Autologous bone marrow transplantation for acute leukaemia in remission

Between 1980 and 1985, 175 patients with acute leukaemia in first or subsequent complete remission (CR) were treated by chemotherapy or chemoradiotherapy followed by transfusion of autologous bone marrow cells that had been collected days or months previously. In 85 cases, autologous marrow cells were treated ex vivo with cytotoxic drugs or monoclonal antibodies with the intention of removing residual leukaemic cells. The actuarial relapse-free rate was 52% at 2 years. Of 89 patients autografted for acute non-lymphocytic (myeloid) leukaemia (ANLL), 60 were treated in first remission and 18 in second CR; their relapse-free rates at 2 years were 67% and 41% respectively (P less than 0.001). In contrast, of 77 patients autografted for acute lymphoblastic leukaemia (ALL), 32 were treated in first CR and 28 in second CR and their actuarial relapse free rates at 2 years were 56% and 55% respectively (P = NS). There was no significant difference in leukaemia relapse rates between patients autografted with purged and those autografted with non-purged marrow cells. These preliminary results suggest that autologous bone marrow transplantation may be valuable if offered to patients with ANLL in first CR or to patients with ALL in first or second CR but the need for marrow purging remains uncertain.     

Repeated courses of high dose melphalan and unpurged autologous bone marrow transplantation in children with acute non-lymphoblastic leukemia in first complete remission

Eleven children between the ages of 1 and 16 years with acute non-lymphoblastic leukemia (ANLL) in first remission were included in a study of double unpurged autologous bone marrow transplantation (ABMT). Prior to each ABMT patients received massive chemotherapy with melphalan at a dosage of 140 mg/m2. The first ABMT was done within a median of 4 months after the achievement of complete remission. As soon as the children had adequate hematologic recovery, a second marrow collection was done, followed by a second course of melphalan and a second ABMT. The duration of aplasia was significantly longer after the second ABMT than after the first, but the non-hematologic toxicity was relatively mild in each case and no patient died from the procedure. Four patients relapsed and seven are alive in unmaintained complete remission with a median duration of leukemia-free survival of 29 months (range 15-56 months) after the first ABMT. These data demonstrate the feasibility of repeating ABMT after melphalan in children with ANLL. The eventual impact of such therapy needs to be demonstrated in prospective randomized studies.     

Autologous bone marrow transplantation in acute leukaemia

Intensive chemoradiotherapy with autologous bone marrow rescue has been widely explored as treatment for acute myeloblastic and acute lymphoblastic leukaemia. Encouraging preliminary results have been reported but in no situation has this modality of therapy been proved to be superior to conventional chemotherapy. Attempts to remove minimal residual disease from the harvested marrow have been made by both immunological and pharmacological means, but the value of such procedures has not been tested rigorously. Determination of the precise role of autologous bone marrow transplantation in the treatment of acute leukaemia must await the outcome of randomised controlled trials and will take several years.     

Autologous bone marrow transplantation for acute myeloid leukaemia in remission: a preliminary report

Autologous bone marrow transplantation, using unpurged cryopreserved autologous marrow, was performed on ten adult patients with acute myeloid leukaemia in remission. Seven patients were in first chemotherapy-induced remission of their disease, while three were in later remission. Patients ages ranged from 24 to 52 years, with a median of 38.5 years. Conditioning therapy consisted of oral busulphan 16 mg/kg over four days and intravenous cyclophosphamide 60 mg/kg on two days. Bone marrow cells were thawed and infused two days later. All patients showed signs of marrow engraftment, however this was delayed in comparison with patients receiving allogeneic transplants. All patients developed fever requiring antibiotic therapy and one patient died of overwhelming sepsis. Another patient died of hepatic veno-occlusive disease two months after transplant. Serious, but non-fatal, hepatic complications occurred in two other patients. One patient, transplanted in third remission, relapsed 16 months post-autograft. No other relapses have been seen, with one second remission patient remaining leukaemia-free at 24 months, and six first remission patients in continuing remission 11 to 23 (median 20) months post transplant. These encouraging results require confirmation in a randomised clinical trial comparing autologous marrow transplantation versus standard chemotherapy.     

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purged marrows for children with acute non-lymphoblastic leukemia in second remission

Although autologous bone marrow transplantation (ABMT) following purging with 4-hydroperoxycyclophosphamide (4HC) has been effective for some adults with acute non-lymphoblastic leukemia (ANLL), there are few data on ABMT for children. We have performed ABMT for 13 patients (median age, 5 years) with ANLL in second remission. Bone marrow was treated ex vivo with 4HC to kill residual leukemic cells. In order to enhance the anti-leukemic effect of 4HC, exogenous red blood cells were eliminated from the marrow/4HC mixture. All patients were conditioned for transplantation with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg), followed by infusion of the 4HC treated marrow. Eleven of 13 patients had complete hematologic reconstitution; there were no transplant-related deaths. Five patients relapsed at 2, 4, 5, 6 and 6 months post-BMT. Eight patients are disease-free survivors; the median time for survival is 24 months, with a projected disease-free survival of 61%. ABMT is a safe and efficacious treatment modality for children with ANLL in second remission. Our results suggest that the disease-free survival for pediatric patients may be superior to that seen in adults.     

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.     

Autologous bone marrow transplantation (ABMT) for acute leukaemia in complete remission: a pilot study of 33 cases

Thirty-three leukaemic patients in CR were treated by high-dose therapy followed by ABMT: 18 of them had acute non-lymphoblastic leukaemia (ANLL) in first remission (CR1) with a mean age of 23.7 years (3-44). All but one of them were conditioned with a polychemotherapy regimen including 6-thioguanine, Ara-C, CCNU, and cyclophosphamide. The marrow cells were purged by chemical means in 16 cases. Five transplant-related deaths were observed: three cardiac failures, one interstitial pneumonitis and one aspergillus pneumonia. At the time of analysis (October 1984), four patients had relapsed and eight were still in unmaintained CR1 (44+, 46+, 30+, and five between 2.5+ and 8+ months post transplant). Fifteen patients had acute lymphoblastic leukaemia: four were autografted in CR1 and 11 children were grafted in CR2; the conditioning regimen was fractionated total body irradiation followed by cyclophosphamide for all but one patient who was conditioned with BACT (Burkitt leukaemia); the marrow was purged by a chemical agent in 11 patients and by monoclonal antibodies and C' in four: four out of 15 patients relapsed (two grafted in CR1 and two grafted in CR2); 10 patients are still in unmaintained CR: two adults grafted in CR1 (26+; 12+ months) and eight children with a mean follow-up of 13.4 months post graft (2 + -45+ months). The clinical study leads to the following conclusions: in adult patients the marrow should be harvested during CR1 and at the time of minimal residual disease. The quality of previous chemotherapy and conditioning regimen prior to ABMT play a prominent role in the in vivo eradication of the leukaemic cells. The real impact of marrow purging is still unknown and a larger series of homogeneous patients, conditioned with the same protocols and the same transplant timing, is required before any conclusions can be drawn.     

Autologous bone marrow transplantation for children with AML in first remission

In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.     

Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission

Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.     

Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission.

Patients in first remission of acute lymphoblastic leukaemia (ALL) considered to be at high risk of relapse were offered autologous bone marrow transplantation (ABMT) using purged marrow as a therapeutic alternative to cranial irradiation and maintenance chemotherapy. Twenty-seven bone marrows taken in remission, were purged using monoclonal antibodies (anti CD7 for T lineage and anti CD10 and/or anti CD19 for B lineage leukaemias) plus rabbit complement. Retrospective analysis of 19 purged marrows by immunophenotyping or immunoglobulin gene rearrangement studies demonstrated no evidence of disease. Engraftment was seen in 26 of the patients. No correlation was found between the numbers of infused nucleated cells or colony forming units-granulocyte-macrophage (CFU-GM) and subsequent engraftment kinetics. The actuarial disease-free survival (DFS) is 32% at 7 years (median follow-up 3.4 years). There were two transplant related deaths (actuarial risk 8%); the main cause of treatment failure has been disease recurrence with an overall actuarial risk of 67%; 76% for T-ALL (five of nine), 62% for common ALL (five of 10), two of five pre B and none of three patients with B-ALL. In these 27 high risk patients in vitro purging of remission marrow as part of ABMT appears not to improve patient outcome, although confirmation of this would require a randomized trial.     

Allogeneic or autologous bone marrow transplantation for acute lymphoblastic leukemia in first complete remission

Forty-seven patients with high risk acute lymphoblastic leukemia (ALL) received an allogeneic (allo) or autologous (auto) bone marrow transplant (BMT). Patients in both groups were comparable in terms of age, initial presentation of ALL and induction chemotherapy. Allo patients were transplanted earlier (median 3 months after CR) than auto patients (median 6.5 months after CR). Auto patients received more consolidation chemotherapy before BMT. All patients received total body irradiation 2.2 Gy/day x 5 days after cyclophosphamide 60 mg/kg x 2 (18 allo and five auto) or melphalan 140 mg/m2 (seven allo and 17 auto). Prevention of graft-versus-host disease (GVHD) was by conventional immunosuppression in 17 patients and T cell depletion in eight. Seven patients (28%) developed moderate to severe acute GVHD. Auto marrow was treated in vitro in each case. Seven patients died in CR from BMT complications (five allo and two auto). The probability of relapse was 9% for patients receiving allo BMT and 52% for patients receiving auto BMT (p less than 0.01). The disease-free survival was 71% for allo BMT and 40% for auto BMT (p = NS). Early BMT is an effective form of consolidation for high risk patients with ALL in first CR. An allogeneic anti-leukemia effect was demonstrated in this study.     

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10-year experience

Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group. The median time to an absolute neutrophil count of 0.5 x 109/l was 45 d (range 20-185). Relapse was the major cause of failure with a relapse rate of 55% in CR2 and 44% in CR3, while the non-relapse, transplant-related mortality rate was 15% in CR2 and 33% in CR3. In univariate analysis, patient age, cytogenetics, white blood cell count at presentation, CR1 duration and the sensitivity of clonogeneic leukaemia (CFU-L) in the graft to 4HC were all prognostic for EFS. Using each of these significant variables in multivariate modelling, patient age and sensitivity of CFU-L to 4HC were determined to be predictors of EFS. 4HC-purged autologous BMT produced results similar to allogeneic BMT for AML patients beyond first remission.     

Autologous bone marrow transplantation with negative immunomagnetic purging for aggressive B-cell non-Hodgkin's lymphoma in first complete remission

To evaluate the effect on survival of negative immunomagnetic purging in aggressive B-cell non-Hodgkin's lymphoma (NHL), 20 patients retrospectively staged according to the age-adjusted International Prognostic Index as high-intermediate (11 patients) or high-risk (9 patients) received autologous bone marrow transplantation (ABMT) in first complete remission (CR1). All patients received six to eight cycles of a F-MACHOP-like protocol as induction treatment and then underwent high-dose chemotherapy (HDC) with a CBV-like regimen. Negative purging included a panel of monoclonal antibodies against B-cell antigens and immunomagnetic beads. The data were compared to a historical control of 18 patients with the same characteristics treated in our institution who received unpurged bone marrow support. The median yield of mononuclear cells (MNC), colony-forming units-granulocyte/macrophage (CFU-GM), and CD34+ cells after purging were 52%, 49%, and 57%, respectively. The median B-cell depletion after negative selection was 1.8 logs. All patients obtained a complete engraftment with no significant differences between the purged and unpurged group. Two toxic deaths (one for each group) were observed and the main extrahematological toxicities were mucositis, vomiting, and diarrhea. The event-free survival (EFS) and overall survival (OS) at 3 years for the whole group of 38 patients were 73% (95% CI: 59-88%) and 81% (95% CI, 68-94%), respectively. The comparison between patients receiving purged marrow and patients receiving unmanipulated marrow indicated no significant survival differences between the two groups both for EFS 84% (95% CI: 67-100%) vs 61% (95%CI: 39-84%) ( P=0.12) and OS 84% (95% CI: 69-100%) vs 71% (95% CI: 50-93%) ( P=0.58). Our report shows that HDC followed by reinfusion of autologous bone marrow can produce long EFS and OS in high-intermediate and high-risk patients with B-cell NHL transplanted in CR1, but was not be able to demonstrate a significant clinical advantage using immunomagnetic purged marrow. However, the use of ex vivo negative purging combined with innovative treatment modalities (peripheral blood stem cell transplant, in vivo administration of monoclonal antibodies) needs to be explored.     

Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT. 19 patients had relapsed on and 31 off therapy.
Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II–IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure.
These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.     

Bone marrow transplantation for adults and children with poor risk acute lymphoblastic leukaemia in first complete remission

Thirty-two patients with poor risk acute lymphoblastic leukaemia in first complete remission received bone marrow transplants (BMT) from fully matched family donors. Their ages ranged from 7 to 41 (median 23) years. Nine patients were aged 16 years or less. Patients were selected for BMT because they had risk factors for relapse with standard treatment approaches. In particular the children who were selected for BMT had presenting blast counts of greater than or equal to 90 x 10(9)/l or null immunophenotypes. The overall disease-free survival was 50% with a relapse risk of 31% at 9 years. Patients aged less than 16 years had a much lower risk of both graft-related disease and relapse than did older patients (disease-free survival 89% for those aged 7-16, 48% for those aged 17-26, 24% for those aged 26-41). We conclude that selection of BMT for young patients with poor risk features is entirely justified but that the prognosis for older patients is poor even after BMT.     

Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission

We compared the outcome of children with high-risk acute lymphoblastic leukaemia (HR-ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study.   All children treated by the Italian Paediatric Haematology Oncology Association for HR-ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total-body irradiation ( n  =25/30). 130 matched controls for BMT patients were identified among 397 HR-ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time-to-transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59–3.24), 0.69 (CI 0.27–1.77) and 0.35 (CI 0.06–1{\raise 5mu ..91), with an overall non-significant difference between the two groups ( P  = 0.34). With a median follow-up of 4 years, the disease-free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non-leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR).   The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR.     

Autologous bone marrow transplantation after a long first remission for children with recurrent acute lymphoblastic leukemia

Fifty-one children with acute lymphoblastic leukemia (ALL) in second or subsequent remission after a first remission of at least 24 months underwent purged, autologous bone marrow transplantation (ABMT). Bone marrow was harvested in remission and purged in vitro with monoclonal antibodies specific for leukemia-associated antigens. Ablative chemotherapy included cytarabine, teniposide, and cyclophosphamide followed by total body irradiation. Of the 51 patients treated between November 1980 and June 1991, 5 died of treatment-related complications, 18 relapsed, 1 died of a second tumor at 6.7 years, and 27 remained in continuous complete remission for a median of 39 months (range, 9+ to 124+). Event-free survival (EFS) (+/- SE) at 3 years after ABMT was 53% +/- 7%. Leukemia-free survival (LFS) was 58% +/- 8%. In multivariate analysis, the most significant predictors of EFS were duration of longest pre-ABMT remission and remission duration immediately before ABMT. For LFS, the most significant predictors were cell dose per kilogram of marrow reinfused and duration of longest pre-ABMT remission. We conclude that ABMT for this population is an effective therapy available to the majority of children with relapsed ALL.     

Autologous marrow transplantation in patients with acute nonlymphocytic leukemia in first remission

Thirteen patients with acute nonlymphocytic leukemia underwent autologous bone marrow transplantation (ABMT) following high doses of cyclophosphamide and total body irradiation while in first complete remission. After marrow infusion four patients received human leukocyte interferon and nine received intravenous methotrexate. One patient died on day 16 of septicemia associated with severe gastrointestinal toxicity. In the remaining 12 patients the median day of achieving a circulating granulocyte level of 500/mm3 was 29 (range 15-94 days). Eight of 12 evaluable patients achieved a sustained platelet count of 20,000/mm3 or greater in a median of 44 days (range 12-116 days) and four patients did not achieve this level before death on days 116-396. One patient died on day 116 of interstitial pneumonitis secondary to cytomegalovirus. Eight patients relapsed 58-365 days after AMBT (median 335 days), and all have died. Three patients are alive and well without relapse 26-50 months after ABMT. This study demonstrated that poor engraftment was a frequent complication of ABMT when early posttransplant cytotoxic therapy was attempted. Relapse of leukemia and the number of long-term survivors in this small group of patients was not different from that expected following conventional therapy.