Efficacy of deferred dosing of granulocyte colony-stimulating factor in autologous hematopoietic transplantation for multiple myeloma.

Routine administration of G-CSF following autologous hematopoietic SCT (ASCT) expedites ANC recovery and reduces hospitalization by 1-2 days; it has no impact on febrile neutropenia, infections, morbidity, mortality, event-free survival or OS. To determine whether delayed G-CSF dosage could result in equivalent ANC recovery and thereby improve cost effectiveness, we deferred the administration of G-CSF until WBC recovery had begun. A total of 117 patients with multiple myeloma received ASCT from January 2005 to September 2012. Of these, 52 were in the conventional dosing group (CGD) and received G-CSF from Day +7 for a median of five doses. In the deferred dosing group (DGD), 65 patients received G-CSF from median day 14 post transplant for a median of zero doses. There was no difference between groups in the incidence or duration of febrile neutropenia, duration of grade III mucositis, weight gain, rash, engraftment syndrome or early death (100 days). The DGD group had a significantly longer time to neutrophil engraftment than the CGD group (15 days vs 12 days; P<0.0001), a longer period of severe neutropenia (<100/µL; 8 days vs 6 days; P<0.0001), longer treatment with intravenous antibiotics (7 days vs 5 days; P=0.016) and longer hospital stay (19 days vs 17 days; P=<0.0001). Although the cost of G-CSF was lower in the DGD group (mean $308 vs $2467), the additional hospitalization raised the median total cost of ASCT in this group by 17%. There was, however, no adverse effect of deferred dosing on the rate of febrile neuropenic episodes or Day 100 survival, so that deferred dosing of G-CSF may be suitable for patients receiving ASCT as outpatients, for whom longer hospital stay would not be an offsetting cost.

Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone.

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34(+) cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10(6) cells/kg on day 1 vs 2.92 × 10(6) cells/kg, P=0.0231; myeloma: 4.16 × 10(6) vs 3.69 × 10(6) cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10(6) cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.

Outcome of hematopoietic stem cell transplant as salvage therapy for Hodgkin's lymphoma in adolescents and young adults at a single institution.

For patients with relapsed Hodgkin's lymphoma (HL), high dose chemotherapy with stem cell rescue (HDCT-SCT) may improve survival over chemotherapy alone. We assessed the outcomes of HDCT-SCT in 37 consecutive adolescent and young adult patients with relapsed HL whose malignancy was categorized based on sensitivity to chemotherapy. We determined whether current outcomes supported the use of HDCT-SCT in all of our patients or just those patients with lower-risk characteristics such as chemosensitivity. With a median follow-up of 6.5 years, the 2-year overall survival (OS) was 89% (95% CI: 62-97%) for the chemosensitive patients (n = 21), whereas for patients with resistant disease (n = 16), OS was 53% (95% CI: 25-74%). Both autologous and allogeneic transplants were well tolerated, with 100-day treatment-related mortality under 10%. Our data show encouraging outcomes for patients with chemosensitive relapsed HL who receive hematopoietic stem cell transplant (HSCT) and support the value of the procedure even when the disease is chemoresistant.

Selective elimination of a chemoresistant side population of B-CLL cells by cytotoxic T lymphocytes in subjects receiving an autologous hCD40L/IL-2 tumor vaccine.

Side-population (SP) analysis identifies precursor cells in normal and malignant tissues. Cells with this phenotype have increased resistance to many cytotoxic agents, and may represent a primary drug-resistant population in malignant diseases. To discover whether drug-resistant malignant SP cells are nonetheless sensitive to immune-mediated killing, we first established the presence of a malignant CD5(+)CD19(+) SP subset in the blood of 18/21 subjects with B-cell chronic lymphocytic leukemia (B-CLL). We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5(+)CD19(+) SP cells. T-cell lines and clones generated from vaccinated patients specifically recognized B-CLL SP tumor cells. Elimination of SP cells is likely triggered by their increased expression of target antigens, such as receptor for hyaluronan-mediated motility (RHAMM), after stimulation of the malignant cells by hCD40L, as CD8(+) RHAMM-specific T cells could be detected in the peripheral blood of immunized patients and were associated with the decline in B-CLL SP cells. Hence, malignant B cells with a primary drug-resistant phenotype can be targeted by T- cell-mediated effector activity after immunization of human subjects.

Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both. OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment. METHODS: Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism. RESULTS: No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS. CONCLUSIONS: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.

Transmission of integrated human herpesvirus-6 in allogeneic hematopoietic stem cell transplantation.

Human herpesvirus 6 (HHV-6) viremia, as detected by polymerase chain amplification, occurs in approximately half of allogeneic hematopoietic stem cell transplant recipients. The significance of such viremia is incompletely understood, but HHV-6 encephalitis and bone marrow suppression are increasingly being recognized in patients with high viral DNA. We report two patients in whom donor-to-recipient transmission occurred through hematopoietic transplant by means of chromosomally integrated (CI) HHV-6. Iatrogenic transmission manifested at engraftment as asymptomatic elevation of HHV-6 viral DNA of 3600 and 15 400 DNA copies/ml in plasma and 6.1 x 10(6) and 9.7 x 10(5) DNA copies/ml in the whole blood. Both donors had elevated plasma HHV-6 PCR at 5.6 x 10(4) and 1.3 x 10(5) DNA copies/ml and strikingly elevated whole blood HHV-6 levels at 4.1 x 10(6) and 4.7 x 10(6) DNA copies/ml, respectively. CI of the virus was traced to the mother of one patient and his donor. CI of HHV-6 may confound the interpretation of HHV-6 viremia after stem cell transplantation; consideration of the possibility of CI HHV-6 will avoid unnecessary antiviral therapy.

Human herpesvirus-6 encephalitis following allogeneic hematopoietic stem cell transplantation.

Immunosuppressive monoclonal antibodies directed to immune system cells may reduce rejection and graft versus host disease (GvHD) after allogeneic stem cell transplantation (SCT), but can increase the risks of viral infection. Here, we report human herpes virus-6 (HHV-6) encephalitis despite antiviral prophylaxis in 5 of 43 (11.6%) patients receiving alemtuzumab supported conditioning. Encephalitis occurred at 41-103 days (median 60 days) presenting with confusion in all patients, combined with amnesia (n=3) or seizures (n=2). MRI revealed non-specific white matter changes in two and a non-enhancing medial temporal lobe lesion in three patients. Cerebrospinal fluid (CSF) PCR amplification for HHV-6 was positive in all five patients, (600-2 25 000 (median 4700) copies/ml CSF), while analysis of peripheral blood revealed 100-22 500 (median 1200) viral copies/ml plasma. CSF protein was elevated in four patients, with minimal CSF pleocytosis. Intravenous foscarnet produced neurological improvement at 8-13 (median 11) days and negative plasma PCR at 30-66 (median 50) days. Four patients had complete neurological recovery, but one patient with persistent viral DNA in the CSF succumbed to progressive encephalopathy. Given this high incidence of HHV-6 and the possibility of successful outcome with prompt treatment, a high index of suspicion of this disorder is required in recipients of monoclonal antibody supported allografts.

Central nervous system graft-versus-host disease: report of two cases and literature review.

Two patients with a plausible diagnosis of central nervous system graft-versus-host disease (CNS-GVHD) are described. Both presented with neurological manifestations 6 and 18 months following allogeneic transplant with hemiparesis, seizure, encephalopathy and magnetic resonance findings of hyperintense white matter lesions on T-2 weighed images. Brain biopsy in one and autopsy in the other revealed profound perivascular lymphocytic infiltrates composed predominantly of T-lymphocytes that were of donor origin. Although an unequivocal diagnosis of CNS-GVHD is difficult to establish, the transplantation community should be aware of this controversial entity.

Outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation (RISCT) using antilymphocyte antibodies in patients with high-risk acute myeloid leukemia (AML).

Hemopoietic stem cell transplantation (SCT) with fully ablative conditioning is associated with an age-related increase in treatment-related mortality. It is therefore particularly unsuited to older individuals, who are most at risk of developing acute myeloid leukemia (AML). Reduced-intensity SCT (RISCT) may be of value in this group. We report 17 consecutive patients with high-risk AML whose median age was 58 years and who received stem cells from HLA-matched siblings (n=5), or alternative donors (n=12). We used lymphodepleting antibodies as a part of the reduced-intensity conditioning regimen to limit the risk of graft rejection and graft-versus-host disease (GVHD). All patients engrafted. One patient developed severe fatal GVHD, and two patients died of infection. At a median follow-up of 861 days (372-1957 days), seven patients are alive in remission, which includes two patients treated in relapse and five patients who lacked an MHC identical sibling donor. Both progression-free survival and overall survival are 40% (95% CI, 17-64%). Hence, RISCT using lymphodepleting antibodies may be of value for older patients with AML, even in those with active or high-risk disease, and even if they lack an MHC-identical sibling donor.

Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with Alemtuzumab.

We studied the incidence and recurrence of Cytomegalovirus (CMV) infection and reactivation in 38 recipients of Alemtuzumab reduced intensity conditioning-stem cell transplantation, and used CMV-HLA tetramer studies to discover if these events correlated with recovery of circulating CMV-specific CD8+ T cells (cytotoxic T lymphocyte (CTLs)). The cumulative incidence of CMV infection was 60% at 1 year (95% CI, 45-78%) with a median reactivation time of 24 days (range 5-95 days). All patients with CMV reactivation received Ganciclovir or Foscarnet, and only one developed CMV disease. More strikingly, only 8/21 patients had relapse of CMV antigenemia. Tetramer analysis in 13 patients showed that 11 reconstituted CMV CTLs (7/11 by day 30 and 10/11 by day 90). The development of CMV infection was accompanied by a >5-fold rise of CMV CTLs. Recurrence of CMV infection occurred only in the patients who failed to generate a CTL response to the virus. Hence, recipients of SCT using Alemtuzumab-RIC are initially profoundly immunosuppressed and have a high incidence of early CMV reactivation. However, in the majority of patients, infection is transient, and antiviral T cell reconstitution is rapid. Monitoring with CMV-specific CTLs may help identify the subset of patients at risk from recurrent infection or disease.

CD52 and CD45 monoclonal antibodies for reduced intensity hemopoietic stem cell transplantation from HLA matched and one antigen mismatched unrelated donors.

Allogeneic hemopoietic stem cell transplantation (HSCT) is the only curative option for many patients with hematological malignancies. Since many of these patients lack HLA-identical sibling donors and are older or have comorbidity, a fully ablative HSCT is not feasible and an alternative approach is required. We studied 22 consecutive patients who could not have myeloablative conditioning because of comorbidity or age - 21/22 being over the age of 50 years (median 58 years range 20-70 years). A conditioning regimen consisting of fludarabine, total body radiation 450 cGy and alemtuzumab (CD52 mAb) was used for 15 patients. A second group of seven patients received CD45 monoclonal antibodies in addition. Unrelated donor stem cells were HLA matched (15 patients - 68%) or one locus mismatched (seven patients - 32%). In all, 16 patients had high-risk disease, including 12 with active malignancy at the time of transplant. With a median follow-up of 715 (216-1470) days, nonrelapse mortality, actuarial event-free and overall survival is 27, 45 and 45%, respectively. Hence the outcome of reduced intensity HSCT with lymphodepleting antibodies in older patients with intermediate/high-risk hematological malignancies appears comparable to that obtained with fully ablative transplantation in younger patients, even when these older recipients lack HLA-identical sibling donors.

Use of antithymocyte globulin for treatment of steroid-refractory acute graft-versus-host disease: an international practice survey.

Antithymocyte globulin (ATG) is accepted as a treatment option for steroid-refractory acute graft-versus-host disease (GVHD). We conducted an international survey to determine how steroid refractoriness is defined and how ATG is used in clinical practice. Responses were received from 153 centers in 36 countries. The most common threshold steroid dose to define steroid refractoriness was 2 mg/kg/day (67% of respondents), and the median duration of treatment before failure was declared varied from 3 to 5.5 days, depending on whether failure was defined as 'progressed', 'not improved' or 'not resolved'. The threshold corticosteroid dose was significantly higher in pediatric centers than in adult or combined programs (P = 0.003). ATG was used routinely for treatment of steroid-refractory GVHD by 67% of the respondents. Horse ATG was used more frequently than rabbit ATG overall (50% vs 24%, P < 0.001), and predominance of horse ATG was most evident in the western hemisphere, in small- to medium-sized centers, and in pediatric centers. A wide variety of dose schedules for both drugs was reported. We conclude that there is some degree of variation in the definition of steroid refractoriness, especially between pediatric and nonpediatric programs, and no consensus has emerged in identifying the optimal ATG dose schedule in this setting.

Cutaneous sarcoidosis in a patient with Philadelphia-positive chronic myelogenous leukemia treated with interferon-alpha.

A patient with Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) was diagnosed with cutaneous sarcoidosis after treatment with interferon-alpha (IFN-alpha). Following IFN-alpha dose reduction, the skin lesions disappeared. Few cases of sarcoidosis associated with IFN treatment have been reported, and only in one patient with pre-existing CML. Our patient was unique in that (1) the sarcoidosis was induced by the IFN-alpha treatment alone, (2) it developed de novo, and (3) it was confined to the skin.