Yang O. Huh

Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia

PURPOSE To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results.

PURPOSE This study was undertaken to evaluate the feasibility and therapeutic effect of high-dose chemoradiotherapy with autologous or allogeneic bone marrow transplantation (BMT) in patients with advanced chronic lymphocytic leukemia (CLL) who relapse after fludarabine treatment. PATIENTS AND METHODS Twenty-two patients with advanced CLL received high-dose cyclophosphamide, total-body irradiation, and BMT. Eleven patients with relapsed CLL received autologous BMT with marrow collected during a prior fludarabine-induced remission; leukemia cells were depleted from the autologous marrow in seven patients using an anti-CD19 monoclonal antibody and immunomagnetic separation. Eleven patients received allogeneic or syngeneic BMT, seven of whom had refractory Rai stage III or IV disease. RESULTS Six autologous transplant recipients achieved a complete remission (CR), four a nodular CR (nCR), and one a partial remission (PR). Two recurred with CLL, and three developed Richters transformation. Two patients had recurrence of immune cytopenias while in morphologic remission; one of these patients died of cytomegalovirus pneumonia. Six of 11 patients survive in remission 2 to 29 months following BMT. Of the 11 patients who received allogeneic or syngeneic BMT, seven achieved a CR, two a nCR, and one a PR; 10 survive 2 to 36 months following BMT. CONCLUSION These data indicate that high-dose chemotherapy with allogeneic BMT is effective at producing CRs in patients with CLL. Autologous transplantation in CLL is feasible and is capable of producing remissions in patients with advanced CLL. Further studies are warranted to assess the role of BMT in the treatment of CLL.

Absence of CD26 Expression Is a Useful Marker for Diagnosis of T-Cell Lymphoma in Peripheral Blood

We report flow cytometric characterization of surface CD26 expression in 271 peripheral blood samples from 154 patients evaluated for the presence of a T-cell lymphoproliferative disorder, primarily mycosis fungoides/Sézary syndrome (MF/SS). The presence of morphologically identifiable tumor cells on peripheral blood smears was the criterion for lymphomatous involvement. In 66 of 69 samples from 28 patients, we identified an abnormal CD26-/dim T-cell population that was distinct from the variable CD26 expression seen in normal peripheral blood T cells. This population was CD26- in 23 patients and weakly CD26+ in 5 patients. CD7 was more variably expressed in MF/SS tumor cells, allowing recognition of a distinct, quantifiable abnormal T-cell population in only 34 of 69 involved samples. An increased CD4/CD8 ratio and lower surface expression of CD4 in tumor cells also helped separate the CD26-/dim atypical population for quantification. In 35 blood samples from other types of T-cell tumors, tumor cells in 10 of 11 morphologically involved cases showed absent/dim CD26. Although capable of detecting abnormalities in most cases of MF/SS, CD7 expression does not provide as clear a separation of the neoplastic population and can be replaced by CD26 staining in routine peripheral blood flow cytometric screening of MF/SS patients.

Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia.

One hundred five untreated adult patients with acute lymphocytic leukemia (ALL) were entered on the vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and Decadron (dexamethasone; Merck Sharp and Dohme, West Point, PA) (VAD) regimen. Induction therapy with VAD and VAD plus cyclophosphamide (CVAD) was followed by a 2-year rotating maintenance program with multiple antileukemic combinations, and included early intensifications with Adriamycin and high-dose cytarabine (ara-C) and a late intensification with cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) followed by autologous bone marrow transplantation (BMT). Duration of therapy was 24 to 30 months. Eight-eight patients (84%) achieved complete remission (CR) with VAD-CVAD, and 94 (90%) ultimately had CR with continuation of the maintenance as planned. Induction mortality was 3%; only half of the patients required prolonged hospitalization of 1 week or longer, or intravenous antibiotics. Maintenance therapy was given to 79 patients, while nine with histocompatibility locus antigen (HLA)-matched related donors underwent allogeneic BMT. The median remission duration was 22 months, and the median survival was 19 months. Factors associated with significantly worse CR rates were older age, the presence of hypoalbuminemia or hyperbilirubinemia, L2 or L3 morphology, and myeloid markers on leukemic cells. Those associated with significantly worse remission durations were the presence of elevated leukocyte or absolute peripheral blast counts, Philadelphia chromosome (Ph)-positive or B-cell ALL, L2 morphology, and more than one course to achieve CR. Patients could be divided into standard-risk ALL (28% of patients) and high-risk ALL (72% of patients) with long-term remission rates of 70% versus less than 30%. The 26 patients who underwent CBV autologous BMT had similar long-term outcome compared with 21 patients who did not (older age, medical contraindications, or socioeconomic problems). The presence or absence of myeloid markers on leukemic cells did not affect long-term prognosis. We conclude that VAD therapy is a well-tolerated effective induction regimen. High-risk ALL patients require alternative maintenance investigational approaches.

Factors affecting mobilization of CD34+ cells in normal donors treated with filgrastim

BACKGROUND: Multiple days of apheresis are required for some normal peripheral blood progenitor cell (PBPC) donors, to ensure a sufficient collection of CD34+ cells for allografting. It would be of practical value to be able to identify the patients with poor mobilization on the basis of simple pretreatment clinical or hematologic variables.

Allogeneic blood progenitor cell collection in normal donors after mobilization with filgrastim : the M.D. Anderson Cancer Center experience

BACKGROUND: Information on the safety and efficacy of allogeneic peripheral blood progenitor cell (PBPC) collection in filgrastim‐mobilized normal donors is still limited.

Differences in CD33 intensity between various myeloid neoplasms.

We measured the concentration of CD33 antigen on the surface of cells in 315 bone marrow (BM) samples and 114 corresponding peripheral blood (PB) samples from patients with various leukemias (acute myeloid leukemia [AML], chronic myelogenous leukemia [CML], myeloproliferative disorder [MPD] other than CML, myelodysplastic syndrome [MDS]) and from control subjects. Overall CD33 intensity in total CD33+ cells was significantly higher in BM than in PB. CD33 intensity in total BM CD33+ cells differed significantly with the type of disease. The median number of CD33 molecules per cell was highest in AML, followed by MDS, CML, and control subjects and lowest in MPD. When only CD34+/CD33+ cells were examined, CD33 molecules per cell were highest in CD34+ cells in AML and lowest in MPD (P = .027). Patients with AML or MDS younger than 60 years had significantly higher intensity of CD33 expression on CD34+ cells than patients 60 years or older. Levels of CD33 intensity did not correlate with cytogenetics in patients with AML or MDS. There was no correlation between CD33 intensity and response to therapy or overall survival in 35 patients treated with protocols including Mylotarg. These data demonstrate variation in CD33 intensity between various leukemias.

Higher Levels of Surface CD20 Expression on Circulating Lymphocytes Compared With Bone Marrow and Lymph Nodes in B-Cell Chronic Lymphocytic Leukemia

Differential expression of CD20 surface antigen in B-cell neoplasms at different sites is largely unknown. The number of CD20 antibodies bound per cell (CD20 ABC) in bone marrow (BM), peripheral blood (PB), and lymph node aspirate (LNA) samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) or other B-cell disease was studied using quantitative flow cytometry. CD20 ABC differed significantly with the specimen type in B-CLL, being highest in PB (mean, 9,051) and lower in BM (mean, 4,067) and LNA (mean, 3,951). No difference in CD20 ABC between BM and PB samples was found in splenic lymphoma, mantle cell lymphoma, or follicular lymphoma. Also, we found a significant difference of CD20 ABC by type of disease: lowest in B-CLL; higher in splenic, follicular, and mantle cell lymphoma; and highest in hairy cell leukemia. The lower CD20 surface antigen levels in BM and LNA than in PB in B-CLL may have clinical relevance with regard to the efficacy of rituximab therapy.

MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis

Chromosomal translocations that involve MYC, characteristic of Burkitt lymphoma, are rare in chronic lymphocytic leukaemia (CLL). We report the clinical, morphological, immunophenotypic, cytogenetic and molecular genetic features of eight CLL cases with MYC rearrangement. The patients, five men and three women (median age, 71 years) had bone marrow involvement and an absolute peripheral blood lymphocytosis; five had lymphadenopathy; seven had splenomegaly. Prolymphocytes were increased (≥10%) in all cases. Six cases were classified as CLL with increased prolymphocytes (CLL/PL; prolymphocytes 10–55%), and two were classified as CLL in prolymphocytic transformation (CLL/PT; prolymphocytes >55%). All cases co‐expressed CD5, CD19, and CD23; five of eight expressed ZAP‐70. Of seven cases tested, four had mutated and three had unmutated IGHV genes. Conventional cytogenetic studies demonstrated t(8;14)(q24·1;q32) in five cases, t(8;22)(q24·1;q11) in two cases, and t(2;8)(p12;q24·1) in one case. Seven cases contained additional chromosomal abnormalities. All patients received combination chemotherapy. Two developed Epstein–Barr virus (EBV)‐associated diffuse large B‐cell lymphomas (DLBCL) that were clonally unrelated to the CLL. At follow‐up, two patients are alive, four died of underlying disease, one died of EBV‐associated DLBCL, and one died of an unrelated cancer. In summary, MYC rearrangement, which occurs rarely in CLL patients, is associated with increased prolymphocytes, complex cytogenetic abnormalities, and a poor prognosis.

The t(14;19)(q32;q13)-positive small B-cell leukaemia: a clinicopathologic and cytogenetic study of seven cases.

The t(14;19)(q32;q13), involving the BCL3 locus at chromosome 19q13 and the immunoglobulin heavy chain gene at 14q32, is a rare recurrent cytogenetic abnormality identified in B‐cell neoplasms, most of which have been classified as chronic lymphocytic leukaemia (CLL) in the literature. We describe the clinicopathological, immunophenotypic and cytogenetic findings in seven patients with B‐cell neoplasms associated with t(14;19)(q32;q13). There were five men and two women, with a median age of 48 years (range 33–68). All had absolute lymphocytosis, six had lymphadenopathy, and one had splenomegaly. Lymphocytes in blood and bone marrow aspirate smears were predominantly small and cytologically atypical. Flow cytometric immunophenotyping showed an atypical immunophenotype with low CLL scores. The growth pattern in bone marrow biopsy specimens was interstitial to diffuse; immunohistochemical stains were positive for bcl3 and negative for cyclin D1. Lymph node biopsy specimens of two patients revealed total architectural effacement by neoplasm with proliferation centres. In addition to t(14;19), cytogenetic studies demonstrated trisomy 12 in five patients. These results suggest that B‐cell neoplasms with the t(14;19)(q32;q13) present frequently as leukaemia composed of small B‐lymphocytes and share many features with CLL. However, these neoplasms also differ from CLL cytologically and in their immunophenotype.