Efficacy and safety of lenalidomide treatment in multiple myeloma (MM) patients--Report of the Polish Myeloma Group.

UNLABELLED: The aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for "treatment response" was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles ≥ 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--"overall survival"--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment ≥ 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), ß-2-microglobulin (ß-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%). SUMMARY: LEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles ≥ 6 was the factor which affected treatment response achievement the most, together with an important impact on OS.

Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL.

The role of autologous hematopoietic SCT (autoHSCT) in the treatment of high-risk (HR) adult ALL is controversial. In this study, we retrospectively analyzed the results of autoHSCT according to the status of minimal residual disease (MRD) at transplantation, as a joint analysis of the European Study Group for Adult ALL (EWALL). Data on 123 recipients of autoHSCT, aged 31 (16-59) years, with B-lineage (n=77) or T-lineage (n=46) ALL were included. In a cohort of Ph-negative ALL, the probability of leukemia-free survival at 5 years was higher for patients with MRD <0.1% compared with those with MRD > or = 0.1% (57 vs 17%, P=0.0002). The difference was significant for T-lineage ALL (62 vs 8%, P=0.001), and a tendency was observed for B-lineage ALL (54 vs 26%, P=0.17). In a multivariate analysis, adjusted for other potential prognostic factors, high MRD level remained the only independent factor associated with increased risk of failure (risk ratio, 2.8; P=0.0005). We conclude that MRD determines the outcome of autoHSCT in HR adult ALL. Our results suggest the need to reevaluate the role of this treatment option in prospective trials.

Beta-2-microglobulin level predicts outcome following autologous hematopoietic stem cell transplantation in patients with multiple myeloma.

Despite the widespread use of high-dose therapy combined with autologous hematopoietic stem cell transplantation (autoHSCT), the outcomes of multiple myeloma (MM) treatment remain variable. The aim of this study was to define pretransplantation factors that influence outcomes following autoHSCT in patients with MM. Eighty-one MM patients, aged 51 years (range 31-70 years), undergoing first autoHSCT were included in the analysis. Thirty patients were in complete remission and 51 were in partial remission. The conditioning regimen was based mainly on melphalan (200 mg/m(2) intravenous [iv]). The following factors were tested for their prognostic significance: beta-2-microglobulin (B2M), lactate dehydrogenase, monoclonal protein level, bone marrow plasma cell percentage (PL), hemoglobin level, age, interval from diagnosis to autoHSCT, and number of transplanted CD34-positive cells. The transplant-related mortality at day 100 was 3.7% (3/81). The incidence of progression at 9.2 years was 71% for patients with elevated B2M, and 32% for those where B2M was within normal limits (P = .02.) The probability of PFS was decreased for patients with B2M > or = versus < normal limits (29% vs 68%; P = .02) and PL > or = versus < 5% (0% vs 45%; P = 0.03). In a multivariate analysis B2M remained the only factor associated with increased risk of progression (relative risk [RR] = 3.3; P = .03) and reduced probability of PFS (RR = 3.3; P = .03). We concluded that B2M level measured at first autoHSCT was a useful predictor for progression and PFS in MM patients.

Interferon alpha induces a good molecular response in a patient with chronic eosinophilic leukemia (CEL) carrying the JAK2V617F point mutation.

The JAK2 V617F point mutation is very rare in hypereosinophilic syndrome and/or chronic eosinophilic leukemia. Here we report on a patient with chronic eosinophilic leukemia and detectable JAK2 mutant clone, who achieved a good molecular response to interferon alpha-2a after 4 months of treatment. The molecular response correlated with only moderate haematological improvement.

Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study.

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.

Acute lymphoblastic leukemia in elderly: the Polish Adult Leukemia Group (PALG) experience.

This is a retrospective, multicenter study to evaluate biological features and outcome of elderly patients diagnosed with acute lymphoblastic leukemia (ALL) during the last 10 years in ten hematological centers in Poland. Eighty-seven patients aged 60 years or older were studied. To our knowledge, this is one of the largest group of elderly patients with ALL evaluated. We have not observed differences in immunological subtypes and Ph chromosome incidence as compared with younger adult ALL presented in the literature. Induction chemotherapy was administered in 75 patients. We observed complete remission (CR) in 34 (45%, 95% CI: 33-56%) patients. Induction death occurred in 11 (15%) patients. Thirty patients (40%) showed primary resistance to chemotherapy. Median overall survival (OS) of all patients was 150 days. Median disease-free survival (DFS) of responding patients was 180 days. We observed four long-term survivors (DFS longer than 3 years) in our group of patients. Factors influencing OS were CR achievement, female gender, and WBC below 30 x 10(9)/l. Male gender was the only prognostic factor negatively affecting probability to achieve CR. We have not observed any differences in either biology or outcome between patients aged 60-69 years and those aged more than 70 years. ALL of the elderly is a rare disease with poor prognosis. Further clinical trials evaluating the disease features, outcome, and new therapeutic approaches are warranted.

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 Hodgkin's 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.

Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia.

The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From August 1998 to December 2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m2 on day 1 and cyclophosphamide at 650 mg/m2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P= 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation.

Low-dose zinc administration as an effective Wilson's disease treatment.

A case of a 11-yr-long Wilson's disease treatment in a 16-yr-old boy with neurologic presentation was analyzed and monitored. In the face of severe symptoms of chelator intolerance, a comparatively low dose of 100 mg of zinc has been administered for the entire 11-yr-long treatment. Considerable improvement of clinical status was achieved, with accompanying regression of central nervous system lesion. The parameters of copper metabolism were normalized with effective urine elimination. The low-dose oral zinc intake proved to be therapeutically effective, eliminating further copper tissue toxicity.

[Syndrome of chronic intravascular coagulation in the course of chronic myeloid leukemia]. / Zespól przewleklego wykrzepiania wewnatrznaczyniowego w przebiegu przewleklej bialaczki szpikowej.

The syndrome of chronic intravascular coagulation occurs very often in the course of malignancies including leukaemias, however, it is not always diagnosed. Two cases are presented of chronic syndrome of intravascular coagulation in the course of chronic myeloid leukaemia; in one patient being in chronic phase and in other patient during blastic phase. In the first case the patient required only causative treatment of the basic disease, in the second case, apart from causative treatment of blastic phase, heparin administration, platelet mass and frozen plasma transfusion were necessary.

[Comparison of clinical usefulness of immunophenotyping of leukemia using the immunofluorescence and immunoenzyme APAAP methods]. / Porównanie klinicznej przydatnosci immunotypizacji bialaczek przy uzyciu metody immunofluorescencyjnej i immunoenzymatycznej APAAP.

The clinical utility of the indirect immunofluorescence (IF) and the alkaline phosphatase-anti-alkaline phosphatase (APAAP) techniques was compared in 103 newly diagnosed acute leukaemia patients immunophenotyped using a panel of 19 monoclonal antibodies (MoAb). In spite of slight variations in the percentages of cells reacting with particular MoAbs when comparing the two methods we found no discrepancies in the final classification of each case. In ANLL (n = 73) the best correlation between the two methods was found for CDw65 which is a good screening marker, and for CD15 having a prognostic significance. In ALL (n = 30) the best correlation was observed for CD19 and CD10, both of great diagnostic importance. The following antigens present both in membrane and in cytoplasm displayed higher positivity with the APAAP than in IF HLA-Dr, CD71 and CD11b in ANLL, CD22 and HLA-Dr in nonT-ALL and CD3 in T-ALL. The important advantages of the APAAP technique are: 1) its use with routinely performed bone marrow or peripheral blood films, which can be stored before staining, 2) the possibility of correlating morphology with immunological characterization and documentation of the results.

Sonography in the diagnosis and therapy monitoring of lymphomas.

Multiple ultrasonographic (USG) evaluations of abdomen were performed in 97 patients: 30 with Hodgkin's disease (HD), 60 with non-Hodgkin lymphomas (NHL) and 7 with primary gastric lymphoma (PGL) before or during chemo- or X-ray therapy. In 33% of HD patients USG was normal, while in 63% splenomegaly, in 40% hepatomegaly and in 20% lymph node enlargement were observed. After therapy, in 57% USG was improved and in only 3% of patients worsening was observed. In NHL patients splenomegaly was observed in 70%, hepatomegaly in 60% and lymph node enlargement in 35%. During follow-up, in 49% of patients improvement and in 3% worsening was observed. In 5 patients with PGL no changes were observed, in further 2 patients in Stage IV stomach wall and infiltration of nearest lymph nodes was observed. USG evaluation of abdomen may be useful in staging and therapy monitoring of malignant lymphomas.

CD-15 antigen detected by the VIM-D5 monoclonal antibody for prediction of ability to achieve complete remission in acute nonlymphocytic leukemia.

The prognostic value of cell differentiation antigens detected with the monoclonal antibodies of VI series was studied in 242 cases of acute nonlymphoblastic leukemia (ANLL) treated in 7 cooperating centers. A significantly higher complete remission rate was observed in patients with a higher expression of CD-15 antigen detected by VIM-D5 antibody than in those with lower values. These significant differences were proved when comparing subgroups with VIM-D5 positivity of blastic cells less than 15 and much greater than 15% (p less than 0.01) as well as in the subgroups with values less than 50% (median value) and greater than or equal to 50% (p less than 0.02). Our studies suggest the VIM-D5 positivity of ANLL cells to be favourable prognostic factor predicting the ability to achieve complete remission. Further studies are needed to establish whether the expression of the VIM-D5-defined antigen may serve as a prognostic factor related to survival.

Application of series of monoclonal antibodies against human white cell differentiation antigens and the common ALL antigen in the characterization of leukemia cells.

The specificity and the clinical usefulness of the hybridoma derived monoclonal antibodies raised against the differentiation antigens of granulocytes (VIM-D5, VIM-C6), monocytes (VIM-D2), B lymphocytes (VIB-C5, VIC-Y1), erythrocytes (VIE-G4) and CALLA (VIL-A1) was studied in leukemic cells isolated from peripheral blood and bone marrow of 41 adults with acute leukemia by using indirect fluorescence method. The VIL-A1 positivity was observed in 4/9 of ALL and in none of myeloid leukemia. It was accompanied in 3/4 of cases by VIB-C5 positivity and in one case by VIE-G4 positivity. It is important that 2 out 3 unclassifiable cases (PAS-) could be diagnosed as common ALL due to their VIL-A1 positivity. VIM-D5 like VIM-C6 reacted specifially with granulocytic cells only and gave positive results in 20/30 of acute myeloid leukemias. When classified according to the FAB scheme, the proportion of VIM-D5 + patients rose from M1 toward more mature subtypes, including M4/5. It allowed to identify as AML 2/6 of unclassifiable-Mo leukemias, VIC-Y1 appeared to be helpful in characterization of B cell malignancies and of myelomonocytic leukemias. It is concluded that the monoclonal antibodies of VI series are specific and allow a more precise definition of leukemia, thus helping in optimalization of treatment.

Acid phosphatase activity of the lymphocytes during polychemotherapy of lymphoproliferative diseases.

In 4 adults with malignant lymphoma and in 3 cases of acute lymphoblastic leukemia the acid phosphatase activity in lymphocytes during the consecutive cycles of polychemotherapy was examined paralelly with the estimation of the receptors for sheep erythrocytes. Depression of the enzymatic reaction was observed immediately after the onset of the cytostatic treatment, its normalization between the cycles and after the full remission was reached. A remarkable and lasting decrease of the phosphatase positive lymphocytes and a change in the expression of the enzymatic reaction was noticed in the course of L-asparaginase administration. The presented investigations are the continuation of the authors' earlier studies on the positive correlation between the rosette test with neuraminidase treated sheep erythrocytes and the acid phosphatase activity in lymphoproliferative diseases.