G. B. Vogelsang

Induction of graft-versus-host disease after autologous bone marrow transplantation

To induce graft-versus-host disease (GvHD) in patients undergoing autologous bone marrow transplantation (BMT), five consecutive patients with non-Hodgkin lymphoma or Hodgkins disease in resistant relapse were treated with cyclophosphamide and total body irradiation or busulphan and cyclophosphamide, followed by autologous BMT. The patients received cyclosporin 1 mg/kg per day intravenously for 28 days after BMT. Histologically proven grade II acute GvHD of the skin developed in all the patients at a median of 11 days (range 9-13) after BMT. One patient died and the GvHD resolved in 1-3 weeks in the four remaining patients--spontaneously in two and with corticosteroid treatment in two. Lymphocytes from one patient obtained at the time of GvHD were cytotoxic for the patients own pretransplant lymphocytes. Cytotoxicity was blocked by antibodies directed against class II histocompatibility (HLA-DR or Ia) antigens. Cyclosporin-induced GvHD after autologous BMT resembles mild GvHD after allogeneic grafting. This syndrome appears to be mediated by autoreactive Ia-specific lymphocytes.

Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from The Eastern Cooperative Oncology Group (ECOG)

There have been many advances in the prevention and treatment of GVHD, including cyclosporine, FK506, and combination therapies. This syndrome, however, continues to account for significant morbidity and mortality after allogeneic transplantation. With the expanded use of matched unrelated as well as mismatched related donors, the increase in incidence and severity of GVHD poses a new clinical challenge. Many of the newer agents discussed in this paper may have a role in the future as therapy for acute GVHD. The evaluation of these new agents and the approach to be taken is hampered by the realization that most patients have received and are relatively refractory to standard therapies. Clinical trials must be performed earlier in the course of the syndrome to establish the role of these compounds. Newer strategies are likely to include the use of sequential therapy directed at blocking endogenous cytokines followed by blocking alloreactive donor cells, and immunologic advances such as the induction of tolerance. What impact, if any, such therapy may have on amelioration of a graft-versus-leukemia effect remains unknown.

Impact of age on outcome of patients with cancer undergoing autologous bone marrow transplant.

PURPOSE We examined the impact of age on outcomes in patients with cancer undergoing autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS All 506 adult patients who underwent ABMT at the Johns Hopkins Oncology Center between January 1987 and January 1994 were studied. A total of 405 patients were aged 18 to 49 years and 101 were aged > or = 50. The effect of age and other prognostic variables on transplant-related mortality (TRM), relapse, and event-free survival rates were analyzed. RESULTS Patients aged > or = 50 years has a 2.24-fold increased risk of TRM. Although relapse rates were not different based on age, the increased TRM rate resulted in a slight decrease in overall event-free survival in the older patients. Causes of death were not different by age and were mainly related to preparative regimen toxicity. Length of hospital stay and hospitalization costs were not increased in the older patients. CONCLUSION While the TRM rate was higher in older patients, relapse rates were not increased. Nearly 25% of older patients were expected to be cured of the disease. These data support the use of ABMT in eligible older patients, at least up to the age of 65.

Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin's disease.

Five patients with acute myelocytic leukemia (AML) after combined modality therapy for Hodgkins disease (HD) were treated with cyclophosphamide and busulfan followed by bone marrow transplantation (BMT). Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide. Two patients died of complications of acute graft-v-host disease (GVHD) despite prophylaxis with either low-dose cyclophosphamide or cyclosporine. The remaining three patients were alive and disease-free 382, 617, and 620 days after transplant. These initial results are encouraging and more patients with treatment-related AML need to be evaluated with both allogeneic and autologous BMT to fully elucidate the potentially curative role of this intensive therapy in an otherwise fatal hematologic malignancy.

Allogeneic, syngeneic and autologous marrow transplantation in the acute leukemias and lymphomas--Baltimore experiences.

Allogeneic bone marrow transplants (BMT) in acute lymphoblastic leukemia following cyclophosphamide (Cy) and total body irradiation (TBI) has resulted in disease-free survival (DFS) for CR1, CR2, and CR3 of 10/18 (56%), 16/30 (53%) and 4/17 (24%), respectively. Median follow-up of survivors was 25-43 months. One relapse was seen in CR1, 1 in CR2, and 6 in CR3. Allogeneic BMT in acute nonlymphoblastic leukemia (ANLL) following busulfan (Bu) resulted in DFS for CR1, CR2 + CR3 + early relapse of 21/47 (45%) and 13/41 (32%), respectively. Median DFS of survivors of all groups together was 36 months. DFS of all patients 20 years or less was 15/27 (56%) and 19/61 (31%) for ages 21-46. Three relapses of 47 (6%) were seen in CR1 and 6/41 (15%) in subsequent remission and early relapse. BMT of autologous BMT with 4-hydroperoxy-cyclophosphamide (4-HC) purged marrow in ANLL in CR1 (5), CR2 (32) and CR3 (9) following Bu + Cy resulted in DFS of 19/46 (41%) for 1-67 months (median 15 months). Twenty patients with prior risk non-Hodgkins lymphoma received 4-HC-purged marrow following Cy + TBI. DFS was 10/20 (50%) for 1.4-9.5 years (median 2.9 years).

Using point-of-care CD34 enumeration to optimize PBSC collection conditions

BACKGROUND A PBSC graft containing 4-5 x 10(6) CD34(+) cells/kg is considered optimal in terms of durable engraftment. Tracking CD34 kinetics via point-of-care testing during PBSC mobilization could determine which (and when) patients will yield an optimal product. We evaluated whether microvolume fluorimetry (MVF) would be useful in optimizing PBSC mobilization/harvest and if it will shorten our standard 6 h collection. METHODS Absolute CD34 values were obtained using the IMAGN 2000 and STELLer CD34 assay (50 microL sample volume). Peripheral blood (PB) CD34 values from 30 patients undergoing PBSC mobilization were used to generate a PB CD34-based algorithm that would predict collection day/duration of apheresis. The algorithm was then used prospectively to collect PBSC products on 50 hematologic malignancy (HM) patients. RESULTS Using the algorithm, patients were assigned to either a 6 (11-20 CD34/microL), 4 (21-49 CD34/microL) or 2 (> or = 50 CD34/microL) h collection. Patients with a CD34 value < or = 10/microL were re-tested. All patients (n = 43) predicted to mobilize reached the optimal CD34 (4-5 x 10(6)/kg) value with 1.0 apheresis procedure; seven patients had < or = 10/microL (nonmobilizers). The majority (75%) had apheresis charges decreased by 33-66%; 47% only required a 2 h procedure and 28% required 4 h. All patients demonstrated rapid trilineage engraftment. DISCUSSION Absolute PB CD34 measurement using MVF offers a rapid and reliable approach to obtaining optimal PBSC products with minimal technical expertise. Although not a replacement for conventional flow cytometry, it meets the requirements for a point-of-care procedure.

High incidence of graft failure in children receiving CD34+ augmented elutriated allografts for nonmalignant diseases.

Summary:T-cell depletion of the marrow graft using counterflow centrifugal elutriation reduces the risk of graft-versus-host disease (GVHD). However, because of high rates of graft failure and relapse, elutriation alone has not improved survival. We have carried out a phase II clinical trial in 54 pediatric patients to determine if CD34+ selection to rescue pluripotent stem cells from the small lymphocyte fraction improves engraftment. The processed grafts contained a mean of 5.5 × 107 cells/kg IBW, 4.7 × 106 CD34+ cells/kg IBW, and 6.3 × 105 CD3+cells/kg IBW. Patients achieved an ANC >500 at a median of 16 days and platelet count >20 000 at a median of 28 days. The incidence of clinically significant GVHD was 19%. In total, 10 patients enrolled in this study experienced graft failure, with eight of the 14 patients transplanted for nonmalignant indications failing to engraft stably. Graft failure was statistically significantly associated with nonmalignant diagnosis (P<0.001), but was not associated with CMV seropositivity, donor gender, or cell counts of the allograft. We conclude that although time to engraftment is similar to that seen with unmanipulated grafts, graft failure remains a significant problem in patients with hereditary, nonmalignant diseases. Future efforts will seek to preserve the benefits of elutriation with CD34+ selection by increasing immune ablation of the preparative regimen and/or increasing posttransplant immune suppression.

Chemotherapy does not nullify the ability of donor lymphocyte infusions to mediate graft-versus-host reactions.

Two patients with multiple myeloma in relapse after allogeneic BMT received donor lymphocyte infusions (DLI) but later required chemotherapy for treatment of myeloma-related complications. In both patients, recovery from chemotherapy-induced aplasia was accompanied by manifestations of graft-versus-host reactions. The first patient developed grade II acute GVHD and a complete remission which has lasted >22 months. The second patient developed grade III acute GVHD but died with co-existing GVHD and extensive extramedullary myeloma. These results demonstrate that chemotherapy does not nullify the ability of donor lymphocytes to mediate graft-versus-host reactions.

A case of retroperitoneal fibrosis in a patient following HSCT

The role of hematopoietic stem cell transplantation (HSCT) in the treatment of serious malignant and nonmalignant hematologic disorders has rapidly expanded as a result of advances in histocompatibility typing, conditioning regimens, and supportive care. In fact, it is currently estimated that approximately 18 000 patients worldwide will receive some form of HSCT annually. Even though a tremendous amount of knowledge has been amassed in transplantation biology over the years, the development of chronic graftversus-host disease (GVHD) continues to plague patients receiving HSCT and represents the major cause of late nonrelapse mortality. Chronic GVHD has traditionally been considered to occur after day 100, although recently it has been appreciated that this arbitrary time distinction is not useful given the large number of nonmyeloabative transplants and donor lymphocyte infusions, which are complicated by chronic GVHD. The clinical manifestations generally include cutaneous, hepatic, and mucosal involvement. Skin is the most commonly affected tissue as 81% of cases present with cutaneous findings. These generally include lichenoid eruptions, which may progress to cutaneous sclerodermatous disease. In the sclerodermatous form of the disease, fibrosis of the skin occurs, destroying normal skin appendages. Retroperitoneal fibrosis is a process of unknown etiology, which usually affects males between the ages of 40 and 60 years. It develops gradually with nonspecific symptoms including malaise, anorexia, nausea, and vomiting. The diagnosis is most commonly made using imaging studies, with CT being the exam of choice. There are few effective treatment options available for patients suffering from idiopathic retroperitoneal fibrosis with most cases being managed surgically. Medical therapy is usually not effective unless the fibrosis is in response to an inflammatory condition (ie not idiopathic), in which case steroids may be effective. Here, we present an unusual case of retroperitoneal fibrosis following HSCT presumably caused by chronic GVHD. A 36-year-old female with relapsed follicular mixed lymphoma underwent allogeneic HSCT after conditioning with total body irradiation, cyclophosphamide, and Ara-C. Her immediate post transplant course was complicated by hemorrhagic cystitis requiring nephrostomy tubes/ureteral stents and biopsy proven stage 2 cutaneous GVHD, treated with low-dose steroids. After the transplant, the patient developed persistent nausea and vomiting and multiple urinary tract infections. Although the cystitis resolved, multiple attempts at removing her ureteral stents were complicated with renal insufficiency. This suggested extrinsic ureteral compression and CT scan revealed retroperitoneal fibrosis (Figure 1a). Over time, the patient had increasing fibrosis in the pericalyceal region. Her ureters