Busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for marrow transplantation in patients with advanced hematological malignancies: a phase I study

Thirty-six patients with advanced hematologic malignancy were entered into a phase I study designed to define a tolerable dose of busulfan (BU) and cyclophosphamide (CY) combined with 12 Gy of fractionated total body irradiation (TBI) as preparation for marrow transplantation from HLA-identical siblings, 0-1 locus HLA-non-identical family members or autologous cryopreserved marrow. Five of 18 evaluable patients prepared with 8.7 mg/kg of BU and 69 mg/kg CY + TBI developed severe regimen related toxicity (RRT) while none of 15 patients treated with 6.9 mg/kg of BU and 47 mg/kg of CY + TBI developed severe RRT. Ten of the 15 evaluable patients treated on the lower dose level are alive, nine disease-free, 262-737 days (median, 547) post-transplant with a 87% and 67% actuarial probability of survival at 3 and 18 months respectively. Six of the 18 patients treated on the higher dose level are alive disease-free 273-1039 days (median, 668) post-transplant with a 56% and 27% actuarial probability of survival at 3 and 18 months respectively. Eighteen patients were transplanted with allogeneic marrow for chronic myelogenous leukemia beyond chronic phase and acute non-lymphocytic leukemia beyond first remission or in relapse other than first untreated relapse and only one has relapsed posttransplant. It was concluded that a transplant preparative regimen combining 6.9 mg/kg of BU with 47 mg/kg of CY followed by 12 Gy fractionated TBI is well tolerated. The high probability of surviving this regimen and the low early relapse rate in patients with advanced myeloid malignancies is encouraging.     

Allogeneic bone marrow transplantation for hematological malignancies following etoposide, cyclophosphamide, and fractionated total body irradiation.

Forty-three patients received etoposide, cyclophosphamide, and fractionated total body irradiation before allogeneic marrow transplantation. Fifteen patients had chronic myelogenous leukemia in chronic phase or acute leukemia in first remission (standard risk) and twenty-eight patients with more advanced disease (high risk). All patients received etoposide 1,500 mg/m2 intravenously on day -8, cyclophosphamide 60 mg/kg/day intravenously on days -7 and -6, and total body irradiation at 170 cGy twice a day on days -3, -2, and -1. During the first 100 days 12 high risk patients (43%) died from causes unrelated to relapse while none of the standard risk patients died. Renal and hepatic dysfunction were also significantly increased during the first 14 days in the high risk group. The addition of 1,500 mg/m2 of etoposide to the cyclophosphamide and total body irradiation was well tolerated for patients with standard risk. However, the regimen was poorly tolerated with high mortality in patients with more advanced disease.     

Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission

Summary We treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute nonlymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1 320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (± SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74±9%; acute nonlymphoblastic leukemia = 50±11%; and chronic myelogenous leukemia = 55±11%. Actuarial relapse rates for these three diagnoses were 19±9%, 17±11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59±7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.Abbreviations ALL Acute lymphoblastic leukemia - ANLL Acute non-lymphoblastic leukemia - AP Anterior-posterior - BMT Bone marrow transplantation - CML Chronic myelogenous leukemia - CMV Cytomegalovirus - CP Chronic phase - CR Complete remission - CSA Cyclosporine A - CY Cyclophosphamide - FTBI Fractionated total body irradiation - GVHD Graft-versus-host disease - IP Interstitial pneumonia - MTX Methotrexate - PA Posterior-anterior - Ph¹ Philadelphia chromosome - PSE Prednisone - TBI Total body irradiation - TLD Thermoluminescent dosimetry - UPN Unique patient number - WBC White blood cell count This work was supported by United States Public Health Service Grants CA 30206 and CA 33572 from the National Cancer Institute, DHHSSpecial Fellow of the Leukemia Society of America     

Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation

In a phase I study 28 patients with lymphohematopoietic malignancies were treated with escalating doses of etoposide combined with cyclophosphamide 120 mg/kg and either fractionated total body irradiation (TBI) 1320 cGy in 11 fractions (n = 17) or busulfan 16 mg/kg (n = 11). Twenty transplants were allogeneic, seven autologous and one syngeneic. The maximally tolerated dose of etoposide in combination with TBI and cyclophosphamide was 60 mg/kg; at etoposide doses of 65 mg/kg three patients developed life-threatening or fatal mucosal toxicity. In combination with busulfan, the maximally tolerated dose of etoposide was 30 mg/kg. At an etoposide dose of 40 mg/kg two patients developed life-threatening or fatal toxicity (one mucosal, one hepatic). Mucositis requiring narcotic analgesics, hepatotoxicity, hematologic toxicity and interstitial pneumonitis were otherwise similar in TBI and busulfan-treated patients. Skin toxicity was observed significantly more often in the busulfan group. Five deaths occurred before day +30, two in the TBI group and three in the busulfan group. Eleven patients are surviving, ten in continuous complete remission, at a median of 9 (range 3-23) months following transplantation. Etoposide in combination with TBI and cyclophosphamide or busulfan and cyclophosphamide is associated with significant but acceptable toxicities. The maximally tolerated dose of etoposide is higher when combined with TBI than with busulfan. Promising response rates in this high risk group of hematologic malignancies warrant further evaluation of these etoposide containing conditioning regimens.     

Busulfan and cyclophosphamide as a preparative regimen for bone marrow transplantation in patients with prior chest radiotherapy

In a previous study, we reported that patients with hematologic malignancies who had received prior chest radiotherapy had a 32% risk of developing fatal interstitial pneumonia (IP) when prepared for bone marrow transplantation (BMT) with a regimen containing total body irradiation (TBI). To determine if avoidance of TBI would lessen the incidence of fatal IP, 37 patients who had received prior chest radiotherapy in excess of 2000 cGy were prepared with busulfan (BU, 4 mg/kg x 4 days) and cyclophosphamide (CY, 60 mg/kg x 2 days) followed by autologous (n = 15) or allogeneic (n = 22) BMT. Thirty-five of these patients had recurrent or refractory hematologic malignancies and most were heavily pretreated. Results were compared with the group of similar patients (n = 25) previously treated at our institution with a CY/TBI conditioning regimen. Among those treated with BU/CY, two patients (5%) developed fatal interstitial pneumonia, 12 (32%) died of other transplant related toxicities and 13 (35%) died of relapse. Seven (19%) patients remain alive and well. Among those treated with CY/TBI, eight (32%) died of pneumonia, six (24%) died of relapse, nine (36%) died of other causes and two (8%) remain alive and well. The 5% incidence of fatal interstitial pneumonitis in the chemotherapy conditioned group was significantly less than the 32% incidence in the previously treated CY/TBI group (p = 0.005). However, long-term survival and relapse probabilities were not significantly better than seen previously with CY/TBI, although a trend towards improved survival was observed in the BU/CY group. Avoidance of TBI appeared to lower the incidence of fatal pneumonitis in patients with prior chest radiotherapy.     

Allogeneic bone marrow transplantation for children with acute leukemia: cytoreduction with fractionated total body irradiation, high-dose etoposide and cyclophosphamide

Marrow-ablative chemo-radiotherapy followed by hematopoietic stem cell rescue from an allogeneic source improves outcomes for children with high-risk acute leukemia. The first effective pre-transplant preparative regimens consisted of high-dose cyclophosphamide (CY) and total body irradiation (TBI). Subsequent attempts have been made to improve leukemia-free survival, by adding other chemotherapy agents to these agents. In previous clinical studies of total body irradiation, etoposide, cyclophosphamide (TBI-VP-16-Cy) in adult allogeneic bone marrow transplantation, there has been a high incidence of severe regimen-related toxicity. In this study, we investigated the safety and efficacy of this combination in 41 children who received TBI (12-14 Gy), VP-16 (30 mg/kg), and CY (60 mg/kg x 2) and then either matched sibling or alternative donor transplants for acute leukemia. There was only one case of fatal regimen-related toxicity. The estimated 3-year event-free survival for patients with early or intermediate stage disease was 68% (53-88%). The estimated event-free survival of patients with advanced disease was 17% (5-59%). TBI-VP16-CY is safe in pediatric transplantation, and it has good efficacy for transplant recipients with less advanced disease. Bone Marrow Transplantation (2000) 25, 489-494.     

Ophthalmological and other toxicities related to cytosine arabinoside and total body irradiation as preparative regimen for bone marrow transplantation

Cytosine arabinoside, 3 g/m2, every 12 h for 6 days, followed by fractionated total body irradiation, 200 cGy twice daily for 3 days, was administered to 39 adult patients undergoing bone marrow transplantation. Allogeneic transplant patients received cyclosporin and methotrexate for prophylaxis of graft-versus-host disease. There were 21 autologous transplants (16 with acute leukemia, four with an advanced stage of chronic myelocytic leukemia, and one with lymphoma) and 18 allogeneic transplants (14 with acute leukemia, two with an advanced stage of chronic myelocytic leukemia and two with myelodysplastic syndrome). Toxicities were compared between the two groups. There was a significantly greater degree and duration of mucositis and a greater frequency of radiation-type retinopathy developing in the allogeneic group, predominantly in those having had radiation for prophylaxis or treatment of central nervous system leukemia. Seven of 11 acute leukemic patients who received autologous transplants in remission survive. Two of seven acute leukemias who received allogeneic transplants while in remission survive. Although the increased morbidity, retinitis and mucositis, observed in the allogeneic group indicates that this regimen when combined with methotrexate and cyclosporin is too toxic, the results in autologous transplantation in acute leukemia in remission are encouraging.     

Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin's lymphoma

This study reports on overall and recurrence-free survival (OS and RFS) of 37 consecutive patients with low- and intermediate-grade NHL receiving a related donor allogeneic BMT using a nonradiation-containing preparative regimen. In addition, transplant-related toxicity and factors influencing outcome are discussed. The preparative regimen consisted of busulfan and cyclophosphamide. Median patient age was 44 years (range 20-55). In all, 18 were female. Median follow-up of surviving patients from BMT was 4.2 years. A total of 25 patients had low-grade, and 12 intermediate grade NHL. Most patients (89%) were treated with at least two different chemotherapy regimens prior to BMT. In all, 22 patients (59%) were transplanted in partial remission, 15 (41%) in complete remission. OS at 12 months was 89% (95% confidence interval (CI) of 79-99%) and 79% (64-93%) at 60 months. RFS at 12 months was 86% (75-97%) and at 5 years 70% (54-86%). Four patients (11%) relapsed. Seven patients (19%) died, six because of treatment-related toxicity and one with relapse. Univariate analysis showed improved OS for younger patients and patients of female gender, suggesting that allogeneic BMT using busulfan-cyclophosphamide as a preparative regimen can achieve disease control and possibly cure patients with NHL particularly younger ones.     

Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia.

Thirty-six adults with chronic myelogenous leukemia (CML) in second or greater chronic phase, accelerated phase, or blast crisis underwent marrow or blood stem cell transplantation from an HLA-matched sibling using high-dose thiotepa, busulfan and cyclophosphamide (TBC) as the preparative regimen. All evaluable patients engrafted and had complete donor chimerism. One patient failed to clear meningeal leukemia, and one patient had one of 30 metaphases positive for the Philadelphia chromosome at 2 months post transplant. The remainder of the patients studied had eradication of CML documented by cytogenetics and/or Southern blot for BCR gene rearrangement, and 13 of 15 patients studied became negative for the BCR gene rearrangement by polymerase chain reaction. Three-year relapse rate is 42% (95% CI, 19-64%). The relapse rate was significantly lower for patients transplanted without blast crisis (9% vs 100%, P < 0.001). Eight (22%, 95% CI, 10-39%) patients had severe or fatal veno-occlusive disease (VOD). Elevated liver enzymes within 1 month prior to transplantation and transplantation using marrow were significantly associated with the occurrence of VOD. Three-year survival is 28% (95% CI, 13-43%). Survival was significantly higher for patients transplanted without blast crisis (45% vs 0%, P = 0.01). TBC is an effective preparative regimen for CML in accelerated phase but not refractory blast crisis, and it should be used with caution in patients with prior hepatopathy who have an increased risk of severe VOD.     

Bone marrow transplantation for advanced acute leukemia: a pilot study of high-energy total body irradiation, cyclophosphamide and continuous infusion etoposide

Leukemic relapse following bone marrow transplantation (BMT) for acute leukemia is the most common cause of treatment failure. Because a more intensive pre-transplant preparative regimen may prevent disease recurrence we have designed a novel intensive conditioning regimen for BMT using high-energy total body irradiation (total dose 850 cGy; energy 24 MV; midplane received dose rate 26 cGy/min; day -6) followed by cyclophosphamide (dose 50 mg/kg/day; schedule 2-h infusion; days -5, -4, -3) and continuous infusion high-dose etoposide (dose 500 mg/m2/day; schedule: 22-h infusion; days -5, -4, -3). Between February 1987 and December 1988, 45 patients with advanced acute leukemia received transplants using this regimen. Twenty-five purged auto-transplants were done for B-lineage (n = 18), T-lineage (n = 6) or biphenotypic (n = 1) acute lymphoblastic leukemia, with 12 in remission and 13 in relapse at the time of transplantation. Of these, nine had non-relapse deaths and 16 have relapsed between 1 and 19 months (median 3 months) following transplantation. Of note all the T-lineage patients relapsed including two transplanted in remission and five transplanted in relapse. Nineteen patients received histocompatible allogeneic transplants and one underwent syngeneic transplantation. Of seven patients with acute lymphoblastic leukemia transplanted in refractory relapse, three have had an overt relapse, three died of interstitial pneumonitis and only one survives disease free 15 months after transplantation. Of 13 patients with acute non-lymphocytic leukemia and variants (11 who were transplanted in relapse) three died without relapse, three have relapsed and seven survive disease free from 9 to 27 months (median 20 months) after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Piperazinedione plus total body irradiation: an alternative preparative regimen for allogeneic bone marrow transplantation in advanced phases of chronic myelogenous leukemia

Twenty-one patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in advanced phases were treated with piperazinedione (PIP), total body irradiation (TBI) and allogeneic bone marrow transplantation. Eleven were in blastic transformation, five were in accelerated phase, and five were in second chronic phase. The median age was 29 years (range, 13-41 years); there were 14 males. All patients but one were rendered aplastic by this regimen. Of these, 17 had hematologic engraftment, recovering granulocytes to 1.0 x 10(9)/l in a median of 28 days (range, 11-52 days). Three patients failed to engraft. Of those who engrafted, five relapsed and died of disease, one relapsed and died of a polymicrobial wound infection, nine patients died of treatment-related complications, including graft-versus-host disease, interstitial pneumonitis and sepsis, and one patient developed large-cell lymphoma 27 months after transplant and died of this 18 months later. One patient relapsed after 31 months died of polymicrobial sepsis at 37 months, and one patient remains disease-free at 54+ months. The 3-year survival rate was 14%. Survival at 1 year was related to having a spleen that did not extend beyond 2 cm below the left costal margin at the time of transplantation, and those with a large spleen at initial presentation relapsed more often. PIP-TBI with allogeneic bone marrow transplantation can induce durable remissions in a small proportion of patients in advanced phases of CML, but it is not superior to cyclophosphamide-TBI in this patient group.     

Unrelated bone marrow transplantation in two severe aplastic anemia patients preconditioned with a regimen of cyclophosphamide, antithymocyte globulin, and total body irradiation

We report our experiences with HLA-matched unrelated bonemarrow transplantation combining a preconditioning regimen of cyclophosphamide, antithymocyte globulin (ATG), and total body irradiation for two patients with severe aplastic anemia (SAA) who had already undergone repeated blood transfusions. Short-term methotrexate and cyclosporine were administered for graft-versus-host disease (GVHD) prophylaxis. Both patients achieved rapid engraftment within 3 weeks, furthermore, neither acute nor chronic GVHD developed. Our conditioning regimen appeared to be well-suited for unrelated bone marrow transplantation in heavily transfused SAA patients. However, both patients experienced bouts of fever about 20-30 and 40-50 days after transplantation, and it was difficult to differentiate whether they were affected by acute GVHD, cytomegalovirus (CMV) infections, or serum sickness. Because weakly positive CMV antigenemia was detected, both patients were given ganciclovir. Although their fever did not respond initially, it gradually subsided following the combined administration of prednisolone. These outcomes suggest it is essential that attention be devoted to the potential for serum sickness and the high risk of herpes virus infections, particularly by CMV, following the use of intensive preconditioning regimens that include ATG.     

Thiotepa,busulfan, and cyclophosphamide as a preparative regimen for marrow transplantation: Risk factors for early regimen-related toxicity

Summary One hundred twenty-seven adults with advanced hematologic malignancies received thiotepa 450–750 mg/m², busulfan 10 or 12 mg/kg, and cyclophosphamide 120 or 150 mg/kg as a preparative regimen for autologous (86 patients) or allogeneic (41 patients) marrow transplantation. Early regimen-related toxicity (RRT) was scored according to the Seattle toxicity grading system. Grade 1–4 RRT occurred in 94% of the patients. Grade 3–4 RRT was noted in 19 patients (9% of the autologous and 27% of the allogeneic marrow recipients) and included 6% hepatic, 5% pulmonary, 3% renal, 2% mucosal, 2% bladder, 2% cardiac, and 1% CNS toxicity at the grade 3 or 4 level. No patient experienced life-threatening or fatal gastrointestinal or cutaneous toxicity. A stepwise logistic regression analysis suggested that the higher busulfan dose, Zubrod performance status of 2 or 3, and ten or more previous cycles of chemotherapy were factors predictive of grade 3–4 RRT. The regimen-related mortality for all patients was 8% (95% Cl 4–14%). The incidence and spectrum of RRT for this novel drug combination are similar to those reported for the standard preparative regimens. Heavily pretreated patients with poor performance status receiving the higher busulfan dose have a higher incidence of severe or fatal RRT.     

Allogeneic bone marrow transplantation for leukemia following piperazinedione and fractionated total body irradiation

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty-one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno-occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI. © 1994 Wiley-Liss, Inc.     

Long-term follow-up of allogeneic bone marrow transplantation for patients with chronic phase chronic myeloid leukemia prepared with a regimen consisting of cyclophosphamide, cytarabine and single-dose total body irradiation conditioning

We evaluated long-term toxicities and outcomes in 96 patients with chronic phase chronic myeloid leukemia treated with a single bone marrow allograft regimen. Conditioning was cytosine arabinoside, cyclophosphamide (120 mg/kg) and single fraction total body irradiation (500 cGy). Median follow-up was 12.8 years (0.4-19.9 years). Graft failure occurred in one patient, nonfatal veno-occlusive disease in 13 patients (14%). Overall incidences of acute (a) and chronic (c) graft-vs-host disease (GVHD) were 77 and 63%. The 100-day and 1-year transplant-related mortality (TRM) were 1 and 9.2%, respectively, with no change through 5 years. Five- and 10-year event-free survival rates were 56 and 49%, overall survival (OS) rates 72 and 70%, respectively. Forty patients have relapsed: 8 cytogenetic (20%), 10 hematologic (25%) and 22 molecular (55%). Most have been salvaged with donor-leukocyte infusion, second transplants and/or imatinib therapy. Survival was worse for patients transplanted >2 years from diagnosis (10-year OS 56 vs 78%, P=0.01), for patients over 50 years old (10-year OS 44 vs 75%, P=0.05) and for patients without cGVHD (10-year OS 53 vs 86%, P<0.001). This regimen resulted in successful engraftment, low risk of TRM and long-term survival. In an era when imatinib is first line therapy, this regimen offers a potentially low-toxicity, highly successful alternative in the event of poor imatinib response.     

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy

Nine patients with advanced hematological malignancy were entered into a phase I study to determine the maximum tolerated doses of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) combined with a standard dose of total body irradiation (TBI). Ara-C was administered continuously over 36 h and two doses of CY were given at 24-h intervals during Ara-C administration. TBI was given as 2.0 Gy fractions on each of 6 consecutive days followed by bone marrow transplantation. The initial three patients received a total dose of 6048 mg/m2 of Ara-C and 84 mg/kg of CY, with two of three patients experiencing fatal toxicity. The next two patients received a total dose of 5040 mg/m2 of Ara-C and 70 mg/kg of CY and both experienced fatal toxicity. The next four patients received a total dose of 3024 mg/m2 of Ara-C, 56 mg/kg of CY; two patients had no toxicity but two had grade 4 (fatal) toxicity. Four of the six patients with fatal toxicity did not complete the TBI regimen and two of these did not receive marrow infusion. One patient is alive (greater than 547 days post-transplant) but has relapsed (day 305). It is concluded that phase I trials of regimens containing concurrent administration of Ara-C and CY may not be appropriate due to severe dose-independent toxicity as demonstrated in this study.     

High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation. Four patients are surviving 2-4 years post-transplant, three transplanted for IGL and one for HD. None of the patients transplanted for HGL survived. The result of this phase II study suggests that HDAC followed by TBI and marrow infusion offers no apparent advantage over cyclophosphamide + TBI for patients with relapsed advanced malignant lymphoma. Earlier transplantation currently is the only demonstrated method of achieving better results.     

Non-total body irradiation containing preparative regimen in alternative donor bone marrow transplantation for severe aplastic anemia

Using non-total body irradiation (TBI) containing preparative regimens, 13 patients with severe aplastic anemia (SAA) were transplanted from an alternative donor in a single institute. In total, 12 donors were unrelated volunteers and one was an HLA one-locus mismatched sibling. Median time from diagnosis of SAA to bone marrow transplantation (BMT) was 10.1 months (range, 1.6-180.1). Nine patients had received immunosuppressive treatment with ATG before BMT, while four had not. Preparative regimens consisted of cyclophosphamide plus ATG in nine patients, cyclophosphamide plus fludarabine in two patients, and cyclophosphamide plus fludarabine plus ATG in two patients. All patients received non-T-cell depleted bone marrow from the donor. Cyclosporine plus methotrexate were given for GVHD prophylaxis. All patients engrafted on a median of day 21 (range, 15-27). Grade III-IV acute GVHD developed in three (23%) of 13 patients and extensive chronic GVHD in four (31%) of 12 evaluable patients. With a median follow-up duration of 1138 days (range, 118-1553), 10 patients are alive with durable engraftment showing 74.6% (95% confidence interval, 49.5-99.7%) of survival rate. Cause of the deaths was CNS bleeding in one and chronic GVHD in two. In conclusion, non-TBI containing preparative regimen could ensure durable engraftment in alternative donor BMT for SAA and showed promising results.     

Allogeneic and syngeneic marrow transplantation following high dose dimethylbusulfan, cyclophosphamide and total body irradiation

Fifty-eight patients received an allogeneic or syngeneic marrow transplant following conditioning with high doses of dimethylbusulfan (DMB), cyclophosphamide (CY) and total body irradiation (TBI). Thirty-two patients had either chronic myeloid leukemia (CML) in accelerated phase or blast transformation, or acute leukemia after first relapse. The actuarial survival of these 32 patients at 3 years was 12% compared with 25% for a group of 206 patients with similar diagnoses prepared for transplantation with CY and TBI alone. This reduced survival was associated with a greater incidence of early non-leukemic deaths, in particular as a result of severe hepatic veno-occlusive disease. The incidence of leukemic relapse was not different in the two groups. Of 13 patients with CML in chronic phase who received syngeneic transplants following DMB, CY and TBI, nine are alive in hematologic and cytogenetic remission from 3.9 to 9.4 (median 6.2) years post-transplant.