Claes Karlsson

Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia

Little information is available on long-term immune reconstitution after therapy with alemtuzumab in B-CLL patients. We present long-term follow-up data for blood lymphocyte subsets analysed by flow cytometry in previously untreated B-CLL patients who received alemtuzumab subcutaneously as first-line therapy. All lymphoid subsets were significantly (P<0.001) and profoundly reduced; the median end-of-treatment counts for CD4+, CD8+, CD3−56+ (natural killer (NK)), CD3+56+ (NK–T) and CD19+5− (normal B) cells were 43, 20, 4, 1 and 8 cells/μl, respectively. The median cell count of all subsets remained at <25% of the baseline values for >9 months post-treatment. CD4+ and CD8+ levels in blood had reached >100 cells/μl in >50% of the patients at 4 months after the end of treatment. One patient had a cytomegalovirus reactivation and one patient developed Pneumocystis carinii pneumonia during therapy. No opportunistic or other major infections were recorded during unmaintained, long-term follow-up. There was no correlation between the cumulative dose of alemtuzumab and the severity or length of immunosuppression. CD52− T-cell subsets occurred during the treatment and comprised >80% of all CD4+ and CD8+ cells in the blood at the end of therapy. These subpopulations declined gradually during unmaintained follow-up. The relationship between these observations and the safety/antitumour effects of alemtuzumab is discussed.

Treatment of severe refractory autoimmune hemolytic anemia in B-cell chronic lymphocytic leukemia with alemtuzumab (humanized CD52 monoclonal antibody)

Progressive B-cell chronic lymphocytic leukemia (B-CLL) is often complicated by autoimmune hemolytic anemia (AIHA), which in some cases may be refractory to conventional therapy such as corticosteroids, rituximab and splenectomy. We report here on 5 patients (median age 66 years, range 59–69) with advanced B-CLL, all of whom developed severe transfusion-dependent AIHA resistant to conventional therapy and received subcutaneous (SC) or intravenous (IV) alemtuzumab, a humanized monoclonal antibody that targets the CD52 antigen as salvage treatment for AIHA. Alemtuzumab was well tolerated with only minor ‘first dose’ reactions. All 5 patients responded with a ⩾2.0 g/dl rise in hemoglobin (Hb) concentration, in the absence of further transfusions, after a median time of 5 weeks (range 4–7), and the mean Hb increased from 7.2 g/dl at baseline to 11.9 g/dl at end of treatment. All patients remained stable, without further AIHA episodes, after a median follow-up time of 12 months with a mean Hb of 12.5 g/dl (range 12.2–12.9). For patients with severe, refractory CLL-related AIHA, who have not previously responded to conventional therapy, alemtuzumab is an effective agent.

Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group

Ibrutinib, a Bruton’s tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine health-care are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy ≥10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richter’s transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia.

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.

Reconstitution of the T-cell repertoire following treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with B-cell chronic lymphocytic leukaemia.

In this pilot study, T‐cell receptor B‐variable (TCR‐BV) gene usage in CD4 and CD8 T cells was assessed, by real‐time polymerase chain reaction, as well as complementarity‐determining region 3 (CDR3)‐length polymorphism, before and after therapy in five patients with B‐cell chronic lymphocytic leukaemia who received alemtuzumab (anti‐CD52 monoclonal antibody) as first‐line therapy. A decline in expression of most BV family genes in both CD4 and CD8 T cells was observed after alemtuzumab treatment, which was followed by a gradual increase in most BV families during long‐term follow‐up. After treatment, CDR3‐length polymorphism showed an even more restricted pattern in CD4 T cells compared with pretreatment, with a shift towards a monoclonal/oligoclonal pattern. The clonally restricted pattern was significantly reduced in CD4 (P < 0·01) but not in CD8 T cells. This was followed by a gradual increase in the number of peaks within the CDR3 region of the different TCR‐BV families, i.e. a polyclonal repertoire, during long‐term follow‐up. A restricted CDR3 pattern became even more restricted after treatment, but normalised during unmaintained follow‐up. These results indicate that perturbations in the T‐cell alterations following alemtuzumab are complex and include not only changes in CD4/CD8 T‐cell numbers but also a highly restricted T‐cell repertoire especially in CD4 T cells.

Alemtuzumab to treat refractory autoimmune hemolytic anemia or thrombocytopenia in chronic lymphocytic leukemia

Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) are recognized complications of chronic lymphocytic leukemia (CLL) that can be life-threatening if not managed appropriately. Conventional therapies for these autoimmune disorders, such as corticosteroids, splenectomy, and immunosuppressive agents, may not induce complete resolution in all patients, and relapses are common. In recent years, monoclonal antibodies such as alemtuzumab and rituximab, already used successfully for the management of lymphoproliferative disorders, have been shown to be effective in the treatment of a range of autoimmune disorders. The potent antitumor activity of alemtuzumab, in combination with its profound immunosuppressive activity, prompted investigation of its use in patients with severe CLL-related AIHA and ITP. Results from a range of reports confirm the efficacy of alemtuzumab for the treatment of severe, CLL-related autoimmune cytopenias that have failed to respond to conventional therapies and may even be rituximab-refractory.

Alemtuzumab therapy for severe autoimmune hemolysis in a patient with B-cell chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia (B-CLL) is the most common cause of autoimmune hemolytic anemia (AIHA), and a subgroup of these patients who develop both these conditions fail to respond to corticosteroids, cytotoxic drugs, splenectomy, and iv immunoglobulins. Alemtuzumab is a humanized anti-CD52 monoclonal antibody that is an effective therapy for B-CLL, mycosis fungoides, and T-cell prolymphocytic leukemia. Here we present a case report of a 78-yr-old woman with B-CLL and progressive life-threatening AIHA with hemoglobin count 5.5 g/dL following fludarabine treatment, who was treated successfully with alemtuzumab. The anemia was completely reversed and hemoglobin count remains at 14 g/dL after 15 mo of unmaintained follow-up. No infectious complications were noted during or after alemtuzumab therapy. We conclude that alemtuzumab may be indicated for the treatment of AIHA in B-CLL patients who have failed other treatments.

Outcomes of patients with fludarabine-refractory chronic lymphocytic leukemia: a population-based study from a well-defined geographic region

Abstract Patients with fludarabine-refractory (FR) chronic lymphocytic leukemia (CLL) receive novel agents in pivotal, non-randomised phase-2 trials. Understanding outcome of FR-CLL in health-care may provide important contextual information. Records from 1301 patients (Stockholm-Cancer-Registry 1991–2010) identified 92 FR-patients; bulky lymph-nodes (BFR-group), double-refractory (DR-group), or Others‘-group for outcome-analysis. Median age was 69 years 67% had Rai-stage III/IV with median 3 prior therapies. Overall response-rate was 20%; significantly lower in BFR (8%, p = 0.01) and DR (20%, p = 0.01) than in ‘Others‘ (31%). Time-to-treatment-failure (months) was significantly longer in ‘Others‘ (9.2) than in BFR/DR (5.3/4.4) (p < 0.01) and significantly longer (p < 0.05) in antibody-treated patients (9.1) compared to other regimens (5.2). Early-death occurred in 5%, ≥ grade III-infections in 20%. Median overall-survival (OS) was 18 months; 29 in BFR vs 13 in DR (p = 0.054). Male sex was the only prognostic factor on OS (p = 0.01, HR 2.2, multivariate-Cox-regression). Our results, without external referrals, facilitate interpretation of non-randomised trials/novel drugs in advanced-stage-CLL.

Phase I study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukaemia: maintaining immune functions during therapy-induced immunosuppression

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Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1–45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159–0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454–0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3–4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.