We report two patients with a distinctive biphenotypic hematologic disorder characterized by lymphoblastic lymphoma (LBL), eosinophilia, and myeloid malignancy and/or hyperplasia associated with a t(8;13)(p11;q11) chromosomal translocation in both bone marrow and lymph node specimens. Both patients presented with lymphadenopathy pathologically classified as LBL with a T-cell immunophenotype, myeloid hyperplasia of the bone marrow, and peripheral blood eosinophilia. The first patient achieved clinical complete remission after receiving several regimens of chemotherapy and remains disease-free 16 months after undergoing allogeneic bone marrow transplantation. The second patient developed progressive lymphadenopathy despite several courses of chemotherapy directed against non-Hodgkin's lymphoma. Eight months after his initial presentation, he developed acute myelogenous leukemia that was refractory to therapy. Comparison of these patients with four similar cases recently reported in the literature suggests that this constellation of findings constitutes a distinctive clinicopathologic syndrome. Molecular analysis of the t(8;13) translocation breakpoint may identify genes located in this region and provide insight into the pathogenesis of this interesting biphenotypic hematologic malignancy.

Despite reports to the contrary, only a small minority of adults with ALL are currently cured. Results have improved modestly with more intensive postremission chemotherapy and with tailoring of protocols in individuals with specific subsets of ALL. The use of growth factors may further improve treatment results. The performance of allogeneic BMT in first remission is clearly effective in some individuals, eg, those with Ph1-positive ALL, but it is unclear whether it is advantageous in most individuals. There are little data supporting the effectiveness of autotransplantation, as currently performed in ALL, despite its theoretical potential. Advances in understanding the biology of ALL have led to new approaches currently under basic and clinical investigation. These include serial studies of minimal residual disease by a variety of techniques to tailor treatment, the development of conjugated MoAbs to lymphoid cell antigens and immunologic and biochemical approaches to chimeric RNA and peptides generated by abnormal fusion genes. It seems likely that substantial improvement in the treatment of adult ALL awaits better characterization of the biology of this disease. However, some improvement will occur through empirical clinical research. It is critical that physicians recognize the poor results with current therapeutic approaches and enter patients into large well-designed clinical trials.

Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA-identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo-identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA-haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the western hemisphere. Diagnosis and staging of CLL are usually straightforward, but predicting an individual patient's prognosis is still a challenge. Cytogenetic abnormalities provide important prognostic information in CLL and may show its molecular heterogeneity. A search for oncogene abnormalities continues, although no consistent defects have been identified. New agents such as fludarabine produce high complete remission rates and have generated interest in earlier treatment as a first step in a potential cure. Fludarabine also makes autologous bone marrow transplant feasible as a consolidation therapy. Immunologic abnormalities and minimal residual disease persist in most patients in remission. Combining fludarabine with other active agents and devising effective postremission strategies may change the natural history of CLL.

Transfusion of autologous peripheral blood stem cells (PBSCs) of good quality ensures fast hematopoietic engraftment after myeloablative therapy with a decrease in procedure-related morbidity and mortality. We have analyzed variables influencing the kinetics of engraftment, and therefore reflecting the quality of PBSC collections, in 225 patients with newly diagnosed or refractory multiple myeloma (MM) who received an autotransplant in support of high dose melphalan (200 mg/m2); 132 of these patients also completed a second transplant. All PBSCs were collected before the first transplant after high-dose cyclophosphamide (6 g/m2) and hematopoietic growth factors, mainly granulocyte-macrophage colony-stimulating factor. PBSCs were administered either alone (91 patients) or with bone marrow (134 patients). A highly significant correlation was observed between the number of CD34+ cells per kilogram infused and prompt recovery of both granulocytes (P = .0001) and platelets (P = .0001). After correction for the proportion of patients with > or = 2 x 10(6)/kg CD34 PBSCs infused and with < or = 12 months of prior therapy, no difference in engraftment kinetics was seen between patients receiving PBSCs only and those also receiving bone marrow. Exposure to chemotherapy, even to < or = 6 months of alkylating agents, significantly delayed hematopoietic recovery posttransplantation. The threshold dose of CD34 cells necessary for prompt engraftment was > or = 2.0 x 10(6)/kg for patients with < or = 24 months of chemotherapy before the first transplant, whereas greater than 5 x 10(6)/kg CD34 cells were required to assure rapid recovery also in those with longer exposure. Such quantities, easily collected in the large majority of patients with shorter exposure (91%), were obtained in only 28% of patients with more than 24 months of prior chemotherapy. Rapid platelet recovery within a narrow range of time (before day 14) was almost invariably seen (94%) when greater than 5 x 10(6)/kg CD34 cells were infused, irrespective of the duration of prior therapy, whereas the range widened progressively when less CD34 cells were infused. In the absence of CD34 measurements, fast recovery of platelets to greater than 50 x 10(9)/L within 14 days after high-dose cyclophosphamide and < or = 12 months of prior chemotherapy were the best predictors of early engraftment. Prudent use of stem cell-damaging agents, such as melphalan and nitrosoureas, is recommended in MM patients who might be candidates for autotransplantation. Alternatively, PBSCs should be collected early after diagnosis.

The records were reviewed of 58 patients receiving transplants in Seattle with unmanipulated marrow from HLA-identical siblings during the accelerated phase (AP) of chronic myeloid leukemia. Variables examined for association with survival and relapse included the interval from diagnosis to transplant, the reasons for categorization as AP, age, regimen, and cytomegalovirus serology. Four patients relapsed. The 4-year probabilities of survival, relapse-free survival, nonrelapse mortality, and relapse were 0.49, 0.43, 0.51, and 0.12, respectively. After completion of the stepwise multivariate analysis, age less than 38 years and categorization as AP solely on the basis of chromosomal abnormalities emerged as being independently significantly associated with improved survival. The 4-year probability of survival for the 16 patients categorized as AP because of chromosomal abnormalities and receiving transplant less than 1 year from diagnosis was 0.74. The low probability of relapse in these patients suggests that more aggressive preparative regimens are not indicated for patients receiving transplants in AP because of the increased risk of transplant-related mortality.

We report the outcome of allogeneic bone marrow transplantation (BMT) as treatment for severe combined immunodeficiency disease (SCID) in 31 patients grafted from 1968 until 1992. The patients received a graft from an HLA-identical related (n = 10), an HLA-haplo-identical related (n = 19), or a closely HLA-matched unrelated (n = 2) donor that resulted in the long-term survival of 6 of 10, 9 of 19, and 0 of 2 children, respectively. Major complications included failure of engraftment and early death caused by respiratory failure. The chimerism pattern and immunologic reconstitution were evaluated in 15 children who survived more than 1 year with sustained engraftment. The pattern of engraftment was investigated within flow-sorted peripheral blood (PB) T- and B-lymphoid, natural killer (NK), and myelomonocytic cell populations using the amplification of variable number of tandem repeats by the polymerase chain reaction. The immunologic reconstitution was assessed by various in vitro and in vivo parameters. Although the number of PB T cells and the in vitro T-cell proliferative response was in the lower region of normal in the majority of cases and even subnormal in some, in all cases donor T-cell engraftment and reconstitution of T-cell immunity was observed. Residual host-type T cells (1% to 5%) were detected in eight cases at multiple occasions. All children showed normal serum IgM and IgG subclass levels and produced specific IgG antibodies after vaccination, irrespective of donor B-cell engraftment. However, three HLA haplo-identical graft recipients with host-type B lymphoid and myeloid cells have a persistent selective IgA deficiency. NK cells were either of donor, host, or mixed origin. Donor NK cell engraftment restored defective in vitro NK cell function of the recipient. We conclude that determination of lineage-specific engraftment patterns provides valuable information for the understanding of the immunologic reconstitution after allogeneic BMT for SCID.

All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or "short") was associated with a significantly shorter duration of relapse-free and overall survival (P = .005).(ABSTRACT TRUNCATED AT 400 WORDS)