Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.

Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

c-MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide-dexamethasone in myeloma.

OBJECTIVES: In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT). METHODS: RNA sequencing data were used to investigate the basis of these differences. RESULTS: The PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81. CONCLUSIONS: PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.

Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy. METHODS: QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline. FINDINGS: Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related. INTERPRETATION: We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations. FUNDING: Tesaro.

Real-World Treatment Patterns, Outcomes, and Healthcare Resource Utilization in Relapsed or Refractory Multiple Myeloma: Evidence from a Medical Record Review in France.

BACKGROUND: Limited data are available from real-world practices in Europe describing prevailing treatment patterns and outcomes in relapsed/refractory multiple myeloma (RRMM), particularly by cytogenetic risk. METHODS: A retrospective medical record review was conducted in 200 RRMM patients in France. From first relapse, patients were assessed on second-/third-line treatments, progression-free survival (PFS), overall survival (OS), and healthcare utilization. RESULTS: Fifty-five high risk and 113 standard risk patients were identified. Overall, 192 patients (96%) received second-line therapy after relapse. Lenalidomide-based regimens were most common (>50%) in second line. Hospitalization incidence in high risk patients was approximately twice that of standard risk patients. From Kaplan-Meier estimation, median (95% CI) second-line PFS was 21.4 (17.5, 25.0) months (by high versus standard risk: 10.6 [6.4, 17.0] versus 28.7 [22.1, 37.3] months). Among second-line recipients, 47.4% were deceased at data collection. Median second-line OS was 59.4 (38.8, NE) months (by high versus standard risk: 36.5 [17.4, 50.6] versus 73.6 [66.5, NE] months). CONCLUSIONS: The prognostic importance of cytogenetic risk in RRMM was apparent, whereby high (versus standard) risk patients had decidedly shorter PFS and OS. Frequent hospitalizations indicated potentially high costs associated with RRMM, particularly for high risk patients. These findings may inform economic evaluations of RRMM therapies.

Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting.

Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent-based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients' treatment approaches.

Prolonged Duration of Therapy Is Associated With Improved Survival in Patients Treated for Relapsed/Refractory Multiple Myeloma in Routine Clinical Care in the United States.

BACKGROUND: In clinical trials, an extended therapy duration has been associated with better outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, data on how the therapy duration affects the outcomes for patients with relapsed/refractory multiple myeloma (RRMM) are limited. We conducted a large, retrospective study in the United States to evaluate the effect of the duration of second-line therapy on overall survival. PATIENTS AND METHODS: Adults with NDMM from January 2008 to June 2015 were followed up to identify their second-line therapy. The duration of therapy (DOT) and time to next therapy (TTNT), as a proxy for progression-free survival, were estimated using the Kaplan-Meier method. The relationship between the duration of second-line therapy and overall survival was evaluated with a logistic marginal structural model to mitigate the risk of treatment selection and survival bias. RESULTS: A total of 628 NDMM patients developed a relapse after initial therapy. The median DOT for second-line therapy was 6.9 months (95% confidence interval [CI], 5.9-7.7 months), which was shorter than the corresponding TTNT (median, 15.1 months; 95% CI, 13.4-17.3 months). Each additional month of second-line therapy was associated with a reduced adjusted risk of death at 1 year (odds ratio, 0.78; 95% CI, 0.77-0.83; P < .001). CONCLUSION: In a large database capturing a heterogeneous patient population and varied treatment patterns reflecting routine clinical care, we found a clinical benefit for continued longer DOT at first relapse. Despite the emerging paradigm favoring continuous therapy, second-line progression-free survival (utilizing TTNT as the proxy) was more than twofold longer than the DOT. Understanding the barriers to extended DOT could help to improve the outcomes for RRMM patients.

Treatment patterns and health care resource utilization among patients with relapsed/refractory systemic light chain amyloidosis.

BACKGROUND: Treatment for patients with systemic light chain (AL) amyloidosis remains challenging. Our study aims to describe treatment patterns for both newly diagnosed and relapsed/refractory AL (RRAL) amyloidosis, and to assess clinical outcomes, healthcare costs, and resource utilization during the first year following a diagnosis of RRAL amyloidsis. METHODS: This was a retrospective observational study of adult patients with AL amyloidosis using the US Optum administrative claims data during 1/1/2008 to 6/30/2015. Diagnosis was based on both ICD-9 codes and treatments with a claim for AL-amyloidosis-specific anticancer systemic agents. RESULTS: Of 334 patients with AL amyloidosis, 43.1% were considered as RRAL amyloidosis. The majority (75%) of RRAL amyloidosis patients had organ involvement prior to the second line treatment. Proteasome-inhibitor-based regimens were most frequently used (41.0% for first-line AL, 30.6% for RRAL amyloidosis). Organ deterioration and mortality rates were 49.3% and 10.4%, respectively, during the two years following relapse. The average monthly cost was $14,369 per patient for RRAL amyloidosis including medical costs ($9441) and drug costs ($4928). CONCLUSIONS: RRAL amyloidosis is associated with high morbidity from target organ failure and mortality, which emphasizes the need for novel medications to improve care for patients with RRAL amyloidosis.

A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia.

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25-50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.

The impact of age and comorbidities on practice patterns and outcomes in patients with relapsed/refractory multiple myeloma in the era of novel therapies.

OBJECTIVES: One-third of patients with multiple myeloma (MM) are diagnosed at age≥75years. Older patients have increased incidence of cardiovascular disease (CVD) and renal insufficiency (RI), hallmark complications of MM. We examined cumulative incidence of CVD and RI in relapsed/refractory MM (RRMM) and outcomes by age and RI/CVD. MATERIALS AND METHODS: Retrospective cohort study using a large US electronic medical records database of adult patients with RRMM initiating first- and second-line therapy (2LT) between 1/2008-06/2015. RI and CVD comorbidities were based on diagnosis codes and/or lab values. RESULTS: Among 628 patients, 37.1% were ≥75years. Cumulative incidence of CVD and/or RI increased from 47.7% at MM diagnosis to 67.8% at first relapse. Age≥75years had a trend toward higher risk of relapse post 2LT, proxied by time to next treatment (TTNT), (adjusted HR: 1.28; 95% CI: 1.00, 1.65; P=0.05). TTNT was significantly higher with comorbid CVD+RI (adjusted HR: 1.50; 95% CI: 1.11, 2.02; P<0.01). Age≥75years, RI, CVD, and CVD+RI were associated with increased mortality risk from 2LT initiation; adjusted HR: 1.66 (95% CI: 1.19, 2.33; P<0.01), 1.51 (95% CI: 1.01, 2.26; P=0.04), 1.75 (95% CI: 1.03, 2.96; P=0.04), and 1.95 (95% CI: 1.29, 2.93; P<0.01), respectively. CONCLUSION: Despite treatment with novel agents for RRMM in 86% of patients, an outcome gap persists for older patients and those with RI and/or CVD. Personalized treatment approaches that account for age and comorbidities, and further evaluation of innovative regimens and dosing schedules, are needed to improve outcomes for these patients.

Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1.

Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK-STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies.

Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions.

We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse.

Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL.

Yttrium-90 ibritumomab tiuxetan followed by rituximab maintenance as treatment for patients with diffuse large B-cell lymphoma are not candidates for autologous stem cell transplant.

BACKGROUND: Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. (90)Y ibritumomab tiuxetan ((90)Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. METHODS: This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with (90)Y-IT (0.4 or 0.3 mCi (90)Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. RESULTS: 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. CONCLUSION: The ORR of 36% with (90)Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.

Immune therapy in multiple myeloma.

Although the advent of biologic therapies has resulted in improved outcomes for patients with multiple myeloma (MM), patients ultimately develop progressively resistant disease. As such, novel approaches are needed. There has been a renewed focus on the development of therapies that would allow redirection of patients' own immune systems to target malignant myeloma cells. Compared with healthy individuals, patients with MM exhibit immune dysregulation and an impaired capacity to develop antitumor immunity. Tumor cells induce tolerance by exploiting native immune pathways responsible for preventing autoimmunity and maintaining immunologic equilibrium. In this review, we will discuss the development of potent humoral and cellular agents directed against myeloma antigens, including novel monoclonal antibodies, myeloma vaccines, and T-cell therapies. We will also discuss the development of immune checkpoint inhibitors and immunomodulatory agents that allow manipulation of the immunologic milieu and support a more robust native immune response. There is a growing interest in combining these 2 approaches-such as pairing antimyeloma vaccines with immune checkpoint blockade-to achieve maximum efficacy of immunotherapy.

Primary cardiac burkitt lymphoma presenting with abdominal pain.

We describe the case of a 44-year-old woman with primary Burkitt lymphoma of the heart who presented with abdominal bloating and epigastric discomfort secondary to tamponade physiology caused by a large pericardial effusion. The pericardial fluid contained a large number of highly atypical lymphocytes with moderate basophilic cytoplasm, rare punched-out vacuoles, a vesicular nuclear chromatin, large nucleolus, and marginated chromatin that by FISH were positive for the 8;14 translocation. She had no other sites of disease. She was treated with four alternating cycles of modified CODOX-M and IVAC in combination with rituximab and remains in remission more than 5 years since diagnosis.

A 78-year-old man with acute myeloid leukemia (AML) and acute renal failure.

PATIENT: Male, 78. FINAL DIAGNOSIS: Acute myeloid leukemia (AML). SYMPTOMS: Dyspnea • fatigue. MEDICATION: Idarubicin followed by cytarabine. CLINICAL PROCEDURE: Chemotherapy. SPECIALTY: Hematology. OBJECTIVE: Unusual clinical course. BACKGROUND: Renal failure is a common presentation of acute myelomonocytic and monocytic leukemia. It is usually the result of a combined glomerular and tubular dysfunction and is associated with a poor prognosis. No guidelines exist for treatment. CASE REPORT: We herein describe the case of a 78-year-old Caucasian man who presented with acute myeloid leukemia M5, leukostasis with a white count of 340 000/ml, and acute renal failure with a creatinine of 7.7/dL. The patient was initially treated with leukapheresis and 3 days of idarubicin in the setting of continuous renal replacement therapy that resulted in rapid reversal of his renal failure. He then received 7 days of continuous infusion cytarabine and went into a complete remission. CONCLUSIONS: Renal failure may complicate the presentation of AML but can be reversible with treatment. Dose adjustment of the chemotherapy is not needed and the treatment can be greatly facilitated with the use of continuous renal replacement therapy, as indicated in our case report. In addition, we emphasize that organ dysfunction, even in elderly patients, is not necessarily a contraindication to aggressive treatment if it is felt to be disease-related and reversible.

MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34(+)/lineage(-)/CD38(-) cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34(+) populations as similar results were obtained with leukemic cells from patients with CD34(-) disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1(high)) led to development of leukemia in NOD-SCID IL2Rgamma(null) (NSG) immunodeficient mice. In contrast, MUC1(low) cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication.

Lenalidomide enhances anti-myeloma cellular immunity.

Lenalidomide is an effective therapeutic agent for multiple myeloma that exhibits immunomodulatory properties including the activation of T and NK cells. The use of lenalidomide to reverse tumor-mediated immune suppression and amplify myeloma-specific immunity is currently being explored. In the present study, we examined the effect of lenalidomide on T-cell activation and its ability to amplify responses to a dendritic cell-based myeloma vaccine. We demonstrate that exposure to lenalidomide in the context of T-cell expansion with direct ligation of CD3/CD28 complex results in polarization toward a Th1 phenotype characterized by increased IFN-γ, but not IL-10 expression. In vitro exposure to lenalidomide resulted in decreased levels of regulatory T cells and a decrease in T-cell expression of the inhibitory marker, PD-1. Lenalidomide also enhanced T-cell proliferative responses to allogeneic DCs. Most significantly, lenalidomide treatment potentiated responses to the dendritic cell/myeloma fusion vaccine, which were characterized by increased production of inflammatory cytokines and increased cytotoxic lymphocyte-mediated lysis of autologous myeloma targets. These findings indicate that lenalidomide enhances the immunologic milieu in patients with myeloma by promoting T-cell proliferation and suppressing inhibitory factors, and thereby augmenting responses to a myeloma-specific tumor vaccine.