Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity

2021 ◽  
pp. 107815522110643
Author(s):  
Laura Sánchez Togneri ◽  
Ignacio Duran ◽  
Fernando Rodríguez Fernández ◽  
Leticia de las Vecillas
Keyword(s):  
Skin Testing ◽  
Drug Hypersensitivity ◽  
Cell Cancer ◽  
Symptomatic Treatment ◽  
Cytokine Release ◽  
Release Reaction ◽  
Negative Results ◽  
Disease Stabilization ◽  
Infusion Reactions ◽  
Grade 3

Introduction Nivolumab is a fully human IgG4 monoclonal antibody (moAb) against programmed cell death protein 1, approved for the treatment of over ten types of cancer. The use of this and other moAbs has augmented considerably in recent years and this in turn has caused an increase of hypersensitivity reactions (HSR). Case report We present the case of a patient with metastatic renal cell cancer (RCC) who developed a grade 3 cytokine release reaction (CRR) to nivolumab. The maintenance of the symptoms despite of the administration of symptomatic treatment and slowing down the infusion rate of nivolumab during the 1st and 2nd reaction required an allergy evaluation of our patient. Management and outcome Skin testing to Nivolumab with negative results and baseline tryptase within the normal range were observed during the allergy workout. A desensitization protocol with specific premedication was applied to reintroduce the moAb, with no further issues. Moreover, a follow up of the patient in the oncology setting was done showing disease stabilization. Discussion The CRR should be treated by desensitization, in contrast to infusion reactions. The diagnosis of CRR phenotype is based on the clinical presentation and recently, and elevation of IL-6 levels has been shown to be a useful biomarker along with negative skin testing. We can conclude that after a HSR and an appropriate allergy diagnosis of CRR, nivolumab can be safely reintroduced by desensitization without reducing the target dose or the appropriate dilution concentration.

Phase II study of docetaxel (D) and oxaliplatin (O) in recurrent metastatic transitional cell cancer (mTCC) of the urothelial tract.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 296-296
Author(s):  
Gurkamal S. Chatta ◽  
Leonard Joseph Appleman ◽  
David Friedland ◽  
Gail Tribble ◽  
Diwakar Davar
Keyword(s):  
Stable Disease ◽  
Cell Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Transitional Cell ◽  
Prior Treatment ◽  
Hematological Toxicity ◽  
Disease Stabilization ◽  
Grade 3 ◽  
Number Of Cycles

296 Background: First-line regimens for mTCC of the bladder are either MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the cisplatinum-gemcitabine doublet. There is no approved second-line option for mTCC. Both single agent D and O have response rates of 10 to 20%, and O in cisplatin-resistant patients (pts). Hence the combination of D and O may be useful in recurrent mTCC. Methods: The combination of D and O was primarily tested for efficacy in recurrent mTCC. All pts had histologically proven TCC with measurable disease, and had prior treatment with at least 1 platinum-containing regimen. D 60 mg/m2 followed by O 110 mg/m2 were administered every 3 weeks. Pts were evaluated for response every 2 cycles and were treated either till progression or for a maximum of 6 cycles. Results: 22 pts were enrolled of whom 19 were evaluable for response. Median age was 72 years (range 44 – 87). All pts had prior treatment with at least 1 cytotoxic regimen, with 8 pts having received 2 or more prior regimens. The mean number of cycles administered was 3. Of the 19 pts evaluable for efficacy, objective response was documented in two pts (both partial responses), three had stable disease, and the remaining fourteen progressed on therapy for an overall disease stabilization rate of 26%. Median time to progression (TTP) was 3.0 months (95% CI 0.2 to 5.8) and median overall survival (OS) was 7.0 months (95% CI 4.6 to 9.4). Toxicity, evaluated in all 22 patients, was relatively mild: grade 3-4 diarrhea in 6 patients, grade 3-4 hematological toxicity in 4 pts and grade 3-4 fatigue in 1 pt. No grade 3-4 neuropathy was observed and no toxic deaths were noted. The median follow-up period was 7.0 months (95% CI 4.5 to 9.5). Conclusions: The combination of D and O is active in previously treated pts with mTCC. This regimen appears to be well tolerated with overall mild toxicity. Whilst this study was not powered for assessing survival, the presence of stable disease in 26% of pts suggests that further investigation of the combination in carefully selected pts maybe warranted.

Skin testing and drug challenge in the evaluation of drug hypersensitivity reactions

2021 ◽  
Vol 42 (1) ◽  
pp. 16-21 ◽  
Author(s):  
Anna R. Wolfson ◽  
Aleena Banerji
Keyword(s):  
Negative Impact ◽  
Skin Testing ◽  
Drug Hypersensitivity ◽  
Clinical History ◽  
Hypersensitivity Reactions ◽  
Causative Drug ◽  
Care Assessment ◽  
Drug Hypersensitivity Reactions ◽  
Drug Challenge ◽  
Drug Challenges

Immediate hypersensitivity to drugs is characterized by symptoms such as hives, swelling, and wheezing. To prevent a negative impact on care, assessment by an allergist is important. Evaluation requires a clear clinical history, but it is often lacking or vague, which makes a diagnosis difficult. Allergists instead can use skin testing and drug challenge to evaluate drug hypersensitivity reactions, which help the patient and provider understand the causative drug(s) and, more importantly, enables the use of the exonerated drug(s). Although penicillin skin testing is standardized, well described, and widely used, skin testing for most other drugs requires the use of a nonirritating skin testing concentration that can have a low negative predictive value. Drug challenges are the criterion standard for confirming tolerance. The allergist must obtain an in-depth clinical history and then follow with skin testing and/or drug challenges when indicated to determine which drugs can be de-labelled and which should be avoided. In this review, we focused on the evaluation of drug hypersensitivity reactions to antibiotics, perioperative agents, biologics, and chemotherapeutics.

Systemic reaction during intradermal skin tests with beta-lactams

2021 ◽  
Vol 14 (3) ◽  
pp. e240050
Author(s):  
Joana Carvalho ◽  
Georgeta Oliveira
Keyword(s):  
Skin Testing ◽  
Drug Hypersensitivity ◽  
Systemic Reaction ◽  
Skin Tests ◽  
Beta Lactam ◽  
Provocation Tests ◽  
Maculopapular Eruption ◽  
Intradermal Tests ◽  
Amoxicillin Clavulanate ◽  
Immediate Reactions

Beta-lactam (BL) antibiotics are the most frequent cause of drug hypersensitivity in children, inducing both immediate and non-immediate reactions. Here we report a case of a 4-year-old child with a disseminated maculopapular exanthema 7 days after the first dose of amoxicillin–clavulanate, referred to our paediatric allergy department. Skin prick tests were negative. Intradermal tests were performed and, after 10 hours, indurated wheals larger than 10×10 mm with progressive erythema and disseminated maculopapular eruption were developed, related to amoxicillin and amoxicillin–clavulanate. Systemic reactions to BL skin tests are rarely reported and the majority are immediate reactions. This case illustrates a rare example of a non-immediate systemic reaction to intradermal tests, underlying the importance of skin testing before drug provocation tests in cases of moderate to severe non-immediate reactions.

scholarly journals Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (36) ◽  
pp. 4381-4389 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Recommended Dosage ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11545-11545
Author(s):  
Daniel Pink ◽  
Dimosthenis Andreou ◽  
Anne Flörcken ◽  
Alexander Golf ◽  
Stephan Richter ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Efficacy And Safety ◽  
Disease Stabilization ◽  
Group A ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Group B

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.

scholarly journals Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the TRANSCEND NHL 001 trial

2021 ◽  
Vol 5 (6) ◽  
pp. 1695-1705
Author(s):  
Jeremy S. Abramson ◽  
Tanya Siddiqi ◽  
Jacob Garcia ◽  
Christine Dehner ◽  
Yeonhee Kim ◽  
...  
Keyword(s):  
Health Care ◽  
T Cell ◽  
B Cell Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
System Perspective ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell–specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.

scholarly journals Cytokine Release Syndrome Is an Independent Risk Factor Associated With Platelet Transfusion Refractoriness After CAR-T Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yadan Liu ◽  
Bin Liang ◽  
Yan Liu ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Risk Factor ◽  
Acute Lymphoblastic Leukemia ◽  
Platelet Transfusion ◽  
Independent Risk Factor ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Grade 3 ◽  
Platelet Transfusions

Background: Chimeric antigen receptor T cell (CAR-T) therapy is successful in improving treatment outcomes for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, toxicities associated with CAR-T therapy are being increasingly identified. Pancytopenia is one of the most common complications after CAR-T therapy, and platelet transfusions are an essential part of its supportive care.Study Design and Methods: This study aimed to assess the effectiveness of platelet transfusions for R/R ALL patients at our single center and identify associated risk factors. Overall, 44 R/R ALL patients were enrolled in this study, of whom 26 received CAR-T therapy and 18 received salvage chemotherapy.Result: Patients in the CAR-T group had a higher incidence of platelet transfusion refractoriness (PTR) (15/26, 57.7%) than those in the chemotherapy group (3/18, 16.7%) (p = 0.007). For patients receiving CAR-T therapy, multivariate analysis showed that the grade of cytokine release syndrome (CRS) was the only independent risk factor associated with PTR (p = 0.007). Moreover, higher peak serum IL-6 and IFN-γ levels suggested a higher risk of PTR (p = 0.024 and 0.009, respectively). Patients with PTR received more platelet infusion doses than those without PTR (p = 0.0426). Patients with PTR had more grade 3–4 bleeding events than those without PTR (21.4 vs. 0%, p = 0.230), and the cumulative incidence of grade 3–4 bleeding event was different (p = 0.023).Conclusion: We found for the first time that PTR is associated with the CRS grade. Improved knowledge on the mechanisms of PTR after CAR-T therapy is needed to design a rational therapeutic strategy that aims to improve the efficiency of transfusions.

KRN8602 (MX2-Hydrochloride): An Active New Agent for the Treatment of Recurrent High-Grade Glioma

1999 ◽  
Vol 17 (8) ◽  
pp. 2579-2579 ◽  
Author(s):  
Kerrie Clarke ◽  
Russell L. Basser ◽  
Craig Underhill ◽  
Peter Mitchell ◽  
Jane Bartlett ◽  
...  
Keyword(s):  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
High Grade Glioma ◽  
High Grade ◽  
Intravenous Bolus ◽  
Single Episode ◽  
Group Score ◽  
Nonhematologic Toxicity ◽  
Disease Stabilization ◽  
Grade 3

PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma. PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score ≤ 2) were treated with an intravenous bolus of 40 mg/m2 KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles. RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting. CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

Phase II Trial of Autologous Tumor Vaccination, Anti-CD3-Activated Vaccine-Primed Lymphocytes, and Interleukin-2 in Stage IV Renal Cell Cancer

2003 ◽  
Vol 21 (5) ◽  
pp. 884-890 ◽  
Author(s):  
Alfred E. Chang ◽  
Qiao Li ◽  
Guihua Jiang ◽  
Donna M. Sayre ◽  
Thomas M. Braun ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Lymph Nodes ◽  
Tumor Cells ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Stage Iv ◽  
Autologous Tumor ◽  
Cytokine Release

Purpose: Previous preclinical and clinical studies have demonstrated that autologous tumor vaccines can induce relatively specific tumor-reactive T cells in draining lymph nodes. The adoptive transfer of these cells can result in tumor regression. Patients and Methods: Patients with stage IV renal cell cancer (RCC) were vaccinated with irradiated autologous tumor cells admixed with Calmette-Guérin bacillus. Approximately 7 days later, vaccine-primed lymph nodes (VPLNs) were harvested and the lymphoid cells secondarily activated with anti-CD3 monoclonal antibody and expanded in interleukin 2 (IL-2). The activated cells were subsequently infused intravenously along with the concomitant administration of bolus IL-2 (360,000 U/kg intravenously × 15 doses). Results: Thirty-nine patients were entered onto the study, of whom 34 completed an initial course of cell therapy consisting of a mean (SEM) number of 4.3 (2.2) × 1010 VPLN cells. Among subjects who received cell therapy, there were nine responses (four complete responses [CRs] and five partial responses [PRs]), for an overall response rate of 27%. The durations of the CRs were > 48, 45, > 35, and 12 months, and the durations of the PRs were > 63, 48, 15, 12, and 4 months. Cultured tumor cells were available to assess in vitro cytokine release of VPLN cells in 24 subjects. The median cytokine release ratio of interferon gamma (IFNγ) to IL-10 for responders and nonresponders was 992 and 5, respectively, which was significantly different (P = .047). Conclusion: The treatment protocol resulted in durable tumor responses in patients with advanced RCC. The ratio of IFNγ and IL-10 cytokines released in response to tumor by the VPLN cells was a significant correlate with tumor response.

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).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2120-2120 ◽  
Author(s):  
Hazem Sayala ◽  
Paul Moreton ◽  
Jones A. Richard ◽  
Rawstron C. Andy ◽  
O’Connor Sheila ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Germ Line ◽  
Combined Therapy ◽  
Skin Reactions ◽  
Poor Risk ◽  
Serious Infections ◽  
Infusion Reactions ◽  
Erythematous Skin ◽  
Grade 3 ◽  
Cmv Reactivation

Abstract 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.

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