Additional Doses Of Rituximab Research Articles

Prevention of Early Development of Proteinuria by Rituximab in a Pig to Baboon Thymokidney Model Likely Associated with Modulating Podocyte Function in An SMPDL-3b-Dependent Manner

Background: We have previously reported life-supporting GalT-KO thymokidney (TK) xenograft survival greater than 80 days in baboons. One of major obstacles to long-term success in this model is the persistent development of proteinuria. Despite otherwise normal renal function, EM findings showed podocyte effacement. Recent clinical data suggested that Rituximab might prevent recurrent FSGS by modulating podocyte function in a sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b)-dependent manner. In this study, we determined whether Rituximab prevents proteinuria in this xenogeneic TK model. Methods: 33 baboon recipients of GalT-KO TK received both T and B cell depletion prior to TK transplantation (Tx), followed by anti-CD40L based maintenance therapy. All animals (n=33) received Rituximab to deplete B cells 2 weeks prior to TKTx. In order to test the effect of Rituximab therapy on preventing proteinuria, 29 of 33 did not receive additional dose of Rituximab (Group1), and 4 baboons received Rituximab (10mg/kg) in peri-TKTx period (day 0, POD2 or 5) (Group2). We assessed the development of proteinuria following TKTx as well as immunohistological analysis to determine the mechanism by which Rituximab affects the onset of proteinuria. Results: CD20+ cells in all recipients were nearly completely depleted (< 20/ul) in the peri-Tx period. On average, all baboons without Rituximab therapy in the peri-TKTx period (Group1) developed 2+ (100mg/dl) proteinuria on POD2. In contrast, 4 baboons with Rituximab (Group2) exhibited a markedly delayed first onset of 2+ proteinuria at PODs 9, >10, 11 and 22. One animal given Rituximab on POD5 reversed its proteiunuria from 2+ to trace until POD22. Immunofluorescence data showed (1) Rituximab bound to porcine glomerular epithelium, (2) SMPDL-3b was expressed on porcine glomerular epithelium confirmed by both immunohistologic staining and western-blotting. (3) Anti-SMPDL-3b Abs blocked binding of Rituximab and (4) SMPDL-3b expression decreased after severe proteinuria developed. Conclusion: These data suggest that Rituximab therapy in peri-TKTx period can markedly delay the development of proteinuria. This effect is not due to T or B cell depletion because both T/B cells were depleted similarly in both groups. Histologic examination suggested that this effect is associated with modulating podocyte function in an SMPDL-3b-dependent manner. To our knowledge, this is the first evidence of preventing early development of proteinuria following xenogeneic GalTKO KTx in nonhuman primates.

Outcomes for Adult Lymphoblastic Leukemia (ALL) Are Mainly Influenced by Age and Status of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) After Therapy with the Modified Hyper-CVAD (with or without Rituximab) Regimen

Abstract 1524The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for pts aged 60 years or older. Rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) was administered for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009]. Early anthracycline intensification with liposomal daunorubicin and cytarabine was incorporated from 1999–2000 then omitted from the regimen [Thomas D, Cancer 116: 4580, 2010]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). Maintenance therapy was extended from 24 to 30 months inclusive of early and late intensifications (hyper-CVAD followed by weekly MTX and L-asparaginase mos 6 & 7 then mos 18 & 19) to reduce incidence of late relapses. Results in the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab were encouraging; 3-yr rates of CR duration (CRD) and survival (OS) were 60% and 50% overall, respectively. In younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (70% v 38%; P <.001% and 75% v 47%, P =.003) [Thomas D, JCO 28: 3830, 2010]. Historical experience in the adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (now treated with pediatric augmented BFM regimen) showed that the addition of rituximab improved the 3-yr CRD rates from 26% to 65% (P =.001) and 3-yr OS rates from 47% to 75% (P =.05) compared with standard hyper-CVAD. There were no significant differences in outcome for the AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). In contrast to the Burkitt leukemia experience, elderly pts with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab did not benefit (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR. For the modified hyper-CVAD regimen (no anthracycline intensification), the rate of MRD negativity by 4- or 6-color MFC (sensitivity 0.01%, assay now 8-color MFC) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% v 21%, P =.01) and lower 3-yr CR duration rates (45% v 78%, P =.01). CD20 positive pts treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% v 58%, P =.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% v 82%, P =.002), but survival rates were not statistically different (27% v 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR did not influence 3-yr CR duration rate (58% v 63%). Additional doses of rituximab have been added to the consolidation cycles (Day 1 of cycles 5 – 8) and during the maintenance phase. Upfront dose reductions have been implemented for the induction-consolidation phase according to age and performance status in order to reduce deaths in CR. MTX-cytarabine cycles now include vincristine. All pts receive 8 IT treatments in the absence of CNS disease. Younger pts age 40 – 50 yrs receive pegylated asparginase (2000 Units/m2 with capping) during the induction-consolidation phase and early/late intensifications (augmented hyper-CVAD). Elderly pts or younger pts with B-lymphoblastic leukemia with contraindications to asparaginase are now treated with the hyper-CVAD and ofatumumab regimen regardless of CD20 expression. The cumulative experience of the serial modifications to the hyper-CVAD regimen stratified by age/MRD status and the preliminary experience with the frontline version of the augmented hyper-CVAD regimen will be presented. Disclosures:Off Label Use: Rituximab in Lymphoblastic Leukemia.

Phase II Study of a Novel Reduced Toxicity Preparative Regimen for Hematopoietic Cell Allografting Combining Pentostatin (Nipent) and Targeted Doses of Intravenous Busulfan (Busulfex) with or without Rituximab (PB±R) Using a Novel Principle of CD4-Guided Immune Suppression

Abstract 3022▪FN2▪This icon denotes a clinically relevant abstractIntroduction of reduced toxicity regimens for hematopoietic cell allografting is expanding applicability of this procedure to patients not otherwise eligible to receive myeloablative preparative regimens. This phase II study evaluates the ability of a novel reduced toxicity regimen with pentostatin and busulfan (BU) to achieve ≥ 50% donor chimerism by day +28 (±7) in CD3+ blood lymphocytes. The preparative regimen consisted of a pre-conditioning treatment-phase with pentostatin 4 mg/m2 (days -28, -21, and -14) if host CD4+ counts >100/μL; and, rituximab 375 mg/m2 (days -21, -14, and -7) for CD20+ lymphoid malignancies. Conditioning phase consisted of pentostatin 4 mg/m2 (days -4, -3) and 2 doses of I.V BU: 1st dose (day -4) = 200 mg/m2, 2nd dose (day -2) = adjusted for a target cumulative area under the curve (AUC) =16, 000 micromol*min/L (±10%). Patients (pts) with CD20+ lymphoid malignancies received 2 additional rituximab doses of 375 mg/m2 (days +1, +8) post-transplant. Between 02/04/2008 and 03/18/2011, 42 pts [31(74%) male] with a median age of 53 (29–73) years, underwent allogeneic HCT for the following diagnoses: CLL/SLL=18 (43%), follicular NHL=6 (14%), mantle cell NHL=4 (10%), transformed B-cell NHL=3 (7%), DLBC NHL=2 (5%), PTCL NOS=2 (5%), HL=2 (5%), lymphoplasmacytic NHL=1 (2%), T-cell PLL=1 (2%), and AML/MDS=3 (7%). Disease status was CR1/2 (n = 4), CR3+ (n = 5), PR1/2 (n = 15), PR3+ (n = 8), and refractory disease (n = 10). Seventy six percent of cases had a Karnofsky performance score of ≥ 90. All pts received G-CSF mobilized PBSC from 20 MRD, 18 MUD, and 4 MMUD (7/8 antigen/allele). Median CD34+ dose infused was 8.93 (1.66 − 14.07) x106/kg cells. GVHD prophylaxis consisted of TAC-MTX in 36, TAC-sirolimus in 4, and TAC-MMF in 2 cases. No pts received ATG. Thirty-three pts (79%) received rituximab. Median (range) CD4 levels/μL on days -30, -23, -16, -7, and 0 were 342 (27–844), 165 (33–642), 116 (41–413), 129 (43–344), and 31 (9–161), respectively. BU AUC [median (range)] was 8204 (5830 – 12116) for dose 1, 9303 (4763 – 13433) for dose 2 and 17518 (15010 – 21215) for the total dosing interval. Neutrophil and platelet engraftment occurred at a median (range) of 17 days (15 – 28) days and 13 days (0 – 177), respectively. Donor CD3, CD33 and unsorted BM chimerisms [median (range)] on day 28 (±7) were 87% (61–100%), 100% (95–100%), and 96% (64–100%), respectively. The median (range) follow-up of survivors was 23.8 (3.4–38.6) months. Non-relapse mortality at 100-days and 2-years were 2.4% (95%CI: 0 –9.1%) and 18.6% (95%CI: 7.8–32.6%), respectively. Overall response rate was 86% (CR=74%, PR=12%). Two-year progression-free (PFS) and overall survivals (OS) for all pts were 56.4% (95%CI: 40.4–71.7) and 63.5% (95%CI: 46.7–78.8%), respectively. Disease status (CR, PR or refractory) at time of HCT did not affect 2-year PFS (p=0.83) or OS (p=0.97). Cumulative incidence of grade II-IV and III-IV GVHD by day +100 were 59% (95% CI: 43 – 75%) and 19% (95% CI: 7 – 35%), respectively. Cumulative incidence of moderate/severe chronic GVHD at 2 years was 58% (95% CI: 39 – 75%). In summary, our results demonstrate that this novel conditioning regimen of PB±R facilitates early durable CD3+ donor engraftment and results in excellent response rates with low NRM. Disclosures:Off Label Use: Pentostatin, Busulfan and Rituximab as conditioning regimens for allogeneic HCT. Perkins:PDL BioPharma: Research funding. Fernandez:Genetech: Advisory board; Otsuka: Speakers Bureau.

Rituximab in adult patients with immunosuppressive-dependent minimal change disease

Minimal change disease (MCD) is one of the leading causes of nephrotic syndrome. Steroid therapy is effective in achieving remission, but relapses, steroid dependence, and steroid resistance are therapeutic challenges. The use of second-line agents such as cyclophosphamide is associated with toxicity and adverse effects. Therefore, we studied the effect of rituximab (RTX) on proteinuria in adult patients with immunosuppressive (IS)-dependent MCD. In this single-center, prospective, open series study, 6 consecutive patients with IS-dependent MCD and frequent relapses on different IS regimens - one of them after previous RTX treatment - were included. Patients were treated with a single dose of RTX (375 mg/m²). An additional dose of RTX was administered depending on B-cell count and proteinuria. 5 out of 6 patients achieved complete remission at the end of the follow-up; the other patient had a partial remission. All patients are free of additional IS agents and other medications were remarkably reduced. Three patients had a relapse, which was successfully treated with a further RTX treatment. RTX could be an alternative in the therapy of patients with IS-dependent MCD, leading to successful cessation of other IS treatment.

Rapid Clearance of Rituximab Contributes to the Continued High Incidence of Autoimmune Complications of Chemoimmunotherapy for Chronic Lymphocytic Leukemia

AbstractAbstract 4628 Introduction:Autoimmune cytopenias (AIC) are frequently seen in patients with chronic lymphocytic leukemia (CLL). Autoimmune hemolytic anemia (AIHA) is most common, although immune thrombocytopenia (ITP) and pure red cell aplasia (PRCA) can also occur. Fludarabine (F), the most active agent used to treat CLL, has been associated with the development of AIC. Although rituximab (R) is an effective treatment for F-associated AIC, its incorporation into F-based CLL regimens has failed to consistently prevent the occurrence of AIC (incidence of 6.5% in patients treated with F, R, and cyclophosphamide (FCR) (Borthakur et al, Br J Haematol. 2007)). We hypothesized that differences in R pharmacokinetics can explain the apparent paradox of efficacy in treating but failure in preventing AIC. Patients and Methods:To determine whether the addition of R to F decreased the incidence of autoimmune complications, we compared the incidence of AIC in 2 CLL cohorts - one treated with standard dose F (25 mg/m2/d ×5 q4 wk, 1998–2004, n=21) and the other with standard dose FR (R: 375 mg/m2 q4 wk, 2005–2010, n=29). F-associated AIHA was diagnosed if the patient experienced a hemoglobin drop of ≥ 2 g/dL and had either a positive DAT or at least two of the following: absolute reticulocyte count >50K/μ L, elevated LDH, total bilirubin >1.0 mg/dL, haptoglobin <30 mg/dL. Patients with hemoglobin levels of ≥10 g/dL and either a positive DAT or at least two of the aforementioned criteria prior to the start of therapy were deemed “at-risk” of developing AIHA. We measured R serum levels during FR treatment in order to examine the CLL-specific pharmacokinetic profile of R and its potential relevance to the development of AIC. Rituximab serum levels were determined by flow cytometry, based on the binding of mAb HB43 (anti-human IgG, Fc specific) to Raji cells reacted with standards and serum samples (Beum et al, J Immunol Methods. 2004). Cycle-specific parameters of peak level, trough level, and half-life were analyzed across time. Results:Six of 21 patients (29%) in the F cohort developed AIC during therapy (2 AIHA, 3 ITP, 1 PRCA), compared to 6 of 29 patients (21%) in the FR cohort (4 AIHA, 1 autoimmune neutropenia, 1 amegakaryocytic thrombocytopenia). Four patients in the FR cohort were identified as “at-risk” for AIHA prior to therapy; 2 of these patients developed AIHA during/immediately after therapy and were treated with steroids and R, while 2 were preemptively given an additional dose of R in each of the first 2 cycles and subsequently did not develop AIHA. Within the FR cohort, median serum peak R levels of 90, 111, 135, and 173 μ g/mL were achieved in cycles 1, 2, 3, and 4, respectively. Trough R levels were undetectable in all 14 patients treated with standard dose FR at the end of cycle 1, and increased progressively over time (25%, 50%, and 71% of patients had detectable levels at the end of cycles 2, 3, and 4, respectively). By contrast, 1 of the 2 “at-risk” patients given additional R had a detectable trough level at the end of cycle 1. The serum R half-life was surprisingly short especially in cycle 1 with a median of 26 hours (range 11–73) and increased progressively in subsequent cycles (81, 133, and 194 hours in cycles 2, 3, and 4, respectively). During cycle 1, patients with heavy tumor burden (bulky lymph nodes and/or ALC>100K/μ L, n=7 patients) had a substantially shorter mean R half-life compared to those without (21 hours vs 61 hours, P=.004). Conclusion:Surprisingly, R did not significantly change the incidence of AIC in the FR cohort compared to F alone, despite its efficacy in treating this complication. Here we show that in previously untreated CLL patients, R is rapidly cleared with a half-life of only a few days in the first cycles. This effectively limits the effect of R during the initial cycles and may explain why AIC are common even with R-based chemoimmunotherapy. Furthermore, we find that the serum half-life of R is highly dependent upon tumor burden, suggesting that fixed standard dosing of R is inadequate. In patients at risk for AIC, additional doses of rituximab in the first two cycles may be able to prevent the onset of such complications. Alternatively, such patients might benefit from a non-fludarabine-containing regimen. Disclosures:Off Label Use: Rituximab was used for treatment/prevention of autoimmune hemolytic anemia.

Specific Chemotherapy and Rituximab In HIV-Infected Patients with Burkitt's Leukemia or Lymphoma. Results of a German-Spanish Study and Analysis of Prognostic Factors

AbstractAbstract 3944Background and objective. Specific immunochemotherapy has provided promising results in HIV-infected patients with Burkitt's leukemia or lymphoma (BLL), not significantly different from those observed in non-immunosuppressed patients. The results and prognostic factors in 72 HIV-positive patients with BLL treated with the same protocol in Germany and Spain are presented. Patients and method. Treatment consisted of a prephase with cyclophosphamide and prednisone, followed by cycles (A, B, C) including rituximab, iphosphamide, and high-dose methotrexate and cytarabine, among other drugs. CNS prophylaxis consisted of triple intrathecal therapy (MTX, cytarabine and dexamethasone). Reduction in the doses of MTX and ARAC was scheduled for pts. older than 55 yr. Patients in localized stages (I, II) received 4 cycles (A1,B1,C1 and A2) and those in advances stages (III, IV) or Burkitt's leukemia received 6 cycles (A1, B1, C1, A2, B2, C2) followed by 2 additional doses of rituximab at the end of chemotherapy. Response was evaluated after two cycles of chemotherapy (A1, B1).Results. 34 pts from Spain and 38 from Germany were included. No differences in the clinicobiologic characteristics or in the HIV-infection parameters were observed between the two cohorts, except for the increased use of highly active antiretroviral therapy (HAART) in the Spanish cohort before BLL diagnosis (73% vs. 6%). Overall, median age was 43 yr (range 20–69) and 66/72 (92%) pts were male, 53 pts (75%) were in advanced stages (III-IV), with extranodal involvement in 57/71 (80%) (bone marrow in 24 cases).LDH was elevated in 48 (68%) pts. ECOG score was >2 in 33 (46%) pts. Median time between HIV and BLL diagnoses was 3 (0-22) yr, mean CD4 lymphocyte count/mL 294 (SD 232), CD4 <200/mL 27/70 (39%), HIV viral load <50 copies/mL 19/68 (28%), and 26/69 (38%) received HAART before BLL diagnosis. Complete response (CR) was attained in 49 pts (81%), 7 (12%) died in induction and 4 (7%) were resistant, without differences between the two cohorts. No relapses have been observed after a median follow-up of 2.6 (0-5) yr. The overall survival (OS) probability was 74±10%, without significant differences between the two cohorts. By multivariate analysis CD4 count <200/mL (OR 7.2 [95%CI: 1.3–38.6]) and involvement of 3 2 extranodal areas (OR 7 [95%CI: 1.2–40.6]) had a negative influence on CR, whereas the unfavourable prognostic factors for OS were: CD4 count <200/mL (OR 4.4 [95%CI: 1.2–15.8]) and ECOG>2 (OR 4.4 [95%IC 1.1–17.8]). Grade 3–4 hematological toxicity was observed in 96% of the cycles, whereas grade 3–4 mucositis was registered in 30% of cycles and infections in 35%.Conclusions. In HIV-infected pts with BLL specific chemotherapy and rituximab was highly effective, although the toxicity was relevant. Performance and immunologic status and the degree of extranodal involvement were the most important prognostic factors in this series. Supported in part by grants RD06/0020/1056 from RTICC and DJCL SH 06/03. Disclosures:No relevant conflicts of interest to declare.

Long-Term Follow-Up of Patients With Follicular Lymphoma Receiving Single-Agent Rituximab at Two Different Schedules in Trial SAKK 35/98

We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.

Long-term follow-up of patients with follicular lymphoma (FL) receiving single agent rituximab at two different schedules in study SAKK 35/98

8512 Background: In FL, rituximab as a single agent obtains a response rate of 50–70% with an EFS of 1–3 years depending on the population studied. Some patients respond to this treatment for a prolonged time, so we investigated, in a clinical trial, the proportion of long-term responders and the characteristics predicting long-term response. Methods: Between 1998 and 2002, chemotherapy naïve (n = 64) or pre-treated (n = 138) FL patients received 4 weekly doses of rituximab: those responding or with stable disease were randomized to either no further treatment (observation, n = 78) or 4 additional doses of rituximab given at 2 months intervals (consolidation, n = 73). Results: At a median follow up of 8.9 years, and with all living patients having been followed for at least 5 years, the median event-free survival (EFS: time until progression, relapse, second tumor or death) is 13 months for the observation and 24 months for the consolidation arm (p=0.0012). In the observation arm 10% had no event at 5-years, the figure dropping to 4% (3/78) at 8 years, while in the consolidation arm the EFS was 26% at 5 years and remained 18% (13/73) at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was having received consolidation rituximab (hazard ratio = 0.58, CI = 0.44–0.87, p = 0.008), whereas being chemotherapy naïve, presenting with stage &lt; IV and showing a VV phenotype at position 158 of the Fc receptor RIIIA were not any more significantly prognostic in this long term analysis, in contrast to previous data with shorter follow-up. No long-term toxicity from treatment was observed. There were 21 cases of second malignancy: 11 on observation, 10 receiving the consolidation arm. Conclusions: It appears that the EFS advantage of prolonged versus short course rituximab continues for many years after the end of treatment. This seems to hold true independently from previous treatment, stage or 158-phenotype of the Fc receptor. Patients treated with 8 doses of rituximab over 1 year have approximately 25% and 20% chance to remain in remission at 5 and 8 years respectively. [Table: see text]

Phase II Multicenter Study of Bendamustine Plus Rituximab in Patients With Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma

Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab. Patients received rituximab 375 mg/m(2) intravenously on day 1 and bendamustine 90 mg/m(2) intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs. Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%). Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

Specific Intensive Chemotherapy Plus Rituximab for Advanced Burkitt's Lymphoma or Leukemia in HIV-Positive and Negative Adult Patients.

A previous PETHEMA protocol (PETHEMA ALL3/97) proved that HIV-positive patients with Burkitt's lymphoma (BL) and Burkitt-like acute lymphoblastic leukemia (ALL3) had similar outcome than HIV-negative patients (Haematologica 2003; 88:445–53). We aimed to study the impact of the addition of rituximab to our previous protocol in terms of toxicity and efficacy, with special attention to HIV-positive patients. Consecutive patients between 18 and 55 years and diagnosed with advanced stage (stage III-IV or bulky stage II) BL/ALL3 between July 2003 and August 2006 received induction therapy including a pre-phase with cyclophosphamide (CPM) and prednisone (PDN), followed by cycle A (rituximab, iphosphamide, VCR, dexamethasone -DXM-, HD-MTX, ARA-C and VM-26), cycle B (rituximab, VCR, HD-MTX, CPM, DXM and doxorubicin) an cycle C (rituximab, DXM, VDN, HD-MTX, HD-ARAC and VP-16) up to six cycles (A1,B1,C1,A2,B2,C2) followed by two additional rituximab doses. CNS prophylaxis consisted of IT MTX+ARA-C+DXM given twice in cycles A and once in cycles B for a total of 8 doses.Results: 36 patients (17 HIV-negative and 19 HIV-positive) were included. Both groups of patients were comparable for age, gender, ECOG score, BM and CNS involvement, bulky disease, LDH and albumin serum levels. Fifteen patients had bone marrow infiltration of whom 3 reached ALL3 criteria. Four out of 19 HIV positive patients begun treatment with HAART at the time of diagnosis and 15 were already under treatment. Median follow-up was 1.7 years (range 0.8–4.1). Main results of therapy are summarized in table 1. No significant differences in CR, DFS or OS were observed between HIV-positive and negative patients. Grade 4 neutropenia and thrombocytopenia were almost constant and lasted a median of 7 and 5 days respectively (range 0 – 39). Other frequent grade 3–4 toxicities were hepatic (5% of cycles), mucositis (18%) and infectious (18%). Episodes of grade 3–4 extrahematological toxicity were more frequent in HIV-positive patients (77% of episodes of mucositis, p=0.04 and 72% of infections). Treatment delays >7 days due to toxicity of previous cycle were also more frequent in HIV-positive patients (41% vs 24%, p= 0.04). In conclusion, our results prove that the addition of rituximab to a specific BL/ALL3 treatment is also feasible and highly effective for HIV-positive patients with similar results to HIV- negative patients in terms of efficacy although with higher toxicity.Total (%) (n=36)HIV+ (%) (n=19)HIV- (%) (n=17)CR after two cycles30 (83)15 (79)15 (88)Toxic death (1st 2 cycles)5 (14)3 (16)2 (12)Resistance000Toxic death in CR2 (6)2 (11)0Relapses during treatment1 (3)01 (6)Relapses off treatment000Project. 1-year prob. DFS90%87%93%Project. 1-yr prob. OS78%73%82%

Efficacy and Safety of Rituximab Combined with ESHAP Chemotherapy for the Treatment of Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

BackgroundWe evaluated the efficacy and safety of adding rituximab to nonanthracycline ESHAP (etoposide/methylprednisolone/ cytarabine/cisplatin) chemotherapy for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL). Patients and MethodsPatients with intermediate- or high-grade NHL were to receive 6 rituximab doses and 6 ESHAP cycles. Rituximab 375 mg/m2 was administered 1 week and 1 day before cycle 1 of standard ESHAP (etoposide 40 mg/m2 on days 1-4; methylprednisolone 500 mg/m2 on days 1-5; cytarabine 200 mg/m2 on day 5; and cisplatin 25 mg/m2 on days 1-4). Rituximab was repeated before the third and fifth 21-day ESHAP cycles (on days 48 and 90 of protocol, respectively), followed by 2 additional rituximab doses after cycle 6 (on days 134 and 141 of protocol). Use of growth factors was permitted. Thirteen patients were enrolled (median age, 56 years); all had previously treated NHL, 12 (92%) had diffuse large B-cell lymphoma, 10 (77%) had stage III/IV disease, and 2 (15%) had chemotherapy-refractory disease. ResultsThe most common grade 3/4 toxicities were neutropenia and thrombocytopenia, with 3 cases of febrile neutropenia. Seven patients exhibited complete response (CR) and 3 had partial response, for an objective response rate of 77%. Median duration of response for all responders was 14 months (range, 2-51 months). Among 6 patients completing all 6 cycles, 4 (67%) had a CR, 1 had a partial response, and 1 had progressive disease. Three of the 4 CRs have remained for a median of 48 months (range, 46-51 months). ConclusionRituximab plus ESHAP led to durable responses with acceptable toxicity in patients with relapsed/refractory aggressive NHL, most of whom had advanced disease.

Phase II Results of Bendamustine in Combination with Rituximab in Relapsed Indolent and Mantle-Cell Non-Hodgkin's Lymphoma.

Objective: The objective of this study was to evaluate the efficacy and safety of bendamustine HCl (TREANDA®) in combination with rituximab in patients with relapsed non-Hodgkin's lymphoma (NHL).Background: Bendamustine is a novel hybrid, alkylating agent with single-agent activity in multiple hematologic and solid tumors. It induces cell death via both apoptosis and the apoptosis-independent pathway of mitotic catastrophe. The combination of bendamustine and rituximab has been shown to exhibit a synergistic antitumor effect on NHL cells.Methods: This Phase II, multicenter study enrolled adult patients with relapsed, indolent B-cell or mantle-cell NHL who were not refractory to rituximab (defined as progression ≤6 months of last rituximab dose). Patients received rituximab 375 mg/m2 intravenously (IV) on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week before the first cycle of bendamustine and 4 weeks after the last cycle.Results: The intent-to-treat (ITT) population included 66 patients (59% men) with a median age of 60 years (range, 40–84). Indolent histologic phenotype was seen in 54 patients with the following histologic subtypes: follicular center cell (61%), small lymphocytic (15%), lymphoplasmacytic (3%), and marginal zone (3%); 18% had mantle-cell lymphoma (MCL). A total of 85% of patients had stage III/IV disease. These patients relapsed from a median of 1 prior chemotherapy (range: 0–5), with 56% having had prior treatment with rituximab. Patients with no prior chemotherapy relapsed following biologic therapy. In the ITT population, the overall objective response rate (ORR) was 94% (complete response [CR]/complete response unconfirmed [CRu], 41%; partial response [PR], 53%); 6% had stable disease. The ORR for the 12 MCL patients was 92% (CR/CRu, 42%; PR 50%). For all patients, the median duration of response and progression-free survival has not been reached after a median follow-up of 8.3 months (range, 0.14–31 months). Grade 3/4 neutropenia was seen in 41% of patients (7%, febrile neutropenia). Common nonhematologic toxicities (grade 1/2, grade 3, grade 4) were nausea (68%, 0%, 0%) and fatigue (53%, 5%, 0%); one patient had grade 3 sepsis. No alopecia was observed.Conclusions: Bendamustine administered in combination with rituximab produced a high objective response rate and was generally well tolerated in patients with relapsed indolent and mantle-cell NHL who were not refractory to rituximab. These results suggest that the combination of bendamustine and rituximab may be comparable in activity to R-CHOP, and further studies of this combination are warranted.

A phase II, multicenter study of bendamustine HCl plus rituximab in relapsed indolent B-cell and mantle-cell non-Hodgkin’s lymphoma (NHL)

7528 Background: Bendamustine HCl, a novel alkylating hybrid agent, has single-agent activity in multiple hematologic and solid tumors. In vitro data have demonstrated the multifunctional mechanisms of bendamustine by which cell death occurs via both apoptosis and mitotic catastrophe. Bendamustine has shown activity in NHL cell lines that are refractory to conventional alkylator chemotherapies. The combination of bendamustine and rituximab has shown a synergistic effect on NHL cells. The efficacy and safety of bendamustine in combination with rituximab in patients with relapsed NHL were evaluated. Methods: This phase II, multicenter study enrolled adult patients with relapsed, indolent, rituximab-sensitive B-cell or mantle-cell NHL. Patients received rituximab 375 mg/m2 IV on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat population included 67 patients (57% males; median age, 60 years) with indolent NHL (81%) or mantle-cell NHL (16%) (data not available [3%]). A total of 81% of patients had stage III/IV disease. Patients had relapsed from a median of 1 prior therapy; 37% had prior treatment with rituximab. In the 57 evaluable patients, the overall objective response rate (ORR) was 87% (complete response [CR], 33%). The ORR for the 9 evaluable mantle-cell NHL patients was 89% (CR, 33%). For all patients, the median duration of response and progression-free survival had not been reached after a median follow-up of 3.7 months (range, 0–14.2 months). This therapy was well tolerated. Most commonly reported nonhematologic toxicities were grade 1/2 gastrointestinal events, with nausea being the greatest (38%). The primary grade 3/4 hematologic toxicity was neutropenia (29%), with 1 event of sepsis. Conclusions: Bendamustine in combination with rituximab was well tolerated and produced high response rates in patients with relapsed indolent and mantle-cell NHL. These results suggest bendamustine in combination with rituximab provides a potential benefit over single-agent rituximab therapy. [Table: see text]

ESHAP with Rituximab Is Highly Efficacious with Durable Responses in Patients with Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma.

Introduction: Patients with relapsed/refractory aggressive non-Hodgkins lymphoma have limited options for further therapy; ESHAP is an active regimen in these patients. Velasquez, et al. reported a 37% complete response and 27% partial response; however, the median duration of survival in this group of patients was 14 months. The addition of rituximab to CHOP improved outcomes in front-line therapy for NHL. Since there is no reported data on the safety and efficacy of ESHAP with rituximab, we have evaluated the combination in patients with relapsed/refractory aggressive lymphoma.Methods: The regimen consisted of: rituximab (375 mg/m2) given on days 1 and 6, standard ESHAP therapy (etoposide 40 mg/m2 IV/2h day 1–4; methylprednisolone 500 mg/m2 days 1–4; cytarabine 2 g/m2 IV/3h on day 5 and cisplatin 25 mg/m2 CIV days 1–4) on day 8. Rituximab was repeated prior to the third and fifth ESHAP cycle, followed by two additional doses of rituximab after cycle 6 of ESHAP. Cycles were repeated every 21 days. 13 patients enrolled in the study. Median age was 57 years (range 37–70); there were 11 males and 2 females. 10/13 (77%) of patients had advanced disease (stage III/IV). Histology was: Diffuse Large Cell Lymphoma in 12 patients (92%) and Mantle Cell Lymphoma in 1 patient (8%). 9 of 13 patients, according to the IPI, had intermediate or high risk disease. All patients had one or more of the following therapies: CHOP or CHOP-like regimens (with or without radiation therapy), CHOP with rituximab, fludarabine/rituximab or radioimmunotherapy.Results: Among the 13 patients enrolled, 6 patients completed all 6 cycles. Among these, 4 (66.6%) achieved a CR; 1 PR (16.7%) and 1 PD (16.7%); the overall response rate was 83%. 3 of 4 patients remain in a CR at a median of 48 months (range 46–51 months); 1 pt relapsed after 24 months. The remaining 7 patients received a median of 2 cycles: 1 patient received autologous peripheral blood stem cell transplantation after 3 cycles of therapy with 2.20 x 106/kg CD 34+ cells, 1 patient achieved a CR after 3 cycles for stage 1 disease and remains in a CR at 14 months, 1 patient achieved a CR after two cycles and was lost to follow up, and 1 patient achieved a CR after 3 cycles, however relapsed in five months. 3 patients had PD after cycle 1,1 and 2. 3 of 13 patients had received prior therapy with rituximab; 1 patient achieved a PR and went on to autologous peripheral blood stem cell transplantation, 1 patient achieved a CR of 5 month duration after 3 cycles, and 1 patient had progressive disease. There were five episodes of treatment-related delays in therapy. Two patients required dose reductions. There were three episodes of neutropenic fever.Conclusion: Without high dose therapy and stem cell transplantation, long term remission in relapsed/refractory aggressive NHL is rare. Our study represents the first reported data on the efficacy and safety of ESHAP and rituximab in this group of patients. This combination therapy leads to durable responses with acceptable toxicity and may be considered as a viable alternative therapy in patients who are not candidates for stem cell transplantation. In addition, after effective cytoreduction with ESHAP and Rituximab, stem cell collection was adequate in our patient who underwent autologous stem cell transplantation.

Rituximab as Successful Therapy in a Patient with Refractory Paroxysmal Cold Hemaglobinuria.

Background: Paroxysmal cold hemaglobinuria (PCH) is caused by an IgG autoantibody which behaves as a biphasic hemolysin, attaching to RBCs at cold temperatures and activating complement at warmer temperatures, leading to hemolysis. This antibody, known as the Donath-Landsteiner antibody (DL-A), frequently shows specificity for the P-antigen. PCH was historically associated with syphilis infection. More recently, the DL-A has been found primarily in children with acquired autoimmune hemolytic anemia (AIHA) following a viral illness. In adults, PCH is rare and may occur as an idiopathic disease or in association with a lymphoproliferative disorder. Cases in children usually resolve spontaneously, whereas the adult form can be chronic and pose a therapeutic challenge, since treatment with steroids and splenectomy may be ineffective. Recently rituximab has been demonstrated to be a useful agent in treating AIHA that is resistant to conventional therapies. Case Report: A 64-year-old woman presented to another hospital with three months of progressive weakness. She was found to be severely anemic. Gastrointestinal blood loss was ruled out. Extensive work up was obtained with CT imaging and bone marrow biopsy, which showed no evidence of malignancy. A hemolytic process was identified and she was placed on oral prednisone 60mg daily. The patient then presented to Cedars-Sinai Medical Center three months later with recurrent fatigue and a hemoglobin concentration (Hb) of 6.6 g/dL. Lab values revealed an elevated reticulocyte count (7.9%), WBC 27.6, total bilirubin 3.5 mg/dL, indirect fraction 3.4 mg/dL, elevated LDH 445 U/L, absent haptoglobin, and microspherocytes on peripheral blood smear. The Direct Antiglobulin (Coombs) Test (DAT) was positive with an anti-complement reagent and negative with an anti-IgG reagent, leading to the suspicion of a DL-A or cold agglutinin. Cold agglutinin titer was normal. A Donath-Landsteiner test was positive, confirming the diagnosis of PCH. Steroids were rapidly tapered and she was given rituximab 375 mg/m2. Her Hb increased and evidence of hemolysis ceased. The patient received 3 additional doses of rituximab weekly. Her Hb recovered to normal. The patient did well for 9 months until she presented again with acute hemolysis (Hb 8.8 g/dL.) The DAT was again positive with an anti-complement reagent and negative with an anti-IgG reagent. She was given a single dose of rituximab with cessation of hemolysis. She received another 3 doses, which resulted in stabilization of her Hb. She remains well at 6 months follow-up.Discussion: The most frequent form of AIHA is due to a warm, IgG antibody and is commonly responsive to steroids or splenectomy, whereas in cold agglutinin disease, caused by an IgM antibody these therapies are usually ineffective. The use of rituximab has been reported as a useful treatment for both warm and cold AIHA refractory to conventional therapy. This is the first case report to our knowledge of a patient with adult PCH refractory to steroids successfully treated with rituximab. This patient responded dramatically to rituximab on two separate occasions, and has remained in remission since the second cycle after treatment with this single agent. Rituximab may represent an effective therapy for adult patients with chronic PCH.

Bendamustine HCl (TREANDATM) Treatment in Combination with Rituximab Results in Objective Responses in Patients with Refractory/Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma: Results from Phase II Multicenter Study (SDX-105-02).

Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agent with a purine-like ring system and novel mechanisms of action that exhibits impressive single-agent activity in multiple hematologic and solid tumors. In vitro data indicate that bendamustine induces cell death as a result of both apoptosis and mitotic catastrophe, resulting in potent cell-killing activity in cancer cells that are resistant to traditional chemotherapy (alkylating and fludarabine-containing regimens). In vitro data have also demonstrated a synergistic effect with rituximab for the treatment of non-Hodgkin's lymphomas (NHL). A Phase II multicenter study (SDX-105-02) was conducted to determine the efficacy and toxicity of the combination of bendamustine with rituximab in relapsed NHL patients.Methods: The intent-to-treat (ITT) population consists of 54 patients with relapsed indolent CD20-positive B-cell or mantle cell NHL, enrolled from 22 sites in the US and Canada. Median age of the patients was 60 years (range 40–84); 59% had follicular NHL, 6% had small lymphocytic lymphoma, 4% had lymphoplasmacytoid lymphoma, 4% had marginal zone lymphoma, and 17% had mantle cell lymphoma; and 72% of all patients had Stage III/IV disease. Patients relapsed from a median of 1 prior therapy. Patients received rituximab, 375 mg/m2 IV on day 1, and bendamustine, 90 mg/m2 on days 2 and 3, every 28 days for 4–6 cycles. All patients received an additional dose of rituximab 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle.Results: Of the 54 ITT patients, 37% had prior treatment with rituximab. Forty-three patients are currently evaluable for response, as defined by the International Working Group. The overall response rate was 84%, with complete response in 21% and partial response in 63% of patients. The median duration of response has not yet been reached after a median follow up of 3.6 months. Minimal toxicity was observed. The most common nonhematologic toxicities included grade 1/2 gastrointestinal complications. The primary grade 3/4 hematologic toxicity was neutropenia (with no neutropenic fever), observed in 22% of patients. Grade 3/4 anemia and thrombocytopenia were observed in only 1 patient. No alopecia was observed.Conclusions: Bendamustine, administered in combination with rituximab, produced high objective response rates with minimal toxicity in patients with refractory indolent and mantle cell NHL, including patients that previously failed alkylating and fludarabine-containing regimens. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.

A phase I–II study of rituximab, ifosfamide, mitoxantrone andetoposide (R-IME) for B cell non-Hodgkin’s lymphoma prior to and after high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT)

This phase I-II study describes the safety of rituximab, ifosfamide, mitoxantrone and etoposide (R-IME) as an induction regimen prior to high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT), and rituximab given post-HDC-ASCT for B cell non-Hodgkins's lymphoma. This study also measured the effect on disease burden and stem cell contamination. Patients with relapsed, refractory or poor risk B cell lymphomas were eligible. Patients were treated with two cycles of R-IME; all non-progressing patients under-went a third cycle and peripheral blood stem cell (PBSC) collection. Patients underwent HDC-ASCT and those patients in remission after HDC-ASCT were treated with four additional doses of rituximab. Tumor cell contamination was measured at baseline and in the PBSC. Serial immunoglobulin levels were measured. Patients were followed for time to treatment failure (TTF) and overall survival (OS). Thirty-two patients were enrolled. Thirty patients had at least stable disease after two cycles of R-IME. Twenty-nine underwent stem cell collection. The response rate to R-IME induction was 77% (20/26) with 35% (9/26) complete response(CR). Stem cell mobilization was successful in 93% (27/29) of patients. The response rate to R-IME induction and HDC-ASCT was 95% with a confirmed CR of 68%. Median follow-up was 28 months; the median TTFand OS have not been reached. There was a significant decline in stem cell tumor cell contamination and a significant decline in IgG without an increase in infections. Forty-three per cent of patients had transient neutropenia after post-transplant rituximab. R-IME is an effective cytoreductive and mobilization regimen. There appears to be a reduction in the number of lymphoma cells in the stem cell product and the toxicity is manageable.