Concurrent Fludarabine Research Articles

High ten-year remission rates following rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) with interferon maintenance in indolent lymphoma: Results of a randomized Study.

We report a single-centre, randomized study evaluating the efficacy and safety of concurrent fludarabine, mitoxantrone, dexamethasone (FND) and rituximab versus sequential FND followed by rituximab in 158 patients with advanced stage, previously untreated indolent lymphoma, enrolled between 1997 and 2002. Patients were randomized to 6-8 cycles of FND followed by 6 monthly doses of rituximab or 6 doses of rituximab given concurrently with FND. All patients who achieved at least a partial response received 12months of interferon (IFN) maintenance. Median ages were 54 and 55years. The two groups were comparable with the exception of a higher percentage of females (65% vs. 43%) and baseline anaemia (23% vs. 11%) in the FND followed by rituximab group. Complete response/unconfirmed complete response rates were 89% and 93%. The most frequent grade ≥ 3 toxicity was neutropenia (86% vs. 96%). Neutropenic fever occurred in 21% and 16%. Late toxicity included myelodysplastic syndrome (n=3) and acute myeloid leukaemia (n=5). With 12·5years of follow-up, no significant differences based on treatment schedule were observed. 10-year overall survival estimates were 76% and 73%. 10-year progression-free survival estimates were 52% and 51%. FND with concurrent or sequential rituximab, and IFN maintenance in indolent lymphoma demonstrated high response rates and robust survival.

Alemtuzumab-Cyclosporine Versus Tacrolimus-Methotrexate-Sirolimus for Graft-Versus-Host Disease Prophylaxis in Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors: Final Results of a Randomized Trial

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) can provide a curative therapy for hematological malignancies but may result in complications such as relapse, infection, and acute and chronic graft versus host disease (GVHD). Two divergent approaches to GVHD prophylaxis (post-HSCT depletion of donor lymphocytes vs. suppression of immune activation) in a reduced-intensity, matched-unrelated donor setting were compared in a randomized, open label, phase 2 prospective trial (NCT00520130), powered to assess the incidence of severe cGVHD using NIH criteria.Methods: Hematological malignancy patients received disease-specific induction chemotherapy DA-EPOCH-FR or FLAG (Salit et al, JCO 2012; 30:830) for disease control and host lymphodepletion to CD4+ cell target <100/µl. All patients received identical conditioning with concurrent fludarabine (30 mg/m2/d x4) and cyclophosphamide (1200 mg/m2/d x4), followed by mobilized T-replete peripheral blood allograft from a matched unrelated donor. Patients were randomized to receive alemtuzumab 20 mg/d x5 and cyclosporine (AC) or tacrolimus, sirolimus, and methotrexate (TMS).Results: 81 pts (NHL=25, HL=8, CLL=18, AML/MDS=10, CML=3, CTCL/PTCL=5, ALL=4, MM=2, other=6), median age 50 yrs (range, 21-71) were included in the study (AC=42, TMS=39). The two arms were similar in age, gender, disease, relapse risk (Kahl), HCT-comorbidity index, and donor HLA match (8/8 or 7/8). Median time to neutrophil engraftment was 9 vs. 11 days in AC vs. TMS, respectively (p=0.017). There were no differences in platelet recovery (p=0.96). One case of graft failure occurred in a myeloma patient on the AC arm.D100 mortality probabilities were 12% (95% CI, 5-25) and 10% (95% CI, 4-24) in AC and TMS, respectively (p=0.20). Median survival in AC was 18.8 mo and 41.7 mo in TMS, with a median follow-up of 53 mo in AC and 50.6 mo in TMS. 3yr OS was comparable: AC 42% (95% CI, 28-57) vs. TMS 58% (95% CI, 42-73) (p=0.20). The 3yr malignancy progression rate was higher in the AC arm (AC 51% (95% CI, 34-65) vs. TMS 21% (95% CI, 10-35), p= 0.0062). 3yr relapse related mortality rates were 29% (95% CI, 16-44) vs. 14% (95% CI, 5-29) (p=0.067) and non-relapse mortality 29% (95% CI, 16-43) vs. 28% (95% CI, 14-43) (p=0.75) in AC vs. TMS, respectively. The most common grade ≥3 adverse events (CTCAE 4.03) within 100 d post-transplant were infections (22%) with more viral infections in the AC arm (p=0.0007). Reactivation of CMV occurred earlier in the AC arm, incidence 58% (95% CI, 42-71) vs. 24% (95% CI, 12-38) by D100 (p=0.035).Rates of aGVHD were similar; Gr II-IV at 6 mo in AC 38% (95% CI, 23-53) vs. TMS 41% (95% CI, 26-57) (p=0.59); Gr III-IV at 6 mo AC 21% (95% CI, 11-35) vs. TMS 13% (95% CI, 5-26) (p=0.61). In contrast, significantly lower rates of any grade cGVHD occurred in the AC arm compared to TMS at 36 mo (27% (95% CI, 14-41) vs. 59% (95% CI, 40-74)) (p=0.0076). The incidence of severe cGVHD was strikingly different: AC 5% (95% CI, 1-15) vs. TMS 31% (95% CI, 16-47) (p=0.0007). In the Cox model, the only prognostic factor for severe or any cGVHD was the TMS treatment arm, HR 6.8 (95% CI, 1.5-30.3, p=0.012) and HR 2.3 (95% CI, 1.1-4.8, p=0.026), respectively.Lymphocyte recovery (ALC 500/µL) was markedly delayed in AC, median 76 vs. 16 d (p<0.0001). NK-cell recovery was disparate during the first month (p <0.0001, D28: 31 vs. 270/µl), but similar thereafter. B-cell reconstitution was negligible in both through 6 mo. AC resulted in profound and prolonged deficit in T cells. CD4+ cells were significantly reduced in AC vs. TMS through 1 yr (p <0.0001, D28: 21 vs. 285/µl, 1yr: 131 vs. 447/µl). CD8+ disparity persisted for 6 mo (p<0.0001, D28: 6 vs. 205/µl, 6 mo: 58 vs. 429/µl). Naïve T-cells were significantly reduced in AC through 6 mo (p<0.0001, median naïve cell frequency (AC vs TMS) Treg 2.8 vs 8.4%; nonTreg CD4+ 1.0 vs 23.7%; CD8+ 2.9 vs 20.0%). Assessment of CD4+ and CD8+ TCR Vβ repertoire diversity by spectratyping demonstrated significantly lower diversity in AC at 6 mo (p=0.003).Conclusions: This prospective, randomized trial demonstrates that the use of AC when compared with TMS led to a significant reduction in incidence of severe and overall cGVHD. These two GVHD prophylaxis regimens had similar incidences of aGVHD but very different effects on post-alloHSCT immune reconstitution, infection and relapse. Future strategies for cGVHD prevention will need to further address these issues. DisclosuresOff Label Use: There is currently no FDA approved product for GVHD prevention or therapy. The GVHD prophylaxis regimens described in this study (Alemtuzumab-Cyclosporine and Tacrolimus-Methotrexate-Sirolimus) are used off-label as GVHD prophylaxis regimens in reduced-intensity allogeneic HSCT.

Myeloablative I-131-Tositumomab with Escalating Doses of Fludarabine and Autologous Hematopoietic Transplantation for Adults Age ≥ 60 Years with B Cell Lymphoma

Myeloablative therapy and autologous stem cell transplantation (ASCT) are underutilized in older patients with B cell non-Hodgkin (B-NHL) lymphoma. We hypothesized that myeloablative doses of 131I-tositumomab could be augmented by concurrent fludarabine, based on preclinical data indicating synergy. Patients were ≥ 60 years of age and had high-risk, relapsed, or refractory B-NHL. Therapeutic infusions of 131I-tositumomab were derived from individualized organ-specific absorbed dose estimates delivering ≤ 27 Gy to critical organs. Fludarabine was initiated 72 hours later followed by ASCT to define the maximally tolerated dose. Thirty-six patients with a median age of 65 years (range, 60 to 76), 2 (range, 1 to 9) prior regimens, and 33% with chemoresistant disease were treated on this trial. Dose-limiting organs included lung (30), kidney (4), and liver (2) with a median administered 131I activity of 471 mCi (range, 260 to 1620). Fludarabine was safely escalated to 30 mg/m2 × 7 days. Engraftment was prompt, there were no early treatment-related deaths, and 2 patients had ≥ grade 4 nonhematologic toxicities. The estimated 3-year overall survival, progression-free survival, and nonrelapse mortality were 54%, 53%, and 7%, respectively (median follow up of 3.9 years). Fludarabine up to 210 mg/m2 can be safely delivered with myeloablative 131I-tositumomab and ASCT in older adults with B-NHL.

Fludarabine combined with radiotherapy in patients with locally advanced NSCLC lung carcinoma: a phase I study

Background and purposeFludarabine is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. We designed a phase I trial exploring concurrent fludarabine and radiotherapy in patients with advanced non-small cell lung cancer (NSCLC) to determine the maximum tolerated dose (MTD) of fludarabine given with concurrent irradiation.Materials and methodsThirteen patients with stage IIIB NSCLC received thoracic irradiation of 60 Gy. Fludarabine was administered during the 5th and 6th week of radiotherapy. Doses started at 10 mg/m2 per day and increased by steps of 3 mg/m2 per day.ResultsAt a daily dose of 16 mg/m2, one out of six patients developed a grade 4 leukopenia, and one a grad 3 pneumonitis. Further grade III toxicity was not observed. The dose of 13 mg/m2 was identified as the MTD. All patients developed a fludarabine dose-dependent lymphocytopenia.ConclusionFludarabine can be safely administered concurrently with radiation at a daily dose of 13 mg/m2 during the final 2 weeks of radiotherapy. Further prospective clinical studies are required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of locally advanced inoperable NSCLC.

Concurrent Fludarabine and Cyclophosphamide As a Reduced Intensity Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation Ablates Host T-Cells and Results in Rapid Full Donor Chimerism

Abstract 1937▪▪This icon denotes a clinically relevant abstract Background:Reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) is associated with decreased transplant-related mortality (TRM). However, RIC-HSCT is typically associated with higher rates of mixed chimerism and graft rejection compared to myeloablative conditioning. Host T-cell immunity has been demonstrated to be an important predictor of engraftment and establishment of full donor chimerism in clinical studies. It was previously demonstrated in murine models that concurrent fludarabine (F) and cyclophosphamide (C) ablated host T-cells to the extent of myeloablative total body irradiation with reduced myeloid cell toxicity and prevented rejection of fully MHC-disparate marrow allografts (Petrus et al, BBMT, 2000). While fludarabine and cyclophosphamide are agents commonly used in reduced intensity conditioning regimens, their concurrent use has never been reported. Here, we analyze results from 102 patients who received the reduced intensity conditioning FC regimen in the setting of matched related or unrelated allogeneic stem cell transplantation. Methods:On four consecutive protocols at the National Cancer Institute, hematologic malignancy patients received induction chemotherapy followed by the FC regimen: fludarabine 30 mg/m2/d, days −6 to −3 and cyclophosphamide 1200 mg/m2/d, days −6 to −3. Peripheral blood stem cells were infused on Day 0. GVHD prophylaxis was either a calcineurin inhibitor alone or in combination with other agents. Results:102 patients (females, 36; males, 66) were enrolled on study. Median age was 50 yrs (range, 21–71). Diagnoses included AML/MDS (n = 2), HL (n = 12), DLBCL (n = 35), CLL (n = 13), FL (n = 12), MCL (n = 10) and TCL (n = 10). Median number of prior regimens = 3 (range, 1 – 9); 25 patients had prior autologous transplant. Transplants were performed using HLA - matched sibling donors (n = 82) or 10/10 matched unrelated donors (n = 20). At the time of study entry, disease status was defined as chemosensitive (n = 53) or chemorefractory (n = 49). Patients were in CR (n = 19), PR (n = 26), SD (n = 37), or PD (n = 19); one patient was not evaluable. 101 of 102 patients (99%) proceeded to transplant. Median CD3+, CD4+, and CD8+ lymphocyte counts after induction chemotherapy (pre-FC conditioning) were: 150 cells/μl (1–1557), 80 cells/μl (0–1332), and 52 cells/μl (52–1195), respectively. Following FC conditioning, median CD3+, CD4+, and CD8+ counts were: 3 cells/μl (0–65), 3 cells/μl (0–93), and 0 cell/μl (0–22) (each p< 0.0001). All patients engrafted. Median time to neutrophil engraftment (ANC > 500) was 10 days and platelet engraftment (plt > 20 48 hours post transfusion) was 11 days. At Day +14, median CD3+ chimerism was 100% (range 30–100%), CD14+/15+ chimerism was 100% (range 6–100%), and whole blood chimerism was 100% (range 11–100%). Patients maintained full donor chimerism as evidenced by median 100% (range 50–100%) whole blood chimerism at Day +100. By Day +28 post-transplant, 41 patients (40%) achieved (n=24) or maintained (n=17) a CR and 38 patients (37%) achieved or maintained a PR for an overall response rate of 77%. Fourteen patients had SD and 4 had PD. Day +100 and one year TRM were 7% and 15% respectively. With a median follow-up of 92.4 months, 1 yr and 2 yr EFS were 52% and 41% and 1 yr and 2 yr OS were 68% and 58% respectively. Both EFS (p = 0.0003) and OS (p = 0.01) were significantly associated with response to FC. Acute GVHD grades II-IV and III-IV occurred in 56% and 23% of patients respectively. The rate of chronic GVHD was 65%. Grade IV non-hematologic toxicities as of Day +28 post-transplant included cardiac (n = 7, n = 1 Grade V), pulmonary (n=9), GI (n=9), and neurologic (n=3). While 62% of patients had at least one Grade III infection, only 2 patients had a Grade IV infection. Conclusion:The concurrent FC conditioning regimen resulted in host T-cell ablation and rapid full donor chimerism characteristic of myeloablative conditioning regimens. Furthermore, RIC-HSCT using concurrent FC achieved a high rate of complete remissions with an acceptable safety profile. Disclosures:No relevant conflicts of interest to declare.

A phase 2 study of concurrent fludarabine and rituximab for the treatment of marginal zone lymphomas

The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa-associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37-77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4.3-35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65-96%), with 54% complete responses. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI 63-96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.

A Phase 2 Study of Fludarabine and Rituximab for the Treatment of Marginal Zone Lymphomas.

The marginal zone lymphomas are a recently defined group of related diseases likely arising from a common cell of origin, the marginal zone B cell. The clinical presentation varies; data on therapy for subtypes other than gastric MALT has been largely limited to retrospective case series. We therefore undertook this prospective phase 2 study of fludarabine 25 mg/m2 for 5 days with rituximab 375 mg/m2 on day 1 for the treatment of marginal zone lymphomas. To be eligible, patients were required to have newly diagnosed or relapsed, histologically confirmed MALT, marginal zone lymphoma, or a CD5/CD10 negative low-grade B cell lymphoproliferative disorder. They could not be candidates for curative local therapy. From 2004 to 2007, 26 patients were enrolled with a median age of 64 (31–84) and a median time from diagnosis to treatment of 1.6 months. This was the initial therapy for 21 of 26 patients (81%). Seven were diagnosed with MALT lymphomas (27%), 12 with nodal marginal zone lymphomas (46%), 3 with splenic marginal zone lymphoma (12%) and 4 with CD5/10 negative low-grade lymphoproliferative disorders (15%). FISH for BCL-6, trisomy 3, MALT1 and chromosome 1 rearrangements was attempted on 18 available tissue biopsies. Of these, four were normal, three showed BCL-6 rearrangement with other abnormalities, four had chromosome 3 abnormalities, two MALT1 rearrangements and one chromosome 1 abnormality. The majority of patients had stage IV disease (18; 69%), with 5 stage 3, 2 stage 2 and 1 stage 1E disease. Of the 23 patients who have completed therapy, 18 completed at least 4 cycles (78%), with 12 patients completing the planned 6 cycles (52%). Nine patients discontinued therapy due to unacceptable toxicity (39%), six for hematologic toxicity, two for grade 3 rash and one for a delayed grade 3 reaction to rituximab. Of 26 patients evaluable for toxicity, 46% developed grade 4 toxicity (solely hematologic), and 35% grade 3 toxicity. Grade 3–4 toxicities included: neutropenia 14 (54%), thrombocytopenia 5 (19%), febrile neutropenia 2 (8%), rash 3 (11%), myositis 1 (4%), allergic reaction 1 (4%). Two delayed opportunistic pneumonias were observed, one Nocardia and one P. jiroveci. The ORR in the 23 patients who have completed therapy and are evaluable for response is 83% (95% CI 61–95%), with 12 patients achieving CR/CRu (52%). Three patients have relapsed. Two patients have died, one due to small cell lung cancer diagnosed after study enrollment, and the other due to urosepsis with bone marrow aplasia. At the median follow-up of 1.8 years, the PFS is 84% (95% CI 68–99%), and OS 94% (95% CI 82–99%). Concurrent fludarabine and rituximab is therefore a highly effective regimen in the treatment of marginal zone lymphoma but one which is complicated by significant hematologic toxicity and allergic hypersensitivity. These toxicities prevented half the patients from completing the planned therapy and were more severe than usually seen in other low-grade lymphomas, emphasizing the need to study marginal zone lymphomas as a separate entity.

Final Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab Plus Fludarabine in Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group).

Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab results in 33 to 50% responses in refractory CLL. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3× a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics reveal lower initial levels compared to IV. The UKCLL02 study assessed the safety and efficacy of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3× a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. Of 53 patients (median age 64, range 41 to 79) enrolled 2 patients died before receiving alemtuzumab and 1 withdrew consent. 50 patients have completed therapy and 49 are evaluable. Responses to alemtuzumab monotherapy (n=49) were 5 MRD negative CR, 2 MRD positive CR, 15 PR (including 1 MRD negative patient who remained cytopenic), 25 NR and 2 patients died on treatment. Alemtuzumab was given for a median of 18.8 weeks (range:1.6–24) with a median dose of 1370.5mg (range 106–2323mg). 17 patients (6 PRs and 11 NRs) received concurrent fludarabine and SC alemtuzumab (median 2 courses fludarabine [range 1–3]). 2 NR achieved a PR and 1 PR achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 24/49(49%) including 6 MRD negative patients (5CRs and 1 PR). IgVH gene was unmutated (>98% germ line homology ) in 23/31 patients. FISH revealed poor risk deletions (11q and/or 17p) in 28/46 patients (17p- in 15, 11q- in 7, both in 6). 25/38 patients had dysfunction p53 in a functional assay. 22/38 patients (58%) with poor risk deletions (11q- and/or 17p-) and/or p53 dysfunction responded to treatment, including 5 patients who achieved MRD-negative CRs, 3 MRD-positive CR, and 14 PR. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 26 patients (diameter 1 to 18cm), fever in 8 and rigors in 4. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (18); febrile neutropenia (10); invasive fungal infection (4); pneumonia (7) and septicaemia (2). On the combination, CMV reactivation (3 cases) and septicaemia in (1). All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 26 and 41 patients on alemtuzumab monotherapy as well as in 1 and 5 patients on combined therapy, respectively. The median survival for responders was 25 months compared to 13 months for non-responders. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) was given. The addition of oral fludarabine improves the response rates with acceptable toxicity.

Interim Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab Plus Fludarabine in Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group).

Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab is approved in fludarabine refractory CLL resulting in 33 to 50% responses. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3x a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics suggest the need for prolonged therapy with little efficacy data in fludarabine-refractory CLL. We report on the UKCLL02 study to assess the safety and effectiveness of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3x a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab in the trial could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. In this planned interim analysis of the first 44 patients (median age 66, range 41 to 79) 2 patients died before receiving alemtuzumab, and 5 remain on therapy. Of the remaining 37 patients, one withdrew consent and 36 patients have completed therapy. Responses to alemtuzumab monotherapy (n=36) were 2 MRD negative CR, 1 MRD positive CR, 11 PR (including 1 MRD negative patient who remained cytopenic), 20 NR and 2 died. Alemtuzumab was given for a median 12 weeks (range: 2–24) with a median dose of 913mg (range 106 to 2173mg). 12 patients (8 NR and 4 PR) received concurrent fludarabine and SC alemtuzumab (median 2.5 courses fludarabine [range 1–3]). 2 non-responders achieved a PR and one of the partial reponders achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 16/36 (44%) including 3 MRD negative patients (2 CRs and 1 PR). IgVH gene was unmutated (>98% homology to germ line DNA) in 11/14. FISH revealed poor risk deletions (11q and/or 17p) in 21/34 patients (17p- in 9; 11q- in 6 and both in 6). p53 functional analysis is available for 23. 20/23 had p53/ATM dysfunction or deletion. 10/21 evaluable cases with del (11q23)/del (17p) responded to therapy. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 20 patients (diameter 1 to 18cm), fever in 7 and rigors in 3. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (10); febrile neutropenia (9); invasive fungal infection (3); pneumonia (2). On the combination, CMV reactivation in 2 cases but no other grade 3+ infections. All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 16 and 25 patients on alemtuzumab monotherapy as well as in 1 and 2 patients on combined therapy, respectively. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) is required. The addition of oral fludarabine improves the response rates with acceptable toxicity.

Optimising alemtuzumab therapy for refractory B cell chronic lymphocytic leukaemia (CLL)

6522 Background: Approximately half of CLL patients do not respond to alemtuzumab and others progress after responding to alemtuzumab. We report here factors predictive for lack of response and approaches to achieve the best outcome for these patients. Methods: 91 patients with relapsed or refractory CLL received alemtuzumab aiming for minimal residual disease (MRD) negativity. Factors correlated with response were reviewed and strategies for overcoming resistance or relapse are reported. Results: The chance of response was associated with lymph node size (p <0.0001): High dose methyl prednisolone (HDMP; 1g/m2/day x5 every 4 weeks; 4 patients) or CHOP (1) were used to reduce bulky nodes prior to alemtuzumab. 2 of 5 had a resolution of lymph nodes with both achieving MRD negative remissions with alemtuzumab. The other 3 did not respond to HDMP or alemtuzumab. 8 patients refractory to alemtuzumab, due to bulky lymph nodes, received alemtuzumab with concurrent fludarabine and 6 responded (2 MRD negative, 2 CR, 2 PR). In addition, 9 patients relapsing after a median of 23 months (range 8–46) from alemtuzumab were retreated of which 5 responded (1 MRD negative, 2 CR, 2 PR): 2 of the non-responders then received alemtuzumab combined with fludarabine with 1 achieving MRD negativity. One patient was treated on relapse directly with the alemtuzumab/fludarabine combination and achieved a MRD negative CR. Thus 11 refractory patients received combined alemtuzumab and fludarabine with 8 responding (4 MRD negative, 2 CR, 2 PR). Conclusions: Gross lymphadenopathy predicts for poor response to alemtuzumab but therapy with HDMP or CHOP followed by alemtuzumab can be effective in achieving MRD negative CR. The majority of alemtuzumab refractory patients (8/11) respond to the addition of fludarabine. Retreatment with alemtuzumab was effective for 3 of 7 relapsing patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ilex Oncology Ltd. Ilex Oncology Ltd. Ilex Oncology Ltd.

Optimising alemtuzumab therapy for refractory B cell chronic lymphocytic leukaemia (CLL)

6522 Background: Approximately half of CLL patients do not respond to alemtuzumab and others progress after responding to alemtuzumab. We report here factors predictive for lack of response and approaches to achieve the best outcome for these patients. Methods: 91 patients with relapsed or refractory CLL received alemtuzumab aiming for minimal residual disease (MRD) negativity. Factors correlated with response were reviewed and strategies for overcoming resistance or relapse are reported. Results: The chance of response was associated with lymph node size (p <0.0001): High dose methyl prednisolone (HDMP; 1g/m2/day x5 every 4 weeks; 4 patients) or CHOP (1) were used to reduce bulky nodes prior to alemtuzumab. 2 of 5 had a resolution of lymph nodes with both achieving MRD negative remissions with alemtuzumab. The other 3 did not respond to HDMP or alemtuzumab. 8 patients refractory to alemtuzumab, due to bulky lymph nodes, received alemtuzumab with concurrent fludarabine and 6 responded (2 MRD negative, 2 CR, 2 PR). In addition, 9 patients relapsing after a median of 23 months (range 8–46) from alemtuzumab were retreated of which 5 responded (1 MRD negative, 2 CR, 2 PR): 2 of the non-responders then received alemtuzumab combined with fludarabine with 1 achieving MRD negativity. One patient was treated on relapse directly with the alemtuzumab/fludarabine combination and achieved a MRD negative CR. Thus 11 refractory patients received combined alemtuzumab and fludarabine with 8 responding (4 MRD negative, 2 CR, 2 PR). Conclusions: Gross lymphadenopathy predicts for poor response to alemtuzumab but therapy with HDMP or CHOP followed by alemtuzumab can be effective in achieving MRD negative CR. The majority of alemtuzumab refractory patients (8/11) respond to the addition of fludarabine. Retreatment with alemtuzumab was effective for 3 of 7 relapsing patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ilex Oncology Ltd. Ilex Oncology Ltd. Ilex Oncology Ltd.

A phase I study of fludarabine combined with radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinoma

Background and purpose: Fludarabine, 9-β- d-arabinofuranosyl-2-fluoroadenine, is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. In this framework, we designed two phase I trials (one conducted at M.D. Anderson Cancer Center in Houston, and the other conducted in two Belgian hospitals) exploring concurrent fludarabine and radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinomas (HNSCC). Materials and methods: Fludarabine was administered i.v. daily 3–4 h before the last 10 fractions of a standard radiation fractionation regimen (70 Gy in 7 weeks). The main objective of the trials was to determine the maximum tolerated dose (MTD) of fludarabine in this particular setting. Twenty-eight patients with stage T2–T4, any N, M0 were included in the study. Fludarabine doses started at 7.5 mg/m 2 per day (3 mg/m 2 per day in Houston) and increased by steps of 2.5 mg/m 2 per day (3 mg/m 2 per day in Houston). Results: The addition of fludarabine at increasing doses to radiation did not result in increased intensity or duration of skin (18% grade 3 dermatitis) or mucosal (60% grade 3 mucositis) radiotoxicity compared to what was expected for radiation alone. At a daily dose of 17.5 mg/m 2, two patients out of five (40%) developed a grade 4 neutropenia, of whom one developed a neutropenic fever. This dose was set as the MTD. All patients developed a fludarabine dose-dependant lymphocytopenia. The plasma F-ara-A concentration peaked after the 30-min infusion in a dose-dependent fashion and reached an average peak concentration of approximately 2 μM for doses of 15 mg/m 2 and higher. Conclusions: This study demonstrates that fludarabine can be safely administered concurrently with radiation at a daily dose of 15 mg/m 2 during the final 2 weeks of radiotherapy. A phase II trial will be required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of moderately to locally advanced HNSCC.