Malgorzata Wach

Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study

PURPOSE The goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML). PATIENTS AND METHODS A cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms. RESULTS Complete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% ± 4% at 3 years) compared with the DA arm (33% ± 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 × 10(9)/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02). CONCLUSION The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.

Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial

BACKGROUND Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy and safety of idelalisib in combination with a second-generation anti-CD20 antibody, ofatumumab, in a similar patient population. METHODS In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus ofatumumab (oral idelalisib 150 mg twice daily continuously plus ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or ofatumumab alone (ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021. FINDINGS Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years [IQR 61-74], median previous therapies three [IQR 2-4]). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6-17·8) in the idelalisib plus ofatumumab group and 8·0 months (5·7-8·2) in the ofatumumab group (adjusted hazard ratio [HR] 0·27, 95% CI 0·19-0·39, p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib plus ofatumumab group were neutropenia (59 [34%] patients vs 14 [16%] in the ofatumumab group), diarrhoea (34 [20%] vs one [1%]), and pneumonia (25 [14%] vs seven [8%]). The most frequent grade 3 or worse adverse events in the ofatumumab group were neutropenia (14 [16%]), pneumonia (seven [8%]), and thrombocytopenia (six [7%] vs 19 [11%] in the idelalisib plus ofatumumab group). Serious infections were more common in the idelalisib plus ofatumumab group and included pneumonia (23 [13%] patients in the idelalisib plus ofatumumab group vs nine [10%] in the ofatumumab group), sepsis (11 [6%] vs one [1%]), and Pneumocystis jirovecii pneumonia (eight [5%] vs one [1%]). 22 treatment-related deaths occurred in the idelalisib plus ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia). INTERPRETATION The idelalisib plus ofatumumab combination resulted in better progression-free survival compared with ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population. FUNDING Gilead Sciences, Inc.

High-dose chemotherapy with autologous stem cell transplantation is an effective treatment of primary refractory Hodgkin's disease. Retrospective study of the Polish Lymphoma Research Group

We analysed the treatment outcome of primary refractory HD patients managed with high-dose chemotherapy and haematopoietic cell transplantation. Data of 65 adult patients who underwent HDC/ASCT in nine Polish centres for primary resistant Hodgkins disease between June 1991 and July 2000 were collected retrospectively. Response rate to HDC/ASC: CR, 54%; PR, 20%; less than PR, 15%; early deaths, 11%. Actuarial 3-year OS and PFS were 55% and 36%, respectively. In multivariate analysis, lack of bulky lymph nodes and use of immunotherapy were favourable factors for both OS and PFS. IPF <3 at the time of transplantation was predictive for PFS. However, the prognostic impact of immunotherapy should be interpreted with caution since this group included more patients who achieved CR after HDC/ASCT. The results of HDC/ASCT are encouraging and confirm earlier findings. The role of immunotherapy should be further investigated in prospective trials.

Attempted Reconstruction of the Immune System using Low Doses of Interleukin 2 in Chronic Lymphocytic Leukemia Patients Treated with 2-Chlorodeoxyadenosine: Results of a Pilot Study

This study was designed to investigate the immunostimulatory effect of low dose Il-2 treatment in B-CLL patients previously treated with 2-chlorodeoxyadenosine (2CdA) in whom severe depletion of T lymphocyte subsets was observed. Four patients enrolled into the study had previously been treated with 3-6 courses of 2CdA. All patients suffered from recurrent infections and showed CD4+ and CD8+ immunosuppression. Recombinant Il-2 was given subcutaneously at a dose of 100 micrograms (1.8 x 10(6)IU) daily for 6 weeks. The drug was administered between 2CdA courses. These preliminary studies showed a marked increase in T cell subsets after Il-2 treatment. All patients displayed an increase of NK cells and there was increased expression of Il-2 receptors (CD 25 and CD 122) on lymphocytes. It is possible that the combination of cytotoxic therapy with 2CdA and low dose rIl-2 could stimulate the T-cell immune system and may be a promising regimen in patients with B-CLL with severe depletion in T-cell subsets.

Intravascular B-cell lymphoma in a 38-year-old woman: a case report

Abstract.Intravascular lymphoma (IVL) is a rare aggressive disease characterised by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries. Only about 200 cases have been reported in the world (some of them retrospectively). IVL is predominantly of B-cell lineage origin but occasionally T-cell lineage occurs. Multiple organs may be involved and a variety of clinical presentations have been described. These include nephrotic syndrome, pyrexia and hypertension, breathlessness and haemolytic anaemia, leukopoenia, pancytopoenia and disseminated intravascular coagulation. We report a case of a 38-year-old woman with a highly aggressive clinical course of IVL. She was admitted to the Department of Neurosurgery because of spondylolisthesis of L5-S1 qualified to surgery. During hospitalisation haemolytic anaemia, thrombocytopoenia and splenomegaly were observed and she was admitted to the Department of Haematology for diagnosis. During her staying in the hospital, new symptoms, such as kidney and liver failure, occurred and the central nervous system was involved. The clinical course was very rapid and progressive. Corticosteroid therapy was started but the disease soon led to the fatal outcome. Diagnosis was established at post-mortem examination.

Different prognosis of acute myeloid leukemia harboring monosomal karyotype with total or partial monosomies determined by FISH: Retrospective PALG study

A monosomal karyotype (MK) was identified by banding techniques (BT) in acute myeloid leukemia (AML). However, BT may be insufficient to determine the actual loss of a complete chromosome, especially in complex karyotypes. We have investigated the effect of monosomy type, total (MK-t) and partial (MK-p), reevaluated by FISH, on prognosis. We have found that complete remission rate and probability of overall survival at 1 year was higher in MK-p (n=27) than MK-t (n=15) group (40% vs. 15.4%, P=0.19 and 30% vs. 9%, P=0.046, respectively). Our results indicate for the first time that monosomy type influences the prognosis of MK-AML.

Concomitance of monosomal karyotype with at least 5 chromosomal abnormalities is associated with dismal treatment outcome of AML patients with complex karyotype – retrospective analysis of Polish Adult Leukemia Group (PALG)

Abstract Monosomal karyotype (MK) and complex karyotype (CK) are poor prognostic factors in acute myeloid leukemia (AML). A comprehensive analysis of cytogenetic and clinical factors influencing an outcome of AML-CK+  was performed. The impact of cladribine containing induction on treatment results was also evaluated. We analyzed 125 patients with AML-CK+  treated within PALG protocols. MK was found in 75 (60%) individuals. The overall complete remission (CR) rate of 66 intensively treated patients was 62% vs. 28% in CK+ MK− and CK+ MK+  group (p = .01). No difference in CR rate was observed between DA and DAC arms. The overall survival (OS) in intensively treated patients was negatively influenced by MK, karyotype complexity (≥5 abnormalities), and WBC >20 G/L in multivariate analysis. The addition of cladribine to DA regimen improved OS only in MK− but not in MK+  group. In conclusion, concomitance of MK with ≥5 chromosomal abnormalities is associated with dismal treatment outcome in AMK-CK+.

Treatment of multiple myeloma patients with autologous stem cell transplantation — a fresh analysis

Patients with multiple myeloma (MM) treated with conventional chemotherapy have an average survival of approximately three years. High dose chemotherapy followed by autologous stem cell transplantation (ASCT), first introduced in the mid-1980s, is now considered the standard therapy for almost all patients with multiple myeloma, because it prolongs overall survival and disease free survival. Between November 1997 and October 2006, 122 patients with MM (58 females, 64 males, median age 51.0 years [± 7.98] range: 30-66 years) were transplanted in the Department of Hematooncology and Bone Marrow Transplantation at the Medical University of Lublin: 47 patients were in complete remission or in unconfirmed complete remission, 66 patients were in partial remission, and nine had stable disease. Of these, there were 95 patients with IgG myeloma, 16 with IgA myeloma, one with IgG/IgA, one with IgM myeloma, five with non secretory type, two with solitary tumor and two with LCD myeloma. According to Durie-Salmon, 62 patients had stage III of the disease, 46 had stage II and four had stage I. Most patients (69/122) were transplanted after two or more cycles of chemotherapy, 48 patients were transplanted after one cycle of chemotherapy, one patient after surgery and rtg- -therapy and four patients had not been treated. In mobilisation procedure, the patients received a single infusion of cyclophosphamide (4-6 g/m(2)) or etoposide 1.6 g/m(2) followed by daily administration of G-CSF until the peripheral stem cells harvest. The number of median harvest sessions was 2.0 (± 0.89) (range: 1-5). An average of 7.09 (± 33.28) × 106 CD34(+) cells/kg were collected from each patient (range: 1.8-111.0 × 10⁶/kg). Conditioning regimen consisted of high dose melphalan 60-210 mg/m(2) without TBI. An average of 3.04 (± 11.59) × 10⁶ CD34+ cells/kg were transplanted to each patient. Fatal complications occured in four patients (treatment- -related mortality = 3.2%). In all patients there was regeneration of hematopoiesis. The median number of days for recovery to ANC > 0.5 × 10⁹/l was 13 (± 4.69) (range: 10-38) and platelets recovery to > 50 × 10⁹/l was 25 days (± 11.65) (range: 12-45). Median time of hospitalization was 22 days (± 7.14) (range: 14-50). Patients were evaluated on day 100 after transplantation: 74.9% achieved CR and nCR, 14.3% were in PR, 5.4% had SD and 5.4% had progressed. Median of OS was 45 months (± 30.67). OS at 3-years was 84% and at 7-years 59%. Median PFS was 25 months (± 26.13). PFS at 3-years was 68%, and at 7-years was 43%. At present (November 2009) 52 patients (42%) are still alive. High-dose chemotherapy followed by autologous stem cell transplantation is a valuable, well tolerated method of treatment for patients with MM that allows the achievement of long- -lasting survival.

Therapy - Related Myeloid Neoplasm in a Patient with Prior Treatment for Chronic Lymphocytic Leukemia: A Case Report

Background: Acute myeloid leukemia or myelodysplastic syndrome, during the course of chronic lymphocytic leukemia, is a rare entity. In such a situation, most previous cases were therapy-related after treatment. However, in very rare cases, acute myeloid leukemia has been diagnosed in untreated patients with chronic lymphocytic leukemia. Materials and Methods: In this paper, we present the case-study of a 60-year old woman who was diagnosed six years previously as being afflicted with chronic lymphocytic leukemia with no chromosomal changes. She was successfully treated with fludarabine in combination with cyclophosphamide and rituximab, and she obtained complete remission, yet with incomplete recovery. Subsequently, three years later, she was re-admitted to hospital with deep pancytopenia. Her bone marrow biopsy then revealed that 52% of her blasts cells demonstrated a myelomonocytic immunophenotype, albeit with no chronic lymphocytic leukemia cell clone, showing the following complex chromosomal abnormalities: 45~47, XX, del(5)(q13q33), trisomy 8, trisomy 20, monosomy 21, +mar[cp12]/46, XX. Thus, a diagnosis was made of acute myelomonocytic leukemia preceded by a transforming myelodysplastic syndrome. The patient received induction chemotherapy and obtained complete remission. Unfortunately, one month after completion of her consolidation regimen, a relapse occurred. She died 8 months post-diagnosis of AML. Conclusion: In this case study, we diagnosed therapy-related acute myeloid leukemia. Of note, the theory of a common stem cell malignancy and the coexistence of two malignant clones seem not to be applied in the presented case. This is because an acute myeloid leukemia clone was not seen in her bone marrow, nor was peripheral blood evidenced at the time of her diagnosis of chronic lymphocytic leukemia.

Central nervous involvement by chronic lymphocytic leukaemia

Inclusion of the central nervous system (CNS) in the course of chronic lymphocytic leukaemia (CLL) is rare. At the moment no risk factors or proven treatment methods are known. The disease is described both in its early phase and during its acceleration period, thus it has been suggested that there might be independent mechanisms influencing the development of this condition. As there are no unified diagnostic procedure algorithms each patient needs to be assessed individually. CLL can manifest mostly in elderly people, for whom a possibility of development of neurological disorders with their aetiology different from leukaemia, should also be taken into consideration. The thesis presents a group of seven patients with CLL with CNS infiltration. Patients with prolymphocytic leukaemia, Richters transformation and the original location of leukemic infiltration within the eye socket constitute an especially interesting case.