Jack W. Singer

Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer

Background. The period of neutropenia after autologous bone marrow transplantation results in substantial morbidity and mortality. The results of previous phase I-II clinical trials suggest that recombinant human granulocytemacrophage colony-stimulating factor (rhGM-CSF) may accelerate neutrophil recovery and thereby reduce complications in patients after autologous bone marrow transplantation. Methods. We conducted a randomized, double-blind, placebo-controlled trial at three institutions. The study design and treatment schedules were identical, and the results were pooled for analysis. One hundred twenty-eight patients were enrolled. Sixty-five patients received rhGM-CSF in a two-hour intravenous infusion daily for 21 days, starting within four hours of the marrow infusion, and 63 patients received placebo. Results. No toxic effects specifically ascribed to rhGM-CSF were observed. The patients given rhGM-CSF had a recovery of the neutrophil count to 500×106 per liter 7 days earlier than the patients who...

Graft-versus-Host Disease as Adoptive Immunotherapy in Patients with Advanced Hematologic Neoplasms

The occurrence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation for leukemia is thought to decrease the probability of recurrence. To study this effect (called adoptive immunotherapy) we modified the prophylaxis of GVHD in patients with advanced hematologic neoplasms (mostly leukemia) who received bone marrow transplants. Patients under 30 years of age were randomly assigned to one of three regimens of post-transplantation immunosuppression: Group I (n = 44) received a standard course of methotrexate for 102 days after transplantation, Group II (n = 40) received an abbreviated (11-day) course of methotrexate, and Group III (n = 25) received the standard course of methotrexate plus viable buffy-coat cells from the marrow donors. All 109 patients received cyclophosphamide (60 mg per kilogram of body weight on each of two days), total-body irradiation (2.25 Gy daily for seven days), and unmodified marrow from HLA-identical sibling donors. The frequency of GVHD of Grades II through IV was 25 percent in Group I, 59 percent in Group II, and 82 percent in Group III (P = 0.0001). The incidence of chronic GVHD, however, did not differ significantly among the groups (33, 51, and 44 percent, respectively), nor did the five-year probability of recurrence of disease (38, 45, and 33 percent, respectively). However, mortality from causes other than cancer was 34 percent in Group I, 45 percent in Group II, and 64 percent in Group III (I vs. III, P = 0.024); the deaths were due primarily to infections complicating the course of GVHD. With a median follow-up of 5.1 years (range, 3.9 to 7.4), disease-free survival was 41 percent in Group I, 30 percent in Group II, and 24 percent in Group III (the differences were not statistically significant). We conclude that abbreviating methotrexate prophylaxis or infusing donor buffy-coat cells increased the incidence of acute GVHD and related mortality without altering the incidence of chronic GVHD or the recurrence of malignant disease.

Clonal Development, Stem-Cell Differentiation, and Clinical Remissions in Acute Nonlymphocytic Leukemia

To determine whether acute nonlymphocytic leukemia develops clonally, to study the pattern of differentiation of the involved stem cells, and to determine whether clinical remissions are true remissions, we studied 27 patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked glucose-6-phosphate dehydrogenase. In each case, leukemic blast cells manifested only one type of glucose-6-phosphate dehydrogenase, indicating that the malignant process had developed from a single cell. In six elderly patients, circulating erythrocytes, platelets, or both expressed only the glucose-6-phosphate dehydrogenase found in blast cells, indicating that these leukemias had arisen from stem cells with multipotent differentiative expression. In 16 younger adults and children, erythroid cells and platelets were predominantly derived from normal stem cells. In three other cases, the stem cell that gave rise to leukemic blasts apparently also gave rise to erythroid progenitors but not to mature erythrocytes. Heterogeneity was also found during remissions. In 8 of 13 patients, restoration of nonclonal hemopoiesis and repopulation of the marrow by normal stem cells was observed during remission. In the other five patients, marrow stem cells remained partially or completely clonal, even during remission. These data indicate that acute nonlymphocytic leukemia is a heterogeneous disease with respect to differentiation of the stem cells involved by leukemia and the nature of remissions.

Marrow Transplantation in Thirty Untransfused Patients with Severe Aplastic Anemia

Thirty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. They were conditioned for grafting with cyclophosphamide, 50 mg/kg body weight on each of 4 successive days. All 30 had prompt initial marrow engraftment, which was sustained in 27. Twenty-five of the 30 are alive between 9 to 84 (median, 19.5) months. The actuarial projection of survival for 2 to 6 years is 75%. Twenty of the 25 surviving patients have no problems. Five have chronic graft-versus-host disease, resolving in two and active in three. Five patients died with infection or hemorrhage, four of whom had graft-versus-host disease. These data show that early transplantation should be carried out before transfusions are given for any patient with severe aplastic anemia who has an HLA-identical family member. If sensitization to minor transplantation antigens contained in blood products is avoided, the incidence of marrow-graft rejection will decrease, and survival will improve.

Phase III Trial Comparing Paclitaxel Poliglumex (CT-2103, PPX) in Combination with Carboplatin Versus Standard Paclitaxel and Carboplatin in the Treatment of PS 2 Patients with Chemotherapy-Naïve Advanced Non-small Cell Lung Cancer

Introduction: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. Methods: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m2/10 min without routine steroid premedication) or paclitaxel (225 mg/m2/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. Results: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). Conclusion: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient.

Expression of the gene defect in X-linked agammaglobulinemia.

Although X-linked agammaglobulinemia was one of the first immunodeficiencies described,1 the genetic defect responsible for this disorder has not yet been identified. X-linked agammaglobulinemia is...

TREATMENT OF CHRONIC GRANULOCYTIC LEUKAEMIA IN CHRONIC PHASE BY ALLOGENEIC MARROW TRANSPLANTATION

Ten patients with chronic granulocytic leukaemia in the chronic phase have been treated with chemoradiotherapy followed by transplantation of bone marrow from HLA-identical siblings. Engraftment was achieved in all patients, and Philadelphia chromosome disappeared from the nine patients who had it before transplantation. Four patients have died, three with interstitial pneumonitis and one with severe graft-versus-host disease (GvHD). Six patients are alive and well in complete clinical, cytogenetic, and haematological remission, 1-3 years after transplantation, despite complications in three patients (one had interstitial pneumonitis, one had mild veno-occlusive disease of the liver, and one had severe GvHD).

Acute nonlymphocytic leukemia: expression in cells restricted to granulocytic and monocytic differentiation.

Two patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase were studied to determine the number and type of cells in which the disease arises. Both type A and B isoenzymes were found in normal tissues, but the myeloblasts showed only one enzyme type, indicating that at the time of study, the disease had a clonal origin. The observation in one patient that erythroid cells did not arise from this clone contrasts with conclusions reached in patients previously studied with chromosomal markers. The results suggest that in this patient, the leukemic clone suppressed expression of normal granulopoiesis but did not inhibit erythroid differentiation from normal progenitors. They suggest also that the disease is heterogeneous. In some patients, the disease is expressed in cells with differentiation restricted to the granulocyte-macrophage pathway; in others, it involves stem cells that also differentiate into erythrocytes. This heterogeneity may reflect differences in causation and could have prognostic importance.

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m−2 PPX or 75 mg m−2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m−2 resulted in increased neurotoxicity compared with docetaxel.

Bone Marrow Transplantation for Patients with Myelodysplasia: Pretreatment Variables and Outcome

STUDY OBJECTIVE To determine the efficacy of allogeneic bone marrow transplantation for severe myelodysplasia, and to identify variables predictive of outcome. DESIGN Case series study. SETTING A referral-based bone marrow transplant center. PATIENTS Consecutive series of 59 patients with myelodysplasia or closely related disorders and either life-threatening cytopenia or a progressive increase in marrow blast percentage. INTERVENTION Patients were treated with high-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation from either an HLA-identical (n = 45) or HLA-partially matched (n = 14) donor. MEASUREMENTS AND MAIN RESULTS The product-limit estimate for disease-free survival 3 years after transplant is 45% (95% CI, 32% to 59%). The commonest causes of death after transplant were disease recurrence, interstitial pneumonia, and graft-versus-host disease, accounting for eight deaths each. In a univariate analysis, younger patients, those with shorter disease duration, and those whose disease was characterized by an abnormal cytogenetic karyotype had better survival and disease-free survival than the group as a whole. In a multivariate analysis, younger age and abnormal karyotype were independent predictors of improved disease-free survival and overall survival. Patients who received transplants when they had fewer blasts in their bone marrow had a decreased chance for disease recurrence when compared with patients with excess blasts. CONCLUSIONS Bone marrow transplantation offers a potential cure for many patients with myelodysplasia. Best results can be expected in younger patients who receive transplants relatively early in their disease course.