Early versus late administration of pegfilgrastim after high-dose chemotherapy and autologous hematopoietic stem cell transplantation

Purpose  

Single-dose pegylated filgrastim (pegfilgrastim) after autologous hematopoietic stem cell transplantation (AHSCT) showed similar efficacy compared to daily lenograstim. To address the question of the optimal application time, we randomly assigned patients (pts) to pegfilgrastim on day + 1 (Peg1) or day + 4 (Peg4) after AHSCT.     

Pegfilgrastim compared with filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients

We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high-dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty-seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post-transplant (n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 microg/kg (n = 19 patients) starting on day 5 post-transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively (P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes x 10(9) L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.     

A case of aggressive myeloma recognized shortly after the remission following high-dose chemotherapy with autologous peripheral blood stem cell transplantation

A 45-year-old woman was referred to our hospital with acute renal failure and pyrexia. In August 2005, the patient was diagnosed with IgA-λ type multiple myeloma with chromosome 13 deletion, and received three cycles of vinclistine, adriamycin and dexamethasone followed by high-dose melphalan-based autologous peripheral stem cell transplantation: this resulted in remission 2 months before admission to our hospital. Serum IgA concentration was within the normal limit, but an excess of myeloma cells in bone marrow was confirmed. Immunoelectrophoresis revealed BJP-λ production with no IgA-λ. The patient received several courses of chemotherapy with mechanical ventilation and regular hemodialysis. The progression of the illness was rapid: multiple organ failure promptly developed and the patient died 2 months after admission. Autopsy revealed deposition of light chain λ protein in multiple organs. We report this unusual case of aggressive myeloma recognized shortly after successful autologous transplantation.     

Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders

A third of patients with multiple myeloma (MM) have a preceding diagnosis of plasma cell proliferative disorder (PCPD), mostly monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) or plasmacytoma. While autologous stem cell transplantation (SCT) improves survival in MM, it is not clear if patients with preceding PCPD have a different outcome. We identified 151 patients with preceding PCPD from among 804 patients undergoing SCT, and their outcomes were compared. The response rates, including complete responses, were similar between the groups. Patients with a preceding diagnosis of MGUS had longer time to progression (TTP; 27·5 months vs. 17·2 months, P  = 0·01), and longer overall survival (OS) from transplant (80·2 months vs. 48·3 months, P  = 0·03) compared to those with de novo myeloma. However no differences were seen among those with a preceding diagnosis of SMM or plasmacytoma in terms of TTP or OS from transplant when compared to those with de novo myeloma. Multivariate analysis indicated that the presence of MGUS prior to myeloma was prognostic for post-transplant relapse independent of other known risk factors. Patients with pre-existing MGUS prior to myeloma diagnosis have a better outcome following HDT, reflecting more indolent disease and a favourable biology than those presenting with de novo myeloma.     

Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation

OBJECTIVES: Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem cell transplantation in the context of beta(2) microglobulin and chromosome 13q. METHODS: All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. RESULTS: There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5-128) nine patients (70%) are still alive, and six of them have remained progression free. Among five patients with low beta(2) microglobulin and normal chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated ss(2) microglobulin and/or deletion of chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. CONCLUSIONS: Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.     

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in high-risk multiple myeloma

We compared the effect of high-dose therapy together with autologous peripheral blood stem cell transplantation (autoPBSCT) in 60 patients with multiple myeloma (MM) with 90 patients who underwent conventional chemotherapy. We scored the prognostic factors according to our reported classification system that includes measurements of serum albumin, serum beta-2-microglobulin, and morphology of myeloma cells selected by multivariate analysis. We separated the patients into three risk groups at stratification level I (low, intermediate and high) and into two risk groups at stratification level II (low and high). AutoPBSCT tended to be as effective for high, as for low-risk patients in level I, and was obviously as helpful for high, as for low-risk patients in stratification II. In conclusion, high-risk patients with MM should be treated with high-dose therapy accompanied with autoPBSCT like low-risk patients.     

Tandem autologous stem cell transplantation in multiple myeloma after high-dose chemotherapy with two separate collections: single institution experience

Presented is a retrospective analysis of multiple myeloma patients transplanted at our institution between November 1993 and August 2007. The objective of this analysis was to assess the feasibility and toxicity of tandem autologous stem cell transplantation (T-ASCT) when stem cells were harvested before first and before second transplantation separately. A total of 90 patients transplanted in our center were analyzed, of whom 43 patients were in tandem transplantation group.The overall response rate (ORR) was 83.7% and 95.1%, estimated five-year overall survival (OS) was 40.1% and 60.0%, probability of five-year event-free survival (EFS) was 18.2% and 25.6%, transplant related mortality (TRM) was 6.3% and 4.6% in the single and tandem transplant group, respectively. In multivariable analysis of all 90 patients, tandem transplantation and ORR attained after induction therapy were favourable prognostic factors for OS (p=0.024 and p=0.002) and EFS (p=0.036 and p=0.008), respectively. In conclusion, tandem transplantation with two separate stem cell harvests, performed separately before the each transplantation, is feasible in majority of patients with acceptable toxicity.     

Dermatomyositis and sarcoid-like reaction associated with multiple myeloma treated effectively by high-dose chemotherapy and autologous peripheral blood stem cell transplantation

We report the case of a 46-year-old male who developed dermatomyositis and a sarcoid-like reaction in association with testicular relapse of multiple myeloma. The myositis progressed despite chemotherapy directed at the underlying malignant disorder and immunosuppressive treatment. There was, however, a dramatic and sustained response to high-dose chemotherapy and autologous peripheral blood stem cell transplantation which resulted in resolution of the myopathy and partial resolution of the sarcoid-like reaction. This case report highlights the potential of autologous stem cell transplantation as treatment for para-neoplastic disorders associated with haematological malignancies.     

Infectious complications after high-dose chemotherapy and autologous stem cell transplantation: comparison between patients with lymphoma or multiple myeloma and patients with solid tumors

From November 1994 to May 1998, 117 patients (66 with solid tumor, 36 with lymphoma, 14 with multiple myeloma, one with acute leukemia) underwent 178 cycles of high-dose chemotherapy and autologous stem cell transplantation (ASCT) at our institution. We retrospectively analyzed the infectious complications that occurred after ASCT. Median duration of neutropenia (granulocyte count <0.5 x 10(9)/l ) was 8 days, the overall incidence of fever requiring antimicrobial treatment was 63%. 35.4% of patients had fever of unknown orign (FUO), whereas primary bacteremia occurred in 21.3%, pneumonia in 3.4% and severe skin infection in 1.1% of patients. Invasive fungal infections occurred in three, and enterocolitis in one patient. Infection was fatal in three patients (2.6%), in each case due to septic shock. The most frequently isolated pathogens were Gram-positive cocci. Median time to defervescence with antimicrobial therapy was 4 days (6 days in patients with bacteremia or other severe infection, and 3 days in patients with FUO). First-line antimicrobial therapy was successful in 65% of patients with FUO and 30.6% of patients with documented infections. With respect to the incidence, type and clinical course of infection, no significant differences between patients with lymphoma or multiple myeloma and those with solid tumors were detected.     

Kinetics of peg-filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell transplantation

Peg-filgrastim is a form of G-CSF with a sustained duration of action due to self-limited clearance. We administered 6 mg peg-filgrastim to 18 autograft recipients on day +1 after transplantation for hematologic malignancies. Plasma samples were collected at baseline and during transplantation. Hematopoietic recovery and clinical outcomes were compared to the historical data of 54 patients not receiving G-CSF. Patients receiving peg-filgrastim achieved a serum level of 115 000 pg/ml on day +2, 24 h after drug administration. Drug level maintained a plateau until day +8 and, after day +10, declined concomitantly with myeloid recovery. Patients experienced prompt neutrophil recovery: days +9 and +10 to 500 and 1000 neutrophils per microliter, and 4 days with an absolute neutrophil count <100 cells per microliter. Duration of antibiotic therapy was significantly shortened, but we did not observe significant differences in other end points. In conclusion, peg-filgrastim was well tolerated and efficacious, and hastened myeloid recovery.     

Phase I/II study of tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation for advanced multiple myeloma

The efficacy and safety of high-dose chemotherapy with tandem autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in a multicenter clinical study of patients with advanced multiple myeloma. Eligible patients (n = 40) were consecutively enrolled in the phase I/II study and received 2–4 cycles of vincristine–adriamycin–dexamethasone regimen. The responding patients underwent PBSC harvesting following high-dose cyclophosphamide and filgrastim administration. The first auto-PBSCT (n = 32) following high-dose melphalan (200 mg/m²) was performed within 2 months of PBSC harvesting; the second auto-PBSCT (n = 28) was scheduled 3–6 months later. Treatment-related mortality was 2.5% (n = 1) throughout the protocol. Grade 4 nonhematologic toxicity occurred in 12.5 and 14.3% of the first and second auto-PBSCT patients, respectively. All but one patient (who died) achieved hematopoietic recovery. For the 28 patients completing the second auto-PBSCT, the results were favorable with a response rate of 65% (complete response rate = 27.5%, n = 11); the five-year progression-free survival and overall survival were 20.3 and 66.5%, respectively. In conclusion, high-dose chemotherapy with tandem auto-PBSCT is feasible and safe with a favorable response rate in treating advanced multiple myeloma in Japan.     

Prolonged responses after autologous stem cell transplantation in African-American patients with multiple myeloma

Multiple myeloma (MM) has a double incidence in African-American (AA) than in non-AA patients and previous studies have shown a higher mortality in the former patient population. Here, we retrospectively analyzed the results of autologous stem cell transplantation (ASCT) in 38 AA and 32 non-AA consecutive patients. The two groups were comparable at diagnosis for age, stage of the disease, cytogenetic abnormalities, beta(2) microglobulin and albumin blood levels, and plasma cell marrow infiltration. The rates of complete and partial response observed in AA and non-AA patients after induction chemotherapy (9 and 42 vs 13 and 33%) and at 2 months (31 and 25 vs 30 and 20%) following ASCT were similar. At 6 months after ASCT, a greater relapse rate was observed in non-AA patients (P=0.009). At a median follow-up of 26 months, AA patients had a greater event-free survival (P=0.02) than non-AA patients, whereas overall survival was comparable in the two groups. The initial finding that AA patients with MM, compared to non-AA patients, had more prolonged responses and comparable survival after ASCT suggests that intensified chemotherapy is equally effective in patients of various ethnicities.     

Salvage therapy with thalidomide in multiple myeloma patients relapsing after autologous peripheral blood stem cell transplantation

BACKGROUND AND OBJECTIVES: The introduction of high-dose therapy with stem cell support has significantly improved the outcome of patients with multiple myeloma (MM) in terms of increased complete remission (CR) rate and extended survival, both disease-free and overall. Few options, however, are presently available for patients who relapse after single or double autologous stem cell transplantation (SCT). Thalidomide, a glutamic acid derivative with anti-angiogenetic properties, has been recently proposed as salvage treatment for such patients. The present study was aimed at evaluating thalidomide as single agent therapy for patients who had previously received autologous peripheral blood stem cell transplantation. DESIGN AND METHODS: From October 1999 to August 2000, 11 patients (7 males/4 females) who had relapsed after single (n = 4) or double (n = 7) autologous peripheral blood SCT were enrolled in the trial. Thalidomide, always employed as a single agent, was initially administered at a dose of 100 mg/day; if well tolerated, the dose was increased serially by 200 mg every other week to a maximum of 800 mg/day. RESULTS: The median administered dose was 600 mg/day. WHO grade > II toxic effects were constipation, lethargy, and leukopenia. Four patients (36%) showed > 50% reduction in serum M protein concentration and 4 showed > 25% reduction, for a total response rate averaging 72%. After a median follow-up of 5 months, 3 out of 8 responding patients are alive and progression-free and 5 patients have relapsed. INTERPRETATION AND CONCLUSIONS; These data confirm that thalidomide is active in poor-prognosis MM patients such as those relapsing after autologous SCT, and could thus deserve further testing in combination therapy.     

Myelodysplastic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma

Long-term survivors after autologous peripheral blood stem cell transplantation (APBSCT) for lymphoma or Hodgkin's disease are known to have a high risk of developing myelodysplastic syndrome (MDS), but the risk of MDS is not clear for patients transplanted for myeloma. We reviewed the outcomes for 82 myeloma patients who underwent APBSCT at our center. The group included 47 men and 35 women of median age 56 years (range: 37-74 years). Median time from diagnosis to APBSCT was 8.2 months (range: 2.6-86.1 months). Before coming to transplantation, 28% had received oral melphalan (MEL), 98% received other chemotherapy and 34% received radiation. A single APBSCT was provided for 68, and 32% underwent APBSCT more than once. High-dose MEL alone was used as the preparative regimen for 83%, and the remainder received at least one APBSCT with a more intensive preparative regimen. Ten patients (12%) developed MDS. The 5-year cumulative incidence is 18% (95% confidence interval, 9-30%). There were no demographic factors associated with an increased risk of developing MDS. Median survival after the diagnosis of MDS was 18 months. There is a relatively high risk of MDS after APBSCT for myeloma, and optimal therapy has not been established for these patients.     

Role of high-dose melphalan with autologous stem cell transplantation in multiple myeloma patients receiving botezomib-containing induction therapy

To examine the role of high-dose melphalan therapy with autologous stem cell transplantation (HDM/ASCT) in the final outcomes of multiple myeloma (MM) patients receiving bortezomib-containing induction therapy (IT), we analyzed relationships between quality of response after IT including bortezomib or HDM/ASCT and survival. In total, 92 MM patients who received IT with bortezomib followed by HDM/ASCT were enrolled. The median follow-up was 28.0 months. Three-year progression-free survival (PFS) and overall survival (OS) were 41.1 and 72.0 %, respectively. A complete response (CR) after HDM/ASCT was a strong prognostic factor for PFS and OS (p = 0.002 and 0.001, respectively). Additionally, out of 67 patients who failed to achieve CR after IT, 36 (53.7 %) patients achieved CR after HDM/ASCT. PFS and OS in patients with CR after additional HDM/ASCT were similar to those in patients who had already achieved CR after IT. However, achievement of at least very good partial response following IT with bortezomib failed to improve PFS and OS (p = 0.35 and 0.11, respectively). Thus, we conclude that post-HDM/ASCT CR is the best prognostic factor for both PFS and OS regardless of response to bortezomib. Therefore, HDM/ASCT remains an important therapy in MM patients even after introduction of bortezomib IT.