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Background: No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy.Methods: We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p = .69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib.Results: The median follow-up from maintenance start was 44 months. Three-year progression-free survival (PFS) was 52% (48%-57%) for no EMD, 56% (44%-69%) for paraskeletal involvement, and 45% (22%-68%) for organ involvement (p = .146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three-year overall survival (OS) was 81% (77%-84%), 88% (80%-96%), and 68% (47%-89%; p = .064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD.Conclusion: Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start.

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis.

Background In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. Method We analysed 1,222 ASCT patients who were classified based on (1) the interval between induction and stem cell collection, (2) the type of induction regimen: BID (Bortezomib, IMiDs and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide and Dexamethasone), and (3) the time to best response (Early i.e. best response within 4 or 5 months, depending on the regimen vs Late; Good i.e. VGPR or better vs Poor) RESULTS: The length of induction treatment required to achieve a Good response did not affect PFS (p=0.65) or OS (p=0.61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (p=0.31), and median OS 81.7, 92.7, and 77.4 months, respectively (p=0.83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, p value = 0.02). However, achieving a Good response at induction was associated with a better response (≥ VGPR) post-transplant CONCLUSION: The kinetics of response did not affect outcomes.

Summary The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty-eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P 1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.

The combination of melphalan-prednisone-thalidomide (MPT) has been investigated in several clinical studies that differed significantly with regard to patient characteristics and treatment schedules. This prospective trial differs from previous melphalan-prednisone (MP) vs. MPT trials by treatment dosing, duration, routine anticoagulation, and permission for a crossover. Newly diagnosed patients with multiple myeloma (MM) (n=122) aged greater than 55 yr, not eligible for transplantation were randomized to receive 8 cycles of M (9 mg/m(2) /d) and P (60 mg/m(2) /d) for 4d every 6 wk (n=62) or MP and thalidomide (100 mg/d) continuously (n=60). Primary endpoint was treatment response and toxicities following 4 and 8 cycles of therapy. Secondary endpoints were disease-free (DFS) and overall survival (OS). Overall, MPT-treated patients were younger (median 69 yr vs. 72 yr; P=0.016) and had a higher incidence of renal impairment (RI, 19% vs. 7%, respectively; P=0.057). After 4 cycles of treatment (n=115), there were more partial responses or better in the MPT arm than in the MP arm (57.9% vs. 37.5%; P=0.030). However, DFS and OS were not significantly different between the arms after a median of 23 months follow-up (median OS 26.0 vs. 28.0 months, P=0.655; DFS 21.0 vs. 14.0 months, P=0.342, respectively). Crossover to MPT was required in 11 patients, 57% of whom responded to treatment. A higher rate of grade 3-4 infections was observed in the MPT arm compared with the MP arm (22.4% vs. 7.0%; P=0.033). However, none of these infections were associated with febrile neutropenia. Death within the first 3 months was observed more frequently in the MP arm (n=8, 14.0%) than in the MPT arm (n=2, 3.4%; P=0.053). Long-term discontinuation and dose reduction rates were also analyzed (MPT: 15.5% vs. MP: 5.3%; P=0.072). Although patients treated with MPT were relatively younger and had more frequent RI, better responses and less early mortality were observed in all age groups despite more frequent discontinuation.

Background and objectives: The prognosis of sarcoidosis is highly variable, with spontaneous remission in some patients. Apoptosis may be associated with spontaneous resolution of the granulomata. CD95 (Fas), an apoptotic molecule, and CD29 and CD45RO (T-cell memory markers) are expressed at higher levels on T lymphocytes from sarcoid patients compared with normal subjects. However, the prognostic significance of CD95, CD29 and CD45RO expression in sarcoidosis is not clear. It was hypothesized that expression of CD95 would correlate with spontaneous remission. Methods: CD29, CD45, CD45RO and CD95 expression of BAL fluid and peripheral blood (PB) lymphocytes was studied with flow cytometry in 50 patients with sarcoidosis. Results of the 15 chronic patients and 21 patients who remitted spontaneously were compared. Results: BAL CD95 (59 vs 8, P = 0.002), and PB CD95 (48 vs 18, P = 0.004) and PB CD45RO (50 vs 41, P = 0.003) expression was significantly higher in patients with chronic disease compared with those with spontaneous remission. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for these markers were: BAL CD95 (cut-off: 42.5%) 73.3%, 85.7%, 78.6%, 81.8% and 80.6%; PB CD95 (cut-off: 25%) 86.7%, 66.7%, 65%, 87.5% and 75%; and PB CD45RO (cut-off: 44.5%) 80%, 61.9%, 60%, 81.3% and 69.4%, respectively. Conclusion: Levels of BAL and PB CD95 and PB CD45RO were unexpectedly elevated in patients with chronic disease and may be useful in predicting prognosis in patients with sarcoidosis. Further studies with more patients are necessary to confirm the prognostic role and cut-off value for these markers.

The aim of this study was to evaluate the in vitro activation in platelet suspensions collected with CS 3000 Plus and Cobe Spectra cell separators using platelet storage containers and the role of white blood cell (WBC) concentration of the suspension in this activation. Seventy-seven donors were subjected to automated platelet donations with 1 type of equipment (37 with Cobe Spectra and 40 with CS 3000 Plus). Blood samples were obtained immediately after separation and on the third day of storage at 22 degrees C in constant agitation. The WBC concentrations of these samples were studied before storage. Paraformaldehyde-fixed platelets were incubated with 2 murine monoclonal antibodies: CD42b and CD62. Murine monoclonal antibody immunoglobulin G was used as a negative isotypic control. Bound antibody was then quantitated by flow cytometry. On the third day of storage, a significant increase in CD62 expression rate was observed in platelet suspensions collected with both kinds of equipment. Mean expression rates for Cobe Spectra on Day 0 and Day 3 were 25.6 +/- 6.2% and 69.2 +/- 9.7%, respectively. Mean expression rates for CS 3000 Plus on Day 0 and Day 3 were 23.4 +/- 8.2% and 67.0 +/- 8.2%, respectively. The mean results for both devices were 22.8 +/- 4.56% for Day 0 and 68.7 +/- 13.2% for Day 3. There was no difference between CD42b mean fluorescence intensity on Days 0 and 3 for the 2 devices (p > 0.5). Mean WBC concentrations in the platelet suspensions for Cobe Spectra and CS 3000 Plus were 0.37 x 10(3)/microl and 0.42 x 10(3)/microl, respectively, and there was no relation between WBC concentration and increase in CD62 expression. Both kinds of equipment were found to be similar according to in vitro activation markers.

We evaluated 979 patients for the development of post-transplant lymphoproliferative disease (PTLD) and solid malignancies after allogeneic hematopoietic stem cell transplantations (allo-HSCT) as a late complication. We found 15 (1.5%) subsequent malignancies; three of these malignancies were PTLD, and twelve were solid tumors. The median time from allo-HSCT to the development of PTLD was 9 (3-20) months and that from allo-HSCT to the development of solid tumors was 93 (6-316) months. The cumulative incidence of evolving subsequent malignancy in patients was 1.3% (±0.5 SE) at 5 years and 3.9% (±1.2 SE) at 10 years. The Cumulative incidence of developing subsequent malignancy in patients with benign hematological diseases as the transplant indication was 7.4%±4.2SE at 5 years. More subsequent malignancy developed in patients having ≥1 year chronic GVHD (3.7% in ≥1 year chronic GVHD and 0.7% in

Allogeneic peripheral blood stem cell transplantation (PBSCT) is rarely applied for the treatment of severe aplastic anemia (SAA) because of questionable durability of engraftment and increased risk of graft versus host disease (GVHD). We performed allogeneic PBSCT in 3 SAA patients from their human leukocyte antigen (HLA)–identical siblings. One received bone marrow after conditioning with cyclophoshamide (Cy) plus antithymocyte globulin. He had a second transplant with peripheral blood stem cells from the original donor because of a graft failure (GF). Two other patients received PBSCT as a first option, with Cy as the only conditioning drug. The 3 patients received short-term methotrexate and cyclosporine as a postgrafting immunosupression. In the latter 2 cases, no GF has been observed, and a successful and complete hematological recovery was achieved and maintained for 28 and 25 months, respectively. In conclusion, PBSCT provides a quick and complete hematological recovery in SAA patients.

The objective of this study was to quantify subpopulations of CD34+ cells such as CD41+ and CD42+ cells that might represent megakaryocyte (MK) precursors in peripheral blood stem cell (PBSC) collections of normal, recombinant human granulocyte-colony stimulating factor (rhG-CSF) primed donors and to determine whether there is a statistical association between the dose infused megakaryocytic precursors and the time course of the platelet recovery following an allogeneic PBSC transplantation. Twenty-six patients with various hematologic malignancies transplanted from their HLA identical siblings between July 1997 and December 1999 were used. All patients except one with severe aplastic anemia who had cyclophosphamide (CY) alone received busulfan-CY as preparative regimen and cyclosporine-methotrexate for GVHD prophylaxis. Normal healthy donors were given rhG-CSF 10 microg/kg/day subcutaneously twice daily and PBSCs were collected on days 5 and 6. The median number of infused CD34+, CD41+ and CD42+ cells were 6.61 x 10(6)/kg (range 1.47-21.41), 54.85 x 10(4)/kg (5.38-204.19), and 49.86 x 10(4)/kg (6.82-430.10), respectively. Median days of ANC 0.5 x 10(9)/L and platelet 20 x 10(9)/L were 11.5 (range 9-15) and 13 (8-33), respectively. In this study, the number of CD41+ and CD42+ cells infused much better correlated than the number of CD34+ cells infused with the time to platelet recovery of 20 x 10(9)/L in 26 patients receiving an allogeneic match sibling PBSC transplantation (r = -0.727 and P 0.05 for CD34+ cells). There was an inverse correlation between the number of infused CD41+ and CD42+ cells and duration of platelet engraftment. Therefore, as the number of CD41+ and CD42+ cells increased, duration of platelet engraftment (time to reach platelet count of > or = 20 x 10(9)/L) shortened significantly. Based on this data we may conclude that flow cytometric measurement of CD41+ and CD42+ progenitor cells may provide an accurate indication of platelet reconstitutive capacity of the allogeneic PBSC transplant.

BACKGROUND Despite published reports regarding the association of elevated circulating CD44 and CD54 levels with unfavorable outcome in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), little is known about therapy-related changes in either adhesion molecule. In an attempt to evaluate the effect of interferon-α (IFNα), the authors measured serum CD44 (sCD44) and sCD54 in 22 low grade NHL and 14 CLL patients. METHODS Twenty-six patients fulfilling the criteria for therapy received daily doses of 3 ×106 IU IFNα-2a. Ten patients not requiring therapy also were observed for the same period. Fasting sera were collected at baseline and in 4 monthly intervals from all patients including the IFNα-treated (Group 1) and the untreated group (Group 2). RESULTS Higher baseline sCD44 values were observed in Group 1 as compared with the Group 2 patients (P = 0.057). Within Group 1, patients were further divided between those who responded to IFNα, referred to as responders, and those who did not respond to IFNα, known as nonresponders. Responders showed a gradual decrease in sCD44 starting at the 4th month until the 12th month (P = 0.003, P = 0.002, and P = 0.01). Neither a difference in baseline nor an IFNα effect on the sCD54 levels could be shown. Soluble CD44 levels between responders and nonresponders were not different at the baseline but were significantly lower in responders, starting at month 4 and continuing throughout the therapy period (P = 0.04, P = 0.017, and P = 0.043). This decrease did not accompany a leukocyte or lactate dehydrogenase decrease and was not correlated with an early disappearance of the clinical findings. Similarly, after treatment, the sCD44 values of Group 1 were lower than the Group 2 levels at months 4 and 8 (P = 0.007 and P = 0.05, respectively). CONCLUSIONS Soluble CD44, but not sCD54, can be used for monitoring therapy in patients with low grade NHL and CLL who have received IFNα, and for deciding whether further IFN therapy is necessary for those patients who have not responded to IFNα over a previous 12-month period. Cancer 2000;89:1474–81. © 2000 American Cancer Society.

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR alpha beta and TCR gamma delta. TCR alpha beta and its function are well described but the role of TCR gamma delta in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, we determined levels of seven TCR alpha beta variable regions [beta V5(a), beta V5(b), beta V6(a), beta V12(a), alpha beta V(a), alpha V2(a)] and TCR gamma delta by using monoclonal antibodies (MCA). TCR gamma delta levels did not show any difference, but several variable regions of the TCR alpha beta differed when groups are compared with each other and the control group.