Ben Kennedy

Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival

PURPOSE To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. PATIENTS AND METHODS Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 10(5) normal cells). RESULTS Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. CONCLUSION MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced‐stage, relapsed chronic lymphocytic leukaemia

This phase II study (n = 20) aimed to evaluate type, severity and duration of side‐effects and efficacy following subcutaneous (SC) alemtuzumab, without dose‐escalation, in advanced‐stage relapsed chronic lymphocytic leukaemia (CLL) patients. Alemtuzumab 30 and 3 mg was administered SC simultaneously day 1, followed by 30 mg three times per week. Injection‐site‐reactions were recorded every 6–24 h until resolved using National Cancer Institute criteria and a new skin toxicity subscale. The first doses of 30 mg and 3 mg produced injection‐site‐reactions (all but one were grade 1/2) in 13/20 and 9/20 patients, respectively. The second dose (on day 3) resulted in skin‐reactions in 10/20 patients and the third, fourth, fifth and sixth injections produced reactions in 6/20, 1/20, 2/20 and 0/20 patients, respectively. Mild “flu‐like” symptoms occurred during week 1 in 10/20 patients. All side‐effects had subsided by the sixth dose. 15/20 patients (75%) responded (12 partial responses, three complete responses) with a median time‐to‐treatment‐failure of 20 months. Symptomatic cytomegalovirus‐reactivation occurred in 6/20 patients. Two deaths occurred: one bacterial pneumonia and one adenovirus‐infection. The present study showed how to assess cutaneous‐toxicity in detail and that 30 mg alemtuzumab SC administered upfront was well tolerated. Optimized alemtuzumab therapy in properly selected patients may result in high efficacy even in advanced CLL. Our results need to be confirmed in extended studies.

Pyoderma gangrenosum complicating pegylated granulocyte colony‐stimulating factor in Hodgkin lymphoma

Pegylated granulocyte colony-stimulating factor (GCSF) (Pegfilgrastim/Neulasta, Amgen, Thousand Oaks, CA, USA) is a covalent conjugate of recombinant human GCSF and monomethoxypolyethyene glycol. Its advantage over regular GCSF is its reduced renal clearance and consequent prolonged persistence in vivo, allowing it to be administered in a single subcutaneous injection, once per cycle of chemotherapy. Pegylated GCSF does not routinely result in marked neutrophilia because serum clearance is directly related to the number of neutrophils. It is being used increasingly in oncology as a simple and cost-effective means of maintaining adequate neutrophil levels during intensive combination chemotherapy. We report here the occurrence of pyoderma gangrenosum following pegylated GCSF in a patient being treated for advanced Hodgkin lymphoma, who had previously received regular GCSF without incident. A previously fit 21-year-old female presented with clinical stage IIIB nodular sclerosing Hodgkin lymphoma. She was treated with combination chemotherapy according to the Adriamycin, Bleomycin, Vinblastine and Doxorubicin (ABVD) protocol. She was admitted to hospital following cycles 1A and 1B of chemotherapy with constipation and a urinary tract

Aspergillus fumigatus osteomyelitis in a patient receiving alemtuzumab for B-cell chronic lymphocytic leukaemia.

We report the case of a 79-year-old female who was receiving single agent subcutaneous alemtuzumab therapy for B-cell chronic lymphocytic leukaemia. Previous therapy included chlorambucil followed by combination fludarabine, cyclophosphamide, and rituximab leading to remission for approximately 12 months before relapse. The patient presented during week 12 of alemtuzumab therapy with a dry cough and right hip pain. She was commenced on broad spectrum antibiotics after computed tomography of the chest showed non-specific patchy bilateral infective changes. Initial radiographs and ultrasound of the hip were normal. Magnetic resonance imaging (MRI) of the hip showed proximal femoral osteomyelitis, anterior cortical disruption and a para-osteal abscess (left). Bone biopsy showed necrosis with branching fungal hyphae (right; haematoxylin & eosin), later confirmed on culture as invasive Aspergillus fumigatus. Galactomannan was positive. She received voriconazole and amphotericin therapy with subsequent bronchoalveolar lavage (4 weeks into therapy) showing no evidence of fungi. With clinical improvement and mobilization she was discharged home. Galactomannan on cessation of therapy was negative. Invasive fungal infections are unusual causes of morbidity and mortality with alemtuzumab. MRI should be considered as the imaging modality of choice in patients presenting with persistent joint or limb pain.

The correlation between the eradication of minimal residual disease (MRD) following alemtuzumab for CLL and overall survival

6566 Background: Alemtuzumab can produce remissions with very low or even undetectable levels of CLL. MRD flow cytometry for CLL can detect as few as one malignant cell in 100,000 blood or bone marrow cells. METHODS 91 patients with previously treated or refractory CLL received alemtuzumab between 1996 and 2003. All patients had regular bone marrow assessments by MRD flow cytometry during therapy with the aim of achieving the best possible response including to MRD negativity. RESULTS There were 74 men and 17 women with a median age of 58 (range 32 to 75). Patients received a median of 12 weeks of intravenous alemtuzumab therapy. There were 19 mild (grade 1 or 2) and 33 severe (grade 3 or 4) infectious episodes. Responses according to NCI criteria were: 33 (36%) patients achieved a complete response (CR), 17 (19%) a partial response (PR), and 41 (45%) no response. CLL was eradicated from the marrow below the level of detection by MRD Flow in 18 (20%) patients. There was no significant difference in response or survival between purine analogue refractory and purine analogue sensitive patients. Median survival was significantly longer in MRD negative patients compared to MRD positive CR, a PR, or no response (median not reached for MRD negative CR, 41 months for MRD positive CR, 30 months for PR and 15 months for NR, p=0.0004). Those patients that achieved an MRD negative CR had a significantly longer treatment free survival than patients with MRD positive CR, PR or non-responders (not reached for MRD negative CRs, 20 months for MRD positive CRs, 13 months for PRs, 6 months for NR, p<0.0001). The overall survival for the 18 patients with MRD negative remissions was 84% at 60 months. Eight (47%) of the MRD negative patients have converted to an MRD positive status at a median time of 28 months. CONCLUSIONS MRD negative remissions are an achievable goal with alemtuzumab. Attaining this response leads to an improved overall and treatment free survival. [Table: see text].