Autologous peripheral blood stem cell transplantation for acute myeloid leukemia

We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.     

自体外周血造血干细胞和自体骨髓移植治疗急性髓性白血病的临床疗效比较研究

目的：比较自体外周血干细胞移植（APBSCT）与自体骨髓移植治疗CR1期急性髓性白血病（AML）的临床疗效。方法：用APBSCT治疗AML患者27例，用非净化自体骨髓移植（ABMT）治疗AML患者13例，用净化自体骨髓移植（PABMT）治疗AML患者25例。结果：（1）APBSCT组造血重建校其他两组显著加快；（2）APBSCT组的3年无病生存率（DFS）和复发率（RR）分别为51．％和42．2％，与ABMT组的46．2％、46．7％相当，但与净化ABMT组的72．9％、23．7％相比差异有显著性意义。（3）三组的移植相关死亡率（TRM）差异无显著性意义，死亡的主要原因为感染和内脏出血。结论：APBSCT治疗CR1期AML，其造血重建显著快于ABMT，其疗效与ABMT相当，而显著低于PABMT。     

Autologous peripheral blood stem cell transplantation with induction of autologous graft-versus-host disease in acute myeloid leukemia

We studied whether the induction of autologous graft-versus-host disease (GVHD) has an antileukemic effect and consequently increases the survival of patients undergoing autologous peripheral blood stem cell transplantation (PBSCT). In all, 22 acute myeloid leukemia patients with favorable and intermediate cytogenetic risk, in their first complete remission, were administered cyclosporine c.i.v. from day 0 to day +28 at a dose of 3.0 mg/kg per day and interferon-gamma (IFN-gamma) at 0.025 mg/m(2) s.c. every other day from day +14 to day +42 following autologous PBSCT. Natural-killer (NK)-cell activity assays and skin biopsies were performed. Successful engraftment was achieved in all patients at a median of 13 days without significant additional toxicity. Histologically confirmed cutaneous GVHD developed in 12 patients, and NK-cell activity was significantly augmented after autologous PBSCT in those patients (P=0.03). After a median follow-up duration of 37.7 months (range, 7.3-72.8), the 3-year disease-free survival (DFS) and overall survival (OS) rates were 64.4 and 73.1%, respectively, without significant correlation with GVHD status or augmentation of NK-cell activity. These data suggest that the administration of cyclosporine and IFN-gamma following autologous PBSCT improves OS and DFS, which may be attributable to the antileukemic effect, although no difference in survival could be demonstrated between cutaneous GVHD-positive and -negative groups.     

Autologous stem cell transplantation for acute myeloid leukemia

Autologous bone marrow transplant (ABMT) and stem cell transplantation (ASCT) are important treatment modalities for acute myeloid leukemia (AML). The role of ASCT in first remission patients remains controversial. Phase II and phase III studies demonstrate that patients with favorable-risk cytogenetics benefit from ASCT, with reduction in relapse and improvement in leukemia-free survival (LFS). Patients with poor-risk cytogenetics do not appear to benefit significantly from ASCT and should preferentially be treated with allogeneic transplant. The role of ASCT for patients with intermediate risk disease is uncertain. It appears that ASCT in first remission will improve disease-free survival compared to standard chemotherapy. Sufficient patients who relapse after chemotherapy treatment can be salvaged with ASCT in second remission such that the beneficial effect on overall survival is blunted. ASCT produces equivalent results to ABMT but with reduced morbidity. The collection of stem cells during recovery from intensive dose consolidation therapy appears to be an attractive strategy that can increase the percentage of patients who are able to receive their intended transplant. Consolidation therapy prior to stem cell collection and transplant has been shown to decrease the relapse rate and improve outcomes, but the optimal nature of this consolidation therapy is unknown. For patients with AML in second remission, ABMT/ASCT offers a substantial salvage rate, and is particularly effective for patients with acute promyelocytic leukemia.     

Autologous stem cell transplantation for advanced acute myeloid leukemia

We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (x10(6)/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment.     

Autologous versus allogeneic stem cell transplantation in acute myeloid leukemia

Using the data of the patients in complete remission (CR) up to the age of 45 years included in the EORTC-LG/GIMEMA AML-10 trial we investigated the value of the strategy to perform either an autologous (auto-SCT) or an allogeneic (allo-SCT) stem cell transplantation on an intention to treat basis. Between 1993 and 1999, out of 1198 pts, 822 achieved CR. 734 pts, constituting the study group, received an intensieve consolidation course: 293 had a sibling donor and 441 had not. Allo-SCT and auto-SCT was performed in 68.9% and 55.8%, respectively. Cytogenetics was successfully performed in 446 pts. Risk groups were: good (t(8;21), inv(16)), intermediate (NN or -Y only), bad/very bad (all others). Median follow-up was 4 years. The 4-year disease-free survival (DFS) rate of patients with a donor vs of those without a donor was 52.2% vs 42.2%, p = 0.044; the relapse incidence was 30.4% vs 52.5%, death in first complete remission was 17.4% vs 5.3%, and the survival rate was 58.3% vs 50.8% (p = 0.18). The DFS rates in pts with and without a sibling donor were similar in pts with good or intermediate risk cytogenetics, but 43.4% and 18.4%, respectively, in pts with bad or very bad risk cytogenetics. In younger patients (15-35 yrs), the difference was more pronounced. The strategy to perform an allo-SCT in patients where a family donor was available led to better overall results than to perform an auto-SCT, especially for younger patients or those with bad or very bad risk cytogenetics.     

Autologous stem cell transplantation in chronic myeloid leukemia

Autografting was first attempted for patients with chronic myeloid leukemia (CML) in transformation in order to restore a second chronic phase (CP). The principal rationale for autografting in CP resides on the reduction of the tumor burden and the number of leukemic cells at risk of developing blastic transformation, and the possibility of eradicating already mutated cells. In a European Group for Blood and Marrow Transplantation (EBMT) Registry survey, patients with CML in CP, undergoing autologous stem cell transplantation (auto-SCT) for the first time, had an overall survival of 65% at 5 years from transplant with more than 50% of all patients remaining in CP. The main point made by this retrospective study was that in patients refractory to interferon-alpha (IFN), 70% achieved a cytogenetic response post autografting, which was complete or major in 31%. Since the advent of imatinib, autografting in CML has experienced a substantial decline. Theoretically, there are several possible ways of using auto-SCT in combination with imatinib: (1) to reverse resistance to imatinib; (2) to eliminate a Ph-positive clone bearing a BCR-ABL kinase domain mutation; and (3) to reduce the level of residual disease after a cytogenetic response to imatinib in patients in whom Ph-negative cells had been harvested. The exact role of auto-SCT in the present management of CML remains unanswered.     

Splenic rupture in a patient with acute myeloid leukemia undergoing peripheral blood stem cell transplantation

 Splenic rupture is a rare but well-recognized complication of hematological malignancies. Here, we present the case of a 22-year-old woman with the diagnosis of acute myeloid leukemia who was undergoing peripheral blood stem cell transplantation. On day +10 she developed a hypovolemic shock due to rupture of her spleen and went to emergency laparotomy. This is the first report of splenic rupture during peripheral blood stem cell transplantation. Received: May 7, 1998 / Accepted: October 21, 1998     

Autologous peripheral hematopoietic stem cell transplantation in leukemia

Six cases of acute leukemia patients were treated with APHSCT and the clinical results were satisfactory. The preparatory marrow ablative chemoradiotherapy regimen before APHSCT was same as that for autologous bone marrow transplantation (ABMT). The number of mononuclear cells infused to restore the hematopoietic function ranged from 1.65 to 2.92 x 10(8)/kg and these cells yielded 0.17 to 2.26 x 10(4)/kg CFU-GM. The hematopoietic and immunological function of patients returned to normal level 25 to 38 days after APHSCT; the recovery was faster than that of ABMT and FLT. One patient each died of recurrence of leukemia and fungi septicemia 90 and 70 days after transplantation respectively, whereas the other four patients have survived for 9, 8, 4, and 2 months respectively.     

Autologous peripheral blood stem cell transplantation for acute leukaemias.

Initial interest in autologous blood stem cell transplants (ABSCT) in acute myeloid leukaemia (AML) was based on the postulate that there might be less malignant contamination than with bone marrow transplants. Although this remains presently uncertain, other advantages of ABSCT, such as a rapid haematopoietic recovery, were immediately recognized. In pilot studies, peripheral blood stem cells (PBSC) were collected after standard induction and consolidation courses of chemotherapy. The actuarial disease-free survival (DFS) and relapse rates (RR) at 2-3 years ranged from 28 to 39% and 57 to 60%, respectively. Recently, PBSC collection after high-dose cytarabine, with or without G-CSF, has been associated with DFS ranging from 47 to 57%. Thus, the timing of stem cell collection seems to be crucial in AML and it should be performed following an efficient in vivo purging but before the haematopoietic reserve is exhausted. Clinical results with ABSCT are similar to those seen after autologous bone marrow transplant (ABMT), although important issues such as potential contamination of stem cell collections and optimal timing of PBSC harvest remain to be clarified. Prospective randomized studies comparing ABMT and ABSCT are needed for definitive evaluation of the role of the source of stem cells in AML treatment.     

Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome

We report the results of 65 patients with treatment-related myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) who were transplanted from an autograft and reported to the EBMT. The median age was 39 years (range, 3-69), and stem cell source was bone marrow (n = 31), or peripheral blood progenitor cells (n = 30), or the combination of both (n = 4). The primary disease was solid tumors (n = 37), Hodgkin's disease (n = 13), non-Hodgkin's lymphoma (n = 10), acute lymphoblastic leukemia (n = 2) or myeloproliferative syndromes (n = 3). The types of MDS were as follows: RAEB (n = 1; 2%), RAEB-t (n = 3; 5%), or AML (n = 56; 87%). The median time between diagnosis and transplantation was 5 months (range, 3-86). The Kaplan-Meier estimates of the probability of 3-year overall and disease-free survival were 35% (95% CI: 21-49%) and 32% (95% CI: 18-45%), respectively. The median leukocyte engraftment was faster after transplantation with peripheral blood stem cells than with bone marrow: 12 (range, 9-26) vs 29 (range, 11-67) days (P<0.001). The cumulative incidence of relapse was 58% (95% CI: 44-72%) and of treatment-related mortality 12% (95% CI: 6-38%). Lower relapse rate was seen in patients transplanted in first complete remission (CR1 vs non-CR1: 3 years: 48 vs 89%; P = 0.05). Furthermore, age beyond 40 years resulted in a higher treatment-related mortality (47 vs 7%; P = 0.01). In a multivariate analysis, transplantation in CR1 age as well as their interaction influenced overall survival significantly. Autologous transplantation may cure a substantial number of patients with treatment-related MDS/AML, especially if they are in CR1 and of younger age.     

Brugada syndrome occurring after autologous peripheral blood stem cell transplantation for acute myeloid leukemia

A 74-year-old male was found to be suffering from the Brugada syndrome after undergoing high dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ABSCT) for acute myeloid leukemia. A specific ECG pattern of right bundle-branch block and a coved-type ST-segment elevation in leads V1 through V3, which is compatible with the Brugada syndrome, was unmasked by febrile neutropenia on the 8th day after ABSCT. He experienced syncope on the 11th day due to ventricular tachycardia, which was immediately improved with the administration of intravenous lidocaine. The Brugada syndorome should be considered in febrile patients if they have a episode of syncope or ECG change.     

Autologous transplantation in acute myeloid leukemia: peripheral blood stem cell harvest after mobilization in steady state by granulocyte colony-stimulating factor alone

In order to determine whether granulocyte colony-stimulating factor (G-CSF) alone initiated during steady state was able to mobilize peripheral blood stem cells (PBSC) in acute myeloid leukemia (AML) and to assess predictive factors for engraftment after autologous PBSC transplantation, we studied 49 successive adult AML patients for whom autologous transplantation was planned between July 1994 and November 1998. G-CSF was used as priming agent and was initiated at least 4 weeks after the last day of chemotherapy, while neutrophil count was >0.5 x 10(9)/l and platelet count was >30 x 10(9)/l. A median of three aphereses was performed resulting in a median collection of 14.8 x 10(8) nucleated cells/kg containing 7.7 x 10(8) mononuclear cells/kg, 47.1 x 10(4) CFU-GM/kg, and 3.8 x 10(6) CD34+ cells/kg. A significant correlation was observed between nucleated cell, mononuclear cell, and CFU-GM yields, while no correlation was found with CD34+ cell yield. Recruitment was not significantly different in patients with CD34+ leukemic cells at the time of initial diagnosis when compared to that of those presenting with CD34- blastic cells. Thirty-three patients actually underwent transplantation. Reasons for not autografting were inadequate stem cell harvest (ten patients), early relapse (two patients), prolonged neutropenia (one patient), organ failure (two patients), or patient refusal (one patient). Median time to achieve a neutrophil count greater than 0.5 x 10(9)/l and platelet count >50 x 10(9)/l untransfused was 13 and 36 days, respectively. A predictive factor for a shorter period neutropenia and a shorter thrombopenia was a higher count of harvested nucleated cells (p < 0.01 and p = 0.02, respectively). A higher count of harvested cells was also a predictive factor for less red cell and platelet transfusions (p=0.03 and p=0.02, respectively). The number of CD34+ harvested PBSC was not predictive for engraftment. We conclude that PBSC mobilization with G-CSF alone initiated in steady state is a feasible, safe, and suitable procedure for harvesting cells in sight of autologous transplantation in adult acute myeloid leukemia.     

Therapy-related acute myeloid leukemia following double autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

A 29-year-old male was diagnosed as having non-Hodgkin's lymphoma (NHL, diffuse, large cell, B-cell, stage IV) in June 1999. He underwent 7 courses of chemotherapy and double autologous peripheral stem cell transplantation (total dose: CPA 13,000 mg, BUS 892 mg, L-PAM 150 mg, MCNU 870 mg, MTX 60 mg, Ara-C 160 mg, DXR 350 mg, VP-16 11,190 mg, VCR 8 mg, CBDCA 700 mg, and MIT 22 mg) for NHL and obtained complete remission in April 2000. In September 2000, he suffered from progressive general malaise. Laboratory findings showed marked leukocytosis with 85% leukemia cells, which were positive for alpha-naphthyl butyrate esterase. Surface-marker analysis of the leukemia cells showed positive results for CD11b, CD11c, CD13, CD15, CD33, CD56, CD64, CD65, CD71 and HLA-DR, and chromosomal analysis revealed add(8) (p11), add(9) (p13). He was diagnosed as having AML (M5a) and was still in complete remission for NHL. He did not respond to chemotherapy and died in December 2000, believed to be from therapy-related leukemia induced by the VP-16 used for treating NHL, judging by the patient's short clinical course and monocytic type of leukemia.     

Successful treatment of myeloid/natural killer cell precursor acute leukemia with allogeneic peripheral blood stem cell transplantation

We report a case of myeloid/NK cell precursor acute leukemia, which was successfully treated with allogeneic peripheral blood stem cell transplantation (allo PBSCT). A 31-year-old woman was admitted to our hospital with general fatigue, anorexia and leukocytosis. Bone marrow aspiration showed infiltration of many atypical blasts. She was diagnosed as having myeloid/NK cell precursor acute leukemia by morphological and immunohistochemical analysis. Complete remission was achieved by induction chemotherapy, but as myeloid/NK cell precursor acute leukemia is reported to have an extremely poor prognosis due to frequent relapse, the patient underwent allo PBSCT from her HLA-identical father, together with a myeloablative conditioning regimen. She suffered several transplantation-related complications including acute graft versus host disease (grade II) and ischemic enterocolitis associated with thrombotic microangiopathy, but these were overcome by supportive therapy. She was discharged on day 168 after allo PBSCT, and so far there has been no evidence of relapse during a follow-up period of 15 months.     

Autologous transplantation in chronic myeloid leukaemia using peripheral blood stem cells

Forty-three patients with chronic myeloid leukaemia in first chronic phase were recruited to study intensive chemotherapy (idarubicin plus cytarabine; IdAC) followed by collection of peripheral blood stem cells (PBSC) in the recovery phase. PBSC autografting was performed on 32 patients. One patient died during mobilization and three died following autograft. All procedural deaths occurred in patients who received IdAc more than a year from diagnosis. Nine further patients died, eight following progression of CML. 72% of transplanted patients showed a major cytogenetic response but most cases have returned to Philadelphia-positive haemopoiesis. 62% of autografted patients remain alive (median survival from diagnosis 52 months). Four of the 11 patients who did not receive a transplant remain in chronic phase.     

Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission

We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5 years were 64.0 % (95 % CI 52.5–73.4) and 66.4 % (95 % CI 54.9–75.6) after Auto-PBSCT at a median follow-up time of 103 months (range 3–240 months), respectively. Two patients died of transplant-related pulmonary complications 6 months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3 %, respectively, but there was no significant difference statistically among the risk groups (log-rank p = 0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.