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.     

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.     

Evaluation of dose homogenization and radiation carcinogenesis risk in total body irradiation for bone marrow transplantation

The purpose of this study is to report on the dose homogeneity in total body irradiated patients undergoing Bone Marrow Transplantation (BMT), and carcinogenic risk in surviving patients. Between 1987 and 2001, 105 patients received hyperfractionated (6 fractions in 3 days) 12 Gy Total Body Irradiation (TBI) in our institution with lateral opposed fields. All the patients had measurements with thermoluminiscence dosimetry (TLD100) placed on seven bilateral body sites in vivo, controlled by the randophantom measurements to verify reasonable dose homogeneity achievement. The comorbid effects in the whole TBI conditioning group with at least three months post BMT follow-up were noted and surviving patients who had a minimum 5-year and maximum 14-year follow-up (median 7.8 years) have been evaluated for carcinogenic radiation risk on the basis of tissue weighting factors as defined by ICRP 60. Reasonable dose homogeneity by lateral opposed beam TBI has been obtained in all 105 patients in whom lateral TLD100 measurement means were within +5% of the planned doses. Calculated carcinogenesis risk factor was 11.34% for males and 12.40% for females, and no second-cancer has been detected whilst radiation-induced 5 cataracts and 10 interstitial pneumonia comorbidities were noted. Dose homogenization can be well achieved for hyperfractionated lateral-beam TBI with acceptable comorbidities and estimated second-cancer risk is significant but relatively low compared to the risk from the clinical indications for TBI.     

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.     

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.     

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.     

Influence of total body irradiation on infections after autologous bone marrow transplantation.

Infectious complications were analysed in 50 consecutive autologous bone marrow transplant (ABMT) patients treated with high dose etoposide and melphalan, 30 of whom also received total body irradiation (TBI). Fever developed in 44 patients and bacteremia was documented in 13 (26%). Patients given TBI had increased susceptibility to bacteremia; 11 of 30 patients who received TBI had positive blood cultures, in contrast to two of the 20 who did not (p = 0.035). In addition, patients who received TBI had significantly more severe diarrhea (p = 0.037) when compared with those who received chemotherapy alone. Thirty-five patients treated with trimethoprim-sulfamethoxazole prophylaxis had a signficantly lower incidence of gram-negative bacteremia (p = 0.024). However, when those patients who received trimethoprim-sulfamethoxazole until neutrophil recovery were analysed alone, those who were also given TBI still had significantly more bacteremia (p = 0.047). Forty-seven patients with follow-up of more than 12 months are available for analysis of varicella zoster (VZV) infections. Of the 29 patients who received TBI, 11 (38%) developed VZV infections, in contrast to one of 18 patients (6%) treated with chemotherapy alone (p = 0.013). These results suggest that addition of TBI to the intensive therapy regimen for ABMT is associated with significantly more bacteremia and late VZV infections.     

Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation.

Growth was assessed during the first and second years following bone marrow transplantation (BMT) in 47 children treated by either busulfan plus cyclophosphamide (BU/CY) (n = 24) or cyclophosphamide plus fractionated total body irradiation (CY/TBI) (n = 23). Before transplant, the median height was only 0.2 SD below age- and sex-adjusted means (range, -2.5 to +3.0). Height was greater than 2.0 SD below normal in only three patients (6%). The pretransplant heights were comparable in the BU/CY and CY/TBI groups (-0.1 v -0.6 SD, P = .35). Following transplant, median 1- and 2-year heights were 0.7 and 0.9 SD below normal, respectively. Growth rates were 2.2 SD and 1.4 SD below normal during the first and second years, respectively. Growth rates were greater than 2.0 SD below normal in 24 of 47 (51%) at 1 year and in 12 of 31 (39%) at 2 years after transplant. Growth rates in patients treated with BU/CY were comparable to those treated with CY/TBI during both years: -2.5 versus -1.7 SD during the first year (P = .19, Wilcoxon), and -1.5 versus -1.1 SD during the second year (P = .61). Growth rates during the second year correlated with growth rates during the first year (r = .36, P = .046). Growth rates during the first year were lower in patients who had been given prior cranial irradiation, those who were near pubertal age at the time of transplant, and those who were transplanted for a disease other than acute lymphoblastic leukemia (ALL). During the second year, poor rates of growth were associated only with the use of corticosteroids after transplant.     

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     

Effectiveness and risks of total body irradiation for conditioning in the treatment of autoimmune disease with autologous bone marrow transplantation.

The results of experiments with the induced autoimmune diseases adjuvant arthritis and allergic encephalomyelitis in rats, which led to the discovery of the curative effect of autologous bone marrow transplantation following high-dose myeloablative treatment, are reviewed. The rationale is eradication of the autoreactive lymphocytes and memory cells, and the prevention of relapse due to transfer of lymphocytes with the autograft. Comparison of various conditioning regimens in the animal models indicates that a combination conditioning with low-dose total body irradiation (TBI) and high-dose cyclophosphamide is optimal. These findings were the basis for the conditioning currently employed in the treatment of polyarticular juvenile chronic arthritis (JCA) by the teams in Utrecht and Leiden, which consists of cyclophosphamide 50 mg/kg for 4 days, 4 Gy TBI and anti-thymocyte globulin (ATG). The use of TBI for the treatment of non-malignant disease is regarded as undesirable by many physicians in view of the risks, in particular, of growth inhibition in children and the induction of tumours. Experimental and clinical data show that a dose of 4 Gy does not cause significant inhibition of skeletal growth in infants. The risk of excess cancer due to TBI has been well established in quantitative terms and is compared with the expected risk of high-dose cyclophosphamide and the risk associated with the highly immunosuppressive regimens currently used for the treatment of JCA.     

Treatment of poor prognosis non-Hodgkin's lymphoma using cyclophosphamide and total body irradiation regimens with autologous bone marrow rescue

Twenty patients with poor prognosis non-Hodgkin's lymphoma received regimens which employed cyclophosphamide and total body irradiation followed by autologous bone marrow rescue. There were two toxic deaths. All 10 patients with residual disease prior to treatment achieved a complete remission. Ten patients survive disease free from 1.4 to 9.5 years and median survival exceeds 2.9 years. The actuarial 3-year disease-free survival is 50%. Treatment with cyclophosphamide and total body irradiation followed by autologous bone marrow infusion is an effective salvage regimen for poor prognosis lymphoma. Durable long-term remissions can be achieved.     

Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation.

Following the demonstration that adjuvant arthritis in rats can be cured with total body irradiation (TBI) and allogeneic or syngeneic bone marrow, the efficacy of autologous bone marrow was investigated in the experiments reported here. Bone marrow from arthritic rats, harvested at the same time that the recipients were irradiated, and real autologous bone marrow were found to be similarly effective as bone marrow grafts from naive syngeneic donors. Sublethal TBI with lower doses was less effective, but the highest tolerated doses of 8 Gy approached the effect of 9 Gy and bone marrow rescue. In contrast, partial body irradiation of either the affected limbs, or of the whole body except the limbs, resulted in only partial and temporary regression of the arthritis.     

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.     

Cytogenetic studies on recipients of allogeneic bone marrow transplants after fractionated total body irradiation

Cytogenetic findings from the bone marrow (BM) and the peripheral blood (PB) of nine consecutive patients after allogeneic bone marrow transplantation (BMT) for acute or chronic myelogenous leukaemia are reported. After a conditioning regimen consisting of cyclophosphamide and fractionated total body irradiation (TBI) given in five or six fractions of 2 Gy, persistence of host cells was detected in four out of seven cases with permanent engraftment. While one of these patients relapsed 4 months after host cells had been found in BM and PB, the other patients stayed relapse-free 124, 257 and 347 d after grafting. Before transplantation, the leukaemic cells in all three cases carried unique cytogenetic abnormalities giving us the opportunity to distinguish the leukaemic population from chromosomally non-aberrant cells thought to represent residual normal host cells. As the persisting host cells after BMT lacked any cytogenetic abnormalities, it is suggested that they were members of residual normal clones not involved in the leukaemic process.     

Recovery of immune functions in dogs after total body irradiation and transplantation of autologous blood or bone marrow cells

The restoration of immune functions was followed in dogs for 101 days after fractionated total body irradiation and autologous transfusion of peripheral blood leukocytes (PBL) or bone marrow (BM) cells. Median numbers of 0.9 X 10(5) granulocyte-macrophage progenitor cells per kilogram of body weight were transferred in either group of recipients. The following parameters recovered more rapidly in PBL recipients as opposed to BM recipients: total blood lymphocyte, T- and B-cell counts, serum levels of immunoglobulins IgM and IgA, in vitro blastogenic responses after stimulation with concanavalin A and pokeweed mitogen, and in vitro plasma cell formation after polyclonal B-cell activation with pokeweed mitogen with or without lipopolysaccharide. No major differences were noted for the restoration of serum IgG levels. Circulating lymphocyte and T-cell numbers remained subnormal for more than three months in both groups, whereas B-cell numbers and serum levels of IgA continued to be depressed in BM recipients only. Thus, autologous PBL restored immune functions more rapidly than did BM. Transplantation of PBL, alone or in addition to autologous BM, might also shorten the period of immunodeficiency after cytoreduction in a variety of malignancies in man.     

Specific cardiomyopathy caused by high dose cyclophosphamide immediately after bone marrow transplantation

An 11-year-old girl with CML in chronic phase was treated with allogeneic bone marrow transplantation (BMT). She had had no episode of heart disease, and her chest roentgenogram and electrocardiogram were within normal ranges. She had no anthracycline, but 120 mg/kg (2.01 g/m2/d x 2 days) of cyclophosphamide (CY) for conditioning of BMT. She suffered from an acute heart failure on 14 days after BMT and died 2 days later. Autopsy revealed "specific heart muscular disease" with apparent degeneration and necrosis of heart muscle cells. More than 30 fatal cases of CY cardiotoxicity after BMT have been reported, and most patients developed acute heart failure within 10 days after CY dosing. Goldberg et al. reviewed 14 cases of CY cardiotoxicity, and considered more than 1.55 g/m2/day to be the critical doses for the onset of fatal cardiomyopathy. This case was considered to be first case in Japan. CY cardiomyopathy is an early fatal complication of BMT when CY used for conditioning. The dosing schedule may be considered.     

The role of autologous bone marrow transplantation in the treatment of malignant disease

This short review of autologous bone marrow transplantation (ABMT) has a distinct clinical emphasis and concentrates particularly on adult acute leukaemia and lymphoma in which the greatest amount of current clinical experience lies. In the early part of the review we discuss how escalations of dose of chemoradiotherapy might allow ablation of both marrow-derived (leukaemia) and non-marrow-derived disease (lymphoma and solid tumour) provided that haemopoiesis is reintroduced into the host in the form of autologous marrow stem cells, and how cryopreservation techniques have allowed this to proceed. Whilst discussing ABMT in acute leukaemia we describe initial results possibly suggestive of an improvement on current consolidation/maintenance chemotherapy regimens but emphasise that we are dealing only with heterogeneous registry data and not randomised controlled trials. We also suggest that there is no useful data as yet as to the value of purging autologous acute leukaemia marrow. The lymphoma data is described which may suggest a useful role of high dose therapy with ABMT in relapsed disease—timing of ABMT may need to differ profoundly in HD from NHL. Current ABMT data in lymphoma suggests that local relapse at sites of previous disease remain the major problem and emphasises the difficulties of finding satisfactory ablative regimens and timing the selection of patients at particular points in the natural history of their disease. Finally, we emphasise that although solid tumours may numerically represent the largest group of potential candidates for ABMT, the picture in this area remains essentially one of failure to be able to ablate the underlying disease despite increments in chemoradiotherapy and ABMT.     

Treatment of adult T cell leukemia with mega-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation

A 43-year-old patient with adult T cell leukemia (ATL) was treated with mega-dose cyclophosphamide and total body irradiation (TBI) followed by bone marrow transplantation (BMT) from his HLA-identical sibling who was not a carrier of ATL virus. After BMT, ATL cells rapidly decreased and disappeared, and the engraftment of marrow was confirmed on day 20. The patient showed normal hematologic recovery. However, he died on day 205 with interstitial pneumonitis caused by cytomegalovirus infection. Neither autopsy findings nor serologic and cytologic examinations showed any evidence of ATL relapse after BMT. This pilot study suggests that mega-dose chemotherapy and TBI followed by allogeneic BMT should be considered for such treatment of ATL.     

Safe application of a 13-Gy split dose total body irradiation schedule prior to bone marrow transplantation

Two conditioning regimens for bone marrow transplantation for patients with acute lymphoblastic leukaemia were compared. Both regimens (VVRAPID and VVRAPID-X) incorporated the same cytotoxic chemotherapy but differed in the radiation dose; VVRAPID employed a single fraction of 10.5 Gy and VVRAPID-X employed 10.5 Gy followed 4 days later by a further dose of 2.5 Gy. The 13-Gy split-fraction schedule was well tolerated with no significant increase in infection or requirement for blood products. An increase in gastrointestinal toxicity occurred but responded to increased oral anti-diarrhoeal agents. Overall survival and relapse rates did not differ significantly between the two groups. There was a trend for the 13-Gy schedule to reduce the graft failure rate following T cell-depleted bone marrow transplants.