non-Hodgkin Mantle Cell Lymphoma Research Articles

Tositumomab and Iodine I 131 Tositumomab (The BEXXAR® Therapeutic Regimen) Produced Ongoing, Durable Remissions of More Than 5 Years in 9 Patients with Non-Hodgkin's Lymphoma (NHL) in a Pivotal Study of Patients Refractory to Their Last Chemotherapy.

Introduction: In 2001, we reported results of a pivotal study using BEXXAR in 60 patients (pts) with chemotherapy-refractory NHL who had been previously treated with a minimum of 2 protocol-specified chemotherapy regimens and had either not responded (72%) or had progressed within 6 mos of their last regimen (28%) (JCO . 2001; 19:3918). Enrollment occurred between Nov 1996 and Mar 1998, with a data cutoff for the initial report of 31 Jan 2001. Thirty-six pts had low-grade (LG) NHL, 23 pts had transformed LG NHL, and 1 pt had mantle cell NHL. The median number of prior chemotherapies was 4 (range, 2–13). The overall response rate was 65%. Twelve (20%) of 60 pts achieved a CR; median duration of CR was not reached with 47 mos' follow-up. At the initial data cutoff, an independent review panel verified that 9 (75%) of 12 CR pts had ongoing responses, without further therapy, ranging from 2.7–4.0 yrs.Methods: These 9 pts continue to be followed annually for investigator-assessed response. In addition, all 25 pts alive at the time of the last report continue to be followed for long-term safety (hypothyroidism, secondary cancers) for 10 yrs or until death. With a data cut-off of 1 Mar 2004, the minimum follow-up is now 5 yrs.Results: Of the 9 pts, 3 were >60 yrs of age, 5 had no response to their last chemotherapy; 3 had transformed to a higher histology, 2 had an IPI score ≥3; 4 had BM involvement; 2 had elevated LDH, and 6 had tumors ≥5 cm in diameter. Of the 9 ongoing responders, 7 are still being followed for efficacy and safety. One pt relapsed at 6.9 yrs and continues to be followed for safety. One pt was noncompliant with clinical assessments and was withdrawn from study at 5.0 yrs (still in CR at last follow-up). The remaining 7 pts (~60% of complete responders) remain in continuous CR from 5.0–7.2 yrs. With an additional 37 mos' follow-up, none of the 25 pts developed an elevated TSH level. The rate of hypothyroidism remains at 4.2%. Six pts developed 8 secondary malignancies (7 skin cancers, 1 GI carcinoma). With 3 yrs' longer follow-up, no additional cases of MDS have been reported. The annualized incidence of MDS is 2.4%/yr.Conclusions: In this pivotal study of BEXXAR, durable remissions of ≥5 yrs were achieved following only 1 wk of therapy in 9 heavily pretreated patients with LG, follicular, or transformed NHL who had many poor prognostic features for their disease. With 3 more yrs' follow-up, long-term safety data remain basically unchanged, with no further reported cases of hypothyroidism or MDS.

Description of epidemiological characteristics at time of diagnosis of 3 hematological neoplasms of lymphoid origin in a domestic reference hospital.

Background. Non-Hodgkin mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) have in common that they are neoplasms which originate in B cells, they present in adult patients, and there is no therapeutic option which achieves a definitive cure. In Mexico, there is scant information on the incidence and characteristics of these neoplasms. Objective. The objective of the study was to identify the demographic, clinical characteristics and the most frequently used treatments of patients with diagnosis of MCL, CLL, or MM who received care at a Mexican hospital. Material and methods. Aretrospective study was conducted, analyzing the clinical records of patients with diagnosis of MCL, CLL, or MM who received care at the Siglo XXI National Medical Center Cancer Hospital Hematology Service. Results. 399 patients were included, 214, (54%) men and 185 (46%) women, with median age 60 years (38 to 88). The distribution was 31 (8%) patients with MCL, 21(5%) with CLL, and 347 (87%) with MM. The most common initial clinical manifestation was weight loss in MCL and CLL, and lumbar pain in MM. The median time for a patient to see a doctor was greater in patients with MM than in MCL and CLL(7.2 vs. 5 and 6 months). The common denominator in the 3 neoplasms was that most of the patients were in an advanced stage of the disease at the time of diagnosis.Conclusion. Most of demographic characteristics of patients included were similar to those described in the literature; however, the age of patients with myeloma was lower, the time to diagnosis was greater and stage of disease at diagnosis was higher than expected.Keywords.Mantle lymphoma, lymphocytic leukemia, multiple myeloma.

Multicenter Retrospective Observational Study to Assess the Clinical Characteristics and the Outcome of Patients with Relapsed or Refractory Mantle Cell Non-Hodgkin's Lymphoma Treated in Italy According to the Ibrutinib Named Patient Program

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin Lymphoma. Although a typical presentation as an indolent lymphoma, without systemic symptoms and with a good performance status, the mantle cell lymphoma is an aggressive one, hardly curable with standard chemo-immunotherapy. Although current approaches to mantle cell lymphoma, including newer agents (such as bortezomib, lenalidomide, temsirolimus and ibrutinib) and autologous stem cell transplantation, have greatly improved the outcomes of affected patients, this disease is still characterized by high relapse rates, with most patients eventually dying of lymphoma progression. Before official approval by EMA, patients with relapsed/refractory mantle cell lymphoma with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program in Italy (NPP, DM 8 May 2003). This observational, non-interventional, retrospective, multicenter study focuses on collecting information about the effectiveness and safety of ibrutinib as single-agent in patients who received at least one dose of ibrutinib under the NPP in the period between 29/Jul/2014 and 25/Jan/2015 in Italy. Data from patients treated with ibrutinib outside a controlled clinical trial within a NPP could give additional information about the clinical use, treatment duration, efficacy and toxicity of ibrutinib given to relapsed or refractory MCL patients in a real life context.Fifty-three heavily pretreated patients were enrolled. They had received a median of previous therapies of 3, comprising lenalidomide, bortezomib, temsirolimus and autologous stem transplant. Ninety-one percent had measurable disease and 83.0% had and ECOG performance status ≤2. At the end of therapy there were 11 complete responses (20.8%), 7 partial responses, 5 stable diseases and 30 progressions with an overall response rate of 33.9%. Twenty-six patients received ≥3 concomitant medications during ibrutinib therapy. At 20 months overall survival (OS) was 26.8% (median reached at 9 months) and disease free survival (DFS) 75% at 15 months: 10/11 patients are in continuous complete response with a median of 10.5 months. Hematological toxicities were manageable, 6 thrombocytopenia occurred, of which only 2 grade 4 (due to disease bone marrow infiltration) and the other 4 related to ibrutinib. Main extra-hematological toxicities were diarrhea (9.4%) and lung infections (7.5%) which all lead to early drug discontinuation. The observed occurrence of diarrhea by severity was 0 for CTCAE Grade 1, 4 for Grade 2, 2 for Grade 3 and 0 for Grade 4. Lung infection had a lower occurrence: 0, 2, 2 and 0 split by CTCAE Grade 1, 2, 3 and 4 respectively. There is a boundary zone in the passage from phase III to phase IV trials, i.e. from experimental to marketing and free use phases: in this zone we can find NPP and compassionate and off-label use. Despite the known potential bias of all the observational retrospective studies, reports on the real life experience make an important contribution to medical knowledge prior to widespread utilization: ibrutinib therapy is effective and tolerable also in a clinical setting mimicking the real world. Our results, in fact, are superimposable to those obtained in clinical trials: for safety, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; for effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL. DisclosuresCascavilla:Janssen-Cilag: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

What is the role of autologous transplant for lymphoma in the current era?

The role of autologous hematopoietic stem cell transplantation (ASCT) in the management of non-Hodgkin's lymphoma (NHL) is evolving, in the era of novel agents. Multiple histologies and remission stages have been impacted with changing outcomes. In the 1990s, ASCT could cure 50% of relapsed chemosensitive aggressive NHL; now the percentage maybe as low as 20% for patients relapsing within 1 year of completing rituximab-containing induction. Yet recent trials have clarified the value of first remission ASCT for high-grade NHL, the utility of augmented preparative regimens, the efficacy of ASCT in primary CNS lymphoma and in the elderly and analyses have defined strategies to reduce transplant related myeloid malignancies. In addition, optimizing nontransplant induction therapy for mantle cell and double-hit NHL is leading to improved outcomes and a re-examination of the use of ASCT in first complete remission. Caution is needed, however, as delaying transplants may mean that patients will need more morbid allogeneic transplants to achieve long-term control of refractory disease. As an alternative, maintenance therapy trials to improve ASCT outcome in high-risk patients are starting, based on the efficacy of lenolidomide and brentuximab in myeloma and Hodgkin's lymphoma, respectively. In addition, efforts to define early high-risk patients by minimal residual disease (MRD) assessments and genetic profiling, are beginning even for those with "indolent" phenotypes not currently autotransplanted. These efforts should not only refine but also enhance the value of early potentially curative ASCT, especially if novel agents only delay but do not prevent relapse for patients with NHL.

Results of a phase I study of bendamustine in combination with ofatumumab, carboplatin, and etoposide (BOCE) for refractory or relapsed aggressive B-cell non-Hodgkin lymphomas (NHL).

8556 Background: No salvage regimen has shown clear superiority in relapsed NHL. Bendamustine has single agent activity in relapsed aggressive NHL. We conducted a phase I trial using a novel RICE-like salvage regimen in which ofatumumab was substituted for rituximab and bendamustine replaced ifosfamide, combined with carboplatin and etoposide (BOCE) Methods: Patients (pts) with relapsed or refractory aggressive B NHL were eligible. The design was a standard 3+3 design using escalating doses of bendamustine [70, 90, and 120 mg/m2 D1-2] with ofatumumab (cycle 1: 300 mg D1, 1000 mg D3, cycle 2 and 3: 1000 mg D1), carboplatin AUC 5 D2 and etoposide 100mg/m2 D1-3. Results: Eleven pts were enrolled (7M/4F). Median age was 62 (range 53-75), 5 pts (45%) had diffuse large B NHL, 4 pts (36%) had grade 3 follicular NHL, 1 pt (9%) had mantle cell NHL, and 1 pt (9%) had transformed CLL. Five pts (46%) had refractory disease and 6 pts (56%) had relapsed disease. All pts with refractory disease were refractory to rituxi...

Efficacy and Tolerability Of Frontline Oral Fludarabine and Cyclophosphamide Combination Therapy For Elderly Patients With Chronic B-Cell Lymphocytic Leukaemia and Low Grade Non Hodgkin Lymphoma

BackgroundTreatment of elderly patients needs to be considered in view of patients' physical condition and social environment in addition to diagnosis, staging and risk factors.Fludarabine was the first purine analogue with an oral formulation available for clinical use. The oral formulation offers equivalent efficacy and improved tolerability profile compared to the intravenous (IV) formulation. IV fludarabine requires several administrations that may expose patients to the risk of clinical side effects and potential logistic problems. AimsTo assess whether frontline oral fludarabine and cyclophosphamide (FC) combination therapy for elderly or clinical unfit patients with B-cell chronic lymphocytic leukemia (B-CLL) and low grade non Hodgkin lymphoma (NHL), is well tolerated, effective and cost-saving. MethodsBetween April 2005 and March 2013, 10 elderly untreated patients (mean age 75, range 68-86) with B-CLL requiring treatment, according to ESMO guidelines, and 21 stage ≥3 indolent NHL (mean age 73, range 47 -89) received therapy with low dose oral fludarabine (25mg/mq/die) and cyclophosphamide (150mg/mq/die) from day 1 to 3. Study design consisted of 6 cycles repeated at 4 weeks intervals in the outpatient clinic. Patients received antibiotic prophylaxis with trimethoprim/sulphamethoxazole (160/800 mg once a day, 3 times a week) and allopurinole (300 mg once a day from days 0 to 4). Four follicular NHL, 6 small lymphocytic NHL, 7 marginal zone NHL, 2 indolent mantle cell NHL and 2 lymphoplasmacytic NHL were treated. Performance status was WHO £ 2 in all patients. Comorbidities, which included diabetes, hypertension and chronic heart disease, were present in 12 patients (grade ≤ 2). The median number of cycles was 4 (range 2-6). No patients reduced either the dose or the number of cycles because of hematologic and extra-hematologic toxicities. Specifically, only 2 patients experienced grade III neutropenia, treated with G-CSF. ResultsDefinition of response was reported according to the updated IWCLL-NCI 2008 international general practice criteria, valuated after 3 and 6 cycles. Twenty seven of 31 patients (87%) obtained a clinical response (14 CR and 13 PR). Only 1 responding patient (90 years old) died after 24 months from therapy because of aplastic anemia. In particular, the response rate was 4/4 for follicular NHL (1RP, 3RC), 5/6 for small lymphocytic NHL (2 RC, 3 RP), 7/7 for marginal zone NHL (3 RC, 4RP),1/2 for lymphoplasmacytic and 2/2 mantle cell NHL (PR), 8/10 for B-CLL (3 RC, 5 RP).We consider as Event Free Survival (EFS) time to progression, adverse event with a grade >3 (CTCAE) during treatment, relapse or death. Overall survival (OS) was defined as the time from the start of treatment to death or last follow-up. Survival distributions were calculated using the method of Kaplan and Meier. With a median follow-up of 67 months (range 16-187), we observed a median EFS about 38 months and median OS has not been reached.We used Genzyme-sponsored Excel program to compare direct hospital cost of oral to IV FC (both 3 days regimen). IV treatment required 18 day service admissions with a total cost of € 7.527 while the oral therapy required 6 ambulatory visits with total cost of € 1.642 (costs including: pharmacy, nurses and physicians costs). In this analysis we did not consider social and psychological cost such as transportation, care giver loss of working hours, trauma of repeated venipunctures. ConclusionsThese results suggest that oral FC could be effective and well tolerated for elderly patients unfit for more aggressive treatments. The efficacy of our therapeutic regimen is comparable to intravenous FC (20 mg/m2 and 600 mg/m2) regimen used by Flinn et al. (Blood 2000) with an ORR about 90 %. Hovewer, in that study 17/60 patients experienced a grade 3 or 4 neutropenia with 1 death due to sepsis. In conclusion, most of our patients did not experience severe toxic side effects or required hospitalizations, enjoing a good quality of life. Disclosures:No relevant conflicts of interest to declare.

First-In-Human Study Of AMG 319, a Highly Selective, Small Molecule Inhibitor Of PI3Kδ, In Adult Patients With Relapsed Or Refractory Lymphoid Malignancies

First-In-Human Study Of AMG 319, a Highly Selective, Small Molecule Inhibitor Of PI3Kδ, In Adult Patients With Relapsed Or Refractory Lymphoid Malignancies

Herpes zoster complicating bortezomib therapy of relapsed/refractory indolent B-cell and mantle cell lymphoma: an analysis of two phase II trials

The incidence of herpes zoster (HZ) in patients with non-Hodgkin lymphoma (NHL) receiving bortezomib-based therapy has not been well studied. We reviewed data from two phase II trials in which bortezomib was administered to 236 patients, median age 65 years, with relapsed/refractory mantle cell or indolent NHL. HZ occurred in 24 patients (10.2%) overall, with a comparable incidence in NHL histologic subgroups. Median time to HZ was 39 (range, 11–206) days. In total, 71% of patients who developed HZ were aged ≥ 65 years, compared to 48% without HZ (p = 0.03). Patients with HZ were more likely to have had received ≥ 2 lines of therapy (63% vs. 47%, p = 0.16). Six (25%) of the patients who developed HZ had received purine analogs, compared with 34 (16%) patients without HZ (p = 0.27). As the occurrence of HZ may complicate the course of indolent or mantle cell NHL in patients receiving bortezomib-based therapies, these patients, especially the elderly, should be strongly considered for antiviral prophylaxis.

Low-Dose Radiotherapy in Patients with Non Hodgkin Lymphoma

AbstractAbstract 4875 Background:Some studies have showed high activity for low-dose radiotherapy (LDRT) in low-grade Non-Hodgkin Lymphoma (NHL). However, this therapeutic approach is often forgotten and other approaches are used - chemotherapy and/or conventional radiotherapy - associated with greater toxicity. The efficacy of total body LDRT (1.5–2 Gy, fractions 0.1–0.25 Gy in 2 – 5 times a week) in disseminated disease is associated with 10 year progression free survival (PFS) of 15 – 25%, with response rates of 70 – 90% (Gérard et al., IJ Radiation Oncology 2010; 78), despite hematologic toxicity and leukemogenic effects. Although its mechanism of action is unknown, its effectiveness has been confirmed (Jones et al., Cancer 1973; 32) suggesting that low dose radiation induces localized lymphocytes apoptosis that can trigger local and systemic benefits. More recently, LDRT was used in palliative treatment for patients with localized disease (4Gy into two fractions, for 3 days) with a low toxicity, and with an objective response (partial or complete) in 24/37 patients, 89% (G Ganem et al., Hematol Oncol1997; 42). Objectives:To assess the response to treatment with LDRT. Explore the predictive factors of response. Determine the progression-free survival (PFS) after LDRT. We will present PFS after LDRT and compare PFS in second line treatment: LDRT vs convencional chemotherapy. Methods:Retrospective study of 44 patients with new or recurrent NHL, treated with LDRT (4Gy in 2 fractions) in 1stor more lines, in a cancer care centre between 2004 and 2011.All transformed lymphomas were excluded (4 patients), as well all diagnosis that weren't centrally reviewed. Patients with complete resolution of the disease according to clinical and/or image studies were considered to have achieved complete response (CR). Results:We identified 40 patients undergoing LDRT, with a median follow-up of 69,5 months after LDRT ([28–87]). 52,5% (n = 21) were male, median age at the time of LDRT was 69 years ([31–85]). 75% of patients (n = 30) had follicular NHL, 12,5% (n = 5) Mantle cell NHL, 10% (n = 4) Marginal Zone NHL and 2,5% (n = 1) lymphoplasmacytic lymphoma.The median numbers of lines of chemotherapy completed before LDRT were 2 lines ([0–5]). There wasn’t any impact on PFS on using Rituximab containing regimens after LDRT (p> 0,05). The overall response rate to LDRT was 92,5% (n = 37): 42,5% (n = 17) achieved complete response (CR), 50% (n = 20) partial response (PR) and 7,5% (n = 3) had disease progression. There weren’t any treatment related toxicities, nor was histological transformation recorded after treatment with LDRT. The logistic regression analysis showed that irradiated areas with dimension <40mm are an independent predictive factor of response (p <0,031, 95% CI [1,268-133,285]). We find a median PFS of 4 months ([0–72]) for patients that went on LDRT, and 50% of these patients relapsed after a median 5 months ([0–35]). 56,5% (n = 13) showed relapse at the same location of the irradiated area. Patients who have completed one chemotherapy scheme after relapsing following LDRT, showed a rate of 6 months-PFS of 50% such as the patients that have done a second LDRT treatment.Concerning follicular NHL patients who relapsed after 1st line conventional chemotherapy, 43,8% (n = 7) were treated with LDRT and 56,2% (n = 9) were treated with conventional 2nd line chemotherapy. Comparing these two groups of patients, there weren’t any difference for PFS for both groups (mean 9,5 vs 9 months p> 0,05, for LDRT vs 2ndline chemotherapy), for equal overall survival. Conclusion:LDRT is an effective treatment for patients with relapsed or recurrent advanced stage NHL. We can obtain high response rates with negligible toxicity. In the treatment of first relapse, PFS is similar when using LDRT or 2nd line chemotherapy. Considering that Rituximab promotes a synergistic effect with LDRT-induced apoptosis and decrease the cell turnover (Skvortsova I et al., J Radiat Res (Tokyo) 2006), comparative studies with conventional chemotherapy regimens should be promoted. Treatment with conventional radiotherapy should be used in patients with relapsed low-stage and localized disease, having curative intention or locally controlling involved areas. Disclosures:No relevant conflicts of interest to declare.

Gastrointestinal Bleeding as Manifestation of Intestinal Aspergillosis: Case Report

Introduction: Isolated intestinal aspergillosis or as a disseminated infection has been reported in the literature. Characteristic features of gastrointestinal invasive aspergillosis, suggests that the gut could be a portal of entry for Aspergillus in inmunocompromised patients. Recent ingestion of contaminated food or chronic low burden ingestion with asymptomatic gut colonization could cause symptomatic gastrointestinal disease in inmunocompromised patients. Case Report: A 54 years old male with mantle cell non-Hodgkin lymphoma (NHL), who had recently received six cycles of HYPER-CVAD-R, began with malaise, fever up to 38°C, abdominal cramps, nausea, vomiting and diarrhea. The examination revealed an ill looking patient, dehydrated, pale teguments, soft, but tender abdomen in mesogastric and right flank, normal bowel sounds and no evidence of peritoneal irritation. Laboratory data revealed Hb 12 g/dL, Hct 35%, WBC 100/uL, Segs 100/uL, PLT 55,000. Negative C. difficile toxin. Stool culture with no pathogens. He was admitted with a diagnosis of post-chemotherapy myelosupression, severe neutropenia and probably acute neutropenic colitis and started on meropenem, fluconazole, vancomycin and methronidazole. During the first hours he developed hemodynamic instability and was moved to the ICU. He had periorbital cellulitis and sinusitis, ENT took cultures that revealed Aspergillus flavus. Melena and fresh bloody stools occurred, with a fall of 3 g/dL of hemoglobin in 1 day. A first endoscopic study revealed ulcers in body and antrum of stomach, endoclips were placed; numerous blood clots were seen in distal Ileum. Bleeding continued so an enteroscopy was performed, which revealed a yeyunal ulcer, endoclips were placed. Gastric, yeyunal and colonic endoscopic biopsies were taken and pathology report revealed fundic gastric mucosa, with focal acute gastritis and ulcerations associated with fungal hyphae, suggestive of Aspergillus. Grocott's stain was consistent with Aspergillus hyphae. Discussion: Since symptoms resulting from necrotic lesions, obstruction or hemorrhage are non-specific, there would not be a characteristic clinical picture of intestinal Aspergillus and should make differential diagnosis with typhlitis or neutropenic enterocolitis, it is possible that the latter could have preceded the gut lesions and favored colonization on an altered mucosa but may be a severe GI complication in patients undergoing chemotherapy induced mucositis. Intestinal aspergillosis is uncommon.

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

AbstractGiven the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m2 days 1 and 4; rituximab 375 mg/m2 day 1, and bortezomib 1.3 mg/m2 days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534.

Herpes Zoster (HZ) Complicating Bortezomib Therapy of Relapsed/Refractory Indolent B-Cell and Mantle Cell Lymphoma: An Analysis of Two Phase II Trials.

AbstractAbstract 2818 Background:The use of bortezomib-based therapy is known to be associated with an increased risk of HZ in patients (pts) with multiple myeloma, who have disease-related inherent immune defects. A 13% incidence of HZ occurrence in pts with relapsed/refractory MM who received single agent bortezomib has been previously reported (J Clin Oncol 2008; 26:4784-4790). However, the occurrence of HZ in bortezomib-treated pts with non-Hodgkin lymphoma (NHL) has not been previously examined. Methods:We reviewed clinical data from two phase II trials in which bortezomib therapy was administered to pts with relapsed/refractory mantle cell NHL or indolent B-cell NHL. The occurrence of HZ complicating their treatment course was delineated, and an analysis for potential predisposing risk factors was undertaken. Results:A total of 236 relapsed/refractory pts, median age 65 years (yrs), enrolled on these trials was examined. Mantle cell NHL pts (n=155) received single-agent bortezomib, 1.3 mg/m2, days (D) 1, 4, 8, 11, 21-D cycles; those with indolent B-cell NHL (n=81) received either bortezomib, 1.3 mg/m2, D 1, 4, 8, 11, 21-D cycles, plus rituximab, 375 mg/m2, D 1, 8, 15 (cycle 1) and D 1 (cycle 2) (n=41), or bortezomib, 1.6 mg/m2, D 1, 8, 15, 22, 35-D cycles, and rituximab, 375 mg/m2, D 1, 8, 15, 22 (cycle 1) (n=40). HZ occurred in 24 pts (10.2%) overall, with a comparable incidence in both disease subgroups. Median time to HZ occurrence was 39 (range, 11–206) days (< 2 cycles). Overall, 11% of pts had had a prior episode of HZ. Baseline demographic and clinical variables were examined, including age, gender, disease stage, baseline absolute neutrophil and lymphocyte counts, hemoglobin, lactate dehydrogenase, prior HZ, and number and types of prior therapies, to determine if any may predict for subsequent development of HZ. With regard to age, 71% of pts with HZ were age ≥65 yrs, compared to 48% without HZ (p=0.03). 63% of pts with HZ had received ≥2 lines of prior therapy, compared to 47% in those without HZ (p=0.15). 4% of pts with HZ had undergone prior stem cell transplantation, compared to 13% of pts without HZ. Of the pts with HZ, 25% had received prior purine analog therapy, compared to 9% of pts without HZ. The other baseline variables had no impact on the occurrence of HZ. In the 77 pts who responded to bortezomib protocol therapy (complete/partial responses), the incidence of HZ was 14%, compared to an 8% incidence of HZ in the 159 non-responders (p=0.15). Conclusions:HZ may complicate the course of relapsed/refractory indolent or mantle cell NHL pts receiving bortezomib-based therapies, with an incidence similar to the myeloma population. Pts who are elderly, more heavily-pretreated, or have received prior purine analog therapy may be at greater risk of this complication, and should be strongly considered for antiviral prophylaxis during such therapy. Disclosures:Morrison:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Pfizer: Speakers Bureau. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Fisher:Allos Therapeutics: Consultancy; CytoKinetics: Consultancy; GSK: Consultancy; MundiPharma: Consultancy; Seattle Genetics: Consultancy; Millennium Pharmaceuticals, Inc,: Consultancy. Goy:Millennium, Celgene, GSK and Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bernstein:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Speakers Bureau. Boral:Millennium Pharmaceuticals, Inc.: Employment; Takeda Pharmaceuticals: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity In Relapsed and Refractory Non-Hodgkin's Lymphoma.

AbstractAbstract 2834 Background:A phase 2 study of flavopiridol administered according to a pharmacokinetically- (PK-) derived schedule has demonstrated significant activity in CLL, irrespective of high-risk genomic features. In combination with fludarabine and rituximab, flavopiridol has further shown promising activity in mantle cell lymphoma (MCL) and indolent B-cell non-Hodgkin's lymphoma (NHL). However, the safety and efficacy of single-agent flavopiridol administered on this schedule has not yet been characterized in patients with relapsed/refractory NHL. Methods:We conducted a standard cohorts-of-3 phase 1 trial to determine the maximum tolerated dose (MTD) and safety of single-agent flavopiridol in each of 4 groups: indolent B-NHL, aggressive B-NHL, MCL, and T-NHL. Adult patients (age >18y) with previously-treated (T-NHL '1 prior; B-NHL ≥2 prior), preserved end-organ function, adequate hematologic parameters (unless attributable to disease), and preserved performance status (≤ECOG 2) were eligible. Further, pts were only eligible if they had exhausted all other therapeutic options. All pts signed informed consent. Flavopiridol was given as a 30 min loading dose followed by a 4 hr infusion weekly for 4 weeks of a 6 week cycle (max 6 cycles). Dose levels (DL) 1, 2, and 3 were 30 mg/m2 + 30 mg/m2, 30 mg/m2 + 50 mg/m2, and 50 mg/m2 + 50 mg/m2, respectively. The first infusion was administered in hospital, but treatment could continue outpatient thereafter. Pts received allopurinol, phosphate binders, and Kayexalate (if pre-treatment K+ >4.5) prophylaxis for tumor lysis syndrome (TLS). Steroid pre-medication and/or treatment for cytokine release syndrome (CRS) was given at the discretion of the treating clinician. Dose-limiting toxicity (DLT) was generally defined as any grade 3/4 non-hematologic toxicity not resolving to ≤grade 2 within 2 wks or any grade 4 hematologic toxicity (except leukopenia/neutropenia) resulting in >1 wk treatment delay. Results:28 pts evaluable for toxicity have thus far completed cycle 1, which was used to define DLT: median age 66 years (range 34–84), 13 female (46%), median prior therapies 3 (range 1–8). All B-NHL patients received prior rituximab. Subsequent dose evaluation continues in the MCL and T-NHL arms. Across all pt groups, there were 11 pts at DL 1, 11 pts at DL 2, and 6 pts at DL 3. No DLTs have been observed to date. Median number of cycles received was 2. Seven pts completed all 6 cycles: 4 pts 30+30, 2 pts 30+50, 1 pt 50+50. Although no DLTs were observed, grade 3/4 hematologic toxicity was seen in 26 pts: neutropenia (23 pts), thrombocytopenia (3 pts), and anemia (7 pts). Grade 3 neutropenic fever and infection, however, were only observed in 2 and 5 pts, respectively. Common grade 3 non-hematologic toxicities included diarrhea (15 pts), fatigue (8 pts) and elevated transaminases (3 pts). Grade 3 CRS and TLS occurred in only 2 pts, both during cycle 1. Only 2 grade 4 non-hematologic toxicities (elevated transaminases, elevated lipase) were observed, both of which resolved without sequelae. Among pts completing ≥1 cycle, the most common reason for discontinuing treatment was disease progression (17 pts). One pt withdrew after diagnosis of a second cancer, 2 pts proceeded to transplant, and 2 pts withdrew for toxicity (1 persistent fatigue, 1 persistently elevated transaminases/malaise). Four pts expired on study: 3 progression, 1 sudden cardiac death unrelated to flavopiridol. Of 26 pts evaluable for response, 6 pts (21%) had partial responses: 2 follicular (30+30, 30+50), 1 SLL (50+50), 2 MCL (30+30, 30+50), and 1 DLBCL (50+50). Seven pts had stable disease for ≥1 cycle: 1 follicular (30+50), 1 MCL (30+30), 1 Richter's CLL (30+30), 1 DLBCL (50+50), and 3 PTCL (2 pts 30+30, 1 pt 30+50). Conclusions:Administered according to a PK-derived schedule, single-agent flavopiridol can be successfully delivered to multiply relapsed and/or refractory NHL pts with acceptable hematologic and non-hematologic toxicity. Both the promising activity and relative safety observed in these heavily pre-treated NHL pts warrant further investigation of this agent earlier in the course of disease and/or in combination with other agents, particularly in indolent B-cell and mantle cell NHL. Disclosures:Blum:Celgene : Research Funding.

Fludarabine, Aracytine and Rituximab Based Chemotherapy In Patients with Refractory and Relapsed Mantle Cell Non-Hodgkin Lymphoma

AbstractAbstract 4892 IntroductionMantle cell lymphoma (MCL) is a distinct B cell non Hodgkin lymphoma characterized by CD 5 expression, t (11; 14)(q13; q32) translocation and over-expression of Cyclin D1, and frequently has an aggressive clinical course. There is no standard of care for the treatment of MCL. Current treatment approaches are non curative and pts median survival is 4–6 years. Various studies have reported promising results for a high dose Cytarabine-containing regimen in the treatment of MCL. Fludarabine has also been recognized as effective treatment in pts with MCL, either as a single agent or in combination with other drugs. The addition of Rituximab improves the response to the treatment. The aim of this study is to assess the efficacy and toxicity of a combination of Fludarabine, Aracytine and Rituximab treatment in refractory and relapsed MCL. MethodsWe retrospectively evaluated 20 pts with refractory or relapsed MCL treated in our institution between February 2007 and February 2010.Median age was 59 yrs (54-77 yrs), 14 pts (70%) were males, 18 pts (90 %) had stage IV, 16 pts (80%) had bone marrow involvement, 16 (80%) presented comorbidities. Eight pts (40%) were in first relapse, 12 (60%) in second relapse. Twelve pts (60%) had a “Mantle Cell Lymphoma International Prognostic Index” (MIPI) score ≥ 7. Therapy included: fludarabine 25 mg/m2/daily intravenously for 3 days, aracytine 500 mg/m2/daily for 3 days and Rituximab 375 mg/m2/daily for 1 day, Dexamethasone 8 mg daily for 3 days, every 28 days for 4 cycles. ResultsEight pts (40%) achieved complete response (CR) and 4 pts (20%) a Partial Remission (PR) with an overall response rate (ORR) of 60%. Eight pts (40%) progressed and one of them died of active disease. After a median follow up of 17 months (range 8–36), OS is 70% and PFS is 55%.Toxicity was mainly hematological with grade >=3 neutropenia in 40 (50%) of the 80 cycles performed, grade >=2 anemia in 30 (37%) and grade 4 thrombocytopenia in 24 (30%). In 16 (20%) cycles pts required red blood cells transfusions, in 12 (15%) platelet transfusions. One episode of Herpes Zoster infection was observed. ConclusionsThis study suggests that the combination of Fludarabine, Aracytine and Rituximab appears to be an effective regimen with a promising response rate and manageable toxicity, for pretreated pts often affected by comorbidities and with poor prognosis.Further studies are needed to assess the efficacy of this combination therapy and to further test the role of this approach in MCL. Disclosures:No relevant conflicts of interest to declare.

Temsirolimus Has Activity in Non–Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium

Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

Rituximab And Sargramostim Immunotherapy Following Autologous Stem Cell Transplant For Aggressive Non-Hodgkin's Lymphoma

High dose chemotherapy with autologous stem cell transplant (ASCT) improves survival in patients with aggressive non-Hodgkin's lymphoma (NHL), but relapse occurs in 40-50% of patients. Rituximab exerts its anti-tumor effect through complement and antibody-dependent cell cytotoxicity (ADCC). Sargramostim is involved in the activation and differentiation of macrophages and dendritic cells and increases monocyte-mediated ADCC. The addition of sargramostim to rituximab may potentiate the anti-tumor effect of rituximab by enhancing recruitment and activation of effector cells that mediate ADCC. We evaluated the safety and efficacy of rituximab and sargramostim given as “adjuvant immunotherapy” to patients following ASCT for aggressive NHL. 8 patients (5 male, 3 female; median age 53, range 34-69) with CD20+ diffuse large B cell (6) or mantle cell (2) NHL relapsed, primary refractory or in first complete remission (intermediate-high or high risk IPI) underwent stem cell mobilization using rituximab and cyclophosphamide followed by high dose chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunotherapy consisted of rituximab 375 mg/M2 IV weekly and sargramostim 250 ug s.c. TIW during weeks 5 to 8 and 24 to 27 post transplant. Seven patients had successful mobilization (mean CD34/kg collected 12.5E6 and infused 9E6) and underwent transplant. Median time to neutrophil and platelet engraftment was 9 and 10 days respectively. Six patients are alive with no evidence of disease from 3 to 18 months post transplant. One patient relapsed at 11 months. 4/4 patients receiving at least once cycle of adjuvant immunotherapy developed grade 1 to 4 neutropenia from 3 to 34 weeks post adjuvant rituximab. Neutrophil counts recovered following treatment with G-CSF, but recurred in all 4 patients without additional exposure to rituximab. One patient who had engrafted platelets developed grade 2 thrombocytopenia on day 33 post transplant. Platelets spontaneously recovered. Delayed-onset neutropenia is a known complication of rituximab. The incidence may be higher when rituximab is used following ASCT. It is not clear if the timing of rituximab administration post transplant or the concomitant use of sargramostim contributed to the high incidence of delayed neutropenia in this study. Larger studies and longer followup will be needed to determine if adjuvant immunotherapy decreases relapse.

Rituximab, Cyclophosphamide, Bortezomib and Prednisone (R-CBorP): Final Results of a Phase I Trial Evaluating Two Dosing Schedules and the Safety of Overlapping Pegfilgrastim in Patients with Relapsed/Refractory Indolent and Mantle Cell Lymphomas.

Abstract 3708Poster Board III-644 AimTo determine the safety and efficacy of substituting bortezomib (Bor) for vincristine in standard ‘R-CVP'. A separate safety analysis evaluated the safety of pegfilgrastim (PegG) overlapping with Bor administration. RationaleVincristine has marginal activity in indolent lymphomas, while preclinical and clinical data suggest that single agent Bor has significant activity in indolent and mantle cell (MCL) non-Hodgkin Lymphoma (NHL), and may also be synergistic with rituximab (R) and DNA-damaging agents. MethodsIn this phase I trial, Bor and cyclophosphamide (C) were alternately escalated. R (375 mg/m2) and C (750 mg/m2 or 1000 mg/m2) were dosed on day one, and prednisone (P) (100 mg daily) on days 2-6. In schedule 1, Bor was given on days 2 and 8, with doses escalated from 1.3 to 1.8 mg/m2. In schedule 2, Bor was given on days 2, 5, 9 and 12 with doses escalated from 1.1 to 1.5 mg/m2. Due to 2 neutropenic fevers in schedule 2 (twice-weekly Bor), the protocol was amended to allow for filgrastim (G) support, administered in between Bor dosing days. This allowed accrual to the highest planned dosing level. A separate cohort of 10 patients was added at the twice-weekly Bor 1.3 mg/m2 + C 1000 mg/m2 level to assess the safety of administering overlapping PegG instead of G. In this cohort, PegG was given with Bor on day 2. Patients with PR or SD after 4 cycles received 4 further cycles, those with CR got 2 further cycles. Toxicity was assessed using NCI-CTC, v. 3.0. No DLT was seen at maximum doses of Bor and C in either schedule. Schedule 1 accrued 15 patients, with one DLT requiring cohort expansion at the second dose level. Schedule 2 accrued 40 patients. ResultsDemographic variables were similar between the two groups, and both schedules were well tolerated with similar toxicity profiles. Most hematologic toxicities (HTs) and non-HTs across all dose levels and cycles were grade 1-2. Grade 3-4 non-HTs in the weekly treatment cohorts included grade 3 diarrhea (n=1), dehydration (n=1), neutropenic fever (n=1), infection (n=2) and anal incontinence (n=1, likely unrelated). Grade 3 toxicities in the twice-weekly groups included fatigue (n=3), neutropenic fever (n=2), fever (n=1), hypoxia (n=1) and neuropathy (n=2), along with one grade 4 neuropathy. Of the patients who developed neuropathy above baseline, resolution to baseline occurred in 8 of 9 (89%) of patients in the weekly group after a median of 0.7 months, and in 15 of 26 (58%) of patients in the twice-weekly group after a median of 4 months. To evaluate the safety of pegfilgrastim overlapping with 4 doses of Bor, toxicities and CBCs for patients in the PegG group were compared with those of patients treated at identical doses of R-CBorP given non-overlapping G support. All toxicities and CBC trends were similar, with the exception of a significant but mild decline in platelets in the PegG group. Overall response rates in the 13 evaluable weekly and 33 evaluable twice-weekly patients were 46% (23% CR) and 64% (36% CR), respectively. ConclusionsR-CBorP is a well-tolerated and promising new regimen in patients with NHL. The safety of administering PegG overlapping with Bor has been established, and simplifies this regimen. Although response rates appeared to be greater in the twice-weekly schedule, a randomized study will be required to determine the true difference. Grade 3-4 neuropathy was seen only in the twice-weekly dosing group, and seemed to be less reversible and longer-lasting than in the weekly group. A randomized phase II study will soon begin enrollment to compare the toxicity and efficacy of these two dosing schedules in a larger group of patients with follicular lymphoma.ToxicityWeeklyGr3&4%ToxicityTwice-Weekly%Gr 3Gr 4Gr 3Gr 4G43&4Lymphopenia831173%Lymphopenia2452973%Leukocytes71853%Neutrophils4111538%Neutrophils53853%Leukocytes831128%Platelets32533%Platelets43718%Phosphate, low30320%Fatigue3038%Infection20213%Hemoglobin3038%Potassium, low20213%Neuropathy: sensory3038%Dehydration1017%Febrile neutropenia2025%Diarrhea1017%Bilirubin1013%Febrile neutropenia1017%Fever1013%Glucose, low1017%Hypoxia1013%Incontinence, anal1017%Phosphate, low1013%Sinus tachycardia1017%Potassium, low1013%Best ResponsePODSDPRCRORRWeekly (n=13)1 (8%)6 (46%)3 (23%)3 (23%)6 (46%)Twice-Weekly (n=33)3 (9%)9 (27%)9 (27%)12 (36%)21 (64%) Disclosures:Gerecitano:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Off Label Use: bortezomib in combination with other active agents for indolent and mantle cell non-Hodgkin lymphomas. Hamlin:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Zelenetz:Millenium Advisory board: Membership on an entity's Board of Directors or advisory committees.

Rational Combinations Including a Novel Syk Inhibitor, Fostamatinib Disodium (FosD) in Diffuse Large B Cell Lymphoma.

Abstract 283Certain malignant B-cells rely upon B-cell receptor-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the B-cell receptor-mediated signal. We and others have demonstrated that fostamatinib disodium (FosD: a prodrug of R406, a potent and specific inhibitor of Syk) induces apoptosis in lymphoma cell lines and primary tumors. A recent clinical trial has demonstrated significant clinical activity of FosD in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia, and minimal overlap in toxicities with conventional agents. Given this background, future development in B-cell NHL will include rational combinations of FosD and currently available therapies. Therefore, we conducted in vitro and in vivo studies of rational combinations including FosD, in anticipation of clinical trial development. First, using a human DLBCL cell line of GCB genotype, (OCI-Ly19), we analyzed in vitro the combination of R406 with the following agents: fludarabine, rapamycin, rituximab, bendamustine and bortezomib. Increased cytotoxicity was observed using in vitro culture assays with the addition of fludarabine, rapamycin, or rituximab to R406. Cell viability at 72 hours was 25% with R406 alone, 27% for fludarabine alone, and only 9% for the fludarabine/R406. At 48 hours, cell viability was 49% using R406 alone, 31% using rituximab alone, and 21% for rituximab/R406. At 120 hours using primary lymphoma cells (DLCL27), there were no viable cells treated with the rapamycin/FosD combination, compared with rapamycin alone (7%) or FosD alone (25%) The addition of bortezomib or bendamustine to FosD resulted in only a minimal additive increase in cytotoxicity. Results with all combinations were similar with the OCI-Ly10 human DLBCL line of ABC genotype. We then performed in vivo studies by subcutaneous transplantation of the DLBCL cell line OCI-Ly19, (engineered to express luciferase allowing for real time in vivo imaging) into immune deficient NOD/SCID mice which reproducibly formed tumors. Recipient animals were separated into uniform cohorts when the tumors were less than or equal to 500 mm3 in size. The animals were then simultaneously treated with FosD (n=7; 3 gm/kg ad. lib.; translates into 2-5 micromolar R406 systemically throughout the 24h period) and either bortezomib, (n=6; 0.4 mg/kg weekly IP), or rituximab, (n=13; 3 mg/kg, 2x weekly IP). Analysis of the OCI-Ly19 tumor volumes at day 46 showed a median of 2364 mm3 with bortezomib alone compared with 1823 mm3 with bortezomib and FosD. When FosD was combined with rituximab the most significant cytotoxicity was observed: (p=0.01; median tumor volume of 497 mm3 following the combination) in comparison to either FosD alone (3150 mm3) or rituximab alone (1764 mm3). We conclude that the addition of FosD appears to increase activity against NHL of several drugs, including fludarabine and rapamycin. These agents have significant activity in indolent and mantle cell NHL as well as CLL. Moreover, there is no evidence that FosD impedes rituximab responses in vitro or in vivo; in fact we have suggested possible synergy with the combination of rituximab and FosD. Based upon the documented single agent activity of FosD in humans, and this data, clinical trials are now indicated using these promising combinations in NHL and CLL. Disclosures:Pine:Rigel: Employment. Friedberg:Rigel: Research Funding.

Phase I Study of Bortezomib in Combination with Gemcitabine in Relapsed/Refractory Intermediate Grade B-Cell and Mantle Cell Non-Hodgkin's Lymphoma.

Abstract 1682Poster Board I-708 BackgroundThe outlook for patients with relapsed or primary progressive intermediate to high grade Non Hodgkin's Lymphoma (NHL) remains problematic. The current best strategy is to to identify potential chemosensitive patients who may respond to autologous transplant, by use of high dose chemotherapy protocols However, approximately fifty percent of those who undergo high-dose therapy, and the majority of patients treated with standard salvage regimens alone, will ultimately show progression or relapse; newer regimens are necessary. In-vitro data in a number of tumor cell types shows enhanced activity of gemcitabine (gem) when combined with the proteasome inhibitor bortezomib (B). MethodsPatients with intermediate to high grade relapsed or refractory B cell NHL or mantle cell lymphoma who had been treated with up to 4 prior regimens including autologous transplant were eligible. Starting dose of gemcitabine was 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with bortezomib starting at 1 mg/m2 on days 1, 4, 8, 11. CT (and PET when possible) were performed after cycle 4 and after cycle 6. Patients were allowed to continue therapy in the event of clinical benefit. Results28 patients were enrolled overall, of whom 24 are evaluable for response. 3 of the patients had mantle cell lymphoma. Median Age was 63 (range 34-77). 20 were male, 8 female. Four patients were enrolled on dose level 1, of whom three were evaluable for toxicity. All 3 showed DLT (neutropenia and thrombocytopenia) so enrollment continued at dose level -1 (gem 800 days 1 and 8, B 1.0 mg/m2 d1, 4, 8, 11). One DLT was seen in the five patients treated. In order to make the regimen more easily tolerable, the regimen was changed to increase the time between doses so that dose escalations would begin from gem 800 given on days 1 and 15 and B 1.0 given on days 1 and 15 only, on a 28 day cycle. Dose escalation to the target dose of gem 1000 mg/m2 and B 1.3 mg/m2 was achieved without DLT, and this level was expanded to six patients. A second group of six patient was treated on this dose level with the addition of rituxan 375 mg/m2 given on days 1 and 15 with no DLT seen. Grade 4 toxicities seen on the study were neutropenia (4 pts), and thrombocytopenia (2). Grade 3 toxicities were neutropenia (6) thrombocytopenia (5) and febrile neutropenia (1). Other toxicities of grade 2 or less included elevated transaminases, fatigue, diarrhea, and peripheral neuropathy (grade 2: 3 pts grade 1: 3 patients). 24 patients were evaluable for response. Complete Remission was seen in 3 patients, one at dose level 1, one at dose level 5B (gem 1000 mg/m2 d1 and 15, B 1.3 mg/m2 d1 and 15) and one at dose level 5B1 (5B plus rituxan 375 mg/m2 d1 and 15). ConclusionThe combination of gemcitabine 1000 mg/m2 combined with bortezomib 1.3 mg/m2 with or without rituxan 375 mg/m2 on a day 1, 15 schedule shows activity in patients with relapsed/refractory B cell NHL, and was well tolerated. A phase II study of this combination is ongoing. DisclosuresOff Label Use: bortezomib in lymphoma.

Long‐term survival and late relapse in 2‐year survivors of autologous haematopoietic cell transplantation for Hodgkin and non‐Hodgkin lymphoma

This study described long-term outcomes of autologous haematopoietic-cell transplantation (HCT) for advanced Hodgkin (HL) and non-Hodgkin lymphoma (NHL). The study included recipients of autologous HCT for HL (N = 407) and NHL (N = 960) from 1990-98 who were in continuous complete remission for at least 2 years post-HCT. Median follow-up was 104 months for HL and 107 months for NHL. Overall survival at 10-years was 77% (72-82%) for HL, 78% (73-82%) for diffuse large-cell NHL, 77% (71-83%) for follicular NHL, 85% (75-93%) for lymphoblastic/Burkitt NHL, 52% (37-67%) for mantle-cell NHL and 77% (67-85%) for other NHL. On multivariate analysis, mantle-cell NHL had the highest relative-risk for late mortality [2.87 (1.70-4.87)], while the risks of death for other histologies were comparable. Relapse was the most common cause of death. Relative mortality compared to age, race and gender adjusted normal population remained significantly elevated and was 14.8 (6.3-23.3) for HL and 5.9 (3.6-8.2) for NHL at 10-years post-HCT. Recipients of autologous HCT for HL and NHL who remain in remission for at least 2-years have favourable subsequent long-term survival but remain at risk for late relapse. Compared to the general population, mortality rates continue to remain elevated at 10-years post-transplantation.