Javier Munoz

Erdheim-Chester disease: Characteristics and management

Erdheim-Chester disease is a rare CD68(+), CD1a(-) non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-α, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease.

Concise Review: Umbilical Cord Blood Transplantation: Past, Present, and Future

Allogeneic hematopoietic stem cell transplantation is an important treatment option for fit patients with poor‐risk hematological malignancies; nevertheless, the lack of available fully matched donors limits the extent of its use. Umbilical cord blood has emerged as an effective alternate source of hematopoietic stem cell support. Transplantation with cord blood allows for faster availability of frozen sample and avoids invasive procedures for donors. In addition, this procedure has demonstrated reduced relapse rates and similar overall survival when compared with unrelated allogeneic hematopoietic stem cell transplantation. The limited dose of CD34‐positive stem cells available with single‐unit cord transplantation has been addressed by the development of double‐unit cord transplantation. In combination with improved conditioning regimens, double‐unit cord transplantation has allowed for the treatment of larger children, as well as adult patients with hematological malignancies. Current excitement in the field revolves around the development of safer techniques to improve homing, engraftment, and immune reconstitution after cord blood transplantation. Here the authors review the past, present, and future of cord transplantation.

STAT3 Inhibitors: Finding a Home in Lymphoma and Leukemia

The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is an active mediator of cytokine signaling in the pathogenesis of solid and hematologic malignancies. The seven-member STAT family is composed of latent cytoplasmic transcription factors that are activated by phosphorylation intertwined in a network with activation that ultimately leads to cell proliferation. An activated kinase enzyme phosphorylates one STAT factor or more, which shuttle to the nucleus to regulate gene expression, promoting cell survival. Somatic STAT3 mutations have been recently reported in large granular lymphocytic leukemia, aplastic anemia, and myelodysplastic syndrome. Furthermore, the relationship between BCL6 and STAT3 in diffuse large B-cell lymphomas, particularly on the activated B-cell subtype, needs to be further explored. The search for therapeutic STAT3 inhibitors that abrogate the JAK/STAT pathway is currently under way. Targeting the STAT pathway, which seems to be critical in tumorigenesis, is promising for multiple malignancies including lymphoma and leukemia. In this paper, we review mechanisms of action, failures, and successes of STAT3 inhibitors.

Molecular profiling and the reclassification of cancer: divide and conquer.

Cancer is one of the leading causes of mortality in the world. Choosing the best treatment is dependent on making the right diagnosis. The diagnostic process has been based on light microscopy and the identification of the organ of tumor origin. Yet we now know that cancer is driven by molecular processes, and that these do not necessarily segregate by organ of origin. Fortunately, revolutionary changes in technology have enabled rapid genomic profiling. It is now apparent that neoplasms classified uniformly (e.g., non-small cell lung cancer) are actually comprised of up to 100 different molecular entities. For instance, tumors bearing ALK alterations make up about 4% of non-small cell lung cancers, and tumors bearing epidermal growth factor receptor (EGFR) mutations, approximately 5% to 10%. Importantly, matching patients to therapies targeted against their driver molecular aberrations has resulted in remarkable response rates. There is now a wealth of evidence supporting a divide-and-conquer strategy. Herein, we provide a concise primer on the current state-of-the-art of molecular profiling in the cancer clinic.

Genomically Driven Tumors and Actionability across Histologies: BRAF-Mutant Cancers as a Paradigm

The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-of-origin cancers (e.g., non–small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer—one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533–47. ©2016 AACR.

A Tale of Two Histiocytic Disorders

Histiocytosis is a group of rare disorders of unknown etiology characterized by proliferation and accumulation of histiocytes [1]. Histiocytosis is subclassified as Langerhans cell histiocytosis (LCH) and non-LCH. Non-LCH includes Rosai-Dorfman disease, Erdheim-Chester disease (ECD), interdigitating dendritic cell sarcoma, and histiocytic sarcomas [2]. Both LCH and ECD are caused by accumulation and proliferation of histiocytic cells, but each entity has distinct clinical and pathological features, although rarely both diseases can coexist [3, 4]. LCH is associated with accumulation of dendritic cells and typically presents in children, but less often in adults, with an incidence of nine cases per million per year. ECD is a disease of adults, which is associated with xanthogranulomatous infiltration of foamy macrophages. Only about 500 cases have been reported in the literature to date [3, 5]. It remains unclear whether LCH and ECD are neoplastic or reactive, but in many patients they behave like neoplasms. Advances in genome sequencing technologies led to the identification of BRAF V600E mutations in 57% (35 of 61) of patients with LCH and 54% (13 of 24) of patients with ECD [6, 7]. Both LCH and ECD can vary in clinical presentation and prognosis depending on the extent of disease and organ involvement [8]. Therapeutic options include surgery, radiation, vinblastine, prednisone, 6-mercaptopurine, cladribine, and cytarabine for LCH and corticosteroids, vinca alkaloids, anthracyclines, cladribine, interferon-α, anakinra, imatinib, and, most recently, infliximab for ECD [3, 5, 8–18]. Whereas the treatment of LCH has been defined based on the results of prospective studies, including randomized trials, ECD is currently treated on the basis of information from published case series, mostly from Europe and North America [8–21]. Yin et al. [22] are to be commended for presenting a patient with simultaneous LCH (Hand-Schuller-Christian disease) and ECD and their subsequent retrospective review of an additional 54 patients with LCH and six patients with ECD treated in a single tertiary referral center in China. The coexistence of these two entities is consistent with other previously published reports [4]. The patient presented by Yin et al. [22] had a relatively typical disease course over several years (currently 14 years from diagnosis), with symptoms including central diabetes insipidus, hyperprolactinemia, bone involvement, exophthalmus, and underactive thyroid. The patient had a favorable response to external-beam radiation therapy and systemic therapy with interferon-α. In their analysis of the 54 patients with LCH (eosinophilic granuloma, n = 49; Hand-Schuller-Christian disease, n = 5) and six patients with ECD, they [22] demonstrated that all 35 patients with unifocal eosinophilic granuloma were cured with surgery, and all patients with multifocal eosinophilic granuloma, Hand-Schuller-Christian disease, or ECD were alive, except for one woman who died from unspecified toxicity of chemotherapy. As mentioned, there is some agreement on how LCH should be managed; however, the treatment of patients with ECD remains empiric, based on evidence from case reports and case series [8–21]. The rarity of this entity makes the feasibility of conducting a prospective trial challenging [5]. Traditionally, patients with ECD were deemed to have a poor prognosis, and most patients succumbed to the disease within 3 years. In contrast, our experience suggests that, given the newer therapeutic options, including, but not limited to, interferon-α, imatinib, anakinra, and infliximab, patients can do well for a long period of time [8, 9, 12–14, 16, 17, 23]. These observations are consistent with the experience of Yin et al. [22], and it is also known that interferon-α is associated with a longer survival time than in historical controls [8]. The individual prognosis depends on the degree of organ involvement, infiltration of the central nervous system (CNS) or infiltration of critical visceral organs, and treatment, which can affect outcome [8]. A recent retrospective analysis of 53 patients treated in western European countries and Israel demonstrated 1-year and 5-year survival rates of 96% and 68%, respectively, which is in line with our experience [8, 9, 12]. Factors selected on multivariate analysis that predicted a poor survival outcome included CNS involvement and not being treated with interferon-α [8]. There is no systemic therapy that has been approved by regulatory agencies, and the available treatments are deemed to be not curative; however, they can lead to disease regression accompanied by symptom improvement and, at least for interferon, perhaps even to a longer survival duration. Despite the absence of randomized trials, our treatment options have nevertheless expanded substantially within the last several years. Interferon-α is often used as a frontline therapy for ECD [5, 8, 12]. Unfortunately, patients with ECD can have a poor tolerance to classic doses of interferon-α, such as three million units s.c. three times per week, although doses of one million units s.c. three times per week are usually well tolerated and, in our experience, are effective in about half the patients treated [12]. Interferon-α can be replaced by its pegylated form, which is more costly but has a more convenient weekly dosing schedule [14]. Anecdotal reports have also demonstrated therapeutic responses with the BCR-ABL, KIT, and platelet-derived growth factor receptor tyrosine kinase inhibitor imatinib [9, 13, 24–26]. It has been hypothesized that imatinib can inhibit CD34+ peripheral blood progenitor cells from differentiating into histiocytes; however, beyond that the mechanistic explanation for the activity of imatinib remains unclear [27]. Because natural interleukin-1 receptor antagonist synthesis is induced after stimulation by interferon-α, anakinra, a recombinant human interleukin-1 receptor antagonist approved for rheumatoid arthritis in Europe and the U.S., was anecdotally tested in ECD patients, with encouraging results reported by several investigators [15, 18]. Anakinra mimics the function of a natural inhibitor of interleukin-1 receptor and is well tolerated, with immunosuppression and injection site tenderness being among its very few side effects. Therefore, anakinra can be a reasonable alternative for patients who cannot tolerate interferon-α or who are at risk for suffering deleterious side effects from interferon. The latest potential addition to the therapeutic armamentarium for ECD is the tumor necrosis factor (TNF)-α antibody infliximab [17]. In ECD patients, TNF-α is deemed to regulate the recruitment of histiocytes, and thus, its blockade can lead to disease control. To date, two patients with severe cardiovascular complications of ECD were treated with infliximab in a single institution setting and both showed improvement, with resolution of pericardial effusion and increased cardiac function [17]. Recently, BRAF V600E mutations were found in 57% (35 of 61) and 38% (11 of 29) of patients with LCH and in 54% (13 of 24) of patients with ECD [6, 7, 28]. This mutation predicts a positive response to BRAF kinase inhibitors in patients with advanced melanoma [29, 30]. Recently, we showed that a patient with hairy cell leukemia and a BRAF mutation achieved a remarkable response after only 3 weeks of the BRAF inhibitor vemurafenib [31]. However, treatment of patients with LCH and ECD with BRAF mutations has not been reported. Despite many therapeutic advances, LCH and ECD remain difficult to eradicate. The arrival of new genotyping technologies, such as next-generation sequencing, has the potential to further explicate the molecular background of these disorders. Furthermore, the heterogeneity of these diseases may have biologic and therapeutic implications. It is known that LCH and ECD can coexist, and Yin et al. [22] reported simultaneously occurring Hand-Schuller-Christian disease and ECD. Furthermore, they also described potentially important clinical characteristics to differentiate these entities. Diabetes insipidus and pituitary stalk thickening point to Hand-Schuller-Christian disease; however, diabetes insipidus can also be found in ECD and osteosclerosis may also support an ECD diagnosis. The advent of advanced molecular technologies may help determine if specific molecular aberrations can differentiate these entities and predict therapeutic response.

Expression of estrogen and progesterone receptors across human malignancies: new therapeutic opportunities

Estrogen and progesterone receptors (ERs and PRs) are known for their prognostic as well as treatment predictive value in breast cancer. Although these receptors are differentially expressed in some other malignancies, and likely participate in the biology of those cancer types, the relevance to outcome and therapy is not well established. The use of ER as a highly effective therapeutic target in oncology was pioneered in breast cancer, and the lessons learned from its success could potentially benefit patients with several other malignancies in which hormone receptors are highly expressed. Indeed, there are several potent drugs available that target hormone receptors. These agents show incontrovertible evidence of benefit in patients with hormone receptor-positive breast cancer. It is conceivable that these drugs may have salutary effects in a variety of cancers other than those originating in the breast, based on the overexpression of hormone receptors in some patients, and the preclinical and clinical reports showing responses to these drugs in diverse cancers, albeit in small series or anecdotally. We therefore undertook a literature review in order to summarize the current data regarding the biologic and clinical implications of expression of estrogen and progesterone receptors in various malignancies and the possibilities for deployment of hormone manipulation beyond breast cancer.

Cutaneous Castleman disease.

A 59-year-old Korean man was diagnosed in 1999 with multicentric plasma cell variant of Castleman disease (CD). He received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in 2000 with partial response followed by thalidomide, and then rituximab treatment without success, and finally high dose steroids. He presented to our clinic in 2007 for a second opinion regarding biopsy-proven refractory cutaneous involvement by CD. He had no B symptoms at that point and his main concerns were related to his skin lesions. His baseline positron emission tomography (PET) scan showed increased uptake by multiple lymph nodes. The constitutional symptoms of CD result from secretion of interleukin-6 (IL-6) by the hyperplastic lymph nodes. As CD is an IL-6 driven condition, we used siltuximab, a chimeric human-murine anti-IL-6 antibody for this orphan disease. Following written informed consent, the patient was enrolled in a Phase I study and was treated with the investigational agent siltuximab (CNTO328), 12 mg/kg intravenously every 2 weeks. Prior to this treatment the patient had scattered hyperpigmented CD lesions (top left); partial response had occurred by 6 months (top right) and after 24 months of siltuximab he had achieved an almost complete response (bottom), which has been maintained for more than 4 years of treatment. He has had no side effects and continues to receive silutuximab. His latest PET scan showed no abnormal uptake.

Anticoagulation-induced severe bleeding in a patient receiving bevacizumab therapy.

A 56-year-old female with heavily pretreated stage 4 nonsmall cell lung cancer metastatic to brain, lungs and bone who had been diagnosed with a lower extremity deep vein thrombosis and started on low molecular weight heparin in the previous week presented to the emergency department with severe bilateral flank pain, denied fever, trauma, dysuria or gastrointestinal bleeding. The patient had just finished receiving her second cycle of a clinical trial involving erlotinib, cetuximab and bevacizumab. Restaging imaging studies performed 3 days prior to presentation showed a 43% decrease in the size of her primary lung lesion, and did not show intra-abdominal metastatic disease. Physical exam revealed a chronic diffuse cetuximabinduced rash and new sacral, lumbar, and bilateral flank hematomas (Fig. 1a–c). Hemoglobin was 7.5 g/dL, decreased from 11.5 g/dL, platelets were 120 K/uL, which were at baseline, and coagulation studies, including activated partial thromboplastin time (APTT), international normalized ratio (INR), and fibrinogen, were normal. A computed tomography (CT) of the abdomen showed collections of fluid in the left paravertebral area, bilateral paraspinal regions, and adjacent to the left psoas, likely representing hematomas (Fig. 1d). The patient was transfused with packed red blood cells resulting in normalization of hemoglobin, anticoagulation was stopped, and an inferior vena cava (IVC) filter was placed. Major bleeding has been reported to affect less than 1% of patients receiving anticoagulation. Bevacizumab has been associated with venous thromboembolic events (VTE), and bleeding in patients receiving anticoagulation after a first VTE while receiving bevacizumab-based therapy, leading to temporary or permanent discontinuation of treatment. Some known toxicities of bevacizumab include hypertension, wound healing impairment, thrombosis, bleeding, and gastrointestinal perforation, which have been hypothesized to be related to the action of this monoclonal antibody against vascular endothelial growth factor (VEGF). The concomitant use of an anticoagulant and bevacizumab may have induced such massive hemorrhage in our patient, as no alternative causes were found after a thorough analysis of the bleeding event. The use of bevacizumab together with anticoagulants will inevitably rise, as bevacizumab is increasingly being used in cancer patients, who already have an inherent predisposition to VTE due to their malignancy-induced hypercoagulability state. We should, therefore, exercise caution regarding bevacizumab-induced bleeding in patients who are already receiving anticoagulation due to a previous VTE.

Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With BRAF-Mutated Malignancies

Purpose Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors. Patients and Methods We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily. Results Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles. Conclusion The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.