Judith E Karp

Johns Hopkins Medicine | JHUSOM · Division of Hematologic Malignancies

Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prio...

Background: Acute myeloid leukemia (AML) has been considered an oncologic emergency that requires initiation of chemotherapy immediately after diagnosis. With the introduction of novel targeted therapies, there is a potential benefit associated with delaying definitive treatment for identification of actionable therapeutic targets. Unfortunately,...

The natural history of patients with myelodysplastic syndrome (MDS) is dependent upon the presence and magnitude of diverse genetic and molecular aberrations. The International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R) are the most widely used classification and prognostic systems; however, somatic mutations are not currently incor...

Purpose Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a com...

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment‐related complications, as well as short‐term mortality and overall surviva...

PURPOSE Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The pur...

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by clonal proliferation of neoplastic immature precursor cells. AML impacts older adults and has a poor prognosis. Despite recent advances in treatment, AML is complex, with both genetic and epigenetic aberrations in the malignant clone and elaborate interactions with its microe...

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapeutic modality for patients with acute myelogenous leukemia (AML) with poor risk features. Nonetheless, roughly 30% of such patients have leukemia recurrence and up to 2% of these are donor-derived leukemias, in which malignancy develops in the donor’s transplanted cell...

Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acut...

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation...

Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particu...

FLT3-ITD mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant was...

Purpose Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments o...

Introduction: Adults with AML have immune aberrations leading to immune suppression, exhaustion, evasion, and senescence. Early lymphocyte recovery (ELR) after induction TST is dominated by an expansion of oligoclonal peripherally derived regulatory T cells (Tregs). Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), leads to the se...

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re‐induction chemotherapy. They were randomized to the following regimens: carboplatin‐topotecan (CT), each by continuo...

Background: Our understanding of phenotypic and functional signatures of CD8+ T cell dysfunction in acute myeloid leukemia (AML) is limited. Deciphering these deranged T cell functional states and how they are impacted by induction chemotherapy is essential for incorporation of novel immune-based strategies to restore and maintain antileukemia imm...

We have initially demonstrated in knocking down experiments that decreasing TCTP in cancer cells leads in some tissues to cell death while in others to a complete reorganization of the tumor into architectural structures reminiscent of normal ones. Based on these experiments and a series of other findings confirming the key role of TCTP in cancer,...

Purpose: Cytosine arabinoside (AraC) remains the backbone of most treatment regimens for acute myeloid leukemia (AML). Incorporation of AraC into DNA activates checkpoint kinase 1 (Chk1), leading to cell-cycle arrest and diminished AraC cytotoxicity, which can be reversed by the selective Chk1 inhibitor MK-8776. Building on a Phase I trial, we con...

Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004-2013 with cytarabine, anth...

Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure-response analysis to inform the phase II trial design. Experimental Design: Pharmacokinetic, efficacy and safety data from 95 patients,...

Metabolism of neoplastic cells is shifted toward high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which is comprised of two major subunits, LDH-A and LDH-B, reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. LDH-A has a higher affinity for pyruvate and is a key enzyme in the glycolyti...

Purpose: To elucidate any differences in the exposure-response of alvocidib (flavopiridol) given by 1 hour bolus or a hybrid schedule (30 minute bolus followed by a 4 hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in acute leukemia patients. The hybrid schedule was devised to be pharmacologically s...

Aims: Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukemia, and compare veliparib concentration in various...

Background: T cell dysfunction in Acute Myeloid Leukemia (AML) remains poorly understood. So far, studies on AML T cell dysfunction have focused on phenotypically characterizing immune expression patterns. T cell transcriptional signatures, however, are widely unexplored. Deciphering those transcriptional signatures is critically important for opti...

Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation...

Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation...

Background: T cell dysfunction in AML remains poorly understood. Our previous studies of AML-associated T cell dysfunction (Knaus, ASH 2015) have focused on expression of multiple inhibitory receptors by T cells in AML patients. Transcriptional signatures, however, remain relatively unexplored, as does the role of Blast/T cell interactions on T cel...

Significance: Despite the fact that malignant hematopoietic stem and progenitor cells play critical roles in the initiation, maintenance, and progression of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), information about the effects of investigational chemotherapeutic agents on these cells is limited. Using the Nedd8-activat...

Poster presentation from the 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer.

Background: T-cell dysfunction in AML remains poorly understood. Therefore, we aimed to genotypically, phenotypically and functionally characterize T-cells of AML patients before and after induction-chemotherapy. Methods: To study transcriptional signatures, FACS-purified peripheral blood (PB) CD8+T-cells from 6 patients [3 responders (R) and 3 non...

Purpose: The poly(ADP-ribose) polymerase (PARP) inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin ba...

Purpose: In preclinical studies the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arisin...

Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we eval...

Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPNs). Inhibitors of poly(ADP-ribose) polymerase (PARP) have shown activity in solid tumors with defects in homologous recombination (HR). The present study was performed to assess MPN sensitivity to PARP inhibitors ex vivo. Experimental design: HR pathway...

Key Points Agents that inhibit both complexes containing the mammalian target of rapamycin are particularly toxic to acute lymphocytic leukemia cells. This killing reflects engagement of a 4EBP1/c-MYC/PUMA axis downstream of mTORC1 and an NF-κB/EGR1/BIM axis downstream of mTORC2.

The precise phenotype and biology of acute myeloid leukemia stem cells remain controversial, in part because the "gold standard" immunodeficient mouse engraftment assay fails in a significant fraction of patients and identifies multiple cell-types in others. We sought to analyze the clinical utility of a novel assay for putative leukemia stem cells...

The development of leukemia after chemotherapy and/or radiotherapy for breast cancer has been recognized for 4 decades. In this issue, Churpek et al have conducted a retrospective study that expands on a growing body of knowledge for understanding an individual's genetic risk, not only for breast cancer, but also for second cancers such as leukemia...

Background: Targeting specific immune inhibitory receptors (iRs) with monoclonal antibodies has led to paradigm-shifting treatment practices in a variety of solid cancers. These advances were in part driven by tremendous progress in phenotypic and functional characterization of altered iR expression patterns and memory T cell differentiation states...

Background: FLT3 ITD mutated acute myeloid leukemia remains a therapeutic challenge with very few patients experiencing prolonged disease free survival after standard therapies. FLT3 inhibitors have thus far demonstrated limited single agent activity in this disease. However, administration of FLT3 inhibitors during a state of minimal residual dise...

The mammalian target of rapamycin (mTOR), a kinase that regulates proliferation and apoptosis, has been extensively evaluated as a therapeutic target in hematologic malignancies. Rapamycin analogues, which partially inhibit mTOR complex 1 (mTORC1), showed limited anti-tumor activity due to feedback mechanisms involving mTORC2 and incomplete inhibit...

Background: Targeting specific immune inhibitory receptors (iRs) with monoclonal antibodies has led to paradigm-shifting treatment practices in a variety of solid cancers. These advances were in part driven by tremendous progress in phenotypic and functional characterization of altered iR expression patterns and memory T cell differentiation states...

Among mechanisms underlying cytotoxic drug resistance is activation of diverse DNA damage response (DDR) pathways. Poly(ADP-ribose) polymerases (PARP)-1/2 facilitate both single- and double-strand break (DSB) repair and play a key role in the base excision repair (BER) of chemotherapy-damaged DNA. The PARP inhibitor veliparib (V) potentiates the cy...

Background: We recently showed that early lymphocyte recovery (ELR) following intensive induction chemotherapy in AML patients (pts) is characterized by complex immune system aberrations. (Blood 117(2):608, 2011) Full characterization of lymphoid T cell dynamics during this period can provide critical insights into their dysfunction and rationale f...

Background: Cytosine arabinoside (ara-C) remains the backbone of most regimens for the treatment of AML. The incorporation of ara-C into DNA activates checkpoint kinase 1 (Chk1) causing replication fork slowing, the accumulation of cells in S phase, and diminished ara-C cytotoxicity. The selective Chk1 inhibitor MK-8776 abrogates ara-C-induced S-ph...

Background: Targeting specific immune inhibitory receptors (iRs) with monoclonal antibodies has led to paradigm-shifting treatment practices in a variety of solid cancers. These advances were in part driven by tremendous progress in phenotypic and functional characterization of altered iR expression patterns and memory T cell differentiation states...

Background: We recently showed that early lymphocyte recovery (ELR) following intensive induction chemotherapy in AML patients (pts) is characterized by complex immune system aberrations. Full characterization of lymphoid T cell dynamics during this period can provide critical insights into their dysfunction and rationale for targeted therapeutic i...

Background: Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time. Methods: A retrospective analysis was performed on 711 adult...

There have been minimal therapeutic advancements in acute myeloid leukemia (AML) over the past 4 decades and outcomes remain unsatisfactory. Alvocidib (formerly flavopiridol) is a multi-serine threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen,...

The goal of precision medicine is to personalize therapy based on individual patient variation, to correctly select the right treatment, for the right patient, at the right time. Acute myeloid leukemia (AML) is a heterogeneous collection of myeloid malignancies with diverse genetic etiology and the potential for intra-patient clonal evolution over...

Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage which reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protect...

Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoact...

Background: Cytarabine and an anthracycline, the mainstay of AML therapy, affords a five-year survival below 30%. Accordingly, there is a continuing need for improved AML therapies. CPX-351 encapsulates within liposomes a fixed 5:1 molar ratio of cytarabine and daunorubicin that is synergistic (in vitro) and markedly improved in anti-leukemic activ...

Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and...

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases...

Serial studies have demonstrated that induction therapy with FLAM (flavopiridol 50 mg/m2 days 1-3, cytarabine 667 mg/m2/day continuous infusion days 6-8, and mitoxantrone 40 mg/m2 day 9) yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid le...

The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the curren...

Outcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN). We examined the MN frequ...

Background: Intrinsic immune responses to acute myeloid leukemia (AML) are inhibited by a variety of mechanisms, such as T cell exhaustion, expansion of immunoregulatory cells and activation of inhibitory pathways. An in-depth understanding of the immune evasion mechanisms in patients with AML at diagnosis and following chemotherapy is essential fo...

Background: Intrinsic immune responses to acute myeloid leukemia (AML) are inhibited by a variety of mechanisms, such as T cell exhaustion, expansion of immunoregulatory cells and activation of inhibitory pathways. An in-depth understanding of the immune evasion mechanisms in patients with AML at diagnosis and following chemotherapy is essential fo...

MLN4924, a novel chemotherapeutic agent designed to inhibit the Nedd8 Activating Enzyme (NAE), has shown promise in early clinical testing in relapsed and refractory Acute Myeloid Leukemia (AML). NAE inhibition prevents transfer of the Nedd8 protein to Cullin Ring Ligases (CRLs), leading to their inactivation and subsequent accumulation of the prot...

Introduction: The therapy of relapsed/refractory AML remains poor and new treatment options are sorely needed. The Leukemia Committee of ECOG devised a randomized phase II trial of 3 novel regimens to determine overall response rates could be improved. Methods: Patients between the ages of 18 and 70 years with a prior diagnosis of AML who relapsed...

Introduction: There have been minimal therapeutic advancements in the management of acute myeloid leukemia (AML) over the past 3 decades. Although approximately 70% of younger AML patients will achieve a complete remission (CR) with standard induction chemotherapy regimens, overall outcomes are dismal. It is unclear why drug development has been pa...

Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains u...

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m2; days 1, 4) were given in combination...

Recent advances in molecular technology have unraveled the complexity of leukemogenesis and provided the opportunity to design more personalized and pathophysiology-targeted therapeutic strategies. Despite the use of intensive chemotherapy, relapse remains the most common cause for therapeutic failure in acute myelogenous leukemia (AML). The intera...

Recombinant human Tumor Necrosis Factor-α-related Apoptosis Inducing Ligand (TRAIL), agonistic monoclonal antibodies to TRAIL receptors, and small molecule TRAIL receptor agonists are in various stages of preclinical and early phase clinical testing as potential anticancer drugs. Accordingly, there is substantial interest in understanding factors t...

The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, ind...

In this issue of Blood, Lancet et al report their findings that CPX-351, a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio, produces superior response rates compared with 713 in older patients with acute myeloid leukemia (AML).

Candida kefyr is an emerging pathogen among patients with hematologic malignancies (HM). We performed a retrospective study at Johns Hopkins Hospital to evaluate the epidemiology of C. kefyr colonization and infection in HM patients between 2004 and 2010. Eighty-three patients were colonized and/or infected with C. kefyr, with 8 (9.6%) having invas...

Myeloproliferative neoplasms are a diverse group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform to a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel ribonucleotide reductase inhibitor of the M2 subunit. Sequential inhibition of ribonucleotide reductase with triapine an...

Patient-specific ex vivo drug sensitivity and resistance screening can identify rational drug candidates for the testing of personalized targeted therapy. An iterative approach of genomic and drug susceptibility characterization at sequential time points during clinical trials of targeted therapy in acute myeloid leukemia may be useful both for cha...

Introduction Adult patients (pts) diagnosed with acute lymphocytic leukemia (ALL) are known to have a poor clinical outcome as compared to children. Studies report a 2 year event free survival of 30-40% for Philadelphia chromosome negative (Ph-) patients age >30 yrs and 17% for age >50 yrs. In order to improve outcome for adult ALL, agents that are...

To improve outcome of acute myeloid leukemia, novel combinations targeting new molecular vulnerabilities are needed. We recently identified WEE1 kinase as a novel target in leukemias. To identify genes that are synthetically lethal with WEE1 inhibition, we performed a siRNA screen directed against cell cycle and DNA repair genes during concurrent t...

Although farnesyltransferase inhibitors have shown promising activity in relapsed lymphoma and sporadic activity in acute myelogenous leukemia, their mechanism of cytotoxicity is incompletely understood, making development of predictive biomarkers difficult. In the present study, we examined the action of tipifarnib in human acute myelogenous leuke...

This presentation aims at summarizing today's knowledge on tumor reversion (ref.1) with recent applications and new findings for potential cancer treatment. In order to study the molecular program of tumor reversion we have provided with a series of biological models. In this approach, we derived revertant cells from tumor cell lines ranging from l...

Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk stratification factors in acute myeloid leukaemia (AML). Unfortunately, similar progress has not been made in treatment response criteria, with the definition of 'complete remission' in A...

The CXCR4 chemokine receptor promotes survival of many different cell types. Here, we describe a previously unsuspected role for CXCR4 as a potent inducer of apoptosis in acute myeloid leukemia (AML) cell lines and a subset of clinical AML samples. We show that SDF-1, the sole ligand for CXCR4, induces the expected migration and ERK activation in t...

3104 Background: The ability to target myeloid malignancies using immunotherapy, without allogeneic transplantation, depends on the capability to target leukemic clones while sparing normal tissues. A variety of putative leukemia associated antigens (LAA) have been identified but an evidence-based list of targets for acute myeloid leukemia (AML) ha...

s: Thirty-Fifth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 4‐8, 2012; San Antonio, TX BACKGROUND: Cooperative group trials and institutional series reported the risk of MDS and/or AML after adjuvant chemotherapy for early stage breast cancer (eg, NSABP 0.21%, Smith JCO 2003; ECOG 2197 0.5%, Goldstein ASCO 2012). We examined the inc...