Extracorporeal photopheresis for the treatment of chronic graft versus host disease.

OBJECTIVES: Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP). METHODS: This study was performed as a retrospective single-center study. Medical records of a total of 59 patients treated with ECP for chronic GVHD were reviewed. RESULTS: Best organ responses to ECP were observed in skin, mouth mucosa, eyes and liver. Overall response rate (ORR) to ECP was 81.2% (CR 17% and PR 64.2%). Overall survival (OS) was 84.9% and 36.7%, at 1 and 3 years, respectively. Female sex appears to have an advantage on ORR. Patients achieving ORR were able to maintain their responses with a prolonged continuation of treatments for +6 and +12 months indicating the benefits of longer ECP treatment. DISCUSSION: We found that patients with chronic GVHD who were treated with ECP for 12 months or longer had a higher response rate. Our findings in line with the data reported previously suggest that patients responding to ECP should continue longer therapy schedules to achieve a better and sustained response. In our cohort, long-term ECP therapy was safe and well-tolerated with no significant adverse effects. Best responses were observed in the patients with skin, eye, liver and oral involvement. The ECP procedure offers the advantage relative to the problems with typical immunosuppressive agents. The female sex appeared to have an advantage based on the cumulative probability of the OR after ECP for chronic GVHD.

Prophylactic red blood cell exchange for ABO-mismatched hematopoietic progenitor cell transplants.

BACKGROUND: To enhance donor availability, almost half of hematopoietic progenitor cell transplants (HPCTs) cross ABO blood type boundaries. ABO-incompatible HPCTs are well tolerated; however, there is an increased risk of delayed hemolysis in patients with minor and bidirectional ABO mismatches. Delayed hemolysis generally occurs 1 to 2 weeks after HPCT and is related to production of alloantibodies directed against recipient ABO red blood cell (RBC) antigens by passenger donor lymphocytes. One previous study has suggested that prophylactic RBC exchange in patients with minor and bidirectional ABO-mismatched HPCT reduces the risks of severe immune hemolysis, but this recommendation is controversial. STUDY DESIGN AND METHODS: Herein we describe our experience using prophylactic RBC exchange in patients with minor and bidirectional ABO-mismatched HPCTs who were deemed to be at high risk for immune hemolysis. We compare the group of patients that received prophylactic RBC exchange with a historical cohort of ABO-mismatched patients who underwent HPCT without prophylactic RBC exchange. RESULTS: Our study suggests that prophylactic RBC exchange in minor and bidirectional ABO-mismatched HPCT does not reduce severe immune hemolysis, nor does it improve 1-year survival, the number of RBC units transfused after transplant, or length of hospitalization after HPCT. CONCLUSION: This study failed to identify a clear role for selected prophylactic RBC exchange in patients who were deemed at risk for severe post-HPCT immune hemolysis.

Idiotype immunization following high-dose therapy and autologous stem cell transplantation for non-Hodgkin lymphoma.

The treatment of low- and intermediate-grade subtypes of malignant lymphoma continues to evolve. Mantle cell lymphoma (MCL) accounts for 6% of all non-Hodgkin lymphoma (NHL) and is generally considered incurable. Although high response rates can be achieved with initial chemotherapy, median survival is only 3-4 years. Intensified consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been reported to improve progression-free survival (PFS), but most patients eventually relapse. Indolent lymphoma accounts for 35% of all NHL and is associated with a median survival of 9 years. Similar to MCL, it is also generally considered incurable, and the PFS also appears to be improved following HDT/ASCT. We initiated a pilot study to evaluate idiotype (Id) vaccination following HDT and ASCT for patients with MCL, indolent, and transformed NHL to evaluate the ability of Id-keyhole limpet hemocyanin (KLH) to induce immune responses, and to evaluate overall survival (OS) and PFS. We treated 15 patients: 8 with MCL, 4 with follicular lymphoma, 1 with small lymphocytic lymphoma, and 2 with transformed lymphoma. After a median follow-up of approximately 6.3 years (range: 1-9), PFS and OS at 9.05 years from time of ASCT are 59% and 52%, respectively.

CTLA-4 blockade following relapse of malignancy after allogeneic stem cell transplantation is associated with T cell activation but not with increased levels of T regulatory cells.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of T cell activation and proliferation. Ipilimumab is a human monoclonal antibody that specifically blocks the binding of CTLA-4 to its ligand. To test the hypothesis that blockade of CTLA-4 by ipilimumab could augment graft-versus-malignancy (GVM) effects without a significant impact on graft-versus-host disease (GVHD), we conducted a phase I clinical trial of ipilimumab infusion in patients with relapsed malignancy following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report the analysis of peripheral blood T lymphocyte reconstitution, T regulatory cell (Treg) expression, and T cell activation markers after a single dose of ipilimumab in 29 patients. Peripheral blood samples were collected from all patients before and after ipilimumab infusion. Lymphocyte immunophenotyes, including levels of CD4(+)CD25(high) cells and T cell activation markers, were analyzed in all cases. Levels of CD4(+)CD25(high)Foxp3(+) cells and intracellular CTLA-4 in CD4(+) T cells also were evaluated in the last 11 cases. We found lower baseline levels of CD4(+) and CD45RO(+) T cells in patients compared with normal controls. More than 50% of the patients had abnormally low lymphocyte counts (CD4 or/and CD8 T cells), and some had no circulating B lymphocytes. The percentages of both CD4(+)CD25(high) and CD4(+)CD25(high)Foxp3(+) T cells were significantly higher in patients before ipilimumab infusion than in healthy donors. Twenty of 29 patients exhibited an elevated level of CD4(+)CD25(low) activated T cells at baseline, compared with only 3 of 26 healthy donors. Both CD4(+) and CD8(+) T lymphocyte counts were significantly increased after ipilimumab infusion. There was no consistent change in absolute lymphocyte count or in the number of T cells expressing the activation marker CD69. However, increases in CD4(+)CD25(low) T cells were seen in 20 of 29 patients and increases in CD4(+)HLA-DR(+) T cells were seen in the last 10 patients in the first 60 days after ipilimumab infusion. Although the percentages of both CD4(+)CD25(high) and CD4(+)CD25(high)Foxp3(+) T cells decreased significantly during the observation period, the absolute cell counts did not change. Intracellular CTLA-4 expression in CD4(+)CD25(lo/-) T cells increased significantly after ipilimumab infusion. We conclude that CTLA-4 blockade by a single infusion of ipilimumab increased CD4(+) and CD4(+)HLA-DR(+) T lymphocyte counts and intracellular CTLA-4 expression at the highest dose level. There was no significant change in Treg cell numbers after ipilimumab infusion. These data demonstrate that significant changes in T cell populations occur on exposure to a single dose of ipilimumab. Further studies with multiple doses are needed to explore this phenomenon further and to correlate changes in lymphocyte subpopulations with clinical events.

Review and revision of clinical practice of using G-CSF after autologous and allogeneic hematopoietic stem cell transplantation at UCSD.

There was no consensus on the optimal use of G-CSF after hematopoietic stem cell transplantation. In this study, the practice of using G-CSF, based on the CD34(+) cell number, at the University of California, San Diego Blood and Marrow Transplant Unit (UCSD BMT) was evaluated by performing a five-year retrospective analysis of data from patients undergoing autologous and allogeneic transplantation. Various outcomes, such as time to neutrophil and platelet engraftment and length of post-transplant hospital stay are assessed in relation to use of G-CSF and number of CD34(+) cells infused. It has been found that the use of G-CSF is associated with faster neutrophil engraftment and shorter length of post-transplant hospital stay without affecting time to platelet engraftment in patients undergoing autologous transplantation. In addition, the number of CD34(+) cells do not influence outcomes in autologous and allogeneic transplant patients if they are treated with G-CSF. As a result of this evaluation, the G-CSF protocol at UCSD BMT Unit is revised. The main change is to implement the use of G-CSF in all patients undergoing autologous transplantation regardless of the number of CD34( +) cells. No changes in the allogeneic transplantation protocol are made as a result of this analysis.

Autologous hematopoietic stem cell transplantation as an intensive consolidation therapy for adult patients in remission from acute myelogenous leukemia.

Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myelogenous leukemia (AML). However, its optimal role in treatment for adults in remission has not been clearly established. We performed a retrospective analysis on 45 patients aged 21 to 73 years (median 51 years) with de novo AML who underwent APBSCT stratified by age, complete remission status, and cytogenetic risk. The 5-year disease-free survival (DFS) for all patients was 33.9% (95% confidence interval [CI], 20.1%-53.7%) and overall survival (OS) was 43.6% (CI, 29.2%-62.8%). For patients under the age of 60 years, the 5-year DFS for intermediate and high cytogenetic risk was 53.3% (CI, 23.5%-85.6%) and 50.0% (CI, 16.1%-100.0%); the 5-year OS for patients under the age of 60 years with low, intermediate, and high cytogenetic risk was 80.0% (CI, 40.0%-100.0%), 60.0% (CI, 31.2%-90.7%), and 75.0% (CI, 39.0%-100.0%), respectively. For patients over the age of 60 years, the 5-year DFS and OS for intermediate cytogenetic risk was 21.4% (CI, 7.9%-58.4%) and 21.4% (CI, 7.9%-58.4%). The DFS and OS of these patients are comparable to the historic survival of those who underwent allogeneic stem cell transplantation when adjusted by age. In addition, there was no treatment-related mortality (TRM). We conclude that APBSCT is a reasonable and safe intensive consolidation for patients with AML who do not have a suitable HLA-matched donor.

CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation.

Relapse of malignancy after allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Blockade of the CTLA4 molecule can effectively augment antitumor immunity mediated by autologous effector T cells. We have assessed the safety and preliminary efficacy of a neutralizing, human anti-CTLA4 monoclonal antibody, ipilimumab, in stimulating the graft-versus-malignancy (GVM) effect after allo-HCT. Twenty-nine patients with malignancies that were recurrent or progressive after allo-HCT, received ipilimumab as a single infusion at dose cohorts between 0.1 and 3.0 mg/kg. Dose-limiting toxicity was not encountered, and ipilimumab did not induce graft-versus-host disease (GVHD) or graft rejection. Organ-specific immune adverse events (IAE) were seen in 4 patients (grade 3 arthritis, grade 2 hyperthyroidism, recurrent grade 4 pneumonitis). Three patients with lymphoid malignancy developed objective disease responses following ipilimumab: complete remission (CR) in 2 patients with Hodgkin disease and partial remission (PR) in a patient with refractory mantle cell lymphoma. At the 3.0 mg/kg dose, active serum concentrations of ipilimumab were maintained for more than 30 days after a single infusion. Ipilimumab, as administered in this clinical trial, does not induce or exacerbate clinical GVHD, but may cause organ-specific IAE and regression of malignancy. This study is registered at (http://clinicaltrials.gov) under NCI protocol ID P6082.

Peripheral blood progenitor cell mobilization with intermediate-dose cyclophosphamide, sequential granulocyte-macrophage-colony-stimulating factor and granulocyte-colony-stimulating factor, and scheduled commencement of leukapheresis in 225 patients undergoing autologous transplantation.

BACKGROUND: Interpatient variability in the kinetics of peripheral blood progenitor cell (PBPC) mobilization is commonly seen with conventional chemotherapy-based mobilization regimens. This necessitates the availability of leukapheresis (LP) facilities 7 days a week. STUDY DESIGN AND METHODS: The efficacy of an approach where LP was invariably commenced on Day 11 after intermediate-dose cyclophosphamide followed by sequential administration of granulocyte-macrophage-colony-stimulating factor (CSF) and granulocyte-CSF (Cy/GM/G) was retrospectively analyzed in 225 consecutive, unselected patients undergoing autologous hematopoietic stem cell transplantation for all diagnoses other than acute leukemia at our center. Cy/GM/G was scheduled to avoid weekend LP. RESULTS: After Cy/GM/G, a CD34+ cell yield of at least 2.0x10(6) per kg was achieved in 90.7 percent of patients. Optimal yield (OY; >or=5x10(6) or 10x10(6) CD34+ cells/kg depending on diagnosis) was achieved in 67.6 percent of patients. Only three patients (1.3%) required LP on Saturday or Sunday. Febrile neutropenia (FN) was encountered in 5.3 percent. PBPC yield was highest on Day 1 of LP (p<0.001). In multivariate analyses, platelet (PLT) count on Day 1 of LP (PLT-D1LP) was positively associated with achievement of OY (p<0.001). PLT-D1LP and diagnosis of myeloma were associated with a shorter time to achieve a CD34+ cell yield of at least 5x10(6) per kg (p<0.001 and p=0.002, respectively). CONCLUSION: Cy/GM/G with scheduled LP commencement on Day 11 enables optimal CD34+ cell yields in most patients undergoing autologous transplantation, despite a low risk of FN and avoidance of weekend LP.

Non-anthracycline based remission induction therapy for newly diagnosed patients with acute myeloid leukemia aged 60 or older.

We assessed remission rates and toxicity in 24 consecutive elderly (age>or=60) patients with untreated Acute myeloid leukemia (AML) who received the anthracycline-free combination of fludarabine, cytosine arabinoside and G-CSF (FLAG) as initial induction chemotherapy at our center. CR was achieved following one cycle of FLAG in 14 patients (58%). Another four patients cleared blasts from their bone marrow by day 30 without complete platelet recovery. Three patients died from infections prior to neutrophil recovery (12%). No other grade 3/4 toxicities and no clinically significant mucositis were seen. No significant association was found between age, WBC and cytogenetic risk group with likelihood of achieving CR. Fifteen patients proceeded to consolidation therapy and seven patients received a stem cell transplant (six autologous, one allogeneic). Primary induction with FLAG in elderly AML patients achieves a high remission rate without prohibitive mucosal or cardiac toxicity and may thus be considered as an alternative to standard anthracycline-based regimens in this setting.