Infusions of large numbers (> 10(8)/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 x 10(5) and 5 x 10(8). Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 x 10(7) (n = 8), 5 x 10(7) (n = 4), 1 x 10(8) (n = 3), and 5 x 10(8) (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 x 10(7)/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of > or = 5 x 10(7)/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 x 10(7)/kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.

Manifestations and risk factors of graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age 37 years) transplanted for hematologic malignancies with myeloablative or non-myeloablative conditioning and calcineurin-inhibitor/ mycophenolate mofetil immunosuppression. Incidences of day 180 grade II–IV and III–IV acute GVHD (aGVHD) were 53% (95%CI: 44–62) and 23% (95%CI: 15–31), respectively, with a median onset of 40 days (range 14–169). Eighty percent of patients with grade II–IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome, whereas late GVHD in the form of classical chronic GVHD was uncommon. Notably, grade III–IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A,-B,-DRB1 allele match was > 4/6 to the recipient (HR 0.385, p = 0.031), whereas engrafting unit infused nucleated cell dose and unit-unit HLA-match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA-match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed.

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Summary:Evans syndrome is a rare disorder characterized by combined autoimmune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Standard treatments consist of transfusions, corticosteroids, splenectomy, IVIG, anabolic steroids, vincristine, alkylating agents, or cyclosporine. In a patient with refractory disease, an allogeneic hematopoietic stem cell transplant (HSCT) resulted in complete clinical and serologic remission for more than 30 months. Allogeneic HSCT may be the only current curative therapy for Evans syndrome but may also be complicated by significant toxicities. Bone Marrow Transplantation (2001) 28, 903-905. Keywords: Evans syndrome; allogeneic stem cell transplantationIn December 1998, a 28-year-old male patient with refractory Evans syndrome (Hb of 9.1g/dl and platelets of 27 × 10 9 /l) was referred to Northwestern University for an allogeneic matched sibling HSCT. Symptoms first occurred in February 1996 when epistaxis and ecchymosis developed following flu-like symptoms of headache and diarrhea. Thrombocytopenia and anemia were present with platelets of 2 × 10 9 /l, hemoglobin of 8.8 g/dl, and WBC of 6.3 × 10 9 /l. Evidence of hemolysis included hyperbilirubinemia (3.8 mg/dl), an increased LDH (424 U/l), decreased haptoglobin (7 mg/dl), reticulocytosis (corrected reticulocyte count 5.5%), bone marrow erythroid hyperplasia, and a direct Coombs test (DAT) positive for warm reactive antiIgG and anti-C3D. Evidence for ITP included anti-platelet antibodies and increased megakaryocytes within the marrow. Cytomegalovirus (CMV) antibody was positive for IgM but negative for IgG indicating recent infection. There was no other evidence of coincidental or precipitating infections. Serology was negative for HIV, hepatitis A, B, and C, and indicated past Epstein-Barr virus infection. Anti-nuclear and anti-double stranded DNA antibodies were negative. An initial response was obtained with intravenous immunoglobulin (IVIG) and corticosteroids. Due to inability to wean high-dose corticosteroid therapy, or transfusion-dependent cytopenias, the patient was treated and subsequently failed multiple interventions including splenectomy (August 1996), IVIG, danazol, and vincristine (April 1997), azathioprine 100 mg/day (August 1997), IVIG (March 1998), and cyclosporine, IVIG, and vincristine (April 1998). Upon referral for transplant, the patient was platelet and red blood cell (RBC) transfusion-dependent despite prednisone, cyclosporine, and IVIG.Pre-transplant, the disease and treatment-related complications included hemoglobinuria, malaise, steroid-induced diabetes, vincristine-induced peripheral neuropathy, cyclosporine-induced tremor and nephropathy necessitating daily intravenous hydration, anemia-related syncope, retinal hemorrhage, and respiratory and renal failure that necessitated ICU transfer and respiratory support. Pre-transplant opportunistic infectious included cryptococcal fungemia, persistent CMV viremia, and mycobacterium avium positive blood cultures. Maintenance antimicrobial therapy ...