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N Novitzky

Publications and source records attributed to N Novitzky.

At least 37 records · Page 2Linked to original sources
PubMed1999

Ex vivo depletion of T cells from bone marrow grafts with CAMPATH-1 in acute leukemia: graft-versus-host disease and graft-versus-leukemia effect.

BACKGROUND: Preventing graft-versus-host disease (GVHD) by depletion of T lymphocytes from the stem cell graft for transplantation remains controversial, mainly because of the perceived increase in disease recurrence. METHODS: We retrospectively analyzed the outcome of 50 consecutive individuals in remission of acute lymphoblastic leukemia (n=13; 8 in complete remission [CR]1) or acute myeloblastic leukemia (n=37; 33 in CR1), who had received marrow grafts from HLA-identical siblings. The conditioning regimen included six 2-Gy fractions of total body irradiation, succeeded by cyclophosphamide at 120 mg/kg (with mesna) followed by four fractions of 1.5 Gy to lymphoid areas. Bone marrow (n=38) or peripheral blood mobilized donor mononuclear cells (n=12) were exposed ex vivo to CAMPATH-1 (IgM and complement, or IgG; antiCD52) antibodies, without any further posttransplantation immunosuppression. RESULTS: Median patient age was 31 (range 14-51) years; 12 patients were 40 or older. Thirty-two patients were male. One patient died of pulmonary hemorrhage on day 10; another died on day 29 of interstitial pneumonitis. Except for one early death, all patients engrafted. Ten (21%) of the remaining 48 who were at risk, developed GVHD. In none was it greater than grade II. Eight patients developed serious viral infections. Four died of cytomegalovirus pneumonia, adenovirus hepatitis, and human immunodeficiency. Overall, 11 patients (22%) relapsed (4 of 33 acute myeloblastic leukemia in CR1) at a median of 235 (range 46-528) days. Mean posttransplantation follow-up was 1062 (median 560; range 10-4177) days. Thirty-three patients (66%) remained disease free at a mean of 1,118 (median 1439; range 159-4,177) days. For all patients, the performance status was between 82% and 100% (median 100). CONCLUSION: T-cell depletion with CAMPATH-1 effectively prevents GVHD, particularly the severe acute forms, without leading to excessive risk of relapse in acute leukemia.

Adolescent↗
PubMed1999

Cryopreservation of the bone marrow from patients with acute myeloid leukaemia leads to functional abnormalities.

We compared the performance of the stroma (SL) and haematopoietic progenitors before (group A) or following cryopreservation from patients in complete remission (CR) of acute myeloid leukaemia before autologous transplantation (AML) (group B), to similarly treated normal cells (groups A and B). From each group, fibroblastic (F) colony-forming units (CFU) and SL were established and their growth quantitated. Upon confluence of SL, 1 x 10(4)selected CD34+ cells from patient or control samples (of group A and B) were seeded on pre-formed SL from AML or control group A and B layers and adhesive precursors were scored for the formation of blastic (-b1) CFU (>20 cells). Lastly, CD34+ cells from the 4 progenitor sources were cultured in the presence of growth factors and scored for the production of granulocyte-macrophage (GM) CFU, erythroid burst forming units (BFU-E) and mixed colonies (CFU-MIX). In the patients, CFU-F numbers were decreased and by 5 wk SL failed to reach confluence. Group A AML CD34+ progenitors gave a mean of 119.2 (SD 80.4) CFU-bl/10(4) CD34+ cells, but following cryopreservation these numbers declined (83.2, SD 72.71; p = 0.009). Although AML SL prior to cryopreservation supported control CFU-bl adequately, contrary to the norm, this property decreased in group B stroma (mean 50.9/10(4)CD34+ cells, SD 49.33; p =(0.02). Group B AML samples gave significantly fewer CFU-MIX and BFU-E than pre-freezing cultures and than control samples at the first 2-growth factor combination but numbers improved following further addition of cytokines. We conclude that cryopreservation of the bone marrow of patients in CR of AML results in an inhibition of the proliferation of the CD34+ precursors. It also modifies the stroma, leading to reductions in the support of normal clones.

Acute Disease↗
PubMed1999

In aplastic anemia progenitor cells have a reduced sensitivity to the effects of growth factors.

We have recently shown that in patients with aplastic anemia (AA) recovering following immunosuppressive therapy, the persistent reduction in the bone marrow clonogenic potential is unrelated to suppressive effects of the myeloid stroma and intrinsic to the hematopoietic progenitors. We examined the mechanisms of this defect by determining the response of the aplastic CD34+ clonogenic precursors to proliferative signals induced by hematopoietic growth factors and comparing their results with those of a control population. Light density bone marrow mononuclear cells were lymphocyte and monocyte depleted and enhanced for the CD34+ progenitors by immunomagnetic selection. Selected progenitors were then cultured in the mixed colony assay with incremental concentrations of combinations containing erythropoietin (Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and c-kit ligand. Bone marrow from aplastic patients had significantly fewer light density cells displaying the CD34 antigen (mean 0.65%, SD 0.35 vs. 1.62%, SD 1.4; p=0.002). Dose response studies on aplastic CD34+ cells demonstrated that at low concentrations of Epo, IL-3 and GM-CSF, clonogenic growth was significantly impaired but achieved normal values at concentrations giving plateau growth in control cultures. However, for all colony types, responses to effective concentrations of c-kit ligand corresponded with those of controls. These data suggest abnormalities at the receptor or signal transduction levels.

Adolescent↗
PubMed1997

Alterations in the progenitor cell population follow recovery from myeloablative therapy and bone marrow transplantation.

In a previous study we showed that following recovery from bone marrow transplantation (BMT), there are persistent derangements in the clonogenic growth of hematopoietic progenitors and in the microenvironment. To characterize the abnormalities within the precursor cell population, selected BM CD34+ cells from 15 patients in remission from hematological malignancies who had received myeloablative therapy and grafts (eight allogeneic and seven autologous) were tested in dose-response studies with recombinant cytokines. Preconditioning for transplantation was accomplished with fractionated total body irradiation (fTBI) at 12 Gy, cyclophosphamide at 120 mg/kg and fractionated total lymphoid irradiation fTLI at 6 Gy. The median mononuclear cell number infused was 0.9 x 10(8)/kg (SD 0.31). At the time of BMT, the patient's median age was 26 (SD 8.65) years and eight were female. Grafts were studied at a median of 37 (SD 48.43) months from transplantation. The light density marrow population from the patients and controls was monocyte- and T-lymphocyte depleted; CD34+ precursors were then selected with immunomagnetic beads (median 90.2 and 92% blasts) and cultured in the progenitor cell assay at a cell density of 5 x 10(3) culture with incremental concentrations of recombinant human growth factors (rhGFs). BMT patients' cultures showed significantly lower colony scores at the lowest cytokine concentrations in both erythroid burst-forming units (BFU-Es) and erythroid colony forming units (CFU-Es) as well as in myeloid lineages; colony forming units-granulocyte macrophage (CFU-GM), and did not improve at the highest GF doses. No significant differences in the results were found between the autologous and allogeneic marrow sources. We conclude that following BMT, lineage restricted progenitors within the CD34+ population are significantly reduced, failing to recover even 8 years after transplantation.

Antigens, CD34↗
PubMed1995

Treatment of aggressive non-Hodgkin's lymphoma in the elderly.

A nonanthracycline-containing chemotherapeutic combination for the treatment of intermediate and high-grade non-Hodgkin's lymphoma was evaluated. Thirty-four consecutive and previously untreated patients, with a median age of 75 (range 54-86) years, with aggressive lymphoma, received daily etoposide (60 mg/m2 intravenous infusion [IVI]), cytosine arabinoside (50 mg/m2 subcutaneously), and methylprednisolone (60 mg/m2 IVI) on each of 5 consecutive days. Individuals with limited disease (stages I and II) (n = 9) received six, 3-day cycles of the same therapy and involved field radiation (36 Gy in 20 fractions) between the third and fourth courses. Patients with disseminated lymphoma (n = 25) received 10 cycles over 8 months of the same combination, with the addition of methotrexate (200 mg/m2 on days 8 and 15), followed by leucovorin rescue (10 mg/m2 orally every 6 hr for 8 doses). Of the 34 patients, 44% entered complete remission (CR), and 7 died before completing the first cycle of chemotherapy. Fifty-six percent of the patients with limited disease and 40% with disseminated lymphoma (P > 0.05) achieved CR. For all patients, median survival was 14 months (range 3 days- > 54 months), this being 12 and 15 months, respectively. For the entire population of responding patients, median survival has not been reached at a median follow-up of 39 months, while the median CR duration is 21 months. Ten of the 15 responders are alive in unmaintained CR at a median of 41 (range 30-54) months. Myelotoxicity was the major side effect, leading to adjustments in dose and schedule in two-thirds of the patients, although treatment changes did not affect outcome. Of the 15 deaths that occurred in this trial, in 53.3% it was unrelated to lymphoma or its therapy. Four patients that had achieved CR died of cardiovascular events (n = 2) or of progressive second malignancies (n = 2). It is concluded that cytosine arabinoside in combination regimens is effective in selected patients; this is particularly relevant in the elderly.

Aged↗
PubMed1995

Immunosuppressive therapy in bone marrow aplasia: the stroma functions normally to support hematopoiesis.

In aplastic anemia (AA) patients responsive to antilymphocyte globulin (ALG) therapy, abnormalities in both stroma and progenitor cell (PC) pool have been described. The relevance of each pathophysiologic defect was characterized in 16 individuals, and data were compared to results from seven normal volunteers. Bone marrow mononuclear cells were split into two fractions. Stromal layers (SL) were prepared from the first, and a CD34+ enriched population was obtained by immunomagnetic selection from the second. In cross-culture experiments, 1 x 10(4) of the latter from patients or controls were seeded on preformed SL, and adhesive PC were scored for the formation of blast colonies (CFU-Bl) on day 5 of culture. Nonadherent progenitors were recovered and quantitated in a standard clonogenic assay (CFU-GM). There were significantly fewer CD34+ cells in the AA group (median 0.65%, SD 0.39%, vs. 1.62%, SD 1.4%; p = 0.002). No morphological or cytologic differences between normal and aplastic SL were detected. Both equally supported the growth of CFU-Bl from normal progenitors (mean 117, SD 20.4, and 103.1, SD 30.4), while this value was reduced for the aplastic PC (mean 41.06, SD 42.9; p = 0.0002, exact two-tailed test). Similarly, the AA nonadherent PC had a decreased CFU-GM growth (mean 142.6, SD 104.8, vs. mean 361.7; SD 91.3), with a lower total clonogenic output (p = 0.0009). We conclude that aplastic stroma appropriately supports the growth of normal progenitors, whereas the depressed clonogenicity of the corresponsing population derived from AA is unrelated to their attachment to SL but intrinsic to the CD34+ cells, whether adherent or not.

Adolescent↗
PubMed1995

Alterations in both the hematopoietic microenvironment and the progenitor cell population follow the recovery from myeloablative therapy and bone marrow transplantation.

Experimental data are conflicting, but suggest that after recovery from bone marrow transplantation (BMT), alterations in clonogenic growth and myeloid microenvironment remain. To further characterize this abnormality, light-density marrow cells from 15 patients who were in remission from hematologic malignancies and had undergone BMT (eight allogeneic and seven autologous) were studied in two culture systems after their marrows had reconstituted and were compared to normal. The preconditioning regimen for transplantation was fractionated total-body irradiation (TBI) 12 Gy, cyclophosphamide 120 mg/kg, and total nodal irradiation 6 Gy. Bone marrow mononuclear cells (MNCs) from the patients and controls were divided in two fractions; stromal layers (SL) were prepared from the first fraction. To examine the attributes of the stroma, the petri dish surface covered by the SL was measured after 5 weeks in culture, and representative layers were trypsinized and stained with Sudan black, butirate esterase, and acid and alkaline phosphatases. Stromal layers were also studied for their support in the development of blastic colonies (CFU-BI). From the second fraction, the CD34+ population was selected with immunomagnetic beads, and 1 x 10(4) progenitors from patients or controls were seeded onto the opposite group of preformed stroma. Stroma-adhesive precursors were scored for the formation of CFU-BI (> 20 cells) on day 5 of culture. Nonadherent selected CD34+ cells were recovered by standardized washing and quantitated in clonogenic assays (CFU-GM). The median patient age was 26 (SD 6.65) years, and eight of 15 patients were female. The median infused bone marrow (BM) MNC number was 0.9 x 10(8)/kg (SD 0.31). Grafts were studied at a median of 37 (SD 48.43) months from transplant. SL from the patients failed to reach confluence by 5 weeks (median dish area covered 55.5% [SD 32.38] vs. control: 100% [SD 2.35]; p = 0.0001). BMT CD34+ progenitors gave 19.5 (SD 42.2) CFU-Bl, significantly lower than those from normal individuals (127 [SD 62.2]; p = 0.01) when panned on control stroma, while control CD34+ cells were poorly supported on BMT layers (corrected for surface, median 2.5 [SD 42.2] CFU-Bl; p = 0.039). Although numbers of stroma nonadherent CFU-GM were not different between the groups (median BMT 56 [SD 54.5] vs. control 62.5 [SD 60.76]; p > 0.05), the ratio of CFU-Bl to CFU-GM showed a significant reduction in adherent CD34+ progenitors in BMT patients (median 0.28 [SD 0.44] vs. normal 2.09 [SD 1.3]; p = 0.04). None of the values were significantly different between patients receiving allogeneic or autologous grafts. We conclude that post-BMT stroma is defective and supports CFU-Bl growth poorly. Moreover, we documented a significant reduction within the CD34+ cells in the adherent primitive clonogenic precursors that was compensated by a proportional increase in the more mature CFU-GM.

Adult↗
PubMed1994

Intravenous gammaglobulin has no advantages over oral corticosteroids as primary therapy for adults with immune thrombocytopenia: a prospective randomized clinical trial.

Symptomatic immune thrombocytopenia in adults is potentially lethal, and, when conventionally treated with oral corticosteroid agents, approximately two thirds of patients will have some response in platelet count, but this is seldom durable. Since cytotoxic drugs are of limited benefit at this stage, splenectomy becomes necessary in 70% of patients. Intravenous gammaglobulin has been advocated as an alternative to prednisone as the primary form of treatment. A prospective, randomized comparison was carried out between oral prednisone (1 mg/kg/day; group 1; n = 17), high-dose intravenous gammaglobulin (400 mg/kg on days 1 through 5; group 2; n = 13), or a combination of both agents given on the same schedule (group 3; n = 13). The groups were well matched clinically and hematologically. No mortality occurred after initiating therapy, but one patient experienced a cerebrovascular accident. Response, defined as a platelet count greater than 50 x 10(9)/L, was achieved in 82%, 54%, and 92% of patients in groups 1, 2, and 3, respectively, but was only significant between groups 2 and 3 (P = 0.0365). The median times to peak platelet counts were 8.5 days (range 7 to 21 days), 7 (range 5 to 10 days), and 7 (range 3 to 23 days), respectively. Although there was a trend in favor of the steroid-administered groups, relapse was not significantly different, which occurred at a median of 184, 32, and 76 days, respectively, nor was the average time to splenectomy different at 339, 59, and 98 days, respectively. At a minimum of 2 years of follow-up, 5 of 17 in group 1, 2 of 13 in group 2, and 1 of 13 in group 3 had achieved platelet counts of greater than 100 x 10(9)/L and, therefore, did not require splenectomy. In contrast, where this indication was present for failure to respond, 8 of 12 (67%) in group 1, 4 of 8 (50%) in group 2, and 9 of 12 (75%) in group 3 remain in complete remission. Significantly more patients in group 2 than group 3 experienced a relapse (P = 0.0365). It is concluded that in previously untreated adults with symptomatic immune thrombocytopenia, gammaglobulin offers no advantage over conventional corticosteroid administration as the primary form of therapy. Additionally, more intense immunosuppression, resulting from the use of both agents combined, is no better than single agent corticosteroid agents and appears to be an unnecessary and unwarranted expense.

Administration, Oral↗
PubMed1994

The treatment of thrombotic thrombocytopenic purpura: plasma infusion or exchange?

Classic thrombotic thrombocytopenic purpura has substantial mortality and, because the pathogenesis is uncertain, multiple therapies are often used. These include corticosteroids and antiplatelet drugs, with plasma infusion or exchange most dramatically influencing outcome. To compare the relative efficacy of these latter two options, the records of 20 patients were retrospectively analysed. The groups were well matched for size and disease severity and received equivalent volumes of plasma. No significant difference in response rate or survival was demonstrated, although plasmapheresis may be preferable in the presence of impaired renal function with fluid overload.

Adolescent↗
PubMed1992

Antilymphocyte globulin and high-dose methylprednisolone improve survival in patients with aplastic anaemia without additional financial costs.

The cost-benefit ratio in the treatment of aplastic anaemia with antilymphocyte globulin (ALG) combined with high-dose methylprednisolone (HDMP) was retrospectively compared with supportive palliative treatment alone. Over a 4-year period financial cost, response rate, survival and performance status was documented in 26 consecutive patients receiving this regimen. Outcome was favourable in 69% (group 1; N = 18) and in 13 comprehensive expenditure data were available. In the remainder (group 2; N = 8) treatment failed and they were considered to be the equivalent of a no-treatment population. Here hospital charges were analysed both with and without inclusion of ALG and HDMP. Over the 1-year study period, no significant difference in the median expenditure was found between group 1 at R19 281 (range R35 657-13 379) and group 2 at R18 522 (range R22 449-16 951). The median number of admissions for group 1 was one and for group 2 three, requiring a median of 19 and 20 days of hospitalisation respectively. At the end of the 1-year study period 19 of 26 patients were alive (73%), 69% having responded. At this time, 16 of the 18 patients in group 1 had returned to their previous occupations, but this had not been possible for any of the 8 in group 2. In suitably selected patients who do not have an allogenic bone marrow transplant option the expenditure on ALG and HDMP is both medically and economically sound and the combination can be recommended as a valuable treatment option.

Anemia, Aplastic↗
PubMed1991

Treatment of aplastic anaemia with antilymphocyte globulin and high-dose methylprednisolone.

Twenty-three consecutive adults with bone marrow aplasia who, apart from one individual, lacked a sibling suitable for allogeneic transplantation, received five daily infusions of 50 mg/kg of antilymphocyte globulin (ALG) concurrently with high-dose (500 mg) methylprednisolone (HDMP), followed by oral prednisone at a dose of 30 mg until day 30. One patient died early so that response could not be determined, but data are available and included in the toxicity as well as survival analysis. Haematological response occurred in 13 of the remaining 22 (59%). This followed a single course of treatment in 12, with complete response achieved in five of this group and a second course required in one. At a median follow-up of 20 months (range 5-60), there have been five relapses and 13 patients are alive, including 12 responders who have Karnofsky ratings between 90% and 100%. Of the other nine individuals, only two are alive, with 1 at 12 months still requiring active support and the second, after failing further courses of treatment, at 41 months having a partial response to lymphocytapheresis and plasma exchange. Failure to respond was a significant adverse predictor for survival (P = 0.022). This study involved two distinct batches of ALG, with response occurring in 1/7 (14%) patients treated with the first lot, but in 12/15 (80%) of those individuals who were treated with the second (P = 0.007). Only a pretreatment mean cell volume (MCV) greater than 100 fL predicted for response (P = 0.0088). Confirmation is hereby provided for the efficacy of ALG used in combination with HDMP for treatment of aplastic anaemia, with further support for the observation that not all batches of this product are comparable in bringing about haematologic response in these individuals.

Administration, Oral↗