Hyperfractionated total body irradiation for T-depleted HLA identical bone marrow transplants

doi:10.1016/0167-8140(88)90246-0

Radiotherapy and Oncology

Volume 11, Issue 2, February 1988, Pages 113-118

https://doi.org/10.1016/0167-8140(88)90246-0 Get rights and content

Abstract

Twenty patients suffering from malignant hemopathies (mean age 31.7 years) were given hyperfractionated total body irradiation (TBI) (120 cGy/3 fractions per day: total dose = 1440 cGy/4 days) as conditioning for T-depleted HLA identical allogeneic bone marrow transplantation. At an average of 12 months (range of 4.5–22 months) follow-up there were two cases of early death and two cases (11%) of rejection. There were no cases of acute or chronic graft versus host disease (GVHD) nor cases of interstitial pneumonitis. The average time for durable engraftment was 22 days. Disease-free survival at 12 months was 65%. To improve the results and further reduce the percent of rejection, the authors propose intensifying the immunosuppressive conditioning by increasing the cyclophosphamide dose and that of TBI so that a total dose of 1560 cGy is reached.

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Cited by (9)

Radiobiological and clinical bases for total body irradiation in the leukemias and lymphomas
1995, Seminars in Radiation Oncology
In spite of the recent introduction of conditioning regimens consisting of chemotherapy alone, therapeutic total body irradiation (TBI) remains a powerful antileukemic and immunosuppressive tool in preparative regimens for bone marrow transplantation. However, the question of the “best” TBI schedule has not been answered. Available radiobiological and clinical data show that (1) the role of fractionation (or dose rate) on leukemia cell killing may vary with the leukemia type. Acute myeloid leukemia cells have been found to be insensitive or only slightly sensitive to fractionation, whereas chronic myeloid leukemia cells appear to be sensitive. Data are still controversial for acute lymphocytic leukemia and the non-Hodgkin's lymphomas; (2) the immunosuppressive effect of TBI is very fractionation sensitive; and (3) most normal tissues at risk are also highly sensitive to fractionation and dose rate. These data permit some cautious adaptations of the TBI schemes to the type of leukemia, use of T-cell-depleted donor marrow, and potential normal tissue toxicity. However, we still lack data concerning the precise intrinsic and fractionation radiosensitivity of the leukemia/lymphoma of a given patient. Recent improvements in leukemia-cell cultures allowing the generation of dose survival curves and the study of in vitro radiation-induced apoptosis (mainly for lymphomas) may soon provide radiation oncologists with the data to allow further refinement and individualization of TBI schedules.
Pulmonary complications of bone marrow transplantation: A comparison of total body irradiation and cyclophosphamide to busulfan and cyclophosphamide
1995, International Journal of Radiation Oncology, Biology, Physics
$Purpose$ : To retrospectively compare the acute and long-term pulmonary toxicities of total body irradiation and busulfan in bone marrow transplantation.
$Methods and Materials$ : From March through February 1991, 144 patients received high-dose therapy with cyclophosphamide plus either total body irradiation (TBI-CY) or busulfan (BU-CY) followed by bone marrow rescue. Treatment protocols were based on disease type. Cyclophosphamide dose was 120–200 mg/kg, given in 2–4 days. Total body irradiation was given as 12 Gy in four fractions over 4 days, or 14.4 Gy in eight fractions over 4 days. Busulfan dose was 16 mg/kg given over 4 days.
$Results$ : Seventy-nine patients were treated with TBI-CY and 65 patients with BU-CY. More patients in the TBI group had allogeneic transplants (40 vs. 18). Pulmonary events occurred in 48 patients, 19 in BU-CY and 9 in TBI-CY. Of the 58 patients with allogeneic transplants, 21 (36%) developed chronic graft-vs.-host disease (GVHD), and 10 of those patients developed pulmonary complications (including 2 with obliterative bronchitis and 1 with asthma). Interstitial pneumonitis (IP) occurred in 14 patients, 12 in the TBI-CY group and 2 in the BU-CY group. Cytomegalovirus and pneumocytis infections were associated with IP in 11 of those patients. Fatal idiopathic IP occurred in one patient in each of the TBI-CY and BU-CY groups. Multivariate analysis showed that only chronic GVHD and prior bleomycin use were significant predictors of intersitial pneumonitis: no difference was seen between TBI-CY and BU-CY.
$Conclusion$ : Pulmonary complications were most commonly associated with GVHD and prior bleomycin use. The incidence of cytomegalovirus or pneumocystis carinii pneumonitis was greater in the patients receiving the TBI regimen; fatal pulmonary complications were not significantly different between TBI and nonTBI regimens.
Single dose versus fractionated total body irradiation before bone marrow transplantation: Radiobiological and clinical considerations
1994, International Journal of Radiation Oncology, Biology, Physics
$Purpose$ : This present review is intended to evaluate the specific influence of fractionation of total body irradiation on the outcome of a subsequent bone marrow transplantation.
$Methods and Materials$ : Available experimental and clinical data on the influence of fractionation on leukemia cell killing, immunosuppression, and sparing of normal tissues were analyzed.
$Results$ : Review of available data shows: (a) The role of fractionation on leukemia cell killing may vary with the leukemia type. For acute nonlymphoblastic leukemia, a few experimental and several clinical studies show no or little fractionation effect; a 12–13 Gy fractionated scheme could, therefore, be more efficient than a conventional 10 Gy single dose total body irradiation. For chronic myelogenous leukemia, some sensitivity to fractionation is suggested, so that an increase in total or fractional dose may be necessary in fractionated schemes to equate the efficacy of a 10 Gy single dose. For acute lymphoblastic leukemia, a high fractionation sensitivity was observed for some leukemic cell lines in vitro, without undisputable clinical confirmation for the moment. (b) Numerous experimental studies have demonstrated that the immunosuppressive effect of total body irradiation, a major determinant of engraftment, is highly fractionation sensitive. In humans, high rates of graft failures have been reported when T-cell depletion of the graft was associated to fractionated total body irradiation schedules. (c) A large amount of radiobiological and clinical data have demonstrated that late radiation-induced injuries to normal tissues and organs are highly fractionation sensitive. However, in a context of total body irradiation for bone marrow transplantation, the number of other determinants of normal tissue damage makes it difficult to demonstrate a clear-cut advantage of fractionated over single dose scheme, with a possible exception for children.
$Conclusions$ : In 1994, available data suggest that very cautious attempts could be made to adapt total body irradiation schedules to the potential normal tissue toxicity, T-cell depletion, and to the type of leukemia.
Interstitial pneumonitis after hyperfractionated total body irradiation in hla-matched t-depleted bone marrow transplantation
1992, International Journal of Radiation Oncology, Biology, Physics
Interstitial pneumonia is one of the major causes of morbidity and mortality after bone-marrow transplantation. We here report a series of 58 patients suffering from hematological malignancies who received HLA-matched T-lymphocyte depleted bone-marrow transplants between July 1985 and January 1990. Interstitial pneumonia occurred in 7/58 patients (12%) and was fatal in six. Three different pre-bone-marrow transplantation conditioning regimens were employed. Total body irradiation was delivered according to a hyperfractionated scheme of 12 fractions given three per day 5 hr apart for 4 days. Twenty-three patients received 36 mg/Kg procarbazine, 1275 UL/Kg antithymocite globulin, 14.4 Gy hyperfractionated total body irradiation and 120 mg/Kg cyclophosphamide. Only one patient developed interstitial pneumonia, but two rejected the graft and 10 relapsed. As a consequence, the total hyperfractionated scheme was increased to 15,6 Gy, cyclophosphamide to 200 mg/Kg, antithymocite globulin to 3400 UL/Kg and procarbazine eliminated. There were three cases of interstitial pneumonia, no rejection and four relapses in the 17 patients who received this regimen. In the last 18 patients hyperfractionated total body irradiation was reduced to 15 Gy, cyclophosphamide to 100 mg/Kg, and 10 mg/Kg of the myeloablative agent thiothepa added to enhance the cytoreductive effect without significantly increasing extramedullary toxicity. Three cases of interstitial pneumonia, one relapse but no rejection were recorded. Our results demonstrate that the absence of graft-versus-host disease due to T-cell depletion, and radio-chemotherapy doses and schedules used for the conditioning regimen each contributed to reducing the risk of interstitial pneumonitis. Hyperfractionated total body irradiation therefore, seems to play an important role in lowering the incidence of this complication.
Lung damage following bone marrow transplantation after hyperfractionated total body irradiation
1991, Radiotherapy and Oncology
From July 1985 to December 1989, 72 evaluable patients aged between 6 and 51 (median age 27 years) suffering from haematological malignancies received an allogeneic bone marrow transplant (BMT) depleted of T-lymphocytes to reduce the risk of graft-versus-host-disease (GvHD); 57 were matched and 15 mismatched. Three different conditioning regimens were used in an effort to enhance cytoreduction without increase extramedullary toxicity. Mismatched patients were treated with more immunosuppressive regimens. Total body irradiation (TBI) was given in three doses per day, 5 h apart, over 4 days for a total of 12 fractions. The dose to the lungs was 14.4, 15.6 and 9 Gy according to the conditioning regimen. The incidence of interstitial pneumonia (IP) was 12.3% in matched and 46.7% in mismatched patients. Our results seem to indicate that lung toxicity is correlated with the intensity of the conditioning regimen, the stage of disease and, in mismatched patients, with the degree of human leucocyte antigen (HLA) disparity and the poor post-BMT reconstitution, rather than the radiotherapy dose delivered to the lungs. On the contrary, the hyperfractionated scheme adopted, the absence of GvHD and, perhaps, the post-TBI administration of cyclophosphamide all seem to have contributed to the low incidence of IP in our matched patients.
Total body irradiation for bone marrow transplantation: The Memorial sloan-Kettering cancer center experience
1990, Radiotherapy and Oncology
In May 1979, Memorial Sloan-Kettering embarked on a programme of hyperfractionated TBI (HFTBI), 1320 cGy in 11 fractions over 4 days with partial lung shielding (1 HVL), followed by cyclophosphamide (60 mg/kg/d × 2d) for cytoreduction prior to allogeneic bone marrow transplantation (BMT). Anterior and posterior chest wall electron “boosts” were given to the areas blocked (600 cGy in 2 fractions) on the last two days of treatment. Since then, we have treated over 600 patients with HFTBI, the majority for allogeneic BMT. Several modifications have occurred over the years. We have added a “boost” electron dose of 400 cGy to the testes in all male leukemic patients; this reduced testicular relapses from a rate of 14% (4/28) to 0%. In an attempt to increase engraftment of T-depleted BMTs, we added one additional fraction; since our present dose/fraction was also increased to 125 cGy, we now deliver a total dose of 1500 cGy in 12 fractions over 4 days for allogeneic transplants.
Tolerance to HFTBI has been excellent relative to the single dose (SD) regimen utilised prior to May, 1979. The incidence of fatal interstitial pneumonitis (IP) decreased from 50% in the SD regimen to 18% after the introduction of HFTBI. In children, the incidence of IP was only 4% with HFTBI. With the introduction of T-depleted marrows, fatal IP in adults has decreased also, e.g. to < 10% in CML patients. With conventional BMT after HFTBI, relapse at 5 years has been exceedingly low (e.g. in children, 13% for ALL, 2nd remission and 0% for AML, 1st remission) and engraftment has been 100%. With matched T-depleted BMT, rejections have occurred in 15% overall; the incidence of graft failure has not been reduced by the higher dose of HFTBI. Relapses in this setting are equivalent to relapses with conventional BMT for AML, but appear to be increased for ALL. Radiobiological findings related to HFTBI will also be discussed.

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Hyperfractionated total body irradiation for T-depleted HLA identical bone marrow transplants

Abstract

Int. J. Radiat. Oncol. Biol. Phys.

Lancet

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

Blood

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Les complications pulmonaires des irradiations corporelles totales avant greffe de moelle

J. Eur. Radiother.

La irradiazione corporea totale per il trapianto di midollo osseo

Radiol. Med.

Biological problems of total body irradiation

J. Eur. Radiother.

Trapianto di midollo osseo allogenico neltrattamento della leucemia

Arg. Oncol.