Anna Panovská

Clinical outcome of pretreated B-cell chronic lymphocytic leukemia following alemtuzumab therapy: a retrospective study on various cytogenetic risk categories

BACKGROUND Patients with B-cell chronic lymphocytic leukemia (CLL) with 17p deletion respond poorly to chemotherapy. This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL in the various cytogenetic subgroups. PATIENTS AND METHODS Data were collected from 105 consecutive, pretreated, cytogenetically defined patients who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS The hierarchic incidence of cytogenetic abnormalities was: 13q deletion (as sole abnormality), 18%; trisomy 12, 13%; 11q deletion, 19%; 17p deletion, 33%; and none of these, 16%. Overall response rate (ORR) was 43% in the total cohort and 49% in the subgroup of 17p-deleted patients (n = 35). From the start of alemtuzumab monotherapy, median PFS in the total cohort and in the subgroup of 17p-deleted patients was 7.0 and 7.1 months, respectively. Median OS in the total cohort and in 17p-deleted patients was 32.8 and 19.1 months, respectively. The poor-risk group of patients with CLL (i.e. fludarabine resistant, 17p deletion; n = 20) showed encouraging ORR, PFS, and OS (35%, 7.0 and 19.2 months, respectively). CONCLUSIONS Alemtuzumab was effective in treating patients with CLL across the cytogenetic categories evaluated, but there were differences. In patients with CLL with 17p deletion quite favorable ORR, PFS, and OS were achieved.

Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: Results from a phase II study

The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue. An important treatment option is the use of high‐dose corticosteroids. The purpose of this clinical trial was to determine the efficacy and toxicity of an ofatumumab–dexamethasone (O‐Dex) combination in relapsed or refractory CLL. The trial was an open‐label, multicenter, nonrandomized, Phase II study. The O‐Dex regimen consisted of intravenous ofatumumab (Cycle 1: 300 mg on day 1, 2,000 mg on days 8, 15, and 22; Cycles 2–6: 1,000 mg on days 1, 8, 15, and 22) and oral dexamethasone (40 mg on days 1–4 and 15–18; Cycles 1–6). The O‐Dex regimen was given until best response, or a maximum of six cycles. Thirty‐three patients (pts) were recruited. Twenty‐four (73%) pts completed at least three cycles of therapy. The remaining nine pts were prematurely discontinued owing to Grade 3/4 infections (seven pts), disease progression (one pt), or uncontrollable diabetes mellitus (one pt). Overall response rates/complete remissions (ORR/CR) were achieved in 22/5 pts (67/15%). The median progression‐free survival (PFS) was 10 months. In pts with p53 defects (n = 8), ORR/CR were achieved in 5/2 pts (63/25%) with a median PFS of 10.5 months. The median overall survival (OS) was 34 months. The Grades 3–5 infectious toxicity in 33% of pts represented the most frequent side effect during the treatment period. In conclusion, the O‐Dex regimen shows a relatively high ORR and CR with promising findings for PFS and OS. The study was registered at www.clinicaltrials.gov (NCT01310101). Am. J. Hematol. 90:417–421, 2015.

Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia

BACKGROUND High-dose methylprednisolone is active in treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but infectious toxicity is serious. The aim of this project was to retrospectively assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in this setting. PATIENTS AND METHODS We treated 54 patients (pts) with relapsed/refractory CLL using R-dex regimen at two tertiary centers. Two schedules of rituximab were used (not randomized - based on the choice of the center): group 1, rituximab 500 mg/m(2)day 1, 8, 15, 22 (375 mg/m(2) in 1st dose) every 4 weeks (n=29); group 2, 500 mg/m(2)day 1 (375 mg/m(2) in 1st cycle) repeated every 3 weeks (n=25). The target dose of dexamethasone was 40 mg on days 1-4 and 10-13 or 15-18. Rai III/IV stages were present in 82%, unmutated IgVH genes in 82%, del 11q in 38% and del 17p in 19% pts; 46% had bulky lymph nodes; 82% were pretreated with fludarabine and 29% with alemtuzumab. RESULTS Overall response rate/complete remissions were 62/21% (Group 1) and 72/4% (Group 2). In three patients, R-dex was successfully used for debulking before nonmyeloablative allogeneic stem cell transplantation. R-dex was particularly effective in improvement of anemia and thrombocytopenia (p=0.0055 and p=0.0036); B-symptoms resolved after treatment in 11/17 pts. Hematological toxicity was mild. Serious infections occurred in 32% pts. At the median follow-up of 9 and 10 months, median progression-free survival was 6 months in Group 1 and 6.9 months in Group 2 (p=ns); median overall survival was 14.1 months in Group 1 vs. not reached in Group 2 (p=ns). CONCLUSIONS R-dex appears to be an active and feasible treatment for relapsed/refractory CLL. Infectious toxicity remains an important issue. Further investigation of this regimen in larger studies appears fully warranted.

Chronic Lymphocytic Leukemia and Focusing on Epidemiology and Management in Everyday Hematologic Practice: Recent Data From the Czech Leukemia Study Group for Life (CELL)

PURPOSE Currently, pathogenesis, new prognostic factors, or new therapy in chronic lymphocytic leukemia (CLL) are frequently discussed; however, up-to-date data concerning the incidence and the management of CLL in everyday hematologic practice are still missing. The aim of our study was to find out the accurate epidemiologic situation of CLL and the diagnostic and therapeutic preferences of hematologists in the preselect area: the South Moravian Region (1,127,718 inhabitants, white race). PATIENTS AND METHODS The total number of 540 patients (median age at the time of diagnosis, 65 years; sex, 306 men and 234 women) who had been followed in 2008 were included in the analysis. RESULTS In the years 2006 and 2007, the incidence of CLL was 5.8 and 6.2, respectively, per 100,000; the prevalence was 48 per 100,000. Chronic lymphocytic leukemia treatment was indicated in 194 patients (36%); 93 (17%) of them also underwent the second line of treatment. Of these 194 patients, 64 patients (33%) were given fludarabine-based regimens, and 74 patients (38%) received chlorambucil as a first line of treatment. Thirty patients were treated within clinical trials. Although the treatment was indicated in only one third of patients (36%), new prognostic factors were examined in > 50% of patients. CONCLUSION The ascertained incidence of CLL in our region is higher than declared incidence in the past. Evidently, CLL became an often misdiagnosed and underreported disease.

Clonal evolution in chronic lymphocytic leukemia detected by fluorescence in situ hybridization and conventional cytogenetics after stimulation with CpG oligonucleotides and interleukin-2: A prospective analysis

Chronic lymphocytic leukemia (CLL) patients may acquire new chromosome abnormalities during the course of their disease. Clonal evolution (CE) has been detected by conventional chromosome banding (CBA), several groups also confirmed CE with fluorescence in situ hybridization (FISH). At present, there are minimal prospective data on CE frequency determined using a combination of both methods. Therefore, the aim of our study was to prospectively assess CE frequency using a combination of FISH and CBA after stimulation with CpG oligonucleotides and interleukin-2. Between 2008 and 2012, we enrolled 140 patients with previously untreated CLL in a prospective trial evaluating CE using FISH and CBA after stimulation. Patients provided baseline and regular follow-up peripheral blood samples for testing. There was a median of 3 cytogenetic examinations (using both methods) per patient. CE was detected in 15.7% (22/140) of patients using FISH, in 28.6% (40/140) using CBA, and in 34.3% (48/140) of patients by combining both methods. Poor-prognosis CE (new deletion 17p, new deletion 11q or new complex karyotype) was detected in 15% (21/140) of patients and was significantly associated with previous CLL treatment (p=0.013). CBA provides more complex information about cytogenetic abnormalities in CLL patients than FISH and confirms that many patients can acquire new abnormalities during the course of their disease in a relatively short time period.

The outcome of chronic lymphocytic leukemia patients who relapsed after fludarabine, cyclophosphamide, and rituximab

There are minimal data about the efficacy of subsequent therapy in patients with relapse after FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy.

Detecting minimal residual disease in patients with chronic lymphocytic leukemia using 8-color flow cytometry protocol in routine hematological practice.

Minimal residual disease (MRD) detection has become increasingly important for the assessment of therapy response in chronic lymphocytic leukemia (CLL). However, current MRD analysis methods, both molecular genetic and flow cytometric, are time‐consuming and require experienced laboratory staff.

Specific p53 mutations do not impact results of alemtuzumab therapy among patients with chronic lymphocytic leukemia

A poor prognosis in chronic lymphocytic leukemia (CLL) is associated particularly with the presence of del(17p) aff ecting tumor suppressor gene TP53 . Th is deletion is in almost all cases of progressive leukemia accompanied by a mutation in the other TP53 allele, and in a smaller proportion of patients the TP53 mutation occurs also independently of del(17p) [1]. Recently, we demonstrated that patients with CLL harboring a missense mutation located in the p53 DNA-binding motifs (DBMs) (structurally well-defi ned parts of the DNA-binding domain) manifested a clearly shorter median survival in comparison with those having a missense mutation outside DBMs or a non-missense alteration [2]. However, a limitation of this study resulted from the unpredictable survival impact of diverse therapy given to patients with p53 mutations. Th e therapeutic approach currently taken for patients with CLL with loss and/or mutation of TP53 relies mostly on the use of agents which do not act through DNA damage followed by apoptosis induction. Th e success of this approach has been documented for the monoclonal antibody alemtuzumab. Monotherapy with alemtuzumab is now being recommended as fi rst-line therapy for patients with CLL with del(17p) [3]; however, many unresolved questions need to be addressed. For example, it is unclear whether the type of p53 mutation infl uences the outcome of alemtuzumab therapy. In an eff ort to evaluate the effi cacy of alemtuzumab therapy in relation to specifi c p53 mutations in patients with CLL, we performed a retrospective analysis. Th e patients examined ( n 111) were treated by alemtuzumab between 2003 and 2010. Th e majority of cases concerned pretreated patients ( n 108; see Table I). Our present analysis was performed in the patient cohort which was largely included in the previous survival analysis related to p53 mutation types; this study also involved patients treated with other drugs in addition to alemtuzumab [2] (overlap 88% in group 1; 82% in group 2; 0% in group 3; the groups are defi ned further below). Defects in p53 were assessed by the yeast functional assay coupled to sequencing of DNA templates from mutated yeast colonies. Th e remaining TP53 allele was analyzed using