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.     

High-dose cytosine arabinoside and etoposide with total body irradiation as a preparatory regimen for allogeneic hematopoietic stem-cell transplantation in patients with acute lymphoblastic leukemia

One approach to improving the outcome of allogeneic hematopoietic stem-cell transplantation for acute lymphoblastic leukemia (ALL) is to intensify the pretransplant conditioning regimen without increasing toxicity. We used an intensified conditioning regimen consisting of high-dose cytosine arabinoside (3 g/m(2) twice daily i.v. for 3 consecutive days, total six doses), high-dose etoposide (1 g/m(2) once daily i.v. during the first 2 days) and total body irradiation (TBI) (HDACE-TBI) in ALL patients. We retrospectively analyzed 21 patients treated with HDACE-TBI, of whom 18 were in complete remission (CR) and three were in non-CR at transplantation. Although gastrointestinal toxicities were common, critical regimen-related toxicities were not seen in any patients. One patient demonstrated veno-occlusive disease, which could be controlled conservatively. The disease-free survival rate of 18 patients in CR at transplantation was 61%. These results demonstrate that the HDACE-TBI combination regimen is a feasible alternative to other preparatory regimens and does not increase the regimen-related toxicity.     

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.     

Fractionated total body irradiation in marrow transplantation for leukaemia

Thirty consecutive patients with leukaemia were prepared for bone marrow transplantation (BMT) with cyclophosphamide (CY) 120 mg/kg followed by total body irradiation (TBI). TBI was delivered in a single dose (sTBI) of 10 Gy, at a dose rate of 0.06-0.08 Gy/min, or in fractionated doses (fTBI) of 3.3 Gy/d, on each of 3 consecutive days, at the same dose rate. Lung shielding was adopted for all patients, in order to obtain a homogeneous dose delivered to the lung and at midline. The first 12 patients were prepared with sTBI and the following 18 with fTBI. Several variables (remission status, mode of irradiation, prevention of graft versus host disease (GvHD) with methotrexate (MTX) or cyclosporin A(CyA) were then analysed for their influence on (a) incidence and mortality of GvHD, (b) incidence and mortality of interstitial pneumonia (IP), (c) 100-d survival, and (d) relapses. Our data suggest that fTBI is the single most important factor associated with a lower incidence of IP (P = 0.002), a lower mortality from GvHD and IP (P = 0.03 and 0.001) and a better 100-d survival (P = 0.03). Remission status had no significant influence on GvHD, IP and acute mortality. When compared to MTX, the use of CyA was associated with less GvHD and IP, but when only patients in remission given fTBI were analysed, this was no longer true. Relapses were mostly influenced by the remission status of the patient at transplant (P = 0.001). Although this is not a randomized study, our data suggest that fTBI can reduce the acute risks of marrow transplantation in leukaemia.     

High-dose cytosine arabinoside therapy for refractory leukemia

Fifty-seven patients with refractory acute leukemia were treated with high-dose cytosine arabinoside to establish the maximum tolerated dose and duration and to determine the antileukemic activity. The maximum tolerated regimen was found to be 3 g/sq m every 12 hr for 6 days. At this dose, nonhematologic toxicity was limited to conjunctivitis in approximately half of the patients, and liver toxicity (transient elevations in transaminase, alkaline phosphatase, or bilirubin) was frequently observed, but neither was dose-limiting. Extending the duration of treatment to 8 days resulted in excessive diarrhea and skin toxicity (painful erythema with bullae), while increasing the dose to 4.5 g/sq m q. 12 hr for 6 days resulted in severe cerebellar toxicity. Myelosuppression was severe, but was not related to the intensity of treatment; granulocyte recovery occurred a median of 28 days (range 22- 40 days) after initiating therapy, and platelet recovery occurred after a median of 25 days (range 16-41 days). Antileukemic activity was evaluable in the 46 patients who survived at least 3 wk. Complete remissions were obtained in 1 of 6 patients with chronic myelogenous leukemia (CML) in accelerated phase and 1 of 3 acute lymphoblastic leukemia (ALL) patients. A more detailed analysis of response was possible for the 37 evaluable patients with acute nonlymphoblastic leukemia: 70% of these patients responded, with 51% complete remissions. The median unmaintained response was 4 mo (range 2-26+ mo). The complete response rate was higher in patients who received at least 12 doses of high-dose cytosine arabinoside compared to shorter regimens [17/28 (61%) versus 2/9 (22%), p less than 0.05]. Resistance to cytosine arabinoside in conventional doses was documented in 11 patients, 5 of whom responded (2 complete remissions) to high-dose regimens. We conclude that high-dose cytosine arabinoside in the maximally tolerated regimen of 3 g/sq m every 12 hr for 6 days has substantial antileukemic activity in patients refractory to standard therapy. Durable unmaintained remissions can be achieved, even in patients who fail to respond to cytosine arabinoside in conventional doses.     

High-dose cytosine arabinoside for acute nonlymphocytic leukemia

Eighteen patients with acute nonlymphocytic leukemia (ANLL), aged 17-73 years, were treated with high-dose cytosine arabinoside (HD-Ara-C) using 3 g/m2 IV q 12 hours X 12 doses. Seven patients were treated for relapse and four (57%) obtained a complete remission with a median duration of 19.5 weeks. In nine patients, refractory to conventional chemotherapy, no complete responders were observed. Treatment failure was most commonly due to drug resistance. Two elderly patients with ANLL not previously exposed to chemotherapy died during the initial induction. Recent data on the HD-Ara-C experience in ANLL are presented and compared with this study.     

High-dose cytosine arabinoside. Active agent in treatment of non-Hodgkin's lymphoma

Seventeen extensively pre-treated patients with non-Hodgkin's lymphoma in relapse were treated with high-dose cytosine arabinoside given at a dose of 3 g/m2 on a 12-hour basis for two to eight doses per course. Seventy percent of patients (12 of 17) showed response with this regimen, including three patients who achieved a complete response. The time to response was quite rapid, occurring between three and 14 days, with median duration of complete responses of 12 weeks and of all responses, five weeks. Toxicity was acceptable, including predictable myelosuppression and thrombocytopenia, occasional drug fever, infrequent conjunctivitis and dermatitis, and no central nervous system toxicity. The dramatic, albeit short-lived, responses to high-dose cytosine arabinoside in this refractory population suggest that it is an active agent against non-Hodgkin's lymphoma and should be further evaluated.     

High-dose cytosine arabinoside and fractionated total-body irradiation: an improved preparative regimen for bone marrow transplantation of children with acute lymphoblastic leukemia in remission

Twenty children with acute lymphoblastic leukemia in second (18 patients) or third (two patients) complete remission after bone marrow relapse received allogeneic bone marrow transplants from histocompatible sibling donors. The preparative regimen for marrow transplantation consisted of 12 doses of 3,000 mg/m2 cytosine arabinoside twice daily for six days followed by 1,200 cGy total-body irradiation (six doses of 200 cGy twice daily for three days). The preparative regimen was well tolerated, and all patients showed marrow engraftment promptly. Twelve patients are alive in complete remission 12+ to 79+ months posttransplant; eight patients are over 48 months posttransplant. Six patients died 1 to 9 months posttransplant of nonleukemic causes: (two each of graft-v-host disease, interstitial pneumonitis, and infection). Two patients developed recurrent leukemia at 15 and 30 months posttransplant. Both have died at 19 and 36 months posttransplant. Life table analysis reveals an actuarial survival and event-free survival rate of 58% and a marrow relapse rate of 17%. These results suggest that high-dose cytosine arabinoside and fractionated total-body irradiation is a relatively nontoxic and highly effective preparative regimen for allogeneic bone marrow transplantation for acute lymphoblastic leukemia that deserves further evaluation.     

Bone marrow transplantation for acute lymphocytic leukemia utilizing total body irradiation followed by high doses of cytosine arabinoside: lack of superiority over cyclophosphamide-containing conditioning regimens

The efficacy of a pre-bone marrow transplantation (BMT) preparative regimen consisting of single, high dose rate total body irradiation followed by 12 courses of high dose cytosine arabinoside (Ara-C) over 6 days with allogeneic or autologous rescue was studied in 68 consecutive patients with poor risk acute lymphocytic leukemia (ALL). Toxicity associated with the above preparative regimen included conjunctivitis in the majority of patients, severe gastrointestinal symptoms in seven patients (10%), skin desquamation in four patients (6%), and interstitial pneumonitis of unknown etiology in two patients (3%). One patient died from a 'capillary leak' syndrome that may have been attributable to Ara-C toxicity. With a follow-up of 1.1-4.3 years, the estimated survival is 21% (95% confidence interval, 10-32%), with a disease-free survival of 18% (8-28%) and an estimated relapse rate of 75% (62-88%) at 3 years. These results are not significantly different from overall outcome in 105 patients treated previously at this same institution with cyclophosphamide-containing preparative regimens (31% (22-40%) estimated survival, 29% (20-38%) disease-free survival, and an estimated relapse rate of 63% (52-74%) at 3 years), especially when results are stratified based on allogeneic versus autologous BMTs. Although efficacious for a minority of patients with poor risk ALL, a pre-BMT preparative regimen consisting of total body irradiation followed by high doses of Ara-C did not improve long-term survival over more conventional preparative regimens consisting of cyclophosphamide and total body irradiation. Future strategies may need to investigate novel approaches for reducing leukemic relapse rates in patients with ALL undergoing bone marrow transplantation.     

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.     

Optimal protocol for total body irradiation for allogeneic bone marrow transplantation in mice

We have previously demonstrated, using chimeric resistant MRL/lpr mice, that a fractionated total body irradiation (FTBI) (5 Gy x 2 with a 4 h interval on the day before allogeneic bone marrow transplantation (BMT)) is the best conditioning regimen for the treatment of autoimmune diseases in radiosensitive MRL/lpr mice. In the present study, using various standard strains of mice (not radiosensitive mice), we explore the best protocol for irradiation (doses and intervals) as the conditioning regimen for allogeneic BMT. Recipient mice were exposed to various irradiation regimens: a single total body irradiation (TBI) of 9.5 or 12 Gy and FTBI of (5+5) Gy to (7+7) Gy with a 1 to 24 h interval. The method generally utilized for humans ((2+2) Gy with a 4 h interval for 3 days (total 12 Gy)) was also used. One day after the last irradiation, donor BMCs from BALB/c, C3H, or C57BL/6 (B6) mice were transplanted into C3H or B6 mice. The irradiation protocol of (2+2) Gy for 3 days was found to be insufficient to enable the complete removal of recipient immunocompetent cells, since donor-reactive T cells were observed in the recipient spleens and many recipient-type NK and CD4(+) cells were also detected in the recipient hematolymphoid tissues. In all the combinations, the highest survival rate was achieved in the recipients irradiated with (6+6) or (6.5+6.5) Gy with a 4 h interval. In the surviving mice, the hematolymphoid tissues had been fully reconstituted with donor cells.     

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)     

Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia.

We report successful pregnancies in two young women (aged 24 and 20 years) following allogeneic bone marrow transplantation (BMT) for acute non-lymphoblastic leukaemia. Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI, 12 Gy) in 2 Gy fractions once daily for 6 days or twice daily for 3 days. Graft-versus-host disease prophylaxis was with methotrexate alone. Both women were amenorrhoeic after BMT and gonadal testing indicated hypergonadotrophic hypogonadism. Both women had normal pregnancies (2 years and 5 years after BMT) resulting in normal healthy infants. Previously successful pregnancy has been reported after TBI in three women in whom the TBI dose was less than 8 Gy. Our cases illustrate that normal outcome of pregnancy is possible at even higher doses of TBI.     

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.     

High-dose cytosine arabinoside and mitoxantrone in previously-treated acute leukemia patients

35 patients with refractory or relapsed acute leukemia received salvage chemotherapy using high-dose cytosine arabinoside 2 g/m2 intravenously for 3 hours every 12 h, in 8 doses, followed by continuous infusion of mitoxantrone 12 mg/m2/day for 2 d. 9 patients had acute myeloblastic leukemia (AML), (4 relapsed, 5 refractory), 20 had acute lymphoblastic leukemia (ALL) (11 relapsed, 9 refractory) and 6 had chronic myelogenous leukemia (CML) in the blastic phase (BP). 4 out of 9 AML and 16 out of 20 ALL achieved complete remission. Median survival was 6 months for all patients and 10 months for responders. A short (1.5 months) chronic phase was achieved in 3 patients with CML. The main toxic effect was hematologic. A pharmacokinetic study was performed on mitoxantrone. No correlation was found with clinical response. The combination of mitoxantrone and ara-C is an effective antileukemic regimen, especially in ALL.     

A controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor after total body irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for acute lymphoblastic leukemia or malignant lymphoma.

Infections during granulocytopenia are major complications of autologous bone marrow transplantation (ABMT). Since recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) has proved to accelerate bone marrow recovery after cytostatic chemotherapy, we studied its effects on hematopoietic regeneration and on infectious complications after total body irradiation (TBI) and high-dose chemotherapy followed by ABMT. Eighty-one patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) or with non-Hodgkin's lymphoma (NHL) in CR or partial remission were randomized in a double-blind, placebo-controlled trial. They received either rhuGM-CSF 250 micrograms/m2 (Escherichia coli-derived) daily by continuous infusion after ABMT, or placebo. Treatment was continued until the neutrophil counts reached greater than 500/microL for 1 week. The maximum treatment duration was 30 days. Thirty-nine patients in the rhuGM-CSF group and 40 patients in the placebo group were evaluable. The median time needed to reach a neutrophil count of 500/microL was 15 days with rhuGM-CSF and 28 days with placebo (P = .0001). Bacterial infections occurred in 14 (35.9%) of the patients with rhuGM-CSF and in 25 (62.5%) of the patients given the placebo (P = .024). Nine of the 14 bacterial infections in the rhuGM-CSF group and 20 of the 25 infections in the placebo group were diagnosed within the first 10 days after ABMT. Capillary leakage and a reversible fluid retention were seen in five of the rhuGM-CSF-treated patients. Patients treated with rhuGM-CSF had lower serum protein and albumin levels than patients in the placebo group. There was no statistically relevant difference in overall survival between the two groups (P = .47). Relapse occurred in 14 (34%) patients with rhuGM-CSF and in 18 (45%) patients with placebo. We conclude that continuous infusion of rhuGM-CSF after ABMT accelerates the regeneration of granulocytes and reduces the number of bacterial infections.     

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.     

Gastrointestinal decontamination of dogs treated with total body irradiation and bone marrow transplantation

Procedures for total and selective gastrointestinal decontamination of dogs are described. The selective procedure removed only Gram negative aerobic bacteria, yeast and fungi. Dogs receiving total decontamination were less susceptible to the GI syndrome following total body irradiation (TBI) than dogs receiving conventional care. After TBI and allogeneic bone marrow transplantation, serum albumin levels decreased in conventional animals, but remained normal in totally or selectively decontaminated animals. Exogenous infections occurred frequently in both irradiated, and totally decontaminated animals, but were absent in selectively decontaminated animals. Endogenous infections after total body irradiation were prevented only by total decontamination. Endogenous infections occurred in selectively decontaminated animals, but with milder clinical symptoms than in conventional animals. Appearance of donor type leukocytes and serum gamma globulin was slower in decontaminated animals than in conventionally treated controls. Acute graft versus host disease caused by a limited number of lymphocytes of a DLA identical littermate donor were prevented by selective gastrointestinal decontamination. Complications due to late immune reconstitution obscured the effect of decontamination on delayed graft versus host disease.