Fadi S. Braiteh

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING F Hoffmann-La Roche/Genentech Inc.

Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial

BACKGROUND Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. METHODS We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. FINDINGS Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). INTERPRETATION Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. FUNDING Merrimack Pharmaceuticals.

Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers

Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. Experimental Design: 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 μg/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m2 and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them. Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m2 of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m2 of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m2 for 5-AZA in patients with advanced malignancies.

Abstract 2859: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC)

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: TNBC is a mutationally complex breast cancer subtype with poor prognosis and no current targeted therapy options. Compared with other intrinsic breast cancer subtypes, TNBC has higher programmed death-ligand 1 (PD-L1) expression levels, which may hinder antitumor T-cell responses. MPDL3280A is a monoclonal anti-PDL1 antibody, engineered for optimized efficacy and safety, that blocks signaling through the PD-L1/PD-1 and PD-L1/B7.1 pathways. Methods: MPDL3280A was tested in a metastatic TNBC expansion cohort as part of a multicenter Phase Ia study. Pts received MPDL3280A at 15 mg/kg, 20 mg/kg or 1200 mg flat dose IV q3w. AEs were summarized for the safety follow-up duration from the first dose to 30 days after the last dose before the clinical cutoff on Sept 2, 2014. Responses were assessed by RECIST v1.1 criteria in pts who received MPDL3280A by Jul 21, 2014, evaluable for efficacy (≥ 6-wk follow-up). PD-L1 expression on tumor-infiltrating immune cells (ICs) at baseline was centrally evaluated by IHC in archival or fresh biopsies, and pts were scored as PD-L1 IHC (IC) 0, 1, 2 or 3. Peripheral biomarkers were assayed using FACS and multiplex immunoassays. Results: In the TNBC cohort, 27 pts were selectively enrolled. These pts had a median age of 48 y (29-82 y) and were evaluable for safety; 52% had ECOG PS 0 and 44% had ECOG PS 1. Visceral and bone metastases were present at baseline in 59% and 11% of pts, respectively. In addition, 85% received ≥ 4 prior systemic regimens (neoadjuvant, adjuvant or metastatic), including anthracyclines (78%), taxanes (82%) and platinum agents (15% cisplatin, 41% carboplatin). All-grade treatment-related AEs occurred in 67% of pts, most frequently fatigue (22%), pyrexia (15%), neutropenia (15%) and nausea (15%). 11% of pts experienced a Grade 3-5 related AE (5 Grade 3 events: adrenal insufficiency, neutropenia, nausea, vomiting, decreased WBC count; 1 Grade 5 pulmonary hypertension event in a pt with an atrial septal defect). Among 21 efficacy-evaluable PD-L1 IHC 2 or 3 pts (13 IHC 2 and 8 IHC 3), the unconfirmed RECIST ORR was 24% (95% CI, 8% to 47%); 3 PRs and 2 CRs were observed. Response duration ranged from 0.1+ to 41.6+ wks, with the median not yet reached. Pts with evidence of durable nonclassical responses suggestive of pseudoprogression were also observed. Overall, the 24-wk PFS rate was 33% (95% CI, 12% to 53%). Biomarker analysis revealed transient elevation of plasma cytokines and proliferating CD8 cells following MPDL3280A treatment. Updated clinical data, including PD-L1-negative pts, will be presented. Conclusions: MPDL3280A was generally well tolerated and demonstrated promising efficacy in pretreated metastatic PD-L1 IHC 2 or 3 TNBC pts. Furthermore, circulating biomarker analyses revealed pharmacodynamic responses to MPDL3280A. Clinical evaluation of MPDL3280A in metastatic PD-L1 IHC 0 or 1 TNBC is ongoing ([NCT01375842][1]). Citation Format: Leisha A. Emens, Fadi S. Braiteh, Philippe Cassier, Jean-Pierre Delord, Joseph Paul Eder, Marcella Fasso, Yuanyuan Xiao, Yan Wang, Luciana Molinero, Daniel S. Chen, Ian Krop. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2859. doi:10.1158/1538-7445.AM2015-2859 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01375842&atom=%2Fcanres%2F75%2F15_Supplement%2F2859.atom

Ultimate Fate of Oncology Drugs Approved by the US Food and Drug Administration Without a Randomized Trial

PURPOSE To approve a new anticancer drug, the US Food and Drug Administration often requires randomized trials. However, several oncology drugs have been approved on the basis of objective end points without a randomized trial. We reviewed the long-term safety and efficacy of such agents. METHODS We searched the Web site of the US Food and Drug Administrations Center for Drug Evaluation and Research and MEDLINE for initial applications of investigational anticancer drugs from 1973 through 2006. RESULTS Overall, 68 oncology drugs, excluding hormone therapy and supportive care, were approved, including 31 without a randomized trial. For these 31 drugs, a median of two clinical trials (range, one to seven) and 79 patients (range, 40 to 413) were used per approval. Objective response was the most common end point used for approval; median response rate was 33% (range, 11% to 90%). Thirty drugs are still fully approved. United States marketing authorization for one drug, gefitinib (an epidermal growth factor receptor [EGFR] inhibitor), was rescinded after a randomized trial showed no survival improvement; however, this trial was performed in unselected patients, and it was subsequently demonstrated that patients with EGFR mutation are more likely to respond. Nineteen of the 31 drugs have additional uses (per National Comprehensive Cancer Network or National Cancer Institute Physician Data Query guidelines), and subsequent formal US Food and Drug Administration approvals were obtained for 11 of these (range, one to 18 new indications). No drug has demonstrated safety concerns. CONCLUSION Nonrandomized clinical trials with definitive end points can yield US Food and Drug Administration approvals, and these drugs have a reassuring record of long-term safety and efficacy.

Uncommon tumors and exceptional therapies: paradox or paradigm?

Why does it seem that, repeatedly, when a new treatment with a striking effect is discovered in the cancer field, it is effective for a very rare cancer type? For example, groundbreaking therapeutic discoveries have been made for extremely uncommon malignancies such as hairy cell leukemia, chronic myelogenous leukemia, seminoma, gastrointestinal stromal tumor, (del)5q myelodysplastic syndrome, and acute promyelocytic leukemia. In contrast, progress in the most common and most intensively studied tumors—lung, breast, prostate, and colon cancer—has been slow and incremental. We hypothesize that the reason for this phenomenon is that the pathophysiologic basis for a tumor being rare is one and the same as the reason that it may ultimately be so treatable. That is, if a cancer can be derived only via a single aberrant molecular genetic aberration, then it should be both rare and easily targeted by a molecular cancer therapeutic approach. If, on the other hand, many distinct pathways can lead to the development of a specific tumor type, it should occur much more commonly and be significantly more difficult to treat. The corollary to our hypothesis is the prediction that new therapies will continue to show their most salutary effects in rare cancers. Furthermore, only by stratifying the common tumors, especially when using targeted agents, into the molecular subsets of diseases that compose them are we likely to achieve a substantial effect in these disorders. [Mol Cancer Ther 2007;6(4):1175–9]

Cabozantinib in hepatocellular carcinoma: Results of a phase 2 placebo-controlled randomized discontinuation study

Background Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. Patients and methods Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions. Trial registration number NCT00940225.

Abstract 2986: Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses

Introduction. Triple negative breast cancer (TNBC) has a poor prognosis and limited treatment options. Atezolizumab (atezo) is a humanized mAb that inhibits the binding of PD-L1 to PD-1 and B7.1, thus restoring tumor-specific T-cell immunity. Atezo was evaluated in an expansion cohort of mTNBC patients (pts) in a Phase Ia study (NCT01375842). Methods. Enrollment was initially limited to TNBC pts with PD-L1 on ≥5% of tumor-infiltrating immune cells (IC2/3), then opened to pts regardless of PD-L1 status. Pts received atezo IV in 1L or 2L+ q3w at 15 or 20 mg/kg or 1200 mg for 1 y with option to be retreated at PD, or until loss of clinical benefit. ORR was assessed by RECIST v1.1 and irRC, to capture non-conventional responses. Baseline PD-L1 expression on IC was centrally scored as IC0/1/2/3 (VENTANA SP142 assay). Pretreatment tumors and on-therapy biopsies were evaluated for TILs, CD8 T cells and macrophages by IHC. Results. As of Mar 31, 2016, 115 mTNBC pts were safety evaluable; atezo was generally well tolerated. There were no additional safety signals from prior report (Emens AACR 2015). 112 pts with FU ≥12 wk were evaluable for response. Based on irRC, ORR in 1L and 2L+ pts were 26% and 11%, respectively. ORR for PD-L1 IC2/3 pts were 17% vs 8% in IC0/1. mDoR was 21.1 mo (3 to 34+). mOS of responders (n=15) was not reached (4+ to 37+ mo) with no deaths as of data cutoff. mOS of non-responders who lived ≥ 6 wk (n=87) was 9 mo (1+ to 19+ mo). OS rates in all pts at 1, 2, and 3 y were 41%, 22% and 22%, respectively. OS rates at 1, 2, and 3 y for PD-L1 IC2/3 were 45%, 28% and 28%, respectively. Pts whose tumors had >10% TILs or ≥1.35% CD8 in the tumor center trended toward higher ORR and longer OS. Atezo increased intratumoral TILs, CD8, macrophages and IC PD-L1 expression, but no response association was observed. Conclusions. In mTNBC, atezo was well tolerated. Responders showed durable clinical benefit. Response rates were higher in 1L or PD-L1 IC2/3 pts. Baseline TILs and CD8 were associated with greater clinical benefit. Citation Format: Peter Schmid, Cristina Cruz, Fadi S. Braiteh, Joseph Paul Eder, Sara Tolaney, Irene Kuter, Rita Nanda, Cathie Chung, Philippe Cassier, Jean-Pierre Delord, Michael Gordon, Yijin Li, Bo Liu, Carol O’Hear, Marcella Fasso, Luciana Molinero, Leisha A. Emens. Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2986. doi:10.1158/1538-7445.AM2017-2986

HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

CASE 1. Langerhans cell histiocytosis of the thyroid.

A 46-year-old woman presented to her physician with an enlarging , painful neck mass, mild dysphagia, and right otalgia. Her other health problems included diabetes mellitus, hypertension, and dyslip-idemia. She had been diagnosed with diabetes insipidus 15 years earlier after experiencing polyuria and polydypsia, and this disorder was controlled by desmopressin, 0.1 mg by mouth three times per day. Pertinent findings on physical examination were an asymmetrically enlarged and tender goiter (Fig 1). Thyroid panel was normal. Thyro-globulin level was elevated to 9,235 ng/mL (normal range, 1 to 40 ng/mL). Computed tomography scan of the neck revealed heterogeneous enlargement of both thyroid lobes with anterior lobulated projections (Fig 2A). There was no evidence of enlarged lymph nodes. Magnetic resonance imaging of the brain, nuclear bone scan, and chest computed tomography scan were normal. Attempted thyroidectomy was aborted because of a significant hemorrhage (2 L of blood) during the initial part of the surgery, but a biopsy of the thyroid gland was obtained. It demonstrated histiocytes (Fig 3, arrow) infiltrating the space between the thyroid lobules (Fig 3, star), with phenotypic features and immunohistochemical profile (positive for S100, CD1A, and CD68-PGM1) consistent with Langerhans cell histiocytosis (LCH). The patient was treated initially with interferon-alfa 1 ϫ 10 6 units subcutaneously three times per week, for 4 months. This treatment was ineffective, as reflected by enlargement of the size of her goiter, worsening of the tenderness and dysphagia, and an increase in thyroid size on computed tomography scan. Subsequently, she was treated with two courses of cladribine, with initial response followed by progressive regrowth. The patient was then treated with pentostatin (2Ј-deoxycoformycin), a purine analog with adenosine deaminase inhibitory activity, at a dose of 4 mg/m 2 by intravenous infusion once every 2 weeks. The patient achieved a partial remission and continues to respond to this regimen 6 months (11 cycles) later, with ongoing shrinkage of her goiter (Fig 2B). LCH is most commonly a pediatric disease, but it can affect the adult population. It usually presents as a multisystem granulomatous infiltrate (in two thirds of cases) in adults. 1 Bone involvement predominates (80% of cases) with osteolytic and asymmetric lesions,