Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Negative regulation of the tumor suppressor p53 gene by microRNAs.

The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent studies have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this study, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to downregulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.

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.

Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma.

Diarrhea is a major cause of morbidity and discomfort for patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT). There are multiple causes of diarrhea in patients undergoing transplantation including antineoplastic chemotherapy, antimicrobials and infection, including Clostridium difficile as the most common pathogen involved. The purpose of this study was to determine the incidence of C. difficile-associated diarrhea (CDAD) 1 week before and 30 days after APBSCT, and to identify risk factors for the development of CDAD including diagnosis. Two hundred and forty-two patients underwent APBSCT for multiple myeloma and lymphoma between October 1996 and October 2001 in two teaching hospitals. Diarrhea was reported in 157 (64.9%) subjects. One hundred and thirty-five out of the 157 subjects were tested for the presence of C. difficile toxin A. These subjects constitute the study group. The incidence of CDAD was 15%. Two thirds of the patients who developed CDAD had multiple myeloma and one third had lymphoma; this difference did not attain statistical significance. The use of cephalosporins (P = 0.03) and the use of intravenous vancomycin (P = 0.02) were the only identified risk factors associated with the development of CDAD. Patients treated with paclitaxel as part of the mobilization regimen had a lower incidence of CDAD than patients who received hematopoietic growth factor only (P = 0.01).

Granisetron vs ondansetron for prevention of nausea and vomiting in hematopoietic stem cell transplant patients: results of a prospective, double-blind, randomized trial.

The serotonin type-3 (5-HT3) antagonists represent a significant advance in the prevention of acute nausea and vomiting (N/V) from highly emetogenic chemotherapy. We sought to determine if any differences in efficacy or adverse effects exist between two such agents, ondansetron and granisetron, during conditioning therapy for hematopoietic stem cell transplantation (HSCT). Patients were randomized to receive either ondansetron 0.15 mg/kg intravenously every 8 h or granisetron 10 microg/kg intravenously daily. Additionally, all patients received scheduled dexamethasone and lorazepam. Prophylaxis was continued until 24 h after completion of chemotherapy. Nausea and distress were measured subjectively with visual analog scales and emetic episodes were quantified. Of the 110 randomized patients, 96 were evaluable for efficacy and safety. No significant differences in efficacy were observed between the ondansetron- and granisetron-treated patients, evaluated by comparing the degree of nausea and distress, number of emetic episodes and overall control of emesis. The adverse effects were also comparable and no patients were removed from study because of severe toxicities. This trial demonstrates that ondansetron and granisetron are equally effective at preventing acute N/V associated with conditioning therapy frequently used for HSCT. The agent of choice should be based on drug acquisition cost or preference.

Performance of a hybrid central venous catheter utilized for both peripheral blood stem cell harvest and transplant support of patients undergoing autologous peripheral blood stem cell transplantation.

Patients undergoing autologous peripheral blood stem cell transplantation (PBSC) frequently require the sequential insertion of two central venous catheters, one for leukapheresis and one for transplant support. Hybrid catheters suitable for leukapheresis and long-term use have been increasingly used, but there is limited information regarding their performance and complication rate. The purpose of this study was to determine the performance of the Pheres-Flow hybrid catheter when utilized for both leukapheresis and transplant support, with particular emphasis on the incidence of infectious and occlusive complications. We prospectively analyzed the performance of 92 catheters in 82 consecutive patients who underwent autologous peripheral blood stem cell (PBSC) transplantation. Occlusion was the most frequent complication of this catheter with 29% of the patients experiencing difficulty drawing blood or infusing fluids. Infection was another frequent complication. Twenty-two percent of patients developed catheter-related bloodstream infections and 15 catheters had to be removed because of proven or suspected infection that did not respond to antibiotic therapy. Nevertheless, 77% of patients were able to complete leukapheresis and transplant support with only one catheter. We conclude that the utilization of the Pheres-Flow catheter for both leukapheresis and transplant support is feasible, but that new strategies need to be developed to decrease the incidence of occlusive and infectious complications of hybrid catheters.

Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience.

Conventional preparative regimens for allogeneic stem cell transplantation are associated with excessive regimen-related toxicity (RRT) in some patients because of underlying comorbidities, advanced age, or prior treatment. We studied a preparative regimen designed to reduce RRT, yet allow for adequate engraftment and development of a graft-versus-malignancy effect. Thirty patients (median age, 57 years) were entered on study. Twenty-nine patientsreceived stem cells from HLA-identical siblings and 1 from a sibling mismatched for 1 antigen at the A locus. Sixteen patients had received previous stem cell transplants (6 allogeneic and 10 autologous). The preparative regimen consisted of fludarabine 30 mg/M2 per day IV on day -10 to day -5, busulfan 1 mg/kg per dose PO (n = 6) or 0.8 mg/kg per dose IV (n = 24) for 8 doses every 6 hours on day -6 to day -5, and horse-derived antithymocyte globulin 5 mg/kg per day IV (n = 12) or 15 mg/kg per day IV (n = 18) on day -4 to day -1. GVHD prophylaxis consisted of cyclosporine (CYA) 3 mg/kg BID PO starting on day -3 (n = 13) or CYA and methotrexate 15 mg/m2 IV on day +1 and 10 mg/m2 IV on day +3 and day +6 (n = 17). The median number of CD34 cells transplanted was 3.19 x 10(6)/kg. All patients demonstrated recovery of hematopoietic function. Twenty-six (89%) of 29 evaluable patients achieved greater than 90% donor cell chimerism before day 100. Three patients never achieved greater than 90% donor chimerism, and another 3 patients subsequently lost donor chimerism. All 6 of these patients had autologous reconstitution with progressive disease. RRT was minimal; 7 patients had greater than grade II nonhematologic toxicity and there were no toxic deaths attributable to the conditioning regimen. Transplantation-related mortality was 7% (95% confidence interval [CI], 6%-8%) at 3 months and 28% (95% CI, 23%-34%) at 12 months after transplantation. Non-relapse-related mortality was most often due to infection. Grade II or greater GVHD developed in 56% of evaluable patients, and all patients with disease response developed GVHD. Actuarial estimates of overall and disease-free survival at 12 months were 52% (95% CI, 43%-63%) and 30% (95% CI, 24%-37%), respectively. Although this preparative regimen allowed adequate engraftment with minimal RRT, GVHD and infectious complications caused significant morbidity and mortality. Further study to define appropriate patient populations for this regimen, while limiting GVHD and infection risks, is needed.

Myeloma bone disease.

Bone destruction is a hallmark of myeloma, with 70% to 80% of patients manifesting bone involvement. Destruction is mediated through normal osteoclasts (OCLs), which respond to local osteoclast-activating factors (OAFs) produced by myeloma cells or by other cells in the local microenvironment. OAFs implicated in myeloma bone disease include tumor necrosis factor-beta (TNFbeta), RANK ligand (RANKL), interleukin-1 (IL-1), parathyroid hormone-related protein (PTHrP), hepatocyte growth factor (HGH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and macrophage inflammatory protein-1-alpha (MIP-1alpha). To date, the leading candidates for OAFs are MIP-1alpha and RANKL. Adhesive interactions between marrow stromal cells and myeloma cells induce marrow stromal cells to secrete IL-6, a potent myeloma growth/survival factor that may contribute to the bone disease. Evaluation of myeloma bone disease includes plain radiographs, and newer methods, such as magnetic resonance imaging (MRI), positron emission tomography (PET) scans, technetium-99m-sestamibi (Mibi) scanning, and dual-energy x-ray absorptiometry (DEXA) scanning, may provide more complete information. In addition, biochemical markers of bone resorption are being evaluated, although the limited availability of these assays and lack of extensive testing in patients make their routine use premature. Treatment of myeloma bone disease includes radiation therapy, vertebroplasty, surgery, and bisphosphonates. New developments on the pathogenesis and treatment of myeloma bone disease present great opportunities to combat bone disease.

Myeloablation and autologous peripheral blood stem cell rescue results in hematologic and clinical responses in patients with myeloid metaplasia with myelofibrosis.

Current therapeutic options for myeloid metaplasia with myelofibrosis (MMM) are limited. A pilot study was conducted of autologous peripheral blood stem cell (PBSC) collection in 27, followed by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2), after granulocyte colony-stimulating factor (G-CSF) alone (n = 17), or after anthracycline-cytarabine induction plus G-CSF (n = 8). A median of 11.6 x 10(6) (range 0 to 410 x 10(6)) CD34(+) cells per kilogram were collected. Twenty-one patients then underwent myeloablation with oral busulfan (16 mg/kg) and PBSC transplantation. The median times to neutrophil and platelet recovery after transplantation were 21 (range 10-96) and 21 (range, 13 to > or = 246) days, respectively. Five patients received back-up PBSC infusion because of delayed neutrophil or platelet recovery. The median follow-up is 390 (range 70-1623) days after transplantation, and the 2-year actuarial survival is 61%. After transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response (hemoglobin > or = 100 g/L [10 gm/dL] without transfusion for > or = 8 weeks) occurred in 10 of 17 anemic patients. Four of 8 patients with a platelet count less than 100 x 10(9)/L (100 000/microL) responded with a durable platelet count more than 100 x 10(9)/L (100 000/microL). Symptomatic splenomegaly improved in 7 of 10 patients. It is concluded that (1) PBSC collection was feasible and stable engraftment occurred after transplantation in most patients with MMM, (2) myeloablation with busulfan was associated with acceptable toxicity, (3) a significant proportion of patients derived clinical benefit after treatment, and (4) further investigation of this novel approach is warranted. (Blood. 2001;98:586-593)

Peripheral blood stem cell mobilization with cyclophosphamide in combination with G-CSF, GM-CSF, or sequential GM-CSF/G-CSF in non-Hodgkin's lymphoma patients: a randomized prospective study.

We designed a randomized, prospective three-arm mobilization study to determine the kinetics of peripheral blood stem cell (PBSC) mobilization in 60 non-Hodgkin's lymphoma (NHL) patients primed with cyclophosphamide (CTX) in combination with granulocyte colony-stimulating factor (G-CSF) (arm A), granulocyte-macrophage (GM)-CSF (arm B) or GM-CSF/G-CSF (arm C). We also compared mobilization and transplant-related toxicities, pre- and post-transplant support and the probability of survival among the three arms. To date, 35 patients have been enrolled in the study; 13 patients have been enrolled in arm A, 10 patients in arm B, and 13 patients in arm C. Successful collection of the target of > or = 2 X 10(6) CD34+ cells/kg in one to four apheresis collections was 10/13, 6/10, and 7/12 in arms A, B, and C, respectively. The differences between arms were not statistically significant. The median time to achieve the target CD34+ cells in patients who successfully mobilized the target CD34+ cells was 3 days, 2 days, and 1 day, in patients in arms A, B, and C, respectively. The time for neutrophil engraftment was 11, 10, and 10 days in arms A, B, and C, respectively. The time for platelet engraftment was 11 days for patients in all arms of the study. Most importantly, no significant differences were observed among the three arms in the duration of neutropenic fever, the extent of mucositis, diarrhea, and nausea/vomiting, or in the number of units of platelets or red cells transfused after transplantation. Risk factors associated with poor mobilization were > or = 3 regimens of chemotherapy prior to mobilization, older age, and disease histology (follicular versus diffuse). Therefore, we conclude that the type of growth factor used for mobilization did not play a major role in the outcome of mobilization and recommend mobilizing NHL patients before they receive multiple regimens of chemotherapy.

Integrated sexual healthcare: the development and review of one model of service delivery.

Sexual health is topical with many factors impacting upon its concept and hence provision. In 1995 the Sexual Health Service in East Berkshire was formed by the integration of the clinical services of Family Planning, Genitourinary and HIV Medicine with Sexual Health Promotion. The philosophy of the service is to provide holistic sexual healthcare in one visit, on one site by one clinical team. This article outlines the practical developments and the strengths and weaknesses of this model of service.

PIP: In 1995, the Sexual Health Service in East Berkshire, UK, was formed by the integration of the clinical services of Family Planning, Genitourinary, and HIV Medicine with Sexual Health Promotion. The philosophy of the service was to provide holistic sexual health care in one visit, in one site, by one clinical team. In an outline of the practical developments and the strengths and weaknesses of such a model of service, the critical success factors in the process of developing the service were identified. These include the business case, changing the culture, training, common conditions of service, consumer view, and engineering the patient process. Moreover, the strengths and weaknesses of the model were considered from the viewpoint of the patient, the staff, the public health, and finance. It is noted that the concept of patient-focused care, where related services are brought to the patient, instead of the traditional model of making the patient do the work, has demonstrable effect.

Successful PBSC mobilization with high-dose G-CSF for patients failing a first round of mobilization.

PBSC are the preferred source of stem cells for autologous transplantation. However, regardless of the mobilization procedure used, 10%-20% of patients fail to collect an adequate number to ensure prompt engraftment. There is as yet no standard mobilization procedure for patients who fail a first mobilization attempt. Here, we describe a highly efficient strategy to obtain an adequate number of stem cells for patients who failed a first mobilization attempt. Seventy-four patients with various hematologic malignancies underwent initial mobilization with various regimens including hematopoietic growth factors with or without chemotherapy. In 72% of patients, > or =2 x 10(6) CD34+ stem cells/kg were collected in the initial mobilization attempt, and patients engrafted in a median of 10 days for neutrophils and 12 days for platelets. Eighteen patients failed to mobilize adequate numbers of stem cells, defined as the inability to collect 0.2 x 10(6) CD34+ stem cells/kg/day in the first 2-3 days. These patients had their apheresis halted. Patients were immediately given G-CSF (32 microg/kg/day) for 4 days as a second attempt at mobilization. Eighty-eight percent of these patients achieved the target of > or =2 x 10(6) CD34+ cells/kg, with a median duration of apheresis of 5 days (including the first and second mobilizations). The mean CD34+ cells/kg/day increased after administration of high-dose G-CSF from 0.16 after the first mobilization attempt to 0.61 (p = 0.0002) after the second mobilization. All patients engrafted in a median of 11 and 13 days for neutrophils and platelets, respectively. We conclude that patients whose apheresis yield is <0.4 x 10(6) CD34+ cells/kg after the first two apheresis collections can be successfully mobilized if high-dose G-CSF is administered immediately and continued until achieving > or =2 x 10(6) CD34+ stem cells/kg.

Treatment of oral chronic graft-versus-host disease with PUVA therapy: case report and literature review.

Chronic graft-versus-host disease commonly appears with oral manifestations subsequent to allogeneic bone marrow transplantation. These manifestations include leukoplakia, mucosal atrophy, erythema, ulcers, and xerostomia. Some lesions are resistant to treatment with immunosuppressive medications. Ultraviolet A irradiation therapy with oral psoralen has been shown to be effective in treating these resistant lesions. This article presents a review of the literature and a case report.

Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Hepatic complications are a major cause of illness and death after bone marrow transplantation. OBJECTIVE: To confirm the results of a pilot study that indicated that ursodiol prophylaxis could reduce the incidence of veno-occlusive disease of the liver. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Tertiary care teaching hospital. PATIENTS: 67 consecutive patients undergoing transplantation with allogeneic bone marrow (donated by a relative) in whom busulfan plus cyclophosphamide was used as the preparative regimen and cyclosporine plus methotrexate was used to prevent graft-versus-host disease. INTERVENTION: Before the preparative regimen was started, patients were randomly assigned to receive ursodiol, 300 mg twice daily (or 300 mg in the morning and 600 mg in the evening if body weight was > 90 kg), or placebo. MEASUREMENTS: Patients were prospectively evaluated for the clinical diagnosis of veno-occlusive disease, the occurrence of acute graft-versus-host disease, and survival. RESULTS: The incidence of veno-occlusive disease was 40% (13 of 32 patients) in placebo recipients and 15% (5 of 34 patients) in ursodiol recipients (P = 0.03). Assignment to placebo was the only pretransplantation characteristic that predicted the development of veno-occlusive disease. The most significant predictor of 100-day mortality was the diagnosis of veno-occlusive disease. The difference in actuarial risk for hematologic relapse in patients with chronic myelogenous leukemia and nonhepatic toxicities between the two groups was not statistically significant (13% in the ursodiol group and 20% in the placebo group; P > 0.2). CONCLUSION: Ursodiol prophylaxis seemed to decrease the incidence of hepatic complications after allogeneic bone marrow transplantation in patients who received a preparative regimen with busulfan plus cyclophosphamide.