Purpose: Treatment with alemtuzumab has resulted in negative responses for minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL). In a prior analysis we demonstrated that it is possible to achieved MRD negativity, as assessed by polyclonality of immunoglobulin heavy chain after consolidation with alemtuzumab. This phase II study evaluated 34 patients with CLL who received alemtuzumab consolidation in an effort to improve the quality of their response to fludarabine-based induction. Subsequent peripheral blood stem-cell (PBSC) collection and transplantation, tolerability, and pharmacokinetics also were assessed. Patients and Methods: Thirty-four patients younger than 65 years who had a clinical response to fludarabine-based induction therapy received alemtuzumab 10 mg subcutaneously three times per week for 6 weeks. PBSCs were collected after mobilization with cytarabine and granulocyte colony-stimulating factor. Blood samples for pharmacokinetics study were taken between days 1 and 31. Results: The complete response rate improved from 35% after fludarabine induction to 79.4% after alemtuzumab consolidation, including 19 patients (56%) who achieved MRD negativity. The most common adverse events were injection-site reactions and fever. Cytomegalovirus reactivation occurred in 18 patients, all of whom were successfully treated with oral ganciclovir. PBSC collection was successful in 24 (92%) of 26 patients, and 18 patients underwent autologous PBSC transplantation. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks and accumulated more rapidly thereafter. Conclusion: Subcutaneously administered alemtuzumab was effective, safe, and well tolerated as consolidation therapy in patients with CLL who responded to fludarabine induction therapy. Subsequent PBSCT was feasible thereafter.

Autoimmune cytopenias occur in up to 10% of patients during the course of chronic lymphocytic leukemia (CLL), with autoimmune hemolytic anemia (AIHA) the most common, followed by immune-mediated thrombocytopenia (ITP).1, 2 These disorders may occur at any time during disease course and depend on complex interactions between the malignant clone, impaired T-cell function, microenvironment and the immune system. Prevalence of AIHA ranges from 2.9 to 10.5%, and is generally associated with advanced disease.3 Clinically significant ITP occurs in ~2% of patients.1, 2, 3 Ibrutinib, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase (BTK), is indicated by the US FDA for the treatment of patients with CLL/small lymphocytic lymphoma (SLL), including patients with 17p deletion, and allows for treatment without chemotherapy. In addition to BTK, ibrutinib targets members of the Tec kinase family, ITK and TEC, and TXK which may impact immune function.4 To address the impact of ibrutinib on CLL-associated AIHA/ITP, we retrospectively analyzed data from patients in the phase 3 RESONATE study comparing ibrutinib versus ofatumumab in previously treated CLL, including patients with history of ongoing complications of AIHA and/or ITP.5 History of AIHA and/or ITP was collected as complications of CLL, including status at study entry (ongoing/resolved), from 386 patients who received study treatment for this analysis (n=195 ibrutinib; n=191 ofatumumab). Per the study protocol, AIHA was defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytes (above ULN) or bone marrow erythropoiesis in the absence of bleeding) and at least one marker of autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold agglutinins).6 ITP was defined by platelets 100 000 per μl and increased megakaryocytes on bone marrow exam. Patients with uncontrolled AIHA or ITP (defined as declining counts within the screening period or requirement for steroids >20 mg daily) were excluded from the RESONATE study. Other patients with AIHA/ITP including those meeting IWCLL 2008 criteria for treatment were eligible.7 Standard supportive care medications were permitted per protocol. Protocol-defined AIHA and ITP were reported at the discretion of the investigator at study entry based on assessments made during the screening period. Baseline hemoglobin and platelet counts for the present analysis were based on measurements from the first day of study treatment. Hemoglobin and platelet counts over time were assessed in patients with ongoing AIHA (n=21 ibrutinib; n=9 ofatumumab) and ongoing ITP (n=12 ibrutinib; n=10 ofatumumab) at study entry, respectively. Corticosteroid use for autoimmune complications and treatment-emergent adverse events (AEs) of AIHA and ITP were collected for all treated patients. Ofatumumab data were censored at initiation of crossover to ibrutinib. Ofatumumab regimen was limited to 6 months; AE reporting period for this arm was complete at publication of interim analysis.5 Status of AIHA and ITP associated with CLL at study entry is shown in Table 1. At baseline, patients on ibrutinib with ongoing AIHA had median hemoglobin of 10.4 g/dl (range: 8.1–13.7), which increased to 12.4 g/dl (range: 10.3–14.6) at 24 weeks (Figure 1a). Patients on ibrutinib with ongoing ITP had median platelet count of 49 × 109 per liter (range: 20–138 × 109) at baseline compared with 94 × 109 per liter (range: 64–248 × 109) at 24 weeks (Figure 1b). In patients on ofatumumab, median hemoglobin for patients with AIHA and platelet counts for patients with ITP were 10.2 g/dl (range: 7.3–12.9) and 66 × 109 per liter (range: 23–126 × 109), respectively, at baseline, and 13.9 g/dl (range: 11.1–15.5) and 115 × 109 per liter (range: 58–186 × 109), respectively, at 24 weeks. Baseline hemoglobin in patients with AIHA was similar between arms. Baseline platelet count in patients with ITP was lower with ibrutinib than ofatumumab. Median hemoglobin level and platelet counts improved early following ibrutinib initiation and were generally sustained throughout a median 18.9 months of follow-up. Although data were limited for the patients with ongoing AIHA in the ofatumumab arm, it appears that these patients also experienced some improvement in hemoglobin levels during the follow-up. For all treated patients (n=195 ibrutinib; n=191 ofatumumab), median treatment duration (reflecting AE follow-up) was 18.3 months for patients on ibrutinib versus 5.3 months for ofatumumab. Median treatment duration for patients on ibrutinib with ongoing AIHA and ITP at study entry was 17.7 and 17.3 months, respectively. Five ibrutinib patients with ongoing AIHA were receiving concomitant corticosteroids for autoimmune cytopenias (AIC) at baseline; one discontinued corticosteroids on day 42 of therapy. One ofatumumab patient with ITP was receiving concomitant corticosteroids for autoimmune complications at baseline and during the treatment period. Corticosteroid use was initiated for AIC in four patients on ofatumumab, compared with one on ibrutinib who had prior medical history of AIHA. The AE profile for patients with ongoing AIHA/ITP randomized to ibrutinib (Supplementary Table 1) was similar to the overall ibrutinib population. Among all treated patients, two developed AIHA and two developed ITP; all four were randomized to the ofatumumab arm. Of the two patients with AIHA, one was treated with prednisolone for 16 days and was ongoing at time of analysis; the other was hospitalized and treated with transfusion, prednisolone, folic acid, and eventually splenectomy. Of the two patients with ITP, one received platelets, and the ITP resolved; the other had a longer course of...

Peer reviewed article authored by (Francesca Ricci, Alessandra Tedeschi, Enrica Morra, Marco Montillo). Read article or submit your manuscript for publishing.

Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL.

Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52+ B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m2 per day, oral cyclophosphamide 250 mg/m2 per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.

Fludarabine is a prodrug that is converted to the free nucleoside 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A), which enters cells and accumulates mainly as the 5'-triphosphate, F-ara-ATP. F-ara-ATP has multiple mechanisms of action, which are mostly directed toward DNA. Collectively, these actions affect DNA synthesis, which is the major mechanism of F-ara-A-induced cytotoxicity. Secondarily, incorporation into RNA and inhibition of transcription has been shown in cell lines. As a single agent, fludarabine has been effective for indolent leukemia. Biochemical modulation strategies resulted in enhanced accumulation of cytarabine triphosphate and led to the use of fludarabine for the treatment of acute leukemia. The combination of fludarabine with DNA-damaging agents to inhibit DNA repair processes has been highly effective for indolent leukemia and lymphomas. Other strategies have incorporated fludarabine into preparative regimens for nonmyeloablative stem-cell transplantation.