Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study.

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

Case report: isoimmune inhibition of erythropoiesis following ABO-incompatible bone marrow transplantation.

A 26-year-old ABO-O positive patient with aplastic anemia received a bone marrow transplant from his genotypically HLA identical, but ABO-A positive, brother. Engraftment of myeloid and megakaryocytic lineages occurred within 4 weeks but pure red cell aplasia and transfusion dependent anemia persisted for 160 days. The authors postulated that the failure of erythropoiesis was due to a high titer of anti-A isohemagglutinins. They tested this hypothesis with clonal cell cultures and flow cytometric analysis of ABO antigen expression by colony forming cells in vitro. During the period of prolonged red cell aplasia, the patient had normal numbers (85 +/- 12 per 10(6) cells) of circulating donor derived, burst forming units-erythroid (BFU-E). Immunophenotypic analysis of erythroid burst colonies derived from culture of the patient's bone marrow cells showed that 91 +/- 5% of 274 nucleated red cells were A-antigen positive, confirming full donor engraftment. Autologous plasma and complement added on day 1 of culture did not affect the colony growth (82.5 +/- 15 per 10(6) cells). However, when the addition of complement was delayed until day 7 of culture, there was 90% inhibition of BFU-E (7.5 +/- 5 per 10(6) cells) compared to controls (p less than 0.0004). Based on this, the authors propose a model for expression of ABO antigens during erythropoiesis, in which BFU-E do not express ABO antigens but their progeny do. The data support the hypothesis that the mechanism of prolonged pure red cell aplasia after ABO-incompatible bone marrow transplantation is complement mediated immune destruction of erythroid progenitors past the stage of BFU-E in differentiation.

Role for aldehyde dehydrogenase in survival of progenitors for murine blast cell colonies after treatment with 4-hydroperoxycyclophosphamide in vitro.

We have studied the effects of 4-hydroperoxycyclophosphamide (4-HC) on murine hemopoietic progenitors. We found dose-dependent killing and differential sensitivities of colony forming cells with burst forming units-erythrocyte being most sensitive and colony-forming units-granulocyte/erythrocyte/macrophage/megakaryocyte most resistant. We also tested the effects of 4-HC on more primitive murine progenitors which were identifiable in our assay system when the addition of interleukin-3 was delayed until Day 7. We found that the sensitivities of the progenitors for blast cell colonies are similar to those of colony-forming units-granulocyte/erythrocyte/macrophage/megakaryocyte and that late-appearing blast cell colonies were particularly resistant to 4-HC. In order to study the mechanism of differential sensitivities of murine progenitors to 4-HC, we examined the sensitivities of murine progenitors to 4-HC after brief incubation with diethylaminobenzaldehyde, an inhibitor of aldehyde dehydrogenase. Progenitors for granulocyte/macrophage colonies, granulocyte/erythrocyte/macrophage/megakaryocyte colonies, and blast cell colonies became more sensitive to 4-HC and the differential sensitivities of the progenitors disappeared following this treatment. We also tested the sensitivities of the progenitors to phenylketophosphamide, an analogue of 4-HC which is resistant to inactivation by aldehyde dehydrogenase. Various colony-forming units exhibited a similar dose response to this compound. These data indicate that intracellular levels of aldehyde dehydrogenase might play an important role in differential sensitivities of murine colony-forming units to 4-HC.

The occurrence of a peripheral T-cell lymphoma in a chronically immunosuppressed renal transplant patient.

A 32-year-old man received a cadavaric renal transplant in 1975 for end-stage renal disease and, thereafter, was treated with azathioprine and methylprednisolone for chronic immunosuppression. In 1985, he presented with fever and pancytopenia that persisted despite withdrawal of the immunosuppressive agents. Lymph node and liver biopsies demonstrated malignant lymphoma within the sinuses of the node and the sinusoids of the liver. A splenectomy was performed for persistent pancytopenia, and the spleen demonstrated malignant lymphoma of the diffuse mixed large and small cell type exclusively within the cords of the red pulp. The immunophenotype of the tumor cells was obtained by frozen section immunoperoxidase staining with monoclonal antibodies and flow cytometric analysis. The tumor cells were positive for the Pan T cell markers CD3 and CD2, but were negative for the subset markers CD4 and CD8. A DNA hybridization study conducted on the splenic tissue conclusively identified the clonal nature of the malignant T cells by demonstrating rearrangement of the T cell receptor beta gene. In spite of multiple chemotherapeutic regimens, the patient developed increasing peripheral blood involvement and died with disseminated lymphoma. This case appears to be unique in that it is the first report of a chronically immunosuppressed transplant recipient to develop a malignant lymphoma of the mature T cell type, and several of the pathologic features of the tumor have not been observed previously.

Hemoglobin SC disease and alpha-thalassemia. Prolonged survival and mild clinical course.

An 86-year-old black woman admitted for an elective cataract extraction was found to have moderate hypochromic microcytic anemia. Hematologic evaluation disclosed the presence of hemoglobin SC disease and heterozygous alpha-thalassemia-2 (alpha alpha/alpha-). A red cell density profile of the patient's peripheral blood revealed an absence of the typical uniform shift toward higher-density values seen in hemoglobin SC disease, indicating a "normalization" in the distribution of intracellular hemoglobin types. It is suggested that the co-inheritance of hemoglobin SC disease and heterozygous alpha-thalassemia-2, probably by decreasing the tendency toward intracellular hemoglobin S polymerization, contributed to her prolonged survival and relatively mild clinical course.