bluuebunny/crossref_metadata_2025 huggingface dataset:
A PETHEMA study of high-dose therapy/stem cell support (HDT), including tandem transplant, in primary refractory multiple myeloma (MM): Identification of two populations with different outcomes
Authors: Blade J. , Rosiñol L. , García-Sanz R. , Lahuerta J. , Hernández M. , Sureda A. , de la Rubia J. , Besalduch J. , García- Laraña J. , San Miguel J.
Published: March 2020

8021

Background: It has been claimed that patients with primary refractory myeloma benefit from early HDT. However, the reported series have 2 shortcomings: 1) patients with “unresponsive-progressive disease” vs those “non-responding-non progressing” were not analyzed separately and 2) some included patients had MR or even PR according to the EBMT criteria. Aim: Response and survival after early HDT in the two populations of truly primary refractory MM Methods: From Oct 1999 to Dec 2004, 829 patients with MM received 6 cycles of VBMCP/VBAD and at least one transplant. 79 of the 829 patients were refractory to VBMCP/VBAD. These resistant patients were scheduled to receive a tandem transplant, the first with Bu-12/MEL-140 or MEL-200 and the second “autologous” with CVB or “allo- RIC” (if donor available) with Fluda/MEL-140. Response and progression were defined by the EBMT criteria. Results: 32 of the 79 primary refractory patients had progressive disease under the initial chemotherapy while 47 were “unresponsive, non-progressive”. The prognostic features, including cytogenetics, were similar in both groups. 70% of the patients responded to the first HDT (CR/nCR 8%, PR 48%, MR 13%). 37 patients were given a second transplant (26 “auto”, 11 “allo”). 41% who received a second “auto” up-graded their response (CR 9%, PR 14%, MR 18%) while 42% who underwent “allo-RIC” increased their response (CR 28%, PR 14%). Median survival of the whole series was 3 years. Patients progressing while on therapy had a shorter survival than the “no-change” group (median 2 yrs vs not reached, p=0.00002). Finally, the 47 “non-responsive, non-progressors” patients had similar survival than the 718 with chemosensitive disease intensified with HDT. Conclusions: 1) HDT in patients with primary refractory MM results in a low CR rate, 2) patients progressing while on initial therapy have a short survival despite the intensive approach and 3) patients with “non-responding, non-progressive” disease have similar survival than chemosensitive patients. Whether this good outcome is due to the impact of HDT or to the natural history of a more indolent disease remains to be determined.

No significant financial relationships to disclose.
Outcome of patients relapsing early after autologous stem cell transplantation for multiple myeloma
Authors: Mahmood S. T. , Kumar S. , Lacy M. Q. , Dispenzieri A. , Hayman S. R. , Rajkumar S. V. , Litzow M. R. , Gertz M. A.
Published: March 2020

8022

Background: Autologous stem cell transplant (ASCT) is the standard approach for eligible patients (pts) with multiple myeloma (MM). The median time to relapse after early ASCT is 2–3 yrs and overall survival (OS) is 4–5 yrs. Though various risk factors have been identified for early relapse, the outcome of this group of pts is not clearly described. With the advent of newer therapies, it is important to understand the natural history of MM in these pts to design treatment strategies. Methods: A total of 432 pts with MM, undergoing ASCT within 12 months (mos) of diagnosis, with a minimum follow up of 12 mos were studied. Clinical and laboratory data were obtained from a prospectively maintained database and clinical records. Pts were divided into 2 groups: early relapse (relapse <12 mos from ASCT) and late relapse (either relapsed >12 mos after ASCT or disease free at last follow up). Results: There were 94 pts (22%) in the early relapse group and among the late relapse group (N=338), 171 had relapsed beyond 12 mos and 167 were disease free at last follow up. The median time to ASCT was similar in all groups. The early relapse group had a significantly shorter median OS from diagnosis (23.9 vs. 82.2 months; P < 0.001) and from transplant (17.6 mos vs. not reached; P < 0.001). The median OS from relapse was 7.9 mos in this group compared to 39.6 months for the rest. In univariate analysis, elevated CRP, high BM plasma cell%, labeling index (PCLI) >1%, abnormal cytogenetics, presence of circulating PCs at harvest and lack of CR from ASCT predicted for early relapse. In multivariate analysis, an elevated PCLI (RR=2.9; P=0.002) and failure to achieve CR (RR 2.7; P=0.002) was associated with early relapse. Conclusions: Pts who relapse within 12 mos of an ASCT have a very short survival and should be offered trials evaluating novel therapies and combinations. Survival figures from this study represent the benchmark for the comparison of novel approaches in this population. Pts with poor prognostic factors have a short PFS after ASCT and should be considered for alternative approaches. Inability to achieve CR appears to predict shorter PFS and clinical trials evaluating maintenance therapy should be offered in these pts.

No significant financial relationships to disclose.
I131-tositumomab monotherapy as frontline treatment for follicular lymphoma: Updated results after a median follow-up of 8 years
Authors: Kaminski M. S. , Estes J. , Tuck M. , Ross C. W. , Wahl R. L.
Published: March 2020

8033

Background: Monoclonal antibody-based therapies are improving the outcome for patients (pts) with follicular lymphoma (FL). Radioimmunotherapy has been found to be effective for pts with relapsed/refractory disease, but even more so when used as frontline treatment. Methods and Results. We previously reported the results of a phase II, single-institution, study of anti-CD20 I-131- Tositumomab (Bexxar) given as a single agent and as a single one-week treatment for 76 pts with Stage 3 or 4 FL (NEJM 352:441, 2005). An overall response (OR) rate and complete remission (CR) rate of 95% and 75%, respectively, were observed. With a median follow-up of 5.1 yrs, 5-yr overall survival (OS) and progression-free survival (PFS) were 89% and 59%, respectively, with a median PFS reached at 6.1 yrs. We now report on this pt cohort after a median follow-up of 7.93 yrs. The 8-year and 10-yr OS is estimated (by KM) now at 86% and 8-yr PFS is 50% (95% CI: 38.8 - 61.7%). Only 3 additional relapses have occurred in the additional follow-up period (at 8.0, 8.3, and 9.2 years) in those with CRs. The 8-yr PFS for the 57 pts who achieved CR is now 64%. The median for PFS has now being reached for CRs at 9.2 yrs. When the impact of baseline FLIPI scores were analyzed, only 8-yr OS was significantly affected when low-risk (LR) and intermediate-risk (IR) categories were combined and compared to the high-risk (HR) category (92% vs. 75%; p = 0.029). The 8-yr PFS for LR + IR pts was 56% vs. 35% for HR pts (p = 0.317). 27 of the 76 total pts (35%) had HR scores. Of additional importance, no cases of MDS or AML have yet been observed. Other longterm toxicities including thyroid status and second non-hematologic cancers will be updated at the meeting. Conclusions. These data underscore the high degree of effectiveness and durability of remissions achieved with a single, one-week course of frontline Bexxar and should serve as a benchmark for comparison to other studies using more prolonged and toxic treatments, including those combining unlabeled or radiolabeled antibodies with chemotherapy.

No significant financial relationships to disclose.
Bendamustine and rituximab (BR) are effective in the treatment of relapsed or refractory indolent and mantle-cell lymphomas: Long-term follow-up of a phase II study
Authors: Rummel M. J. , Atta J. , Welslau M. , Kofahl-Krause D. , von Gruenhagen U. , Schalk K. , Boeck H. P. , Banat A. G. , Knauf W. , Niederle N.
Published: March 2020

8034

Bendamustine combines a purine-like benzimidazol and bifunctionally alkylating nitrogen mustard group. The aim of this multicenter- study was to evaluate the progression-free survival (PFS), response rate and toxicity of BR in patients with mantle-cell or low-grade lymphomas in 1st to 3rd relapse or refractory to previous treatment. A median of 4 courses per patient were administered to 63 pts. Bendamustine was given at a dose of 90 mg/m2 on day 1 and 2 combined with 375 mg/m2 Rituximab on day 1 for a max. of 4 cycles every 4 weeks. Histologies: 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, 6 marginal zone lymphoma. 57 of 63 pts responded to BR corresponding to an overall response rate of 90% with a CR-rate of 60%. In mantle cell lymphomas BR showed a considerable activity achieving a response rate of 75% with a CR-rate of 50%. In an updated analysis the median time of PFS was 30 months and the median duration of overall survival has not yet been reached. With a median follow-up period of 3 years two secondary neoplasms have been observed (bronchial carcinoma). No MDS was observed to date. These results demonstrate that the combination of Bendamustine and Rituximab is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas. Based upon these encouraging results the Studiengruppe indolente Lymphome (StiL) initiated two Phase III trials that compare BR to established chemo-immunotherapy regimens: BR vs R-CHOP in untreated pts, and BR vs Fludarabine- R in relapsed pts. These studies should provide considerable guidance for the appropriate role of Bendamustine in the treatment of low-grade and mantle cell lymphomas.

No significant financial relationships to disclose.
R-Dhaox, high dose chemotherapy (HDC) and rituximab maintenance as salvage treatment in relapsed/refractory (R/R) follicular (F) and mantle cells (MC) lymphomas (NHL)
Authors: Rupolo M. , Michieli M. , Spina M. , Bulian P. , Degan M. , Mazzucato M. , Abbruzzese L. , Tirelli U.
Published: March 2020

8036

Second line regimens in NHL are mainly based on cisplatin (DDP). The substitution of DDP with oxaliplatin in DHAP- like regimens may result in lower toxicity and higher activity. In R/R CD20+ follicular (F) and mantle cell (MC) NHL the sinergistic activity of rituximab with chemotherapy and the maintenance immunotherapy obtain and prolong clinical and molecular remission. We assessed the tolerability and the activity in terms of clinical and molecular remission of R-Dhaox (rituximab 375 mg/m2 i.v., day 1, dexametazone 40 mg i.v. days 1–4, Oxaliplatin 130 mg/m2, day 2 and cytarabine 2,000 mg/m2 i.v. twice a day day 3) regimen for 4 courses in phase II study. The pts in response underwent to HDC with the scheme BEAM-R and further were treated with maintenance therapy with rituximab 375 mg/m2 i.v. 75+ from ABMT. After three monthly doses, pts were treated with further five every 4 months (for a total of two years). From June 2002 to September 2006, 31 pts were enrolled. 19 were male and 12 female. Median age was 51 (30–66). 21 (68%) pts were follicular G1-G2, 9 (29%) mantle cells and 1 a transformed follicular. The stage was III for 8 (26%) and IV for 23 (74%) pts. 22 (70%) pts were previous treated with rituximab and 30 (96%) with adryamicin based schedules. CD34+ harvest was after 4th cycle with a median collection of 5,5 ×106/Kg (2,1–20); 2 were positive for BCL-2 and 1 for BCL-1. Overall clinical response before ABMT was 94% for F and 100% for MC. 26 pts underwent ABMT with the schedule BEAM-R. At relapse 54% (12/22) of F were BCL-2 positive and 66% (6/9) of MC for BCL-1. Before ABMT 4/17 pts were BCL-2 positive and 1/9 for BCL-1. Among F, 3 pts relapsed after ABMT: 2 with reexpression of BCL-2 and 1 without. No relapse among MC, all negative for BCL-1 after ABMT. No pt showed severe or fatal infections during maintenance immunotherapy. Three- year projected free survival was 100% for MC and 68% for F NHL. These preliminary data suggested that R-DHAOX, HDC and rituximab maintenance is a novel approach highly effective for R/R F and MC NHL.

No significant financial relationships to disclose.
Prognostic significance of p53/p21 expression in DLBCL treated with CHOP or R-CHOP: A correlative study of E4494
Authors: Aurora V. , Li S. , Horning S. J. , Variakojis D. , Nelson B. P. , Krajewska M. , Habermann T. M. , Fisher R. I. , Gascoyne R. D. , Winter J. N.
Published: March 2020

8038

Background: P21 is a downstream effector protein of p53 that induces cell cycle arrest by inhibiting cyclin/cyclin dependent kinase (cdK) complexes. In this prospective correlative study, we investigated the prognostic significance of p21, p53, Bcl-6, and Bcl-2 in diffuse large B cell lymphoma (DLBCL) in the context of E4494, a randomized trial comparing conventional CHOP to rituximab(R)-CHOP induction, and maintenance R (MR) to observation for responding patients. Methods: Protein expression was quantified by immunohistochemical (IHC) staining of 198 DLBCL paraffin-embedded biopsy specimens and scored by an expert panel of hematopathologists. Results: No differences in the distribution of patient characteristics were detected between p21+ and p21- cases and between p53+ and p53- cases as well as across treatment arms. Among all study patients, there were no differences in clinical outcomes between p21+ and p21- cases. However, when analyzed by induction arm (removing the effect of MR), R-CHOP patients had marginally better FFS (p=0.06) if p21+; among CHOP-treated patients, p21 status had no effect on outcome. For R-CHOP patients but NOT CHOP patients, p21+ was an independent, favorable prognostic factor after adjusting for Bcl-6, IPI and Bcl-2 in multivariate analysis (FFS relative risk 0.3; p=0.003; OS relative risk 0.4; p=0.02). P21+ patients treated with R-CHOP had higher %FFS at 5 years compared to p21+ patients treated with CHOP (61 ± 7% vs. 24 ± 7%; p=0.007) but p21- R-CHOP and CHOP patients had similar FFS (37 ± 7% vs. 35 ± 7%; p=0.64). P53 staining (+ scored as either >20% or 50%) did not predict for FFS or OS in uni- or multivariate analyses. The p53+/p21- phenotype, a possible surrogate for mutated p53, was not prognostic. Further, no significant correlation was seen between p53 and p21 expression by IHC. Conclusions: These data suggest that p21 expression by IHC predicts for favorable outcome in older DLBCL patients treated with R-CHOP but not in those treated with CHOP. Furthermore, p21+ identifies patients who benefit from the addition of rituximab to CHOP. Complex interactions between p53, p21, and Bcl-6, as well as other unknown pathways, may account for this treatment-related effect and should be further investigated.

[Table: see text]
IgG and IgA hypogammaglobulinemia is pervasive in Waldenstrom's macroglobulinemia (WM) and persists regardless of response or type of therapeutic intervention
Authors: Hunter Z. R. , O'Connor K. , Soumerai J. , Branagan A. , Leleu X. , Hatjiharissi E. , Treon S.
Published: March 2020

8042

Background: IgG and IgA hypogammaglobulinemia (HG) is a commonly observed in patients with WM and has often been attributed to the extensive infiltration of lymphoplasmacytic cells in the bone marrow (BM). Methods: In this retrospective study we analyzed immunoglobulin and BM infiltration levels from 196 previously untreated patients at their first visit to our clinic who met the clinical and pathological criteria for WM. In addition, we also serially evaluated 65 WM patients who received various therapies for changes in IgA and IgG. All lab values and biopsies used were conducted at our clinic at the Dana-Farber Cancer Institute to insure consistency. Pre-therapy, end of therapy, and best Ig response post therapy were evaluated and patients were followed up to the point of their next treatment regimen. Results: Of the 197 previously untreated patients, 117 (59.7%) demonstrated abnormally low levels of IgG (<700 mg/dl), whereas 131 (66.8%) had abnormally low levels of IgA (<70 mg/dl), and 102 (52.0%) had abnormally low levels of both IgG and IgA. Median value for IgM was 2820 mg/dl (Range 179 - 12400), for IgG 623 mg/dl (Range 127–2770), for IgA 48.5 mg.dl (range 7 - 509), and for the 94 patients for whom BM biopsies were available, the median intratrabecular space involvement was 37.5% (range 5 - 95). No correlation was found between BM involvement and any Ig level. Results from each of the trials is summarized in the table below. Median follow up was 455 days. No correlation between degree of response and Ig recovery was observed. No Ig level that started abnormally low was ever restored to normal levels in this study despite the fact that some recovery is noted in the non-rituximab based trials. Conclusions: These studies indicate that there is no relationship between BM involvement HG in WM. Moreover, therapeutic intervention does not restore IgG or IgA levels indicating a possible constitutive Ig dysregulation problem in patients with WM.

No significant financial relationships to disclose.

[Table: see text]
Prospective comparison of subcutaneous to intravenous administration of bortezomib in patients with multiple myeloma: Pharmacokinetics, efficacy and toxicity
Authors: Moreau P. , Coiteux V. , Hulin C. , Facon T. , van de Velde H. , Acharya M. , Harousseau J.
Published: March 2020

8046

Bortezomib (Bz) is a novel proteasome inhibitor that is registered for treatment of relapsed or refractory MM as an IV bolus injection. Animal toxicology studies have indicated good local tolerability and an acceptable PK profile of SC injection of Bz supporting together with preliminary clinical data the exploration of this route of administration in humans. We conducted a randomized trial to compare pharmacokinetics/pharmacodynamics (PK/PD), toxicity and efficacy of SC and IV injections of Bz, both at standard dose of 1.3 mg/m2 twice weekly for 2 wks (day 1–4-8–11), with 1 wk rest, for up to 8 cycles. From 01/06 to 10/06, 24 pts with relapsed/refractory MM were randomized to receive Bz either IV (arm A, n = 12) or SC (arm B, n = 12); Patients received a median number of 5 cycles in both groups. The local tolerance of SC injections was good. Response rates were similar in both groups (CR+VGPR/PR/MR: 3/2/1 in arm A, vs 3/2/2 patients in arm B. Grade 3 / 4 adverse events occurred in 7 cases in arm A, vs 5 in arm B, leading to study discontinuation in 5 and 3 cases, respectively. PK analysis: average plasma Cmax values were lower for SC as compared to IV (15 ng/mL at day 1, and 23 at day 11, vs 130 and 127, p < .001), but overall systemic availability as measured by plasma AUC values were comparable between SC and IV administration for both day 1 & 11 (145 and 388 ng.h/mL, vs 133 and 386, p =.7 & .98, respectively). Average Tmax values were less than 1 hour for both routes. PD analysis (20S proteasome inhibition): average area under the curve for effect (AUE) values were comparable between SC and IV administration both for day 1 & 11 (761 and 1,324 %.h, vs 1,089 and 1,110, p = .29 & .54, respectively), while average Emax values were lower for SC administration (Emax day 1 & day 11 SC, 58 and 56%, vs 72 and 69% IV, p =.003 & .01 respectively). The overall systemic availability of Bz was comparable between SC and IV administration for both day 1 and 11. Similarly, the average AUE results were comparable between SC and IV, while average Emax was lower for SC administration. Response rates were identical in the 2 groups of patients, with similar toxicity profile. Given the good local tolerance of SC injection, this route of administration could be an alternative option to IV injection.

[Table: see text]
Factors predictive of outcome in relapsed, refractory multiple myeloma patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)
Authors: Palumbo A. P. , Ambrosini M. T. , Benevolo G. , Pescosta N. , Callea V. , Cangialosi C. , Caravita T. , Morabito F. , Gay F. , Boccadoro M.
Published: March 2020

8048

Background: In relapsed/refractory multiple myeloma (MM) patients, the addition of thalidomide and bortezomib to the standard oral melphalan/prednisone (VMPT) significantly increased response rate and progression-free survival (PFS) (Blood. 2006 Dec 5; [Epub ahead of print]). Baseline parameters which may predict outcome after VMPT have been investigated to identify which patient subgroups most benefit from this drug combination. Methods: Thirty patients with relapsed or refractory MM after 1 or 2 lines of treatment, were treated with six 35-days courses of bortezomib (3 dose levels: 1.0,1.3 and 1.6 mg/m2) on days 1,4,15,22, plus melphalan (6 mg/m2) and prednisone (60 mg/m2) on days 1–5 and thalidomide (50 mg) on days 1–35. Several parameters such as age, β2-microglobulin, C-reactive protein, chromosome 13 abnormalities, albumin, haemoglobin, stage, creatinine, bone marrow plasmacytosis, line of therapy and dosage of bortezomib were analyzed in association with response rate and PFS, using χ2 and Cox model. Results: At least a very good partial response was achieved in 43% of patients and at least a partial response in 67%. The 1-year PFS was 61%, and the 1- year overall survival was 84%. Subgroup analyses did not show any statistical difference between responses and either age, β2 microglobulin, C-reactive protein, chromosome 13 abnormalities, line of treatment or dosage of bortezomib. Serum albumin <3.5 mg/dL was loosely associated with a lower response rate (p=0.09). Factors predictive of shorter PFS were C-reactive protein = 6 mg/L (p=0.02) and 3rd line of therapy (p=0.009). Factors loosely associated with shorter PFS were β2-microglobulin = 3.5 mg/L (p=0.06) and creatinine = 2 mg/dL (p=0.09). No difference in PFS was observed between patients with or without chromosome 13 abnormalities. Conclusions: VMPT induced a high proportion of responses and appeared to overcome the poor prognosis of patients with chromosome 13q deletion.

[Table: see text]
Prognostic significance of maximal tumor size (MTS) in young patients with good-prognosis diffuse large B-cell lymphoma (DLBCL) treated with CHOP-like chemotherapy with and without rituximab: Analysis of the MabThera International Trial Group (MInT) study
Authors: Pfreundschuh M. G. , Hensel M. , Cavallin-Stahl E. , Vasova I. , Kvaloey S. , Gill D. , Walewski J. , Zinzani P. , Pettengell R. , Kuhnt E.
Published: March 2020

8053

Purpose: To determine the impact of MTS in young (18 to 60 years) patients with DLBCL and aaIPI=0,1. Patients and Methods: Outcome of patients treated with CHOP-like chemotherapy with (R-CHEMO) or without rituximab (CHEMO) was analyzed according to MTS. Results: A Martingale residual analysis revealed a linear negative prognostic impact of MTS on event-free (EFS) and overall (OS) survival. The hazard ratios for MTS per centimeter increase were significant for EFS (1.07; 95%-CI: 1.04–1.11; p<0.001) and OS (1.11; 95%-CI: 1.06–1.16; p<0.001). CHEMO 3-year EFS rates ranged between 78% for MTS <5cm and 41% for MTS >10cm. R-CHEMO 3-year EFS ranged from 83% (MTS <5cm) to 73% (MTS >=10cm). CHEMO 3-year OS rates decreased from 93% (MTS <5cm) to 74% (MTS >=10cm). R-CHEMO 3-year OS decreased from 98% (MTS <5cm) to 85% (MTS >=10cm). With CHEMO, any cut-off point between 5 and 10 cm separated a thus defined “non-bulky” from a “bulky” population with a 3-year EFS difference >20% (p<0.0001) and OS difference >12% (p<0.003), while with R-CHEMO only cut-off points >=10cm separated two populations with a significant EFS difference (9.1%; p=0.047), and cut-off points >=6cm discriminated two populations with a significant OS difference (7.6%-11.3%; p=0.037–0.0009). Conclusion: Due to the linear prognostic impact of MTS on outcome, cut-off points for “bulky” disease can be set rather arbitrarily between 5 and 10cm depending on clinical considerations. Rituximab reduces, but does not eliminate the negative prognostic impact of MTS in young patients with good-prognosis DLBCL.

[Table: see text]
A two-arm prospective trial evaluating the ability of EBV PCR to diagnose and monitor posttransplant lymphoproliferative disorder
Authors: Tsai D. E. , Douglas L. , Andreadis C. , Arnoldi S. , Blood R. , Olthoff K. , Brozena S. , Stadtmauer E. A. , Kotloff R. , Ahya V.
Published: March 2020

8057

Background: EBV PCR is known to be useful in the management of patients with PTLD. However, the optimal DNA target, relative importance of peripheral blood intracellular versus free plasma EBV, and baseline profile of these EBV PCR variations in a transplant population remains unclear. This study explored these issues as well as assessed the utility of a 6 assay EBV PCR panel in the management of patients with suspected PTLD. Methods: A prospective 2-arm study was performed. Arm A consisted of 31 patients who underwent lung transplantation. Arm B consisted of 35 patients evaluated for possible PTLD. All patients underwent an initial evaluation with EBV PCR and EBV VCA antibody titer. Arm B patients were evaluated for PTLD with CT scans and biopsies of lesions. All patients in Arm A and those in Arm B with documented PTLD were then followed. For the EBV PCR panel, peripheral blood was separated into plasma and whole blood cells and then DNA was purified. Real time EBV PCR was then performed on both samples using primer sets against LMP, EBER and EBNA. Results: No patients on control Arm A developed PTLD. Seventeen (49%) patients on Arm B were found to have PTLD. Thirteen of 17 (76%) had EBV(+) PTLD. Eighteen Arm B patients were given non-PTLD diagnoses. Of 62 patients evaluable for EBV antibody titers, 60 (97%) had IgG for EBV VCA. In Arm A, only 1/31 (3%) patients developed a transient positive low level plasma EBV load. Fourteen of 31 (42%) had detectable low-level intracellular EBV. In patients with EBV(+) PTLD, 11/13 had EBV in plasma and intracellular samples, 1 had intracellular EBV only and 1 patient with isolated CNS PTLD had a negative EBV panel. The EBV PCR panel had high sensitivity (92%) and specificity (67%) for diagnosing EBV(+) PTLD. Comparing the individual PCR assays, whole blood EBER had the best sensitivity (92%) and plasma EBNA & EBER had the best specificity (100%). The EBV PCR panel tracked patient's clinical course well (p=0.06) as they proceeded through treatment. EBV plasma (p=<0.01) and whole blood (p=0.04) copy numbers by EBNA PCR inversely correlated with EBV VCA IgG titers. Conclusion: Peripheral blood EBV PCR is useful in the diagnosis and monitoring of patients with EBV(+) PTLD.

No significant financial relationships to disclose.
Is rituximab (R) the optimal therapeutic intervention (TI) for post-transplant lymphoproliferative disorder (PTLD) following solid organ transplant (SOT)?
Authors: Tsao R. E. , Jin T. , Richendollar B. , Hsi E. , Pohlman B.
Published: March 2020

8074

Background: PTLD is a rare, often fatal, complication of SOT. Most are derived from CD20+ B-cells. Historically, patients (pts) received a variety of TIs ranging from decreased immunosuppression to chemotherapy (CT). Based on promising initial study results, most pts now receive rituximab (R) without CT as part of 1st TI. Methods: We searched the Cleveland Clinic pathology archives for SOT pts, who were diagnosed with PTLD between 1987 and 2006; reviewed the medical records; extracted clinical information and outcomes; and analyzed the data by Cox proportional univariate and multivariate analyses. Results: We identified 55 SOT pts (heart, 18; lung, 16; kidney 14; liver, 6; pancreas, 1), who were diagnosed with PTLD at median age 47 years (range 7–66). The median time from SOT to PTLD was 1.7 years (range .2–20.9). 1st TI (usually >1) included “complete” resection (4), decreased immunosuppresion (53), acyclovir or ganciclovir (28), interferon (4), radiation therapy (6), CT (12), and/or R (17). Response to 1st TI was CR (30) or PR (10). The median follow-up among surviving pts is 5.0 years (range .1–11.4). 29 (including 5 CT and 5 R) pts have died; only 2 CT but all 5 R pts died from PTLD. On univariate analysis, younger age+, <2 prior rejection episodes+*, PS <2+*, normal LDH+*, <2 extranodal sites+, lower IPI+*, >1 1st TI+, and 1st TI with CT* were associated with an improved overall survival (OS)+ and/or PTLD-specific survival (PSS)*. On multivariate analysis, only PS <2 (HR 0.04 [CI 0.01–0.14], p<0.001) and >1 1st TI (HR 0.43 [CI 0.19–0.97], p=0.041) were associated with improved OS while PS <2 (HR 0.04 [0.01- 0.16], p<0.001) and 1st TI with CT (HR 0.19 [CI 0.04–0.84], p<0.028) were associated with improved PSS. Conclusions: A significant minority of SOT pts that receive R without CT as part of 1st TI still die from PTLD. PS is the most important predictor of outcome. In conjunction with the improved survival observed in de novo B-cell NHL pts treated with R+CT (compared to CT alone), this retrospective analysis suggests that some SOT PTLD pts should receive R+CT as part of 1st TI.

No significant financial relationships to disclose.
First-line treatment with single agent rituximab, followed by maintenance rituximab plus anti-idiotype Id-KLH active immunotherapy vaccine (FavId) in patients (pts) with low-grade non-Hodgkin lymphoma (NHL): Preliminary results of a phase II trial
Authors: Raefsky E. , Greco F. A. , Spigel D. R. , Litchy S. , Gian V. , Bender J. , Hainsworth J. D.
Published: March 2020

8080

Background: Single agent rituximab produces a high response rate when used as first-line treatment, and maintenance rituximab prolongs remission duration. Active immunotherapy is a promising treatment approach, when administered following remission induction by initial therapy. In this phase II trial, we evaluate the feasibility, toxicity, and efficacy of administering concurrent maintenance rituximab plus Id-KLH vaccine in pts with low-grade NHL. Methods: Pts with previously untreated low-grade NHL (grade 1/2 follicular or SLL) who were judged to be candidates for single agent rituximab therapy were eligible. All pts had initial biopsy for production of the Id-KLH vaccine. All pts received rituximab 375mg/m2 IV, weekly × 4. Pts with CR/CRu, PR, or stable disease at 8 weeks proceeded with maintenance rituximab (standard 4 week courses at 6 month intervals for 3 courses) and Id-KLH vaccination (Id-KLH 1cc day 1; GMCSF 250μg SQ days 1–4) monthly × 8, beginning month 3, then every 2 months during the second year. Pts were monitored for response rate, progression- free survival, and toxicity. Results: To date, 36 of a planned 56 pts have been enrolled. Idiotype vaccine was successfully manufactured in 27 of 32 pts (84%), with 4 in production. Of the 27 pts for whom Id-KLH was successfully manufactured, 2 progressed during rituximab. 19 of 25 pts (14FL;5SLL) have had response determined after rituximab: 8 PR (42%), 11 stable (58%; 4 of 5 SLL). Pts have now received rituximab maintenance therapy plus Id-KLH for durations of 6 - 34 months. 6 of 19 pts (3 SLL) progressed at months 5, 6, 9, 9, 10, and 12, respectively. Treatment has been well tolerated, with no unusual toxicities observed. Rituximab-related hypotension and atrial fibrillation occurred in 1 pt. The most common Id-KLH related adverse event has been injection site reaction. Conclusions: Concurrent maintenance therapy with rituximab plus Id-KLH is safe and well tolerated. At present, 6 of 25 pts (24%) have progressed (including 3 of the 5 SLL pts) with a median followup of 19 months. This trial is continuing.

No significant financial relationships to disclose.
Use of absolute lymphocyte counts to predict response to chemotherapy and survival in diffuse large B-cell lymphoma
Authors: Kim D. , Chae Y. , Baek J. , Kim J. , Kim Y. , Park Y. , Do Y. , Chung J. , Kim M. , Song H.
Published: March 2020

8082

Background: Absolute lymphocyte counts (ALCs) at diagnosis has been shown to be an independent prognostic factor in patients with follicular lymphoma (FL) although the precise mechanism was not fully elucidated. The current study evaluated the impact of Absolute lymphocyte counts (ALCs) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL) on the response to chemotherapy and survival. Methods: The treatment outcomes of the patients receiving CHOP (n=101) or R-CHOP chemotherapy (n=122) were compared according to ALCs at diagnosis (<1.0 vs. = 1.0×109/L). Results: Forty-two patients (19%) had a lower ALC count at diagnosis (CHOP, 23 [23%]; R-CHOP, 19 [16%]). The lower ALCs showed a good correlation with IPI (p<0.001), performance (p<0.001), LDH (p<0.001), stage (p=0.004), extranodal involvement (p=0.011), but not with age or sex. A significant difference of response rate was noted according to ALCs in favor of a higher ALCs (CR: 80% vs. 60%, p=0.005; ORR: 93% vs. 78%, p=0.003). In addition, event-free survival (EFS) was worse in a lower ALC group than higher ALC group: median duration of EFS, 1,773 days vs. 326 days (p<0.001). The OS was also in favor of a higher ALC group: median duration of OS, 3,000 days vs. 695 days (p<0.001). In multivariate analysis, ALC at diagnosis was an independent predictive factor for CR (HR 2.717, p=0.009) and prognostic factor for EFS (HR 2.148, p=0.004) or OS (HR 2.863, p=0.002). Conclusion: The ALCs at diagnosis appears to predict the survival of DLBCL patients. Our findings suggested that the ALCs at diagnosis may reflect host's immune status against DLBCL, implying that immune system of host will play a critical role on survival of DLBCL patients.

No significant financial relationships to disclose.
Use of C-terminal deletion mutation of CD20 molecule to predict CD20 expression and time to progression after rituximab in non- Hodgkin lymphoma
Authors: Terui Y. , Mishima Y. , Yokoyama M. , Mishima Y. , Takeuchi K. , Ito Y. , Takahashi S. , Hatake K.
Published: March 2020

8088

Background: Rituximab was the first chimeric antibody that is most frequently used for CD20-posistive B-cell lymphomas and gives better response and prognosis. However, resistance to rituximab is one of the important issues to be clarified in the increasing number of monoclonal antibody therapy, and we experienced the case whose lymphoma cells never expressed CD20 at the relapsed phase during rithuximab therapy. We investigated whether CD20 mutation is related to expression level of CD20, relapse or resistance to rituximab therapy, and prognosis. Methods: We analyzed 50 patients with fresh or relapsed/resistant B- cell lymphomas and DNA sequencing analysis of CD20 products from genomic PCR and RT-PCR was performed. CD20 mutants were subcloned by TA cloning, and tested CD20 expression after transfection to K562 cells. Results: Four types of CD20 mutations were found in 11 of 50 NHL patients (22.0%), which include C- terminal deletion (8.0%) extracellular domain (2.0%) transmembrane domain (2.0%) and early termination (10.0%). The group of C-terminal deletion mutations significantly showed lower CD20 expression (3.26, 95%CI = 0.09 to 6.89) than non-mutation (30.8, 95%CI = 22.4 to 39.2) (p 0.05). Although there was no significant difference between the groups with non-mutation and C-terminal deletion mutation in CR rate (49% versus 25%, Fisher's exact test; p = 0.6137), time to progression after rituximab therapy in C-terminal deletion mutation (7 months, 95%CI = 0 to 18 months) was significantly shorter than that in non-mutation (31 months, 95% CI = 18 to 44 months) by log-rank test (p = 0.0481). Non-mutation and early termination groups did not show any significant differences in TTP and CD20 expression. Conclusion: The important mutations of CD20 gene related to shorter duration to progression disease after rituximab therapy were discovered. Especially, point mutations bearing during rituximab therapy should be examined at progression disease after partial remission.

No significant financial relationships to disclose.
Trend and geographic variations in the incidence of mantle cell lymphoma in the United States from 1975 to 2003
Authors: Zhou Y. , Wang H. , Zhang Y. , Du X. , Kwak L. , Romaguera J. , Wang M.
Published: March 2020

8091

Background: Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin's lymphoma (NHL). To better understand the incidence and epidemiological features of MCL in the United States, we conducted a population-based study with 3943 patients (pts) of MCL identified from the Surveillance, Epidemiology, and End Results (SEER) tumor registries over 28 years. Methods: From SEER public database, we identified 157,035 pts of all ages diagnosed with NHL between 1975 and 2003 in 9 SEER areas. Of these pts, 3,943 (2.5%) had histologically confirmed MCL, acccounting for 2.51% of NHL. The incidence with 95% confidence intervals were generated from SEER*Stat Software. Incidence was age-adjusted to the U.S. 2000 standard population. Annual percent change (APC) for the incidence was calculated and considered to be statistically significant if P<0.05. The crude 1-year survival rate was calculated as the ratio of the number of pts who survived over 1 year and the number of pts diagnosed with MCL. Results: Of 3,943 pts with MCL, 69.4% were late-stages (stages III IV), 24.2% were early-stages (stages I-II), and 7.1% were unstaged. Median age at diagnosis for MCL was 68.0. Overall incidence was 0.380/100,000/year, which increased by age from 0.02 in pts aged <40 to 2.02 for 70–79 and 1.81 in pts aged 80 or older. The age-adjusted incidence increased from 0.077 in 1975 to 0.641 in 2003. APC was 4.71% (P<0.001). Incidence of MCL was higher in men (0.555) than in women (0.250) (P<0.001). Annual increase was greater in men (5.84%) than in women (2.82%). There were also substantial geographic variations (P<0.001) in the incidence of MCL. The age-adjusted incidence was highest in Seattle (0.455) and the lowest in Hawaii (0.314). The incidence appeared to be higher in Caucasians (0.405) than in African-Americans (0.235) and other races (0.238). Annual increase was 5.1% in Caucasians, and 1.1% in African-Americans and other races. The 1-year survival rate was 85.0% for pts diagnosed in 1975–84, and increased to 90.4% for pts diagnosed in 1985–1994 and 82.0% for pts diagnosed in 1995–2003. Conclusions: The incidence of MCL increased progressively from 1975 to 2003, and was significantly higher in males and in Caucasians. There were substantial geographical variations in the incidence of MCL.

No significant financial relationships to disclose.
Macrophage levels in large cell lymphoma are associated with survival
Authors: McGrath M. S. , Shagrun L. , Morris A. , Behler C.
Published: March 2020

8097

Background: Recent studies of follicular lymphoma have suggested that the presence of high levels of tumor associated macrophages (MO) conferred a poor prognosis. The current study evaluated large cell lymphomas for the presence of MOs and “proliferative MOs” (promacs), in HIV+ and HIV- LCL. Methods: Formalin-fixed and paraffin-embedded tissues from patients with LCL (and controls) were obtained from the ACSR (URL: http://acsr.ucsf.edu ) and evaluated for expression of CD68 (MO), PCNA (proliferation) and HIVp24 via the use of 0.6mm section tissue microarrays (TMA). Survival data was also evaluated. Results: 64 cases of LCL were evaluated, 31 of which were HIV+ (33 cases were HIV-). HIV p24 staining was seen with 13 of the 31 HIV+ cases(42%) , with staining only in MOs. Promacs (CD68+/PCNA+MOs) were more frequent in cases of HIV+ LCL (median of 18) and HIV- LCL (median of 5), than normal lymph nodes and reactive tonsillar tissue (p<.001). In both HIV+ and HIV- cases of LCL, there was a trend towards shorter survival (p<0.07) with increased numbers of MOs and promacs; p24 reactivity was unrelated to survival. Conclusions: In this preliminary study of MOs in LCL, MO number per TMA core was significantly correlated with promac number in all cases of LCL (p<.001). HIV p24 localized to MOs in 42% of HIV+ LCL cases and was unrelated to survival. Increased promac numbers in cases of LCL correlated with decreased survival in all cases of LCL, but cases of HIV+LCL tended to demonstrate shorter survival than in cases of HIV- LCL. Of the latter group, higher numbers of macrophages (for example, greater than 46 macrophages/core) portend a worse prognosis, but this finding was not statistically significant in this preliminary study.

No significant financial relationships to disclose.
Outcomes after autologous stem cell transplantation in relapsed or refractory Hodgkin disease: The Duke experience
Authors: Kim D. W. , Misra D. , Clough R. W. , Long G. D. , Prosnitz R. G.
Published: March 2020

8100

Background: High dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) offers patients with relapsed or refractory Hodgkin's disease (HD) the possibility of durable long term remission. We examined the characteristics and outcomes of patients treated at Duke University Medical Center between May 1997 and May 2006. Methods: We performed a retrospective chart review on all patients with relapsed or refractory HD who received HDT followed by ASCT at our institution. Various prognostic factors were also analyzed for their impact on overall survival (OS) and disease free survival (DFS). Results: Sixty-one patients received HDT followed by ASCT for relapsed or refractory HD. Median age was 33 years (range: 16 years to 64 years). The patient population was comprised primarily of males (64%), Caucasians (80%), and patients with nodular sclerosing histology (77%). Fifty-six percent of patients had primary refractory HD. At the time of relapse, 44% of patients had stage I-II disease, and 21% had B symptoms. For patients with relapsed disease, the median time from initial diagnosis to relapse was 17 months. Most patients (64%) received cyclophosphamide, etoposide, and BCNU chemotherapy as HDT. Thirty-one percent of patients received consolidative radiotherapy after HDT. Twenty-eight percent of patients had chemotherapy- responsive disease prior to undergoing HDT. Following ASCT, 46/61 (75%) of patients achieved a complete response. Transplant-related deaths occurred in 2/61 (3%) patients. With a median follow-up of 2.5 years (range: 3 months to 8.8 years), the actuarial 5-year OS and DFS were 79% and 50%, respectively. The most common post-therapy complication was pneumonitis, which occurred in 62% of patients. Three (5%) patients developed second malignancies. On univariate analysis, gender, stage at diagnosis, stage at relapse, presence of B symptoms at relapse, and the interval to first relapse did not significantly affect OS or DFS. Conclusions: Our results confirm that HDT followed by ASCT offers an excellent chance for long-term DFS and OS in patients with relapsed or refractory HD, with a low risk of treatment-related mortality.

No significant financial relationships to disclose.
Identification of specific immune responses in monoclonal gammopathy of undetermined significance with therapeutic implications
Authors: Blotta S. , Mitsiades C. , Tassone P. , Negri J. , Tai Y. , Prabhala R. , Franco B. , Venuta S. , Anderson K. , Munshi N.
Published: March 2020

8103

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition with only 30% patients developing symptomatic multiple myeloma (MM). The events leading to the transformation from MGUS to MM remain unclear, however several evidences have supported the idea that immune surveillance play a role in preventing progression. Therefore, identification of antigenic targets with immune response in MGUS may provide insight into disease biology and immune-based therapeutic applications. Methods: Using the Serological identification of antigen by Recombinant Expression cloning (SEREX) technique, we have screened a MM cDNA library with 3 MGUS patients sera. Results: We have identified 11 gene products with an antibody response in MGUS. The response appeared to be directed against intracellular proteins involved in apoptosis (SON, Hip1), DNA and RNA binding proteins (KIAA0530, GPATC4), signal transduction regulators (AKAP11), developmental proteins (OFD1), transcriptional co-repressors (IRF2BP2), protein of the ubiquitin-proteosome pathways (PSMC1). We have further analyzed frequency of antibody response against these antigens in additional 26 MGUS sera, 10 newly diagnosed, 11 post-transplant remission and 12 relapsed MM patients and 25 normal donors. Whereas an antibody response was observed against OFD1 (20.6%), KIAA0530 (10.3%), AKAP11 (10.3%) and GPATC4 (6.8%) in MGUS patients, no responses were observed in normal donors or MM patients except against OFD1 in 3 post transplant patients. We have further focused our studies on OFD1, a developmentally expressed Hedgehog (Hh)-pathway-related protein with most frequent antibody response. We have previously showed that Hh-pathway genes are involved in development of MGUS. Our microarray analysis showed that OFD1 and other Hh pathway-related genes (Sonic, Smothened, Patched, Gli-1 and Gli-3) are selectively expressed in MM cell lines and primary cells. We have further evaluated a specific inhibitor of Hh- pathway, Cyclopamine, in MM and observed an inhibition of the proliferation in 5 MM cell lines with an IC50 between 13 - 20 μM. Conclusion: We have confirmed a specific immune response in MGUS and have identified a novel therapeutic target for treatment of MM.

No significant financial relationships to disclose.
Determining familial risk of multiple myeloma
Authors: Coleman E. A. , Lynch H. , Enderlin C. , Stewart C. B. , Kennedy R. , Barlogie B.
Published: March 2020

8111

Background: The etiology of multiple myeloma (MM) remains unknown although genetic and environmental factors have been implicated. Familial MM has been reported; however, whether this familial tendency is due to genetic factors or environmental exposures or both is not known. Analysis of SEER data showed that Iowa, an agricultural state, had the highest incidence of MM; however, once we adjusted for race, sex, age, and year of diagnosis, the effect of geographic area was small and the main effect was race. This project aims to build a Familial MM Registry of families and investigate the families’ pedigrees and environmental factors to determine the familial risk of MM. The long term goal is to identify myeloma susceptibility loci which ultimately could lead to finding myeloma prone germline mutations. Methods: Patients (n = 67) from the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences and their family members with MM or a related malignancy (amyloidoses, lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, Waldenstrom's macroglobulinemia, Hairy cell leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, Hodgkin's disease) were interviewed for environmental factors associated with MM and for family history data to complete pedigrees. Pedigrees were analyzed to determine the patterns of inheritance. Results: Data show that 26 patients (39%) have family members with MM (one having five family members with MM) and 34 patients (51%) have family members with related malignancies. Eighteen families (27%) have a putative autosomal dominant mode of genetic transmission of MM. Pancreatic cancer, malignant melanoma, breast cancer and lymphoma may be part of a myeloma syndrome. Pesticide/insecticide exposure, raising cattle or growing cotton were the most prevalent environmental risk factors. Conclusions: The pedigrees suggest the existence of genetic traits affecting MM susceptibility. This work will be part of the efforts to create an international consortium to study familial MM. Research in the area of molecular epidemiology is needed to discover the genetic and environmental determinants of this disease and the reasons for the racial and gender differences.

No significant financial relationships to disclose.