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Head and neck cancers are unique in so far that two major oncogenic viruses, Epstein Barr virus (EBV) and Human papillomavirus (HPV) infect adjacent anatomy and cause nasopharyngeal and oropharyngeal cancers, respectively. Dominant recognized carcinogens are alcohol and tobacco but some head and neck cancers have been found to have mixed carcinogens (including betel leaf, areca nuts, slaked lime, viruses, etc.) involved in their oncogenesis and conversely, groups of patients with unknown or less dominant carcinogens involved in their development. These cancers may have had viral involvement in the past but then lost most of their viral nucleic acids (be they DNA and/or RNA) below a detection threshold, thus rendering them virus‐negative. Some of these virus‐negative tumors appear to have mutagenic signatures associated with virus‐positive cancers, for example, from the APOBEC defense mechanism which is known to mutate viral nucleic acids as well as cause collateral damage to host DNA, with subsequent development of strongly viral prejudiced mutational signatures. These mechanisms are likely to be less efficient at oncogenesis than traditional EBV and HPV oncogenes directly driving mutagenesis, thus accounting for the smaller frequencies of these cancers found. More profound investigations of these unusual tumors are warranted to dissect out these mechanistic pathways. [ABSTRACT FROM AUTHOR]

Objective Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma ( RMM). Methods Peripheral blood stem cells ( PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G- CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the Re LApsE trial of the German-Speaking Myeloma Multicenter Group ( GMMG). Results Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G- CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×106 vs 17×106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events ( SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). Conclusions These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic. [ABSTRACT FROM AUTHOR]

Background: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients.Methods/design: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS.Discussion: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients.Trial Registration: ISRCTN16345835 (date of registration 2010-08-24). [ABSTRACT FROM AUTHOR]

Simple Summary: For multiple myeloma (MM) patients with measurable disease, there is no recommendation to monitor serum free light chains during therapy. However, this could provide important information in terms of prognosis. We investigated the prognostic impact of serum free light chain ratio (FLCr) normalization in 590 patients with secretory MM during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. We are able to show that there is an increasing percentage of patients who achieve FLCr normalization during therapy. Importantly, we demonstrate that FLCr normalization at any time before the start of maintenance is significantly associated with prolonged progression-free and overall survival in multivariable time-dependent Cox regression analyses. This suggests that FLCr normalization during therapy is an important and simple way to assess prognostic factor in MM and supports the serial measurement of serum free light chains during therapy, even in patients with secretory MM. We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) (p < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47–0.79) and overall survival (OS) (p = 0.02, HR = 0.67, 95% CI = 0.48–0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS (p = 0.04, HR = 0.77, 95% CI = 0.60–0.99) and OS (p = 0.01, HR = 0.59, 95% CI = 0.41–0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM. [ABSTRACT FROM AUTHOR]

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m 2 ), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61-65 years (S2, n = 107) and 66-70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray's p = 0.83) and non-relapse mortality (Gray's p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m 2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1-21 of 28 day cycles) followed by 10-15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

Targeted therapies have made their way into clinical practice during the past decade. They have caused a major impact on the survival of cancer patients in many areas of clinical oncology and hematology. Indeed, in some hematologic malignancies, such as chronic myelogenous leukemia or non-Hodgkin's lymphomas, biologicals and antibodies specifically designed to target tumour-specific proteins have revolutionized treatment standards. In solid tumours, new drugs targeting EGF- or VEGF- receptors are now approved and are entering clinical practise for treatment of colon, lung, kidney and other cancers, either alone or in combination with conventional treatment approaches. Recent data have now shown that molecular targeted therapy might display efficacy in patients with head and neck squamous cell carcinoma (HNSCC) as well. The evaluated biologicals are generally well tolerated from HNSCC patients, who usually have the burden of multiple co-morbidities that interfere with conventional systemic treatment options. Therefore, molecular targeted therapies offer new treatment options even for heavily pretreated and seriously ill patients usually unable to tolerate chemotherapy or radiation therapy. The two most promising and advanced strategies are the blockage of growth-factor based cellular signalling and interference with angiogenesis-related pathways. But inhibitors of alternative targets, such as Scr and proteasomes, have already been evaluated in early clinical trials with HNSCC patients.

CD4+CD25+ regulatory T cells (T(REG)) are engaged in the regulation of murine and human immune responses as well as graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation. Despite their suppression of GvHD they do not impair graft-versus-tumor activity in the mouse, which makes T(REG) especially attractive candidates for cellular immunotherapy. T(REG) comprise only 5% to 10% of CD4+ T cells in peripheral blood and are naturally anergic, which prevented their use as therapeutic suppressor cells in the context of autoimmune or alloimmune reactions so far. We therefore developed an in vitro expansion protocol for human T(REG), breaking their anergy with anti-CD3/anti-CD28-coupled paramagnetic beads and a combination of interleukin (IL)-2 and IL-15. Highly purified human T(REG) can be expanded 285-fold to 1000-fold within 20 days and keep their phenotype as well as all their suppressor functions even in the context of stimulation with mature allogeneic dendritic cells. However, we demonstrate that FoxP3 is not a reliable marker for human T(REG) as it is transiently inducible in CD4+CD25- cells upon activation with cytokines or via their T cell receptor. In addition, we successfully expanded CD4+CD25+ cells from patients after allogeneic stem-cell transplantation with or without GvHD and show that different suppressor functions might be lost independently, demonstrating that human T(REG) biology is likely more complicated than previously thought.

Background: The use of monoclonal antibodies against interleukin-2 receptor (IL-2R)-alpha chains could be an effective treatment of acute graft-versus-host disease (GvHD). Experimental model and clinical studies have reported various results., Methods: Inolimomab is a murine anti-IL-2R. Eighty-five patients were evaluated retrospectively for the safety and efficacy of inolimomab given for the treatment of steroid-resistant acute GvHD (aGvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Diseases were immune deficiency, hematological malignancies, or solid tumors. Seventy-six percent of the patients received a myeloablative regimen. The source of HSCT was bone marrow for 45 patients, peripheral blood for 36 patients, and cord blood for 4 patients. Donors were 49 siblings and 36 unrelated. Acute GvHD was diagnosed within a median of 28 days after transplantation (grade II, 26 patients; grade III, 26 patients; grade IV, 33 patients). Inolimomab was administered in the event of steroid-resistant aGvHD with a median dose of 0.468 mg per kg (median period of treatment: 18 days)., Results: Twenty-five complete responses and 29 partial responses (total response rate: 63%) were observed with no side effects. There was no correlation between aGvHD grading and quality of response. Better responses were observed in cutaneous aGvHD. The overall survival probability was 26% (median follow-up: 20 months). Fifty-seven percent of patients died of toxicity related mortality, mostly aGvHD. Response to inolimomab seemed sustained (11% relapse in responders)., Conclusion: Inolimomab is well-tolerated and effective for severe steroid-resistant aGvHD. The optimum regimen remains to be defined.

The optimal stem cell source for stem cell gene therapy has not been defined. Most gene transfer studies have used peripheral blood or marrow repopulating cells collected after administration of granulocyte colony-stimulating factor and stem cell factor (G-CSF/SCF). For clinical applications, however, growth factor administration may not be feasible. Thus, in the current study we used a competitive repopulation assay in the dog to directly compare transduction efficiency of steady-state marrow, G-CSF/SCF-primed marrow, and G-CSF/SCF-mobilized peripheral blood. Cells from all three sources were transduced, cryopreserved, and thawed together before infusion into myeloablated dogs. Gene marking in hematopoietic repopulating cells was assessed by polymerase chain reaction. While primed marrow resulted in the highest long-term marking levels, steady-state marrow was transduced at least as efficiently as mobilized peripheral blood in all three dogs. These results suggest that steady-state marrow may be an appropriate source for genetic modification of hematopoietic stem cells.

Despite prophylaxis with immunosuppressive drugs, severe graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic stem cell transplantation. T cell depletion of the graft has decreased incidence and severity of GVHD but has resulted in a higher incidence of graft failure and relapse. To reduce the risk of severe GVHD, but at the same time to maintain the graft-versus-tumor effect, we administered a fixed low number of 1 x 10(5) donor T cells per kilogram of body weight to recipients of CD34(+) cell-enriched allogeneic peripheral blood stem cells (PBSCs). Donor lymphocyte infusions (DLI) were then given in incremental doses when mixed chimerism persisted or signs of relapse occurred. A total of 23 patients receiving allografts from related and unrelated donors were treated according to this protocol after myeloablative or reduced intensity conditioning. One patient did not engraft and 3/20 evaluable patients developed acute (a) GVHD > or = grade II, with a corresponding estimated cumulative incidence of 15.6% (95% CI 0-30.5%). DLI (n = 13) induced aGVHD > or = II in 6 patients, but the severity of the syndrome was reduced. Overall GVHD-related mortality was low (13%). The probability of disease-free survival and overall survival at 2 years was 0.40 (95% CI 0.21-0.75) and 0.36 (95% CI 0.21-0.63). Progression-free survival and overall survival was significantly better in patients with acute or chronic myelogenous leukemia compared to patients with lymphoproliferative disorders (p = 0.002; p = 0.02). We conclude that the combination of allografts with a T cell content of about 1 x 10(5)/kg and escalating doses of DLI is a viable transplant strategy in patients with myeloid leukemias, which results in stable engraftment and a reduction of mortality from aGVHD.

Allogeneic stem cell transplantation (SCT) after reduced intensity conditioning (RIC) provides a new curative treatment option for patients usually not eligible for allogeneic SCT. Because the majority of patients lack HLA-identical sibling donors (SD), unrelated donor (UD) transplantation is performed increasingly. In this retrospective analysis, we have reviewed our experience with reduced-intensity conditioning regimens, comparing related and unrelated donors. From November, 1997, to February, 2002, 51 patients with hematological malignancies received allogeneic SCT after various RIC regimens. A total of 31 had a related donor, and the remaining 20 had an unrelated donor (UD). Both groups were comparable with respect to age and gender. We observed a trend toward higher rate of graft failure in the unrelated donor group with 11% compared to 3% in the related donor group (p = 0.55). The rate of acute graft-versus-host disease (GVHD) II-IV was 36% in the RD group versus 44% for the UD group; severe GVHD III-IV occurred in 26% and 22%, respectively. There were more serious infections in the unrelated donor group with 25% compared to 16%. Transplant-related mortality was 13% (RD group) versus 30% (UD group). At 21 months, progression-free survival was 30% in both groups. The Kaplan Meier estimate of overall survival was 40% (RD) and 30% (UD group). In summary, we found no statistically significant difference regarding progression free and overall survival, despite a trend for more graft failure and increased transplant-related complications associated with the use of stem cells from unrelated donors.