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Michaela Liedtke, MD

  • Michaela Liedtke

Specialties

Hematology

Work and Education

Professional Education

Medizinische Hochschule Hannover, Hannover, Germany, 06/30/1996

Residency

Albert Einstein College of Medicine Office of the Registrar, Bronx, NY, 06/30/2002

Fellowship

Memorial Sloan-Kettering Cancer Center, New York, NY, 06/30/2004

Stanford University Medical Center, Stanford, CA, 06/30/2006

Board Certifications

Hematology, American Board of Internal Medicine

All Publications

Twice-weekly ixazomib in combination with lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma BRITISH JOURNAL OF HAEMATOLOGY Richardson, P. G., Hofmeister, C. C., Rosenbaum, C. A., Htut, M., Vesole, D. H., Berdeja, J. G., Liedtke, M., Chari, A., Smith, S. D., Lebovic, D., Raje, N., Byrne, C., Liao, E., Gupta, N., Di Bacco, A., Estevam, J., Berg, D., Baz, R. 2018; 182 (2): 23144

Abstract

Weekly ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral ixazomib 30 or 37mg plus lenalidomide 25mg and dexamethasone 20mg (10mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 30mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% very good partial response; 24% complete response). Median progression-free survival was 249months. Responses (median duration 369months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib-Rd in this setting.

View details for DOI 10.1111/bjh.15394

View details for Web of Science ID 000437830100010

View details for PubMedID 29938772

View details for PubMedCentralID PMC6055619

Effect of Fitbit and iPad Wearable Technology in Health-Related Quality of Life in Adolescent and Young Adult Cancer Patients. Journal of adolescent and young adult oncology Yurkiewicz, I. R., Simon, P., Liedtke, M., Dahl, G., Dunn, T. 2018

Abstract

PURPOSE: Adolescent and young adult (AYA) patients with cancer face significant challenges with regard to fatigue, reduced physical activity, and social isolation, which may negatively impact quality of life. This study investigated whether the use of digital wearable technology (Fitbits, along with synced iPads) can affect health-related quality of life (HRQOL) in AYA aged patients with cancer.MATERIALS AND METHODS: This was a prospective cohort study that offered Fitbits and iPads to all AYA patients aged 15 to 29 at an academic medical center at the time of cancer diagnosis. Patients completed the Short Form Health Survey developed by RAND (RAND-36) assessing eight dimensions of HRQOL on entering the study and at the time of their 6-month follow-up or the end of treatment, whichever occurred first. At the time of follow-up, patients also completed a questionnaire that assessed user experience, including frequency of wearable device use, enjoyment, challenges, and participation, in online communities.RESULTS: Thirty-three patients participated in the study. Most patients reported enjoying the digital technology and using the devices to track multiple aspects of their health (85%). Most also reported a subjective increase in physical activity (79%). After the intervention, participants demonstrated significant improvements across all eight dimensions of HRQOL measured by the RAND-36 (p<0.00 to 0.01).CONCLUSION: Distributing wearable technology at the time of diagnosis may provide an avenue for improving HRQOL in adolescents and young adults with cancer.

View details for DOI 10.1089/jayao.2018.0022

View details for PubMedID 29924668

Efficacy and Safety Analysis by Age Cohort of Inotuzumab Ozogamicin in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia Enrolled in INO-VATE CANCER Jabbour, E. J., DeAngelo, D. J., Stelljes, M., Stock, W., Liedtke, M., Gokbuget, N., O'Brien, S., Wang, T., Paccagnella, M., Sleight, B., Vandendries, E., Advani, A. S., Kantarjian, H. M. 2018; 124 (8): 172232

Abstract

Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8mg/m2 /cycle (0.8mg/m2 on day 1 and 0.5mg/m2 on days 8 and 15 of a 21- to 28-day cycle [6 cycles]); 60 patients were aged 55 years, and 104 were aged <55 years.For older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged <55 years and those aged 55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018;124:1722-32. 2018 American Cancer Society.

View details for DOI 10.1002/cncr.31249

View details for Web of Science ID 000429411900013

View details for PubMedID 29381191

Long-Term Outcomes in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia Treated with Inotuzumab Ozogamicin: Results from the Phase 3 INOVATE Study Ali, S., Stelljes, M., DeAngelo, D. J., Liedtke, M., Stock, W., Gokbuget, N., O'Brien, S., Jabbour, E., Wang, T., White, J. L., Sleight, B., Vandendries, E., Advani, A. S., Kantarjian, H. M. WILEY. 2018: 38
Clinical implications of gastrointestinal symptoms in systemic amyloidosis NEUROGASTROENTEROLOGY AND MOTILITY Yen, T., Chen, F. W., Witteles, R. M., Liedtke, M., Nguyen, L. A. 2018; 30 (4): e13229

Abstract

Gastrointestinal (GI) symptoms in systemic amyloidosis patients are poorly characterized. This purpose of this study is to define the epidemiology and clinical implications of such symptoms.This was a retrospective cohort study of 583 amyloid patients seen at a tertiary referral center. Of 96 symptomatic patients, 82 received endoscopic biopsies, subsequently grouped into those with histologic evidence of GI amyloid (biopsy proven) vs without (biopsy absent).16.8% of patients had GI symptoms, and had more abnormal NT-proBNP, cardiac ejection fraction, serum albumin, and alkaline phosphatase (P<.01). Of those who received endoscopy, the sites of highest diagnostic yield were stomach, duodenum and colon. The most common symptom was abdominal pain, nausea, or vomiting (50.0%). Of the symptomatic patients, only 37 (45%) had biopsy proven GI amyloid. Biopsy proven patients more often had cardiac involvement (P<.005), and more often received hematologic therapy or transplant (P=.01). Biopsy absent patients had more frequent neurologic involvement (P=.17). Biopsy status had no significant correlation with other indicators of amyloid burden, GI symptoms or management.Nearly one in six amyloid patients have GI symptoms, and half do not have GI amyloid. The type of symptom does not predict endoscopic findings. Most biopsy absent patients are not managed as a functional disorder despite no alternative etiology. Gastroenterologists may have an increased role to play in the care of systemic amyloidosis beyond performing endoscopies, such as evaluating cardiac amyloid patients for concurrent GI amyloid.

View details for DOI 10.1111/nmo.13229

View details for Web of Science ID 000428850800003

View details for PubMedID 29024324

Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML). Leukemia research Advani, A. S., Li, H., Michaelis, L. C., Medeiros, B. C., Liedtke, M., List, A. F., O'Dwyer, K., Othus, M., Erba, H. P., Appelbaum, F. R. 2018; 67: 1720

Abstract

Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting 3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p=.062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.

View details for DOI 10.1016/j.leukres.2018.01.021

View details for PubMedID 29407182

Prognostic impact of incomplete hematologic count recovery and minimal residual disease on outcome in adult acute lymphoblastic leukemia at the time of second complete response LEUKEMIA & LYMPHOMA Saygin, C., Papadantonakis, N., Cassaday, R. D., Liedtke, M., Fischer, K., Dunn, T., Patel, B. J., Sobecks, R., Kalaycio, M., Sekeres, M. A., Mukherjee, S., Gerds, A. T., Hamilton, B. K., Carraway, H. E., Advani, A. S. 2018; 59 (2): 36371

Abstract

Outcomes of relapsed adult acute lymphoblastic leukemia (ALL) have improved over time with the introduction of new therapies as well as better supportive care. However, there is still a need for easy-to-use and accurate prognostic tools for patients in first relapse. Whether complete response (CR) with incomplete count recovery (CRh) can be grouped with CR in relapsed ALL trials has not been formally studied. We analyzed 106 ALL patients at first relapse who were treated at three academic centers and achieved CR/CRh. White blood cell count at initial diagnosis and receiving hematopoietic cell transplant (HCT) were independent predictors of overall survival after relapse, while minimal residual disease (MRD) positivity and performance of HCT were predictors of relapse free survival (RFS). Patients who achieved MRD negativity and underwent HCT had the best outcomes. Our results suggest that MRD is a more powerful predictor of outcome than CRh.

View details for DOI 10.1080/10428194.2017.1344842

View details for Web of Science ID 000413728300012

View details for PubMedID 28693363

NEOD001 Demonstrates Organ Biomarker Responses in Patients with Light Chain Amyloidosis and Persistent Organ Dysfunction Independently of Previous Hematological Response Gertz, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Merlini, G., Schonland, S., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Liedtke, M. KARGER. 2018: 19
NCCN Guidelines (R) Insights Multiple Myeloma, Version 3.2018 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kumar, S. K., Callander, N. S., Alsina, M., Atanackovic, D., Biermann, J., Castillo, J., Chandler, J. C., Costello, C., Faiman, M., Fung, H. C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C., Kang, Y., Kassim, A., Liedtke, M., Malek, E., Martin, T., Neppalli, V. T., Omel, J., Raje, N., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Weber, D., Yahalom, J., Kumar, R., Shead, D. A. 2018; 16 (1): 1120

Abstract

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

View details for DOI 10.6004/jnccn.2018.0002

View details for Web of Science ID 000419099800003

View details for PubMedID 29295877

Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia DRUG DESIGN DEVELOPMENT AND THERAPY Yurkiewicz, I. R., Muffly, L., Liedtke, M. 2018; 12: 22932300

Abstract

Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 expression is detected on leukemic blasts in over 90% of patients with ALL. Based on promising results from preclinical studies, inotuzumab ozogamicin was tested in Phase 1/2 and Phase 3 clinical trials and it demonstrated improved complete remission rates, progression-free survival and overall survival in relapsed or refractory adult ALL compared to standard therapy. Ongoing studies are evaluating the value of inotuzumab ozogamicin when given in combination with chemotherapy as part of upfront treatment. This review discusses the drug's biochemical properties and mechanism of action, preclinical research outcomes, clinical trial results, adverse events and toxicities, drug approval and ongoing investigations.

View details for DOI 10.2147/DDDT.S150317

View details for Web of Science ID 000439928700001

View details for PubMedID 30087554

View details for PubMedCentralID PMC6063246

A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma. International journal of hematology Dinner, S., Dunn, T. J., Price, E., Coutr, S. E., Gotlib, J., Berube, C., Kaufman, G. P., Medeiros, B. C., Liedtke, M. 2018

Abstract

This phase 1 study investigated the safety of the anthracycline amrubicin combined with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma. A standard 3+3 design was used. Patients received intravenous amrubicin 40-80mg/m2 on day one, lenalidomide 15mg orally on days 1-14, and dexamethasone 40mg orally weekly on 21day cycles. 14 patients were enrolled, and completed a median of three cycles. The maximum tolerated dose was not reached. One patient experienced dose limiting toxicity of dizziness and diarrhea. The most frequent non-hematologic toxicity was infection (79%). Serious adverse events included cord compression and sepsis. Three patients (21%) had a partial response or better, and seven (50%) had stable disease. The median duration of response was 4.4months, and the median progression-free survival was 3months. Amrubicin combined with lenalidomide and dexamethasone, was safe and demonstrated clinical activity in relapsed or refractory multiple myeloma.Clinicaltrials.gov identifier: NCT01355705.

View details for DOI 10.1007/s12185-018-2468-5

View details for PubMedID 29802551

NEOD001 DEMONSTRATES ORGAN BIOMARKER RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS AND PERSISTENT ORGAN DYSFUNCTION INDEPENDENTLY OF PREVIOUS HEMATOLOGIC RESPONSE Gertz, M. A., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Merlini, G., Walling, J., Kinney, G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Liedtke, M. FERRATA STORTI FOUNDATION. 2017: 26
Epidemiology and Clinical Implications of Gastrointestinal Symptoms in Systemic Amyloidosis Yen, T., Chen, F., Witteles, R., Liedtke, M., Nguyen, L. NATURE PUBLISHING GROUP. 2017: S240
Novel therapeutic approaches for AL amyloid Liedtke, M. KARGER. 2017: 194
NEOD001 DEMONSTRATES DURABLE PERIPHERAL NEUROPATHY RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS AND PERSISTENT ORGAN DYSFUNCTION: RESULTS FROM A PHASE 1/2 STUDY Gertz, M., Comenzo, R. L., Landau, H., Sanchorawala, Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Alvarez-Baron, E., Liedtke, M. WILEY. 2017: 28990
NEOD001 demonstrates organ biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction independently of previous hematologic response Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Schoenland, S. O., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Gertz, M. A. KARGER. 2017: 3435
Clonal Expansion and Interrelatedness of Distinct B-Lineage Compartments in Multiple Myeloma Bone Marrow CANCER IMMUNOLOGY RESEARCH Hansmann, L., Han, A., Penter, L., Liedtke, M., Davis, M. M. 2017; 5 (9): 74454

Abstract

Multiple myeloma is characterized by the clonal expansion of malignant plasma cells in the bone marrow. But the phenotypic diversity and the contribution of less predominant B-lineage clones to the biology of this disease have been controversial. Here, we asked whether cells bearing the dominant multiple myeloma immunoglobulin rearrangement occupy phenotypic compartments other than that of plasma cells. To accomplish this, we combined 13-parameter FACS index sorting and t-Stochastic Neighbor Embedding (t-SNE) visualization with high-throughput single-cell immunoglobulin sequencing to track selected B-lineage clones across different stages of human B-cell development. As expected, the predominant clones preferentially mapped to aberrant plasma cell compartments, albeit phenotypically altered from wild type. Interestingly, up to 1.2% of cells of the predominant clones colocalized with B-lineage cells of a normal phenotype. In addition, minor clones with distinct immunoglobulin sequences were detected in up to 9% of sequenced cells, but only 2 out of 12 of these clones showed aberrant immune phenotypes. The majority of these minor clones showed intraclonal silent nucleotide differences within the CDR3s and varying frequencies of somatic mutations in the immunoglobulin genes. Therefore, the phenotypic range of multiple myeloma cells in the bone marrow is not confined to aberrant-phenotype plasma cells but extends to low frequencies of normal-phenotype B cells, in line with the recently reported success of B cell-targeting cellular therapies in some patients. The majority of minor clones result from parallel nonmalignant expansion. Cancer Immunol Res; 5(9); 744-54. 2017 AACR.

View details for DOI 10.1158/2326-6066.CIR-17-0012

View details for Web of Science ID 000409018400003

View details for PubMedID 28768640

View details for PubMedCentralID PMC5590392

Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis BLOOD Kaufman, G. P., Schrier, S. L., Lafayette, R. A., Arai, S., Witteles, R. M., Liedtke, M. 2017; 130 (7): 900902

Abstract

The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.

View details for DOI 10.1182/blood-2017-01-763599

View details for Web of Science ID 000407779500011

View details for PubMedID 28615223

FIRST-IN-HUMAN MULTICENTER STUDY OF BB2121 ANTI-BCMA CAR T CELL THERAPY FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA: UPDATED RESULTS Lin, Y., Berdeja, J., Raje, N., Munshi, N., Siegel, D., Liedtke, M., Jagannath, S., Maus, M., Turka, A., Lam, L. P., Hege, K., Morgan, R., Quigley, M. T., Kochenderfer, J. FERRATA STORTI FOUNDATION. 2017: 21
TWICE-WEEKLY IXAZOMIB PLUS LENALIDOMIDE-DEXAMETHASONE IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA: LONG-TERM FOLLOW-UP DATA FOR PATIENTS WHO DID NOT UNDERGO STEM CELL TRANSPLANTATION Richardson, P., Hofmeister, C., Rosenbaum, C., Htut, M., Vesole, D., Berdeja, J., Liedtke, M., Chari, A., Smith, S., Lebovic, D., Raje, N., Liao, E., Zhang, X., Berg, D., Baz, R. FERRATA STORTI FOUNDATION. 2017: 31718
PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS TREATED WITH NEOD001 ACHIEVE RAPID ORGAN RESPONSES THAT ARE INDEPENDENT OF PREVIOUS PLASMA CELL-DIRECTED THERAPIES Gertz, M. A., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Liedtke, M. FERRATA STORTI FOUNDATION. 2017: 3
PROGNOSTIC IMPLICATIONS OF PRETREATMENT CYTOGENETICS IN ADULTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH INOTUZUMAB OZOGAMICIN Jabbour, E., Advani, A., Stelljes, M., Stock, W., Liedtke, M., Goekbuget, N., Martinelli, G., O'Brien, S., White, J., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., DeAngelo, D. J., Kantarjian, H. M. FERRATA STORTI FOUNDATION. 2017: 198
Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study BLOOD ADVANCES DeAngelo, D. J., Stock, W., Stein, A. S., Shustov, A., Liedtke, M., Schiffer, C. A., Vandendries, E., Liau, K., Ananthakrishnan, R., Boni, J., Laird, A., Fostvedt, L., Kantarjian, H. M., Advani, A. S. 2017; 1 (15): 116780

Abstract

This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m2 per cycle on days 1, 8, and 15 over a 28-day cycle (6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15), with reduction to 1.6 mg/m2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.

View details for DOI 10.1182/bloodadvances.2016001925

View details for Web of Science ID 000404535700019

View details for PubMedID 29296758

View details for PubMedCentralID PMC5728308

NEOD001 demonstrates organ biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction independently of previous haematological response Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Gertz, M. A. WILEY. 2017: 441
NEOD001 DEMONSTRATES CARDIAC BIOMARKER RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS: RESULTS FROM THE PHASE 1/2 STUDY Liedtke, M., Comenzo, R., Landau, H., Sanchorawala, V., Weiss, B., Zonder, J., Walling, J., Kinney, G., Koller, M., Schenk, D. B., Guthrie, S., Liu, E., Gertz, M. ELSEVIER SCIENCE INC. 2017: 825
Recommendations from the Amyloidosis Research Consortium Educational Roundtable at the American College of Cardiology Annual Meeting, 1 April 2016 Maurer, M., Lousada, I., Hanna, M., Ruberg, F., Mohty, D., Dispenzieri, A., Liedtke, M., Paulson, I., Vest, J., Grogan, M. TAYLOR & FRANCIS LTD. 2017: 16566
Multiple Myeloma, Version 3.2017 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kumar, S. K., Callander, N. S., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Faiman, M., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Liedtke, M., Martin, T., Omel, J., Raje, N., Reu, F. J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2017; 15 (2): 230-?

Abstract

Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenstrm's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

View details for Web of Science ID 000394927100008

View details for PubMedID 28188192

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia DeAngelo, D. J., George, T. I., Linder, A., Langford, C., Perkins, C., Ma, J., Westervelt, P., Merker, J. D., Berube, C., Coutre, S., Liedtke, M., Medeiros, B., Sternberg, D., Dutreix, C., Ruffie, P. A., Corless, C., Graubert, T. J., Gotlib, J. 2017

Abstract

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a 50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.Leukemia advance online publication, 25 August 2017; doi:10.1038/leu.2017.234.

View details for DOI 10.1038/leu.2017.234

View details for PubMedID 28744009

Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M., Kobayashi, Y., Wheeler, M., Barrett, C., Liedtke, M., Lafayette, R., Schrier, S., Haddad, F., Witteles, R. 2017; 120 (8): 138186

Abstract

Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as 50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.98.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r=-0.43, p=0.01; LA stiffness: r=-0.35, p=0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

View details for DOI 10.1016/j.amjcard.2017.07.025

View details for PubMedID 28844519

Inotuzumab ozogamicin (InO) for relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) in the global phase 3 randomized controlled ino-vate trial: efficacy and safety by age and prior therapy Stelljes, M., Kreuzer, K., Deangelo, D. J., Advani, A. S., Goekbuget, N., Liedtke, M., Stock, W., Martinelli, G., O'Brien, S., Wang, K., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., Jabbour, E. J., Kantarjian, H. M. KARGER. 2016: 2012
Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. New England journal of medicine Kantarjian, H. M., DeAngelo, D. J., Stelljes, M., Martinelli, G., Liedtke, M., Stock, W., Gkbuget, N., O'Brien, S., Wang, K., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., Advani, A. S. 2016; 375 (8): 740-753

Abstract

The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy.In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy.The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).

View details for DOI 10.1056/NEJMoa1509277

View details for PubMedID 27292104

NEOD001 demonstrates cardiac biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction: results from the expansion phase of a phase 1/2 study Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Gertz, M. A. OXFORD UNIV PRESS. 2016: 220
NEOD001 Demonstrates Cardiac Responses in Patients with Light Chain Amyloidosis and Persistent Organ Dysfunction in a Phase 1/2 Study Expansion Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B., Zonder, J., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Gertz, M. A. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2016: S64
INOTUZUMAB OZOGAMICIN FOR RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA IN THE GLOBAL PHASE 3 RANDOMIZED CONTROLLED INO-VATE TRIAL: EFFICACY AND SAFETY BY PRIOR THERAPY DeAngelo, D. J., Jabbour, E. J., Stelljes, M., Liedtke, M., Stock, W., Goekbuget, N., Martinelli, G., O'Brien, S., Wang, K., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., Advani, A. S., Kantarjian, H. M. FERRATA STORTI FOUNDATION. 2016: 184
OOVERALL SURVIVAL IN RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS RECEIVING INOTUZUMAB OZOGAMICIN VS STANDARD CARE IN THE PHASE 3 INO-VATE STUDY Kantarjian, H. M., DeAngelo, D. J., Advani, A. S., Liedtke, M., Stock, W., Goekbuget, N., O'Brien, S., Martinelli, G., Wang, K., Wang, T., Pacagnella, M. L., Sleight, B., Vandendries, E., Stelljes, M. FERRATA STORTI FOUNDATION. 2016: 339
EFFICACY AND SAFETY OF INOTUZUMAB OZOGAMICIN IN OLDER PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA ENROLLED IN THE GLOBAL PHASE 3 RANDOMIZED CONTROLLED INO-VATE TRIAL Jabbour, E. J., Advani, A. S., Stelljes, M., Stock, W., Liedtke, M., Goekbuget, N., Martinelli, G., O'Brien, S., Wang, K., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., DeAngelo, D. J., Kantarjian, H. M. FERRATA STORTI FOUNDATION. 2016: 32
NEOD001 DEMONSTRATES RENAL BIOMARKER RESPONSES IN A PHASE 1/2 STUDY IN PATIENTS WITH IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS AND PERSISTENT RENAL DYSFUNCTION Liedtke, M., Comenzo, R. L., Landau, H., Seldin, D., Weiss, B., Zonder, J., Walling, J., Kinney, G., Koller, M., Gertz, M. A. OXFORD UNIV PRESS. 2016: 103
NEOD001 DEMONSTRATES CARDIAC AND RENAL BIOMARKER RESPONSES IN A PHASE 1/2 STUDY IN PATIENTS WITH AMYLOID LIGHT CHAIN AMYLOIDOSIS AND PERSISTENT ORGAN DYSFUNCTION Liedtke, M., Comenzo, R., Landau, H., Seldin, D., Weiss, B., Zonder, J., Walling, J., Kinney, G., Koller, M., Gertz, M. A. ELSEVIER SCIENCE INC. 2016: 1301
A phase 1, open-label, dose-escalation study of pralatrexate incombination with bortezomib in patients with relapsed/refractory multiple myeloma. British journal of haematology Dunn, T. J., Dinner, S., Price, E., Coutr, S. E., Gotlib, J., Hao, Y., Berube, C., Medeiros, B. C., Liedtke, M. 2016; 173 (2): 253-259

Abstract

Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3+3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30mg/m(2) and intravenous bortezomib at a dose of 13mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4months, the median time to next treatment was 34months and the median time to progression was 4months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

View details for DOI 10.1111/bjh.13946

View details for PubMedID 27040320

First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction. Journal of clinical oncology Gertz, M. A., Landau, H., Comenzo, R. L., Seldin, D., Weiss, B., Zonder, J., Merlini, G., Schnland, S., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liedtke, M. 2016; 34 (10): 1097-1103

Abstract

Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264).Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria.Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease.Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

View details for DOI 10.1200/JCO.2015.63.6530

View details for PubMedID 26858336

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016. Journal of the National Comprehensive Cancer Network Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Reu, F. J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2016; 14 (4): 389-400

Abstract

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

View details for PubMedID 27059188

Multiple Myeloma, Version 3.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Reu, F. J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2016; 14 (4): 389-400

Abstract

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

View details for Web of Science ID 000374082300004

Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia & lymphoma Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

Abstract

The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

View details for DOI 10.3109/10428194.2015.1091930

View details for PubMedID 26374199

Identification of Doxorubicin as an Inhibitor of the IRE1a-XBP1 Axis of the Unfolded Protein Response. Scientific reports Jiang, D., Lynch, C., Medeiros, B. C., Liedtke, M., Bam, R., Tam, A. B., Yang, Z., Alagappan, M., Abidi, P., Le, Q., Giaccia, A. J., Denko, N. C., Niwa, M., Koong, A. C. 2016; 6: 33353-?

Abstract

Activation of the IRE1-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1-XBP1-dependent tumors such as MM.

View details for DOI 10.1038/srep33353

View details for PubMedID 27634301

View details for PubMedCentralID PMC5025885

Recurrent Subepidermal Blistering Dermatosis Heralding Disease Relapse in IgA Kappa Multiple Myeloma: Report of a Case and a Review of the Literature. Clinical lymphoma, myeloma & leukemia Leatham, H. W., Novoa, R., Liedtke, M., Kwong, B. Y. 2016; 16 (1): e1-5

View details for DOI 10.1016/j.clml.2015.11.007

View details for PubMedID 26708980

Report of the Relapsed/Refractory Cohort of SWOG S0919: A Phase 2 Study of Idarubicin and Cytarabine in Combination with Pravastatin for Acute Myelogenous Leukemia Advani, A. S., Li, H., Michaelis, L. C., Medeiros, B. C., Liedtke, M., List, A. F., O'Dwyer, K., Othus, M., Erba, H. P., Appelbaum, F. R. AMER SOC HEMATOLOGY. 2015
Multiple Myeloma, Version 2.2016 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Singhal, S., Smith, C., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2015; 13 (11): 1398-1435

Abstract

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM.

View details for Web of Science ID 000364277500010

View details for PubMedID 26553768

View details for PubMedCentralID PMC4891187

CD93 Marks a Non-Quiescent Human Leukemia Stem Cell Population and Is Required for Development of MLL-Rearranged Acute Myeloid Leukemia. Cell stem cell Iwasaki, M., Liedtke, M., Gentles, A. J., Cleary, M. L. 2015; 17 (4): 412-421

Abstract

Leukemia stem cells (LSCs) are thought to share several properties with hematopoietic stem cells (HSCs), including cell-cycle quiescence and a capacity for self-renewal. These features are hypothesized to underlie leukemic initiation, progression, and relapse, and they also complicate efforts to eradicate leukemia through therapeutic targeting of LSCs without adverse effects on HSCs. Here, we show that acute myeloid leukemias (AMLs) with genomic rearrangements of the MLL gene contain a non-quiescent LSC population. Although human CD34(+)CD38(-) LSCs are generally highly quiescent, the C-type lectin CD93 is expressed on a subset of actively cycling, non-quiescent AML cells enriched for LSC activity. CD93 expression is functionally required for engraftment of primary human AML LSCs and leukemogenesis, and it regulates LSC self-renewal predominantly by silencing CDKN2B, a major tumor suppressor in AML. Thus, CD93 expression identifies a predominantly cycling, non-quiescent leukemia-initiating cell population in MLL-rearranged AML, providing opportunities for selective targeting and eradication of LSCs.

View details for DOI 10.1016/j.stem.2015.08.008

View details for PubMedID 26387756

View details for PubMedCentralID PMC4592469

NEOD001 Demonstrates Cardiac and Renal Biomarker Responses in a Phase 1/2 Study in Patients With AL Amyloidosis and Persistent Organ Dysfunction Liedtke, M., Landau, H., Comenzo, R., Seldin, D., Weiss, B., Zonder, J., Walling, J., Kinney, G., Koller, M., Gertz, M. A. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2015: S15
NEOD001 DEMONSTRATES CARDIAC AND RENAL BIOMARKER RESPONSES IN A PHASE 1/2 STUDY IN PATIENTS WITH AL AMYLOIDOSIS AND PERSISTENT ORGAN DYSFUNCTION Liedtke, M., Landau, H., Comenzo, R., Seldin, D., Weiss, B., Zonder, J., Walling, J., Kinney, G., Koller, M., Gertz, M. A. FERRATA STORTI FOUNDATION. 2015: 23
EFFICACY AND SAFETY OF INOTUZUMAB OZOGAMICIN (INO) VS STANDARD OF CARE (SOC) IN SALVAGE 1 OR 2 PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): AN ONGOING GLOBAL PHASE 3 STUDY DeAngelo, D. J., Stelljes, M., Martinelli, G., Kantarjian, H., Liedtke, M., Stock, W., Goekbuget, N., Wang, K., Pacagnella, L., Sleight, B., Vandendries, E., Advani, A. S. FERRATA STORTI FOUNDATION. 2015: 337
Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma CANCER IMMUNOLOGY RESEARCH Hansmann, L., Blum, L., Ju, C., Liedtke, M., Robinson, W. H., Davis, M. M. 2015; 3 (6): 650-660

Abstract

It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals, and thus high-resolution technologies are likely required. We used cytometry by time-of-flight and next-generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related precancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 precancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T-cell, B-cell, and natural killer-cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0% 0.7% (mean SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27(+)) and nave (CD24(lo)CD38(+)) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells.

View details for DOI 10.1158/2326-6066.CIR-14-0236-T

View details for Web of Science ID 000357430000010

View details for PubMedID 25711758

View details for PubMedCentralID PMC4457663

The VITAL study: A randomized, double-blind, placebo-controlled, global, phase III study of NEOD001 in patients with AL amyloidosis and cardiac dysfunction. Liedtke, M., Merlini, G., Landau, H., Comenzo, R., Seldin, D. C., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G., Koller, M., Gertz, M. A. AMER SOC CLINICAL ONCOLOGY. 2015
Cardiac and renal biomarker responses in a phase 1/2 study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction. Gertz, M. A., Landau, H., Comenzo, R., Seldin, D. C., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G., Koller, M., Liedtke, M. AMER SOC CLINICAL ONCOLOGY. 2015
Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

Abstract

We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

View details for DOI 10.1111/ajt.13025

View details for PubMedID 25648766

A Phase I Dose-Escalation Study of Carfilzomib in Patients with Previously-Treated Systemic Light-Chain (AL) Amyloidosis Cohen, A. D., Scott, E. C., Liedtke, M., Kaufman, J. L., Landau, H., Vesole, D. H., Gomes, C. L., Gasparetto, C., Lentzsch, S., Rosenzweig, M., Sanchorawala, V., Smith, D. D., Comenzo, R. L., Durie, B. M. AMER SOC HEMATOLOGY. 2014
Favorable Outcomes for Older Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of US Intergroup Trial C10403 Stock, W., Luger, S. M., Advani, A. S., Geyer, S., Harvey, R. C., Mullighan, C. G., Willman, C. L., Malnassy, G., Parker, E., Laumann, K. M., Sanford, B., Marcucci, G., Paietta, E. M., Liedtke, M., Claxton, D. F., Foster, M. C., Appelbaum, F. R., Erba, H., Litzow, M. R., Tallman, M. S., Stone, R. M., Larson, R. A. AMER SOC HEMATOLOGY. 2014
Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia LEUKEMIA RESEARCH Liedtke, M., Dunn, T., Dinner, S., Coutre, S. E., Berubea, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

Abstract

The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

View details for DOI 10.1016/j.leukres.2014.09.018

View details for Web of Science ID 000345614400011

Indolent T-lymphoblastic Proliferation With Disseminated Multinodal Involvement and Partial CD33 Expression. American journal of surgical pathology Ohgami, R. S., Sendamarai, A. K., Atwater, S. K., Liedtke, M., Fleming, M. D., Natkunam, Y., Warnke, R. A. 2014; 38 (9): 1298-1304

Abstract

Although indolent T-lymphoblastic proliferations (iT-LBP) are rare, this diagnosis should be excluded in any patient with an extrathymic proliferation of immature TdT+T cells. Unlike T-lymphoblastic leukemia/lymphoma, patients with iT-LBP do not require chemotherapy. We report a case of iT-LBP with disseminated multinodal involvement in an otherwise healthy 49-year-old woman. Multiple lymph node biopsies were performed over the course of several months demonstrating persistent and anatomically diffuse involvement. Over 18 months, and without therapy, she has remained healthy, and her lymphadenopathy significantly improved. No bone marrow or peripheral blood involvement was ever identified. Atypical T cells showed an immunophenotypic spectrum of T-cell antigen expression with partial CD33 on a subset of T cells detected by both flow cytometry and immunohistochemistry. Both T-cell clonality and Human Androgen Receptor Assay (HUMARA) studies, performed on lymph node biopsy specimens, were negative. This case represents the first detailed clinical, morphologic, molecular, and immunophenotypic description of disseminated multinodal involvement by nonclonal iT-LBP with partial CD33 expression on T cells.

View details for DOI 10.1097/PAS.0000000000000197

View details for PubMedID 24618611

Current therapy and novel agents for relapsed or refractory acute lymphoblastic leukemia LEUKEMIA & LYMPHOMA Dinner, S., Lee, D., Liedtke, M. 2014; 55 (8): 1715-1724

Abstract

Despite high rates of complete remission in newly diagnosed adult acute lymphoblastic leukemia (ALL), rates of long-term leukemia-free survival are disappointingly low. Treatment of relapsed disease with chemotherapy, even in patients able to pursue consolidation with allogeneic stem cell transplant, has demonstrated limited success. There are no established standards of care in this setting and few standard treatment options. Novel agents targeting antigens on the lymphoblast cell surface offer unique side effect and anti-leukemic profiles which suggest that their use alone or in combination with chemotherapy may achieve improved outcomes for relapsed or refractory ALL.

View details for DOI 10.3109/10428194.2013.856428

View details for Web of Science ID 000340224100006

View details for PubMedID 24251864

ORAL INVESTIGATIONAL PROTEASOME INHIBITOR IXAZOMIB CITRATE (MLN9708) PLUS LENALIDOMIDE-DEXAMETHASONE IN ELDERLY PATIENTS (PTS) WITH PREVIOUSLY UNTREATED MULTIPLE MYELOMA Richardson, P. G., Rosenbaum, C. A., Hofmeister, C. C., Htut, M., Vesole, D. H., Berdeja, J. G., Liedtke, M., Chari, A., Smith, S. D., Lebovic, D., Berg, D., Liao, E., Tejura, B., Hui, A. M., Baz, R. FERRATA STORTI FOUNDATION. 2014: 106
Effects of serum and plasma matrices on multiplex immunoassays. Immunologic research Rosenberg-Hasson, Y., Hansmann, L., Liedtke, M., Herschmann, I., Maecker, H. T. 2014; 58 (2-3): 224-233

Abstract

Multiplexed fluorescence or electrochemiluminescence immunoassays of soluble cytokines are commonly performed in the context of human serum or plasma, to look for disease biomarkers and to monitor the immune system in a simple and minimally invasive way. These assays provide challenges due to the complexities of the matrix (serum or plasma) and the presence of many cytokines near the limit of detection of the assay. Here, we compare the readout of matched serum and plasma samples, which are generally correlated. However, a subset of cytokines usually have higher levels in serum, and the non-specific background is significantly increased in serum versus plasma. Presumably as a result of this non-specific background, disease-related decreases in low-abundance cytokines can sometimes be detected in plasma but not in serum. We further show, through spike recovery experiments, that both serum and plasma inhibit the readout of many cytokines, with some variability between donors, but with serum causing greater inhibition than plasma in many cases. Standard diluents from different vendors can partially reverse this inhibition to varying degrees. Dilution of samples can also partly overcome the inhibitory effect of the matrix. We also show that dilution is nonlinear and differentially affects various cytokines. Together, these data argue that (1) plasma is a more sensitive matrix for detecting changes in certain low-abundance cytokines; (2) calculation of concentrations in serum or plasma matrices is inherently inaccurate; and (3) dilution of samples should not be assumed to be linear, i.e., all comparisons need to be made among similarly diluted samples.

View details for DOI 10.1007/s12026-014-8491-6

View details for PubMedID 24522699

Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

View details for DOI 10.1016/j.hrthm.2013.10.026

View details for Web of Science ID 000329119200027

View details for PubMedID 24121001

A single-center experience of the nationwide daunorubicin shortage: substitution with doxorubicin in adult acute lymphoblastic leukemia. Leukemia & lymphoma Patel, S., Liedtke, M., Ngo, D., Medeiros, B. C. 2013; 54 (10): 2231-2235

Abstract

Due to a national shortage of daunorubicin we evaluated the effects of substituting doxorubicin 1:1 in the induction phase for adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). We identified 10 patients receiving doxorubicin instead of daunorubicin as part of their induction on Cancer and Leukemia Group B (CALGB) 9511 or CALGB10403 and retrospectively compared them to 83 patients who received treatment on the same protocols with daunorubicin. Response rates were similar, independent of anthracycline received, with either CALGB9511 or CALGB10403. In either regimen, doxorubicin resulted in longer absolute neutrophil count (ANC) recovery time and hospitalization. Doxorubicin as part of CALGB9511 resulted in greater than three-fold higher mucositis. Sepsis and death during induction were significantly more frequent in patients who received doxorubicin on CALGB10403. While remission rates were similar, the use of doxorubicin was associated with prolonged neutropenia, higher risk of mucositis, infection and sepsis, and prolonged hospitalization. Higher induction mortality observed with doxorubicin substitution in this analysis needs further study.

View details for DOI 10.3109/10428194.2013.772606

View details for PubMedID 23383599

Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

Abstract

Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

View details for DOI 10.3324/haematol.2013.084574

View details for PubMedID 23716538

AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Penchala, S. C., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H., Liedtke, M., Witteles, R. M., Powers, E. T., Reixach, N., Chan, W. K., Wilson, I. A., Kelly, J. W., Graef, I. A., Alhamadsheh, M. M. 2013; 110 (24): 9992-9997

Abstract

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

View details for DOI 10.1073/pnas.1300761110

View details for Web of Science ID 000320930100085

View details for PubMedID 23716704

The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

Abstract

The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

View details for DOI 10.1111/bjh.12269

View details for Web of Science ID 000317602300009

View details for PubMedID 23432783

Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

Abstract

There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

View details for DOI 10.3324/haematol.2012.076414

View details for PubMedID 23242596

View details for PubMedCentralID PMC3659990

Multiple Myeloma, Version 1.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Cohen, A. D., Devine, S., Djulbegovic, B., Faber, E. A., Gasparetto, C., Hernandez-Illizaliturri, F., Huff, C. A., Kassim, A., Krishnan, A. Y., Liedtke, M., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Yunus, F., Shead, D. A., Kumar, R. 2013; 11 (1): 11-17

Abstract

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

View details for Web of Science ID 000313575200004

Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012
Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012
Azacitidine Plus Lenalidomide for Untreated AML Patients Ineligible for Conventional Chemotherapy Pollyea, D. A., Zehnder, J. L., Coutre, S., Gotlib, J., Gallegos, L., Greenberg, P., Zhang, B., Liedtke, M., Levine, R. L., Medeiros, B. C. AMER SOC HEMATOLOGY. 2012
Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia AMERICAN JOURNAL OF HEMATOLOGY Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A., Bates, J., Sekeres, M. A., Coutre, S., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. 2012; 87 (10): 957-960

Abstract

We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC 350 cells/L at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/L (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC 350 cells/L on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/L (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/L vs. 350 cells/L, P .0004 for OS and EFS) along with WBC at diagnosis (6.0 or >30.0 K/L vs. >6.0-30.0 K/L, P 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

View details for DOI 10.1002/ajh.23279

View details for Web of Science ID 000309065700081

View details for PubMedID 22729847

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

Abstract

Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

View details for DOI 10.1038/leu.2011.294

View details for Web of Science ID 000303883500005

View details for PubMedID 22033493

More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

View details for Web of Science ID 000305415100012

View details for PubMedID 22652951

Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

Abstract

Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

View details for DOI 10.1016/j.healun.2011.09.010

View details for Web of Science ID 000300806500015

View details for PubMedID 22051505

Hemophagocytic lymphohistiocytosis in pregnancy: A case report and review of treatment options. Hematology (Amsterdam, Netherlands) Dunn, T., Cho, M., Medeiros, B., Logan, A., Ungewickell, A., Liedtke, M. 2012

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory disorder characterized by uncontrolled proliferation and activation of histiocytes with phagocytosis of normal hematopoietic cells. A 41-year-old woman, 19 weeks pregnant with twins, and a history of Still's disease, presented with rash, fever, and headache. Laboratory studies revealed transaminitis, hyperbilirubinemia, and eventually severe neutropenia as well as elevations in ferritin, lactate dehydrogenase, and C-reactive protein. A bone marrow biopsy confirmed HLH. She declined standard HLH-treatment but responded well to high-dose corticosteroids. Her blood counts remained stable following corticosteroid taper, and she delivered healthy twin girls at 30-week gestation. Few cases of HLH during pregnancy have been reported. In some cases, the condition has proved fatal. Therefore recognizing signs and symptoms of HLH is essential to avoid treatment delay. In our case, high-dose corticosteroids alone were a safe and effective therapy for the mother and fetuses resulting in long-term disease control.

View details for DOI 10.1179/1607845412Y.000000007

View details for PubMedID 22980356

The Transcription Factor Encyclopedia GENOME BIOLOGY Yusuf, D., Butland, S. L., Swanson, M. I., Bolotin, E., Ticoll, A., Cheung, W. A., Zhang, X. Y., Dickman, C. T., Fulton, D. L., Lim, J. S., Schnabl, J. M., Ramos, O. H., Vasseur-Cognet, M., de Leeuw, C. N., Simpson, E. M., Ryffel, G. U., Lam, E. W., Kist, R., Wilson, M. S., Marco-Ferreres, R., Brosens, J. J., Beccari, L. L., Bovolenta, P., Benayoun, B. A., Monteiro, L. J., Schwenen, H. D., Grontved, L., Wederell, E., Mandrup, S., Veitia, R. A., Chakravarthy, H., Hoodless, P. A., Mancarelli, M. M., Torbett, B. E., Banham, A. H., Reddy, S. P., Cullum, R. L., Liedtke, M., Tschan, M. P., Vaz, M., Rizzino, A., Zannini, M., Frietze, S., Farnham, P. J., Eijkelenboom, A., Brown, P. J., Laperriere, D., Leprince, D., de Cristofaro, T., Prince, K. L., Putker, M., del Peso, L., Camenisch, G., Wenger, R. H., Mikula, M., Rozendaal, M., Mader, S., Ostrowski, J., Rhodes, S. J., Van Rechem, C., Boulay, G., Olechnowicz, S. W., Breslin, M. B., Lan, M. S., Nanan, K. K., Wegner, M., Hou, J., Mullen, R. D., Colvin, S. C., Noy, P. J., Webb, C. F., Witek, M. E., Ferrell, S., Daniel, J. M., Park, J., Waldman, S. A., Peet, D. J., Taggart, M., Jayaraman, P., Karrich, J. J., Blom, B., Vesuna, F., O'Geen, H., Sun, Y., Gronostajski, R. M., Woodcroft, M. W., Hough, M. R., Chen, E., Europe-Finner, G. N., Karolczak-Bayatti, M., Bailey, J., Hankinson, O., Raman, V., LeBrun, D. P., Biswal, S., Harvey, C. J., DeBruyne, J. P., Hogenesch, J. B., Hevner, R. F., Heligon, C., Luo, X. M., Blank, M. C., Millen, K. J., Sharlin, D. S., Forrest, D., Dahlman-Wright, K., Zhao, C., Mishima, Y., Sinha, S., Chakrabarti, R., Portales-Casamar, E., Sladek, F. M., Bradley, P. H., Wasserman, W. W. 2012; 13 (3)

Abstract

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

View details for DOI 10.1186/gb-2012-13-3-r24

View details for Web of Science ID 000308544200009

View details for PubMedID 22458515

View details for PubMedCentralID PMC3439975

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

Abstract

This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

View details for DOI 10.3324/haematol.2011.045997

View details for Web of Science ID 000299870500009

View details for PubMedID 21993685

View details for PubMedCentralID PMC3248928

Absolute Lymphocyte Count At Day 28 Independently Predicts Event-Free and Overall Survival in Adults with Newly Diagnosed Acute Lymphocytic Leukemia Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A. A., Bates, J., Sekeres, M. A., Coutre, S. E., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. AMER SOC HEMATOLOGY. 2011: 1095
Cardiac Amyloidosis: Screening Criteria for Heart Transplantation and New Strategies for Post-Transplant Therapy 15th Annual Scientific Meeting of the Heart-Failure-Society-of-America Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2011: S45S46
Sequential azacitidine and lenalidomide in elderly acute myeloid leukemia: completed results of the phase I study Pollyea, D. A., Kohrt, H. E., Gallegos, L., Zhang, B., Figueroa, M., Melnick, A., Berube, C., Coutre, S. E., Gotlib, J. R., Zehnder, J. L., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC CLINICAL ONCOLOGY. 2011
A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML) 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Pollyea, D. A., Kohrt, H. E., Gallegos, L., Berube, C., Coutre, S., Gotlib, J., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 134747
AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions. Witteles, W., Witteles, R., Liedtke, M., Arai, S., Lafayette, R., George, T. I., Schrier, S. L. AMER SOC HEMATOLOGY. 2010: 1649
Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Medeiros, B. C., Kohrt, H. E., Rajwanshi, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Zhang, M., Arber, D. A., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 135758
Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

Abstract

The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

View details for DOI 10.1002/ajh.21857

View details for Web of Science ID 000283568200010

View details for PubMedID 20872554

Plasma cell leukemia: concepts and management. Expert review of hematology Liedtke, M., Medeiros, B. C. 2010; 3 (5): 543-549

Abstract

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia. Patients with PCL have a very poor prognosis with median survival measured in months. PCL can present de novo or following a prodrome of plasma cell myeloma. Patients with PCL tend to present with aggressive clinical features, such as extramedullary disease, bone marrow failure, advanced stage disease and expression of distinct immunophenotypic markers, such as lack of CD56 and presence of CD20. Historically, the treatment of PCL has primarily been palliative, with only a small minority of patients achieving a durable remission. The impact of newer agents, such as bortezomib and lenalidomide, in conjunction with autologous and allogeneic stem cell transplantation is uncertain, but emerging data suggest that use of these modalities may help improve the poor prognosis of patients with PCL.

View details for DOI 10.1586/ehm.10.52

View details for PubMedID 21083471

Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6 BLOOD Liedtke, M., Ayton, P. M., Somervaille, T. C., Smith, K. S., Cleary, M. L. 2010; 116 (1): 63-70

Abstract

MLL is a common target for chromosomal translocations associated with acute leukemia resulting in its fusion with a large variety of nuclear or cytoplasmic proteins that may activate its oncogenic properties by distinct but poorly understood mechanisms. The MLL-AF6 fusion gene represents the most common leukemogenic fusion of mixed lineage leukemia (MLL) to a cytoplasmic partner protein. Here, we identified a highly conserved Ras association (RA1) domain at the amino-terminus of AF6 as the minimal region sufficient for MLL-AF6 mediated myeloid progenitor immortalization in vitro and short latency leukemogenesis in vivo. Moreover, the ability of RA1 to activate MLL oncogenesis is conserved with its Drosophila ortholog, Canoe. Although the AF6 RA1 domain has previously been defined as an interaction surface for guanosine triphosphate-bound Ras, single amino acid substitutions known to abolish the AF6-Ras interaction did not abrogate MLL-AF6-mediated oncogenesis. Furthermore, fusion of MLL to heterologous RA domains of c-Raf1 or RalGDS, or direct fusion of MLL to constitutively active K-RAS, H-RAS, or RAP1 was not sufficient for oncogenic activation of MLL. Rather, the AF6 RA1 domain efficiently mediated self-association, suggesting that constitutive MLL self-association is a more common pathogenic mechanism for MLL oncogenesis than indicated by previous studies of rare MLL fusion partners.

View details for DOI 10.1182/blood-2009-09-243386

View details for Web of Science ID 000279641400012

View details for PubMedID 20395419

View details for PubMedCentralID PMC2904581

An early-phase study of azacitidine and lenalidomide for untreated elderly acute myeloid leukemia (AML) patients Pollyea, D. A., Kohrt, H. E., Rajwanshi, R., Gallegos, L., Berube, C., Coutre, S. E., Gotlib, J. R., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC CLINICAL ONCOLOGY. 2010
Therapeutic targeting of MLL BLOOD Liedtke, M., Cleary, M. L. 2009; 113 (24): 6061-6068

Abstract

Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.

View details for DOI 10.1182/blood-2008-12-197061

View details for Web of Science ID 000267147100009

View details for PubMedID 19289854

View details for PubMedCentralID PMC2699228

Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma LEUKEMIA & LYMPHOMA Kohrt, H., Logan, A., Temmins, C., Witteles, R., Liedtke, M., Medeiros, B. 2008; 49 (3): 581-585

View details for DOI 10.1080/10428190701861702

View details for Web of Science ID 000253513300029

View details for PubMedID 18297538

Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population ANNALS OF ONCOLOGY Liedtke, M., Hamlin, P. A., Moskowitz, C. H., Zelenetz, A. D. 2006; 17 (6): 909-913

Abstract

Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment.One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms.Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13).These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.

View details for DOI 10.1093/annonc/mdl049

View details for Web of Science ID 000237696000005

View details for PubMedID 16672295

Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase ONCOGENE Liedtke, M., Pandey, P., Kumar, S., KHARBANDA, S., Kufe, D. 1998; 17 (15): 1889-1892

Abstract

The oncogenic Bcr-Abl variant of the c-Abl tyrosine kinase transforms cells by a mechanism dependent on activation of the stress-activated protein kinase (SAPK). Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress. The present studies demonstrate that Bcr-Abl binds constitutively to SHPTP1. We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites. The functional significance of the Bcr-Abl/SHPTP1 interaction is supported by the finding that SHPTP1 regulates Bcr-Abl-induced SAPK activity. Importantly, SHPTP1 also decreases Bcr-Abl-dependent transformation of fibroblasts. These findings indicate that SHPTP1 functions as a tumor suppressor in cells transformed by Bcr-Abl.

View details for Web of Science ID 000076423500001

View details for PubMedID 9788431

A SITE-DIRECTED MUTAGENESIS STUDY TO IDENTIFY AMINO-ACID-RESIDUES INVOLVED IN THE CATALYTIC FUNCTION OF THE RESTRICTION ENDONUCLEASE ECORV BIOCHEMISTRY SELENT, U., RUTER, T., Kohler, E., Liedtke, M., THIELKING, V., Alves, J., Oelgeschlager, T., Wolfes, H., Peters, F., Pingoud, A. 1992; 31 (20): 4808-4815

Abstract

We have used site-directed mutagenesis of the EcoRV restriction endonuclease to change amino acid side chains that have been shown crystallographically to be in close proximity to the scissile phosphodiester bond of the DNA substrate. DNA cleavage assays of the resulting mutant proteins indicate that the largest effects on nucleolytic activity result from substitution of Asp74, Asp90, and Lys92. We suggest on the basis of structural information, mutagenesis data, and analogies with other nucleases that Asp74 and Asp90 might be involved in Mg2+ binding and/or catalysis and that Lys92 probably stabilizes the pentacovalent phosphorus in the transition state. These amino acids are part of a sequence motif, Pro-Asp...Asp/Glu-X-Lys, which is also present in EcoRI. In both enzymes, it is located in a structurally similar context near the scissile phosphodiester bond. A preliminary mutational analysis with EcoRI indicates that this sequence motif is of similar functional importance for EcoRI and EcoRV. On the basis of these results, a proposal is made for the mechanism of DNA cleavage by EcoRV and EcoRI.

View details for Web of Science ID A1992HW13800010

View details for PubMedID 1591242