Stefano Tarantolo

Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies.

PURPOSE To analyze the risk of developing myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) following autologous bone marrow transplantation (ABMT) or peripheral stem-cell transplantation (PSCT) and to determine the impact on failure-free survival (FFS). PATIENTS AND METHODS Patients underwent ABMT or PSCT for the treatment of Hodgkins disease (HD) and non-Hodgkins lymphoma (NHL) at the University of Nebraska Medical Center. For those patients who went on to develop MDS/AML, controls were selected and a case-control-within-a-cohort study undertaken. RESULTS Twelve patients developed MDS or AML a median of 44 months following ABMT/PSCT. The cumulative incidence (P = .42) and the conditional probability (P = .32) of MDS/AML were not statistically different between HD and NHL patients. Age greater than 40 years at the time of transplant (P = .05) and receipt of a total-body irradiation (TBI)-containing regimen (P = .06) were predictive for developing MDS/AML in patients with NHL. CONCLUSION There is an increased risk of MDS/AML following ABMT/PSCT for lymphoid malignancies. NHL patients age > or = 40 years at the time of transplant and who received TBI are at greatest risk.

Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group

PURPOSE This phase II study evaluated the efficacy and safety of sorafenib plus dacarbazine in patients with advanced melanoma. PATIENTS AND METHODS This randomized, double-blind, placebo-controlled, multicenter study enrolled chemotherapy-naive patients with stage III (unresectable) or IV melanoma. A total of 101 patients received placebo plus dacarbazine (n = 50) or sorafenib plus dacarbazine (n = 51). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1,000 mg/m(2) for a maximum of 16 cycles. Oral sorafenib 400 mg or placebo was administered twice a day continuously. The primary end point was progression-free survival (PFS) by independent assessment. Secondary and tertiary end points included time to progression (TTP), response rate, and overall survival (OS). RESULTS Median PFS in the sorafenib plus dacarbazine arm was 21.1 weeks versus 11.7 weeks in the placebo plus dacarbazine arm (hazard ratio [HR], 0.665; P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months, and in TTP (median, 21.1 v 11.7 weeks; HR, 0.619) in favor of the sorafenib plus dacarbazine arm. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo plus dacarbazine and sorafenib plus dacarbazine arms, respectively; HR, 1.022). The regimen was well tolerated and had a manageable toxicity profile. CONCLUSION Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population.

Purging of Autologous Peripheral-Blood Stem Cells Using CD34 Selection Does Not Improve Overall or Progression-Free Survival After High-Dose Chemotherapy for Multiple Myeloma: Results of a Multicenter Randomized Controlled Trial

PURPOSE Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.

PURPOSE To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT. RESULTS The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654). CONCLUSION In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.

Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia

The objective of this study was to describe the outcome of allogeneic stem cell transplantation (alloSCT) in a series of patients with B cell chronic lymphocytic leukemia (B-CLL). Twenty-three B-CLL patients were transplanted between 1988 and 1997 using stem cells from a related (n = 20) or an unrelated donor (n = 3). The median age of the patients was 46 years, and the median number of prior chemotherapy regimens received was two. At transplantation, 14 patients had chemorefractory disease and 12 of these were refractory to fludarabine. The preparative regimens included total body irradiation (TBI) in 22 of the 23 cases. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine and methotrexate. Twenty patients (87%) achieved a complete remission (CR). The incidence of grade II–IV acute GVHD was 54%. Fourteen (61%) patients are alive and disease-free, including two with unrelated donors, at a median of 26 months (range, 9–115 months). Nine patients (39%) have died, one of whom had progressive B-CLL. The only favorable prognostic factor for failure-free survival (FFS) and overall survival (OS) after alloSCT was the use of a cyclophosphamide/TBI rather than an etoposide/ cyclophosphamide/TBI regimen (P = 0.03). The projected 5-year FFS, OS, and relapse rates after alloSCT were 65% (95% CI, 48–88%), 62% (95% CI, 43–88%), and 5% (95%, CI 0–13%), respectively. These findings demonstrate the potential of high-dose therapy and alloSCT for inducing and maintaining a remission in patients with advanced or chemorefractory B-CLL. The low relapse rate may be due to an allogeneic graft-versus-leukemia effect. Bone Marrow Transplantation (2000) 25, 717–722.

Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies

Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) ⩾500/μl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8+ ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8+ cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.

Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma

Tanespimycin (17‐allylamino‐17‐demethoxygeldanamycin, 17‐AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open‐label multicentre study, we compared 1·3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource‐based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.

Phenotypic Heterogeneity in Multiple Myeloma Families

PURPOSE To describe a series of families with familial multiple myeloma (MM). Observations were used to generate hypotheses about the role of genetic factors, the mode of inheritance of these factors, and the association of other cancers with familial MM. PATIENTS AND METHODS This observational study consisted of 39 families with multiple cases of MM or related disorders from four collaborating research centers. Each center followed its usual family study method. Probands were interviewed, and, when possible, cancers were verified by medical records and pathology review. A working pedigree was compiled on each family. RESULTS Seventeen families had affected members in two or more generations, and eight families had two or more affected members in a single generation. Four families had two or more members with plasma cell dyscrasias, with or without a single case of MM. In the remaining 10 families, a single MM case occurred with a family history of other cancers. Other cancers observed in family members included hematologic malignancies and solid tumors. In families with MM in multiple generations, there was a decrease in the age at MM diagnosis in successive generations. CONCLUSION The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. Population-based epidemiologic studies are crucial, but because of the rarity of familial MM, a concerted case-finding approach may also be fruitful. Therefore, we propose an international consortium to study familial MM, and we invite all interested colleagues to participate.

Epstein–Barr virus-associated lymphoproliferative disorder after autologous bone marrow transplantation: report of two cases

Epstein–Barr virus-associated lymphoproliferative disorders have been frequently reported as a complication of solid organ and allogeneic bone marrow transplantation. Their occurrence is rare after autologous bone marrow transplantation (BMT) with only five published reports in the literature. We report two cases of post-transplant lymphoproliferative disorder occurring after autologous BMT for Hodgkin’s disease and non-Hodgkin’s lymphoma. Post-transplant lymphoproliferative disorders can occur after autologous BMT and should be included in the differential diagnosis of patients with persistent fever, adenopathy or pulmonary infiltrates.

Valuing clinical strategies early in development: a cost analysis of allogeneic peripheral blood stem cell transplantation.

Allogeneic peripheral blood stem cell transplantation (alloPBSCT) is an emerging technology. As this technology develops, transplant centers are concerned with looking for technologic advances that will result in improvements in clinical outcomes and lower costs. We provide comparative estimates of costs and resource use for alloPBSCT in comparison to allogeneic bone marrow transplantation (alloBMT) for persons with hematologic malignancies from the time of harvest to 100 days post transplant. A retrospective, cost-identification analysis was conducted for patients in two consecutive phase II clinical trials at the University of Nebraska Medical Center. Identical preparative regimens, graft-versus-host disease prophylaxis, post-transplant hematopoietic colony-stimulating factor treatment regimens, and discharge criteria were used. Total median costs were