Sheila Weitzman

How I treat hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.

Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses.

Histiocytic disorders are currently identified by their component cells. The non‐Langerhans Cell Histiocytoses (non‐LCH) are a group of disorders defined by the accumulation of histiocytes that do not meet the phenotypic criteria for the diagnosis of Langerhans cells (LCs). The non‐LCH consist of a long list of diverse disorders which have been difficult to categorize. A conceptual way to think of these disorders that make them less confusing and easier to remember is proposed based on immunophenotyping and clinical presentation.

Complications of indwelling venous access lines in the pediatric hematology patient : a prospective comparison of external venous catheters and subcutaneous ports

Since 1984, 316 subcutaneous ports (SP) and 339 external venous catheters (EC) [Roko Catheter, The Hospital for Sick Children (HSC)] have been inserted in hematology/ oncology patients at HSC. During a 22-month period (July 1987 to April 1989), a committed central line nurse (J.I.) prospectively collected clinical and microbiologic data on 144 consecutive SPs and 130 consecutive ECs. Children with the SP had 0.6 infected lines and 0.7 infectious episodes per 1,000 patient days compared to 2.9 infected lines and 4.3 infectious episodes per 1,000 patient days with the EC (p < 0.001). This lower infectious complication rate with SP was demonstrated in the entire group of unselected patients and in a cohort of children with acute lymphoblastic leukemia (ALL) receiving intensive chemotherapy, and it was evident in all age groups. In view of the other advantages of SP–normal activity, absence of the need for home maintenance, improved body image, less expense–these data suggest that SPs are the preferred device in pediatric patients and provide effective venous access with acceptable complication rates.

Langerhans cell histiocytosis: Current concepts and treatments

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of cells with the phenotype of activated Langerhans cells. The diagnosis of LCH is often delayed or missed. Many questions about LCH remain to be answered, including whether it is caused by a malignancy or by immune dysregulation. Data from the early 1990s showed that LCH consisted of an accumulation of monoclonal LCH cells, suggesting a neoplastic disorder. However, further investigations with current sophisticated techniques have not shown consistent genomic aberrations. Recent data which suggests a role for an IL-17A dependant pathway of dendritic cell fusion in LCH remains to be proven. The most recent data taken together swing the pendulum towards an immunologic aberration. The clinical course of LCH is highly variable, ranging from a self-healing solitary bone lesion to widely disseminated life-threatening disease. Patients with multisystem (MS) disease with organ dysfunction, particularly those refractory to front line therapy, and those with multiple reactivations of disease associated with significant permanent sequelae represent the greatest challenge. Early switch of refractory patients to salvage therapies has contributed to the improvement in survival of MS-LCH patients. Due to the rarity of LCH in children and adults, patients must be enrolled on multi-national clinical trials, whenever possible, to advance our knowledge of the optimal therapeutic strategies and long-term outcomes.

Langerhans Cell Histiocytosis (LCH): Guidelines for Diagnosis, Clinical Work-Up, and Treatment for Patients Till the Age of 18 Years

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work‐up, and treatment and long‐term follow‐up of LCH patients are presented. Pediatr Blood Cancer 2013;60:175–184.

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH)-III tested risk-adjusted, intensified, longer treatment of multisystem LCH (MS-LCH), for which optimal therapy has been elusive. Stratified by risk organ involvement (high [RO+] or low [RO-] risk groups), > 400 patients were randomized. RO+ patients received 1 to 2 six-week courses of vinblastine+prednisone (Arm A) or vinblastine + prednisone + methotrexate (Arm B). Response triggered milder continuation therapy with the same combinations, plus 6-mercaptopurine, for 12 months total treatment. 6/12-week response rates (mean, 71%) and 5-year survival (84%) and reactivation rates (27%) were similar in both arms. Notably, historical comparisons revealed survival superior to that of identically stratified RO+ patients treated for 6 months in predecessor trials LCH-I (62%) or LCH-II (69%, P < .001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P < .001). RO- patients received vinblastine+prednisone throughout. Response by 6 weeks triggered randomization to 6 or 12 months total treatment. Significantly lower 5-year reactivation rates characterized the 12-month Arm D (37%) compared with 6-month Arm C (54%, P = .03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P < .001). Thus, prolonging treatment decreased RO- patient reactivations in LCH-III, and although methotrexate added no benefit, RO+ patient survival and reactivation rates have substantially improved in the 3 sequential trials. (Trial No. NCT00276757 www.ClinicalTrials.gov).

Comparison of Long-Term Neurocognitive Outcomes in Young Children With Acute Lymphoblastic Leukemia Treated With Cranial Radiation or High-Dose or Very High-Dose Intravenous Methotrexate

PURPOSE Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established. PATIENTS AND METHODS Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 x 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory. RESULTS Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures. CONCLUSION Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.

Posterior fossa medulloblastoma in childhood: Treatment results and a proposal for a new staging system

Seventy-two children with posterior fossa medulloblastoma were diagnosed at the Hospital for Sick Children, Toronto, from 1977 to 1987 and treated by standard methods. The 5- and 10-year survival and disease-free survival rates were 71% and 63%, and 64% and 63%, respectively. Total tumor resection, as determined by the surgeon was the most significant favorable prognostic factor. Post-operative meningitis, a residual enhancing mass lesion on the post-operative, pre irradiation CT scan and dissemination to the brain or cord at diagnosis were unfavorable factors. These four easily definable factors were used to define a staging system with prognostic significance. Five-year disease-free survival rates were for Stage I (total resection, no adverse factor) 100%, Stage II (total resection with one or more adverse factor or less than total resection with no other adverse factor) 78%, and Stage III (less than total resection with one or more adverse factor) 18%. Evaluation of treatment results in medulloblastoma requires that these prognostic factors be known.

Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome with prolonged high fever, hepatosplenomegaly and characteristic laboratory findings. HLH may be inherited (primary) or may be secondary to any severe infection, malignancy or rheumatologic condition. The last several years have witnessed an explosion in our understanding of HLH. Of the inherited causes for which the underlying genetic cause is known, most involve abnormalities of proteins important in the exocytosis cytolytic pathway, whereby perforin and granzymes are delivered to a target cell to induce apoptosis. The exact mechanisms underlying this process remain unclear. However, when a known genetic defect is not present, the diagnosis of HLH is still made on a constellation of clinical features and good clinical judgment. Rapid diagnosis is crucial, as early therapy with immunosuppressive agents and/or proapoptotic chemotherapy can be life-saving. This article examines recent advances in our understanding of the pathophysiology, clinical features, diagnosis, etiology and treatment of HLH, as well as the challenges that lie ahead.

Optic glioma in children : surveillance, resection, or irradiation ?

Eighty-seven consecutive children with newly diagnosed optic glioma were managed at University of Toronto hospitals 1958-1990. Overall the 10-year survival, relapse-free survival and freedom from second relapse rates were 84%, 68% and 85%. Twenty-seven patients relapsed or progressed, of whom 40% were free of a second relapse 10 years after the first relapse. Fourteen patients had a second relapse. Thirteen are dead. None survived 5 years after second relapse. Patients with anteriorly located tumors (N = 35), which involved the optic nerve, or chiasm and optic nerves, fared better than those with posteriorly located tumors (N = 52) with spread beyond the chiasm, 10-year survival 95% versus 76%, (p = .02), 10-year relapse-free survival 80% versus 59% (p = .02), respectively. For posterior tumors primary irradiation was more effective than primary subtotal resection for prevention of subsequent relapse, 10-year relapse-free survival 75% versus 41% (p = .02), but salvage therapy was, in part, successful and multivariate analysis of prognostic factors influencing survival for posterior tumors indicated that neither primary resection nor primary irradiation were significant factors. For first relapse, primary irradiation and the presence of neurofibromatosis were the significant favorable factors. Since 1977 and for posterior optic glioma subtotal resection or surveillance were used in 21/29 (72%) patients compared with 4/23 (17%) previously. Ten-year survival rates before and after 1977 were 78% and 67% and 10-year relapse-free survival 64% and 56%, respectively.