V. Shepherd

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 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 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.

Comparison of marrow and blood cell yields from the same donors in a double-blind, randomized study of allogeneic marrow vs blood stem cell transplantation.

Forty healthy adult donors underwent marrow (BM) as well as peripheral blood (PBSC) stem cell collections for their HLA-identical adult siblings with hematologic malignancies. BM was harvested on day 1 (target 3 × 108 nucleated cells/kg, 10 μg/kg lenograstim (glycosylated G-CSF) administered on days 2–6, and a single leukapheresis performed on day 6. The blood volume processed was the higher of 200% donor blood volume or 10 liters. The total nucleated cell (TNC) yields from PBSC were 1.1- to 4.3-fold higher than BM (median 7.0 vs 3.1 × 108/kg, P 7lt; 0.0001). Although bm contained a higher proportion of cd34+cells (1.3% vs 0.7%, P < 0.0001) and a comparable proportion of cd3+ cells (median 29% vs 26%, P = 0.4), the absolute numbers of CD34+ and CD3+ cells and their subsets were several times higher in PBSC. There was a poor correlation between BM and PBSC CD34 and TNC numbers, but a significant correlation between BM and PBSC CD3 numbers. Only five of 40 BM harvests contained ⩾2 × 106 CD34+ cells/kg compared with 35 of 40 PBSC harvests (P < 0.0001). we conclude that the numbers of progenitor and immunocompetent cells in pbsc are several times higher than in bm. it is possible to collect adequate numbers of progenitor cells from blood after lenograstim stimulation more frequently than from marrow, and donors yielding low quantities of progenitor cells from bm usually deliver better quantities from pbsc. Bone Marrow Transplantation (2000) 25, 501–505.

The importance of CD34 + /CD33 − cells in platelet engraftment after intensive therapy for cancer patients given peripheral blood stem cell rescue

The study was designed to determine whether the number of CD34+/CD33− cells given at autologous peripheral blood stem cell (PBSC) rescue after intensive therapy for cancer was a better predictor of platelet engraftment than the total number of CD34+ cells infused. Comparison between the total number of CD34+ cells/kg infused with the number of CD34+/CD33− cells/kg infused showed that, generally, 2 × 106 total CD34+ cells contained 1.38 × 106 CD34+/CD33− cells. There was poor correlation between the number of CD34+/CD33− and CD34+/ CD33+ cells in the graft (r = 0.332). Engraftment times for platelets and neutrophils were evaluated in 68 patients. There was no significant difference between the times for platelets to reach >25 × 109/l or neutrophils to reach >0.5 × 109/l among patients who received > or <2 × 106 total CD34+ cells or > or <1.38 × 106 CD34+/CD33− cells although the latter was consistently the better predictor. Platelet recovery to >50 × 109/l and >100 × 109/l was delayed significantly in patients who received <1.38 × 106 CD34+/CD33−/kg infused (P < 0.02 and P < 0.05, respectively). The number of cd34+/ CD33− cells/kg infused was a stronger predictor of platelet recovery than the total number of CD34+ cells infused (P < 0.05 for platelets >50 or >100 × 109/l). Although platelet recovery was delayed significantly in patients who had <4 × 104 granulocyte–macrophage colony-forming units (CFU-GM)/kg infused, the time delay between receipt of PBSCs and availability of the colony counts limits the use of this assay to patients who do not require stem cells to be given immediately. Our data suggest that the number of CD34+/CD33− cells given at PBSC rescue provide information about the quality of the graft necessary for long-term platelet engraftment. However, since the percentage of CD34+/CD33− cells shows considerable inter-patient variation, measurement of this cell population may be important in patients who experience poor stem cell mobilization or when a target dose of 2 × 106 total CD34+ cells/kg is not achieved.

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission : long-term follow-up

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5–19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2–11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited. Bone Marrow Transplantation (2000) 25, 599–603.

Autologous Transplantation with CD52 Monoclonal Antibody-Purged Marrow for Acute Lymphoblastic Leukemia: Long-Term Follow-Up

During 1984-86, 23 patients (5-37 years, median 16) with acute lymphoblastic leukemia (ALL) in first remission (n = 11) or beyond (n = 12) underwent autologous transplantation (ABMT) using marrow purged with the rat anti-CD52 monoclonal antibody Campath-1M after melphalan and total-body irradiation (TBI). Median time to 0.5 x 10(9)/L neutrophils and 50 x 10(9)/L platelets was 38 and 51 days respectively. Myeloid engraftment was significantly slower compared with ALL patients receiving unpurged marrow (P = .01). Eight patients died due to transplant-related causes 53-205 days after the procedure. Six of eight patients receiving 1150 cGy TBI died of toxicity compared with two of 15 receiving less than 1150 cGy (P = .006, Fishers exact test). Nine patients relapsed at 45-195 days (median 97); eight died and one is alive at nine years in a chemotherapy-induced remission. Six patients are alive and well in continuous remission 9-10 years (median 10) after transplant. The 10-year probabilities of disease-free survival and relapse are 26% (95% CI: 11-45%) and 51% (95% CI: 37-59%) respectively. We conclude that it is feasible to purge marrow for autografting using Campath-1M without killing normal stem cells. Myeloid engraftment is slow but consistent, and long-term survival is seen in a proportion of patients. The role of CD52 monoclonal antibodies for purging in ALL still requires further study.

Comparison of marrow vs blood-derived stem cells for autografting in previously untreated multiple myeloma

Sixty-three new untreated patients with multiple myeloma under the age of 70 years received C-VAMP induction treatment followed by high-dose intravenous melphalan (200 mg m(-2)) and autologous stem cell transplant, either with marrow [autologous bone marrow transplants (ABMT), n = 26] or with granulocyte colony-stimulating factor (G-CSF)-mobilized stem cells from the blood [peripheral blood stem cell transplants (PBSCT), n = 37]. This was a sequential study and the two groups were not significantly different for all known prognostic variables. The complete remission (CR) rate after high-dose treatment was the same for both groups [ABMT 84% and PBSCT 70%; P = not significant (NS)]. Neutrophil recovery to 0.5 x 10(9) l(-1) occurred at a median of 22 days in the ABMT patients compared with 19 days for the PBSCT patients (P = NS). Platelet recovery to 50 x 10(9) l(-1) was significantly faster in PBSCT patients (19 days vs 33 days; P = 0.0015), and the PBSCT patients spent fewer days in hospital (median 20 vs 27 days; P = 0.00001). There was no difference in the two groups with respect to starting interferon (58 days for ABMT vs 55 days for PBSCT), and tolerance to interferon was identical. The median overall survival (OS) and progression-free survival (PFS) for the PBSCT patients has not yet been reached. The OS in the ABMT patients at 3 years was 76.9% (95% CI 60-93%) compared with 85.3% (95% CI 72-99%) in the PBSCT patients (P = NS), and the PFS at 3 years in the ABMT patients was 53.8% (95% CI 34-73%) and in the PBSCT patients was 57.6% (95% CI 34-81%) (P = NS). The probability of relapse at 3 years was 42.3% in the ABMT arm compared with 40% in the PBSCT patients (P = NS). Thus, PBSCT patients had a faster engraftment and a shorter stay in hospital than ABMT; the survival outcome and probability of relapse was the same for both groups.

Prospective, concurrent comparison of the Cobe Spectra and Haemonetics MCS-3P cell separators for leukapheresis after high-dose filgrastim in patients with hematologic malignancies

A prospective study was undertaken to compare the mononuclear cell, CD34+ cell, and CFU‐GM yields of the Haemonetics MCS‐3P and the Cobe Spectra cell separators in ten patients (nine multiple myeloma and one non‐Hodgkin lymphoma) on two consecutive days after mobilization with high‐dose filgrastim (12–16 μg/k) for 4 days. All patients were harvested once on each machine, five starting on each machine. The target duration of the procedure on the Spectra was 160 minutes, and the target blood volume processed on the MCS‐3P was 60–70 ml/kg body weight. Both machines were operating on the 1995 software versions supplied by the respective manufacturers. The time taken for the procedure was significantly longer with the Haemonetics machine. The volumes of blood processed and the product collected were significantly higher with the Spectra, as were the absolute mononuclear and CD34+ cell yields, and yields per unit time. Mononuclear and CD34+ cell yields per unit volume of blood processed were comparable for both machines. The differences in CFU‐GM yields were not significant, largely because of wide interpatient variations. The extent of platelet depletion as a result of the procedure was greater with the Spectra because of the higher blood volume being processed. We conclude that the Cobe Spectra is a significantly faster machine than the Haemonetics MCS‐3P; and consequently, its use is associated with higher mononuclear and CD34+ cell yields. J. Clin. Apheresis 12:63–67, 1997.

Bone-marrow transplant from father to son and subsequent graft from son to father

An 11-year-old boy with acute myeloblastic leukaemia in first remission received an allogeneic mismatched bone-marrow transplant (BMT) from his father in 1979; subsequent HLA typing showed that his haemopoietic system had been repopulated by the donor cells. In 1986 hypereosinophilic syndrome, secondary to a T-cell lymphocytic lymphoma, developed in the father, then aged 45 years. A full haematological remission was obtained by means of standard acute lymphoblastic leukaemia treatment. He then received melphalan, total body irradiation, and a BMT from his son. Graft-versus-host disease was transient in both patients, and father and son remain well and disease-free 20 months and 10 years, respectively, after BMT.