Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.     

Indications, technique and risks in bone marrow transplantation in adulthood

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.     

Bulky lymphadenopathy in acute myeloid leukemia

Two cases of acute myeloid leukemia (AML) presenting with bulky adenopathy are reported. Both patients were febrile at admission and showed massive and diffuse lymph node involvement, hepatomegaly, and splenomegaly. Erythematopapular leukemic skin lesions were present in one case at the onset and developed in the other at the time of relapse. Anemia, thrombocytopenia, and moderate leukocytosis were present in both. The presence of immature cells in peripheral blood and bone marrow allowed a rapid diagnosis of AML, FAB M1, in one patient. In the other case, owing to the paucity of immature cells in peripheral blood and bone marrow, lymph node biopsy with histology, imprint cytology, and immunocytochemistry were essential for the diagnosis (AML, FAB M2, with trilineage dysplasia and basophilic involvement). Both patients achieved complete remission (CR), followed by an early relapse 3 months later. They underwent allogeneic bone marrow transplantation (BMT) from HLA identical siblings. One patient is actually alive and in CR at 6 months after BMT; the other patient showed a leukemic regrowth after transplantation and died 4 months later.     

A new radiation-free conditioning in bone marrow transplantation and dibromo-mannitol therapy in chronic myeloid leukemia

A new, radiation-free, conditioning protocol, containing the original Hungarian mitobronitol (DBM) (DBM/ cytosine arabinoside/cyclosphosphamide) has been applied to 36 chronic myeloid leukemia (CML) patients followed by bone marrow transplantation (BMT) from HLA identical sibling donors between 1990-1997. In spite of some prognostically disadvantageous factors (half of them were above 40 years, 10 out of 36 patients were in accelerated phase, the disease history was longer than 2 years in average) the overall survival (30/36) and the leukemia free survival rate (26/36) were in accordance with the best international results. Transplantation-related toxicity was remarkably reduced in comparison to bone marrow transplantation performed by total body irradiation/cyclophosphamide (TBI/Cy) or busulphan/cyclophosphamide (Bu/Cy) conditioning protocols. Acute graft versus host disease was present in lower percentage (9/36) and the number of serious cases was only 2/36. Chronic GVH disease, generally known to be associated with antileukemic effect (GVL), occurred in 25 of cases. Early haematological relapse among the 34 patients with functioning graft occurred in 6 patients which rate is slightly higher than reported after TBI/Cy or Bu/Cy conditioning treatment. There was no relapse among patients transplanted within one year post-diagnosis and patients having CML with accelerated phase. The leukemia free post-transplant period was in association with the chronic GVH disease and full chimeric state.     

Treatment of Ph1-positive chronic myelogenous leukemia in children: comparison between allogeneic bone marrow transplantation and conventional chemotherapy. Spanish Working Party for BMT in Children (GETMON)

BACKGROUND AND OBJECTIVE: To compare the estimated survival and disease-free survival between children with Ph1-positive chronic myeloid leukemia treated with allogeneic bone marrow transplantation or conventional chemotherapy. DESIGN AND METHODS: In this retrospective study we compared the results obtained in a group of 14 children who received allogeneic bone marrow transplantation (BMT) between 1983 and 1993, and another group of 27 children treated with busulfan, hydroxyurea or alpha-interferon during the same time period. Patients were transplanted at a median of 7 months from diagnosis and all except one were in their first chronic phase. Conditioning consisted in total body irradiation and cyclophosphamide in 12 cases, and busulfan was added in two. RESULTS: Of the 14 patients treated with BMT, two died of transplant-related complications and two relapsed 18 and 48 months after the BMT. Ten children remain alive and disease free at a median follow up of 60 months. The probability of DFS at 5 years is 70%. Of the 27 patients treated with chemotherapy, 22 have died at a median of 36 months from diagnosis. The probability of survival at 5 years is 5% versus 83% for the BMT group (p = 0.001). INTERPRETATION AND CONCLUSIONS: Allogeneic BMT is a safe and very effective treatment for Ph-positive CML in children. Patients who have an HLA-identical sibling donor must receive a transplant as soon as possible after being diagnosed.     

Allogenic bone marrow transplantation in the treatment of malignant hematologic disease

We have treated 28 patients (pts) with malignant hematological diseases with allogeneic bone marrow transplantation (BMT). 18 pts had acute lymphoblastic (ALL) and non lymphoblastic leukemia (ANLL), 5 chronic myeloid leukemia (CML), 2 severe aplastic anemia (SAA), 1 myelodisplasia, 1 Fanconi's anemia and 1 advanced Non Hodgkin's lymphoma. All but three received the graft from HLA identical sibling donors. We used conditioning with total body irradiation and chemotherapy (cyclophosphamide, cytarabine and etoposide) in 17 pts and chemotherapy alone in 11. 24 pts had full hematological recovery 18 to 25 days post BMT. 15 pts died after BMT as a consequence of toxicity or early infection (4), graft failure (2), graft versus host disease (4) or relapse (5). Actuarial event free survival for the group with favorable prognosis (SAA, ALL and ANLL in first or second remission and CML in chronic phase) is 57% at 36 months. Allogeneic BMT is an effective and feasible therapeutic procedure for selected patients with hematological malignancies.     

Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML

Relapse after autologous bone marrow transplantation for chronic myelogenous leukemia (CML) can be due either to the persistence of leukemia cells in systemic tissues following preparative therapy, or due to the persistence of leukemia cells in the autologous marrow used to restore marrow function after intensive therapy. To help distinguish between these two possible causes of relapse, we used safety-modified retroviruses, which contain the bacterial resistance gene NEO, to mark autologous marrow cells that had been collected from patients early in the phase of hematopoietic recovery after in vivo chemotherapy. The cells were then subjected to ex vivo CD34 selection following collection and 30% of the bone marrow were exposed to a safety-modified virus. This marrow was infused after delivery of systemic therapy, which consisted of total body irradiation (1,020 cGy), cyclophosphamide (120 mg/kg), and VP-16 (750 mg/m2). RT PCR assays specific for the bacterial NEO mRNA, which was coded for by the virus, and the bcr-abl mRNA showed that in two evaluable CML patients transplanted with marked cells, sufficient numbers of leukemia cells remained in the infused marrow to contribute to systemic relapse. In addition, both normal and leukemic cells positive for the retroviral transgenome persisted in the systemic circulation of the patients for at least 280 days posttransplant showing that the infused marrow was responsible for the return of hematopoiesis following the preparative therapy. This observation shows that it is possible to use a replication-incompetent safety-modified retrovirus in order to introduce DNA sequences into the hematopoietic cells of patients undergoing autologous bone marrow transplantation. Moreover, this data suggested that additional fractionation procedures will be necessary to reduce the probability of relapse after bone marrow transplantation in at least the advanced stages of the disease in CML patients undergoing autologous bone marrow transplantation procedures.     

Importance of mixed chimerism to predict relapse in persistently BCR/ABL positive long survivors after allogeneic bone marrow transplantation for chronic myeloid leukemia

Determination of hematological chimerism could be helpful in understanding the biology of leukemic relapse after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML), because the detection of malignant residual cells carrying the bcr/abl message by qualitative RT-PCR is of limited value in predicting disease progression for individual patients. We have studied the chimerism pattern and the bcr/abl status by Southern-blot in 15 CML patients (M/F:6/9) transplanted with unmanipulated BM from HLA identical sibling donors, persistently bcr/abl positive by RT-PCR. The median age of the series was 31 years (18-49) and disease status at BMT was: chronic phase: 11, accelerated phase: 3 and blast crisis: 1 patient. Of the 15 patients, 9 are alive and in complete remission (CR), 4 have died in CR and 2 are alive but suffered relapse at + 19 and +26 months post-BMT. The median follow-up is 81 months (13,7-168). Rearrangement of the BCR gene was performed by Southern-blot using P32-labeled transprobe-1. PCR analysis of chimerism was assessed using primers for the following VNTR loci: D1S80, D1S111, 33.1, APO-B, YNZ-22, lambdag3 and DXS52. Seventy-nine samples were analyzed (median per patient 5 (range 2-9)). Thirteen patients showed complete chimerism and lacked BCR rearrangement over time by Southern-blot. The 2 patients who relapsed showed mixed chimera status from +9 and +5 months respectively until the end of the study. Persistent BCR rearrangement was observed in these 2 patients from +12 and +11 months respectively. Our data suggest that mixed chimerism may predict hematologic or cytogenetic relapse by several months in those patients who are persistently PCR-positive post-BMT.     

Filgrastim for the treatment of leukemia relapse after bone marrow transplantation

The absence of an effective therapy for most patients with leukemia who relapse after allogeneic BMT has generated interest in new strategies. We present our experience on the use of filgrastim 5 micrograms/kg/day s.c., in four patients with leukemia (three with AML and one with CLL) who relapsed after allogeneic transplantation. One patient with AML achieved CR after 55 days of treatment. No response was observed in the remaining three. The patient who responded developed extensive chronic GVHD but relapsed 10 months later. In one of the unresponsive patients a dramatic increase in bone marrow infiltration and WBC count followed administration of filgrastim. We conclude that filgrastim can occasionally induce CR in leukemic patients who relapse after BMT.     

Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia: a metaphase-FISH study

Metaphase-FISH was adopted for the detection of proliferating Philadelphia-positive (Ph+) residual leukaemic cells in 25 patients with chronic myeloid leukaemia treated with allogeneic bone marrow transplantation (BMT). Patients were followed up during their clinical remission for 4-50 months (median 17 months) after BMT. 80 bone marrow samples were studied. For most of the cases no fewer than 1000 metaphases were analysed. Six patients (24%) showed residual Ph+ cells during the first 6 months and two others by the end of the first year after BMT. Three patients relapsed during the study and in two of them residual Ph+ cells were detected during the first 6 months after BMT. In 17 patients no Ph+ cells were detected at any stage of follow-up and 16 (94.1%) of them continue in complete clinical and haematological remission. Our results indicate that metaphase-FISH is a reliable tool in the quantitation of proliferating residual leukaemic cells. We suggest that consecutive findings of equal amounts of residual leukaemic cells do not necessarily predict a relapse. However, their presence calls for follow-up at shorter intervals where an increasing number of these cells predicts an ensuing relapse.     

Second allogeneic bone marrow transplantation in acute leukemia: a multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

Thirty-eight second allogeneic bone marrow transplants (BMT) for acute leukemia relapsed after first BMT were performed in 13 Italian centers between 1987 and 1994. Twenty-one patients had acute myelogenous leukemia (AML), 17 acute lymphoblastic leukemia (ALL); at second BMT 24 patients were in complete remission (CR) and 14 in relapse. The median time to relapse after first BMT was 10 months (range 1-70). Grade II or greater acute graft-versus-host disease (GVHD) after second transplant occurred in 34.2% of patients and a chronic GVHD in 31.5% of patients. Twenty-four patients died: seven from early transplant-related mortality (TRM), 13 from relapse and four from late toxicity. As of 31 July 1996, at a median follow-up of 47 months (range 22-85), there are 14 survivors. The three-year probability of TRM, relapse and event-free survival (EFS) is 28%, 40% and 42% respectively. In 20 of 27 evaluable patients, remission duration after second BMT was longer than after the first BMT. A diagnosis of AML was correlated with a better outcome. These data support the usefulness of second allograft in selected patients with AML relapsing after a first BMT.     

bcr-abl mRNA检测在慢性粒细胞白血病诊治中的意义

目的 探讨bcr-abl mRNA在慢性粒细胞白血病(CML)诊断、治疗及微小残留病变监测中的意义.方法 采用实时定量聚合酶链反应(real-time PCR)方法检测324例CML患者518份标本的bcr-abl mRNA表达情况.结果 CML慢性期、加速期和急变期患者的bcr-abl mRNA定量结果逐渐增高,分别为12.6%、25.4%和57.2%(P<0.05).异基因造血干细胞移植后的bcr-abl mRNA定量结果随时间延长逐渐降低,一般在移植6个月后转阴,服用伊马替尼(商品名:格列卫)与异基因造血干细胞移植病程相似,但融合基因转阴所用时间较长.结论 real-time PCR检测bcr-abl mRNA对于诊断、评价疗效、监测微小残留病变以及预测疾病进展具有重要的临床应用价值.     

Detection of BCR/ABL RNA transcripts using the polymerase chain reaction is highly predictive for relapse in patients transplanted with unrelated marrow grafts for chronic myelogenous leukaemia

Relapse after allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia (CML) is thought to result from residual leukaemia cells which survive the intensive conditioning regimen and are not eradicated by donor-derived immune effector cells capable of mediating a graft-versus-leukaemia (GVL) effect. Early relapse can be detected using highly sensitive assays such as the polymerase chain reaction (PCR) which have been shown to have predictive value for subsequent relapse in selected patient populations. The validity of PCR for predicting CML relapse in unrelated marrow transplant recipients where the GVL effect appears to be augmented due to increased HLA disparity between donor and recipient, however, has not been well defined. In this study we assessed the prognostic value of PCR in a cohort of 52 patients transplanted with T-cell-depleted unrelated marrow grafts for CML. The actual probability of relapse at 3 years was 71% in patients with at least one positive assay versus 6% in patients with no positive assays post-transplant. Patients with one or more positive assays at any time post-transplant had a 56-fold increased risk of relapse which was significantly higher (P=0.0002) than that observed in patients who remained persistently PCR negative. Moreover, PCR detected relapse a median of 5 months earlier than cytogenetic analysis in a subgroup of patients in whom concurrent sampling had been performed. These data validate the use of PCR as a prognostic test in this patient population and may help to identify a cohort of patients to be considered as candidates for pre-emptive adoptive immunotherapy.     

Colony growth in cultures from bone marrow and peripheral blood after curative treatment for leukemia and severe aplastic anemia

The recovery of colony-forming cell numbers after curative treatment for leukemia and severe aplastic anemia (SAA) was studied. We examined 191 patients (85 acute myeloid leukemia [AML], 48 acute lymphocytic leukemia [ALL], 32 chronic myeloid leukemia [CML], 17 SAA, and nine myelodysplastic syndrome [MDS]) who were in hematologic remission 6 months to 13 years after either curative chemotherapy (n = 69) or allogeneic bone marrow transplantation (BMT) (n = 122) by culturing their precursor cells from bone marrow (BM) (n = 548) and peripheral blood (PB) (n = 529) in methylcellulose. Thirty-six BM donors and 25 PB donors served as controls. BM colony-forming cell numbers were abnormally low in all patients (p < 0.002) irrespective of underlying disorder and type of treatment (chemotherapy or irradiation). These numbers did not normalize with time--colony-forming cells were still strongly reduced up to 10 years after therapy, whether or not the patient had received an allogeneic bone marrow graft (p < 0.002). We also compared patients who remained in stable hematologic remission with those who later relapsed (6 months to 2 years after treatment). BM colony-forming cell numbers were significantly lower in patients who subsequently relapsed (p = 0.004). In contrast to BM cultures, we found normal colony-forming capacity by PB precursors in all patients. We conclude that (1) after chemotherapy or BMT, colony-forming cell numbers of BM in culture are permanently reduced; (2) this defect is probably due to a dysfunction of the BM environment rather than to a numerical reduction of the precursor cell pool; and (3) very low colony-forming capacity may be related to relapse.     

Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias

PURPOSE: Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues. A therapeutic dose-escalation study of M195 labeled with iodine 131 was conducted in patients with relapsed or refractory myeloid leukemias. METHODS: Twenty-four patients (16 relapsed or refractory acute myeloid leukemias, five blastic myelodysplastic syndromes [MDS], two chemotherapy-related secondary leukemias, and one blastic chronic myelogenous leukemia [CML]), including seven who had failed to respond to prior bone marrow transplantation (BMT), received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. RESULTS: In 22 patients, whole-body gamma-imaging demonstrated marked uptake of antibody into all areas of bone marrow. Twenty-three patients (96%) demonstrated decreases in peripheral-blood cell counts, with decreased percentage of bone marrow blasts seen in 83% of cases. Eighty-nine percent of bone marrow biopsies examined quantitatively demonstrated substantial decreases in the number of blasts, with greater than 99% of blasts killed in some patients. The two cases that failed to demonstrate leukemic cytoreduction occurred in the first two dose levels. For 131I doses of 135 mCi/m2 or greater, pancytopenia was profound and lasted for at least 12 days. Eight patients had sufficient marrow cytoreduction to proceed to BMT. Three of these achieved marrow remission, one of 6+, and one of 9 months' duration. Two patients in blastic phase temporarily reverted to their original myelodysplastic states. Thirty-seven percent of assessable patients developed human anti-mouse antibody (HAMA). In two patients with HAMA who were re-treated, plasma 131I-M195 levels could not be maintained and no therapeutic effect resulted. Significant nonhematologic toxicity (hepatic) was seen in one patient and the maximum-tolerated dose (MTD) was not reached. CONCLUSION: These data suggest that safe leukemic cytoreduction can be achieved with 131I-M195 even in multiply relapsed or chemotherapy-refractory leukemias. This agent may be useful as part of a preparative regimen for BMT.