Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.     

Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias

The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ((131)I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether (131)I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received (131)I-M195 or (131)I-HuM195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90-120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272-1470 cGy. The median survival was 4.9 months (range 0.3-90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.     

131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.     

Analysis of pulmonary function in leukemia patients after bone marrow transplantation: effects of prior chemotherapy

To evaluate the effects of prior chemotherapy on pulmonary function after bone marrow transplantation(BMT), pulmonary function tests were performed prior to and after BMT on 7 acute leukemia (AL) and 13 chronic myelogenous leukemia (CML) patients given with CY (60 mg/kg x 2 days), total body irradiation (3 Gy x 4 days, 10 cGy/min), and CyA plus short-term MTX. No patient had graft-versus-host disease or lung complications. Pulmonary function after BMT did not deteriorate in the AL patients; however, both %Vital Capacity(%VC) and DL/VA decreased significantly in the CML patients (%VC before BMT: 112.1 +/- 11.5%, after BMT: 93.7 +/- 9.4%; DL/VA before BMT: 79.2 +/- 14.6%, after BMT: 54.1 +/- 10.6%). Although prior regimens of busulfan (BU) or interferon (IFN) were equal risk factors for decreased %VC after BMT, decreases in DV/VA were more significant in CML patients who received IFN. CML patients, especially those who have received BU or IFN, should be carefully monitored for pulmonary function to prevent respiratory failure after BMT.     

Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens

To compare the outcome of hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) conditioned with two different regimens: (1) single dose of VP16 (60 mg/kg over 4 h) and total body irradiation (TBI; 1200 cGy, in six fractions) or (2) Cyclophosphamide 50 mg/kg over 1 h daily for 4 days followed by the same dose of TBI. One hundred and seven children with ALL received fully matched HSCT from 1990 to 2003 in the Hospital for Sick Children, Toronto. All received cyclosporin A and a short course of methotrexate for graft-versus-host disease (GVHD) prophylaxis. The VP16 group, there were 36 matched related donor transplants (MRD) and 26 matched unrelated donor transplants (MUD), and in the cyclophosphamide group there were 23 MRD and 22 MUD transplants. Neutrophil engraftment occurred at a median of 18 and 17 days for the VP16/TBI and the CY/TBI groups, respectively. The 3 year event-free survival and overall survival were 47 +/- 7 and 55 +/- 7% for those receiving VP16/TBI, and 51 +/- 8 and 53 +/- 8% for the CY/TBI group. There were no significant differences in the prevalence of acute or chronic GVHD and transplant-related mortality between the two groups. Both VP16/FTBI and CY/FTBI regimen are equally effective regimens.     

In vitro and in vivo radiation resistance associated with CD3 surface antigen expression in T-lineage acute lymphoblastic leukemia.

The radiobiologic features of primary clonogenic blasts (referred to also as T-lineage leukemic progenitor cells) from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia (ALL) patients were analyzed. Intrinsic radiation sensitivity differed substantially among primary clonogenic blasts from 34 newly diagnosed patients. The mean D0 (37% dose slope), SF2 (surviving fraction at 200 cGy), and alpha values (initial slope of the survival curve) were 141 +/- 15 cGy, 0.31 +/- 0.04, and 0.630 +/- 0.093 Gy-1, respectively. Among newly diagnosed cases, nine had SF2 values of greater than or equal to 0.50 and alpha values of less than or equal to 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic blasts using the multitarget and linear quadratic models of cell survival. Of these nine radiation resistant cases, seven were CD3+. Furthermore, the mean D0 (162 +/- 20.8 cGy) and SF2 (0.377 +/- 0.057) values for the 20 CD3+ cases were significantly higher than the D0 (108.6 +/- 18.2 cGy) and SF2 (0.204 +/- 0.051) values for the 14 CD3- cases (P less than or equal to .05). Thus, clonogenic blasts from CD3+ newly diagnosed T-lineage ALL patients were more resistant to radiation than clonogenic blasts from CD3- newly diagnosed T-lineage ALL patients. Nineteen T-lineage ALL patients received autologous bone marrow transplants during complete remission. Pretransplant conditioning consisted of total body irradiation (TBI) combined with high-dose chemotherapy. Primary clonogenic blasts from patients who relapsed after bone marrow transplantation (BMT) displayed a particularly high degree of intrinsic radiation resistance with a mean D0 value of 333 cGy and an alpha value of 0.112 Gy-1. The expression of CD3 antigen appeared to predict the outcome of relapsed T-lineage ALL patients undergoing autologous BMT after TBI plus high-dose chemotherapy. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 60% +/- 22% (mean relapse - free interval = 1.6 +/- 0.7 years) for CD3- patients and 0% +/- 0% (mean relapse - free interval = 0.2 +/- 0.0 years) for CD3+ patients (P = .002). Furthermore, the mean percentage of CD3-positive leukemic marrow blasts at presentation or relapse before BMT was significantly lower than the mean percentage of CD3-positive leukemic marrow blasts at relapse after BMT. Notably, in cultured leukemic bone marrow specimens from newly diagnosed as well as relapsed patients, colony blasts surviving in vitro radiation expressed CD3 more vividly than did colony blasts in unirradiated cultures.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of Radiation Dose Rate and Lung Dose on Interstitial Pneumonitis after Fractionated Total Body Irradiation: Acute Parotitis May Predict Interstitial Pneumonitis

This study evaluated patients for the influence of the dose rate and lung dose of fractionated total body irradiation (TBI) in preparation for allogeneic bone marrow transplantation (BMT) on the subsequent development of interstitial pneumonitis (IP). Sixty-six patients at our institute were treated with TBI followed by BMT. All of the patients received a total TBI dose of 12 Gy given in 6 fractions over 3 days and were divided into 3 groups according to the radiation dose rate and lung dose: group A, lung dose of 8 Gy (n = 18); group B, lung dose of 12 Gy at 8 cGy/min (n = 25); and group C, lung dose of 12 Gy at 19 cGy/min (n = 23). The overall survival rate, the cumulative incidence of relapse, and the cumulative incidence of IP were evaluated in relation to various potential indicators of future IP. There were no significant differences in survival and relapse rates between patient group A and combined groups B and C. Clinically significant IP occurred in 13 patients. The cumulative incidence of IP was significantly higher in patients who developed acute parotitis as indicated by either an elevation in the serum amylase level or parotid pain of grade 1 to 2. There was no difference in IP incidence among groups A, B, and C. There was no significant difference in IP incidence between lung dose values of 8 Gy (with lung shielding) and 12 Gy (without lung shielding) and between dose rate values of 8 cGy/min and 19 cGy/ min, at least when TBI was given in 6 fractions. The presence of acute parotitis during or just after TBI may be a predictor of IP.     

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.     

Marrow transplantation for acute nonlymphoblastic leukemia in first remission: toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation

Seventy-five patients with acute nonlymphoblastic leukemia (ANL) in first remission were treated with cyclophosphamide, 60 mg/kg on each of two consecutive days followed by total body irradiation (TBI) at an exposure rate of 4-6 cGy/min from two opposing 60Co sources. The first 22 patients were given 9.2 Gy of TBI as a single dose. Subsequently 53 patients were randomized to receive either 10 Gy single dose TBI (n = 27) or 6 x 2 Gy fractionated TBI (n = 26). All patients received marrow transplants from HLA-identical siblings and all had sustained engraftment. Patients given 10 Gy of TBI had more early toxicity, especially veno-occlusive disease of the liver, than patients given 9.2 or 6 x 2 Gy of TBI. Idiopathic interstitial pneumonitis appeared to be more frequent in patients given 9.2 or 10 Gy single-dose TBI than in patients given 6 x 2 Gy fractionated TBI. Patients have now been followed from 5 to 9 years. Survival (+/- 95% confidence limits) at 5 years is 54 +/- 31% among patients given 9.2 Gy single dose TBI, 33 +/- 31% among patients given 10 Gy single dose TBI, and 54 +/- 26% among patients given 6 x 2 Gy fractionated TBI (P = 0.04). These results indicate that about half the patients with ANL transplanted while in first chemotherapy-induced remission can be expected to become long-term survivors.(ABSTRACT TRUNCATED AT 250 WORDS)     

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

Thirty-seven patients with advanced hematologic malignancy were entered into a phase I study designed to define a maximum tolerable dose (MTD) of etoposide (VP-16) and cyclophosphamide (CY) combined with 12 Gy fractionated total body irradiation (TBI) as preparation for marrow transplantation from an HLA-identical sibling (n = 13) or with cryopreserved autologous marrow (n = 24). Dose levels ranged from 36 mg/kg of VP-16 combined with 67 mg/kg of CY to 52 mg/kg of VP-16 combined with 103 mg/kg of CY followed by 12 Gy TBI. The MTD for allogeneic marrow recipients was 36 mg/kg of VP-16 + 52 mg/kg of CY followed by 12 Gy TBI and for autologous marrow recipients 44 mg/kg of VP-16 + 103 mg/kg CY followed by 12 Gy TBI. Pulmonary and liver toxicities were dose limiting. All of 31 evaluable patients transplanted in relapse achieved a complete remission. However, in all but three of these patients the disease relapsed 28-899 (median 110) days post-transplant. Currently, six of 24 autologous marrow recipients are surviving, three in remission 256, 340 and 764 days post-transplant. None of 12 allogeneic marrow recipients have survived. In conclusion, a preparative regimen combining 44 mg/kg of VP-16 + 103 mg/kg CY followed by 12 Gy TBI is well tolerated by autologous marrow recipients and 36 mg/kg VP-16 + 67 mg/kg CY followed by 12 Gy TBI is well tolerated by allogeneic marrow recipients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclophosphamide-induced enhancement of stem cell recovery from whole-body irradiation is radiation dose-dependent

Although the enhancement of CFU-S recovery by CY pretreatment has been described for combinations of TBI greater than 4 Gy, no information exists as to whether such enhancement is operative at lower TBI doses (less than 3 Gy). B6D2F1 mice received intraperitoneal injections of CY (2 and 5 mg/mouse) at various time intervals prior to 2, 5 or 9 Gy TBI. The control group received the same dose of TBI without CY pretreatment. Six days after TBI, we determined the femoral content of CFU-S. Administration of 5 mg CY per mouse 3 days prior to 5 or 9 Gy TBI enhanced recovery of CFU-S with a substantial increase in CFU-S of 3- and 30-fold over control, respectively. In contrast, the administration of CY prior to 2 Gy TBI delayed recovery with CFU-S remaining at only 10 to 40% of control. This prolongation in CFU-S recovery was similar for CY doses of either 2 or 5 mg per mouse at all the time intervals tested (2, 3, 4 and 7 days prior to TBI). Our results demonstrate an enhancement of CFU-S recovery by pretreatment with CY for high doses of TBI that is reversed if the subsequent TBI dose is too low.     

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.     

Induction of donor-type chimerism in murine recipients of bone marrow allografts by different radiation regimens currently used in treatment of leukemia patients

Three radiation protocols currently used in treatment of leukemia patients before bone marrow transplantation (BMT) were investigated in a murine model (C57BL/6----C3H/HeJ) for BM allograft rejection. These include (a) a single dose of total body irradiation (8.5 Gy TBI delivered at a dose rate of 0.2 Gy/min), (b) fractionated TBI (12 Gy administered in six fractions, 2 Gy twice a day in 3 days, delivered at a dose rate of 0.1 Gy/min, and (c) hyperfractionated TBI (14.4 Gy administered in 12 fractions, 1.2 Gy three times a day in 3 days, delivered at a dose rate of 0.1 Gy/min). Donor-type chimerism 6 to 8 weeks after BMT and hematologic reconstitution on day 12 after BMT found in these groups were compared with results obtained in mice conditioned with 8 Gy TBI delivered at a dose rate of 0.67 Gy/min, routinely used in this murine model. The results in both parameters showed a marked advantage for the single dose 8.5 Gy TBI over all the other treatments. This advantage was found to be equivalent to three- to fourfold increment in the BM inoculum when compared with hyperfractionated radiation, which afforded the least favorable conditions for development of donor-type chimerism. The fractionated radiation protocol was equivalent in its efficacy to results obtained in mice irradiated by single-dose 8 Gy TBI, both of which afforded a smaller but not significant advantage over the hyperfractionated protocol. This model was also used to test the effect of radiation dose rate on the development of donor-type chimerism. A significant enhancement was found after an increase in dose rate from 0.1 to 0.7 Gy/min. Further enhancement could be achieved when the dose rate was increased to 1.3 Gy/min, but survival at this high dose rate was reduced. These results demonstrated indirectly that dose rate affects the expression of host-type pluripotent stem cells, the progeny of which appear 3 to 6 weeks after treatment with 8 Gy TBI delivered at a dose rate of 0.1 Gy/min, but which are eradicated if radiation is delivered at a dose rate of 1.3 Gy/min.     

Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM)

From March 1988 to March 1991, 19 French bone marrow transplant (BMT) centers participated in a prospective randomized trial comparing two conditioning regimens for patients with chronic myeloid leukemia transplanted in first chronic phase with an HLA identical sibling donor. A total of 120 consecutive patients were randomized to receive either 120 mg/kg of cyclophosphamide followed by total body irradiation (CY-TBI; n = 55) or 16 mg/kg of busulfan followed by 120 mg/kg of CY (BU-CY; n = 65). Two different TBI regimens were used. Thirteen patients received a 10-Gy single-dose TBI (SDTBI), and 42 received a fractionated TBI (FTBI). Median time between diagnosis and BMT was 315 days. Overall 5-year actuarial survival was 62.9% (65.8% +/- 12.5% for CY-TBI and 60.6 +/- 11.7% for BU-CY; P = .5), and overall disease-free survival was 55% (51% +/- 14% for CY-TBI and 59.1% +/- 11.8% for BU-CY; P = .75). All patients conditioned with CY-TBI experienced sustained engraftment; in contrast, 4 of 65 patients conditioned with BU-CY rejected the graft (P = .18). There was no significant statistical difference between the two groups regarding transplant-related mortality (29% for CY-TBI and 38% for BU-CY; P = .44). So far, with a median follow up of 42 months, 11 patients have relapsed; 9 relapses occurred after CY-TBI, mostly after FTBI (8 of 9) and 2 after BU-CY (P = .02). The actuarial risk of relapse was 4.4% +/- 6.7% after BU-CY, 11.1% +/- 20.8% after SDTBI, and 31.3% +/- 18.1% after FTBI (P = .039). In addition, independently of the conditioning regimen, the increase of posttransplant immunosuppression in 16 patients with an anti- interleukin-2 receptor monoclonal antibody (MoAb) in addition to a short course of methotrexate and cyclosporine was shown to increase the actuarial risk of relapse (57% +/- 30% with MoAb v 9% +/- 7.3% without MoAb; P = .001). We conclude that BU is an acceptable alternative to TBI for patients with chronic myeloid leukemia in first chronic phase receiving BMT from HLA identical sibling donors. Both BU-CY and CY-TBI regimens gave similar transplant-related mortality, and the antileukemic efficiency of BU-CY regimen was either similar or even higher than that of CY-TBI.     

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     

Radiolabeled anti-CD45 monoclonal antibodies target lymphohematopoietic tissue in the macaque.

Despite bone marrow transplantation, many patients with advanced leukemia subsequently relapse. If an additional increment of radiation could be delivered to lymphohematopoietic tissues with relative specificity, the relapse rate may decrease without a marked increase in toxicity. We have examined the biodistribution of two 131I-labeled monoclonal antibodies reactive with the CD45 antigen in Macaca nemestrina. Three animals received 0.5 mg/kg BC8, an IgG1 of low avidity (6 x 10(7) L/mol). Three received 0.5 mg/kg AC8, an IgG2a of moderate avidity (5 x 10(8) L/mol), and two received 4.5 mg/kg AC8. Estimates of radiation absorbed dose demonstrated that these antibodies could deliver up to five times more radiation to lymph nodes, and up to 2.6 times more to bone marrow, than to lung or liver. The higher avidity AC8 antibody at 0.5 mg/kg was cleared more rapidly from blood and resulted in lower antibody uptake in lymph nodes than did BC8 at 0.5 mg/kg. Increasing the dose of AC8 to 4.5 mg/kg resulted in slower blood clearance and higher lymph node uptake. These studies suggest that radiolabeled anti-CD45 antibodies can deliver radiation with relative specificity to lymphohematopoietic tissues. This approach, in combination with marrow transplantation, may improve treatment of hematologic malignancies.     

The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

One-hundred and five patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n = 61) and chronic myeloid leukaemia (n = 44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. There was a difference of +/- 18% between the nominal total dose of 990 cGy and the actual dose received as indicated by dosimetric recordings. While interstitial pneumonitis had minimal impact on survival (4%) there was a considerable difference in the incidence of relapses. The incidence of relapse was 55% versus 11% in patients receiving less or more than 990 cGy respectively and this had a major impact on survival (38% v. 74% at 7 years) since transplant-related mortality was comparable in the two groups. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%. 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GVHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced but a small reduction of the dose may significantly increase the risk of relapse.     

Interstitial pneumonitis in T cell-depleted bone marrow transplantation

The incidence of interstitial pneumonitis (IP) was reviewed in 80 consecutive patients who received allogeneic T lymphocyte-depleted bone marrow transplantation (BMT) for malignant and non-malignant diseases. Pretransplant conditioning used in malignant disorders included total lymphoid irradiation (TLI) 150 cGy x 4, total body irradiation (TBI) 200 cGy x 6, and cyclophosphamide (CY) 120 mg/kg. In non-malignant diseases conditioning included no TBI, but adjusted doses of TLI in addition to CY (severe aplastic anemia) or CY and busulfan (severe beta-thalassemia major). In the malignant group only one patient developed graft-versus-host disease (GVHD) grade I; IP developed in 12 out of 61 patients (19.7%) and IP-associated fatality occurred in five patients (8.2%). Cytomegalovirus (CMV) was associated with only two of the five fatal IP. In the non-malignant group there was no GVHD; one patient out of 19 (5.2%) had IP, which was fatal and not associated with CMV. These data indicate that fatal IP may appear in the absence of GVHD. The relatively low incidence of IP-related mortality in recipients of allogeneic T lymphocyte-depleted BMT suggests that although prevention of GVHD and elimination of drugs used for GVHD prevention may reduce the incidence of fatal pulmonary complications, other approaches have to be investigated for complete prevention of IP which still represents a major complication in patients with malignant hematologic disorders treated by allogeneic BMT.     

Total lymphoid irradiation to prevent graft rejection in recipients of HLA non-identical T cell-depleted allogeneic marrow

Patients who undergo transplantation with genotypically non-identical T cell-depleted bone marrow are at high risk of graft failure. We have previously shown that graft failure in this setting is an active immunologic process in which CD3+ CD8+ host T cells specifically cytotoxic for donor hematopoietic cells mediate rejection of the graft. In order to reduce the incidence of graft rejection in these patients, we conducted a pilot trial of total lymphoid irradiation (TLI) as an adjunct to total body irradiation (TBI) in an attempt to suppress the activity of residual host derived alloreactive lymphocytes capable of mediating rejection. Ten adults (ages 17-42 years) with hematologic malignancies were treated with TLI prior to hospitalization for allogeneic bone marrow transplantation (BMT). The BMT preparative regimen consisted of cyclophosphamide (60 mg/kg x 2) followed by TBI. The majority of patients received 750 cGy TLI delivered to two complementary radiation ports in five equal 150 cGy fractions. Nine of 10 recipients of genotypically non-identical CD6-depleted marrow who were pre-treated with TLI experienced full hematologic engraftment compared with none of four similar patients previously transplanted without TLI (p = 0.001). TLI induced significant lymphopenia in patients prior to marrow infusion, but had no suppressive effects on the reconstitution of donor lymphocytes. TLI, in combination with T cell depletion of donor marrow, may decrease the rate of graft rejection in individuals who lack perfectly matched HLA-identical sibling donors.     

What radiation dose for DLA-identical canine marrow grafts? [published erratum appears in Blood 1989 Feb;73(2):624]

In view of reported attempts at marrow grafting after nuclear accidents with a broad range of radiation exposures, the present study explored the total-body irradiation (TBI) conditions needed for engraftment in a canine model by using marrow from DLA-identical littermates. Previous studies have shown that such grafts are consistently successful when recipients are exposed to 920 cGy of TBI delivered at a rate of 7 cGy/min from opposing dual cobalt sources. The present TBI doses were all in the lethal range. Five dogs were administered 450 cGy; seven dogs, 600 cGy; five dogs, 700 cGy; and five dogs, 800 cGy of TBI administered at 7 cGy/min. They received a median of 3.3 x 10(8) marrow cells/kg intravenously after completion of radiation. Results showed transient allogeneic marrow engraftment in all dogs administered the lowest dose of TBI studied (450 cGy). Importantly, transient grafts permitted four of five dogs to live long enough for autologous marrow recovery to occur. At increasing radiation doses, 600, 700, and 800 cGy, the risk of graft failure lessened, with 3 of 7, 2 of 5, and 1 of 5 dogs, respectively, showing graft rejection. Fewer dogs survived with autologous marrow recovery, and more showed sustained allogeneic engraftment (4 of 7, 3 of 5, and 4 of 5 dogs, respectively). We conclude that DLA-identical littermate marrow grafts are beneficial in the setting of otherwise lethal radiation exposures, with most dogs either experiencing sustained allogeneic engraftment or surviving with autologous marrow recovery due to the extended support provided by a transient allogeneic graft.