Fludarabine And Rituximab Research Articles

Sequencing Therapy for Elderly Chronic Lymphocytic Leukemia Patients in the Era of Novel Therapies: An Overview of Randomized Clinical Trials

Background:For most of the elderly or unfit CLL patients, treatment algorithms focus on achievement of clinical response, relief of symptoms and prolongation of life expectancy. Comorbidities, frailty and reduced functional status in elderly patients make some of the standard treatments intolerable and less efficacious. However, recent advancements in understanding of CLL biology, approval of target agents including novel monoclonal antibodies and kinase inhibitors have expanded the horizons for treatment of CLL in elderly.Methods:We conducted a literature search on PubMed, Embase, Web of Science and ClinicalTrials.gov which was completed on July 1, 2018. To assess the CLL treatment protocols in the elderly population, we included data from phase II and phase III clinical trials from the last decade (Jan 2008 to Jan 2018).Results:From a total of 1259 studies, we selected 34 studies (n=3122) after inclusion criteria were met. The patients included are from the age group of ≥65 years with the mean age of 68.8 years. Male to female ratio was 3:2. On comparison of different parameters to look for the drug or regimen efficacy, we found that ibrutinib is very effective and tolerable in older (aged ≥65 years) treatment-naïve (TN) as well as relapsed refractory patients (RR), with overall response rate (ORR) of 91% for combined group in one study when compared to ofatumumab. When used in combination with ublituximab, the ORR peaked to 80% as compared to ibrutinib alone in patients with high risk cytogenetics (ORR=47%, p<0.001). Phase III RESONATE trial showed a comparison between ibrutinib and chlorambucil treated del 17p negative elderly patients; ibrutinib was superior in terms of ORR (86% vs. 35%) and overall survival (OS) (2-year OS, 98% vs. 85%, p=0.001). The OS with ibrutinib turned out to be 89% showing better disease control as compared to idelalisib (OS= 61%) when used in combination with rituximab, with a 33% reduction in mortality with ibrutinib as compared with idelalisib in RR patients. The combination of rituximab with idelalisib has shown promising results in patients with specific mutations (i.e. 100% ORR in those with del (17)/ Tp53 mutations, 97% ORR in those with unmutated IGHV). Similarly, when compared with placebo and rituximab combination progression free survival (PFS) was 13%, idelalisib is found to have PFS of 66% at 12 months in patients with del 17p/ Tp53 mutations and unmutated IGHV status. Moreover, in a phase II study, ofatumumab monotherapy showed ORR of 72%. In newly diagnosed (ND) CLL, an ORR of 98% is found with the pentostatin, cyclophosphamide, rituximab, and lenalidomide regimen. Other worth sharing results include; complete remission (CR) in 71% (24 out of 34 included) patients who were given lenalidomide as an initial therapy, with OS of 88% and ORR of 65%. The OS is surprisingly as high as 97.9% in those who were given pentostatin and cyclophosphamide in combination with ofatumumab. Traditional chemotherapy with fludarabine and rituximab (FR) showed OS of 67% in one study with rates of grades II and III-IV acute GVHD as 60% and 15% respectively. The most common hematological side effects seen with ibrutinib in one of the studies are neutropenia (12%), thrombocytopenia (4%) and anemia (7%). The non-hematological complications may be secondary due to cytopenias (infections, pneumonia, bleeding, and neutropenic fever) or due to constitutional symptoms like myalgia, fatigue, vomiting, or nausea.Conclusion:The rapid clinical development of novel therapy agents has changed the prognosis for CLL patients. Ibrutinib is considered as a standard option and an up front therapy for high risk CLL patients especially who are elderly and have del 17p, despite its significant toxicity profile in very elderly patients (80 years and above) where multiple deaths were reported. Future prospects include ibrutinib combinations with frontline chemo-immunotherapy (CIT) and other novel agents for TN and RR del 17p negative patients. DisclosuresNo relevant conflicts of interest to declare.

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register (www.clinicaltrialsregister.eu, 2008-001430-27)

First immunochemotherapy outcomes in elderly patients with CLL: A retrospective analysis

To date, the majority of trials on chronic lymphocytic leukemia (CLL) focused on patients considerably younger than the median age of onset for CLL. As a result, no definitive treatment exists for elderly patients, especially less medically fit patients. The objectives of this study are to examine the impact of comorbidities on outcome as well as to compare three different therapeutic regimens in outcome efficacy. We retrospectively identified 143 patients aged >65 years, who received fludarabine, cyclophosphamide, and rituximab (FCR) (n=49), fludarabine and rituximab (FR) (n=74), or rituximab with chlorambucil (R-CLB) (n=20) as first initial immunochemotherapy. At current follow-up (median: 24 months), the proportion of patients with a clinical response was higher with FCR (75%) than FR (57%) and R-CLB (28%). For FCR, FR, and R-CLB patients, 2-year overall survival (OS) was 94%, 76%, and 73%, respectively, (p=0.14), while 2-year progression-free survival (PFS) was 90%, 58%, and 30% (p<0.001). In the fludarabine based regimen (FR and FCR) population, higher rituximab doses (500mg/m(2) vs. 375mg/m(2)) correlated with prolonged PFS. Despite the retrospective nature of this study, we demonstrate that elderly patients with CLL benefit from frontline immunochemotherapy, and emphasize the importance of maintaining rituximab dose intensity.

Fludarabine and rituximab for relapsed or refractory hairy cell leukemia

AbstractThe purine analogs, pentostatin and cladribine, induce high remission rates when used as first-line monotherapy for hairy cell leukemia (HCL); however, patients continue to relapse. Re-treatment with the same or alternate purine analog produces lower response rates and a shorter duration of response. Fludarabine is another purine analog widely used in indolent lymphoid cancers, often in combination with rituximab, but there are few reports of its use in HCL. We identified 15 patients treated in British Columbia with fludarabine and rituximab (FR) from 2004 to 2010 for relapsed/refractory HCL after first-line cladribine (n = 3) or after multiple lines of therapy (n = 12). All patients with available response data responded to FR. With median follow-up of 35 months, 14 patients remain progression-free, whereas 1 patient has developed progressive leukemia and died. Five-year progression-free and overall survivals are 89% and 83%, respectively. FR is a safe and effective therapeutic option for relapsed/refractory HCL.

Obatoclax in Combination with Fludarabine and Rituximab (FR) Is Well-Tolerated and Shows Promising Clinical Activity in Relapsed CLL/SLL

Abstract 2865Obatoclax is a small molecule mimetic of the BH3 domain of Bcl-2 family proteins. Obatoclax is broadly specific, with activity against Bcl-2, Bcl-X, Bcl-w and Mcl-1. CLL cells overexpress Bcl-2, Bcl-XL and Mcl-1 in particular, and obatoclax can induce apoptosis of CLL cells in vitro. A phase 1 study of single-agent obatoclax in heavily pretreated largely refractory CLL patients demonstrated that the dose-limiting toxicity was neurologic, including euphoria and ataxia, leading to a maximum tolerated dose of 28 mg/m2 given over 3 hours every 3 weeks. One PR was observed along with biologic activity demonstrated by reductions in lymphocyte counts and improvements in cytopenias. We therefore undertook this phase 1 study of the combination of obatoclax with FR in CLL patients relapsed after at least one prior therapy and in need of therapy again. Obatoclax was given as a three hour infusion on days 1 and 3 at three dose levels, 10, 14, and 20 mg/m2 per dose. Fludarabine was given at 25 mg/m2 days 1–5, and rituximab 375 mg/m2 day 1 following an option to split the dose in cycle 1. Thirteen patients were enrolled, seven men and six women, with median age 58. 5 (38%) had stage 3–4 disease. FISH showed one patient with del17p, one with complex karyotype, and five with del11q. Six of nine patients evaluable had high risk unmutated IGHV, and nine of ten patients evaluable were positive for ZAP-70. The median number of prior therapies was two, with 9 patients having had prior fludarabine-based combination chemotherapy, 10 patients having had prior rituximab, and 8 patients having had prior alkylator-based combination chemotherapy. The study therapy was well-tolerated, with a median of five cycles administered. One dose-limiting toxicity (DLT) was observed at the 20 mg/m2 obatoclax dose; this DLT was a greater than two week treatment delay for persistent grade 2–3 neutropenia in a patient who had had a similar event previously with FR alone. This DLT led to expansion of the third and highest cohort, which enrolled seven patients with no further DLTs observed. Other grade 3–4 toxicities have been limited and include neutropenia (n=5), thrombocytopenia (n=2), fever without neutropenia (n=2), increased ALT/AST (n=1), and dizziness (n=1). Neurologic side effects were easily managed and resembled alcohol intoxication, including grade 1–2 euphoria (n=6), ataxia (n=5), dizziness (n=6), anxiety (n=4), speech impairment (n=4) and confusion (n=3). The ORR by NCI-WG criteria was 85% (11/13; 90% CI 59–97%) with 15% CR (2/13; 90% CI 3–41%) and 38% nPRs (5/13; 90% CI 17–65%). With the addition of CT scan measurement of lymphadenopathy the ORR declined to 54% (7/13; 90% CI 29–78%) with no CRs. With a median follow-up of 26 months from the start of the study, three patients are in ongoing remission, six have relapsed with three receiving further therapy to date, two patients have gone on to stem cell transplantation, and two patients have died of disease. The median time to progression is 20 months (95% CI 9, 35 mos). We were able to demonstrate increased apoptosis compared to baseline in peripheral blood CLL lymphocytes during cycle 1 therapy in 9 of 13 patients, using Annexin V propidium iodide staining. We conclude that the FR-obatoclax regimen is well-tolerated and highly active in a relapsed CLL population. An extension of this study to increase the frequency of obatoclax dosing to days 1–3, and to change the chemotherapy backbone to FCR, is planned pending the availability of obatoclax. Disclosures:Brown:Calistoga: Consultancy, Research Funding; Celgene: Honoraria, Research Funding; Genzyme: Research Funding; GSK: Research Funding; Pharmacyclics: Consultancy.

Oral fludarabine and rituximab as initial therapy for chronic lymphocytic leukemia or small lymphocytic lymphoma: population-based experience matches clinical trials

Clinical trials report that fludarabine and rituximab (FR) as initial therapy for chronic lymphocytic leukemia (CLL) improves progression-free and overall survival (OS) when compared historically to fludarabine alone. To determine whether similar results are achievable with oral FR in a community-based setting, we conducted a population-based analysis of patients treated for CLL or small lymphocytic lymphoma (SLL) in British Columbia, where FR is standard initial therapy. Ninety-eight patients received FR for CLL/SLL from 2004 to 2009. Two- and 4-year OS was 90% and 73%, respectively (median not reached); 2- and 4-year treatment-free survival (TFS) was 69% and 54% (median 4.0 years). Age ≥ 60 years or ≥ 70 years had no effect on OS or TFS. Toxicity led to treatment discontinuation in 13%. FR with oral fludarabine was safely, conveniently and successfully given to community-based patients, irrespective of age, for first-line therapy for CLL/SLL, achieving OS and TFS similar to those in clinical trials.

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab After Fludarabine and Rituximab (FR) Induction Therapy Improves the Complete Response (CR) Rate in Chronic Lymphocytic Leukemia (CLL) and Eradicates Minimal Residual Disease (MRD) but Is Associated with Severe Infectious Toxicity: Final Analysis of CALGB Study 10101.

Abstract 210 Background:Alemtuzumab (Campath-1H) is approved for the treatment of CLL. CALGB sought to determine whether alemtuzumab can improve the CR rate and eradicate MRD after induction chemoimmunotherapy by performing a phase II study administering FR followed by alemtuzumab consolidation to previously untreated, symptomatic CLL patients (pts). We previously reported preliminary toxicity data (Lin et al. ASH 2007) and now report final toxicity and response data. Methods:Pts received fludarabine 25 mg/m2 IV on days 1–5, and rituximab 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and then only on day 1 of cycles 2–6, repeated every 28 days for up to 6 cycles. Four months after the last fludarabine dose, pts with stable (SD) or responsive disease by NCI 96 criteria received SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Pts received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia. When unacceptable serious infectious toxicity was noted in pts who received alemtuzumab after achieving CR from FR induction, the study was amended so that only PR or SD pts received alemtuzumab after FR. Results:Median age of pts (n=102) was 61 years (range, 23–82), 74% were male, and 30% were Rai stage III/IV. FR was well tolerated; 93% of pts received at least 3 cycles, and 77% completed all 6 cycles. Overall, complete and partial response (OR, CR, PR) rates after FR induction were 90%, 29% and 61%, and 15% were MRD negative by flow cytometry. Fifty-eight pts received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab (n=58) were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. By intent-to-treat for all patients enrolled, OR, CR, and MRD negativity were attained by 90%, 57% and 42% of pts. With a median follow up of 34 months, median progression free survival (PFS) was 37 months (95% CI, 33–43 months); PFS was 73% and overall survival (OS) 86% at 2 years. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. Similarly, there were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small. Grade 3–4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3–4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. As we previously reported, 5 pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These grade 5 toxicities occurred both during and for up to 7 months after alemtuzumab therapy. Conclusions:Alemtuzumab consolidation improved the CR and MRD negative rates after FR induction. However, alemtuzumab consolidation resulted in significant toxicity, particularly severe infections in pts who achieved a CR after FR induction. Longer follow up is needed to determine if the improved CR and MRD negative rates following alemtuzumab consolidation will eventually result in improved PFS or OS, especially among pts who achieved a PR after FR induction. Disclosures:Lin:GlaxoSmithkline: Consultancy, Employment; Genentech: Consultancy; Bayer: Consultancy. Off Label Use: Use of alemtuzumab as consolidation therapy. Byrd:Genentech: Consultancy, Research Funding. Link:Genentech: Consultancy. Rai:Genentech: Consultancy; Bayer: Consultancy.

Brisk Lymphocytosis with Aberrant Expression of CD5 in the Leukemic Phase of Follicular Lymphoma.

Abstract 5033 BackgroundFollicular lymphoma (FL) is generally considered to be an indolent, low-grade lymphoma. However, rarely, FL can present with a marked lymphocytosis, in a so-called leukemic phase, with a significant impact on response to therapy and outcome. We summarize here our experience with two such cases. Case 1Pt #1 was diagnosed with stage IVB/S (FLIPI 5) FL on 6/2006. He presented to us after failing to obtain a remission with 9 cycles of CVP+R (Cyclophosphamide, Vincristine, Prednisone, and Rituximab), followed by 6 cycles of FR (Fludarabine and Rituximab). After consultation with our service, he elected to be treated with BR (Bendamustine+Rituximab) in 8/2008 in preparation for allogeneic transplantation. He later opted to defer transplant, and died 3/2009, approximately 33 months from the time of diagnosis. Case 2Pt #2 was diagnosed with stage IVB/S (FLIPI 3) FL on 5/2006. He was initially treated with 2 cycles of CVP+R. Because of progressive disease during therapy, his regimen was changed to CHOP+R (Cyclophosphamide, Adriamycin, Vincristine, Prednisone, and Rituximab). Following his third cycle he was found to have hydronephrosis from progressive lymphadenopathy. A biopsy was obtained and revealed a transformation to diffuse large b-cell lymphoma. This occurred approximately 4 months from the time of diagnosis. He went on to receive 3 cycles of ESHAP+R (Etoposide, Methylprednisolone, Cytarabine, Cisplatin, and Rituximab), followed by 2 cycles of a regimen composed of Ifosfamide, Navelbine, Gemcitabine, and Rituximab, both without improvement. He was ultimately discharged to Hospice and died 3/2007, approximately 11 months from the time of diagnosis.Clinical and pathologic features of these two cases at presentation are shown in Table 1.Table 1Clinical and Pathologic Features of the Two Cases of FLCaseAge/GenderWBC(ul)/ Lymphocyte (ul) (%)Lymph Node, Liver, Spleen and BM Involvement (%)PhenotypeFISH for t(14;18)Other Karyotype FindingsPt#160/M267,000/226,950 (85%)Hepatosplenomegaly, BM (90%)Kappa+ CD5+ CD10+ CD23+Positive (92.5%)6q-, 5q- (12.5%)Pt#259/M99,100/68,380 (69.0%)Massive Lymphadenopathy, Splenomegaly, BM (60%)Lambda+ CD5+ CD10+ CD23-Positive (96%)del(13q14) (95%) ConclusionIn our case series, leukemic presentation in FL was associated with a poor response to therapy and limited survival. Interestingly, both patients demonstrated aberrant expression of CD5, and required further molecular characterization to rule out alternative diagnoses such as chronic lymphocytic leukemia and mantle cell lymphoma.Although not uniformly seen in FL with lymphocytosis, small series in FL, as well as other lymphomas, suggest that lymphocytosis is more likely to occur with CD5 expression. An even smaller data set exists on outcomes in CD5 positive leukemic FL, with much of data similarly suggesting poor outcomes despite aggressive chemotherapy regimens and autologous stem cell transplant.FL when accompanied by a brisk lymphocytosis and aberrant CD5 expression may herald a more aggressive disease. Whether similarly aggressive chemotherapy regimens and stem cell transplant can alter the dismal outcome in these patients has yet to be determined. DisclosuresOff Label Use: Lenalidomide is an immune modulator drug currently being studied for efficacy in conjunction with Rituxan in chronic lymphocytic leukemia. This abstract summarizes a unique side effect, hypercalcemia, seen among a small cohort of patients on this study.

Anthracycline-fludarabine-containing regimens with or without rituximab in the treatment of patients with advanced follicular lymphoma

: Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients. : In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments. : The complete remission (CR) rate for BACOP/FND was 62%. After a median follow-up of 60 months, the failure-free survival (FFS) and overall survival (OS) rates at 4 years were 53% and 77%, respectively. The CR rate for BACOP/FR was 79%. After a median follow-up of 36 months, the FFS and OS rates at 4 years were 56% and 97%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty-five of 42 bcl-2-positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia. : The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline-fludarabine-containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. (c) 2009 American Cancer Society.

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab Results in Severe Infectious Toxicity in Previously Untreated CLL Patients Who Achieve a Complete Response (CR) after Fludarabine and Rituximab (FR) Induction Therapy: Interim Safety Analysis of the CALGB Study 10101.

Alemtuzumab (Campath-1H) is approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Given the increasing role of chemoimmunotherapy in the treatment of CLL, the Cancer and Leukemia Group B initiated a phase II study administering FR followed by alemtuzumab for remission consolidation to previously untreated, symptomatic CLL patients (pts). Pts received fludarabine 25 mg/m2 IV on days 1–5; rituximab 50 mg/m2 IV on day 1, 325 mg/m2 IV on day 3, and 375 mg/m2 IV on day 5 of cycle 1, and 375 mg/m2 IV on day 1 of cycles 2–6; every 28 days for up to 6 cycles. Four months after the last dose of fludarabine, pts with stable or responsive disease by NCI 96 response criteria received consolidation therapy with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, 30 mg on day 5, and 30 mg thrice weekly thereafter for 6 weeks. Pts received standard pneumocystis (PCP) and Varicella Zoster Virus prophylaxis and were monitored weekly for Cytomegalovirus (CMV) reactivation by PCR, antigen test, or hybrid capture. We report safety data on the first 51 pts who received alemtuzumab. Median age was 60 years (range, 23–82), and 75% were male. Of 34 pts who attained an NCI 96 partial response (PR) after FR induction, 9 (26%) experienced unacceptable toxicity to alemtuzumab, as defined prospectively by the study. Eight grade 3 toxicities (4 opportunistic infections, 3 CMV reactivation, 1 hemorrhagic cystitis), and 1 grade 5 EBV lymphoproliferative disorder were observed. In contrast, 17 pts had CR after FR induction and 8 (47%) had unacceptable toxicity. Complications included grade 3 infections in 3 pts (2 CMV, 1 cryptococcus) and 5 grade 5 infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia). These infections occurred both during therapy and for up to 16 months following therapy. Analysis of alemtuzumab pharmacokinetics and genomic tumor features is currently ongoing. Continuous real-time safety monitoring prompted a study amendment to prohibit further pts in CR after FR induction from receiving alemtuzumab consolidation. Accrual of new pts to the trial is complete. Only pts in PR or with stable disease after FR induction continue to receive alemtuzumab consolidation, with close monitoring for infectious and other toxicities. Detailed response and outcome data will be reported when all pts have completed therapy. We conclude that alemtuzumab cannot be safely administered as consolidation therapy to pts who achieve an NCI 96 CR following induction chemoimmunotherapy. The safety and feasibility of alemtuzumab consolidation for pts in PR after FR induction remains under study, and such therapy should not be pursued outside of a clinical trial due to concerns about serious infectious morbidity and mortality.

Predictive Factors to Hypogammaglobulinemia and Non-Neutropenic Infection Complications after Rituximab/Chemotherapy Treatment

Rituximab is a chimerical human/mouse monoclonal anti-CD20 antibody successfully applied in B-cell lymphoproliferative disorders. The suppression of B-lymphocytes may induce hypogammaglobulinemia and increased risk for infection. These complications are rarely observed as a result of monotherapy with rituximab but have been often noted following combination with aggressive chemotherapy or in the setting of autologous stem cell transplantation (ASCT). In an attempt to study the role of rituximab in induction of hypogamma, we analyzed the frequency of this phenomenon, its possible causes, infectious complications and infection-related mortality in lymphoma patients treated with different chemotherapy regimens with or without rituximab. We analyzed 136 patients who received rituximab concurrently with chemotherapy (R-Chemo) and 46 patients who were treated with chemotherapy only, with follow-up period of up to five years. Following R-Chemo, 17 cases (12.5%) of severe hypogamma (defined as <60% of normal IgG range) were diagnosed, 21 patients (15.5%) had mild and moderate hypogammaglobulinemia, and 16 (12%) were found with decreased IgM alone. Multivariate analysis showed a significant increase of severe hypogamma when >6 doses of rituximab were given. Moreover, rituximab in >8 doses leaded to severe hypogamma in 50% of patients compared to 11.8% in patients treated with <8 doses (p .006) associated with 3 times more infections. The type of chemotherapy regimen didn't influence development of the hypogamma. Even myeloablative chemotherapy used in combination with rituximab before ASCT slightly increased the rate of severe hypogamma (p .06). Only the combination of fludarabine and rituximab (FR) compared to other Chemo-R, induced non-significant increase of severe hypogammaglobulinemia (21% vs 11%; p .02), severe non-neutropenic infection 19.4% vs 5.0% (p .005) and infection-related mortality 24% vs. 6% (p. 004). Multivariate analysis showed that patients post FR treatment were 6.4 times more prone to have severe infections than post other Chemo-R regimens (95% CI 1.49–27.0). Age and gender of patients, type of lymphoma, bone marrow involvement didn't affect the immunoglobulin level. We found a strong correlation between the IgG level and frequency of severe infections and mortality from infection (p <.01). Finally, the pre-treatment hypogamma was not found as a risk factor for infection. However, the duration of this phenomenon was found important: patients with severe hypogamma lasted >6 months were 4.5 times more likely to have severe infection (95%CI 1.19–18.5). In conclusion, we emphasized the importance of follow-up on immunoglobulin level in patients receiving rituximab. Hypogammoglobulinemia is not rare and is a clinical important phenomenon, leading to increase in infection and mortality rate in patients receiving R-Chemo. Longer treatment with more than six doses of rituximab significantly increases the incidence of hypogammoglobulinemia. The type chemotherapy regimen, except for fludarabine didn't affect the incidence of hypogammaglobulinemia and infection rate in our patients.

Salvage therapy following failure or relapse after FCR chemo-immunotherapy as initial treatment for chronic lymphocytic leukemia (CLL)

7009 Background: CLL treatment evolved from single agents to combination chemotherapy to chemo-immunotherapy e.g. fludarabine and rituximab (FR) or with cyclophosphamide (FCR). Reports usually describe initial response, time-to-treatment failure (TTF), and survival. Follow-up of relapsed/failed patients (pts) is rarely reported. This report summarizes our experience with such pts after FCR. Methods: 300 pts initially treated with FCR were analyzed. 15 pts failed, 6 died in remission, six developed Richter's transformation (RT) or another malignancy (14) or relapsed (77). Ten have not required therapy. Results: 67 pts received first salvage therapy (S1) with a variety of regimens. The median age was 59 years and 70% were male. Most pts were Rai stage III - IV (56%). Median TTF after initial FCR was 31 months. Initial FCR responses were CR (36 pts), NPR (10 pts), PR (14 pts), and failure (7 pts). Following S1 therapy, CR was obtained in 17%, NPR (8%) and PR (14%). Initial FCR response of CR or NPR, Rai stage, and β2-microglobulin significantly predicted S1 response. The initial TTF did not predict salvage response. OR rate for FCR-based regimen alone or with alemtuzumab (A) or lumilixamab was 62%, rituximab (R) regimens (31%) and A + R (6/9, 67%). Median survival after S1 therapy was 30 months (28 deaths) and was significantly longer for CR/NPR pts (46 months) than PR/Fail (10 months) P&lt;.001. Duration of initial FCR response, β2-microglobulin level and Rai stage predicted survival (P&lt;.01) but the S1 regimens did not. 9/13 pts who eventually received an allogeneic transplant (allo SCT) are still alive (8 in CR). Conclusions: The results of salvage therapy following FCR initial treatment are unsatisfactory. Patients who failed to obtain a CR or NPR to FCR or S1 therapy should be considered for allo SCT. No significant financial relationships to disclose.

BACOP/FR combination chemotherapy as front-line treatment of follicular lymphoma. A phase II study of the Gruppo Italiano Studio Linfomi (GISL)

7571 Background: Doxorubicin, fludarabine and rituximab are all considered active drugs in the treatment of follicular lymphoma (FL). Howevere, the best induction regimen is still matter of debate. In 2003 the GISL started a phase II trial to assess efficacy and tolerability of a combination of bleomycin, adriamycin, ciclophosphamide, vincristine and prednisone (BACOP) followed by fludarabine and rituximab (FR). Methods: To be included in the study pts should have: histologically confirmed diagnosis of FL, stage II-IV disease, age 18–70, active disease. Pts were assessed for t(14:18) by PCR on bone marrow at diagnosis and at time of response assessment. Treatment consisted in three courses of BACOP followed by 4 courses of FR for pts in partial remission (PR) or complete remission with persistent t(14:18) positivity (CRM+). Pts achieving molecular complete remission (CRM-) stopped therapy after BACOP. The main endpoints of the study were overall response rate (CR+PR) (ORR) and failure free survival (FFS). A final accrual of 60 assessable pts was planned, however a faster accrual than expected allowed to enrol 91 pts between May 2003 and Dec 2005. Results: At time of present analysis 61 pts were valuable for final response: Median age was 56 yrs (25–70), male gender 56%, 18% with systemic symptoms, 88% in stage III-IV disease, 13% had elevated LDH and 21% bulky disease. Molecular marker was present in 30 out of 57 pts. 19 pts achieved a CR after three courses of BACOP; four of them, being in CRM- stopped therapy. 28 pts achieved CR with four additional courses of FR. At the end of treatment CR and ORR were 77% and 90% respectively; relatively to pts with molecular marker at diagnosis CRM- was 60%. Toxicity data are available for 57 patients: grade III/IV anemia and neutropenia were observed in two (3%) and 18 (32%) cases respectively; severe infections occurred in two cases, both bacterial pneumonia. After a median follow-up of 17 months (0.5–31) 12 events were observed: Major toxicity, four; non responders, two; relapse, six. Conclusions: BACOP/FR is a feasible and safe regimen for the treatment of patients with FL with promising efficacy. More mature follow-up is required to confirm these preliminary results. No significant financial relationships to disclose.