Longitudinal Humoral and Cellular Immune Responses Following SARS-CoV-2 Vaccination in Patients with Myeloid and Lymphoid Neoplasms Compared to a Reference Cohort: Results of a Prospective Trial of the East German Study Group for Hematology and Oncology (OSHO).

Purpose: To assess humoral responses longitudinally and cellular immunogenicity following SARS-CoV-2-vaccination in patients with hematologic and oncologic malignancies receiving checkpoint-inhibitors. Methods: This prospective multicenter trial of the East-German-Study-Group-for-Hematology-and-Oncology, enrolled 398 adults in a two (patients; n = 262) to one (controls; n = 136) ratio. Pre-vaccination, day 35 (d35), and day 120 (d120) blood samples were analyzed for anti-spike antibodies and d120 IL-2+IFNγ+TNFα+-CD4+- and CD8+-cells. Laboratories were blinded for patients and controls. Results: Patients belonged to the myeloid (n = 131), lymphoid (n = 104), and checkpoint-inhibitor (n = 17) cohorts. While d35 seroconversion was higher in controls (98%) compared to patients (68%) (p < 0.001), d120 seroconversion improved across all patient cohorts [checkpoint-inhibitors (81% to 100%), myeloid (82% to 97%), lymphoid (48% to 66%)]. CD4+- and CovCD8+-cells in the lymphoid (71%/31%) and control (74%/42%) cohorts were comparable but fewer in the myeloid cohort (53%, p = 0.003 /24%, p = 0.03). In patients with hematologic malignancies, no correlation between d120 humoral and cellular responses was found. A sizeable fraction of lymphoid patients demonstrated T-cell responses without detectable spike-specific-IgGs. Conclusions: Evidence of vaccine-elicited humoral and/or cellular immunogenicity in most patients is provided. Both humoral and cellular responses are crucial to determine which patients will generate/maintain immunity. The findings have implications on public health policy regarding recommendations for SARS-CoV-2 booster doses.

Prognostic impact of rapid reduction of involved free light chains in multiple myeloma patients under first-line treatment with Bendamustine, Prednisone, and Bortezomib (BPV).

INTRODUCTION: Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free light chain (iFLC) is of potential prognostic value. METHODS: This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV). RESULTS: After a median number of two (range 1-5) BPV cycles, the majority of pts (n = 86; 93%) responded with either sCR (n = 21), CR (n = 1), nCR (n = 25), VGPR (n = 20), or PR (n = 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (p = 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (p > 0.05). CONCLUSION: These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment.

Successful treatment of patients with newly diagnosed/untreated light chain multiple myeloma with a combination of bendamustine, prednisone and bortezomib (BPV).

INTRODUCTION: Patients with light chain myeloma frequently have a light chain tubular cast nephropathy, which can lead to severe renal impairment. In the present retrospective study, bortezomib was combined with other active substances like bendamustine and prednisone (BPV), in order to assess the efficacy and toxicity of the combination therapy in patients with light chain multiple myeloma. METHODS: Between September 2008 and May 2015, 25 patients with newly diagnosed light chain multiple myeloma were treated with bendamustine 60 mg/m2 on days 1 and 2, bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 once every 21 days (BPV). Prior to treatment, 4 patients (16%) had moderate renal dysfunction and 14 patients (56%) severe renal dysfunction or renal failure/dialysis. RESULTS: The median number of the BPV cycles was 2 (1-5). 24 patients (96%) responded with 4 stringent complete responses, 6 near-complete responses, 5 very good partial responses and 9 partial responses. The myeloma light chains decreased rapidly, reaching the best response after the first cycle in 9 and after the second cycle in additional 12 patients. 17 patients discontinued therapy after median 2 cycles of BPV treatment to receive autologous or allogeneic SCT. All together 12 of 18 patients with at least moderate renal failure improved their renal function. 3 of the 6 dialysis-dependent patients became dialysis-independent. With a median follow-up of 27 months, median progression-free survival and overall survival for patients at 30 months were 68 and 96%, respectively. The most common severe side effect was grade 3/4 leukocytopenia in 20% of the patients. Grade 3/4 thrombocytopenia was observed in 12% of the patients. Moderate to severe infection were seen in six patients. We conclude that BPV is effective and well tolerated in patients with newly diagnosed/untreated light chain multiple myeloma.

Stem cell mobilization and autologous stem cell transplantation after pretreatment with bendamustine, prednisone and bortezomib (BPV) in newly diagnosed multiple myeloma.

INTRODUCTION: Reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after induction treatment with a combination of bendamustine, prednisone and bortezomib (BPV) is missing. MATERIALS AND METHODS: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 35 patients with MM who had received at least one cycle of a BPV-induction therapy consisting of bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 between October 2008 and May 2014. The mobilization regimen consisted of cyclophosphamide 4 g/m(2) and G-CSF (2 × 5 µg/kg). Apheresis was started as soon as peripheral CD34(+) counts exceeded 20 × 10(6)/L with a harvest target of 8 × 10(6) CD34(+)/kg. The minimal accepted target was 2 × 10(6) CD34(+)/kg. The transplantation conditioning therapy consisted of melphalan 200 mg/m(2). RESULTS: A median number of two (range 1-5) BPV cycles were given. The majority of patients (n = 31, 89 %) responded with two sCR, five nCR, 11 VGPR and 13 PR after BPV induction. Three patients had MR, and one SD. Stem cell mobilization and harvest were successful in all patients. In 19 of 35 patients (54 %), a single apheresis was sufficient to reach the target. The median number of aphereses was one (range 1-4), and the median CD34(+) cell-count/kg was 13.5 (range 3.2-33.1)  × 106. All patients received an autologous SCT. Engraftment was successful in 34 of 35 patients. The median time to a leukocyte count >l × 10(9)/L was 11 days, and the time to untransfused platelet count of >50 × 10(9)/L was 13 days. Thirty-four patients (97 %) responded after the autologous SCT with 11 sCR, two CR, seven nCR, seven VGPR and seven PR. The progression-free survival at 18 months was 87 %, and overall survival was 92 %. CONCLUSION: Stem cell mobilization and autologous SCT are feasible in MM patients who have received BPV-induction therapy .

A retrospective review of diagnosis and treatment modalities of neuroendocrine tumors (excluding primary lung cancer) in 10 oncological institutions of the East German Study Group of Hematology and Oncology (OSHO), 2010-2012.

RATIONALE: There is a paucity of data on the incidence of neuroendocrine tumors (NET) outside pulmonary primaries and on treatment modalities applied to patients with NET in clinical practice. Only very little therapeutic progress has been made with respect to response and overall survival, particularly among patients with poorly differentiated, WHO grade 3 neuroendocrine carcinomas (G3-NEC). We sought to document the incidence and treatment modalities in patients with NET/NEC within a period of 2 years. METHODS: We conducted a retrospective data analysis using a simple documentation file to be completed in written form or electronically, including localization, WHO grading, treatment modalities, and specific therapeutic regimens applied. Primary lung cancer was excluded. The time period to be covered was 2010 through 2012. Individual patient data such as names or age were not documented, so that no ethics committee approval was required. RESULTS: Ten different hospital- or practice-based institutions contributed their data. One to 35 patients were documented per institution, summing up to 149 patients with 154 tumor localizations. Midgut (n = 46), foregut (n = 42), hindgut (n = 17), lung (n = 9), bladder (n = 8), unknown primary (n = 11), and other including prostate and liver (n = 21) were documented as tumor sites. Histological gradings were G1 (n = 71), G2 (n = 27), G3 (n = 34), undifferentiated "G4" (n = 4), and not specified (n = 13). Treatment modalities were surgical resection (n = 102), chemotherapy (n = 49), somatostatin analogs (n = 39), radiotherapy (n = 22), receptor-directed radionuclide therapy (n = 12), and systemic tyrosine kinase inhibition (n = 5). Chemotherapy was given to patients not only with G3-NEC (n = 31), but also with G2 (n = 12) and G1 NET (n = 7). Somatostatin analogs as well as receptor-directed radionuclides were applied to patients throughout all gradings. CONCLUSIONS: NET and NEC are not very rare tumor entities, but are diagnosed with very different frequencies, possibly depending upon the alertness of pathologists and clinicians. Chemotherapy, receptor-directed radionuclide application, and somatostatin analog therapy are applied without a clear correlation to different histologic gradings. Diagnostic and therapeutic progress in the field of NETs/carcinomas is urgently needed.

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma.

INTRODUCTION: Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination in patients with multiple myeloma (MM). In the present protocol, bortezomib was combined with bendamustine and prednisone, in order to assess the efficacy and safety of this combination therapy in patients with newly diagnosed/untreated MM. METHODS: Between June 2006 and October 2013, 49 patients with newly diagnosed/untreated MM were treated with bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 bendamustine, prednisone and bortezomib (BPV) once every 21 days. Patients were divided into three groups: group A (n = 19) consisted of patients with normal renal function or mild dysfunction (eGFR ≥ 60 ml/min), group B (n = 15) patients with moderate or severe renal dysfunction (eGFR 15-59 ml/min) and group C (n = 15) patients with renal failure/dialysis (eGFR <15 ml/min). RESULTS: A median number of two (range 1-5) BPV treatment cycles were given to the patients. The majority of the patients (n = 40, 82 %) responded after at least one cycle of BPV therapy with five stringent complete responses (CRs), nine near complete responses, 12 very good partial responses and 14 partial responses. Five patients had MR, three stable and one progressive disease. After a median observation time of 13 months, progression-free survival (PFS) and overall survival (OS) at 12 months were 92 and 94 %, respectively, for patients with normal renal function or mild renal dysfunction (group A) and 83 and 93 %, respectively, for patients with moderate or severe renal dysfunction (group B). Outcome for these patients was slightly better but not statistically significantly better than that for patients with renal failure/dialysis (group C), who had a PFS, and OS of 66 % (p = 0.08) and 73 % (p = 0.05), respectively. These results indicate that this BPV combination is feasible, effective and well tolerated in patients with newly diagnosed MM and normal or impaired renal function.

Successful treatment of patients with newly diagnosed/untreated multiple myeloma and advanced renal failure using bortezomib in combination with bendamustine and prednisone.

PURPOSE: Renal failure is a frequent complication of multiple myeloma (MM) and, if present at diagnosis, a considerable risk factor for outcome. Treatment with chemotherapy and/or new agents may result in recovery of renal function in up to 50 % of patients. The window of opportunity to reverse renal impairment is, however, rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as bendamustine has been demonstrated to be potent drugs in the treatment of MM. METHODS: A total of 18 patients with newly diagnosed/untreated MM and renal insufficiency (GFR < 35 ml/min) were treated with bendamustine, prednisone, and bortezomib (BPV). RESULTS: The majority of them (n = 15; 83 %) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow-up of 17 months, PFS at 18 months was 57 % and OS was 61 %. The myeloma protein decreased rapidly, reaching the best response after the first cycle in four and after the second cycle in additional seven patients. Thirteen patients (72 %) improved their renal function after treatment. CONCLUSION: We conclude that the combination of bortezomib, bendamustine, and prednisone is effective and well tolerated in patients with a newly diagnosed MM and renal failure.