J. Treleaven

Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial

BACKGROUND Autologous transplantation with peripheral blood stem cells (PBSC) results in faster haematopoietic-cell repopulation than with bone marrow. We prospectively compared bone marrow and PBSC for allogeneic transplantation. METHODS Adult HLA-identical sibling donors provided bone marrow and lenograstim-mobilised PBSC. 39 patients with malignant haematological disorders were infused with either bone marrow (n=19) or PBSC (n=20) after standard conditioning regimens in a double-blind, randomised fashion. The identity of the infused products for all patients remained masked until 1 year after the last patient had received transplantation. FINDINGS The PBSC group had significantly faster neutrophil recovery to 0.5x10(9)/L (median 17.5 vs 23 days, p=0.002), and platelet recovery to 20x10(9)/L (median 11 vs 18 days, p<0.0001) and to 50x10(9)/L (median 20.5 vs 27 days, p=0.02) than the bone-marrow group. PBSC patients were discharged from hospital earlier than were bone-marrow patients (median 26 vs 31 days, p=0.01). At 4 weeks after transplantation, absolute lymphocytes (0.48 vs 0.63, p=0.08) and CD25 cells (0.04 vs 0.08, p=0.007) were higher in the PBSC group, and the proportion of patients with absolute lymphopenia (74% vs 33%, p=0.03) and CD4 lymphopenia (59% vs 24%, p=0.05) was significantly higher in the bone-marrow group. There was no significant difference in the occurrence of acute or chronic graft-versus-host disease and overall survival. The probability of relapse was significantly higher in the bone-marrow group than in the PBSC group (p=0.01); all five relapses occurred among bone-marrow recipients. INTERPRETATION Our small study indicates that PBSCs are better than bone marrow for allogeneic transplantation from HLA-identical siblings in terms of faster haematopoietic and immune recovery, and have the potential to reduce disease recurrence.

A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma : long-term follow-up results

High‐dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high‐dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 × 106 units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high‐dose chemotherapy (melphalan 140–200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression‐free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow‐up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu‐like symptoms and malaise which were usually self‐limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multi‐centre studies in the setting of minimal residual disease following autologous transplantation.

Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial

In a randomised, double-blind trial 20 patients with leukaemia received human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and 20 received placebo, for 14 days after allogeneic, matched sibling, bone-marrow transplantation. The neutrophil count recovered to 0.5 x 10(9)/l 3 days earlier in the GM-CSF group than in the placebo group (not significant), and the median neutrophil count at 14 days was significantly higher in the GM-CSF group (1.90 vs 0.46 x 10(9)/l). The lymphocyte count was significantly higher in the GM-CSF than in the placebo group between days 10 and 15 after transplantation, but this difference was not associated with a higher incidence of graft-versus-host disease. There was no evidence that GM-CSF was associated with a greater incidence of leukaemic relapse. The GM-CSF group had lower haemoglobin concentrations and platelet counts and higher plasma urea, creatinine, and bilirubin than the placebo group. The duration of hospital stay was the same for both patient groups. Further studies are now indicated to assess the overall effect of GM-CSF on outcome after allogeneic bone-marrow transplantation.

The role of autologous transplantation in patients with multiple myeloma aged 65 years and over

Autologous stem cell transplantation after high-dose melphalan for the treatment with multiple myeloma has resulted in prolonged progression-free survival and overall survival in patients under 65 years. We have examined the role of autologous transplantation in 17 patients with multiple myeloma over 65 years at our centre using a matched pair analysis with younger patients. The median age of this cohort of patients over 65 years was 67 years (65–74) and their outcome and transplant-related morbidity was compared with 17 younger pair mates with a median age of 55 years (31–64). Sixteen patients received high-dose melphalan, and one received busulphan with autologous stem cell rescue. The high-dose therapy was well tolerated in both elderly patients and the matched pairs, with comparable time to recover neutrophils and platelets. Treatment-related mortality also did not differ significantly in both the groups. Median overall survival of the elderly patients was 3.59 years similar to 3.01 years of the pair mates (P = 0.92). Autologous stem cell transplantation after high-dose melphalan conditioning was equally well tolerated in groups of patients above and below 65 years. There was no difference in relapse rate, OS and myelotoxicity in both the groups. These findings suggest that advanced age should not be an exclusion criterion from autologous transplant programmes. Bone Marrow Transplantation (2000) 25, 533–539.

A low CD34+ cell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings : should 2 x 106 CD34+ cells/kg be considered the minimum threshold?

We studied the effect of the CD34+ cell dose on transplant-related mortality (TRM) and survival in 39 patients randomized to receive lenograstim-mobilized PBSCT (n= 20) or BMT (n = 19) from HLA-identical siblings. Both marrow and blood were harvested, and one infused in a double-blind fashion. The median nucleated (7.0 vs 3.2 × 108/kg; P < 0.0001), cd34+ (3.7 vs 1.5 × 106/kg; P = 0.002), CFU-GM (42 vs 19 × 104/kg; P= 0.002), and CD3+ (1.9 vs 0.3 × 108/kg; P < 0.0001) cell doses with pbsct were higher. thirteen patients (6 bmt and 7 pbsct) experienced trm at 15–733 days (median 57); 10 of 20 receiving <2 × 106 CD34+ cells/kg compared with three of 19 receiving ⩾2. Eight of 20 patients receiving <2 × 106 CD34+ cells/kg are alive compared with 14 of 19 receiving ⩾2. In Cox analysis, CD34+ cell dose ⩾2 × 106/kg was associated with lower TRM (RR 0.2, P = 0.01), and higher overall (RR 3.7, P = 0.01) and event-free (RR 3.2, P = 0.02) survival. Other cell populations and the source of stem cells did not affect TRM or survival. We conclude that 2 × 106 CD34+ cells/kg may be the ideal minimum cell dose for allogeneic transplantation although lower doses do not preclude successful therapy. Since the likelihood of obtaining this threshold CD34+ cell number is significantly greater from blood than marrow, PBSCT may be preferable to marrow for allografts from HLA-identical siblings. Bone Marrow Transplantation (2000) 26, 489–496.

Outcome of acute leukemia relapsing after bone marrow transplantation: utility of second transplants and adoptive immunotherapy

We studied 231 acute leukemia patients relapsing after allogeneic (n = 114) or autologous (n = 117) BMT to assess the outcome of further therapy. In general, all patients in good condition were eligible for second transplants except for post-allograft relapses from 1993–1994 onwards who received cytokine- or cell-mediated immunotherapy. The major reason for patients not progressing to second graft was death from progressive disease or toxicity of salvage chemotherapy. Seventeen of 231 patients (7%) were alive at the last follow-up. Six of 14 post-autograft relapses treated with second transplants were alive and well, compared with five of 103 not undergoing second grafts (P < 0.0001). one of 23 post-allograft recipients treated with second allografts was alive with an extramedullary relapse, compared with five of 13 receiving immunotherapy and none of 78 receiving standard-dose or palliative therapy (P < 0.0001). we conclude that only a small proportion of highly selected acute leukemia patients relapsing after a transplant reach the stage of a conventional second transplant. in our experience, second allografts after myeloablative therapy in patients relapsing after one allograft are associated with very poor results, and immunotherapy may be a better approach in such cases. selected patients relapsing after an autograft may become long-term survivors following a second autograft or an allograft.

Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma.

Two hundred and twenty-two myeloma patients autografted after 200 mg/m2melphalan were studied to examine the relationship between response to induction chemotherapy and outcome. Induction comprised cyclophosphamide, vincristine, doxorubicin and methylprednisolone (C-VAMP) every 3 weeks for one cycle beyond maximum response. 81% responded to C-VAMP (chemosensitive) with 40 complete (CR) and 139 partial (PR) remissions, and 43 did not respond (NR; <50% reduction in paraprotein; primary refractory). Overall, 130 patients (59%) attained or remained in CR post-transplant; including 40% of NR, 53% of PR, and 97% of CR after C-VAMP (P < 0.0001). Amongst these 130 patients, the 5-year OS was independent of response to C-VAMP (NR 79%, PR 74%, CR 60%; P = 0.69). Similarly, among the 69 patients in PR post-transplant, the 5-year OS was independent of response to C-VAMP. In Cox analysis, lack of response to C-VAMP did not affect outcome significantly. These data show that lack of response to induction therapy does not automatically predict poor long-term outcome in myeloma, since a substantial proportion of these patients attain CR after autograft and enjoy extended survival. Myeloma patients should not be disqualified from an autograft based upon lack of response to induction chemotherapy.

Bone Marrow Transplantation for Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Between 1986 and 1995, 19 patients with Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukemia underwent 20 autologous (n = 9) or allogeneic (n = 11) blood or marrow transplant procedures in first (n = 12) or second (n = 3) remission, or in relapse (n = 5). Four patients died due to transplant-related causes, 11 relapsed at 3-39 months, one survives with disease which did not remit after transplant, and three are alive in continuous remission at 1, 26 and 65 months. Two of the relapsing patients are alive; one autografted patient after an allograft in second remission and one allografted patient after a donor leukocyte infusion. The projected overall survival is 37.5% at 3 years and 12.5% at 5 years. The 3-year probabilities of relapse and disease-free survival for autografted patients are 65.9% and 25.6% respectively, and for allografted patients, 63.4% and 21.8% respectively. The stage of the disease at the time of transplant or the type of transplant did not affect the outcome significantly, and late relapses beyond 3 years were seen after allogeneic as well as autologous transplantation. In our experience, the outcome of patients with Ph + acute lymphoblastic leukemia continues to be poor despite high-dose therapy due to high relapse rates, and the development of additional measures to enhance the antileukemic efficacy of bone marrow transplantation is necessary.

Outcome assessment of a population-based group of 195 unselected myeloma patients under 70 years of age offered intensive treatment

A single centre series of 195 consecutive newly diagnosed untreated myeloma patients under 70 years, seen between September 1986 and March 1994, were analysed to assess the impact of current intensive treatment methods upon remission rate, response rate and subsequent outcome. They were predominantly an unselected population based group of patients (other than by age) that could be used by purchasers of health care as a model for outcome assessment. All patients were scheduled to receive a care plan which included a sequential package of treatment consisting initially of courses of infusional chemotherapy using vincristine, adriamycin and methyl prednisolone (VAMP) and 90 of these also received cyclophosphamide (C-VAMP). Thirty-eight patients received verapamil in addition to C-VAMP(V-C-VAMP). After VAMP all patients were planned to receive high-dose treatment with melphalan and an autograft (marrow or blood) and 112 received this treatment; a further 29 patients received modified high-dose treatment with melphalan alone (23) or busulfan (6) and 54 (28%) did not proceed to high-dose treatment because of refusal, resistant disease, poor performance or treatment-related death. The patients who received melphalan or busulfan alone instead of high-dose melphalan/autografts did so because of increasing age (P = 0.001) and a raised creatinine (P = 0.05). The complete remission rate was 53% for the whole group and 74% for those receiving high-dose melphalan and an autograft. From July 1988, the sequential therapy package included continuous three times weekly interferon (IFN) after high-dose treatment as maintenance therapy, initially as part of a controlled randomised trial and then for all suitable patients. Fifty-seven patients received IFN. The median overall survival (OS) and progression-free survival (PFS) from first treatment for the whole group of 195 patients is 4.5 years and 25 months, respectively. The 112 patients receiving the melphalan autografts fared significantly better than the rest of the patients with OS and PFS (from high-dose treatment) of 6.6 years and 27 months, respectively (P < 0.005), and the 57 patients also receiving ifn have a os yet to reach a median at 8 years and a pfs of 44 months, significantly better than non ifn high-dose patients (P < 0.0036). however, although we showed benefit for selected patients in studies and trials (particularly with ifn) during the 8-year period of the series, this did not translate into overall pfs benefit in our study for unselected cohorts of patients for 1986–1988 (64 patients) 1989–1992 (100 patients) and 1992–1994 (31 patients) in spite of progressive increases in the proportion of patients receiving ifn (respectively 6, 35 and 58%). this is likely to be due to the dilution of benefit to specific patients by the overall number of patients involved. outcome data from unselected patients are now expected by purchasers and presented in this way, help qualify the activity impact of advances made from research trials for the treatment of population-based cancer problems.

Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease

Veno-occlusive disease (VOD) is a common and high-risk complication of allogeneic stem cell transplantation (SCT). Defibrotide has recently been used successfully to treat the disorder. We report on 58 patients who received defibrotide prophylaxis without concurrent heparin. No patients fulfilled the Baltimore criteria for VOD or died of the condition within 100 days of SCT. None of this group developed haemorrhagic complications secondary to defibrotide. These observations suggest that prophylaxis with defibrotide alone may reduce the incidence of VOD post-SCT although a randomised controlled trial is warranted to further evaluate its role.