Monoclonal B cells detected in autologous PBSC grafts from patients with classical Hodgkin lymphoma: impact on relapse and survival following transplantation.

Autologous peripheral blood stem cell transplantation (PBSCT) for Hodgkin lymphoma (HL) is curative for many patients with relapsed or refractory disease. Relapsing disease, however, remains a major problem. Neoplastic transformation of B-lymphocytes probably underlies the development of classical HL. Whether clonal B cells are critical for disease evolution and response to therapy in HL remains uncertain. We investigated the impact of clonal B cells detected in peripheral blood stem cell (PBSC) collections on the outcome of patients with HL undergoing transplant. Qualitative semi-nested PCR was carried out on genomic DNA from mononuclear cells from PBSCs to determine the presence of clonal immunoglobulin heavy chain (IgH) complementary-determining region 3 (CDR3) gene rearrangements. Clinical factors were assessed for their association with relapse, overall survival (OS) and progression-free survival (PFS). Among 39 patients undergoing PBSCT, 12 grafts (31%) were PCR positive for clonal IgH rearrangements. OS was better in the PCR-negative group (logrank test, P=0.041). The OS at 5 years was 81% in PCR-negative versus 39% in PCR-positive patients; hazard ratio was 3.23 (95% confidence interval: 0.98-10.63). There was a trend towards better PFS (logrank test, P=0.12), estimated as 71% at 5 years in PCR-negative versus 41% in PCR-positive patients. Clonal B-lymphocytes in PBSC collections of patients with HL identify patients at risk of poor outcome. Larger series are needed to confirm our observations. Insight regarding the role of monoclonal B cells may lead to improved therapies.

Contaminating tumour cells in autologous PBSC grafts do not influence survival or relapse following transplant for multiple myeloma or B-cell non-Hodgkin's lymphoma.

Relapsed disease remains a major obstacle following autologous haematopoietic SCT (HSCT) for non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Studies regarding the importance of detectable tumour cells in PBSC collections have been inconclusive. Patients undergoing autologous HSCT for NHL and MM between 2001 and 2006 were enrolled (n=158). PBSC grafts were assessed for clonal IgH CDR3 gene rearrangements using qualitative semi-nested PCR. In comparison to patients with PCR-positive PBSC grafts, patients negative for detectable disease had no improvement in overall survival (OS) or PFS for MM (P=0.91 and 0.91) or NHL (P=0.82 and 0.85). Further, no significant difference in OS was observed between patients with PCR-positive compared with PCR-negative PBSC grafts with aggressive NHL histology (P=0.74) or indolent disease (P=0.29). Patients with contaminating tumour cells in autologous PBSCs do not have worsened OS or PFS in MM or NHL. Tumour cells detected by sensitive molecular methods in PBSC collections may be distinct from cells contaminating marrow and appear to have limited utility in identifying patients with MM and B-cell NHL who would benefit from purging strategies.

Incidence of symptomatic venous thromboembolism following hematopoietic stem cell transplantation.

BACKGROUND: The incidence of symptomatic venous thromboembolism (VTE) following hematopoietic stem cell transplantation (HSCT) is not well described, particularly with increased use of ambulatory care in the transplant setting. METHODS: A retrospective analysis involving 589 patients (382 autologous HSCT, 207 allogeneic HSCT) undergoing transplantation between 2000 and 2005 in a single Canadian institution was undertaken to identify the incidence of proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) in HSCT patients. RESULTS: The total 1-year incidence of symptomatic VTE was 3.7% [95% confidence interval (CI) 2.5-5.6]. Among the HSCT patients, 7/589 (1.2%, 95% CI 0.6-2.4) developed symptomatic non-catheter-related VTE following HSCT (four PE and three DVT). All VTE events occurred after hematopoietic engraftment. Patients undergoing autologous HSCT did not receive thromboprophylaxis, whereas most patients undergoing allogeneic HSCT (79.7%) received enoxaparin 20 mg daily for the prevention of veno-occlusive disease of the liver, starting 6 +/- 3 days before transplantation for a mean of 22 +/- 14 days. CONCLUSION: HSCT patients have a high incidence of VTE. Thromboprophylaxis should potentially be considered in these patients. However, future studies assessing the risk and benefits of thromboprophylaxis are needed in this specific population.

Leading change: Retrospective evaluation of a nurse-led initiative in vascular access options for autologous stem cell transplant recipients ranging from Hickman catheters to peripherally inserted central catheters.

Central venous access is essential for patients undergoing autologous hematopoietic stem cell transplantation (ASCT). Traditionally, tunneled silastic catheters have been inserted in these patients. However, changes in resource allocation, resulting in reduced surgery and surgeon time and decreasing toxicity associated with ASCT, have caused changes in venous access needs and options. This led the advanced practice nurse in the transplant program to evaluate other central access devices, which resulted in the introduction of peripherally inserted central catheters (PICCs) for this patient population. This study reports the results of a retrospective analysis comparing efficacy and complication profiles between 50 patients with the traditional Hickman catheter and 70 patients with PICCs.

Selection of appropriate venous access for the collection of peripheral blood progenitor cells by experienced apheresis nurses.

Peripheral blood progenitor cells (PBPC) have been extensively used to restore hematopoiesis after myeloablative chemotherapy. While collection regimens designed for optimal mobilization of PBPC are becoming standardized, the ideal venous access option for collection remains unresolved. The purpose of this study was to determine if the venous access of patients could be accurately assessed and appropriate intervention, if necessary, electively undertaken prior to PBPC collection. In this prospective study, 95 consecutive patients about to undergo PBPC collection were evaluated at time of referral to determine the type of venous access necessary for adequate PBPC collection. There were three possible interventions: 1. No access device for patients determined to have an adequate antecubital vein for apheresis access. 2. Insertion of a double lumen Quinton PermCath for those patients with poor antecubital veins. 3. Insertion of a double lumen Hickman catheter for patients with adequate antecubital veins for apheresis but poor peripheral veins for chemotherapy administration. The blood and marrow transplant nurse coordinator evaluated the patients' veins. Of the 95 patients having 192 PBPC collections, 65 were collected using antecubital veins, 21 were collected from PermCaths, and 9 from Hickman catheters. All patients predicted to collect peripherally did so and achieved flow rates equivalent to the PermCath. No patient required urgent line placement at time of PBPC collection. There was no difference in the number of cells collected between the three groups. The result of this study strongly supports a policy of appropriate venous access based on patient vein assessment by experienced nurses.

Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis.

BACKGROUND: Acute deep vein thrombosis has traditionally been treated with unfractionated heparin (UFH), administered intravenously, but low-molecular-weight heparins (LMWH), administered subcutaneously, have recently become available. The authors sought to determine which therapy was more cost-effective for inpatient and outpatient treatment of deep vein thrombosis. METHODS: An incremental cost-effectiveness analysis based on a decision tree was performed for 4 treatment strategies for deep vein thrombosis. Rate of major hemorrhage while receiving heparin, rate of recurrence of venous thromboembolism 3 months after treatment and mortality rate 3 months after treatment were determined by meta-analysis. Costs for the UFH therapy were prospectively collected by a case-costing accounting system for 105 patients with deep vein thrombosis treated in fiscal year 1995/96. The costs for LMWH therapy were modelled, and cost-effectiveness was determined by decision analysis. RESULTS: Meta-analysis revealed a mean difference in risk of hemorrhage of -1.1% (95% confidence interval [CI] -2.4% to 0.3%), a mean difference in risk of recurrence of venous thromboembolism of -2.6% (95% CI -4.5% to -0.7%) and a mean difference in risk of death of -1.9% (95% CI -3.6% to -0.4%), all in favour of subcutaneous unmonitored administration of LMWH. The cost to treat one inpatient was $2993 for LMWH and $3048 for UFH. Even more would be saved if LMWH was delivered on an outpatient basis (cost of $1641 per patient). The cost-effectiveness analysis showed that LMWH in any treatment setting is more cost effective than UFH. A sensitivity analysis demonstrated the robustness of this conclusion. INTERPRETATION: Treatment of deep vein thrombosis with LMWH is more cost effective than treatment with UFH in both inpatient and outpatient settings.

Effect of pentoxifylline on regimen related toxicity in patients undergoing allogeneic or autologous bone marrow transplantation.

An unblinded, historical controlled study of 49 bone marrow transplant (BMT) patients was carried out in our institution to assess the effect of oral pentoxifylline (PTX) on BMT regimen related toxicity (RRT). Twenty-eight consecutively treated BMT patients (17 allogeneic, 11 autologous) were entered into the PTX treatment group and treated with oral PTX 400 mg at intervals of 4 h from day -10 until day +35 or discharge, whichever came sooner. These were compared with a control group of 21 BMT patients (14 allogeneic, 7 autologous). Patient groups were very similar with respect to age, sex, conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and baseline liver and renal function. Compliance with the drug was 85%. Despite this, no significant difference in days of mucositis or hyperalimentation, incidence or severity of renal or hepatic dysfunction, hypertension, GVHD, weight gain > 5%, day 100 mortality or length of hospitalization was observed. Median follow-up is > 2 years in both groups and no difference in relapse or survival was observed. We were unable to confirm an effect of oral PTX on BMT related morbidity or mortality.

A regional autologous bone marrow transplant network: transfers to designated centers on the day after transplant.

Autologous bone marrow transplantation (ABMT) is becoming increasingly prevalent for treatment of advanced malignant disease. In order to increase the availability and utility of this therapy, we assessed the feasibility of transferring patients to their regional referral centers on the day after marrow infusion (day 1), for management post-transplant. This prospective study compares the outcome of 77 patients either transferred the day after marrow transplant for subsequent management at one of six selected Canadian regional centers closest to their domicile, or treated entirely at The Toronto Hospital, according to a common protocol. Study end-points included frequency of complications during transfer, transplant-related morbidity and mortality and hematopoietic recovery. Assessment of eligibility for transplant, bone marrow harvesting, autograft cryopreservation, administration of intensive therapy and marrow infusion were conducted in all cases at The Toronto Hospital. Thirty patients received marrow transplants and were transferred on day 1. There were no complications during transfer. Compared with 47 consecutive patients treated entirely at The Toronto Hospital, there were no differences in treatment-related morbidity or mortality, use of intravenous antifungal therapy or total days of hospitalization. We conclude that day 1 transfer of patients after ABMT to designated centers is feasible and safe. The operation of a regional ABMT network appears to benefit patients, relatives, referring physicians, the transplant center and may also improve health care delivery.

Allogeneic bone marrow transplantation using unrelated donors: a pilot study of the Canadian Bone Marrow Transplant Group.

Between February 1988 and January 1990, 35 patients underwent allogeneic bone marrow transplantation (BMT) from unrelated donors using measures routinely employed for matched related donors. Median patient age was 34 years (range 2-49). Thirty-two patients had hematologic malignancies, including chronic myelogenous leukemia (CML) in 16; three patients had severe aplastic anemia. Donor-patient pairs were matched at the HLA loci tested serologically (HLA-A, -B, -DR) in 29 cases; mixed leukocyte culture results were variable but often reactive. Five patients died prior to day +28 without evidence of myeloid engraftment, and one patient developed fatal graft failure several months after initial engraftment. Acute graft-versus-host disease (GVHD) occurred in 77% (95% confidence interval [CI] 60-90%) of all patients, and GVHD contributed to the death of 10 patients. Fatal regimen-related toxicity occurred in four patients and another died due to neurologic complications of a process that resembled the hemolytic-uremic syndrome. Two acute leukemia patients relapsed, and a CML patient was found to have a localized non-Hodgkin's lymphoma at necropsy. As of 1 June 1991, 14 patients are alive and in remission at a median follow-up of 1.9 years (range 1.5-3.3); all except one have normal performance scores. The 2-year actuarial event-free survival for all patients is 40% (95% CI 24-56%). Proportional hazards analysis revealed favorable significance for female patient sex, less advanced disease status and shorter interval from diagnosis to BMT. While unrelated-donor transplants need not necessarily duplicate the results of related-donor transplants to be of benefit, the event-free survival in this series was roughly similar to that expected in the related-donor situation, with the high transplant-related mortality somewhat offset by a low recurrence rate. Further studies using unrelated donors, employing new methods of preventing transplant-related complications, are indicated.

Disorders of platelet function: mechanisms, diagnosis and management.

Platelets play an important role in hemostasis, and alterations in platelet function may be the cause of abnormal bleeding in a wide variety of congenital and acquired clinical disorders. Platelet dysfunction may be classified as disorders of (1) substrate connective tissue, (2) adhesion, (3) aggregation and (4) platelet-release reaction. The congenital defects of platelet function, although uncommon, have provided important insights into platelet physiology and pathophysiology and, as a group, are less common, better characterized and more readily classified than the acquired defects. The severity of bleeding resulting from platelet dysfunction varies greatly and is substantially increased when another defect of hemostasis coexists. A disorder of platelet function is suspected on the basis of the history and physical examination and is confirmed by the finding of a prolonged bleeding time in the presence of an adequate number of platelets. A specific diagnosis often requires measurements of the factor VIII and von Willebrand factor complex and other tests of platelet function. Some of these tests may be available only in specialized laboratories. Therapy for bleeding episodes resulting from platelet dysfunction is directed at (1) removing or treating the underlying cause of the platelet disorder; (2) replacing the missing plasma cofactors needed to support normal platelet function (such as by the transfusion of cryoprecipitate in patients with von Willebrand disease, and (3) transfusing functional platelets in the form of platelet concentrates in patients with disorders of intrinsic platelet dysfunction.