Tandem Autologous Peripheral Blood Stem Research Articles

Development of Hodgkin's Lymphoma-Like Post-Transplant Lymphoproliferative Disorder after Tandem Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

Post Transplant Lymphoproliferative Disorders (PTLDs) are serious complication after solid organ or Hematopoietic Stem Cell Transplantation (HSCT). Hodgkin's Lymphoma (HL)-like PTLD is grouped with HL type PTLD in the World Health Organization. HL type PTLD is the rarest form of PTLD.

Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: A Pediatric Oncology Group study: A Report from the Children's Oncology Group

The Pediatric Oncology Group performed a pilot study to assess the feasibility of tandem high dose chemotherapy (HDC) with stem cell rescue (HDC/SCR). We report here the results of this single arm trial of induction chemotherapy, local control measures (surgery and local radiation), and tandem HDC/SCR. Patients with high risk neuroblastoma (NBL) underwent five cycles of induction chemotherapy and resection of primary tumors. Peripheral blood stem cells (PBSC) were collected after Course 3 without exvivo manipulation. Myeloablative chemotherapy was performed in rapid sequence after induction chemotherapy and surgery. The ability of patients to complete both cycles of HDC/SCR was a primary endpoint. Transplant-related toxicity, progression-free survival (PFS) and overall survival (OS) were recorded. A total of 33 patients were enrolled. Twenty-two patients completed at least one HDC/SCR procedure and 17 patients completed both. Only one patient had insufficient stem cells collected for both transplants. There was one transplant-related death; engraftment was rapid and toxicity was as expected. The PFS of the 33 patients treated on this study is 24.2% ± 7.5% and OS is 36.4% ± 8.4% at 5 years. For patients who received at least one transplant PFS is 36.4% ± 11.0% and OS is 45.5% ± 11.2% at 5 years. The treatment of high risk NBL with tandem HDC/SCR is feasible in terms of transplant-related mortality and the ability to collect adequate PBSC for two transplants. The outcomes from this intensified treatment have been used to design a Children's Oncology Group Phase III study testing the efficacy of tandem HDC/SCR.

Management of Multiple Myeloma in Pregnancy: Strategies for a Rare Challenge

Multiple myeloma is the second most commonly diagnosed hematologic malignancy. It is characterized by the accumulation of monoclonal plasma cells. It typically manifests in the sixth decade of life or later, whereas the incidence in patients who are younger than 40 years old is extremely rare. Here, we report the case of a 34-year-old prima gravida, diagnosed with a κ light-chain myeloma (Durie&Salmon stage IIIA, International Staging System I) in the 23rd week of pregnancy. Our multimodal therapeutic approach during pregnancy, the delivery of a healthy male, and initiation of intensive anti-myeloma treatment thereafter (induction with bortezomib, cyclophosphamide, and dexamethasone, followed by tandem autologous peripheral blood stem cell transplantation) are described. Furthermore, we provide a comprehensive review of all 18 cases published between 1965 and 2010 in which a multiple myeloma was diagnosed and treated following different regimes and approaches before, during, or shortly after pregnancy. All delivered newborns were healthy, whereas the mothers' outcomes varied strongly. In our specific case, complete remission was achieved after tandem autologous peripheral blood stem cell transplantation. Emerging from these literature data and our case, we conclude that while awaiting delivery, the application of prednisolone as a nontoxic, but active anti-myeloma therapy can be recommended. Intensified postpartum anti-myeloma therapy should be induced as soon as possible to efficiently reduce myeloma burden and avoid organ damage in these young females.

The Risk of Secondary Myelodysplastic Syndrome/Acute Leukemia Following High-Dose Yttrium-90 Ibritumomab Tiuxetan Is Analogous to That Observed Following High-Dose Chemotherapy: a Matched-Pair Analysis In Non-Hodgkin Lymphoma Patients.

AbstractAbstract 1289 Introduction:Myeloablative doses of Yttrium-90 (90Y)-Ibritumomab Tiuxetan combined with tandem autologous peripheral blood stem cell (PBSC) support can be safely administered to patients aged up to 76 years (Devizzi L et al, J Clin Oncol 2008). Whether marrow exposure to myeloablative doses of radiolabelled antibodies (hd-radio-immunotherapy) could increase the risk of secondary myelodysplastic syndrome and acute leukemia (sMDS/AL) remains a matter of concern. Therefore, we prospectively investigated by means of a longitudinal study the incidence of sMDS/AL in a cohort of high-risk non-Hodgkin lymphoma (NHL) patients receiving hd-radio-immunotherapy. The cumulative incidence of sMDS/AL in the study group was compared with that observed in a historical group of patients autografted following chemotherapy-based myeloablative conditioning. Additionally, to further investigate marrow damage induced by hd-radio-immunotherapy, hematopoietic and stromal progenitors, as well as telomere length (TL) were assessed. Patients and Methods:From July 2004 through December 2007, 53 relapsed/refractory (n= 36) or de novo high-risk (n= 17) NHL patients (median age, 64 years; range, 26 – 76 years) received a high-dose sequential (HDS) chemotherapy program, including a myeloablative phase with 90Y-Ibritumomab Tiuxetan (1.2 mCi/kg body weight). Patients were monitored for frequency of colony-forming cells (CFCs), cytogenetic and TL analysis. Bone marrow (BM) samples were collected prior to hd-radio-immunotherapy, every six months for two years and annually thereafter. The study was approved by the Institutional Ethical Committee and written informed consent was obtained from each patient. The study group included 29 patients with aggressive lymphoma (diffuse large B-cell lymphoma, n = 19; mantle cell lymphoma, n = 8; Richter syndrome, n = 2) and 24 with indolent NHL subtypes (follicular lymphoma, n = 20; marginal zone lymphoma, n = 3; lymphocytic lymphoma, n = 1). Thirty patients were relapsed after one (n=15) or more (n=15) previous chemotherapy regimens, 6 patients were refractory and 17 patients were previously untreated with high-risk prognostic index. Pre-exposure to alkylating agent involved 68% of the patients. A historical group of 55 NHL patients who received an analogous HDS program with final chemotherapy-based autografting was used as control group. Study and control groups were pair-matched for age, gender, histological subtype, disease status at transplant and type of grafted PBSC. Results:At a median follow-up of 49 months (range, 32 – 74), 4 out of 53 patients of the study group developed sMDS/AL at 6, 12, 27 and 36 months from transplant. According to WHO criteria, refractory anemia with excess of blasts 1 (RAEB-1) was diagnosed in one patient, whereas refractory cytopenia with unilineage dysplasia (RCUD) was diagnosed in the other three cases, with acute leukemia transformation being observed in two patients at 12 and 18 months after initial detection of abnormal cytogenetics, respectively. The cumulative incidence of sMDS/AL resulted of 8.29% at 5-years. An analogous 5-year cumulative incidence of 8.05% was observed in the historical control group autografted following a chemotherapy-based conditioning. Radioimmunotherapy-treated patients showed a significant but transient decrease in granulocyte-macrophage colony forming unit (CFU-GM) at 6 months after transplant, with recovery to baseline values at 12 months. Multilineage colony-forming units (CFU-Mix), erythroid burst-forming units (BFU-E) and fibroblast CFU (CFU-F) were not show significantly affected over time. In contrast, a progressive and significant decrease in BM TL was evident from 12 months after transplant. Conclusion:In our series of elderly NHL patients receiving hd-radio-immunotherapy, the incidence of sMDS/AL was found increased compared to recently reported series of younger lymphoma patients receiving chemotherapy-based conditioning. However, the increased risk of sMDS/AL was not associated with the type of myeloablative conditioning, i.e. chemotherapy vs radio-immunotherapy. Other factors may have favored the development of sMDS/AL, including advanced age at transplant, extensive pre-transplant therapy and type of reinfused PBSC. The observed progressive TL loss gives support to the concept that TL loss might be involved in sMDS/AL development. Disclosures:No relevant conflicts of interest to declare.

Successful treatment of cryoglobulinemic glomerulonephritis derived from Waldenström’s macroglobulinemia by rituximab-CHOP and tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation

Waldenström's macroglobulinemia (WM) is a slowly progressive, low-grade B cell lymphoproliferative disorder. In contrast to the indolent progression, the development of cryoglobulinemic glomerulonephritis associated with WM is a rare, aggressive, and life-threatening complication. We describe the case of a 53-year-old man who suffered from WM, which was accompanied by cryoglobulinemic glomerulonephritis. WM was diagnosed on the basis of an increase in monoclonal IgM kappa and infiltration of abnormal lymphoplasmacytic cells in the bone marrow. Moreover, the case was complicated by increase in the levels of urinary protein, serum creatinine, and serum cryoglobulin. Histological findings showed endocapillary glomerulonephritis with hyaline plugs. Electron microscopy demonstrated the accumulation of electron-dense deposits in the subepithelial, subendothelial, intramembranous, and mesangial areas, which revealed cryoglobulinemic proliferative glomerulonephritis. The patient received four courses of rituximab therapy followed by four courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) in combination with cryofiltration. Subsequently, the patient underwent high-dose chemotherapy (melphalan [L-PAM]) followed by tandem autologous peripheral blood stem cell transplantation. After these treatments, the patient remained disease-free for 26 months. Histological findings of cryoglobulinemic glomerulonephritis were markedly improved after these treatments. Our case suggests that these treatments may be a feasible, safe, and effective strategy for critical cryoglobulinemic glomerulonephritis derived from WM.

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/m(2)) 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.

Late effects in survivors of tandem peripheral blood stem cell transplant for high-risk neuroblastoma.

Increasing numbers of children with advanced neuroblastoma are achieving cure. We describe the clinical late effects specific to survivors of stage IV neuroblastoma all similarly treated using tandem autologous peripheral blood stem cell rescue with TBI. The medical records of 35 neuroblastoma patients treated at CHOP between 1997 and 2001 were examined. Eighteen of the 35 patients died of progressive disease, and 4 were lost to follow-up. Thirteen patients continue to follow-up in our Multidisciplinary Cancer Survivorship Clinic where they are evaluated and monitored by a consistent group of subspecialists that evaluate long-term sequelae. Data on treatment exposures including TBI and treatment related sequelae identified by clinician assessment and/or diagnostic testing were collected. Results indicate late effects were present in all 13 subjects, 12 of whom suffered from multiple negative sequelae, including issues with growth hormone deficiency, dental problems, osteochondromas and hearing deficiencies, among others, most at higher rates than reported previously. The findings in this small cohort indicate the need for future prospective studies of this intensive pediatric cancer treatment, and underscore the importance of medical intervention and long-term monitoring of these at-risk subjects to increase overall quality-of-life.

Single and Tandem Autologous Peripheral Blood Stem Cell Transplantation for Patients with Multiple Myeloma: A Korean Multicenter Retrospective Study.

High-dose therapy with autologous stem cell transplantation (ASCT) is now considered the standard of care in patients with multiple myeloma (MM). This retrospective case analysis evaluated the prognostic influence of pre-transplant characteristics, transplant modalities, and disease status at post ASCT on survival to define patients with better prognosis. A total of 269 MM patients (median age: 53 years) who were transplanted between 1997 and 2007 from 6 centers in Korea were analyzed. All patients received peripheral blood stem cell support after conditioning with melphalan 140 mg/m2 or 200 mg/m2. In all, 190 patients received single ASCT and 79 patients received tandem ASCT. After a median follow-up of 28.5 months for surviving patients form single transplant, median progression-free survival (EFS) and overall survival (OS) were 19.2 months (95% CI, 15.9–22.6 months) and 71.3 months (95%CI, 56.9–85.7 months) with 18% and 55% probabilities of being progression-free and survival after 5 years, respectively. Treatment-related mortality within 90 days after ASCT was occurred in 12 patients (4.4%). Univariate analysis revealed that significant prognostic factor of PFS included age ≤ 50 at ASCT (p=0.024) and tandem ASCT (p<0.001). Significant prognostic factor for OS was tandem ASCT (p=0.029). The absence of unfavorable cytogenetic abnormalities was marginally significant for OS (p=0.074). In Cox analysis, it was seen that significantly longer PFS occurred for patients who received tandem ASCT (p=0.002). Age ≤ 50 at the time of ASCT was marginally significant prolonged PFS (p=0.054). Tandem ASCT independently correlated with better OS (p=0.044). We conclude that tandem ASCT independently correlated with better PFS and OS.

T-cell receptor excision circles: a novel prognostic parameter for the outcome of transplantation in multiple myeloma patients.

This study investigated whether T-cell receptor excision circles (TRECs) are a prognostic marker for the outcome of myeloma patients undergoing a tandem autologous peripheral blood stem cell transplantation (PBSCT). Twenty-five patients were enrolled. Samples were obtained at study enrollment, after conventional therapy, between first and second transplantation and 3, 6, 12 and 24 months after the second PBSCT. TRECs were quantified using real-time polymerase chain reaction. A high variation in TREC levels was found at diagnosis (median TREC level 136/10(5) peripheral blood mononuclear cells (PBMCs); range 1-1729), suggesting individual differences in thymic output of naive T cells. Patients with more than 136 TRECs/10(5) P BMCs at diagnosis had a statistically significant better overall survival (P=0.05) and event-free survival (P=0.045), whereas low TREC levels correlated with a higher incidence of infectious complications. Median TREC values were lowest after the first PBSCT (52/10(5) PBMCs) and reached the baseline 12 months after the second transplantation. Patients with high TREC levels after the second PBSCT had a significantly higher probability of being in complete or partial remission 30 months after the second PBSCT. TREC levels were not correlated with beta2-microglobulin and C-reactive protein levels at diagnosis. These data suggest that TRECs could be a relevant prognostic factor for patients who receive high-dose chemotherapy and autologous PBSCT.

Novel biologically based therapeutic strategies in myeloma.

Multiple myeloma remains incurable despite advances in conventional chemotherapy and wider applicability of high dose chemotherapy with single and/or tandem autologous peripheral blood stem cell transplantation. Although a complete remission rate of 41% and an event-free survival of 43 months have been reported after tandem transplantation, it is highly unlikely that further improvements in the outcome of multiple myeloma will be achieved by escalating cytotoxic chemotherapy alone. Novel biologically based therapies are therefore urgently required. Targeted therapeutic approaches based on: identification of genetic abnormalities in malignant plasma cells; interrupting growth of myeloma cells; triggering apoptotic signaling cascades in tumor cells; modulating growth and survival of multiple myeloma cells in the bone marrow microenvironment, i.e. angiogenesis and cytokine networks; enhancing allogeneic and autologous antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy are under development. These therapies offer great promise, used alone/or in combination with conventional treatment approaches, to improve the outcome in this disease in newly diagnosed/refractory or relapsed patients with multiple myeloma.