Donor leukocyte infusions after unrelated donor hematopoietic stem cell transplantation

PURPOSE OF REVIEW: Donor leukocyte infusions provide direct and potent graft-versus-tumor activity to treat relapse after allogeneic stem cell transplantation. Extensive data are available on the use of donor leukocyte infusion after matched-sibling stem cell transplantation, but reports are remarkably few on the use of donor leukocyte infusion after unrelated-donor stem cell transplantation. But the role for unrelated-donor leukocyte infusion is not well established. RECENT FINDINGS: The dramatic success of donor leukocyte infusion to treat relapse after matched-sibling stem cell transplantation has led to the use of unrelated-donor leukocyte infusion in many patients. Several case studies suggest that unrelated-donor leukocyte infusion effectively induces direct graft-versus-tumor reactions with toxicity comparable to that of matched-sibling donor leukocyte infusion. Important issues include the relationship between dose and response/toxicity appropriate timing, dose, and schedule; and identification of the best tumor targets. In particular nonmyeloablative transplant strategies using unrelated donors are expanding rapidly, but relapse rates are high. There is a paucity of data on unrelated-donor leukocyte infusion in this setting. SUMMARY: This review summarizes recent data on the use of unrelated-donor leukocyte infusion. We discuss anticipated outcomes and identify areas under active investigation in both ablative and nonmyeloablative unrelated-donor stem cell transplantation.     

Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions.

In this prospective study we analyzed pre-emptive donor leukocyte infusions (DLI) in 82 consecutive patients transplanted with partially T cell-depleted grafts for acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation and multiple myeloma. Donors were HLA-identical siblings. Patients without significant acute (>grade 1) and/or chronic GVHD were scheduled to be treated with DLI (35 patients) and 31 actually received DLI. Patients who developed acute GVHD >grade 1 and/or chronic GVHD were not scheduled to receive DLI and served as a comparison group (47 patients). The median interval between BMT and DLI was 22 weeks. The first six patients received 0.7 x 10(8) CD3+ cells/kg body weight (b.w.). Five out of these six patients developed acute GVHD (grade 1: n = 2, grade 3: n = 2 and grade 4: n= 1) which was more frequent and more severe than we had anticipated. In the next 25 patients the number of T lymphocytes was diminished to 0.1 x 10(8) CD3+ cells/kg b.w. which resulted in less frequent and less severe GVHD. Eight patients in this group developed acute GVHD (grade 1: n = 4, grade 2: n = 4) and three patients had limited chronic GVHD. Patients in the DLI group needed more time to establish complete donor chimerism confirmed by a higher number of mixed chimeras at 6 months after BMT. The projected 3-year probability of disease-free survival was 77% for the 35 patients intended to treat with DLI and 45% for the patients of the comparison group (P = 0.024). Relapse rate at 36 months after transplantation was 18% in the patients who were intended to treat with DLI and 44% in the comparison group (P = 0.026). We conclude that pre-emptive DLI is feasible and generates favorable relapse rates in patients who are at high risk for relapse. Furthermore, the incidence and severity of GVHD disease after DLI is dependent on the number of CD3+ cells infused.     

Unrelated donor bone marrow transplantation in adults: some current controversies

The results of unrelated donor bone marrow transplantation are continually improving. These improved results are due to a better understanding of the complications of the procedure and the devising of strategies to avoid them. Nonetheless, many problems remain. This review will address some of the major controversies of the field including the indications for UD-BMT, infection, GVHD prophylaxis and treatment and whether UD-BMT should only be performed in specialist centres. Conclusions will be supported by evidence from the limited published literature and the authors' experience in 3 major transplant centres.     

Extramedullary relapse of acute lymphoblastic leukemia in the breast after unrelated allogeneic bone marrow transplantation

A 28-year-old female presented with an isolated extramedullary relapse in the breast following an unrelated allogeneic bone marrow transplantation(UBMT)for acute lymphoblastic leukemia. She complained of a tumor in her right breast with hematological complete remission 23 months after her first UBMT. The extramedullary lesion resolved with chemotherapy, and she then received a second UBMT. Although there had been no relapse of leukemia in the bone marrow and extramedullary sites, she died from a herpes simplex virus infection in the central nervous system. Extramedullary relapses in the so-called 'sanctuary'sites after hematopoietic stem cell transplantation are unusual, and breast recurrences are even more rare. A treatment strategy for unusual sites of relapse after BMT should be established.     

Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation.

PURPOSE: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)-primed DLIs. PATIENTS AND METHODS: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF-primed DLIs. No prophylactic immunosuppression was provided. RESULTS: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A posttransplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission. CONCLUSION: Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem.     

Filgrastim as an alternative to donor leukocyte infusion for relapse after allogeneic stem-cell transplantation.

PURPOSE: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT. PATIENTS AND METHODS: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse. RESULTS: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively. CONCLUSION: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT.     

Post-liver transplantation lymphoproliferative disorders with and without infusions of donor bone marrow cells.

Donor bone marrow cells (DBMC) infusions have been used in an attempt to decrease the untoward effects of immunosuppressive treatment and to improve immunocompetence in the post-liver transplantation (PLT) period. Between March 1987 and July 1996, 558 orthotopic liver transplantations were performed at Jackson Memorial Hospital/University of Miami. Of these, 164 patients (29%) received 10 x 10(8) DBMC/Kg using various schedules. All patients received similar immunosuppressive therapy. After a minimum follow up of 1 year, five cases of Posttransplant Lymphoproliferative Disorder (PTLD) were diagnosed in patients without DMBC (1.3%, 5/394) when compared with none (0/164) in patients who received DBMC (p = 0.15, Fisher). Four patients had malignant lymphoma and one a diffuse atypical lymphoproliferative disorder. All lymphomas were non-Hodgkin's B-cell type, three diffuse large cell lymphoma, and one mixed cell lymphoma. All PTLD tested positive for EBV by in situ hybridization. Lymphomas occurred at 2, 4, 6 months and 4 years PLT. The outcome was poor with one patient diagnosed at autopsy while two patients died a few days after diagnosis. An 8-year-old girl is the only long-term survivor (> 5 years) after a partial response to combination chemotherapy and radiation therapy. The patient with diffuse atypical lymphoproliferative disorder died 3 months later. All patients with PTLD had histologic evidence of liver rejection. Although there is no statistical significant difference between the two groups, a larger cohort of patients will determine the significance of DBMC in preventing PTLD. We believe that the infusion of cytotoxic donor T cells found in the DBMC might suppress EBV-related lymphomagenesis.     

Very late relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation

Allogeneic stem cell transplantation is considered to be a curative treatment modality in patients with chronic myelogenous leukemia. However patients are at risk for relapse years after transplantation. Currently we present two patients who relapsed 16 and 24 years after allogeneic bone marrow transplantation, respectively. These patients emphasize the need for long term follow-up of such patients.     

Central nervous system relapse after bone marrow transplantation for acute myeloid leukemia

Central nervous system (CNS) relapse with meningeal leukaemia occurred 6 months after allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia, without systemic relapse. Despite intrathecal chemotherapy a severe progressive proprioceptive impairment of the lower limbs developed. Autopsy revealed selective ascending tract degeneration of the gracile fasciculi of the posterior columns of the spinal cord and residual endoneurial deposits were found in lumbosacral dorsal nerve roots and ganglia. While CNS relapse may occur in acute leukaemia after chemotherapy, it has rarely been reported following BMT.     

Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse.

For patients with acute myeloid leukemia (AML) relapsed after allogeneic bone marrow transplantation (BMT), donor leukocyte infusion (DLI) as sole therapy has very limited efficacy. We tested the effects of cytoreductive chemotherapy, followed immediately by G-CSF-primed DLI (chemotherapy followed by DLI, Chemo-DLI), in 16 AML patients who relapsed after allogeneic BMT. In all, 10 of these patients achieved complete remission (CR), four of whom remain alive in CR at a median follow-up of 1488 days after DLI. The 2-year overall survival (OS) for the entire cohort was 31%. The 1-year OS for patients with post-BMT remission of 6 months or longer was 55%, compared with 0% for patients with post-BMT remission of less than 6 months, making post-BMT remission duration the only significant prognostic factor for OS (P=0.015). These findings suggest that Chemo-DLI could induce durable remissions in a proportion of relapsed AML patients with relatively long post-BMT remission duration. All five patients who relapsed after achieving CR with Chemo-DLI relapsed at extramedullary sites in the presence of continuous bone marrow remission, suggesting uneven graft-versus-leukemia effects in different parts of the body. Although our data should be interpreted cautiously considering the limited number of patients, isolated extramedullary relapse seems to be common after Chemo-DLI.     

An unusual extramedullary relapse of acute nonlymphocytic leukemia after allogeneic bone marrow transplantation

Recurrent leukemia following allogeneic bone marrow transplantation (BMT) for acute nonlymphocytic leukemia (ANLL) continues to be a cause of morbidity and mortality. Most relapses occur within the first 6-12 months, although disease-free survival curves do not begin to plateau until 24 months posttransplant. The majority of relapses occur in the bone marrow. Extramedullary relapses usually occur in "sequestered sites," i.e., the testis and central nervous system. Although the true incidence of extramedullary relapse in "nonsequestered" sites after allogeneic BMT for ANLL is unknown, it appears that this type of relapse is distinctly unusual. The authors present a case of an unusual extramedullary relapse of ANLL in the breast at day +613 after allogeneic BMT for ANLL. In addition, we briefly review the English BMT literature and discuss the differential diagnosis of breast masses in women who survive allogeneic BMT for ANLL.     

In relapsed patients after lymphocyte depleted bone marrow transplantation the percentage of donor T lymphocytes correlates well with the outcome of donor leukocyte infusion

Donor leukocyte infusions (DLI) from the original marrow donor have been shown to induce remission in patients with relapse after BMT. We analyzed factors that were associated with remission. Twenty-six patients with a relapse after T cell depleted BMT received DLI. The following pre-DLI factors were analyzed: sex and age of the patients and donors, GVHD after BMT, indication for DLI, percentage of donor T lymphocytes in the patient at the time of DLI, interval between relapse and DLI, and number of T lymphocytes infused. Remission was achieved in 11 of 15 patients (73%) treated for relapsed CML and in one of 11 patients (9%) treated for relapsed AML, ALL or RAEB-t (P = .002). Two of 13 patients (15%) with < or =40% of T lymphocytes from donor origin attained remission compared with 10 of 13 patients (77%) with >40% (P = .002). Two of 13 patients (15%) with an interval of < or =18 months between BMT and first DLI entered remission compared with 10 of 13 patients (77%) with an interval of >18 months (P = .002). Multivariate analysis demonstrated that indication for DLI (CML versus AML/ALL and RAEB-t) and the percentage T lymphocytes from donor origin (< or =40 versus >40) were significantly correlated with remission (P = .03). The occurrence of GVHD post DLI was highly associated with achievement of remission (P = .0001). DLI res ults in remission in a high percentage of patients with relapsed CML after BMT. The percentage of T lymphocytes from donor origin still present in the patient at the time of DLI is highly correlated with achievement of remission.     

Multiple unrelated clonal abnormalities in host bone marrow cells after allogeneic stem cell transplantation

A 22-year-old man with chronic myeloid leukemia (CML) received fractionated total body irradiation (TBI) (1440cGy) and etoposide (60 mg/kg) followed by infusion of 10 x 10(6) /kg CD34+ selected stem cells from his mother. Donor and recipient were 50% matched at the HLA-A and -B loci and 100% at HLA-DR. Mixed lymphocyte culture reaction was negative. Post-stem cell transplant (SCT) immunosuppression consisted of antithymocyte globulin, cyclosporine, and prednisone, and was discontinued after 7 months. The donor graft was rejected 2 years post-SCT. At 7 years post-SCT, he is clinically well with normal blood counts and no evidence of CML or myelodysplasia despite the presence over 6 years of multiple clones with balanced translocations and deletions in host bone marrow cells. The emergence of clonal hematopoiesis may provide insights into therapy-related leukemogenesis.     

Preparations for unrelated donor transplantation

This mini-review briefly describes some of the issues that are important for a transplant physician preparing a patient for an unrelated donor (UD) stem cell transplant. It is primarily directed at referring hemato-oncologists and trainees in transplantation and aims to provide them with the information they require to deal with these patients appropriately and efficiently. It discusses search strategies, the need for urgency and early identification of the major problems that will determine the outcome of the transplant. Excellent communication with the histocompatibility and immunogenetics laboratory and the referring physician are emphasized. Many of the recommendations are derived from personal experience; there is a need for more of an evidence base to aid decision-making.     

Successful unrelated cord blood transplantation for relapse after autologous transplantation in non-Hodgkin's lymphoma

We report a 34-year-old male with relapsed non-Hodgkin's lymphoma (NHL) after autologous peripheral blood stem cell transplantation successfully treated with unrelated cord blood transplantation (CBT). The conditioning regimen included 12 Gy total body irradiation and cyclophosphamide. After the conditioning, a total of 3.14 x 10(7)/kg cord blood nucleated cells was infused on 14 February 2000. An absolute neutrophil count greater than 5 x 10(8)/l and a self-sustained platelet count greater than 50 x 10(9)/l were achieved on days 21 and 43, respectively. During the follow up period, grade I acute graft-versus-host disease (GVHD) and limited chronic GVHD occurred, but both were successfully treated with a dose modification of cyclosporine. After a follow-up period of 16 months, the patient is alive and free of disease. To our knowledge this is the first report of a successful unrelated CBT for an adult NHL patient who relapsed after autologous transplantation.     

Fibrous dysplasia masquerading as extramedullary relapse after bone marrow transplantation for chronic myeloid leukemia

A 19-year old girl suffered from relapse of chronic myeloid leukemia (CML) after bone marrow transplantation. The disease was controlled by interferon and imatinib mesylate, but was complicated by autoimmune hyperthyroidism. She presented with unilateral proptosis with no extraocular muscle or visual defect at 26 months follow-up. Systemic investigations showed no recurrence of leukemia or thyrotoxicosis. Magnetic resonance imaging revealed an extensive retro-orbital base of skull lesion. A trans-oral biopsy showed fibrous dysplasia and continuous observation was advised. The unusual sequence of events and the differential diagnoses for unilateral proptosis in post bone marrow transplantation (BMT) cases are discussed.     

Incidence of hyperthyroidism after unrelated donor allogeneic stem cell transplantation

We report on three patients who developed overt thyrotoxicosis after volunteer unrelated donor bone marrow transplantation for Philadelphia chromosome positive chronic myeloid leukemia shortly after the onset of chronic graft versus host disease. In all three cases, the etiology of hyperthyroidism is likely to be a combination of toxic factors and an immune process. Systematic evaluation of thyroid function tests in 97 unrelated allograft recipients from our center who survived at least 100 days from stem cell or bone marrow transplantation for hematological diseases gave a rate of overt thyrotoxicosis at 3.1% in this cohort.