Peter A. McSweeney

Treatment for Acute Myelogenous Leukemia by Low-Dose, Total-Body, Irradiation-Based Conditioning and Hematopoietic Cell Transplantation From Related and Unrelated Donors

Purpose The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors. Patients and Methods The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m2/d from days −4 to −2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day −3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Results Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after relate...

Phase I/II trial of autologous stem cell transplantation in systemic sclerosis : procedure related mortality and impact on skin disease

BACKGROUND Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. METHODS Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3–55). RESULTS An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49–255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. CONCLUSION Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkins lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.

Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning

PURPOSE We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. PATIENTS AND METHODS Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. RESULTS Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy > or = 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. CONCLUSION Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients.

Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic Leukemia

PURPOSE Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). PATIENTS AND METHODS Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. RESULTS Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. CONCLUSION CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.

Mini-allografts: ongoing trials in humans.

Conventional allogeneic stem cell transplantation is a valuable approach to therapy for many hematologic malignancies. However, high-dose conditioning regimens designed both to control the malignancy and to prevent graft rejection are associated with a high incidence of acute and long-term side-effects. This has largely precluded the use of allografting for patients older than 55 years or for younger patients with certain pre-existing organ damage. In order to manage the side-effects, transplants have traditionally been delivered in highly specialized hospital wards or intensive care settings. Thus, an important goal is to develop safer allografting procedures that can be extended to older patients or patients with pre-existing organ dysfunction who are currently excluded from consideration for transplant. Recent observations have shown that donor lymphocyte infusions (DLI) can eradicate some malignancies that relapse after conventional allografting. These observations confirmed earlier evidence in favor of a graft-versus-leukemia effect based on the association of graft-versus-host disease (GVHD) with a lower likelihood of relapse of malignancy after allografting. Given the potential efficacy of DLI as the sole modality for eradication of malignancy, new strategies for allografting can incorporate the concept of less intensive conditioning therapy which is given with the sole aim of facilitating allogeneic engraftment. Recent pre-clinical studies in a canine model have shown that conditioning regimens for allografting can be markedly reduced in intensity yet still achieve the goal of engraftment. This review briefly summarizes the initial translational clinical studies, using a minimally myelosuppressive-conditioning regimen based on low dose total body irradiation (TBI) or fludarabine alone or in combination with other drugs followed by a short course of immunosuppression with post-grafting cyclosporine and methotrexate or mycophenolate mofetil. Bone Marrow Transplantation (2000) 25, 345–350.

Hematopoietic cell transplantation‐comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation

Elderly and medically infirm cancer patients are increasingly offered allogeneic nonmyeloablative hematopoietic cell transplantation (HCT). A better understanding of the impact of health status on HCT outcomes is warranted. Herein, a recently developed HCT‐specific comorbidity index (HCT‐CI) was compared with a widely acceptable measure of health status, the Karnofsky performance status (KPS).

Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies

CONTEXT A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions. OBJECTIVE To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT. DESIGN, SETTING, AND PARTICIPANTS From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m(2), before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor. MAIN OUTCOME MEASURES Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models. RESULTS Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P < .001 overall). CONCLUSION Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.

Autologous haematopoietic stem cell transplants for autoimmune disease – feasibility and transplant-related mortality

This ongoing multicentre prospective phase I/II trial enrolled 74 consecutive patients from 22 centres worldwide with severe autoimmune disease, 35 with rheumatological disorders, 31 with neurological, five with haematological and three with vasculitides. They were treated with autologous peripheral blood or bone marrow transplants according to predetermined criteria. Two patients died after mobilisation before transplant. Seventy-two patients were given 73 transplants, seven bone marrow, and 66 mobilised peripheral blood stem cell transplants. The graft was manipulated to remove T and/or B cells in 43 cases. All 73 transplants engrafted. Five patients died of transplant-related complications: two from bleeding, three from infections. Two patients died of progressive disease. The transplant-related mortality at 1 year of 9% (1–17%; 95% CI) is comparable to the transplant-related mortality of 6% (3–9%; 95% CI) in patients transplanted during the same period in Europe for non-Hodgkin’s lymphoma in sensitive relapse (P = 0.39). Sixty patients are evaluable for response, 40 patients (65%) showed some improvement in their disease. Haematopoietic stem cell transplants are feasible for patients with severe refractory autoimmune disease. Transplant-related mortality is comparable to results in patients with non-Hodgkin’s lymphoma in responsive relapse. Two-thirds of the patients show at least some response. These preliminary data are promising. Although associated with considerable risk, randomised trials comparing autologous stem cell transplants to conventional therapy are warranted.

Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis.

OBJECTIVE The realization that fetal cells pass into the maternal circulation and can survive for many years has raised the question of whether fetal microchimerism can cause subsequent disease in the mother. Available data suggest that fetal-maternal transfusion may be related to some autoimmune diseases, notably systemic sclerosis (SSc). The goal of the current work was to identify and quantify tissue-specific fetal microchimerism in women with SSc. METHODS We analyzed multiple tissue specimens obtained at autopsy from women with SSc as well as women who had died of causes unrelated to autoimmunity, using fluorescence in situ hybridization to detect the presence of male cells in women with sons. Tissues analyzed included adrenal gland, heart, intestine, kidney, liver, lung, lymph node, pancreas, parathyroid, skin, and spleen. RESULTS Male cells were observed in tissue from at least 1 site in each woman with SSc and were found most frequently in spleen sections. After spleen, male cells were observed most frequently in lymph node, lung, adrenal gland, and skin tissue. The only tissue type in which male cells were not seen in any patient was pancreatic tissue. Male cells were not observed in tissue from women who had died of causes unrelated to autoimmunity. CONCLUSION The results of this study suggest that fetal cells migrate from the peripheral circulation into multiple organs in women with SSc. All of the women studied had previously given birth to sons, so it is likely that these cells are of fetal origin. While the relevance of this finding to the pathogenesis of SSc remains to be elucidated, the presence of fetal cells in internal organs suggests that they could play a role in disease pathogenesis and that they may preferentially sequester in the spleen. The presence of these male cells may also be a result of disease, possibly through the migration of terminally differentiated and/or progenitor cells to areas of tissue damage.

Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor

Article abstract Four of 10 patients who were enrolled on protocols of high-dose immunosuppression with peripheral blood stem cell rescue for MS experienced neurologic worsening while receiving recombinant human granulocyte colony-stimulating factor. There was improvement when methylprednisolone was given to three of the patients, but one patient died of respiratory failure. The mechanism of the neurologic worsening is uncertain.