherapy can enhance antitumor effects. We report findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab (R) in previously untreated MCL patients. METHODS:From 6/2004 to 10/2007, 36 patients with previously untreated MCL received standard CHOP-21 with rituximab (375 mg/m2 per cycle) plus bortezomib at 1.0 mg/m2 (n=4) or 1.3 mg/m2 (n=32) on days 1 and 4 of each cycle for a total of 6 cycles. Study endpoints included safety and efficacy assessment. RESULTS:At study entry, median age (n=36) was 66 years (range 45–80), and M:F ratio was 5:1. Thirty-four subjects (94%) had stage III/IV disease, and 18 (50%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores (42% with IPI of 2, and 47% with IPI of 3–5), as well as MIPI scores (28% with intermediate risk and 39% with high risk). Treatment was generally well tolerated. Peripheral neuropathy (sometimes reversible) occurred in 20 subjects (56%) with 16 grade 1, 3 grade 2, and 1 grade 3. Grade 3/4 cytopenias included anemia (11%), neutropenia (23%) and thrombocytopenia (14%). At a median followup of 30 months (range 8–61 months), 32 patients are evaluable for efficacy. For all patients (n=36), the intent-to-treat (ITT) overall response rate (ORR) is 81% with 64% CR/CRu. For evaluable patients (n=32), the ORR is 91%, and CR/CRu 72%. The median progression free survival for all patients (n=36) is 21 months (95% CI 17-29) by Kaplan-Meier estimate, and 2 year overall survival is 86% (95% CI 69–94%). Currently eight patients remain in ongoing response (range 15–39 months). In a univariate Cox regression analysis, IPI correlated with PFS (HR 1.85, p=0.023), while MIPI correlated with both PFS (HR 1.81, p=0.027) and OS (HR 2.6, p=0.033). CONCLUSIONS:Bortezomib in conjunction with R-CHOP-21 can be safely administered in an outpatient regimen to previously untreated MCL patients, including the elderly. Further evaluation of combinations of bortezomib with R-CHOP is warranted. Disclosures:Vose:Genentech, Inc.: Consultancy, Research Funding. Coleman:Millenium: Speakers Bureau. Leonard:Millenium: Consultancy, Honoraria; Johnson & Johnson: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Biogen Idec: Consultancy, Honoraria.

A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma

BackgroundProtein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Patients and methodsPatients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. ResultsSixty patients, median age 66 years (range 45–85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3–5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median=2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for ≥3 cycles (one cycle=28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. ConclusionFreedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.

CHOP-R + bortezomib as initial therapy for diffuse large B-cell lymphoma (DLBCL)

8031 Background: Bortezomib is a proteasome inhibitor with anti-tumor activity in B cell malignancies. These effects, which may relate to NF-kappaB associated pathways, could sensitize tumor cells to standard chemotherapy-based regimens and enhance efficacy. We report findings of a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL patients (accrual of the MCL cohort of this study remains ongoing). Methods: Patients with previously untreated DLBCL (n=40) received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n=8) or 1.3 mg/m2 (Arm 2, n=28 including phase I and all phase II) on days 1 and 4 of each cycle Results: Median age (n=40) was 58 years (range 21–86), thirty-five subjects (88%) had stage III/IV disease at study entry, and 29 (73%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 16 subjects (40%) and 3–5 in 19 subjects (48%). Median follow-up is 21 months (range 9 - 35 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 22 subjects (55%), with 45% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity included thrombocytopenia (15%) and leukopenia (15%). Four subjects (3 over age 75 and all with high risk IPI) died prior to first response assessment. Intent to treat (ITT) overall response rate (n=40) is 90% with 68% CR/CRu. For the evaluable subset (n=36), ORR was 100% with CR/CRu 75%. Kaplan-Meier estimate (n=40) of 2-year progression-free survival is 72%. Of all 19 enrolled (ITT) patients in the high-intermediate or high-risk IPI groups, 14 (74%) were alive without progression at last assessment. Correlation of outcome with cell of origin type (activated B cell vs germinal center) is ongoing. Conclusions: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Efficacy findings with this combination regimen in newly-diagnosed DLBCL are encouraging and warrant further study. No significant financial relationships to disclose.

Results of a Phase II Study of Pixantrone in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin's Lymphoma.

Background: Pixantrone is a novel aza-anthracenedione with less cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in murine leukemia and lymphoma tumor models. Pixantrone as single agent therapy led to major responses in patients (pts) with multiply relapsed aggressive non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLCL). In a phase I dose-ranging study of pixantrone (80 to 180 mg/m2) replacing doxorubicin (CPOP) in a CHOP-like regimen, the optimal dose (RD) from that study was found to be 150 mg/m2.Methods: In this international, multi-center, phase II study the primary objective was to assess the efficacy and safety of the CPOP regimen (cyclophosphamide 750 mg/m2d1, pixantrone 150 mg/m2d1, vincristine 1.4 mg/m2 d1, limited to 2 mg, and prednisone 100mg d1 to 5) in pts with relapsed DLCL, transformed follicular lymphoma (tFL) and mantle cell lymphoma (MCL) for a total of 6 cycles, given every 3 weeks. Response was assessed according to the standardized response criteria for NHL. Hematopoietic growth factors were not permitted for the first cycle and were used thereafter according to the ASCO guidelines. Main eligibility criteria included at least one but not more than two previous chemotherapy lines containing an anthracycline/anthracenedione with a cumulative dose of less than 450 mg/m2doxorubicin equivalent, a left ventricular ejection fraction (LVEF) > 50%, absence of CNS lymphoma, and negative HIV serology.Results: Thirty pts were included in this phase II study and are available for efficacy and safety assessment. Main baseline characteristics were: median age, 66 y (range 26–76); median baseline International Prognostic Index (IPI), 2 (11/30 pts had IPI 3 or 4); median number of previous therapy lines, 2 (1–7); median time since last chemotherapy, 14 months (1–202). Median number of cycles of study drug received was 6 (1–6). The overall response rate (ORR) was 73%, with 14 (47%) pts achieving complete response (CR/CRu) and 8 (26%) pts with partial responses (PR). For responses lasting at least 8 weeks (63%), the median duration of response was 10.3 months (range 2.5 to 27). The most common severe toxicities were gr 3/4 neutropenia, 29 (97%) pts; gr 3 febrile neutropenia, 6 (20%); gr 3 anemia, 9 (30%); gr 3/4 thrombocytopenia, 6 (20%); gr 3/4 infections, 5 (17%). Four pts had a decrease in LVEF >10% and ≤20% as determined by MUGA-scan. One of these patients developed symptomatic right heart failure classified by the investigator as related to progressive NHL. Two pts experienced transient LVEF decline > 20% during long-term follow up.Conclusions: The CPOP combination therapy with 150 mg/m2 pixantrone results in a high ORR (73%) with 47% CRs. Furthermore, it exhibits an acceptable toxicity profile and can be administered safely in an outpatient setting even in this cohort of elderly, anthracycline-pretreated patients. Based on these results, a randomized Phase II study comparing CPOP-rituximab with CHOP-rituximab in patients with untreated diffuse large-B-cell NHL has been initiated.

Phase I/II Trial of Bortezomib + CHOP-Rituximab in Diffuse Large B Cell (DLBCL) and Mantle Cell Lymphoma (MCL): Phase I Results.

BACKGROUND: Bortezomib (PS-341, VelcadeR) is a proteasome inhibitor with anti-tumor activity in B cell malignancies including MCL. These effects, which in part may be mediated via NF-kappaB pathways, could sensitize tumor cells to standard chemotherapy-based treatment regimens and enhance efficacy. We report phase I findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL and MCL patients.METHODS: Thirty-five patients have been enrolled and initiated treatment, with the first 20 subjects comprising the phase I group. Patients received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n= 9) or 1.3 mg/m2 (Arm 2, n=7 in phase I, then all subsequent patients in phase II) on days 1,4 of each cycle. Phase 1 dose assignments were conducted according to the continual reassessment method as patients entered the study.RESULTS: Phase I included 16 DLBCL and 4 MCL patients. Median age was 65 years (range 29–84) and all patients were treatment-naïve except for 1 MCL subject who had received prior local radiotherapy. Fourteen subjects (70%) had stage IV disease at study entry, and 11 (55%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 7 subjects (35%) and 3 or 4 in 10 subjects (50%). Median followup of the phase I cohort is 9 months (range 5 – 18 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 15 subjects (75%), with 65% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity (platelets and/or white blood cells) was observed in 7 subjects (35%). Three subjects did not complete therapy (1 withdrawal by patient request with subsequent death, 1 due to dose-limiting pulmonary toxicity and 1 with concurrent lyme meningitis). Intent to treat overall response rate (n=20) is 95% with 80% CR/CRu and 80% of subjects currently alive without progression.CONCLUSIONS: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Further safety and efficacy analyses, as well as molecular correlative studies, are ongoing with both the phase I and II cohorts. Preliminary findings with the combination regimen in this adverse prognosis group of patients are encouraging.