Potential Leukemic Cells Engraftment After Hematopoietic Stem Cell Transplantation From Unrelated Donors With Undiagnosed Chronic Leukemia.

BACKGROUND: Donor-related neoplasms are a potential complication of treatment strategies involving stem cell transplantation. Although mechanisms for detection of short-term complications after these procedures are well developed, complications with delayed onset, notably transmission of chronic diseases such as chronic myeloid leukemia (CML), have been difficult to assess. Consequently, we studied the potential of human CML cells to engraft hematopoietic tissues after intravenous implantation in mice. METHODS: Human peripheral blood cells, collected from CML patients presenting with moderately increased white blood cells count before treatment, were transplanted into sub-lethally irradiated, immunodeficient mice. Five weeks after transplantation the nuclear cells were isolated from the murine bone marrow, spleen, and peripheral blood and were used to quantitatively detect human CD45 antigen by flow cytometry; qRT-PCR was used to detect the BCR-ABL1 fusion gene, and the human or murine beta-glucuronidase housekeeping gene was used to examine human-murine chimerism. RESULTS: We found that all evaluated animals had donor chimerism at the selected interval after transplant and the presence of a specific BCR-ABL1 fusion gene transcript was also detected. CONCLUSIONS: Our results suggest that the risk of neoplasm transmission cannot be eliminated during hematopoietic stem cell transplantation from undiagnosed CML donors with borderline leukocytosis. The obtained data confirms the potential of leukemic cells to viably engraft the hematopoietic organs post-transplantation in an immunosuppressed recipient.

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.

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.

The effect of 2-h infusion of 2-chlorodeoxyadenosine (cladribine) with prednisone in previously untreated B-cell chronic lymphocytic leukaemia.

2-Chlorodeoxyadenosine (2-CdA) is a new antimetabolite chemotherapeutic agent active in indolent lymphoid malignancies. In this retrospective study, 69 previously untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL) were treated with 2-CdA administered at a dose of 0.12 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. 45 patients also received prednisone 30 mg/m2 orally each day for 5 days starting with 2-CdA courses. Patients were given 2-6 courses (mean 4.6) of 2-CdA repeated usually at monthly intervals. If a complete response was achieved, no further 2-CdA courses were administered. Guidelines for response were those developed by the NCI Sponsored Working Group. Complete response (CR) was achieved in 26 (38%) and partial response (PR) in 27 (39%) cases, giving an overall response rate of 77%. 16 patients (23%) did not respond to 2-CdA. In the subgroup of 45 patients receiving 2-CdA with prednisone, CR was obtained in 15 (33%) and PR in 20 (44%) patients giving an overall response rate of 78%. CR was achieved in 11 (46%) out of 24 patients treated only with 2-CdA and in 7 cases (29%) PR was observed, giving an objective response rate of 75%. The differences between both subgroups were not statistically significant. However, we observed a relationship between the response and the number of courses of 2-CdA given in patients receiving and those not receiving prednisone. In the subgroup receiving 2-CdA with prednisone, an earlier response to 2-CdA was observed. In this group a response was achieved in 9 (20%) patients after two courses of 2-CdA and in 18 (40%) after four courses. In the subgroup receiving only 2-CdA, 17 (71%) responses were obtained after six cycles.

2-chlorodeoxyadenosine (2-CdA) in 2-hour versus 24-hour intravenous infusion in the treatment of patients with hairy cell leukemia.

Forty one patients with hairy cell leukemia (HCL) were treated with 2-chloro-deoxyadenosine (2-CdA) administered in various schedules. Complete remission (CR) was achieved in 31 (76%) patients and partial remission (PR) in 9 (22%). The mean duration of remission (CR + PR) was 25.2 months (range 9-45 months). One patient did not respond to therapy. Twelve out of 16 patients (75%) achieved CR after 5-day intravenous infusions of 2-CdA and 19 out of 25 patients (76%) after 7-day courses. In 19 out of 23 patients (82.6%) CR was achieved after intermittent 2-hour infusions and in 12 out of 18 (66.7%) after continuous 24-hour infusion. The differences were not statistically significant. Side effects of 2-CdA were similar in both groups except for infections, which were less frequently observed in the group treated for 5 days. The results of our study suggest that 2-CdA can be effectively administered to patients with HCL using 5-day courses and a 2-hour daily infusion.

Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia.

The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.

Computerized morphometric analysis of the cerebellum in patients with lymphoblastic lymphomas of various survival time.

Post-mortem neuropathological investigations of the cerebellum were carried out in 15 patients deceased due to lymphoblastic lymphoma (LBL). In patients with survival time of LBL longer than 20 months, neuronal structures of the cerebellum appeared to be significantly rarefied. It was especially observed within granular layer, less frequently in Purkinje and dentate nuclei cells. In cases with longer survival time shrinkage and deformation of neurons, especially Purkinje and dentate nuclei cells were observed. The morphometric analysis suggests that the cerebellar neuronal changes might be a consequence of remote effects of LBL on nervous tissue. The longer survival time contribute to the nervous system exposure on remote effects of neoplasm. The dentate nuclei cells are damaged due to remote effect of lymphoma, irrespective of Purkinje cells destruction.

Computerized morphometric analysis of human leukemic and lymphomatous cells in various histological environments of central nervous system.

The leukemic and lymphomatous cells appear within the central nervous system (CNS) in 5 different environments: in CNS vessels, perivascular spaces, meninges, nervous tissue and in CNS hemorrhages. A computerized analysis of geometric and densitometric parameters of neoplastic cells in these compartments were done for better recognition of penetration and spreading of leukemia and lymphoma within the CNS. A post-mortem neuropathological investigations were carried out on 16 patients deceased due to acute myeloblastic leukemias (M1, M2), blastic phase of chronic myelogenous leukemia, lymphoblastic lymphoma and acute lymphoblastic leukemia. Following nuclear parameters of neoplastic cells were analyzed: area, "form factor", mean, minimal and maximal density. An evident differentiation of nuclear parameters within the CNS environments was found. The nuclei within the perivascular spaces and especially in CNS hemorrhages were significantly shrunken and dense (p < 0.01), but not evidently deformed. The intracerebral infiltrates appeared to be most differentiated group (p < 0.01). Morphometric values of leukemic and lymphomatous cells show regressive changes of neoplastic cells within the CNS perivascular spaces, nervous tissue and in CNS hemorrhages. These changes depend on unfavorable factors in the mentioned CNS environments, and also on time of cell persistence in these regions. Meninges were found to be the only CNS structure facilitating the survival and proliferation of leukemic and lymphomatous cells.

Central nervous system leukostasis in patients with leukemias and lymphomas.

The clinical and neuropathological investigations have been done on 133 autopsied patients died of leukemia or non-Hodgkin's lymphoma of high malignancy. A study was performed to analyse the role of various factors particularly with respect to adhesion and aggregation in the CNS leukostasis development. The findings were also designated to evaluate the distribution of leukostasis in different CNS regions and to recognize its intensity in various CNS vessels. Basing on the studies the authors conclude that the risk of CNS leukostasis increases evidently when the leukocyte counts are elevated above 50 G/l. The adhesion and aggregation of leukemic and lymphomatous cells as well as local anatomical factors in the CNS vessels play and important role in the CNS leukostasis development, which is more intensive in the white matter and leptomeninges. The medium-sized vessels are much involved, whereas cortical capillaries are relatively less affected by leukostasis. The CNS leukostasis appears to be dynamic and reversible phenomenon, which undergoes fluctuations according to the leukocyte counts increase or decrease.

[Patient's age as a risk factor for central nervous system involvement in chronic myeloid leukemia]. / Wiek chorych jako czynnik ryzyka zajecia osrodkowego ukladu nerwowego w przewleklej bialaczce szpikowej.

Clinical and neuropathological examinations were carried out in 32 cases of chronic myeloid leukaemia dying in the blast phase. The hypothesis is put forward that in chronic myeloid leukaemia lower age of the patient (below 45 years) is a risk factor for development of central nervous system involvement which may be related possibly to high leucocytosis occurring more frequently in these cases in the blast phase leading to leucostasis and leukaemic infiltrations in the brain. The duration of the chronic phase and blast phase, and the pattern of leucocytosis in the chronic phase were similar in younger and older patients.

[Neurologic complications in high-grade non-Hodgkin's lymphomas. Clinico-neuropathological correlations]. / Powiklania neurologiczne w chloniakach nieziarniczych o wysokiej zlosliwosci. Korelacje kliniczno-neuropatologiczne.

The neurological and electroneurographic assessment was carried out in 56 patients with high-grade non-Hodgkin lymphomas. In 37 patients the neuropathological examination was also done. Polyneuropathy was the most frequent sign of nervous system involvement, observed in 40% of patients before chemotherapy and markedly enhanced by cytostatics. The signs of the central nervous system involvement were usually caused by lymphomatous infiltrations within leptomeninges, especially in lymphoblastic and immunoblastic lymphomas. The authors stress that cerebro-spinal fluid should be investigated several times for avoiding of false negative results. Signs of lymphomatous infiltrations disappeared after treatment, while signs of polyneuropathy due to chemotherapy increased during cytostatic treatment.

[A case of centroblastic lymphoma of the thyroid gland]. / Przypadek chloniaka centroblastycznego tarczycy.

A case of a 49-year male patient with centroblastic lymphoma of the thyroid gland is presented. Centroblastic lymphoma was diagnosed with cytological and immunocytochemical examination of the biopsy specimen, and verified with histological examination of tumor section collector intraoperationally. Diagnosed tumor was classified as II AE degree. No signs of lymphocytic thyroiditis co-existing with centroblastic lymphoma were noted. The patient was treated chemically with CBVPM/AVBP regimens for 8 months. Complete remission still lasting, i.e. 96 months after completion of chemotherapy, was achieved.

[Results of treating patients with highly malignant non-Hodgkin's lymphomas; comparison of treatment efficacy with CHOP and CBVPM-AVBP]. / Wyniki leczenia chorych na chloniaki nieziarnicze o wysokiej zlosliwosci; porównanie skutecznosci leczenia schematami CHOP i CBVPM-AVBP.

The treatment of highly of 43 patients with highly malignant non-Hodgkin lymphomas were analysed and assessed. These patients were treated at the Department of Hematology, Pomeranian Medical Academy within 1981-1990. The process was advanced in 76% of and localization of the tumour outside lymph nodes was also seen in 79%. The results of treatment with CHOP regimen used during the first 5 years were compared with CBVPM-AVBP used in 1986-1990. CBVPM-AVBP regimen proved more 4 effective (55% of the complete remissions) than CHOP regimen (37.5% of the complete remission). Mean duration of the complete remission (survival free from the relapse) was 27.5 (1-88) months. Complete remissions were easier to achieve in patients with centroblastic lymphoma in higher percentage. These patients survived longer than those with other highly malignant lymphomas. The authors conclude that further intensification of chemotherapy in case of highly malignant non-Hodgkin lymphomas is justified.

Leukemic cells growth fraction in the central nervous system in blastic phase of chronic myelogenous leukemia.

Clinical and neuropathological investigations were carried out in 6 patients, deceased due to blastic phase of chronic myelogenous leukemia (BPCML). Growth fraction of leukemic cells in peripheral blood, cerebrospinal fluid and in the central nervous system (CNS) was studied, using mitotic index and immunohistochemical staining technique with the monoclonal antibody antiproliferating cell nuclear antigen (anti-PCNA). The results suggest that in BPCML the proliferative activity of leukemic cells is low both in peripheral blood, cerebrospinal fluid, cerebral leukostasis and within the leptomeningeal and intracerebral infiltrates, even in cases with a very high white blood cells count. It can confirm the opinion that in BPCML, accumulation rather than proliferation of leukemic cells plays an important role in the development of the CNS leukemia.

["Critical point" as a risk factor of central nervous system hemorrhagic complications in patients with blastic phase of chronic myelogenous leukemia]. / "Punkt krytyczny" jako czynnik ryzyka powiklan krwotocznych w osrodkowym ukladzie nerwowym u chorych z faza blastyczna przewleklej bialaczki szpikowej.

Clinical and neuropathological investigations have been performed on 29 patients deceased due to blastic phase of chronic myelogenous leukemia. The authors tried to determine if the risk of death due to hemorrhagic complications in the central nervous system (CNS) increased in the period of blastic phase with simultaneous hyperleukocytosis above 100 G/l and thrombocytopenia below 25 G/l. The results have revealed that in the above mentioned period named "critical point" the probability of death due to hemorrhages is over 7 times as high as during hyperleukocytosis without thrombocytopenia and almost twice as high as during thrombocytopenia without hyperleukocytosis.

[Dysfunction of the blood-brain barrier in patients with acute leukemias or lymphomas of high grade malignancy]. / Zaburzenia funkcji bariery krew-mózg u chorych z ostrymi bialaczkami lub chloniakami o wysokim stopniu zlosliwosci.

In 38 patients with acute leukemias or non-Hodgkin's lymphomas of high malignancy the blood-brain barrier (BBB) was prospectively analysed by means of QAlb value (QAlb = cerebrospinal fluid albumin/serum albumin). Cerebro-spinal fluid and serum were taken before each intrathecal methotrexate administration according to central nervous system (CNS) prophylaxis or treatment of CNS involvement by neoplasm. Patients were divided into two groups. Group I consisted of 5 individuals with clinical manifestations of CNS involvement by leukemia or lymphoma. Group II contained 33 patients without neurological symptoms. Besides, group II was subdivided into other two groups: group IIa-patients with BBB analysis before cytostatics application, and group IIb-patients in which BBB was analysed after the administration of at least one cycle of protocols, used in general chemotherapy, including intrathecal methotrexate injection. In group I BBB changes were observed in 10 out of 12 assessments (sensitivity 83.3%). In group II BBB impairment was revealed in 11 out of 52 assessments (specificity 78.8%). The differences in QAlb values between groups I and II were statistically significant (p = 0.0008), whereas there were no significant differences between QAlb values in groups IIa and IIb. Basing on their investigations, the authors conclude that neoplasm invading CNS should be considered as essential risk of BBB impairment, whereas intrathecal and general chemotherapy appear to be less important in BBB injury.

[Transthyretin and albumin in cerebrospinal fluid in patients with acute leukemias or lymphomas of high grade malignancy]. / Transtyretyna i albumina w plynie mózgowo-rdzeniowym u chorych na ostre bialaczki lub chloniaki o wysokim stopniu zlosliwosci.

Transthyretin and albumin in lumbar cerebrospinal fluid (CSF) and in serum were repeatedly assessed in 40 patients with acute leukemias or high grade non-Hodgkin's lymphomas. The patients were divided into 3 groups. Group I-5 individuals with clinical manifestations of leukemic or lymphomatous meningosis; Group II-33 cases with no clinical data of central nervous system involvement by neoplasm (leukemia/lymphoma); Group III-2 patients in whom extramedullary solid leukemic or lymphomatous infiltrations were diagnosed. It was revealed that blood-brain-barrier dysfunction due to neoplastic infiltration of leptomeninges went with an increase of albumin blood-CSF barrier dependent- and with decrease of blood-CSF barrier-independent transthyretin concentrations. In patients with extramedullary tumors an evident increase of albumin and total-CSF transthyretin and no blood-CSF barrier-independent transthyretin concentrations below the tumor location were observed. It can betray a complete block of the vertebral canal subarachnoid space below the neoplastic compression of the spinal cord. Cytostatics application, either general or intrathecal, did not influence the CSF albumin and transthyretin levels.

[Treatment of inflammatory changes and stomatitis in patients with acute leukemias and malignant lymphomas using low pressure hydrotherapy--preliminary report]. / Leczenie zmian zapalnych i owrzodzeniowych jamy ustnej u chorych na ostre bialaczki i chloniaki zlosliwe przy pomocy hydroterapii niskocisnieniowej--doniesienie wstepne.

The management of stomatitis, commonly complicating intensive chemotherapy in patients with acute leukemias and malignant lymphomas has been presented. The hydrotherapy equipment of our own construction was designed to wash the oral cavity with large amounts of fluid given at low pressure and constant temperature. This washing solution contained the addition of drugs; its pH was adjusted to the pH of the patients saliva. Preliminary results of this treatment modality have been reported.

[Bone marrow changes in patients with hairy cell leukemia after 2-chlorodeoxyadenosine treatment]. / Zmiany w szpiku chorych na bialaczke wlochatokomórkowa po leczeniu 2-chlorodeoksyadenozyna.

Bone marrow abnormalities were assessed in 6 patients with hairy cell leukemia after 2-chlorodeoxyadenosine treatment. In spite of clinical and haematological remission in all patients, hairy cells and fibrosis were found within the marrow. However, the hairy cells number, the thickness of argentophilic fibres and the extent of fibrosis. It was stressed that in addition to histological analysis with hematoxylin-eosin also other stainings for fibrosis should be applied in the bone marrow evaluation, followed by immunohistochemical and molecular methods which allow to exclude minimal residual disease after leukemia treatment.