Allogeneic peripheral blood progenitor cells for treatment of relapse after bone marrow transplantation

Donor leukocyte infusions (DLI) are an effective therapy for patients who relapse with leukemia after bone marrow transplantation (BMT). Severe graft-versus-host disease and prolonged periods of pancytopenia compromise the success of this treatment in a substantial number of patients. We used filgrastim-mobilized peripheral blood progenitor cells (PBPCs), in some cases preceded by cytoreductive therapy, to circumvent some of the problems associated with DLI. Eleven patients (median age 41 years) received a total of 20 donor cell infusions. Their diagnosis was CML in hematological (two patients) or cytogenetic relapse (two patients), six patients suffered from acute myeloid leukemia (AM; n = 5) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+). One patient had multiple myeloma (MM). All six patients with acute leukemias received cytoreductive therapy prior to PBPC infusions; three patients with CML were pretreated with IFN alpha. Four of four patients with CML responded to PBPC infusions and currently are in complete clinical and molecular remission for time periods between 1 and 12 months. Six of six patients with acute leukemias achieved a complete remission. All of them relapsed after a median remission duration of 24 weeks (range 11-49 weeks). Three patients relapsed at extramedullary sites (CNS, testes, skin). Four of six acute leukemia patients received further cytoreductive therapy. All patients responded again and are in complete remission for time periods between 14 and 615 days. Two patients with acute leukemias have died due to dissemination of the disease. The patient with MM did not respond and is alive with disease. Severe (grade III) acute GVHD developed in two of 11 patients, three patients developed grade II disease, six patients did not show any signs of GVHD. Extensive chronic GVHD has developed in two cases to date. Patients with chemotherapy prior to PBPC infusion developed neutropenia and thrombocytopenia with a maximum duration of 20 and 14 days, respectively; prolonged periods of neutropenia did not occur. Two patients developed long-lasting thrombocytopenia in spite of PBPC infusion, in one case followed by leukemic relapse. Repeated courses of chemotherapy and PBPC infusion were generally tolerated well; no early deaths due to treatment-related toxicity or GVHD were observed. We conclude that the use of allogeneic PBPC instead of DLI in patients with relapse after BMT is technically feasible and safe. The efficacy of PBPC infusions seems comparable to DLI in patients with CML. Patients with acute leukemias also achieved complete albeit transient remissions. Aggressive chemotherapy followed by PBPC infusions resulted in only limited duration of cytopenia. The usage of PBPC infusion instead of non G-CSF-mobilized donor cells for treatment of relapse after BMT may reduce pancytopenia-related complications and merits further investigation.     

Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation

Increasing numbers of patients have received autologous stem cell transplants (ASCT) for hematologic malignancies. Since only a fraction of these patients are cured, physicians are more frequently faced with the dilemma of how to manage relapse post-transplant. Potential advantages of allogeneic transplantation (alloBMT) over ASCT include lack of graft tumor contamination and presence of a graft-versus-tumor effect. For this reason, patients who relapse after ASCT are often considered candidates for allogeneic bone marrow transplantation. However, there is limited knowledge on the outcome of alloBMT in patients who relapse after ASCT. We retrospectively analyzed the outcome of 20 patients with malignant lymphoma (n = 14) and AML (n = 6) who underwent alloBMT after failing an ASCT. The median age was 30 (17-41) years and the interval from ASCT to alloBMT was 10.5 (2-25) months. Seventeen patients died between 0.3 to 11 months (median 2.0) after alloBMT, all due to BMT-related toxicities. Three patients remain alive and free of disease at 1.1, 1.2 and 2.5 years after alloBMT. Sixteen of the 18 evaluable patients (89%) developed grade II-IV acute GVHD. Patients undergoing alloBMT after ASCT have a very high treatment-related mortality and incidence of grade II-IV acute GVHD. Alternative treatments with salvage chemotherapy, radiation or investigational approaches should be considered in patients who relapse after ASCT.     

Rapid tapering of cyclosporine for cytogenetic relapse shortly after bone marrow transplantation in a patient with chronic myeloid leukemia

A new therapy for the treatment of oral leukoplakia by 5-aminolevulinic acid (ALA) and photodynamic therapy (PDT) is presented. ALA, a precursor in the biosynthesis of haeme, induces the production of the endogenous photosensitizer protoporphyrin IX which can be used for PDT. Twelve patients, who had been suffering from leukoplakia of the oral mucosa for several years, were treated by ALA-mediated PDT. ALA was used as a topical photosensitizer and 20% ALA cream was applied to the leukoplakia lesion of the oral mucosa for two hours and then light activated at 630 nm, 100 mW/cm2 and 100 J/cm2. Five patients showed complete response to the treatment, four patients showed a partial response and in three patients treatment was unsuccessful. One patient with partial response was retreated, after which the lesion disappeared.     

Donor leukocyte transfusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation

We reviewed 4 cases of high-grade transitional-cell carcinoma (TCC) of the urinary tract with solitary pulmonary metastases that were studied by transthoracic needle aspiration biopsy cytology. There were two grade II and two grade III TCCs. The two grade II tumors yielded, in needle aspirates, syncytial tumor-cell clusters showing ill-defined, granular cytoplasm and slightly pleomorphic nuclei with inconspicuous nucleoli. In one case the tumor-cell cluster showed a focal acinar arrangement, mimicking cells of an adenocarcinoma. In both cases the electron microscopy (EM) study of aspirated tumor cells revealed epithelial cells with well-formed cell junctions, intracytoplasmic vesicles, apical short microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial neoplasm. The two grade III TCCs yielded, in needle aspirates, pleomorphic malignant cells singly and in small clusters, showing well-defined, granular cytoplasm and pleomorphic nuclei containing prominent nucleoli, suggesting a poorly differentiated adenocarcinoma or an anaplastic large-cell carcinoma. By EM examination the aspirated tumor cells from one case revealed well-formed cell junctions, intracytoplasmic vesicles, poorly formed microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial differentiation. In the other case the tumor cells were pleomorphic cells with occasional cell junctions and no ultrastructural features as seen in the other 3 cases of TCC. The tumor cells from the two grade II TCCs showed strong immunopositive reaction with keratin 7 antibody and weakly positive reaction with carcinoembryonic antigen antibody (CEAA), while those of the two grade III TCCs displayed only a weak and focal immunopositive staining with keratin 7 antibody and strong reaction with CEAA.     

Transient complete remission of acute lymphoblastic leukemia in relapse after allogeneic bone marrow transplantation induced by donor leukocyte transfusions

We report the case of a young patient with refractory acute lymphoblastic leukemia relapse, after allogeneic bone marrow transplantation, who was treated by donor leukocyte infusions. We observed potent adoptive immunotherapy which produced a cytologic complete remission and total chimeric state. This was of short duration and the patient died of severe graft-versus-host disease. We present a short summary of the literature concerning acute lymphoblastic leukemia and donor leukocyte infusions.     

Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation

Relapse remains a significant problem after allogeneic bone marrow transplantation (BMT). For patients with relapsed chronic myelogenous leukemia (CML), infusions of donor mononuclear cells (MNC) provide a potent graft-versus-leukemia (GVL) reaction inducing complete remissions in the majority of patients. Little is known about the efficacy of donor MNC infusions for patients who relapse with other diseases. We have studied the GVL effects of donor MNC in eight patients with relapsed acute leukemia or myelodysplasia (MDS). One patient with relapsed MDS achieved complete remission and another patient had a transient response. Five of six non-responders died of progressive leukemia and one non-responder died of complications during second BMT. Three patients developed grade I-II acute GVHD responsive to immunosuppression. These data, and review of the literature, suggest that GVL induction with donor MNC infusions is less effective for patients with relapsed acute leukemia than for patients with relapsed CML; too few patients with relapsed MDS have been treated to draw definite conclusions. However, some patients respond, and given the high mortality associated with alternative procedures such as second BMT, donor MNC infusions are a reasonable approach for relapsed acute leukemia and MDS after allogeneic BMT.     

Allogeneic matched T-cell-depleted bone marrow transplantation for acute leukemia patients

It has been shown that high doses of human recombinant erythropoietin (r epo) increase haemoglobin levels by augmentation of F-cells, and Hb-F production in animal models and in human trials. In this study, r epo was used in patients with beta thalassemia intermedia. Our purpose was to improve haemoglobin levels by at least 2 g and maintain an average level between 10 and 12 g/dl. Ten patients aged 6-29 years (mean 14 +/- 7.6 years) with thalassemia intermedia were treated with r epo. It was given subcutaneously in rising doses from 500 to 1000 U/kg three times weekly for 3 months. During r epo therapy eight cases (80 per cent) showed an increase in haemoglobin, haematocrit, and reticulocyte levels, and an increase of at least 2 g of haemoglobin was obtained. Blood transfusion was not needed during the study except in one case. Five cases (50 per cent) improved life quality with therapy. Hb levels of all patients returned to baseline values over 1 or 2 months after r epo was discontinued. There was no significant change in absolute Hb-F, F-cells, and ferritin levels during treatment. Generally, the drug was well tolerated. No patient had hypertension. Recombinant erythropoietin seems to be an effective treatment for anaemia of beta-thalassemia intermedia, but longer term randomized trials are needed especially in patients with beta thalassemia major.     

Unrelated donor bone marrow transplantation for children with acute leukemia

PURPOSE: To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS: Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS: The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION: URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.     

Importance of mixed chimerism to predict relapse in persistently BCR/ABL positive long survivors after allogeneic bone marrow transplantation for chronic myeloid leukemia

Determination of hematological chimerism could be helpful in understanding the biology of leukemic relapse after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML), because the detection of malignant residual cells carrying the bcr/abl message by qualitative RT-PCR is of limited value in predicting disease progression for individual patients. We have studied the chimerism pattern and the bcr/abl status by Southern-blot in 15 CML patients (M/F:6/9) transplanted with unmanipulated BM from HLA identical sibling donors, persistently bcr/abl positive by RT-PCR. The median age of the series was 31 years (18-49) and disease status at BMT was: chronic phase: 11, accelerated phase: 3 and blast crisis: 1 patient. Of the 15 patients, 9 are alive and in complete remission (CR), 4 have died in CR and 2 are alive but suffered relapse at + 19 and +26 months post-BMT. The median follow-up is 81 months (13,7-168). Rearrangement of the BCR gene was performed by Southern-blot using P32-labeled transprobe-1. PCR analysis of chimerism was assessed using primers for the following VNTR loci: D1S80, D1S111, 33.1, APO-B, YNZ-22, lambdag3 and DXS52. Seventy-nine samples were analyzed (median per patient 5 (range 2-9)). Thirteen patients showed complete chimerism and lacked BCR rearrangement over time by Southern-blot. The 2 patients who relapsed showed mixed chimera status from +9 and +5 months respectively until the end of the study. Persistent BCR rearrangement was observed in these 2 patients from +12 and +11 months respectively. Our data suggest that mixed chimerism may predict hematologic or cytogenetic relapse by several months in those patients who are persistently PCR-positive post-BMT.     

Alpha-interferon treatment of chronic hepatitis C after bone marrow transplantation for homozygous beta-thalassemia

The standard modality of the treatment for the patients with T4 esophageal cancer, whose prognosis still remains quite poor, is not established yet. Salvage surgery for the T4 esophageal cancer following downstaging by neoadjuvant chemo-radiotherapy has become to be available. During the period from 1992 to 96, 30 patients with the suspected T4 esophageal cancer underwent chemoradiotherapy, which consisted of two courses of CDDP/5-FU with-sequential or concurrent 50-60Gy radiotherapy. Among them eleven patients became to be resectable by means of thoracotomy and laparotomy and pathological CRs were obtained in either primary lesions or lymph nodes. The longest survival term following surgery is 36 months. Three patients died of cancer recurrence including the organ metastasis and one died from pyothorax without cancer due to severe immunosuppression attributable to chemoradiation. Our results warrants further studies of neoadjuvant chemoradiotherapy for the patients with T4 esophageal cancer.     

Reimmunization after allogeneic bone marrow transplantation

BACKGROUND/AIMS: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia. METHODS: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection. RESULTS: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin. CONCLUSIONS: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.     

Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is the only effective treatment for hematologic malignancies resistant to conventional chemotherapy. Until recently, no cure existed for patients who relapsed post-BMT. We present our long-term observations on remission induction, after relapse post-BMT, by allogeneic cell therapy (allo-CT) and the feasibility of remission induction in allo-CT-resistant patients by activation of antileukemia effector cells with recombinant human interleukin-2 (rhIL-2) in vitro and in vivo. The longest observation of successful allo-CT (event-free survival, greater than 8 years) was made in a patient with resistant pre-B lymphoblastic leukemia who received infusions with graded increments of donor (female) peripheral blood lymphocytes (PBL) as soon as bulky hematologic and extramedullary relapse was noticed early post-BMT. The patient is currently without evidence of residual host (male) cells as determined by polymerase chain reaction (PCR). Of 17 patients with acute and chronic leukemia in relapse after BMT, 10 were reinduced into complete remission. Four patients with cytogenetic relapse responded to allo-CT alone, while five of six patients with overt hematologic relapse responded only after additional activation of donor with rhIL-2. Allo-CT can, therefore, successfully reverse chemoradiotherapy-resistant relapse of both acute and chronic leukemia. Moreover, in patients resistant to donor lymphocyte infusion, remission can be accomplished by additionally activating donor PBL in vitro and/or in vivo with rhIL-2. Based on our observations, after BMT, allo-CT should be considered the treatment of choice for patients with hematologic malignancies resistant to conventional anticancer modalities. Allogeneic activated cell therapy (allo ACT) should be considered for patients with tumor cells resistant to allo-CT. Although allo-CT, followed if indicated by allo-ACT, can be effective for patients with overt hematologic relapse, reversal of persistent minimal residual disease or documented molecular/cytogenetic relapse early after BMT may also be considered as a possible indication for allo-CT.     

Long-term follow-up of immunosuppressive treatment for obstructive airways disease after allogeneic bone marrow transplantation

BACKGROUND: Locally advanced thyroid cancer invading the tracheal cartilage represents a difficult treatment dilemma during thyroidectomy. METHODS: A retrospective chart review was performed to determine the results of laryngotracheal resection or tracheal cartilage shave with adjuvant radiotherapy in patients with locally advanced thyroid cancer invading the upper airway. RESULTS: Of 597 patients undergoing thyroidectomy for thyroid cancer, 40 were found to have laryngotracheal invasion. Thirty-five patients with superficial invasion underwent cartilage shave procedures with adjuvant radiotherapy; five with full-thickness invasion underwent radical resection, including tracheal sleeve resection (n = 3) or total laryngectomy (n = 2). Histologic subtypes included papillary (n = 32), follicular (n = 2), Hurthle cell (n = 1), medullary (n = 3), and anaplastic (n = 2). Of the cartilage shave group, 25 are currently alive with no evidence of disease at a mean follow-up of 81 months (range 1-290). Six developed isolated local/regional recurrence and were managed with total laryngectomy (n = 1), tracheal resection (n = 1), cervical lymphadenectomy (n = 1), or repeat radiotherapy (n = 3). All six patients remain free of disease at a mean follow-up of 5 years. Of those who underwent initial laryngotracheal resection, four remain free of disease at a mean follow-up of 5 years. The rates of 10-year disease-free survival and overall survival for all patients were 47.9% (95% confidence interval [CI] 24.8, 71.0) and 83.9% (95% CI 70.3, 97.5), respectively. CONCLUSIONS: These data suggest that adequate management of thyroid cancer with laryngotracheal invasion can be achieved with a more conservative surgical approach and adjuvant radiotherapy, reserving more radical resections for extensive primary lesions or locally recurrent disease.