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Twenty-nine of 172 patients (17%) who received an allogeneic bone marrow transplant (BMT) from histocompatible sibling donors for hematologic malignancies were mixed hematopoietic chimeras; ie, they had a mixture of donor and host hematopoietic or lymphohematopoietic cells at greater than or equal to 14 days after transplantation. Twenty- four of the 29 mixed chimeras (83%) have remained in continuous complete remission for up to 116 months (greater than 9 years) following BMT. Four of the 29 patients (14%) have had recurrent leukemia, and 7 of the 29 (24%) have had moderate or severe graft-v- host disease (GVHD). Twelve of these 29 patients have persisted as stable mixed chimeras for greater than or equal to 2 years after BMT, whereas other patients converted to all donor-type hematopoiesis. The incidence of mixed chimerism was independent of the pretransplant regimen, the donor or recipient age (less than 20 v greater than 20 years), remission status (first complete remission of acute leukemia and first chronic phase of chronic myelocytic leukemia v later stages of disease), and type of leukemia. Our data indicate that mixed hematopoietic chimerism is not rare after BMT for hematologic malignancies and that its presence is compatible with long-term disease- free survival. Prospective studies of mixed chimerism after BMT are warranted to achieve better understanding of its biologic importance.

Within the Lukes-Collins classification system of malignant lymphoma, a tumor of large transformed lymphocytes, termed immunoblastic sarcoma (IBS), is described. This morphological type would have been included within the “histiocytic” category of Rappaport. Immunoblastic sarcoma may be of B-lymphocytic or T-lymphocytic origin. Since differences or similarities of these two variants have not yet been described, we reviewed the case histories of 35 such patients, all of whom had immunologic marker studies performed. Nineteen patients had T-cell IBS (T-IBS), whereas 16 had B-cell IBS (B-IBS). Median age for both groups was approximately 50 yr. A history of prior immune disorder was found in 31% of B-IBS and 16% of T-IBS cases. Prior lymphoproliferative malignancy was noted in 21% of T-IBS and 13% of B-IBS patients. All T- IBS patients first presented because of lymphadenopathy, whereas 56% of B-IBS cases initially presented because of extranodal disease. Systemic “B” symptoms were common in both. Similarly, most patients had widespread disease (stage III or IV) at diagnosis. Clinically suspected hepatic (p = 0.05) and retroperitoneal node (p = 0.01) involvement were more often found in T-IBS. Forty-one percent of T-IBS patients demonstrated polyclonal hypergammaglobulinemia, a finding seen in no B- IBS patient (p = 0.02). Although not statistically significant because of small numbers of patients, data on therapy and survival suggest that IBS of B-cell type may be successfully treated with aggressive, multiagent chemotherapy, while alternative approaches appear warranted in T-cell disease.

Of 33 patients who had undergone allogeneic bone marrow transplantation during first complete remission of acute nonlymphocytic leukemia, 21 patients have now been followed in continued complete remission for 6- 64 mo (median greater than 18 mo) without maintenance chemotherapy. The median age of the surviving patients is 27 yr. Transplant-related complications occurring throughout the first year after marrow grafting were fatal in 7 patients, and leukemic recurrence led to the death of 5 patients. The actuarial long-term disease-free survival is 60% and the actuarial remission rate is 79%.

In a phase I/II study, 47 patients (median age, 24 years) with hematologic malignancies (33 patients with acute leukemia not in first remission and 14 patients with other advanced malignant hematologic disorders) were treated with total body irradiation and high doses of etoposide (VP16–213) followed by bone marrow transplantation. At the time of analysis, 21 patients were alive, and 19 of them were in continued complete remission for 101 days to greater than 40 months (median, 12 months). The actuarial disease-free survival rate of the 33 acute leukemia patients is 43% (2 SEM, 18%) and the actuarial relapse rate is 32% (2 SEM, 20%). Five of the 14 patients with the other hematologic malignancies are alive, and four of them continue to be free of disease for 8 to 27 months. Pharmacokinetic studies established a strong correlation between the administered drug doses and their plasma levels and also demonstrated complete drug clearance prior to marrow grafting. An etoposide dose of 60 mg/kg body weight was found to be the maximum tolerated dose. This new preparatory regimen was well tolerated and was not associated with specific acute or long-term regimen-related toxicities. Our data suggest that total body irradiation with high-dose etoposide presents a viable alternative to other preparatory regimens. The role of this novel combination remains to be defined by future prospective randomized trials.

We designed a treatment program to improve the outcome for adults with acute lymphoblastic leukemia (ALL). Treatment included a remission- induction phase followed by intensive alternating cycles of non-cross- resistant chemotherapy and prolonged oral maintenance therapy. Eighty- one consecutive previously untreated patients were entered on this study. Ninety-four percent of patients entered complete remission. A Kaplan-Meier analysis predicts that 53% +/- 9% (SEM) of patients in remission will remain free of disease at 3 years. Neither age, sex, WBC count, nor immunophenotype had a significant effect on remission duration. This program of intensive cyclical chemotherapy has improved the disease-free survival of patients with adult ALL.

Although rare cases of chronic lymphocytic leukemia (CLL) of the T-cell type have been reported, CLL is more commonly found to be a neoplastic lymphoproliferative disease of B-cell origin. In this article, we describe a patient with long-standing CLL that was immunologically shown to be of the B-cell type, who, during the course of his disease, developed cutaneous T-cell lymphoma (CTCL), which was shown to be of the helper/inducer subtype. The neoplastic lymphoid cells in the skin infiltrate differed morphologically and immunologically from those in the peripheral blood. The occurrence of CTCL during this patient's clinical course represents a second neoplasm arising from a different cell line, rather than a tissue manifestation of the patient's CLL. To our knowledge, this is the first report in which the occurrence of CTCL is documented in a patient with immunologically known B-cell CLL. In addition to establishing the presence of B-cell CLL and CTCL of the helper/inducer T-cell type in the same patient, this case report demonstrates the usefulness and necessity of evaluating lymphoproliferative disorders by means of a multidisciplinary approach.

Fifteen adult patients with biopsy-proven convoluted T-lymphoblastic lymphoma were treated with an aggressive regimen, modified from the LSA2-L2 protocol used for childhood lymphoma. The treatment schema consisted of induction phase, including cyclophosphamide, vincristine, prednisone, adriamycin, and 2000 rads to mediastinum, as well as intrathecal methotrexate. Consolidation phase included cytosine arabinoside, 6-thioguanine, L-asparaginase, and CCNU, along with cranial irradiation and further intrathecal methotrexate. Maintenance consisted of cyclical chemotherapy and intrathecal methotrexate, continuing for a total of 3 yr. Median age in the group was 25 yr (range 16–73). There were 8 males and 7 females. At diagnosis, 9 patients had mediastinal involvement, and 9 had bone marrow involvement. Five of these demonstrated malignant cells in the peripheral blood. Complete clinical response was attained in 11 patients. Three patients achieved partial response. Four complete responders have relapsed, 1 in the central nervous system at 6 mo. and 1 in nodal sites at 3 mo, 1 in multiple sites at 24 mo. and 1 in bone marrow at 42 mo while off all chemotherapy for 6 mos. At this time, median survival of all patients is 28.3 mo. and median relapse-free survival is 21 mo. The median survival for complete responders in excess of 71 mo. while the median relapse-free survival for this group is 41 mo.

Human cyclic neutropenia shows many features in common with the animal model of cyclic neutropenia in grey collie dogs. Until now, however, evidence was lacking that cyclic neutropenia in man as in the dog is caused by a defect in a transplantable hematopoietic stem cell. A patient is presented who, while undergoing bone marrow transplantation as treatment for acute lymphoblastic leukemia in relapse, acquired cyclic neutropenia from her histocompatible sibling donor.

To clarify the clinicopathologic characteristics of Coombs' positivity in Hodgkin's disease, the records of 71 cases were reviewed. The direct Coombs test was positive in seven. Mean age of the seven was 22 yr (range 11–33). All were males. All had extensive disease (pathologic stage III or IV) and six had systemic (B) symptoms. Four had mixed cellularity; three had nodular sclerosis. The positive Coombs test was detected at original diagnosis in three and at time of relapse in four. Although all were anemic, only three had evidence of overt hemolysis. The antibody responsible for Coombs positivity was characterized in three and fulfilled the criteria for IgG anti-It. The presence of a positive direct Coombs test in the patient with Hodgkin's disease suggests active and advanced disease. The presence of IgG anti-It may represent a unique antibody in the Coombs-positive hemolytic anemia associated with Hodgkin's disease.

We have analyzed the T-cell receptor (TCR) V beta repertoire using polymerase chain reaction (PCR) in a cohort of eight patients receiving allogeneic bone marrow transplantation (BMT) from related and unrelated donors at the City of Hope. Results of PCR studies from graft-versus- host disease (GVHD) skin lesions show a bias in the usage of TCR V beta families, whereas examination of peripheral blood (PB) withdrawn at the same time did not reveal a similar phenomenon. In one such family, TCR V beta 2 is predominantly expressed in 7 of 7 biopsy specimens examined. V beta 2 TCR expression from these patients was analyzed more extensively using a combination of individual TCR gene cloning, followed by sequence analysis. We found evidence of oligoclonal expansion of single V beta 2-bearing TCRs in GVHD lesions, and in the PB of some patients after diagnosis of GVHD. In contrast, GVHD-negative biopsy samples showed no evidence for clonotypic TCR amplification. Sequence-specific TCR CDR3 region probes were derived from analysis of the predominant expressed TCR in GVHD lesions, and used to probe Southern blots of amplified V beta 2 TCR mRNA from PB and tissue from BMT recipients and their respective donors. In most cases the probes are highly specific in detecting TCR expression from GVHD lesions alone, although in several instances expression could be detected in PB after GVHD diagnosis. These data provide supporting evidence for the hypothesis that acute GVHD is associated with expansion of T-cell clones expressing antigen-specific TCRs that may contribute to the disease pathology.