Predicting Long-term (> or = 5 Years) Event-free Survival in Multiple Myeloma Patients Following Planned Tandem Autotransplants

British Journal of Haematology. Jan, 2002  |  Pubmed ID: 11841419

Although outcome in multiple myeloma (MM) patients has improved significantly with the introduction of autotransplants (AT), the curability of this approach remained to be demonstrated. Therefore, we analysed outcome and prognostic factors using a logistic regression model in 515 consecutive newly diagnosed and previously treated patients intended to receive melphalan-based tandem transplants with follow up of > or = 5 years. One quarter of patients had event-free survivals (EFS) > or = 5 years with no further relapses seen after 7 years (46 patients on plateau). On multivariate analysis, factors associated with EFS > or = 5 years were absence of chromosome 11 and 13 abnormalities (odds ratio: 6.1), < or = 12 months of preceding standard-dose therapy (SDT) (OR: 2.6) and beta-2 microglobulin (B2M) level < or = 2.5 mg/l at time of first AT (OR: 1.7). Patients with only favourable variables (25%) had a 7-year EFS in excess of 35%, compared with 15% and 10%, respectively, with one (43%) or two unfavourable variables (27%), and 0% for 5% of patients with three unfavourable variables (P < 0.0001). Using a 1-year landmark analysis to allow for guaranteed time and thereby excluding early treatment failures, attaining a complete remission (CR) had no significant effect on long-term survival. Our data are consistent with cure in MM patients with a CR duration . or = 7 years and re-establishment of a monoclonal gammopathy of undetermined significance (MGUS) phase in those with persistent evidence of disease post transplantation, but without disease progression > or = 7 years.

Myeloma of the Central Nervous System: Association with High-risk Chromosomal Abnormalities, Plasmablastic Morphology and Extramedullary Manifestations

British Journal of Haematology. Apr, 2002  |  Pubmed ID: 11918539

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.

ABO Mismatch May Affect Engraftment in Multiple Myeloma Patients Receiving Nonmyeloablative Conditioning

Transfusion. Feb, 2002  |  Pubmed ID: 11896336

Blood group incompatibility does not appear to affect the overall outcome in patients undergoing myeloablative conditioning before allogeneic BMT. Data on ABO-mismatched transplantation in the nonmyeloablative setting are limited.

Infection--an Underappreciated Cause of Bone Pain in Multiple Myeloma

British Journal of Haematology. Mar, 2003  |  Pubmed ID: 12648075

Bone pain, especially back pain, is a common presenting feature of myeloma patients. We report three multiple myeloma patients with exacerbations of back pain and referred shoulder pain resulting from vertebral infections. Two patients were treated with surgery, and one patient had computerized tomography-guided percutaneous needle aspiration for diagnostic purposes. All three patients received a prolonged course of antibiotics. Vertebral infection resolved with this treatment in all three patients without any recurrence. Previous dexamethasone therapy, together with an episode of bacteraemia, appears to be a predisposing factor for vertebral infection. Magnetic resonance imaging enabled the diagnosis in all three patients.

BEAM Allogeneic Transplantation for Patients with Hodgkin's Disease Who Relapse After Autologous Transplantation is Safe and Effective

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Mar, 2003  |  Pubmed ID: 12652468

Because few patients failing autologous transplantation for Hodgkin's disease survive long-term, we explored reduced-intensity allografts using BEAM conditioning and early withdrawal of immunosuppression as an alternative to palliative chemotherapy. Ten patients with Hodgkin's disease underwent an allograft, receiving either matched sibling peripheral blood stem cells (5), partially matched sibling bone marrow (1), or matched unrelated bone marrow (4). Graft-versus-host disease (GVHD) prophylaxis was mini-methotrexate and FK-506 with weaning at day 60. The median age of patients was 35 years (range: 21 to 49 years). The median time from initial diagnosis was 73 months (range: 12 to 172 months) and from autograft was 49 months (range: 5 to 143 months). One patient was in CR, 5 patients were in partial remission, 3 were in relapse, and 1 patient had primary refractory disease. All patients' transplants engrafted rapidly, and the 100-day mortality was 0. Two patients developed acute GVHD. Five of the 9 patients beyond 100 days have developed mild chronic GVHD, of which 1 case was progressive and required systemic therapy. All 10 responded: 8 complete responses and 2 partial remissions. Three patients have relapsed (at 2, 6, and 8 months, respectively), 1 has died at 4 months. At a mean of 12 months (range: 1 to 21 months) after allograft, 9 of 10 patients are alive, with 7 in continuous remission. BEAM allogeneic transplantation with early reduction in immunosuppression is safe (no treatment-related deaths) and effective in advanced Hodgkin's disease where autografts have failed. A graft versus lymphoma effect appears to be a significant contributing factor in responding patients.

Post-transplant Air-leak Syndrome

British Journal of Haematology. Sep, 2004  |  Pubmed ID: 15352978

Overexpression of the NOTCH Ligand JAG2 in Malignant Plasma Cells from Multiple Myeloma Patients and Cell Lines

Blood. Dec, 2004  |  Pubmed ID: 15292061

The NOTCH ligand, JAG2, was found to be overexpressed in malignant plasma cells from multiple myeloma (MM) patients and cell lines but not in nonmalignant plasma cells from tonsils, bone marrow from healthy individuals, or patients with other malignancies. In addition, JAG2 overexpression was detected in 5 of 5 patients with monoclonal gammopathy of undetermined significance (MGUS), an early phase of myeloma disease progression. This overexpression appears to be a consequence of hypomethylation of the JAG2 promoter in malignant plasma cells. An in vitro coculture assay was used to demonstrate that JAG2 induced the secretion of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) in stromal cells. Further, the induction of IL-6 secretion was blocked in vitro by interference with anti-Notch-1 monoclonal antibodies raised against the binding sequence of Notch-1 with JAG2. Taken together, these results indicate that JAG2 overexpression may be an early event in the pathogenesis of multiple myeloma involving IL-6 production.

Favourable Results with a Single Autologous Stem Cell Transplant Following Conditioning with Busulphan and Cyclophosphamide in Patients with Multiple Myeloma

British Journal of Haematology. Mar, 2004  |  Pubmed ID: 15009065

Both single and tandem cycles of high dose therapy and autologous peripheral blood stem cell transplantation (ASCT) have been shown to improve survival in multiple myeloma (MM) patients. We report outcomes in 104 MM patients undergoing a single transplant after conditioning with a conventional myeloablative regimen, busulphan and cyclophosphamide. The patients were either in a first (71%), or subsequent remission (29%). Peripheral blood stem cells were mobilized using cyclophosphamide and granulocyte colony stimulating factor. The conditioning regimen consisted of busulphan 0.85 mg/kg given orally every 6 h (16 doses) and cyclophosphamide 60 mg/kg/d given intravenously for 2 d. The entire conditioning, transplant and post-transplant course were in the outpatient setting for 45% patients. At a median follow-up of 26 months (range 2-98 months), the median overall and progression-free survival were 57 months [95% confidence interval (CI) 47-68] and 26 months (95% CI 20-32) respectively. Younger age and higher CD34+ cell dose infused were independently predictive of improved overall and progression-free survival. Busulphan and cyclophosphamide is an effective and well-tolerated preparative regimen for ASCT that can be given to MM patients in the outpatient setting.

Cardiac Nonamyloidotic Immunoglobulin Deposition Disease

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. Feb, 2006  |  Pubmed ID: 16341150

Cardiac nonamyloidotic immunoglobulin (Ig) deposition disease (CIDD) is a rare disorder characterized by Ig deposition in the myocardium associated with plasma cell dyscrasias. A retrospective review of cardiac biopsies performed at two different institutions identified eight patients with CIDD. All patients had plasma cell dyscrasias with monoclonal gammopathy. Three had IgG lambda, two had IgG kappa, one had IgD kappa and one each had free kappa and free lambda light chain. Four patients had concurrent amyloidosis involving other organs. One had amyloidosis of kidney alone, one had amyloidosis of kidney and abdominal fat pad and two others had amyloidosis of bone marrow vasculature. Three patients had dialysis-dependent renal insufficiency. None of the patients had symptoms of heart failure. Six patients had echocardiographically demonstrable concentric left ventricular hypertrophy with diastolic dysfunction. Two patients had significant cardiac arrhythmias requiring medical intervention. On endomyocardial biopsy, all eight had normal appearing myocardium on light microscopy with negative Congo Red and Thioflavin T stains. On immunofluorescent staining of the cardiac biopsies, all eight stained positive for interstitial Ig deposition. Electron microscopy (EM) confirmed the presence of granular deposits of Igs in the myocardium in five of the eight patients. EM studies were not available in one patient and two others had normal EM studies. In conclusion, CIDD should be considered in the spectrum of cardiovascular pathology in patients with plasma cell dyscrasias. They often, but not always, have left ventricular hypertrophy. These patients may be at risk for developing arrhythmias as well as diastolic dysfunction. Unless immunofluorescent and EM studies are performed routinely in biopsy material, this entity may be missed in the absence of amyloidosis. Concurrent amyloidosis in other organs sheds a unique perspective into the role of local microenvironment in the pathogenesis of systemic Ig deposition disease and amyloidosis.

The Administration of Polymerized Human Hemoglobin (Pyridoxylated) to a Jehovah's Witness After Submyeloablative Stem Cell Transplantation Complicated by Delayed Graft Failure

Comprehensive Therapy. 2006  |  Pubmed ID: 17435270

A 55-yr-old woman with a history of B-cell lymphoma of the nasopharynx diagnosed in March 1999 eventually underwent submyeloablative allogeneic stem cell transplantation from a sibling donor in December 2002 after conventional treatment options were exhausted. The treatment approach was somewhat altered by the fact that the patient was a practicing Jehovah's Witness and refused blood-blood product transfusion. The course of her treatment was unremarkable until around day 100 posttransplant when she developed graft failure, leading to severe anemia. Blood transfusions were refused. Donor cells were re-infused. During this treatment period, the patient's hemoglobin dropped to a low of 2.7 g/dL, with the patient experiencing severe fatigue, dyspnea on exertion, headaches, and blurred vision. Polymerized human hemoglobin (pyridoxylated) (Poly- Heme, Northfield Laboratories Inc., Evanston, IL) was given under an emergency, compassionate use protocol and successfully bridged the patient's hemoglobin and relieved symptoms during her marrow recovery period.

Alefacept in Corticosteroid Refractory Graft Versus Host Disease: Early Results Indicate Promising Activity

The Journal of Dermatological Treatment. 2007  |  Pubmed ID: 17365261

Steroid refractory graft versus host disease (GVHD) presents a significant therapeutic challenge due to the limited efficacy and safety of second-line treatments. Three patients with extensively pretreated, refractory GVHD were treated with a targeted anti-T-cell agent, alefacept, and demonstrated rapid and clinically significant improvement in their GVHD, facilitating tapering of corticosteroids. The pathological and immunohistochemical findings of GVHD also improved, validating our clinical impression. These preliminary findings indicate that alefacept may have beneficial activity in GVHD warranting further study.

Tandem Autologous Stem Cell Transplantation for Patients with Primary Refractory or Poor Risk Recurrent Hodgkin Lymphoma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2007  |  Pubmed ID: 17448919

Although autologous stem cell transplantation (ASCT) for patients with relapsed/refractory Hodgkin lymphoma (HL) appears to offer a survival advantage over conventional therapy, only approximately 25% to 35% of patients with primary progressive or poor-risk recurrent HL can achieve durable remission after ASCT, with disease progressive after transplant accounting for most of the treatment failures. We conducted a pilot study to evaluate the toxicities and efficacy of a tandem transplant approach in this subgroup of patients. Between April 1998 and March 2000, 46 patients were enrolled in the study. Eligibility criteria: primary progressive (n = 28) or recurrent HL (n = 18) with at least 1 of the following poor prognostic factors: first complete remission (CR) <12 months (n = 15) or extra-nodal disease (n = 4) or B symptoms at relapse (n = 4). The first cycle consisted of melphalan (150 mg/m(2)) alone. The second cycle consisted of fractionated total body irradiation (FTBI) 1200 cGy or BCNU (450 mg/m(2)) in combination with etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg). Of the 46 patients, 5 (11%) did not receive the planned tandem transplants because of inadequate stem cell collection for 2 ASCT. After a median of 64 days (25-105), 41 patients received the second ASCT. With a median follow-up of 5.3 years (1.6-8.1), the 5-year estimate of overall survival, progression-free survival, and freedom from progression were 54% (95% confidence interval [CI] 40%-69%), 49% (95% CI, 34%-63%), and 55% (95%CI, 40%-70%), respectively. Our mature results from this study suggest that in patients with primary progressive or poor risk recurrent HL, this tandem ASCT program is effective and well tolerated and compares favorably with the conventional single transplant.

Rearrangements of the MLL Gene Are Influenced by DNA Secondary Structure, Potentially Mediated by Topoisomerase II Binding

Genes, Chromosomes & Cancer. Sep, 2009  |  Pubmed ID: 19530238

The location of MLL translocation breakpoints within therapy-related acute myeloid leukemia linked to drugs targeting Topoisomerase II and infant acute leukemia (IAL) are biased toward the intron 11-exon 12 region of MLL, although lacking a comprehensive explanation. To address this, blood samples were taken from breast cancer and lymphoma patients receiving Topoisomerase II inhibitor therapy. Inverse PCR analysis was used to interrogate the exon 12 region of MLL for rearrangements. Eleven of 19 observed translocations showed breakpoint junctions restricted to a single 5 bp location within exon 12. A similarly restricted distribution (11/20 breakpoint junctions) was observed in TK6 cells exposed to either estrogen (linked to IAL) or anti-CD95 antibody. The translocation hotspot was at the 5' edge of a 10-bp tract matched with a perfect palindrome, 101 bp distant. A high stringency Topoisomerase II consensus sequence binding site was noted at the geometric midpoint of the palindromes. Ligation-mediated PCR to screen TK6 cells exposed to anti-CD95 antibody showed 14/37 (38%) of DNA breaks adjacent to the 5' palindrome and 10/37 (27%) at the 3' partner. We propose a model whereby Topoisomerase II facilitates the organization of nuclease-sensitive secondary structures, stabilized by palindrome association, which are prone to rearrangement.

Impaired NHEJ Function in Multiple Myeloma

Mutation Research. Jan, 2009  |  Pubmed ID: 19028508

Multiple myeloma (MM) is characterized by multiple chromosomal aberrations. To assess the contribution of DNA repair to this phenotype, ionizing radiation was used to induce DNA double strand breaks in three MM cell lines. Clonogenic survival assays showed U266 (SF4=15.3+6.4%) and RPMI 8226 (SF4=12.6.0+1.7%) were radiation sensitive while OPM2 was resistant (SF4=78.9+4.1%). Addition of the DNA-PK inhibitor NU7026 showed the expected suppression in radiation survival in OPM2 but increased survival in both radiation sensitive cell lines. To examine non-homologous end joining (NHEJ) repair in these lines, the ability of protein extracts to support in vitro DNA repair was measured. Among the three MM cell lines analyzed, RPMI 8226 demonstrated impaired blunt ended DNA ligation using a ligation-mediated PCR technique. In a bacterial based functional assay to rejoin a DNA break within the beta-galactosidase gene, RPMI 8226 demonstrated a 4-fold reduction in rejoining fidelity compared to U266, with OPM2 showing an intermediate capacity. Ionizing radiation induced a robust gamma-H2AX response in OPM2 but only a modest increase in each radiation sensitive cell line perhaps related to the high level of gamma-H2AX in freshly plated cells. Examination of gamma-H2AX foci in RPMI 8226 cells confirmed data from Western blots where a significant number of foci were present in freshly plated untreated cells which diminished over 24h of culture. Based on the clonogenic survival and functional repair assays, all three cell lines exhibited corrupt NHEJ repair. We conclude that suppression of aberrant NHEJ function using the DNA-PK inhibitor NU7026 may facilitate access of DNA ends to an intact homologous recombination repair pathway, paradoxically increasing survival after irradiation. These data provide insight into the deregulation of DNA repair at the site of DNA breaks in MM that may underpin the characteristic genomic instability of this disease.

Dose Intense Therapy for Relapsed Lymphoproliferative Disorders: the More Things Change, the More They Are the Same

Leukemia & Lymphoma. May, 2009  |  Pubmed ID: 19452313

Randomized Phase III Trial of Pegfilgrastim Versus Filgrastim After Autologus Peripheral Blood Stem Cell Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2010  |  Pubmed ID: 20045479

Nonrandomized trials suggest that pegfilgrastim, a pegylated granulocyte colony-stimulating factor, could be used in lieu of filgrastim after autologus peripheral blood stem cell transplantation. This phase III, randomized, double-blinded, placebo-controlled trial compared the efficacy, costs, and safety of single-dose pegfilgrastim (single 6 mg dose) versus daily filgrastim (5 microg/kg/day) for this indication. Seventy-eight patients, matched for age, sex, underlying disease, stage, and CD34/kg transplant dose were enrolled. Cytokines were started on day +1 posttransplant and continued to an absolute neutrophil count (ANC) of 5x10(9)/L for 3 days or 10x10(9)/L for 1 day. The median time to neutrophil engraftment (ANC >1.5x10(9)/L for 3 days or 5x10(9)/L for 1 day) was the same in both groups (12 days). No differences in platelet engraftment (11 versus 13 days), number of platelet transfusions (5 versus 4), percent with positive cultures for bacterial pathogens (23% versus 15%), days of fever (1 versus 2), deaths prior to engraftment (1 versus 1), or duration of hospital stay (19 versus 19 days) were seen between the pegfilgrastim and filgrastim groups, respectively. Using the average wholesale price for doses used in this trial, there was a per-patient savings of $961 for the pegfilgrastim group (P < .001). This phase III study failed to demonstrate a difference in time to neutrophil engraftment or any clinical sequelae between pegfilgrastim and filgrastim when given post-APBSCT, with pegfilgrastim achieving a cost savings over filgrastim.

Comment on "Cutting Edge: CD8+ T Cell Priming in the Absence of NK Cells Leads to Enhanced Memory Responses"

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2011  |  Pubmed ID: 21597038

Favorable Outcomes in Patients with High Donor-Derived T Cell Count After In Vivo T Cell-Depleted Reduced-Intensity Allogeneic Stem Cell Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2011  |  Pubmed ID: 22005648

Patients with hematologic malignancies were conditioned using a rabbit antithymocyte globulin-based reduced-intensity conditioning regimen for allogeneic stem cell transplantation. Donor-derived CD3(+) cell count (ddCD3), a product of CD3(+) cell chimerism and absolute CD3(+) cell count, when <110/μL at 8 weeks post-stem cell transplantation predicted a high risk of sustained mixed chimerism and relapse. Alternatively, patients with a higher ddCD3 developed graft-versus-host disease more frequently, and when partially chimeric, had higher rates of conversion to full donor chimerism after withdrawal of immunosuppression. Early data from our small cohort of patients indicate that ddCD3 at 8 weeks may be used to guide decisions regarding withdrawal of immunosuppression and administration of donor lymphocyte infusion in partially T cell-depleted reduced-intensity regimens.

Activated NKT Cells and NK Cells Render T Cells Resistant to Myeloid-derived Suppressor Cells and Result in an Effective Adoptive Cellular Therapy Against Breast Cancer in the FVBN202 Transgenic Mouse

Journal of Immunology (Baltimore, Md. : 1950). Jul, 2011  |  Pubmed ID: 21670315

Attempts to cure breast cancer by adoptive cellular therapy (ACT) have not been successful. This is primarily due to the presence of tumor-induced immune-suppressive mechanisms as well as the failure of tumor-reactive T cells to provide long-term memory responses in vivo. To address these clinically important challenges, we developed an ex vivo protocol for the expansion of tumor-reactive immune cells obtained from tumor-bearing animals prior to or after local radiation therapy. We used an Ag-free protocol that included bryostatin 1/ionomycin and sequential common γ-chain cytokines (IL-7/IL-15 + IL-2). The proposed protocol expanded tumor-reactive T cells as well as activated non-T cells, including NKT cells, NK cells, and IFN-γ-producing killer dendritic cells. Antitumor efficacy of T cells depended on the presence of non-T cells. The effector non-T cells also rendered T cells resistant to myeloid-derived suppressor cells. Radiation therapy altered phenotypic distribution and differentiation of T cells as well as their ability to generate central memory T cells. ACT by means of the expanded cells protected animals from tumor challenge and generated long-term memory responses against the tumor, provided that leukocytes were derived from tumor-bearing animals prior to radiation therapy. The ex vivo protocol was also able to expand HER-2/neu-specific T cells derived from the PBMC of a single patient with breast carcinoma. These data suggest that the proposed ACT protocol should be studied further in breast cancer patients.