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The correlation between the incidence of GVHD and the number of infused CD34+ cells remains controversial for PBSC transplantation after a reduced-intensity-conditioning (RIC) regimen. We evaluated 99 patients transplanted with an HLA-identical sibling after the same RIC (2-Gy-TBI/fludarabine). Donor and recipient characteristics, donor's blood G-CSF-mobilized CD34+ cell count, and number of infused CD34+ and CD3+ cells were analyzed as risk factors for acute and chronic GVHD There was a trend for an increased incidence of extensive chronic GVHD in the quartile of patients receiving more than 10 × 106 CD34+ cells/kg (P=0.05). Interestingly, the number of donor's blood CD34+ cells at day 5 of G-CSF mobilization was closely associated with the incidence of extensive chronic GVHD, that is, 48% (95% CI: 28-68) at 24-months in the quartile of patients whose donors had the highest CD34+ cell counts versus 24.3% (95% CI: 14-34) in the other patients (P=0.007). In multivariate analysis, the only factor correlating with extensive chronic GVHD (cGVHD) was the donor's blood CD34+ cell count after G-CSF (HR 2.49; 95% CI: 1.16-5.35, P=0.019). This study shows that the incidence of cGVHD is more strongly associated with the donor's ability to mobilize CD34+ cells than with the number of infused CD34+ cells. [ABSTRACT FROM AUTHOR]

Allogeneic BMT for patients with acute myeloid leukemia (AML) is presently a reference therapy. The indications for this therapy mainly rely upon prognostic factors, and their importance is constantly reassessed. To examine the impact of time from diagnosis to transplant on survival and leukemia-free survival (LFS), we analyzed 109 patients from the database of the SFGM comprising patients who had all received an HLA-identical allogeneic BMT for a diagnosis of AML in first complete remission (CR1) between January 1987 and December 1992. All patients were conditioned with cyclophosphamide (CY) and total body irradiation (TBI) (CY-TBI), and methotrexate (MTX) + cyclosporin A (CsA) were used as graft-versus-host disease (GVHD) prophylaxis. Patient characteristics were: age = 33 ± 9, M/F = 64/45, white blood cell count (WBC) at diagnosis = 27 ± 42 × 109/l, FAB distribution: M1 and M2 = 55; M3 = 15, M4 and M5 = 33, M0, M6 and M7 = 6. Karyotyping was carried out for 64 patients: 32 had a normal karyotype, 16 had good prognosis abnormalities (t(8;21), t(15;17), inv 16) and 16 patients had other abnormalities. Eleven patients needed two courses of induction to achieve CR. Time between diagnosis and BMT was 120 (64–287) days. Forty-nine patients developed grade 2 acute GVHD (actuarial probability = 46%). With a median follow-up of 50 months (27–100), the 5-year probabilities for transplant-related mortality (TRM), relapse, overall survival and LFS are respectively 25%, 26%, 59% and 55%. A multivariate analysis showed that survival is adversely influenced by three independent factors: time to transplant (>120 days vs 120 days), acute GVHD (grade 2–4 vs grade 0–1) and age (>33 vs 33). LFS is only influenced by the first two of these factors. The favorable impact of a shorter time from diagnosis to transplant should lead to performing the transplant as early as possible. Practically speaking,... [ABSTRACT FROM AUTHOR]

We previously demonstrated the potential of anti-IL-2R and anti-TNF alpha moAbs in the treatment of acute graft-versus-host disease (GVHD). However, one major problem was the recurrence of acute GVHD on treatment discontinuation. To target the two main effectors of acute GVHD lesions, T and NK cells on the one hand and TNF alpha on the other, we combined anti-CD2 and anti-TNF alpha moAbs. Then to prevent acute GVHD recurrence, we administered anti-IL-2R moAbs known for their inhibitory effect on activated cells. We included 15 patients with steroid-resistant acute GVHD. Seven were grafted from a genotypically-identical sibling, 5 from HLA-matched unrelated donors and 3 from partially-matched related donor. Prophylaxis of acute GVHD consisted of cyclosporin A +/- methotrexate or corticosteroids. Before treatment 6 patients had grade II, 2 patients grade III and 7 patients grade IV acute GVHD. Anti-TNF alpha (B-C7) moAbs (10 mg/day/4 days) were combined with anti-CD2 (B-E2) moAbs (10 mg/day/10 days) on the fifth day (day 5), anti-IL-2 receptor (B-B10) moAbs were given at 10 mg/day/10 days followed by 5 mg every other day for another 50 days. On day 15, 5 patients achieved a complete remission, 4 a very good partial response (62% a good response), 2 had a partial response and 4 did not respond. GVHD recurred in 4 of the 9 responders, although anti-IL-2R moAb treatment was maintained. Three patients are long-term survivors without chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)

In a retrospective multicentre study, we analyzed 184 consecutive patients who underwent bone marrow transplantation (BMT) from identical siblings for adult acute lymphoblastic leukemia in first complete remission between March 1980 and May 1989. The main causes of transplant-related mortality were GVHD and interstitial pneumonitis. Univariate and multivariate analyses identified the mode of total body irradiation (TBI) as the only independent predictive factor of transplant-related mortality. Ninety-one patients received single-dose TBI and 93 received fractionated-dose TBI as part of the conditioning regimen prior to BMT. Transplant-related mortality was more frequent in the single dose group (p = 0.017). The incidence of interstitial pneumonitis, acute and chronic GVHD and veno-occlusive disease of the liver was not statistically different between the two irradiation groups. However, fatal interstitial pneumonitis was significantly more frequent in the single dose irradiation group (p = 0.031). These results show that transplant-related mortality is closely associated with the mode of TBI administration. The increased relapse rate in the fractionated group explains why there was no difference between the two groups in terms of overall leukemia-free survival.

Ganciclovir which has proved effective in the treatment of cytomegalovirus (CMV) infection was given prophylactically to 40 bone marrow transplant (BMT) patients pre and post-transplant in seropositive patients and post-transplant in seronegative patients with a seropositive donor. All patients were transfused with screened blood products and 33 received CMV hyperimmune globulin. They were compared with an historical control group consisting of 39 patients who had received significantly more unscreened blood products (p = 0.01) and less HLA-mismatched marrow transplants (p = 0.05). Toxicity of ganciclovir was hematological-neutropenia was responsible for cessation of the drug in seven patients and transfusion requirements were significantly higher in the ganciclovir group. Non-hematological toxicity did not occur in any patient. Only one patient (2.5%) experienced symptomatic CMV infection and no patient developed CMV pneumonitis. In contrast, in the control group, 23 (59%) patients had clinical symptoms of CMV infection (p < 0.0001) and 4 (10%) experienced CMV pneumonitis (p < 0.01). Ganciclovir significantly reduced the incidence of positive CMV antigenemia (7.5% in the treated group vs 72% in the control group; p < 0.01). However, ganciclovir delivery did not result in an improved overall survival due to a higher rate of regimen-related deaths and chronic GVHD mostly in patients transplanted from an HLA-mismatched donor. The prophylactic administration of ganciclovir abrogates CMV pneumonitis and considerably reduces the incidence of CMV infection in BM recipients at high risk of developing this disease after transplantation.

Fourteen S/S children with severe SCD were transplanted with marrow from HLA identical siblings. All developed frequent (> 4/y) vasoocclusive crises (VOC) and recurrent acute chest syndrome episodes (n:10), osteitis (n:3), osteonecrosis (n:3), strokes (n:3) or frequent massive deglobulisation (n:2). Two children undergone splenectomy, 2 were chelated and 2 had erythroid allo-immunization. Ethnic origins were from various countries in Africa (n:10), North-Africa (n:3) or West Indies (n:1). At BMT, they were 2y 3m to 14y 9m old (mean:8y 7m). Donors were AS (n:11) or AA (n:3). At first, various conditioning regimens were used consisting of busulfan (BU) plus Cyclophosphamide (CY) at different doses: CY:200 mg/kg (n:12) or 260 mg/kg (n:2); BU:14 mg/kg (n:1), 16 mg/kg (n:9), > 16 mg/kg (n:4); 1 patient received also TLI and one other antithymoglobulin (ATG): 20 mg/kg. GVHD prophylaxis was CSA alone (n:4) or CSA plus short-term MTX (n:10). Median follow-up was 23 months (8 m. to 48 m.). All patients had an engraftment (d13 to d32) with a stable total chimerism in 10/14 patients who are cured. In the 4 others, partial chimerism was observed: one patient had a early and progressive rejection of his graft but is doing very well (28 m. follow-up) without any manifestation of SCD, with a high stable 22% Hb F level. One patient developed an aplastic anaemia 15 m after BMT: a second BMT was achieved 21 m after the first one with engraftment and total chimerism. Two patients have a relatively stable partial chimerism with still undergoing CSA therapy (11 m. and 23 m. follow-up).(ABSTRACT TRUNCATED AT 250 WORDS)

A total of 62 patients with high-risk acute lymphoblastic leukemia (ALL) were treated with fractionated total body irradiation, high-dose cytosine arabinoside and melphalan followed by bone marrow transplantation (BMT). Thirty-six patients received allogeneic and 26 autologous BMT. Eight patients were treated in CR1, 36 in CR2 (first relapse occurring on therapy for 32), seven in further CR, 10 in relapse (five early first relapse, four second relapse and one fourth relapse) and one with refractory ALL. Severe toxicity occurred in 26 of the 62 patients (42%) and 14 died (22.5%) from non-leukemic causes. The actuarial event-free survival at 3.6 years was 28% after autologous BMT and 52% after allogeneic BMT with actuarial relapse rates of 62% and 35%, respectively. The results of this pilot study seem promising for this group of poor risk ALL, but the relapse rate remains high after autologous BMT and needs to be improved.

Twenty-five patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) were treated by allogeneic bone marrow transplantation. For the nine patients transplanted in first complete remission the disease-free survival was 100%; of the nine patients transplanted in subsequent remissions four (44%) achieved long-term disease-free survival but two died of relapsed lymphoma. For the seven patients transplanted at a time when they had active disease, the initial complete remission rate was high but four died of progressive lymphoma and no patient achieved long-term disease-free survival. The incidence of complications associated with allogeneic bone marrow transplantation was similar to that observed in other series of patients transplanted for haematological malignancy and was related to the status of the disease at the time of transplant. Thus allogeneic bone marrow transplantation is a radical but effective treatment for patients with NHL who have 'minimal residual disease'. Efforts to define further the subset of patients who can most successfully be treated by transplantation may improve the overall results.