Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were ⩽6 months from the initial treatment). Patients received conditioning with BCNU, melphalan±gemcitabine and auto-PBSCT followed by two cycles of the DCEP±G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin±gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.

Purpose Bcl-2 regulates the mitochondrial apoptosis pathway that promotes chemotherapy resistance. Bcl-2 antisense oligonucleotide, G3139, targets Bcl-2 mRNA. Patients and Methods G3139 was administered (3 to 7 mg/kg/d for 7 days) by continuous intravenous infusion. On day 4, patients started thalidomide (100 to 400 mg as tolerated) and dexamethasone (40 mg daily for 4 days) on 21-day cycles for three cycles. Stable and responding patients continued on 35-day cycles for 2 years. Results Thirty-three patients (median age, 60 years; range, 28 to 76 years) received 220 cycles. Patients received a median of three prior regimens including thalidomide (n = 15) and stem-cell transplantation (n = 31). The regimen was well tolerated; the median number of cycles per patient was eight (range, one to 16+ cycles). Toxicities included reversible increase in creatinine, thrombocytopenia, neutropenia, fatigue, anorexia, constipation, fever, neuropathy, edema, electrolyte disturbances, and hyperglycemia. Fifty-five percent of patients had objective responses, including two complete responses (CRs), four near CRs (positive immunofixation), and 12 partial responses; six patients had minimal responses (MRs). Of patients who received prior thalidomide, seven had objective responses, and three had MRs. The median duration of response was 13 months, and estimated progression-free and overall survival times were 12 and 17.4 months, respectively. Responding patients had significant increase in polyclonal immunoglobulin M (P = .005), indicating innate immune system activation. Western blot analysis of Bcl-2 protein isolated from myeloma cells before and after G3139 demonstrated a decrease of Bcl-2 levels in three of seven patients compared with six of nine patients using reverse transcriptase polymerase chain reaction. Conclusion G3139, dexamethasone, and thalidomide are well tolerated and result in encouraging clinical responses in relapsed multiple myeloma patients.

Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkin's disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine-BCNU-melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI=42-76%) and 86% (95% CI=71-99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS=87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study.

Summary: The purpose of the study was to examine the yield of CD34 + cells, response rates, and toxicity of high-dose cyclophosphamide with or without etoposide in patients with multiple myeloma. In total, 77 myeloma patients received either cyclophosphamide 4.5 g/m 2 ( n =28) alone or with etoposide 2 g/m 2 ( n =49) in a nonrandomized manner, followed by G-CSF 10 μ g/kg/day for the purpose of stem cell mobilization. The effects of various factors on CD34 + cell yield, response rate and engraftment were explored. A median of 22.39 × 10 6 CD34 + cells/kg were collected on the first day of leukapheresis (range 0.59–114.71 × 10 6 /kg) in 71 (92%) of patients. Greater marrow plasma cell infiltration ( P =0.02) or prior radiation therapy ( P =0.02) adversely affected CD34 + cell yield. In total, 45% of patients receiving cyclophosphamide and 56% of those receiving cyclophosphamide/etoposide had at least a minimum response by EBMT criteria. In all, 25% of patients who received cyclophosphamide alone vs 75.5% of patients who received combined chemotherapy required hospitalization mainly for treatment of neutropenic fever. Cyclophosphamide alone is associated with impressive CD34 + cell yields and clear antimyeloma activity. The addition of etoposide resulted in increased toxicity without significant improvement in CD34 + cell yield or response rates.

PURPOSE:Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity.EXPERIMENTAL DESIGN:A Phase I MMF dose escalation study was conducted in relapsed and refractory myeloma patients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response.RESULTS:Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5 g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3 g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease.CONCLUSIONS:MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.

Clinical results in AML continue to need improvement, particularly for age ≥60, prior MDS or secondary AMLs, and AMLs with adverse cytogenetics (CG) where complete remission (CR) rates are <50% and cure rates are <10%. In an attempt to improve these outcomes, we developed a TST regimen of the topoisomerase I inhibitor Topotecan with ara-C and Mitoxantrone (TAM) as induction therapy for adults with newly diagnosed AML: T, 4.5 mg/m2 IV continuous infusion (CI) over 72 hrs days (d) 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and M, 40 mg/m2 IV d 10. CR patients with poor risk features received consolidation TST with T, 4.5 mg/m2 CI over 72 hrs d 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and etoposide (E), 300 mg/m2 IV CI over 72 hrs d 10-12 (TAE); CR patients without poor risk features received consolidation TST with A, 2 gm/m2 CI over 72 hrs d 1-3 and 10-12; and idarubicin (I) 12 mg/m2 IV d 1,2,3 (AIA). From 04/02-2/04, 60 newly diagnosed AML patients (median age 49 yrs, 21–79) received TAM induction chemotherapy. Of 60 pts, 47 (78.5%) had at least one poor prognostic feature: age ≥60, 16 (27%); adverse CG, 28 (47%); MDS/AML, 10 (17%); secondary AML, 3 (5%); and/or WBC >25,000/μl, 23 (38.5%). Of the 41 (68.5%) pts who achieved CR, 32 (78%) received consolidation TST (22 TAE; 10 AIA). The remaining 9 pts received alloBMT (2), alternate therapy (5), or no consolidation (2) due to incomplete reversal of organ damage. Furthermore, 8 pts who finished 2 cycles of TST subsequently received alloBMT (3), autoBMT (2) and maintenance Zarnestra (3). Median overall survival (OS) for all pts is 10.1 mos, with 1yr survival 45.7% (95% CI; 32.5%–58.9%). On multivariate analysis, only antecedent MDS was a significant risk factor for poor OS (HR=2.5, 95% CI 1.13–5.65; p=0.02). For patients who achieved CR, median disease free survival (DFS) was 9.9 mos (95% CI; 5.8–18.2) with 1yr DFS 45.9% (95% CI; 29.4%–62.4%). Preceding MDS (p=0.02), adverse CG (p=0.04) and age ≥50 (p=0.06) were associated with low CR. Induction and consolidation mortality were <10%. Median time for ANC >100/μl was 28 days (22–56) and platelets >50,000/μl was 30 days (22–81) following TAM. For consolidation, median time to ANC >100/μl was 27.5 days (19–48) for TAE and 39 days (26–43) for AIA, and plts >50,000/μl 34 days (19–87) for TAE and 54 days (33–79) for AIA. Toxicities during induction and consolidation were generally ≤grade 3 and consisted of infection (bacteremias, pneumonias), oral and/or GI mucositis, transient elevation in liver function tests, reversible renal insufficiency. Pulmonary hemorrhage (1), GI bleed (3), CNS bleed/infarct (2) and decreased ejection fraction (2) occured during induction/consolidation but resolved. Causes of death during induction were sepsis/multiorgan failure (3), progressive fungal pneumonia (1), grade 5 marrow aplasia (1); during consolidation multiorgan failure (1), renal failure/sepsis (1), pulmonary hemorrhage (1). In summary, TAM induction for AML is associated with significant CR rates and acceptable toxicity, but did not appear to overcome the poor DFS and OS in a high-risk group of adults.

We describe a case of severe coagulopathy after mesenteric revascularization. Laboratory investigation results revealed the presence of plasma inhibitors of factor V believed to result from exposure to bovine thrombin used for intraoperative hemostasis. Vascular and cardiothoracic surgeons commonly use topical thrombin for surgical hemostasis, and many patients undergo multiple exposure. More patients likely have factor V inhibitors develop than has previously been realized, and this may account for some otherwise unexplained postoperative coagulation disorders. This report may alert surgeons to coagulation disturbances that can result from exposure to bovine thrombin and provide guidelines for diagnosis and management.

Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m2) + etoposide (2.0 g/m2) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m2) on day −5, BCNU (300 mg/m2) + gemcitabine (1.0 g/m2) on day −2, melphalan (140 mg/m2) on day −1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m2) weekly for 4 weeks + GM-CSF (250 μg thrice weekly) (weeks 4–8); post-transplant involved-field radiotherapy (HD): 30–40 Gy to pre-transplant areas of disease (weeks 4–8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m2/day)/etoposide (30 mg/m2/day)/cisplatin (15 mg/m2/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m2, day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m2)/cisplatin (75 mg/m2) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan–Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan–Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3–4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD. Bone Marrow Transplantation (2002) 29, 303–312. doi:10.1038/sj.bmt.1703363

A 66-year-old man presented with cough and joint pain. He had a long history of pain in his wrists and lower back. Three days before presentation, he noted the onset of dry cough and shortness of breath associated with fever, chills, diaphoresis, generalized weakness, and worsening joint pain, especially in the wrists and lower back. He also complained of constant, nonradiating, right-sided epigastric pain. He was admitted to an outside hospital and treated with levofloxacin for presumed pneumonia. An abdominal CT scan demonstrated pneumobilia, marked splenomegaly, and tiny calcifications in the tail of the pancreas. Abdominal sonogram revealed an enlarged, homogenous liver without evidence of ductal dilatation. Intravenous fluids and acetaminophen were administered. A monospot test was negative. Cultures of blood and urine were obtained. He was transferred to the Baltimore VA Medical Center.

Isolated neutropenia developed in a patient who had been treated 4 years previously for Stage IIA nodular sclerosing Hodgkin's disease with mantle radiation therapy. Bone marrow revealed myeloid hyperplasia with a virtual absence of bands and polymorphonuclear leukocytes. The serum was positive for antigranulocyte antibodies. There was no evidence of recurrent Hodgkin's disease. Guidelines for the evaluation and treatment of immune neutropenia in Hodgkin's disease are suggested.