Biomedical subjects
Publications and source records attributed to J Reiffers.
Blood cell transplantation is rapidly replacing bone marrow transplantation for restoration of hematopoiesis after high-dose chemotherapy in both the autologous and allogeneic settings. Future developments of BCT will be discussed.
Twenty-three patients with acute myelogenous leukemia (AML) in first relapse were treated with high-dose cytosine-arabinoside (Ara-C) and amsacrine or idarubicin. To prime the cells, the patients were given rhGM-CSF. We studied the influence of 48-h infusion of rhGM-CSF on proliferation and Ara-C sensitivity of leukemic cells both ex vivo and in vitro. We found that a 48-h infusion of rhGM-CSF increased both white blood cell counts and peripheral blood blast cell percentages. Using a Bromodeoxyuridine/DNA (BrdUrd/DNA) staining in flow cytometry, we found an non-constant increase in cells in the S-phase. Ex vivo 48-h culture of leukemic cells with or without rhGM-CSF, with or without other hematopoietic growth factors (HGFs), showed a greater increase of the cells in the S-phase with GF but no correlation with the ex vivo results. We used a method of quantitation of the DNA synthesis previously described (Lacombe F., et al. (1992) Cytometry 13, 730) to monitor the Ara-C sensitivity of the cells in S-phase before and after 48-h infusion with rhGM-CSF. We observed a great variation in the Ara-C sensitivity of the leukemic cells before and after infusion with rhGM-CSF from one patient to another. The BrdUrd/DNA method seems a convenient method to study the influence of HGFs on Ara-C sensitivity of the patients.
Bone marrow transplantation (BMT) from matched sibling donors has been useful for the treatment of acute lymphoblastic leukaemia in children with a poor prognosis but is not available to more than two-thirds of patients who do not have a matched allogeneic donor. This study was undertaken to assess one strategy of marrow graft rejection prevention when alternative marrow sources such as HLA-phenoidentical unrelated volunteers and HLA-partially incompatible relatives were used. Results have been compared with two matched groups of children with the same risks factors and disease status who underwent HLA-genoidentical or autologous BMT. The conditioning regimen was the same for the three groups of patients; in the study group anti-LFA-1 and anti-CD2 monoclonal antibodies combined with T-cell depletion of the marrow was added to prevent graft rejection and graft-versus-host disease. Nineteen patients were included and followed for a median of 25 months (14 months to 3 years). Bone marrow engraftment occurred in 83% of the evaluable patients. Post-transplantation infectious diseases were the most frequent causes of death in the study group, occurring in 31% of patients. No fatal infections occurred in the two control groups. Post-transplantation relapse of leukaemia occurred in 26% of study group's patients, in 58% of autologous BMT control group's patients and 5% of HLA-genoidentical allogeneic group's patients. The event-free survival was 83% in the HLA-genoidentical control group, and 30% and 24% in the study group and in the autologous control group, respectively. In conclusion, a high rate of engraftment was achieved by the use of anti-LFA-1 and anti CD2 antibodies. Occurrence of a long-lasting immunodeficiency, however, led to a high incidence of lethal infections and relapses. Combined approaches are therefore to be investigated accelerating immune reconstitution after transplantations of T-depleted HLA partially incompatible marrow.
PURPOSE: The aims of the current study were to evaluate in patients with high-risk multiple myeloma (MM) the feasibility and usefulness of high-dose chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support with autologous peripheral-blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC). PATIENTS AND METHODS: Seventy-three patients with high-risk MM were entered onto the study. Before the procedure, all patients had received HDCYC to collect PBPC by leukapheresis. One patient died of infection after HDCYC. All other patients subsequently received high-dose melphalan (HDM) (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were reinfused either alone in 61 patients or together with back-up bone marrow cells in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM) cell content of the leukapheresis was low. RESULTS: One patient died of acute cardiac failure after reinfusion of PBPC; three patients did not respond after autologous blood progenitor cell transplantation (ABPCT), while the other 68 patients achieved either a complete response (CR; n = 32) or partial response (PR; n = 36). Thirty-six patients relapsed or progressed after a median response duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four other patients died while still responsive of lung cancer (n = 1) or infection (n = 3). The remaining 28 patients are currently alive and still responding with a median follow-up duration of 27 months (range, 6 to 66). The 3-year probability of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/- 51% (95% CI) from diagnosis. CONCLUSION: High-dose chemotherapy or chemoradiotherapy followed by autologous PBPC support in MM is feasible and efficient. Further studies are needed to confirm these encouraging, although preliminary, results and to compare this technique with other therapeutic strategies.
In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.
The best therapy for persons with acute myelogenous leukemia (AML) in 2nd remission is unknown. Bone marrow transplants from an HLA-identical sibling are reported to be better than chemotherapy but this is controversial. The objective of the study was to compare 3-year leukemia-free survival (LFS) in comparable subjects receiving chemotherapy or a transplant. 485 persons with AML in 2nd remission were studied. The chemotherapy cohort included 244 persons treated on trials of the British Medical Research Council, Eastern Cooperative Oncology Group and MD Anderson Hospital. The transplant cohort included 257 persons transplanted worldwide and reported to the international Bone Marrow Transplant Registry (16 were also chemotherapy subjects.) Subjects were selected for comparable age and year of treatment. Preliminary analyses identified two factors correlated with LFS: age < or = or > 30 years and 1st remission duration < or = or > 1 year; subsequent analyses were partitioned accordingly. Three-year probabilities of treatment-related mortality with chemotherapy and transplants were 7% (95% confidence interval, 3-15%) vs 56% (49-63%). Three-year leukemia relapse probabilities were 81% (74-86%) vs 41% (33-49%). Three-year probabilities of LFS were 17% (12-23%) vs 26 (20-32%). Cohort analysis showed significantly higher LFS with transplants vs chemotherapy in persons < or = 30 years and 1st remissions > 1 year (41% (29-53%) vs 17% (7-32%); P = 0.017) and those in > 30 years with 1st remissions < or = 1 year (18% (9-29%) vs 7% (2-16%); P = 0.046). Others had comparable LFS with both treatments. These data indicate better LFS with HLA-identical sibling transplants than chemotherapy in some persons with AML in 2nd remission.
Autografting could become a promising treatment for patients with chronic myeloid leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or failed to respond to recombinant alpha-interferon (IFN). In this review, we analyze the results which have been published for patients transplanted in chronic phase and which suggest that autografting could prolong survival, at least in some patients. We also discuss the different methods of purging whose clinical efficacy remains to be assessed.
A prospective randomized study was conducted comparing the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myeloid leukemia (AML) between 55 and 75 years. A total of 220 patients were randomized to receive as induction chemotherapy cytosine arabinoside (Ara-C: 100 mg/m2/day; continuous infusion for 7 days) combined with either daunorubicin (DNR: 50 mg/m2/day, i.v. bolus for 3 days) (n=108) or idarubicin (IDA: 8 mg/m2/day, i.v. bolus for 5 days) (n=112). The complete remission (CR) rate was similar (P=0.296) after IDA (76/112; 68%) and DNR (66/108; 61%) (P=0.3). For patients aged 55-65, the CR rate was significantly higher after IDA (39/47; 83%) than after DNR (29/50; 58%) (P=0.007). Persistent leukemia was more frequent after DNR (26/108) than after IDA (13/112; P=0.015). Hematological and extra-hematological toxicities were similar. The CR patients were given a consolidation course of chemotherapy with Ara-C: 50 mg/m2/12 h, subcutaneously for 5 days, combined with either DNR:30 mg m2/day, i.v. bolus for 3 days or IDA:8 mg/m2/day i.v. bolus for 3 days according to the initial randomization, and then received a continuous maintenance treatment for 2 years. The survival and disease-free survival (DFS) were similar in both groups; there was no difference in the risk of relapse. However, there was a trend for a longer event-free survival (EFS) in the IDA group than for the DNR patients (P=0.07). Our results seem to indicate that IDA is probably more efficient than DNR for AML patients between 55 and 75 years, and confirm the data published in other studies comparing prospectively IDA and DNR in adults.
To evaluate whether the results of bone marrow transplantation have improved in Europe with time, we analyzed the outcome for 2195 patients with acute leukemia. 1405 had acute myeloid leukemia (AML) and 790 had acute lymphoblastic leukemia (ALL), and were allografted in first complete remission between September 1979 and December 1991 with marrow from an HLA-identical sibling donor. We found a continuing improvement more evident since 1987 for AML and since 1986 for ALL. A substantial reduction in the 3 years transplant related mortality (TRM): 26 vs 39% for AML (P = 10(-4)), and 25 vs 39% for ALL (P = 10(-4)), has resulted in an increase of the 5-year actuarial leukemia-free survival (LFS). 57 vs 45% for AML (P < 10(-4)) and 54 vs 45% (P = 10(-4)) for ALL. Four important changes have occurred. (1) Graft-versus-host disease (GVHD) prevention has involved an increased use of cyclosporin A (CsA) alone and subsequently its use in combination with methotrexate: this was associated with lower TRM both in AML and ALL; (2) Use of total body irradiation as pretransplant regimen has decreased; (3) a shorter interval from remission to BMT is more common; (4) an older population of patients has undergone BMT. Multivariate analyses were performed separately in AML and ALL. In AML four variables significantly influenced TRM favorably: year of BMT (P = 10(-4)), younger age at BMT (P = 10(-4)), prevention of GVHD including CsA (P = 0.008), sex match other than female donor to male recipient (P = 0.002). The relapse incidence (RI) was lower in patients with FAB M1-2-3 vs M4-5 (P = 0.0004). The LFS improved by year of BMT (P = 0.0004), younger age at BMT (P = 10(-4)), prevention of GVHD including CsA (P = 0.01), FAB M1-2-3 (P = 0.03). In ALL, three variables were associated with a lower TRM: year of BMT (P = 10(-4)), younger age at BMT (P = 10(-4)), sex combination other than female to male (P = 0.008). The LFS was better after 1986 (P = 0.0004) and in younger patients (P = 10(-4)). However a better outcome after 1986/87 was observed in patients receiving the same GVHD prophylaxis: therefore, other unidentified factors resulting in better patient care have also contributed to this. The improved results of allogeneic BMT are entirely related to a reduction in TRM without loss of the antileukemic effect since relapse incidence has not changed over the years.
The objective was to analyze risk factors for veno-occlusive disease of the liver (VOD) after allogeneic bone marrow transplantation. A cohort of 1717 recipients of HLA-identical sibling transplants for leukemia between 1988 and 1990, in 200 transplant teams worldwide, was studied. Patients were scored as having VOD if liver tissue showed typical histologic features or if they had all three of the following: (1) jaundice; (2) hepatomegaly and right upper quadrant abdominal pain; and (3) ascites and/or unexplained weight gain. Patients surviving more than 7 days post-transplant without histologic or any of these clinical features of VOD were classified as not having VOD. Patient-, disease- and transplant-related characteristics of 95 patients with VOD were compared to those of 1514 without VOD. Variables correlated with an increased risk of VOD were: pretransplant conditioning with busulfan and cyclophosphamide compared to total body radiation (relative risk (RR) 2.8; P < 0.0001), pretransplant fungal infection (RR 4.1; P = 0.011), pretransplant Karnofsky performance score < 90% (RR 1.9; P = 0.012), prior liver disease (RR 1.9; P = 0.05) and age > 20 years (RR 1.8; P = 0.05). In patients receiving radiation for conditioning, intravenous immune globulin decreased VOD risk (RR 0.26; P = 0.003). This analysis identifies risk factors for VOD. The data suggest several strategies for modifying transplant regimens to reduce VOD risk and which patients might be suitable subjects for trials of strategies of VOD prevention.
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The pericentric inversion on chromosome 16 [inv(16)(p13q22)] and related t(16;16)(p13;q22) are recurrent aberrations associated with acute myeloid leukemia (AML) M4 Eo. Both abberations result in a fusion of the core binding factor beta (CBFB) and smooth muscle myosin heavy chain gene (MYH11). A selected genomic 6.9-kb BamHl probe detects MYH11 DNA rearrangements in 18 of 19 inv(16)/t(16;16) patients tested using HindIII digested DNA. The rearranged fragments were not detectable after remission in two cases tested, while they were present after relapse in one of these two cases tested.
To improve the management of chronic myeloid leukemia (CML) in a single center, we have used interferon-alpha (IFN-alpha) to treat newly diagnosed Ph-positive CML patients and investigated the factors predictive of a major cytogenetic response. Eighty-one patients with a median age of 50.5 y (17-70) were given IFN-alpha (5 x 10(6)/sqm/day, s.c.). The median interval between diagnosis and IFN-alpha was 45 days (0-160). IFN-alpha doses were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 39), intermediate (n = 32) and high risk (n = 10). A complete hematological response (CHR) was achieved in 66 cases (81.5%). Cytogenetic response was evaluated in these 66 responders. Thirty-six patients (44.4%) achieved a major cytogenetic response (MCR) (> or = 65% Ph-negative cells), 31 of them having a complete cytogenetic response. The 5-y transformation-free survival (TFS) of the 81 patients was 77 +/- 14% (95% CI) and was statistically influenced by the CHR rate at three months (p = 0.008) and the achievement of MCR or CCR (p < 0.0009 and p < 0.0005, respectively). Moreover, we found that the MCR or CCR were significantly influenced by the obtaining of CHR at three months (p < 0.001 and p < 0.0001, respectively). These results show that IFN-alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within three months could be useful to identify early those patients who will not respond to IFN-alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.
We analyzed retrospectively data from 1696 patients with AML transplanted in Europe from January 1987 to December 1992 and reported to the acute leukemia EBMT registry. Groups of patients were analyzed according to age (adults and children) and status at transplant (first remission = CR1; second remission = CR2). (1) 1114 adult patients were transplanted in CR1; 516 received an allograft; 598 received an autograft. Following alloBMT, the transplant-related mortality (TRM) was significantly higher (27 vs 13%, P < 10(-4)), the relapse incidence (RI) lower (25 vs 52%, P < 10(-4)) and the leukemia-free survival (LFS) better (55 vs 42%, P = 0.006). Favorable prognostic factors for alloBMT were a FAB type other than M4-M5, a donor-recipient combination excluding a female donor to a male recipient, and a younger age. Favorable prognostic factors for ABMT were a younger age of the patients at time of transplant, the AML3 FAB type, and a longer interval from CR1 to ABMT. (2) 288 adult patients were transplanted in CR2: 98 received an allograft; 190 received an autograft. The TRM was higher following allogeneic BMT (32 vs 20%, P = 0.02) and the RI lower (42 vs 63%, P = 0.001). The LFS was not significantly different (alloBMT: 39%; ABMT: 30%, P = 0.22). (3) 242 children were transplanted in CR1; 129 received an allograft; 113 received an autograft. Following alloBMT, the RI was lower (25 + 5 vs 48 + 6%, P < 10(-4)), and the LFS better (68 vs 47%, P = 0.002). The use of TBI was a favorable prognostic factor in allografted patients with a lower RI and a better LFS. (4) The number of children transplanted in CR2 was too small for a comparative analysis. These results confirm that both allogeneic and autologous BMT are suitable curative approaches for AML. They favor the use of an HLA identical related allogeneic transplant when available, especially in younger patients, over ABMT with unpurged marrow. The role of purging in ABMT could not be addressed in this study.
A total of 1634 recipients of HLA-identical sibling bone marrow with acute leukemia were treated with the combination of cyclosporin A (CsA) and methotrexate as prophylaxis against graft-versus-host disease (GVHD). The probability of relapse decreased with an increasing grade of acute GVHD, especially in patients grafted in first remission (CR-1): P < 0.01 and P < 0.001 for acute lymphoblastic leukemia and acute myeloid leukemia, respectively. Among patients surviving at least 3 months without a relapse, chronic GVHD was associated with a decreased incidence of relapse in CR-1 (P < 0.0001 for both diagnoses), and a better LFS. Among patients in CR-1, the probability of relapse was the same in those with limited or with extensive chronic GVHD. However, in patients with intermediate stage of the disease (> or = 2nd remission or 1st relapse) with previous acute GVHD, those with extensive chronic GVHD had a reduced probability of relapse (P = 0.05). The graft-versus-leukemia effect of acute and especially chronic GVHD was confirmed by multivariate analyses. Overall, the highest LFS was seen in patients with chronic GVHD and no or grades I-II acute GVHD. The lowest LFS was seen in patients having acute GVHD grades III-IV without chronic GVHD.
Changes in endothelial cell activity are likely to play a role in the thrombotic complications of bone marrow transplantation (BMT) such as the development of veno-occlusive disease. Accordingly, we measured established plasma endothelial cell markers von Willebrand factor (vWf), soluble thrombomodulin (sTM), soluble ICAM-1 (sICAM-1), and possible inducers of these molecules, TNF alpha and elastase, in the plasma of 25 patients, 1 week before as well as 1 and 3 weeks after BMT. Compared to healthy age and sex-matched controls, patients exhibited increased vWf and sTM. One week after transplantation, there were significant increases in vWf and sICAM-1, with a significant fall in elastases. Three weeks after the transplantation, sICAM-1 and, to a lesser extent, vWf increased still further, whereas elastases were unchanged. There were no significant changes in sTM and in TNF alpha through the serial study. Our data suggest that before conditioning, vascular endothelium is damaged by both injury and activation, as seen by the variations of vWf and sTM. After transplantation, the enhancement of this damage seems to be more specifically related to activation, since we observed a strong subsequent increase in vWf and markedly in sICAM-1.
In 204 adult patients with de novo acute myeloid leukemia (AML), we prospectively compared allogeneic bone marrow transplantation (alloBMT), autologous stem cell transplantation (ASCT) and chemotherapy (Chemo). 162 patients (79.4%) achieved a complete remission (CR). Of the 135 patients who were still in CR after consolidation, 96 patients were less than 46 years of age: 36 patients had an HLA-identical sibling donor and were allocated for alloBMT (group I); they were compared to the 60 other patients who did not have an HLA-identical sibling donor and were treated with either ASCT or chemotherapy (group II). The 3-year disease-free survival was higher for group I patients (66.5 +/- 16%) than for the 60 group II patients (42.4 +/- 13%) (P < 0.05). The actuarial risk of relapse at 3 years was significantly lower for group I patients (24 +/- 15%) than for the other 60 group II patients (56 +/- 13%; P < 0.009). By multivariate analysis, the disease-free survival and risk of relapse were influenced by the initial WBC count (P < 0.02 and P < 0.006), the number of chemotherapy courses for CR (P < 0.001 and P < 0.01) and the type of post-induction treatment (alloBMT vs no alloBMT; P < 0.1 and P < 0.02). The 99 patients who did not fulfill the inclusion criteria for alloBMT were given intensive chemotherapy including high-dose aracytine. When they were still in CR (n = 77), these patients were then randomized for either ASCT (n = 39) or Chemo (n = 38). We were unable to detect any statistical difference between ASCT and Chemo for either disease-free survival, risk of relapse or survival. These results indicate that alloBMT seems to produce results which are at least superior to those of other therapeutic modalities. The results of either ASCT or Chemo look similar.
Endothelial cell (EC) may represent a major source of cytokines in the bone marrow. In this study we have examined the production and the regulation of the production of leukemia inhibitory factor/human interleukin for DA cells (LIF/HILDA) by EC. Human umbilical vein endothelial cells (HUVEC) were chosen as a working model as they are a well known source of cytokines. These cells secrete LIF/HILDA (90 pg/mL/10(6) cells/48 h) in basal conditions. This secretion is profoundly altered by interleukin-1 alpha (IL-1 alpha). Secretion of LIF/HILDA is increased threefold on stimulation with IL-1 alpha at a concentration of 100 IU/mL. The secreted protein is bioactive as demonstrated by its proliferative effects on DA1a cells. Modulation of the production of LIF/HILDA by glucocorticoids (GC) was also examined. In striking contrast to what was observed for IL-1 alpha, the synthetic GC dexamethasone (DXM) at a concentration of 10(-6) mol/L consistently inhibited the basal secretion of LIF/HILDA by an average of threefold and suppressed the IL-1 alpha-induced increase of the secretion of this cytokine by HUVEC. In an effort to extend results obtained with HUVEC to the bone marrow endothelium, we have also examined the production of LIF/HILDA by human bone marrow endothelial cells (HBMEC). Our study shows that HBMEC are quantitatively a very important source of this cytokine (above 7.25 ng/mL/10(6) cells/48 h) suggesting that they are a major source of LIF/HILDA in the bone marrow. Again, IL-1 alpha proved to be a very potent stimulus for the secretion of LIF/HILDA and synthetic GC such as DXM when used at a concentration of 10(-6) mol/L inhibited by an average of threefold the basal secretion of LIF/HILDA and had suppressive effect on the IL-1 alpha-induced increase of this secretion. The downregulation of LIF/HILDA production in the bone marrow by GC may be important to understand the effects of GC on hematopoiesis.