Conditioning Total Body Irradiation Research Articles

The Two-Step Approach to Haploidentical Transplant: Can Altering Timing in the Conditioning Regimen Increase Graft Versus Tumor Effects?

In the two-step approach to haploidentical hematopoietic stem cell transplantation (HI-HSCT), following conditioning, recipients receive the lymphoid portion of their graft (“DLI”) containing a fixed dose of 2 x 10 8/kg CD3+ cells (Step 1 of the transplant). After the DLI, a 2 day period of alloreactivity and haploimmunostorm occurs which resolves with the administration of Cyclophosphamide (CY) for GVHD prophylaxis/rejection prevention. After the completion of CY, a CD34-selected donor product is infused (Step 2 of the transplant). It has been postulated that a rapid reduction in quantity and a functional impairment of alloreactive T cells by CY contributes to the establishment of tolerance between the donor and recipient immune systems. Based on their degree of disease burden at HSCT, a potentially important difference between patients undergoing HI-HSCT is the percentage of graft versus tumor (GVT) versus graft versus host (GVH) reactive T cells that are likely to become activated during the haploimmunostorm, and as a result of this activation, their subsequent inhibition by CY. In the initial two-step trial (2006-2010-initial group), relapsed disease was the major barrier to long-term survival (OS). In the follow-up trial (2013-2016-later group), extra time between the end of conditioning and the DLI was added to allow for a greater reduction in disease burden prior to the introduction of the DLI (Figure). We hypothesized that by allowing more of the malignancy to die off, less GVT specific T-cells in the DLI would become activated prior to CY administration. The result would be the avoidance of suppression of these cells by CY resulting in reduced relapse rates.We compared the outcomes of patients treated on the initial trial to those treated on the later trial. The number and median age of subjects in the initial and the later groups were 27 vs 40 and 51 vs 52 years. Diagnoses were AML (59% vs 33%), MDS (7% vs 18%), ALL (15% vs 27.5%), Burkitt's (0% vs 5%), NHL (11% vs 10%), and other (8% vs 6.5%). There was no significant differences between the groups in Revised Disease Risk Index on chi square analysis or HCT-CI on Mann-Whitney analysis. All patients received 12 Gy total body irradiation for conditioning; the initial group over 4 days, the later group over 3 days. Patients in both groups received a fixed dose of 2 x 10 8/kg of T cells in the DLI, and tacrolimus and mycophenolate mofetil for additional GVHD prophylaxis. Median CD34 cell dose was 3.6 x 10 6/kg versus 6.0 x 10 6/kg (p=0.01) in the initial versus later groups respectively.At two years in the initial and later groups, the cumulative incidence of relapse-related mortality was 30% vs 10% (p=0.04), non-relapse mortality was 22% vs 30% (p=0.28), acute GVHD 48% vs 38% (p=0.198), and chronic GVHD 15% vs 20% (p=0.591). Kaplan-Meier probability of OS at 2 years was 48% vs 63% (p=0.431).The analysis was limited by its retrospective comparison of two groups and small sample size. However, the data supports a potential relapse benefit, without increased toxicity, of the later approach. Improved GVT effects due to the alteration in DLI timing potentially contributed to lower relapse related-mortality, although superior tumor control based on a different radiation strategy should be considered. A prospective, randomized two arm trial comparing the two conditioning approaches is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Does allogeneic stem cell transplantation in survivors of pediatric leukemia impact regular physical activity, pulmonary function, and exercise capacity?

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life.MethodsA convenience sample of 17 patients after allo-HSCT (HSCT—12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing.ResultsHSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7%pred; FVC 88.4±19.3 vs. 107.6±6.9%pred, DLCO 75.3±23.6 vs. 104.9±12.8%pred) and exercise capacity (VO2peak 89±30.8%pred, CG 98±17.5%pred; Wmax 84±21.7%pred, CG 115±22.8%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake.Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau −0.48, p=0.023).ConclusionsThis pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients.

Nonmyeloablative Conditioning Regimen Including Low-Dose Total Marrow/Lymphoid Irradiation Before Haploidentical Transplantation with Post-Transplantation Cyclophosphamide in Patients with Advanced Lymphoproliferative Diseases

Low-dose total body irradiation (TBI) has long been used in nonmyeloablative conditioning (NMAC) regimens before allogeneic stem cell transplantation from haploidentical donors (haplo-SCT). More recently, the use of total marrow lymphoid irradiation (TMLI) instead of TBI in conditioning is increasing. This study aimed to evaluate outcomes in a cohort of patients treated with low-dose TMLI in terms of engraftment, full donor chimerism status, graft-versus-host disease (GVHD), and extrahematologic toxicities, and to compare these outcomes with those in a cohort of patients receiving conventional TBI-containing conditioning. This retrospective single-center study included 100 patients with advanced hematologic malignancies who underwent haplo-SCT. Between 2009 and 2011, the NMAC regimen consisted of cyclophosphamide, fludarabine, and low-dose TBI (2 Gy), and after 2011, TBI was replaced with TMLI (2 Gy). Patients received post-transplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil as GVHD prophylaxis. For all patients, the median time to absolute neutrophil count (ANC) recovery to >0.5×109/L was 21 days (range, 15 to 49 days), the 30-day incidence of ANC recovery was 97% (95% confidence interval [CI], 89% to 99%), the median time to achieve an unsupported platelet count >20×109/L was 26 days (range, 12 to 67 days), and the 60-day rate of platelet engraftment was 99% (95% CI, 89% to 100%). Cumulative incidence of full donor chimerism by day 100 was 88% (95% CI 79-90). Grade II-IV acute GVHD occurred in 35% of the patients (95% CI, 26% to 45%) at a median of 40 days (range, 23 to 166 days). The incidence of moderate to severe chronic GVHD was 5% (95% CI, 2% to 10%). No differences between the TBI and TMLI cohorts were seen in terms of engraftment, full donor chimerism, and GVHD. No organ toxicity was observed in the first months after transplantation in either cohort. The overall 2-year OS and PFS rates were 63%, and 54%, respectively, and were comparable in the 2 groups (P=.548). The strongest finding was that TBI can be safely replaced by TMLI in terms of engraftment, achievement of full donor chimerism status, GVHD incidence, and extrahematologic toxicities.

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report

AbstractThere is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Ocular complications in children after hematopoietic stem cell transplantation without total body irradiation.

The purpose of the study was to evaluate whether hematopoietic stem cell transplantation (HSCT) without conditioning Total Body Irradiation (TBI) had lower or milder ocular complication rates in the pediatric population. This study included all children who underwent HSCT without conditioning TBI at the Chaim Sheba Medical Center between the years 2001 and 2008. All children had an ophthalmic evaluation prior to and every four months after HSCT. Of the 33 children who initially comprised this study, ten did not complete the minimal follow-up of four months, and were, thus, excluded from the study. Follow-up of the remaining 23 children ranged from four to 117 months. Dry eye related to chronic graft-versus-host disease (cGVHD) developed in eight children (35 %). In three cases, an additional complication was observed : corneal abscess, herpes zoster ophthalmicus, and bilateral subcapsular cataract (one case each). Posterior segment or neuro-ophthalmological complications were not observed in any patient. In our study group, the preclusion of conditioning TBI before HSCT did not result in a decreased ocular complication rate compared to past publications, but complications were relatively mild and confined only to the anterior segment.

High Incidence of Radiation-Induced Cavernous Hemangioma in Long-Term Survivors Who Underwent Hematopoietic Stem Cell Transplantation with Radiation Therapy during Childhood or Adolescence

Radiation-induced cavernous hemangioma (RICH) is a late complication of cerebral radiation therapy. Long-term survivors of hematopoietic stem cell transplantation (HSCT) who underwent radiation therapy could be at increased risk for RICH. We investigated records of 68 patients who underwent HSCT during childhood or adolescence and were assessed by magnetic resonance imaging (MRI), including T2*-weighted imaging of the brain, annually for 5 years over a range of 6 to 29 years after HSCT. We developed a scoring and grading system for RICH to monitor the process and the progress of radiologic changes. Among the 68 patients investigated, 28 (41.2%) were diagnosed with CH. All 28 patients had received total body irradiation as a conditioning treatment for HSCT and/or cranial radiation therapy before HSCT as part of the treatment of their primary disease. RICH was diagnosed in none of the patients who did not receive radiation (n = 19), in 46.2% of those who received 6 to 12 Gy (n = 39), and in all of those who received 18 to 36 Gy (n = 10). Total RICH scores were correlated with higher radiation doses. Careful and long-term evaluation with MRI, including T2*-weighted imaging, is necessary for HSCT recipients who received radiation therapy before and/or during HSCT.

Allogeneic Hematopoietic Cell Transplantation with Full-Intensity Conditioning for Adult Acute Lymphoblastic Leukemia: Results from a Single Center, 1998-2006

A retrospective analysis identified 161 consecutive adults with acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) with full-intensity (myeloablative) conditioning between 1998 and 2006. Median patient age was 36.1 years. Seventy-six patients were in first complete remission (CR1), and 85 were in second or greater CR or in relapse. Fifty-nine patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 159 patients received chemotherapy plus total body irradiation for conditioning. Graft-versus-host disease prophylaxis included a calcineurin inhibitor plus methotrexate or mycophenolate mofetil. Sixty of the donors were related, and 101 were unrelated. A total of 110 patients received granulocyte-colony stimulating factor-stimulated peripheral blood, 47 received bone marrow, and 4 received cord blood as the stem cell source. Fifty-five patients relapsed at a median of 231 days after transplantation. The estimated 5-year probabilities of relapse-free survival, relapse, and nonrelapse mortality were 47%, 30%, and 29%, respectively. By multivariate analyses, transplantation while in CR1 was the most important predictor of successful transplantation. Pretransplantation evidence of minimal residual disease, especially as detected by flow cytometric analysis, was associated with both lower overall survival and lower relapse-free survival. Compared with a similar cohort of patients undergoing transplantation between 1990 and 1997, overall survival was similar for patients undergoing transplantation in CR1, with lower nonrelapse mortality being offset by higher rates of relapse in patients who underwent transplantation more recently.

Febrile Neutropenia Associated with Painful Lesions of the Palms and Digits

A 47-year-old African American woman with a history of multiple myeloma was admitted to the hospital to undergo allogeneic stem cell transplantation. At admission to the hospital, the patient underwent conditioning total body irradiation and then received high-dose melphalan. On the day before she underwent transplantation, the patient developed a temperature >38.6?C. At the time, the findings of her physical examination were unremarkable except for moderate mucositis. The patient was treated with empirical piperacillin-tazobactam and vancomycin. Despite this treatment, she continued to have daily fevers, and after 2 days, voriconazole was added to the patient's regimen. The patient was neutropenic throughout this time. On day 7 after admission to the hospital, the patient developed exquisitely tender lesions on the palms of both hands and on her second and third digits. These lesions were purplish

Thyroid dysfunction after bone marrow transplantation for primary immunodeficiency without the use of total body irradiation in conditioning.

Thyroid dysfunction, a common long-term complication following bone marrow transplantation (BMT), is frequently associated with total body irradiation (TBI) given in the pre-BMT conditioning protocol. We report our preliminary observation of the prevalence of thyroid dysfunction in children transplanted for primary immunodeficiency (PID) who were given cytoreductive conditioning with busulphan and cyclophosphamide, but without TBI. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (fT4) in 83 survivors transplanted between 1987 and 2002. We found nine children (10.8%) with clinical and/or biochemical thyroid dysfunction at 4 months to 4.5 years post-BMT of which three had positive antithyroid microsomal antibodies. Two patients were classified as primary and seven as compensated hypothyroidism (hyperthyrotropinaemia). Four patients with clinical features of hypothyroidism received replacement thyroxine, while five of the seven patients with compensated hypothyroidism remain off thyroxine because we suspect this may be a transient phenomenon. Abnormalities of thyroid function including severe primary hypothyroidism may occur post-BMT in children receiving chemotherapy conditioning without TBI. Thyroid function should be assessed regularly in this group of patients.

Tolerance and chimerism.

Stem-cell transplantation from human leukocyte antigen (HLA)-haploidentical family members carries a high risk of rejection and graft-versus-host disease (GVHD) if donor and recipient differ by more than one HLA antigen. The authors have developed treatment protocols from studies in dog leukocyte antigen-haploidentical dogs that prevent rejection and modify GVHD to the extent that patients with aggressive hematologic neoplasia can be treated with success. Principal improvements have been achieved in the use of cyclophosphamide and total-body irradiation for conditioning and T-cell depletion for prevention of GVHD. More recently, the combination of marrow and CD6-depleted mobilized donor blood cells (MDBC) has been introduced for HLA-haploidentical transplantation on the basis that CD6-depleted MDBC contain immunoregulatory cells besides stem cells and natural killer cells. Clinical results are reported on 36 patients with high-risk hematologic neoplasia. The results encourage the use of HLA-haploidentical stem-cell transplantation at an earlier stage of the disease. This method could also be of use for tolerance induction in organ transplantation.

Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR).

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse.

Induction of autologous graft-versus-host disease with cyclosporin A after peripheral blood stem cell transplantation: Analysis of factors affecting induction

Background: Induction of autologous graft-versus-host disease after peripheral blood stem cell transplantation has not been studied well. Objective: The purpose of this study was to analyze the factors that affect the development of autologous graft-versus-host disease. Methods: Nineteen patients with non-Hodgkin’s lymphoma underwent peripheral blood stem cell transplantation followed by the administration of cyclosporin A for 28 days (group A) or 21 days (group B) and IFN-γ. Results: Autologous graft-versus-host disease failed to develop in the any of the group A patients, who did not receive total body irradiation for conditioning and underwent the transplantation with unmanipulated peripheral blood stem cells, although cytotoxic activity against autologous lymphocytes was detectable in peripheral blood mononuclear cells obtained from all of them after the transplantation. Autologous graft-versus-host disease developed in 2 of 4 patients in group A who received enriched CD34+ cells and in 7 of 11 patients who underwent conditioning with total body irradiation. Maculopapular erythema that was compatible with graft-versus-host disease developed on days 19 to 27 after the transplantation in these patients and resolved after 3 to 9 days without treatment. Conclusions: Either the depletion of regulatory cells from the graft by enrichment of CD34+ cells or the abolition of the autoregulation by including total body irradiation in the conditioning regimen may be effective in inducing autologous graft-versus-host disease after peripheral blood stem cell transplantation. Three weeks of cyclosporin A therapy appears to be sufficient to induce autologous graft-versus-host disease in recipients of peripheral blood stem cells. (J Allergy Clin Immunol 2000;106:S51-7.)

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.

Haemolytic uraemic syndrome following bone marrow transplantation. Case report and review of the literature

Thrombotic microangiopathy (TMA) can be a late complication of bone marrow transplantation (BMT). A patient is described in whom the haemolytic uraemic syndrome developed 10 months after BMT and who died of E. coli sepsis while on maintenance haemodialysis. The literature is reviewed, regarding clinical presentation, incidence, pathogenesis and therapy. TMA can be observed, after an interval of 3-12 months, in about 6-26% of patients following BMT. Reported cases vary considerably in clinical severity, from mild presentations to severe TMA with high mortality rates despite intensive therapy. Important pathogenetic roles are ascribed to the conditioning total body irradiation and the use of cyclosporin A, but other factors may be involved as well. Next to supportive therapy, plasma exchange and the use of ACE inhibitors may be of value in treating BMT-associated TMA.

Radiation-induced changes in lung tissue and development of fibrosis determined by quantitative morphometric methods

This study presents results of morphometric investigations of mouse lungs after single irradiation. An automatic image analyser was used to monitor pathological changes in morphological structure, especially the size and distribution of collagen fibres, the thickness of the septa and the diameters of alveoli in the lung. Radiation-induced changes in the area of alveoli and septa as well as collagen content were seen 11 weeks after irradiation. A dose-dependent increase in tissue and decrease in alveolar surface as well as a quantifiable increase in radiation oedema were seen. The septa were thickened and the total collagen content increased in a dose-dependent manner. The morphometric methods used here are suitable for determining changes in lung structure, particularly those in collagen content in the early phase of a pathological response after thorax or total body irradiation for conditioning in bone marrow transplantation.

CHRONIC CYCLOSPORINE-ASSOCIATED NEPHROTOXICITY IN BONE MARROW TRANSPLANT PATIENTS

This study describes the prevalence and degree of chronic cyclosporine-associated nephropathy and its risk factors. For this purpose we reviewed all available renal histology specimens in 169 bone marrow transplant recipients treated during an eight year period with cyclosporine for prevention of graft-versus-host-disease, and determined their pattern and degree of histomorphological changes. A total of 51 specimens obtained from 49 patients by biopsy (n = 12) or autopsy (n = 39) was evaluated. The pattern of histomorphological changes was compared with diagnosis, age, sex, and potential risk factors--such as cyclosporine dose, levels, duration of therapy, changes in serum creatinine and onset of hypertension. Morphological lesions of chronic cyclosporine-associated nephropathy were found in 67% of the specimens. They were more frequent and more severe with increasing duration of cyclosporine therapy, in patients with a higher increase in serum creatinine during the first 3 months and in patients given total-body irradiation for conditioning. These latter findings suggest that additional damage sensitizes the kidney to irreversible toxic effects of cyclosporine.