Heinz-August Horst

Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia

PURPOSE Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell-engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. PATIENTS AND METHODS Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). RESULTS Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. CONCLUSION The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3‐positive T cells to recognize and eliminate CD19‐positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B‐cell precursor ALL on the basis of single‐group trials that showed efficacy and manageable toxic effects. Methods In this multi‐institutional phase 3 trial, we randomly assigned adults with heavily pretreated B‐cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard‐of‐care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event‐free survival than that with chemotherapy (6‐month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem‐cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B‐cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167.)

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082.

High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation

Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.

AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping.

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.

Establishment and optimization of a flow cytometric method for evaluation of viability of CD34+ cells after cryopreservation and comparison with trypan blue exclusion staining.

BACKGROUND:  Trypan blue exclusion staining is probably the most frequently applied method (Method I) for assessment of viability in peripheral blood progenitor cell grafts after cryopreservation. Alternatively, a flow cytometry–based method (Method II) was established and optimized.

Lymphoreticular infiltrates in invasive ductal breast cancer. A histological and immunohistological study.

Fifty-two invasive ductal breast cancers were investigated histologically and immunohistologically to assess localization and composition of the lymphoreticular infiltrates. The tumour-infiltrating cells were mainly located in the intervening stroma, whereas tumour foci often exhibited lower numbers of lymphoreticular cells. Macrophages (Mono 1+ and KiM 6+) and helper/inducer cells bearing the T4 surface antigen (Leu-3a+) regularly constituted the majority of the tumour-infiltrating lymphoreticular cells. In more than 80% of cases large numbers of macrophages were found, and many T4 cells occured in about 60%. Next in frequency were the T lymphocytes (Leu-1+) which were mostly observed in high (46%), or in moderate (39%) numbers. In about 2/3 of the cases moderate numbers of T8 (suppressor/cytotoxic) lymphocytes (Leu-2a+) were detected. B lymphocytes (T0 15+) and natural killer cells (Leu-7+) were generally encountered in very low numbers, while eosinophilic granulocytes were virtually absent from the lymphoreticular infiltrates. Tissue mast cells and plasma cells were present in very low numbers in about one half of the tumours but cases with low, moderate or - rarely - even high numbers of infiltrating cells also occured. It must be emphasized that an in situ histomorphological analysis of the cellular part of the stromal reaction of invasive ductal breast cancers allows only limited conclusions concerning the functional properties of the tumour-infiltrating lymphoreticular cells. From the present study, macrophages and T4 cells but also T8 lymphocytes might be of significance in immunooncological reactions “against” clinically detectable stages of invasive breast cancer.

AIDS-associated Burkitt or Burkitt-like lymphoma : short intensive polychemotherapy is feasible and effective

The objective was to evaluate the feasibility and efficacy of a short-term, multi-agent and dose intensive regimen in AIDS patients with Burkitt or Burkitt-like lymphoma (BL/BLL) and to compare its efficacy with that of a conventional regimen. This was a retrospective, multi-center cohort study of all HIV-1-infected patients diagnosed with BL/BLL between 1990 – 2004. Patients were assigned to two different chemotherapy approaches. Group A received a protocol which was adapted from the German multi-center study group for adult acute lymphoblastic leukemia (GMALL). Group B received a conventional CHOP-based chemotherapy. Fifty-one patients were included in the analysis. In group A (n = 20), significantly more patients achieved complete remission (75% vs 40%, P = 0.02) than in group B (n = 31). One-year survival in group A was 65% compared to 44% in group B (P = 0.17). In a multi-variable Cox regression analysis, treatment according to the GMALL protocol was significantly associated with prolonged survival with a relative hazard rate of 0.13 (95% CI 0.03 – 0.63, P = 0.01). In conclusion, the short and intensive GMALL protocol for B-ALL/NHL is feasible in patients with AIDS-BL/BLL. Outcome may be improved compared to patients treated with CHOP-based regimens. In the era of HAART, more intensive chemotherapy regimens should be considered in patients with highly aggressive lymphomas.

A CD44 variant exon 6 epitope as a prognostic indicator in breast cancer

The CD44 variant exon 6 sequence is associated with metastasizing clones of rat pancreatic and mammary carcinoma. In human breast and colorectal carcinoma epitopes on the cell surface encoded by exon v6 have been shown to predict poor chances of survival. Breast cancers in 55 patients whose clinical follow-up was available for 6 to 8 years were immunophenotyped for the presence of the CD44 exon v6 epitope and the results were correlated with survival. There was a difference in survival in the first 2.5 years following surgery: of the eight patients with negative tumours none had died during this period. The advantage of the negative group faded at later time points. However, the log-rank analysis revealed that differences between CD44 exon v6-negative and -positive groups were just below statistical significance. Studies with a larger number of patients are needed to establish the role of this CD44 variant as an early prognostic indicator in metastatic dissemination of breast cancer.

Blinatumomab for minimal residual disease in adults with B-precursor acute lymphoblastic leukemia

Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10-3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.